Pharmacology

One of the more alarming trends that has emerged during the coronavirus crisis is the concomitant rise in the use of benzodiazepines, such as Xanax. It has been reported that at-risk individuals began seeking prescription anxiolytics as early as mid-February with a consequent peak of 34% the following month, coinciding with the World Health Organization’s declaration of a global pandemic.¹

Consistent with the available literature indicating that women are twice as likely to be affected by anxiety disorders, the prescription spikes were almost double when compared with those of their male counterparts.² The pandemic has instilled a sense of fear in people, leading to social repercussions, such as estrangement, insomnia, and paranoia for at-risk populations.^3,4

“Benzos” are commonly prescribed to help people sleep or to assist them in overcoming a host of anxiety disorders. The rapid onset of effects make Xanax a desirable and efficacious benzodiazepine.⁵ The use of these medications might not be an immediate cause for concern because patients might be taking it as intended. Nevertheless, clinicians are shying away from medical management in favor of counseling or therapy.
 

Dangerous trends

We are concerned that renewed interest in Xanax, coupled with physician reluctance to prescribe antianxiety medications, might trigger the return of an illicit drug boom. Numerous factors might contribute to this grim scenario, including patient dependence on benzodiazepines, paranoia about engaging with health care professionals because of fear tied to potential COVID-19 exposure, and/or increased access to illicit counterfeit pills from drug dealers or the dark web markets.

Lessons can be gleaned from the most extensive dark web drug busts in Britain’s history, in which a deluge of “pharmaceutical grade” Xanax pills made it to the hands of drug dealers and consumers between 2015 and 2017.⁶ A similar phenomenon emerged stateside.⁷ Virtually indistinguishable from recognized 2-mg Xanax pills, these fake pills posed a serious challenge to forensic scientists.⁸ The threat of overdose is very real for users targeted by the counterfeit Xanax trade, especially since those at risk often bypass professional health care guidelines.

In broad daylight, the drug dealers ran their operations revolving around two fake Xanax products: a primary knockoff and a limited edition – and vastly more potent “Red Devil” variant that was intentionally dyed for branding purposes. Because the “Red Devil” formulations contained 2.5 times the dose of the 2-mg pill, it had even more pronounced tolerance, dependence, and withdrawal effects (for example, panic attacks, anxiety, and/or hallucinations) – fatal consequences for users involved in consuming other drugs, such as alcohol or opioids. Preexisting drug users tend to gravitate toward benzodiazepines, such as alprazolam (Xanax), perhaps in part, because of its relatively rapid onset of action. Xanax also is known for inducing proeuphoric states at higher doses, hence the appeal of the “Red Devil” pills.

Benzodiazepines, as a class of drugs, facilitate the neurotransmitter gamma-aminobutryric acid’s (GABA) effect on the brain, producing anxiolytic, hypnotic, and/or anticonvulsant states within the user.⁹ Unbeknownst to numerous users is the fact that drugs such as alcohol and opioids, like Xanax, also serve as respiratory depressants, overriding the brain’s governance of the breathing mechanism. This, in turn, leads to unintended overdose deaths, even among seasoned drug seekers.

Overdose deaths have been steadily climbing over the years because it is common for some users to consume alcohol while being on Xanax therapy – without realizing that both substances are depressants and that taking them together can lead to side effects such as respiratory depression.

Forensic cases also have revealed that preexisting opioid consumers were drawn to Xanax; the drug’s potent mechanism of action would likely appeal to habituated users. A typical behavioral pattern has emerged among users and must be addressed. According to Australian Professor Shane Darke: “So they take their Xanax, they take their painkiller, then they get drunk, that could be enough to kill them.”

Fatalities are more likely when benzodiazepines are combined with other drug classes or if the existing supply is contaminated or laced (for example, with fentanyl).⁸

As far as deaths by accidental benzodiazepine overdose are concerned, a similar epidemic has been recorded in the United States. In 2013, almost one-third of all prescription overdose deaths can be attributed to the use of benzodiazepines (for example, Xanax, Valium, and Ativan). However, media attention has been considerably muted, especially when compared with that of narcotic abuse. This is even more puzzling when taking into account that three-quarters of benzodiazepine mortalities co-occur within the context of narcotic consumption. Substance Abuse and Mental Health Services Administration data confirm the ubiquitous nature of benzodiazepine (such as alprazolam) coprescriptions, accounting for roughly half of the 176,000 emergency department cases for 2011. The Centers for Disease Control and Prevention noted that there was a 67% increase in benzodiazepine prescriptions between 1996 and 2013, which warranted more stringent regulations for this particular class of drugs.

In 2016, the CDC issued new guidelines for opioid use acknowledging the danger of benzodiazepine coprescriptions. Food and Drug Administration “black box” warnings now grace the prescriptions of both of these drug classes.¹⁰ This trend remains on an upward trajectory, even more so during the pandemic, as there are 9.7 million prescriptions of anxiolytics/hypnotics such as Xanax, Ativan, and Klonopin in the United States as of March 2020, which represents a 10% increase over the previous year. The evolving landscape of this “new normal” may necessitate frequent patient updates and feedback via telepsychiatry, as well as the implementation of urine drug screening monitoring for drug adherence/compliance and diversion in those with suspected benzodiazepine addiction or a history of polysubstance abuse.^11,12

Clinical correlates

For patients who present acutely with Xanax toxicity in the emergency room setting, we will need to initially stabilize the vital signs and address the ongoing symptoms. It is advisable to arrange health care accommodations for patients with physical dependence to monitor and treat their withdrawal symptoms. The patient should be enrolled in a comprehensive addiction facility after undergoing formal detoxification; a tapered treatment protocol will need to be implemented because quitting “cold turkey” can lead to convulsions and, in some cases, death. Patient education, talk therapy, and alternatives to benzodiazepines should be discussed with the clinician.^13,145

However, to truly address the elephant in the room, we will need to consider institutional reforms to prevent a similar situation from arising in the future. Primary care physician shortages are compounded by changes in insurance policies. Nurses and physician assistants will need to be trained to manage benzodiazepine prescriptions. If there are community shortages in physicians, patients might turn to illegal means to secure their benzodiazepine supply, and it is imperative that we have the necessary fellowship and education programs to educate nonphysician health care clinicians with benzodiazepine management. Because physicians were prescribing benzodiazepines liberally, the Prescription Drug Monitoring Programs (PDMP) was enacted to monitor physician practices. Unfortunately, this ultimately intimidated physicians and effectively curbed reasonable physician prescribing patterns. It might be necessary to revisit existing prescription monitoring programs, encourage drug evaluations and guidelines based on evidence-based medicine and embrace telemedicine in order to facilitate patient-physician communication.

As of now, it is too early to prescribe Xanax routinely for ongoing anxiety experienced during the coronavirus crisis, and several physicians are cautious about prescribing antianxiety medications for more than a few months.¹⁷ Surprisingly, researchers in Barcelona have even explored the role of Xanax as potentially inhibiting Mpro, the primary protease of coronavirus, thereby forestalling the virus’s ability to replicate.¹⁶ However, it is worth noting that, given the preliminary nature of the results, any attempts at conclusively integrating Xanax within the context of coronavirus therapy would be premature.
 

References

1. Luhby T. Anti-anxiety medication prescriptions up 34% since coronavirus. CNN. 2020 Apr 16.

2. Women and Anxiety. Anxiety and Depression Association of America.

3. Shigemura J et al. Psychiatry Clin Neurosci. 2012 Apr 7;74(4):281-2.

4. Petersen A. More people are taking drugs for anxiety and insomnia, and doctors are worried. The Wall Street Journal. 2020 May 25.

5. Downey M. Xanax overdose and related deaths. National Drug & Alcohol Research Centre. UNSW Sydney.

6. Bryant B. Fake Xanax: The UK’s biggest ever dark net drugs bust. BBC. 2018 Mar 10.

7. Reinberg S. Fatal overdoses rising from sedatives like Valium, Xanax. HealthDay. 2016 Feb.

8. Is counterfeit Xanax dangerous? American Addiction Centers. Updated 2018 Nov 14.

9. McLaren E. Xanax history and statistics. Drugabuse.com.

10. Benzodiazepines and opioids. National Institute on Drug Abuse. 2018 Mar 15.

11. Choudhry Z et al. J Psychiatry. 2015;18(5). doi: 10.4172/2378-5756.1000319.

12. Islam FA et al. Current Psychiatry. 2018 Dec 17(12):43-4.

13. Adams M. Xanax death rate on the rise. White Sands Treatment. 2017 Sept.NEED LINK

14. Storrs C. Benzodiazepine overdose deaths soared in recent years, study finds. CNN. 2016 Feb. 18.

15. Hanscom DA. Plan A – Thrive and survive COVID-19. Back in Control. 2020.

16. Smith C. Xanax, a common anxiety medication, might actually block coronavirus. BGR. 2020 May 29.

Dr. Islam is a medical adviser for the International Maternal and Child Health Foundation (IMCHF), Montreal, and is based in New York. He also is a postdoctoral fellow, psychopharmacologist, and a board-certified medical affairs specialist. Dr. Islam disclosed no relevant financial relationships.

Mr. Choudhry is a research assistant at the IMCHF. He has no disclosures.

Dr. Choudhry is the chief scientific officer and head of the department of mental health and clinical research at the IMCHF and is Mr. Choudhry’s father. He has no disclosures.

One of the more alarming trends that has emerged during the coronavirus crisis is the concomitant rise in the use of benzodiazepines, such as Xanax. It has been reported that at-risk individuals began seeking prescription anxiolytics as early as mid-February with a consequent peak of 34% the following month, coinciding with the World Health Organization’s declaration of a global pandemic.¹

Consistent with the available literature indicating that women are twice as likely to be affected by anxiety disorders, the prescription spikes were almost double when compared with those of their male counterparts.² The pandemic has instilled a sense of fear in people, leading to social repercussions, such as estrangement, insomnia, and paranoia for at-risk populations.^3,4

“Benzos” are commonly prescribed to help people sleep or to assist them in overcoming a host of anxiety disorders. The rapid onset of effects make Xanax a desirable and efficacious benzodiazepine.⁵ The use of these medications might not be an immediate cause for concern because patients might be taking it as intended. Nevertheless, clinicians are shying away from medical management in favor of counseling or therapy.
 

Dangerous trends

We are concerned that renewed interest in Xanax, coupled with physician reluctance to prescribe antianxiety medications, might trigger the return of an illicit drug boom. Numerous factors might contribute to this grim scenario, including patient dependence on benzodiazepines, paranoia about engaging with health care professionals because of fear tied to potential COVID-19 exposure, and/or increased access to illicit counterfeit pills from drug dealers or the dark web markets.

Lessons can be gleaned from the most extensive dark web drug busts in Britain’s history, in which a deluge of “pharmaceutical grade” Xanax pills made it to the hands of drug dealers and consumers between 2015 and 2017.⁶ A similar phenomenon emerged stateside.⁷ Virtually indistinguishable from recognized 2-mg Xanax pills, these fake pills posed a serious challenge to forensic scientists.⁸ The threat of overdose is very real for users targeted by the counterfeit Xanax trade, especially since those at risk often bypass professional health care guidelines.

In broad daylight, the drug dealers ran their operations revolving around two fake Xanax products: a primary knockoff and a limited edition – and vastly more potent “Red Devil” variant that was intentionally dyed for branding purposes. Because the “Red Devil” formulations contained 2.5 times the dose of the 2-mg pill, it had even more pronounced tolerance, dependence, and withdrawal effects (for example, panic attacks, anxiety, and/or hallucinations) – fatal consequences for users involved in consuming other drugs, such as alcohol or opioids. Preexisting drug users tend to gravitate toward benzodiazepines, such as alprazolam (Xanax), perhaps in part, because of its relatively rapid onset of action. Xanax also is known for inducing proeuphoric states at higher doses, hence the appeal of the “Red Devil” pills.

Benzodiazepines, as a class of drugs, facilitate the neurotransmitter gamma-aminobutryric acid’s (GABA) effect on the brain, producing anxiolytic, hypnotic, and/or anticonvulsant states within the user.⁹ Unbeknownst to numerous users is the fact that drugs such as alcohol and opioids, like Xanax, also serve as respiratory depressants, overriding the brain’s governance of the breathing mechanism. This, in turn, leads to unintended overdose deaths, even among seasoned drug seekers.

Overdose deaths have been steadily climbing over the years because it is common for some users to consume alcohol while being on Xanax therapy – without realizing that both substances are depressants and that taking them together can lead to side effects such as respiratory depression.

Forensic cases also have revealed that preexisting opioid consumers were drawn to Xanax; the drug’s potent mechanism of action would likely appeal to habituated users. A typical behavioral pattern has emerged among users and must be addressed. According to Australian Professor Shane Darke: “So they take their Xanax, they take their painkiller, then they get drunk, that could be enough to kill them.”

Fatalities are more likely when benzodiazepines are combined with other drug classes or if the existing supply is contaminated or laced (for example, with fentanyl).⁸

As far as deaths by accidental benzodiazepine overdose are concerned, a similar epidemic has been recorded in the United States. In 2013, almost one-third of all prescription overdose deaths can be attributed to the use of benzodiazepines (for example, Xanax, Valium, and Ativan). However, media attention has been considerably muted, especially when compared with that of narcotic abuse. This is even more puzzling when taking into account that three-quarters of benzodiazepine mortalities co-occur within the context of narcotic consumption. Substance Abuse and Mental Health Services Administration data confirm the ubiquitous nature of benzodiazepine (such as alprazolam) coprescriptions, accounting for roughly half of the 176,000 emergency department cases for 2011. The Centers for Disease Control and Prevention noted that there was a 67% increase in benzodiazepine prescriptions between 1996 and 2013, which warranted more stringent regulations for this particular class of drugs.

In 2016, the CDC issued new guidelines for opioid use acknowledging the danger of benzodiazepine coprescriptions. Food and Drug Administration “black box” warnings now grace the prescriptions of both of these drug classes.¹⁰ This trend remains on an upward trajectory, even more so during the pandemic, as there are 9.7 million prescriptions of anxiolytics/hypnotics such as Xanax, Ativan, and Klonopin in the United States as of March 2020, which represents a 10% increase over the previous year. The evolving landscape of this “new normal” may necessitate frequent patient updates and feedback via telepsychiatry, as well as the implementation of urine drug screening monitoring for drug adherence/compliance and diversion in those with suspected benzodiazepine addiction or a history of polysubstance abuse.^11,12

Clinical correlates

For patients who present acutely with Xanax toxicity in the emergency room setting, we will need to initially stabilize the vital signs and address the ongoing symptoms. It is advisable to arrange health care accommodations for patients with physical dependence to monitor and treat their withdrawal symptoms. The patient should be enrolled in a comprehensive addiction facility after undergoing formal detoxification; a tapered treatment protocol will need to be implemented because quitting “cold turkey” can lead to convulsions and, in some cases, death. Patient education, talk therapy, and alternatives to benzodiazepines should be discussed with the clinician.^13,145

However, to truly address the elephant in the room, we will need to consider institutional reforms to prevent a similar situation from arising in the future. Primary care physician shortages are compounded by changes in insurance policies. Nurses and physician assistants will need to be trained to manage benzodiazepine prescriptions. If there are community shortages in physicians, patients might turn to illegal means to secure their benzodiazepine supply, and it is imperative that we have the necessary fellowship and education programs to educate nonphysician health care clinicians with benzodiazepine management. Because physicians were prescribing benzodiazepines liberally, the Prescription Drug Monitoring Programs (PDMP) was enacted to monitor physician practices. Unfortunately, this ultimately intimidated physicians and effectively curbed reasonable physician prescribing patterns. It might be necessary to revisit existing prescription monitoring programs, encourage drug evaluations and guidelines based on evidence-based medicine and embrace telemedicine in order to facilitate patient-physician communication.

As of now, it is too early to prescribe Xanax routinely for ongoing anxiety experienced during the coronavirus crisis, and several physicians are cautious about prescribing antianxiety medications for more than a few months.¹⁷ Surprisingly, researchers in Barcelona have even explored the role of Xanax as potentially inhibiting Mpro, the primary protease of coronavirus, thereby forestalling the virus’s ability to replicate.¹⁶ However, it is worth noting that, given the preliminary nature of the results, any attempts at conclusively integrating Xanax within the context of coronavirus therapy would be premature.
 

References

1. Luhby T. Anti-anxiety medication prescriptions up 34% since coronavirus. CNN. 2020 Apr 16.

2. Women and Anxiety. Anxiety and Depression Association of America.

3. Shigemura J et al. Psychiatry Clin Neurosci. 2012 Apr 7;74(4):281-2.

4. Petersen A. More people are taking drugs for anxiety and insomnia, and doctors are worried. The Wall Street Journal. 2020 May 25.

5. Downey M. Xanax overdose and related deaths. National Drug & Alcohol Research Centre. UNSW Sydney.

6. Bryant B. Fake Xanax: The UK’s biggest ever dark net drugs bust. BBC. 2018 Mar 10.

7. Reinberg S. Fatal overdoses rising from sedatives like Valium, Xanax. HealthDay. 2016 Feb.

8. Is counterfeit Xanax dangerous? American Addiction Centers. Updated 2018 Nov 14.

9. McLaren E. Xanax history and statistics. Drugabuse.com.

10. Benzodiazepines and opioids. National Institute on Drug Abuse. 2018 Mar 15.

11. Choudhry Z et al. J Psychiatry. 2015;18(5). doi: 10.4172/2378-5756.1000319.

12. Islam FA et al. Current Psychiatry. 2018 Dec 17(12):43-4.

13. Adams M. Xanax death rate on the rise. White Sands Treatment. 2017 Sept.NEED LINK

14. Storrs C. Benzodiazepine overdose deaths soared in recent years, study finds. CNN. 2016 Feb. 18.

15. Hanscom DA. Plan A – Thrive and survive COVID-19. Back in Control. 2020.

16. Smith C. Xanax, a common anxiety medication, might actually block coronavirus. BGR. 2020 May 29.

Dr. Islam is a medical adviser for the International Maternal and Child Health Foundation (IMCHF), Montreal, and is based in New York. He also is a postdoctoral fellow, psychopharmacologist, and a board-certified medical affairs specialist. Dr. Islam disclosed no relevant financial relationships.

Mr. Choudhry is a research assistant at the IMCHF. He has no disclosures.

Dr. Choudhry is the chief scientific officer and head of the department of mental health and clinical research at the IMCHF and is Mr. Choudhry’s father. He has no disclosures.

One of the more alarming trends that has emerged during the coronavirus crisis is the concomitant rise in the use of benzodiazepines, such as Xanax. It has been reported that at-risk individuals began seeking prescription anxiolytics as early as mid-February with a consequent peak of 34% the following month, coinciding with the World Health Organization’s declaration of a global pandemic.¹

Consistent with the available literature indicating that women are twice as likely to be affected by anxiety disorders, the prescription spikes were almost double when compared with those of their male counterparts.² The pandemic has instilled a sense of fear in people, leading to social repercussions, such as estrangement, insomnia, and paranoia for at-risk populations.^3,4

“Benzos” are commonly prescribed to help people sleep or to assist them in overcoming a host of anxiety disorders. The rapid onset of effects make Xanax a desirable and efficacious benzodiazepine.⁵ The use of these medications might not be an immediate cause for concern because patients might be taking it as intended. Nevertheless, clinicians are shying away from medical management in favor of counseling or therapy.
 

Dangerous trends

We are concerned that renewed interest in Xanax, coupled with physician reluctance to prescribe antianxiety medications, might trigger the return of an illicit drug boom. Numerous factors might contribute to this grim scenario, including patient dependence on benzodiazepines, paranoia about engaging with health care professionals because of fear tied to potential COVID-19 exposure, and/or increased access to illicit counterfeit pills from drug dealers or the dark web markets.

Lessons can be gleaned from the most extensive dark web drug busts in Britain’s history, in which a deluge of “pharmaceutical grade” Xanax pills made it to the hands of drug dealers and consumers between 2015 and 2017.⁶ A similar phenomenon emerged stateside.⁷ Virtually indistinguishable from recognized 2-mg Xanax pills, these fake pills posed a serious challenge to forensic scientists.⁸ The threat of overdose is very real for users targeted by the counterfeit Xanax trade, especially since those at risk often bypass professional health care guidelines.

In broad daylight, the drug dealers ran their operations revolving around two fake Xanax products: a primary knockoff and a limited edition – and vastly more potent “Red Devil” variant that was intentionally dyed for branding purposes. Because the “Red Devil” formulations contained 2.5 times the dose of the 2-mg pill, it had even more pronounced tolerance, dependence, and withdrawal effects (for example, panic attacks, anxiety, and/or hallucinations) – fatal consequences for users involved in consuming other drugs, such as alcohol or opioids. Preexisting drug users tend to gravitate toward benzodiazepines, such as alprazolam (Xanax), perhaps in part, because of its relatively rapid onset of action. Xanax also is known for inducing proeuphoric states at higher doses, hence the appeal of the “Red Devil” pills.

Benzodiazepines, as a class of drugs, facilitate the neurotransmitter gamma-aminobutryric acid’s (GABA) effect on the brain, producing anxiolytic, hypnotic, and/or anticonvulsant states within the user.⁹ Unbeknownst to numerous users is the fact that drugs such as alcohol and opioids, like Xanax, also serve as respiratory depressants, overriding the brain’s governance of the breathing mechanism. This, in turn, leads to unintended overdose deaths, even among seasoned drug seekers.

Overdose deaths have been steadily climbing over the years because it is common for some users to consume alcohol while being on Xanax therapy – without realizing that both substances are depressants and that taking them together can lead to side effects such as respiratory depression.

Forensic cases also have revealed that preexisting opioid consumers were drawn to Xanax; the drug’s potent mechanism of action would likely appeal to habituated users. A typical behavioral pattern has emerged among users and must be addressed. According to Australian Professor Shane Darke: “So they take their Xanax, they take their painkiller, then they get drunk, that could be enough to kill them.”

Fatalities are more likely when benzodiazepines are combined with other drug classes or if the existing supply is contaminated or laced (for example, with fentanyl).⁸

As far as deaths by accidental benzodiazepine overdose are concerned, a similar epidemic has been recorded in the United States. In 2013, almost one-third of all prescription overdose deaths can be attributed to the use of benzodiazepines (for example, Xanax, Valium, and Ativan). However, media attention has been considerably muted, especially when compared with that of narcotic abuse. This is even more puzzling when taking into account that three-quarters of benzodiazepine mortalities co-occur within the context of narcotic consumption. Substance Abuse and Mental Health Services Administration data confirm the ubiquitous nature of benzodiazepine (such as alprazolam) coprescriptions, accounting for roughly half of the 176,000 emergency department cases for 2011. The Centers for Disease Control and Prevention noted that there was a 67% increase in benzodiazepine prescriptions between 1996 and 2013, which warranted more stringent regulations for this particular class of drugs.

In 2016, the CDC issued new guidelines for opioid use acknowledging the danger of benzodiazepine coprescriptions. Food and Drug Administration “black box” warnings now grace the prescriptions of both of these drug classes.¹⁰ This trend remains on an upward trajectory, even more so during the pandemic, as there are 9.7 million prescriptions of anxiolytics/hypnotics such as Xanax, Ativan, and Klonopin in the United States as of March 2020, which represents a 10% increase over the previous year. The evolving landscape of this “new normal” may necessitate frequent patient updates and feedback via telepsychiatry, as well as the implementation of urine drug screening monitoring for drug adherence/compliance and diversion in those with suspected benzodiazepine addiction or a history of polysubstance abuse.^11,12

Clinical correlates

For patients who present acutely with Xanax toxicity in the emergency room setting, we will need to initially stabilize the vital signs and address the ongoing symptoms. It is advisable to arrange health care accommodations for patients with physical dependence to monitor and treat their withdrawal symptoms. The patient should be enrolled in a comprehensive addiction facility after undergoing formal detoxification; a tapered treatment protocol will need to be implemented because quitting “cold turkey” can lead to convulsions and, in some cases, death. Patient education, talk therapy, and alternatives to benzodiazepines should be discussed with the clinician.^13,145

However, to truly address the elephant in the room, we will need to consider institutional reforms to prevent a similar situation from arising in the future. Primary care physician shortages are compounded by changes in insurance policies. Nurses and physician assistants will need to be trained to manage benzodiazepine prescriptions. If there are community shortages in physicians, patients might turn to illegal means to secure their benzodiazepine supply, and it is imperative that we have the necessary fellowship and education programs to educate nonphysician health care clinicians with benzodiazepine management. Because physicians were prescribing benzodiazepines liberally, the Prescription Drug Monitoring Programs (PDMP) was enacted to monitor physician practices. Unfortunately, this ultimately intimidated physicians and effectively curbed reasonable physician prescribing patterns. It might be necessary to revisit existing prescription monitoring programs, encourage drug evaluations and guidelines based on evidence-based medicine and embrace telemedicine in order to facilitate patient-physician communication.

As of now, it is too early to prescribe Xanax routinely for ongoing anxiety experienced during the coronavirus crisis, and several physicians are cautious about prescribing antianxiety medications for more than a few months.¹⁷ Surprisingly, researchers in Barcelona have even explored the role of Xanax as potentially inhibiting Mpro, the primary protease of coronavirus, thereby forestalling the virus’s ability to replicate.¹⁶ However, it is worth noting that, given the preliminary nature of the results, any attempts at conclusively integrating Xanax within the context of coronavirus therapy would be premature.
 

References

1. Luhby T. Anti-anxiety medication prescriptions up 34% since coronavirus. CNN. 2020 Apr 16.

2. Women and Anxiety. Anxiety and Depression Association of America.

3. Shigemura J et al. Psychiatry Clin Neurosci. 2012 Apr 7;74(4):281-2.

4. Petersen A. More people are taking drugs for anxiety and insomnia, and doctors are worried. The Wall Street Journal. 2020 May 25.

5. Downey M. Xanax overdose and related deaths. National Drug & Alcohol Research Centre. UNSW Sydney.

6. Bryant B. Fake Xanax: The UK’s biggest ever dark net drugs bust. BBC. 2018 Mar 10.

7. Reinberg S. Fatal overdoses rising from sedatives like Valium, Xanax. HealthDay. 2016 Feb.

8. Is counterfeit Xanax dangerous? American Addiction Centers. Updated 2018 Nov 14.

9. McLaren E. Xanax history and statistics. Drugabuse.com.

10. Benzodiazepines and opioids. National Institute on Drug Abuse. 2018 Mar 15.

11. Choudhry Z et al. J Psychiatry. 2015;18(5). doi: 10.4172/2378-5756.1000319.

12. Islam FA et al. Current Psychiatry. 2018 Dec 17(12):43-4.

13. Adams M. Xanax death rate on the rise. White Sands Treatment. 2017 Sept.NEED LINK

14. Storrs C. Benzodiazepine overdose deaths soared in recent years, study finds. CNN. 2016 Feb. 18.

15. Hanscom DA. Plan A – Thrive and survive COVID-19. Back in Control. 2020.

16. Smith C. Xanax, a common anxiety medication, might actually block coronavirus. BGR. 2020 May 29.

Dr. Islam is a medical adviser for the International Maternal and Child Health Foundation (IMCHF), Montreal, and is based in New York. He also is a postdoctoral fellow, psychopharmacologist, and a board-certified medical affairs specialist. Dr. Islam disclosed no relevant financial relationships.

Mr. Choudhry is a research assistant at the IMCHF. He has no disclosures.

Dr. Choudhry is the chief scientific officer and head of the department of mental health and clinical research at the IMCHF and is Mr. Choudhry’s father. He has no disclosures.

Swapping out intravenous fentanyl in favor of IV acetaminophen in patients with ST-elevation MI (STEMI) provides comparable pain relief but with desirably higher blood levels of ticagrelor both immediately after primary percutaneous intervention and 1 hour post procedure.

Bruce Jancin/Frontline Medical News

That’s according to results of the Dutch ON-TIME 3 trial, presented by Anne H. Tavenier, MD, at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“Our trial results have implications for the prehospital treatment of STEMI patients,” said Dr. Tavenier, a cardiologist at the Isala Clinic in Zwolle, the Netherlands.

The explanation for the success of this novel STEMI pain management strategy? The synthetic opioid fentanyl impairs gastrointestinal absorption of oral P2Y12 receptor antagonists such as ticagrelor. Opiates do so as well, whereas acetaminophen does not, she explained.

The potent platelet inhibition provided by oral P2Y12 inhibitors is crucial to successful primary PCI for STEMI. But these platelet inhibitory effects are inherently slowed in STEMI patients owing to hemodynamic changes and delayed GI absorption. And even though both American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend the use of opioids for pain control in STEMI patients, the fact is that these medications further delay the absorption of oral P2Y12 inhibitors. And this delay is further exacerbated by the nausea and vomiting which are common side effects of IV fentanyl, she continued.

The impetus for the ON-TIME 3 trial was straightforward, the cardiologist said: “For years, STEMI patients have been treated with morphine or morphinelike drugs like fentanyl because of pain or sympathetic stress. To date, trials investigating alternative analgesics to opioids have been scarce.”

ON-TIME 3 was a multicenter, open-label, phase 4 clinical trial in which 195 STEMI patients with a self-reported pain score of at least 4 on a 0-10 scale received crushed ticagrelor in the ambulance along with either 1,000 mg of IV acetaminophen or fentanyl at 1-2 mcg/kg.

Ticagrelor blood levels were significantly higher in the IV acetaminophen group when measured just prior to primary PCI (151 ng/mL versus 60 ng/mL in the IV fentanyl group; immediately after PCI (326 versus 115 ng/mL), and 1 hour post PCI (488 versus 372 ng/mL).

However, there was no significant between-group difference in levels of platelet reactivity units measured immediately after primary PCI, Dr. Tavenier added.

Discussant Christoph K. Naber, MD, PhD, confessed that prior to ON-TIME 3 he was unaware that administering opioids to STEMI patients results in delayed absorption of oral P2Y12 inhibitors. Upon delving into the literature, however, he found that this is indeed a well-documented problem.

“The open question I have about this very elegant trial is whether the increased P2Y12 levels will translate into a measurable difference in clinical outcomes,” said Dr. Naber, an interventional cardiologist at the Wilhemshaven (Germany) Clinic.

The answer to that question would require a larger, longer-term trial. And he’s disinclined to wait around for that to happen.

“I think when we look at the risk balance, the risk of switching from an opioid to acetaminophen, if it works for the patient, is rather low. So this might be something to introduce in my practice,” the cardiologist said.

Dr. Tavenier and Dr. Naber reported having no financial conflicts of interest.

bjancin@mdedge.com

SOURCE: Tavenier AH. EuroPCR 2020.

Swapping out intravenous fentanyl in favor of IV acetaminophen in patients with ST-elevation MI (STEMI) provides comparable pain relief but with desirably higher blood levels of ticagrelor both immediately after primary percutaneous intervention and 1 hour post procedure.

Bruce Jancin/Frontline Medical News

That’s according to results of the Dutch ON-TIME 3 trial, presented by Anne H. Tavenier, MD, at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“Our trial results have implications for the prehospital treatment of STEMI patients,” said Dr. Tavenier, a cardiologist at the Isala Clinic in Zwolle, the Netherlands.

The explanation for the success of this novel STEMI pain management strategy? The synthetic opioid fentanyl impairs gastrointestinal absorption of oral P2Y12 receptor antagonists such as ticagrelor. Opiates do so as well, whereas acetaminophen does not, she explained.

The potent platelet inhibition provided by oral P2Y12 inhibitors is crucial to successful primary PCI for STEMI. But these platelet inhibitory effects are inherently slowed in STEMI patients owing to hemodynamic changes and delayed GI absorption. And even though both American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend the use of opioids for pain control in STEMI patients, the fact is that these medications further delay the absorption of oral P2Y12 inhibitors. And this delay is further exacerbated by the nausea and vomiting which are common side effects of IV fentanyl, she continued.

The impetus for the ON-TIME 3 trial was straightforward, the cardiologist said: “For years, STEMI patients have been treated with morphine or morphinelike drugs like fentanyl because of pain or sympathetic stress. To date, trials investigating alternative analgesics to opioids have been scarce.”

ON-TIME 3 was a multicenter, open-label, phase 4 clinical trial in which 195 STEMI patients with a self-reported pain score of at least 4 on a 0-10 scale received crushed ticagrelor in the ambulance along with either 1,000 mg of IV acetaminophen or fentanyl at 1-2 mcg/kg.

Ticagrelor blood levels were significantly higher in the IV acetaminophen group when measured just prior to primary PCI (151 ng/mL versus 60 ng/mL in the IV fentanyl group; immediately after PCI (326 versus 115 ng/mL), and 1 hour post PCI (488 versus 372 ng/mL).

However, there was no significant between-group difference in levels of platelet reactivity units measured immediately after primary PCI, Dr. Tavenier added.

Discussant Christoph K. Naber, MD, PhD, confessed that prior to ON-TIME 3 he was unaware that administering opioids to STEMI patients results in delayed absorption of oral P2Y12 inhibitors. Upon delving into the literature, however, he found that this is indeed a well-documented problem.

“The open question I have about this very elegant trial is whether the increased P2Y12 levels will translate into a measurable difference in clinical outcomes,” said Dr. Naber, an interventional cardiologist at the Wilhemshaven (Germany) Clinic.

The answer to that question would require a larger, longer-term trial. And he’s disinclined to wait around for that to happen.

“I think when we look at the risk balance, the risk of switching from an opioid to acetaminophen, if it works for the patient, is rather low. So this might be something to introduce in my practice,” the cardiologist said.

Dr. Tavenier and Dr. Naber reported having no financial conflicts of interest.

bjancin@mdedge.com

SOURCE: Tavenier AH. EuroPCR 2020.

Swapping out intravenous fentanyl in favor of IV acetaminophen in patients with ST-elevation MI (STEMI) provides comparable pain relief but with desirably higher blood levels of ticagrelor both immediately after primary percutaneous intervention and 1 hour post procedure.

Bruce Jancin/Frontline Medical News

That’s according to results of the Dutch ON-TIME 3 trial, presented by Anne H. Tavenier, MD, at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“Our trial results have implications for the prehospital treatment of STEMI patients,” said Dr. Tavenier, a cardiologist at the Isala Clinic in Zwolle, the Netherlands.

The explanation for the success of this novel STEMI pain management strategy? The synthetic opioid fentanyl impairs gastrointestinal absorption of oral P2Y12 receptor antagonists such as ticagrelor. Opiates do so as well, whereas acetaminophen does not, she explained.

The potent platelet inhibition provided by oral P2Y12 inhibitors is crucial to successful primary PCI for STEMI. But these platelet inhibitory effects are inherently slowed in STEMI patients owing to hemodynamic changes and delayed GI absorption. And even though both American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend the use of opioids for pain control in STEMI patients, the fact is that these medications further delay the absorption of oral P2Y12 inhibitors. And this delay is further exacerbated by the nausea and vomiting which are common side effects of IV fentanyl, she continued.

The impetus for the ON-TIME 3 trial was straightforward, the cardiologist said: “For years, STEMI patients have been treated with morphine or morphinelike drugs like fentanyl because of pain or sympathetic stress. To date, trials investigating alternative analgesics to opioids have been scarce.”

ON-TIME 3 was a multicenter, open-label, phase 4 clinical trial in which 195 STEMI patients with a self-reported pain score of at least 4 on a 0-10 scale received crushed ticagrelor in the ambulance along with either 1,000 mg of IV acetaminophen or fentanyl at 1-2 mcg/kg.

Ticagrelor blood levels were significantly higher in the IV acetaminophen group when measured just prior to primary PCI (151 ng/mL versus 60 ng/mL in the IV fentanyl group; immediately after PCI (326 versus 115 ng/mL), and 1 hour post PCI (488 versus 372 ng/mL).

However, there was no significant between-group difference in levels of platelet reactivity units measured immediately after primary PCI, Dr. Tavenier added.

Discussant Christoph K. Naber, MD, PhD, confessed that prior to ON-TIME 3 he was unaware that administering opioids to STEMI patients results in delayed absorption of oral P2Y12 inhibitors. Upon delving into the literature, however, he found that this is indeed a well-documented problem.

“The open question I have about this very elegant trial is whether the increased P2Y12 levels will translate into a measurable difference in clinical outcomes,” said Dr. Naber, an interventional cardiologist at the Wilhemshaven (Germany) Clinic.

The answer to that question would require a larger, longer-term trial. And he’s disinclined to wait around for that to happen.

“I think when we look at the risk balance, the risk of switching from an opioid to acetaminophen, if it works for the patient, is rather low. So this might be something to introduce in my practice,” the cardiologist said.

Dr. Tavenier and Dr. Naber reported having no financial conflicts of interest.

bjancin@mdedge.com

SOURCE: Tavenier AH. EuroPCR 2020.

The Food and Drug Administration has approved expanded use of Dysport to treat upper- and lower-limb spasticity – including that caused by cerebral palsy – for patients as young as 2 years and older, according to manufacturer Ipsen Biopharmaceuticals.

When Dysport (abobotulinumtoxinA) initially was approved for treating pediatric lower limb spasticity by the FDA in 2016, Ipsen was granted Orphan Drug exclusivity for children whose lower-limb spasticity was caused by cerebral palsy. In 2019, Dysport was approved by the FDA for treating of upper-limb spasticity in children 2 years older. But if that spasticity was caused by cerebral palsy, Dysport could be used to treat it only through Orphan Drug exclusivity granted to another manufacturer, according to an Ipsen press release.

“The proactive step to resolve the uncertainty created by the previous CP [cerebral palsy] carve out enables us as physicians to prescribe consistent therapy for pediatric patients experiencing both upper- and lower-limb spasticity,” Sarah Helen Evans, MD, division chief of rehabilitation medicine in the department of pediatrics at the Children’s Hospital of Philadelphia, said in the press release.

The most common adverse effects among children with lower-limb spasticity treated with Dysport were nasopharyngitis, cough, and pyrexia. Among children with upper-limb spasticity, the most common effects associated with Dysport treatment were upper respiratory tract infection and pharyngitis.

The press release also included a warning of the distant spread of the botulinum toxin from the area of injection hours to weeks afterward, causing symptoms including blurred vision, generalized muscle weakness, and swallowing and breathing difficulties that can be life threatening; there have been reports of death.

Suspected adverse effects can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The Food and Drug Administration has approved expanded use of Dysport to treat upper- and lower-limb spasticity – including that caused by cerebral palsy – for patients as young as 2 years and older, according to manufacturer Ipsen Biopharmaceuticals.

When Dysport (abobotulinumtoxinA) initially was approved for treating pediatric lower limb spasticity by the FDA in 2016, Ipsen was granted Orphan Drug exclusivity for children whose lower-limb spasticity was caused by cerebral palsy. In 2019, Dysport was approved by the FDA for treating of upper-limb spasticity in children 2 years older. But if that spasticity was caused by cerebral palsy, Dysport could be used to treat it only through Orphan Drug exclusivity granted to another manufacturer, according to an Ipsen press release.

“The proactive step to resolve the uncertainty created by the previous CP [cerebral palsy] carve out enables us as physicians to prescribe consistent therapy for pediatric patients experiencing both upper- and lower-limb spasticity,” Sarah Helen Evans, MD, division chief of rehabilitation medicine in the department of pediatrics at the Children’s Hospital of Philadelphia, said in the press release.

The most common adverse effects among children with lower-limb spasticity treated with Dysport were nasopharyngitis, cough, and pyrexia. Among children with upper-limb spasticity, the most common effects associated with Dysport treatment were upper respiratory tract infection and pharyngitis.

The press release also included a warning of the distant spread of the botulinum toxin from the area of injection hours to weeks afterward, causing symptoms including blurred vision, generalized muscle weakness, and swallowing and breathing difficulties that can be life threatening; there have been reports of death.

Suspected adverse effects can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The Food and Drug Administration has approved expanded use of Dysport to treat upper- and lower-limb spasticity – including that caused by cerebral palsy – for patients as young as 2 years and older, according to manufacturer Ipsen Biopharmaceuticals.

When Dysport (abobotulinumtoxinA) initially was approved for treating pediatric lower limb spasticity by the FDA in 2016, Ipsen was granted Orphan Drug exclusivity for children whose lower-limb spasticity was caused by cerebral palsy. In 2019, Dysport was approved by the FDA for treating of upper-limb spasticity in children 2 years older. But if that spasticity was caused by cerebral palsy, Dysport could be used to treat it only through Orphan Drug exclusivity granted to another manufacturer, according to an Ipsen press release.

“The proactive step to resolve the uncertainty created by the previous CP [cerebral palsy] carve out enables us as physicians to prescribe consistent therapy for pediatric patients experiencing both upper- and lower-limb spasticity,” Sarah Helen Evans, MD, division chief of rehabilitation medicine in the department of pediatrics at the Children’s Hospital of Philadelphia, said in the press release.

The most common adverse effects among children with lower-limb spasticity treated with Dysport were nasopharyngitis, cough, and pyrexia. Among children with upper-limb spasticity, the most common effects associated with Dysport treatment were upper respiratory tract infection and pharyngitis.

The press release also included a warning of the distant spread of the botulinum toxin from the area of injection hours to weeks afterward, causing symptoms including blurred vision, generalized muscle weakness, and swallowing and breathing difficulties that can be life threatening; there have been reports of death.

Suspected adverse effects can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Injections of cabotegravir (ViiV Healthcare) given every other month are more effective in blocking HIV transmission than is the once-a-day combination of tenofovir disoproxil fumarate and emtricitabine (Truvada, Gilead Science), new data from the HPTN 083 trial show.

The findings “could transform the HIV prevention landscape for so many people,” said Megan Coleman, DNP, from Whitman-Walker Health in Washington, DC, who regularly prescribes Truvada as pre-exposure prophylaxis (PrEP).

At Whitman-Walker alone, about 3000 people were taking the pill in early 2020, but “for some people, taking a pill every day just isn’t a viable option,” said Coleman. “To have something that can support a patient’s choice and a patient’s ability to reduce their own risk of HIV is amazing.”

Final results from the trial — which looked at the drug in cisgender men and transgender women who have sex with men — were presented at the International AIDS Conference 2020.
 

Early Study Termination

Half of the 4566 study participants — from 43 sites in Africa, Asia, Latin America, and the United States — were younger than 30 years, 12.4% were transgender women, 29.7% were black, and 46.1% were Hispanic.

By design, ViiV Healthcare, the study sponsor, required that 50% of American participants be black to reflect the population at risk for HIV in the United States, said Raphael Landovitz, MD, from the UCLA David Geffen School of Medicine in Los Angeles, who is protocol chair for HPTN 083. In fact, 49.7% of the American cohort was black and 17.8% was Hispanic.

Patients randomized to the cabotegravir group received daily oral cabotegravir plus daily oral placebo for 5 weeks, to assess safety, followed by a cabotegravir injection at weeks 5 and 9 and every 2 months thereafter out to week 153 plus daily oral placebo. Patients randomized to the Truvada group received daily oral Truvada plus daily oral placebo for 5 weeks, followed by daily oral Truvada plus placebo injection, on the same schedule, out to week 153.

After the final injection, all participants continued on daily oral Truvada for 48 weeks.

The researchers expected to wait until 172 participants acquired HIV; they decided at the outset that this number would be sufficient to power a decision on whether or not cabotegravir injections are better than daily oral Truvada. But by May 2020, when 52 of the study participants had acquired HIV, the results were so lopsided in favor of cabotegravir that the trial was stopped. At that point, all participants were offered cabotegravir injections every 2 months.

Thirty-nine of the 52 (75%) new HIV infections occurred in the Truvada group. In fact, people in the cabotegravir group were less likely to acquire HIV than those in the Truvada group (hazard ratio, 0.34).

“This definitively establishes the superiority of cabotegravir,” said Landovitz.

He and his colleagues had been legitimately concerned that HIV acquisition would be so low in the trial that they wouldn’t be able to show how effective the injectable was. The success of Truvada PrEP has made it difficult to design prevention trials.

“We know that Truvada works extremely well, so the fact that we were able to show that cabotegravir in this population works better” is a powerful observation, said Landovitz. This is especially true because the rates of sexually transmitted infections — which are thought to increase risk for HIV transmission — were so high. Overall, 16.5% of the participants tested positive for syphilis during the trial, 13.3% tested positive for gonorrhea, and 21.1% tested positive for Chlamydia.
 

Five Surprising Seroconversions

Eleven of the 15 HIV infections in the cabotegravir group occurred in people who had received at least one injection. Three of these infections actually occurred during the first 5 weeks of the study when participants were taking oral cabotegravir, two occurred when participants chose to discontinue the injection and return to daily oral Truvada, and one occurred after a participant missed the injection for a prolonged period of time.

But five of the transmissions occurred in participants who appeared to be perfectly adherent.

Landovitz offered a number of possible reasons for this surprising finding.

“Number one could be that there’s something about these five particular individuals such that they grind up and eliminate the cabotegravir faster than other people, so an 8-week interval is too long for them,” he explained. “Another possibility, although pretty rare, is that there is a rare circulating virus that is intrinsically resistant to cabotegravir.”

Breakthrough HIV transmissions have been rare in people taking oral PrEP.

Disruptions caused by the COVID-19 pandemic have meant that the researchers don’t yet have the data on drug-resistant mutations or drug levels for these five participants, but they will.

“I suspect the truth is that there will never be a 100% failsafe HIV prevention mechanism,” said Landovitz.
 

“Impressive” Findings

The findings were greeted with excitement, although questions remain.

They are “impressive,” especially the data on black and Hispanic participants, said Paul Sax, MD, medical director of the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston.

However, he said he is interested in the data showing that although participants in both groups gained weight during the study, there was early weight loss in the Truvada group, meaning that those in the cabotegravir group weighed more at the end of the study than those in the Truvada group.

“I’ve been watching the data on weight with integrase inhibitors,” he explained, including weight data specific to Truvada and to the combination of emtricitabine and tenofovir alafenamide (Descovy, Gilead). It looks like Truvada “has some sort of weight-suppressive effects. That’s going to be a thing we’re going to have to watch.”

Coleman said she is already thinking about patients at Whitman-Walker who might do well on cabotegravir and those who can start PrEP for the first time with this option.

“Not only would people probably switch to this option, but maybe people would be interested in starting a biomedical prevention approach that isn’t a pill every day,” she said. “It’s just exciting to have another option. Hopefully, in a few years, we’ll have implantable devices and rings; I can’t even imagine what all those brilliant minds are coming up with.”

But that’s still a ways off. First, cabotegravir has yet to be approved for HIV prevention, and ideally, eventually, there will be a way to determine if cabotegravir is safe for each patient that doesn’t involve a month of daily pills.

“We need to solve that problem because it’s so complicated to do an oral lead-in for a month or so,” said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. “Otherwise it’s not going to be feasible.”

We need to make sure this gets licensed for men and women and transgender individuals.

Even with these positive data, Dieffenbach and other officials are not keen to have ViiV apply for licensing right away. Last October, Descovy was the second oral PrEP pill approved for HIV prevention, but only for use by gay men and transgender women — it hadn’t been well studied in cisgender women — causing an outcry. Now, officials are suggesting that ViiV not make the same mistake.

They are urging the company to hold off until data from the sister study of the medication in women — HPTN 084 — is completed in 2022.

“We need to make sure this gets licensed for men and women and transgender individuals,” Dieffenbach told Medscape Medical News. “We just need to give this a little more time and then build a plan with contingencies, so that if something happens, we still have collected all the safety data in women so we can say it’s safe.”
 

ViiV seems to be making such a plan.

“Our goal is to seek approval across all genders and we will work with the FDA and other regulatory agencies to map out a plan to achieve this goal,” said Kimberly Smith, MD, head of research and development at ViiV Healthcare.

The World Health Organization (WHO), meanwhile, doesn’t expect to change its guidelines on HIV prevention medications until data from HPTN 084 are reported.

“What’s important when we look at guidelines is that we also look across populations,” said Meg Doherty, coordinator of treatment and care in the Department of HIV/AIDS at WHO. “We’re waiting to know more about how cabotegravir works in women, because we certainly want to have prevention drugs that can be used in men and women at different age ranges and, ideally, during pregnancy.”

International AIDS Conference 2020: Abstracts OAXLB01. Presented July 8, 2020.
 

This article first appeared on Medscape.com.

Injections of cabotegravir (ViiV Healthcare) given every other month are more effective in blocking HIV transmission than is the once-a-day combination of tenofovir disoproxil fumarate and emtricitabine (Truvada, Gilead Science), new data from the HPTN 083 trial show.

The findings “could transform the HIV prevention landscape for so many people,” said Megan Coleman, DNP, from Whitman-Walker Health in Washington, DC, who regularly prescribes Truvada as pre-exposure prophylaxis (PrEP).

At Whitman-Walker alone, about 3000 people were taking the pill in early 2020, but “for some people, taking a pill every day just isn’t a viable option,” said Coleman. “To have something that can support a patient’s choice and a patient’s ability to reduce their own risk of HIV is amazing.”

Final results from the trial — which looked at the drug in cisgender men and transgender women who have sex with men — were presented at the International AIDS Conference 2020.
 

Early Study Termination

Half of the 4566 study participants — from 43 sites in Africa, Asia, Latin America, and the United States — were younger than 30 years, 12.4% were transgender women, 29.7% were black, and 46.1% were Hispanic.

By design, ViiV Healthcare, the study sponsor, required that 50% of American participants be black to reflect the population at risk for HIV in the United States, said Raphael Landovitz, MD, from the UCLA David Geffen School of Medicine in Los Angeles, who is protocol chair for HPTN 083. In fact, 49.7% of the American cohort was black and 17.8% was Hispanic.

Patients randomized to the cabotegravir group received daily oral cabotegravir plus daily oral placebo for 5 weeks, to assess safety, followed by a cabotegravir injection at weeks 5 and 9 and every 2 months thereafter out to week 153 plus daily oral placebo. Patients randomized to the Truvada group received daily oral Truvada plus daily oral placebo for 5 weeks, followed by daily oral Truvada plus placebo injection, on the same schedule, out to week 153.

After the final injection, all participants continued on daily oral Truvada for 48 weeks.

The researchers expected to wait until 172 participants acquired HIV; they decided at the outset that this number would be sufficient to power a decision on whether or not cabotegravir injections are better than daily oral Truvada. But by May 2020, when 52 of the study participants had acquired HIV, the results were so lopsided in favor of cabotegravir that the trial was stopped. At that point, all participants were offered cabotegravir injections every 2 months.

Thirty-nine of the 52 (75%) new HIV infections occurred in the Truvada group. In fact, people in the cabotegravir group were less likely to acquire HIV than those in the Truvada group (hazard ratio, 0.34).

“This definitively establishes the superiority of cabotegravir,” said Landovitz.

He and his colleagues had been legitimately concerned that HIV acquisition would be so low in the trial that they wouldn’t be able to show how effective the injectable was. The success of Truvada PrEP has made it difficult to design prevention trials.

“We know that Truvada works extremely well, so the fact that we were able to show that cabotegravir in this population works better” is a powerful observation, said Landovitz. This is especially true because the rates of sexually transmitted infections — which are thought to increase risk for HIV transmission — were so high. Overall, 16.5% of the participants tested positive for syphilis during the trial, 13.3% tested positive for gonorrhea, and 21.1% tested positive for Chlamydia.
 

Five Surprising Seroconversions

Eleven of the 15 HIV infections in the cabotegravir group occurred in people who had received at least one injection. Three of these infections actually occurred during the first 5 weeks of the study when participants were taking oral cabotegravir, two occurred when participants chose to discontinue the injection and return to daily oral Truvada, and one occurred after a participant missed the injection for a prolonged period of time.

But five of the transmissions occurred in participants who appeared to be perfectly adherent.

Landovitz offered a number of possible reasons for this surprising finding.

“Number one could be that there’s something about these five particular individuals such that they grind up and eliminate the cabotegravir faster than other people, so an 8-week interval is too long for them,” he explained. “Another possibility, although pretty rare, is that there is a rare circulating virus that is intrinsically resistant to cabotegravir.”

Breakthrough HIV transmissions have been rare in people taking oral PrEP.

Disruptions caused by the COVID-19 pandemic have meant that the researchers don’t yet have the data on drug-resistant mutations or drug levels for these five participants, but they will.

“I suspect the truth is that there will never be a 100% failsafe HIV prevention mechanism,” said Landovitz.
 

“Impressive” Findings

The findings were greeted with excitement, although questions remain.

They are “impressive,” especially the data on black and Hispanic participants, said Paul Sax, MD, medical director of the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston.

However, he said he is interested in the data showing that although participants in both groups gained weight during the study, there was early weight loss in the Truvada group, meaning that those in the cabotegravir group weighed more at the end of the study than those in the Truvada group.

“I’ve been watching the data on weight with integrase inhibitors,” he explained, including weight data specific to Truvada and to the combination of emtricitabine and tenofovir alafenamide (Descovy, Gilead). It looks like Truvada “has some sort of weight-suppressive effects. That’s going to be a thing we’re going to have to watch.”

Coleman said she is already thinking about patients at Whitman-Walker who might do well on cabotegravir and those who can start PrEP for the first time with this option.

“Not only would people probably switch to this option, but maybe people would be interested in starting a biomedical prevention approach that isn’t a pill every day,” she said. “It’s just exciting to have another option. Hopefully, in a few years, we’ll have implantable devices and rings; I can’t even imagine what all those brilliant minds are coming up with.”

But that’s still a ways off. First, cabotegravir has yet to be approved for HIV prevention, and ideally, eventually, there will be a way to determine if cabotegravir is safe for each patient that doesn’t involve a month of daily pills.

“We need to solve that problem because it’s so complicated to do an oral lead-in for a month or so,” said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. “Otherwise it’s not going to be feasible.”

We need to make sure this gets licensed for men and women and transgender individuals.

Even with these positive data, Dieffenbach and other officials are not keen to have ViiV apply for licensing right away. Last October, Descovy was the second oral PrEP pill approved for HIV prevention, but only for use by gay men and transgender women — it hadn’t been well studied in cisgender women — causing an outcry. Now, officials are suggesting that ViiV not make the same mistake.

They are urging the company to hold off until data from the sister study of the medication in women — HPTN 084 — is completed in 2022.

“We need to make sure this gets licensed for men and women and transgender individuals,” Dieffenbach told Medscape Medical News. “We just need to give this a little more time and then build a plan with contingencies, so that if something happens, we still have collected all the safety data in women so we can say it’s safe.”
 

ViiV seems to be making such a plan.

“Our goal is to seek approval across all genders and we will work with the FDA and other regulatory agencies to map out a plan to achieve this goal,” said Kimberly Smith, MD, head of research and development at ViiV Healthcare.

The World Health Organization (WHO), meanwhile, doesn’t expect to change its guidelines on HIV prevention medications until data from HPTN 084 are reported.

“What’s important when we look at guidelines is that we also look across populations,” said Meg Doherty, coordinator of treatment and care in the Department of HIV/AIDS at WHO. “We’re waiting to know more about how cabotegravir works in women, because we certainly want to have prevention drugs that can be used in men and women at different age ranges and, ideally, during pregnancy.”

International AIDS Conference 2020: Abstracts OAXLB01. Presented July 8, 2020.
 

This article first appeared on Medscape.com.

Injections of cabotegravir (ViiV Healthcare) given every other month are more effective in blocking HIV transmission than is the once-a-day combination of tenofovir disoproxil fumarate and emtricitabine (Truvada, Gilead Science), new data from the HPTN 083 trial show.

The findings “could transform the HIV prevention landscape for so many people,” said Megan Coleman, DNP, from Whitman-Walker Health in Washington, DC, who regularly prescribes Truvada as pre-exposure prophylaxis (PrEP).

At Whitman-Walker alone, about 3000 people were taking the pill in early 2020, but “for some people, taking a pill every day just isn’t a viable option,” said Coleman. “To have something that can support a patient’s choice and a patient’s ability to reduce their own risk of HIV is amazing.”

Final results from the trial — which looked at the drug in cisgender men and transgender women who have sex with men — were presented at the International AIDS Conference 2020.
 

Early Study Termination

Half of the 4566 study participants — from 43 sites in Africa, Asia, Latin America, and the United States — were younger than 30 years, 12.4% were transgender women, 29.7% were black, and 46.1% were Hispanic.

By design, ViiV Healthcare, the study sponsor, required that 50% of American participants be black to reflect the population at risk for HIV in the United States, said Raphael Landovitz, MD, from the UCLA David Geffen School of Medicine in Los Angeles, who is protocol chair for HPTN 083. In fact, 49.7% of the American cohort was black and 17.8% was Hispanic.

Patients randomized to the cabotegravir group received daily oral cabotegravir plus daily oral placebo for 5 weeks, to assess safety, followed by a cabotegravir injection at weeks 5 and 9 and every 2 months thereafter out to week 153 plus daily oral placebo. Patients randomized to the Truvada group received daily oral Truvada plus daily oral placebo for 5 weeks, followed by daily oral Truvada plus placebo injection, on the same schedule, out to week 153.

After the final injection, all participants continued on daily oral Truvada for 48 weeks.

The researchers expected to wait until 172 participants acquired HIV; they decided at the outset that this number would be sufficient to power a decision on whether or not cabotegravir injections are better than daily oral Truvada. But by May 2020, when 52 of the study participants had acquired HIV, the results were so lopsided in favor of cabotegravir that the trial was stopped. At that point, all participants were offered cabotegravir injections every 2 months.

Thirty-nine of the 52 (75%) new HIV infections occurred in the Truvada group. In fact, people in the cabotegravir group were less likely to acquire HIV than those in the Truvada group (hazard ratio, 0.34).

“This definitively establishes the superiority of cabotegravir,” said Landovitz.

He and his colleagues had been legitimately concerned that HIV acquisition would be so low in the trial that they wouldn’t be able to show how effective the injectable was. The success of Truvada PrEP has made it difficult to design prevention trials.

“We know that Truvada works extremely well, so the fact that we were able to show that cabotegravir in this population works better” is a powerful observation, said Landovitz. This is especially true because the rates of sexually transmitted infections — which are thought to increase risk for HIV transmission — were so high. Overall, 16.5% of the participants tested positive for syphilis during the trial, 13.3% tested positive for gonorrhea, and 21.1% tested positive for Chlamydia.
 

Five Surprising Seroconversions

Eleven of the 15 HIV infections in the cabotegravir group occurred in people who had received at least one injection. Three of these infections actually occurred during the first 5 weeks of the study when participants were taking oral cabotegravir, two occurred when participants chose to discontinue the injection and return to daily oral Truvada, and one occurred after a participant missed the injection for a prolonged period of time.

But five of the transmissions occurred in participants who appeared to be perfectly adherent.

Landovitz offered a number of possible reasons for this surprising finding.

“Number one could be that there’s something about these five particular individuals such that they grind up and eliminate the cabotegravir faster than other people, so an 8-week interval is too long for them,” he explained. “Another possibility, although pretty rare, is that there is a rare circulating virus that is intrinsically resistant to cabotegravir.”

Breakthrough HIV transmissions have been rare in people taking oral PrEP.

Disruptions caused by the COVID-19 pandemic have meant that the researchers don’t yet have the data on drug-resistant mutations or drug levels for these five participants, but they will.

“I suspect the truth is that there will never be a 100% failsafe HIV prevention mechanism,” said Landovitz.
 

“Impressive” Findings

The findings were greeted with excitement, although questions remain.

They are “impressive,” especially the data on black and Hispanic participants, said Paul Sax, MD, medical director of the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston.

However, he said he is interested in the data showing that although participants in both groups gained weight during the study, there was early weight loss in the Truvada group, meaning that those in the cabotegravir group weighed more at the end of the study than those in the Truvada group.

“I’ve been watching the data on weight with integrase inhibitors,” he explained, including weight data specific to Truvada and to the combination of emtricitabine and tenofovir alafenamide (Descovy, Gilead). It looks like Truvada “has some sort of weight-suppressive effects. That’s going to be a thing we’re going to have to watch.”

Coleman said she is already thinking about patients at Whitman-Walker who might do well on cabotegravir and those who can start PrEP for the first time with this option.

“Not only would people probably switch to this option, but maybe people would be interested in starting a biomedical prevention approach that isn’t a pill every day,” she said. “It’s just exciting to have another option. Hopefully, in a few years, we’ll have implantable devices and rings; I can’t even imagine what all those brilliant minds are coming up with.”

But that’s still a ways off. First, cabotegravir has yet to be approved for HIV prevention, and ideally, eventually, there will be a way to determine if cabotegravir is safe for each patient that doesn’t involve a month of daily pills.

“We need to solve that problem because it’s so complicated to do an oral lead-in for a month or so,” said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. “Otherwise it’s not going to be feasible.”

We need to make sure this gets licensed for men and women and transgender individuals.

Even with these positive data, Dieffenbach and other officials are not keen to have ViiV apply for licensing right away. Last October, Descovy was the second oral PrEP pill approved for HIV prevention, but only for use by gay men and transgender women — it hadn’t been well studied in cisgender women — causing an outcry. Now, officials are suggesting that ViiV not make the same mistake.

They are urging the company to hold off until data from the sister study of the medication in women — HPTN 084 — is completed in 2022.

“We need to make sure this gets licensed for men and women and transgender individuals,” Dieffenbach told Medscape Medical News. “We just need to give this a little more time and then build a plan with contingencies, so that if something happens, we still have collected all the safety data in women so we can say it’s safe.”
 

ViiV seems to be making such a plan.

“Our goal is to seek approval across all genders and we will work with the FDA and other regulatory agencies to map out a plan to achieve this goal,” said Kimberly Smith, MD, head of research and development at ViiV Healthcare.

The World Health Organization (WHO), meanwhile, doesn’t expect to change its guidelines on HIV prevention medications until data from HPTN 084 are reported.

“What’s important when we look at guidelines is that we also look across populations,” said Meg Doherty, coordinator of treatment and care in the Department of HIV/AIDS at WHO. “We’re waiting to know more about how cabotegravir works in women, because we certainly want to have prevention drugs that can be used in men and women at different age ranges and, ideally, during pregnancy.”

International AIDS Conference 2020: Abstracts OAXLB01. Presented July 8, 2020.
 

This article first appeared on Medscape.com.

Transitioning from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone therapy increased proteasome inhibitor (PI)–based treatment adherence and duration, according to early results from a clinical trial designed to include patients representing the real-world U.S. multiple myeloma population.

The US MM-6 study was designed to evaluate a novel in-class therapy (iCT) transitioning approach from intravenous to oral treatment in the community-based setting with the aims of increasing PI-based treatment duration and adherence, maintaining health-related quality of life (HRQoL), and improving outcomes in a representative, real-world, community population of multiple myeloma patients, according to Sudhir Manda, MD, of Arizona Oncology/U.S. Oncology Research, Tucson, and colleagues.

Dr. Manda and colleagues reported on the early results of the US MM-6 trial (NCT03173092), which is a community-based, real-world, open-label, single-arm, phase 4 study of adult multiple myeloma patients who do not meet transplant-eligibility criteria, or for whom transplant would be delayed for 2 years or more, and who are receiving first-line bortezomib-based induction. All patients in the study had no evidence of progressive disease after three treatment cycles.

By the data cutoff for the reported analysis, 84 patients had been treated. The patients had a median age of 73 years; 49% were men; 15% black/African American; 10% Hispanic/Latino. A total of 62% of the patients remain on therapy, with a mean duration of total PI therapy of 10.1 months and of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) of 7.3 months.

The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after induction to all-oral ixazomib-Rd.

“The use of this novel iCT approach from parenteral bortezomib-based to oral ixazomib-based therapy facilitates long-term PI-based treatment that is well tolerated in real-world, nontransplant [newly diagnosed multiple myeloma] patients,” according to Dr. Manda and colleagues. In addition, “preliminary findings indicate that the iCT approach results in promising efficacy and high medication adherence, with no adverse impact on patients’ HRQoL or treatment satisfaction.”

The study was sponsored by Millennium Pharmaceuticals. Four of the authors are employees of Millennium Pharmaceuticals and several authors disclosed relationships with various pharmaceutical companies, including Millennium Pharmaceuticals.

mlesney@mdedge.com

SOURCE: Manda S et al. Clin Lymphoma Myeloma Leuk. 2020 Jun 30. doi: 10.1016/j.clml.2020.06.024.

Transitioning from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone therapy increased proteasome inhibitor (PI)–based treatment adherence and duration, according to early results from a clinical trial designed to include patients representing the real-world U.S. multiple myeloma population.

The US MM-6 study was designed to evaluate a novel in-class therapy (iCT) transitioning approach from intravenous to oral treatment in the community-based setting with the aims of increasing PI-based treatment duration and adherence, maintaining health-related quality of life (HRQoL), and improving outcomes in a representative, real-world, community population of multiple myeloma patients, according to Sudhir Manda, MD, of Arizona Oncology/U.S. Oncology Research, Tucson, and colleagues.

Dr. Manda and colleagues reported on the early results of the US MM-6 trial (NCT03173092), which is a community-based, real-world, open-label, single-arm, phase 4 study of adult multiple myeloma patients who do not meet transplant-eligibility criteria, or for whom transplant would be delayed for 2 years or more, and who are receiving first-line bortezomib-based induction. All patients in the study had no evidence of progressive disease after three treatment cycles.

By the data cutoff for the reported analysis, 84 patients had been treated. The patients had a median age of 73 years; 49% were men; 15% black/African American; 10% Hispanic/Latino. A total of 62% of the patients remain on therapy, with a mean duration of total PI therapy of 10.1 months and of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) of 7.3 months.

The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after induction to all-oral ixazomib-Rd.

“The use of this novel iCT approach from parenteral bortezomib-based to oral ixazomib-based therapy facilitates long-term PI-based treatment that is well tolerated in real-world, nontransplant [newly diagnosed multiple myeloma] patients,” according to Dr. Manda and colleagues. In addition, “preliminary findings indicate that the iCT approach results in promising efficacy and high medication adherence, with no adverse impact on patients’ HRQoL or treatment satisfaction.”

The study was sponsored by Millennium Pharmaceuticals. Four of the authors are employees of Millennium Pharmaceuticals and several authors disclosed relationships with various pharmaceutical companies, including Millennium Pharmaceuticals.

mlesney@mdedge.com

SOURCE: Manda S et al. Clin Lymphoma Myeloma Leuk. 2020 Jun 30. doi: 10.1016/j.clml.2020.06.024.

Transitioning from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone therapy increased proteasome inhibitor (PI)–based treatment adherence and duration, according to early results from a clinical trial designed to include patients representing the real-world U.S. multiple myeloma population.

The US MM-6 study was designed to evaluate a novel in-class therapy (iCT) transitioning approach from intravenous to oral treatment in the community-based setting with the aims of increasing PI-based treatment duration and adherence, maintaining health-related quality of life (HRQoL), and improving outcomes in a representative, real-world, community population of multiple myeloma patients, according to Sudhir Manda, MD, of Arizona Oncology/U.S. Oncology Research, Tucson, and colleagues.

Dr. Manda and colleagues reported on the early results of the US MM-6 trial (NCT03173092), which is a community-based, real-world, open-label, single-arm, phase 4 study of adult multiple myeloma patients who do not meet transplant-eligibility criteria, or for whom transplant would be delayed for 2 years or more, and who are receiving first-line bortezomib-based induction. All patients in the study had no evidence of progressive disease after three treatment cycles.

By the data cutoff for the reported analysis, 84 patients had been treated. The patients had a median age of 73 years; 49% were men; 15% black/African American; 10% Hispanic/Latino. A total of 62% of the patients remain on therapy, with a mean duration of total PI therapy of 10.1 months and of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) of 7.3 months.

The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after induction to all-oral ixazomib-Rd.

“The use of this novel iCT approach from parenteral bortezomib-based to oral ixazomib-based therapy facilitates long-term PI-based treatment that is well tolerated in real-world, nontransplant [newly diagnosed multiple myeloma] patients,” according to Dr. Manda and colleagues. In addition, “preliminary findings indicate that the iCT approach results in promising efficacy and high medication adherence, with no adverse impact on patients’ HRQoL or treatment satisfaction.”

The study was sponsored by Millennium Pharmaceuticals. Four of the authors are employees of Millennium Pharmaceuticals and several authors disclosed relationships with various pharmaceutical companies, including Millennium Pharmaceuticals.

mlesney@mdedge.com

SOURCE: Manda S et al. Clin Lymphoma Myeloma Leuk. 2020 Jun 30. doi: 10.1016/j.clml.2020.06.024.

Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosis, cataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated with serious risks.

Most recently, a population-based study of more than 2.6 million people found that taking corticosteroids for 14 days or less was associated with a substantially greater risk for gastrointestinal (GI) bleeding, sepsis, and heart failure, particularly within the first 30 days after therapy.

In the study, Tsung-Chieh Yao, MD, PhD, a professor in the division of allergy, asthma, and rheumatology in the department of pediatrics at Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues used a self-controlled case series to analyze data from Taiwan’s National Health Insurance Research Database of medical claims. They compared patients’ conditions in the period from 5 to 90 days before treatment to conditions from the periods from 5 to 30 days and from 31 to 90 days after therapy.

With a median duration of 3 days of treatment, the incidence rate ratios (IRRs) were 1.80 (95% confidence interval, 1.75-1.84) for GI bleeding, 1.99 (95% CI, 1.70-2.32) for sepsis, and 2.37 (95% CI, 2.13-2.63) for heart failure.

Given the findings, physicians should weigh the benefits against the risks of rare but potentially serious consequences of these anti-inflammatory drugs, according to the authors.

“After initiating patients on oral steroid bursts, physicians should be on the lookout for these severe adverse events, particularly within the first month after initiation of steroid therapy,” Dr. Yao said in an interview.

The findings were published online July 6 in Annals of Internal Medicine.

Of the 15,859,129 adult Asians in the Taiwanese database, the study included 2,623,327 adults aged 20-64 years who received single steroid bursts (14 days or less) between Jan. 1, 2013, and Dec. 31, 2015.

Almost 60% of the indications were for skin disorders, such as eczema and urticaria, and for respiratory tract infections, such as sinusitis and acute pharyngitis. Among specialties, dermatology, otolaryngology, family practice, internal medicine, and pediatrics accounted for 88% of prescriptions.

“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the authors wrote. They acknowledged that the database did not provide information on such potential confounders as disease severity and lifestyle factors, nor did it include children and vulnerable individuals, which may limit the generalizability of the results.

The findings echo those of a 2017 cohort study conducted by researchers at the University of Michigan in Ann Arbor. That study, by Akbar K. Waljee, MD, assistant professor of gastroenterology, University of Michigan, Ann Arbor, and colleagues, included data on more than 1.5 million privately insured U.S. adults. The researchers included somewhat longer steroid bursts of up to 30 days’ duration and found that use of the drugs was associated with a greater than fivefold increased risk for sepsis, a more than threefold increased risk for venous thromboembolism, and a nearly twofold increased risk for fracture within 30 days of starting treatment.

Furthermore, the elevated risk persisted at prednisone-equivalent doses of less than 20 mg/d (IRR, 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P < .001).

The U.S. study also found that during the 3-year period from 2012 to 2014, more than 20% of patients were prescribed short-term oral corticosteroids.

“Both studies indicate that these short-term regimens are more common in the real world than was previously thought and are not risk free,” Dr. Yao said.

Recognition that corticosteroids are associated with adverse events has been building for decades, according to the authors of an editorial that accompanies the new study.

“However, we commonly use short corticosteroid ‘bursts’ for minor ailments despite a lack of evidence for meaningful benefit. We are now learning that bursts as short as 3 days may increase risk for serious AEs, even in young and healthy people,” wrote editorialists Beth I. Wallace, MD, of the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and the Institute for Healthcare Policy and Innovation at Michigan Medicine, Ann Arbor, and Dr. Waljee, who led the 2017 study.

Dr. Wallace and Dr. Waljee drew parallels between corticosteroid bursts and other short-term regimens, such as of antibiotics and opiates, in which prescriber preference and sometimes patient pressure play a role. “All of these treatments have well-defined indications but can cause net harm when used. We can thus conceive of a corticosteroid stewardship model of targeted interventions that aims to reduce inappropriate prescribing,” they wrote.

In an interview, Dr. Wallace, a rheumatologist who prescribes oral steroids fairly frequently, noted that the Taiwan study is the first to investigate steroid bursts. “Up till now, these very short courses have flown under the radar. Clinicians very commonly prescribe short courses to help relieve symptoms of self-limited conditions like bronchitis, and we assume that because the exposure duration is short, the risks are low, especially for patients who are otherwise healthy.”

She warned that the data in the current study indicate that these short bursts – even at the lower end of the 1- to 2-week courses American physicians prescribe most often – carry small but real increases in risk for serious AEs. “And these increases were seen in young, healthy people, not just in people with preexisting conditions,” she said. “So, we might need to start thinking harder about how we are prescribing even these very short courses of steroids and try to use steroids only when their meaningful benefits really outweigh the risk.”

She noted that a patient with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. In that specific case, the benefits of short-term steroids may outweigh the risks, Dr. Wallace said.

But not everyone thinks a new strategy is needed. For Whitney A. High, MD, associate professor of dermatology and pathology at the University of Colorado at Denver, Aurora, the overprescribing of short-term corticosteroids is not a problem, and dermatologists are already exercising caution.

Bruce Jancin/MDedge News

“I only prescribe these drugs short term to, at a guess, about 1 in 40 patients and only when a patient is miserable and quality of life is being seriously affected,” he said in an interview. “And that’s something that can’t be measured in a database study like the one from Taiwan but only in a risk-benefit analysis,” he said.

Furthermore, dermatologists have other drugs and technologies in their armamentarium, including topical steroids with occlusion or with wet wraps, phototherapy, phosphodiesterase inhibitors, calcipotriene, methotrexate and other immunosuppressive agents, and biologics. “In fact, many of these agents are specifically referred to as steroid-sparing,” Dr. High said.

Nor does he experience much pressure from patients to prescribe these drugs. “While occasionally I may encounter a patient who places pressure on me for oral steroids, it’s probably not nearly as frequently as providers in other fields are pressured to prescribe antibiotics or narcotics,” he said.

According to the Taiwanese researchers, the next step is to conduct more studies, including clinical trials, to determine optimal use of corticosteroids by monitoring adverse events. In the meantime, for practitioners such as Dr. Wallace and Dr. High, there is ample evidence from several recent studies of the harms of short-term corticosteroids, whereas the benefits for patients with self-limiting conditions remain uncertain. “This and other studies like it quite appropriately remind providers to avoid oral steroids when they’re not necessary and to seek alternatives where possible,” Dr. High said.

The study was supported by the National Health Research Institutes of Taiwan, the Ministry of Science and Technology of Taiwan, the Chang Gung Medical Foundation, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Dr. Yao has disclosed no relevant financial relationships. Dr. Wu has received grants from GlaxoSmithKline outside the submitted work. The editorialists and Dr. High have disclosed no relevant financial relationships. Dr. Wallace received an NIH grant during the writing of the editorial.
 

A version of this article originally appeared on Medscape.com.

Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosis, cataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated with serious risks.

Most recently, a population-based study of more than 2.6 million people found that taking corticosteroids for 14 days or less was associated with a substantially greater risk for gastrointestinal (GI) bleeding, sepsis, and heart failure, particularly within the first 30 days after therapy.

In the study, Tsung-Chieh Yao, MD, PhD, a professor in the division of allergy, asthma, and rheumatology in the department of pediatrics at Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues used a self-controlled case series to analyze data from Taiwan’s National Health Insurance Research Database of medical claims. They compared patients’ conditions in the period from 5 to 90 days before treatment to conditions from the periods from 5 to 30 days and from 31 to 90 days after therapy.

With a median duration of 3 days of treatment, the incidence rate ratios (IRRs) were 1.80 (95% confidence interval, 1.75-1.84) for GI bleeding, 1.99 (95% CI, 1.70-2.32) for sepsis, and 2.37 (95% CI, 2.13-2.63) for heart failure.

Given the findings, physicians should weigh the benefits against the risks of rare but potentially serious consequences of these anti-inflammatory drugs, according to the authors.

“After initiating patients on oral steroid bursts, physicians should be on the lookout for these severe adverse events, particularly within the first month after initiation of steroid therapy,” Dr. Yao said in an interview.

The findings were published online July 6 in Annals of Internal Medicine.

Of the 15,859,129 adult Asians in the Taiwanese database, the study included 2,623,327 adults aged 20-64 years who received single steroid bursts (14 days or less) between Jan. 1, 2013, and Dec. 31, 2015.

Almost 60% of the indications were for skin disorders, such as eczema and urticaria, and for respiratory tract infections, such as sinusitis and acute pharyngitis. Among specialties, dermatology, otolaryngology, family practice, internal medicine, and pediatrics accounted for 88% of prescriptions.

“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the authors wrote. They acknowledged that the database did not provide information on such potential confounders as disease severity and lifestyle factors, nor did it include children and vulnerable individuals, which may limit the generalizability of the results.

The findings echo those of a 2017 cohort study conducted by researchers at the University of Michigan in Ann Arbor. That study, by Akbar K. Waljee, MD, assistant professor of gastroenterology, University of Michigan, Ann Arbor, and colleagues, included data on more than 1.5 million privately insured U.S. adults. The researchers included somewhat longer steroid bursts of up to 30 days’ duration and found that use of the drugs was associated with a greater than fivefold increased risk for sepsis, a more than threefold increased risk for venous thromboembolism, and a nearly twofold increased risk for fracture within 30 days of starting treatment.

Furthermore, the elevated risk persisted at prednisone-equivalent doses of less than 20 mg/d (IRR, 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P < .001).

The U.S. study also found that during the 3-year period from 2012 to 2014, more than 20% of patients were prescribed short-term oral corticosteroids.

“Both studies indicate that these short-term regimens are more common in the real world than was previously thought and are not risk free,” Dr. Yao said.

Recognition that corticosteroids are associated with adverse events has been building for decades, according to the authors of an editorial that accompanies the new study.

“However, we commonly use short corticosteroid ‘bursts’ for minor ailments despite a lack of evidence for meaningful benefit. We are now learning that bursts as short as 3 days may increase risk for serious AEs, even in young and healthy people,” wrote editorialists Beth I. Wallace, MD, of the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and the Institute for Healthcare Policy and Innovation at Michigan Medicine, Ann Arbor, and Dr. Waljee, who led the 2017 study.

Dr. Wallace and Dr. Waljee drew parallels between corticosteroid bursts and other short-term regimens, such as of antibiotics and opiates, in which prescriber preference and sometimes patient pressure play a role. “All of these treatments have well-defined indications but can cause net harm when used. We can thus conceive of a corticosteroid stewardship model of targeted interventions that aims to reduce inappropriate prescribing,” they wrote.

In an interview, Dr. Wallace, a rheumatologist who prescribes oral steroids fairly frequently, noted that the Taiwan study is the first to investigate steroid bursts. “Up till now, these very short courses have flown under the radar. Clinicians very commonly prescribe short courses to help relieve symptoms of self-limited conditions like bronchitis, and we assume that because the exposure duration is short, the risks are low, especially for patients who are otherwise healthy.”

She warned that the data in the current study indicate that these short bursts – even at the lower end of the 1- to 2-week courses American physicians prescribe most often – carry small but real increases in risk for serious AEs. “And these increases were seen in young, healthy people, not just in people with preexisting conditions,” she said. “So, we might need to start thinking harder about how we are prescribing even these very short courses of steroids and try to use steroids only when their meaningful benefits really outweigh the risk.”

She noted that a patient with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. In that specific case, the benefits of short-term steroids may outweigh the risks, Dr. Wallace said.

But not everyone thinks a new strategy is needed. For Whitney A. High, MD, associate professor of dermatology and pathology at the University of Colorado at Denver, Aurora, the overprescribing of short-term corticosteroids is not a problem, and dermatologists are already exercising caution.

Bruce Jancin/MDedge News

“I only prescribe these drugs short term to, at a guess, about 1 in 40 patients and only when a patient is miserable and quality of life is being seriously affected,” he said in an interview. “And that’s something that can’t be measured in a database study like the one from Taiwan but only in a risk-benefit analysis,” he said.

Furthermore, dermatologists have other drugs and technologies in their armamentarium, including topical steroids with occlusion or with wet wraps, phototherapy, phosphodiesterase inhibitors, calcipotriene, methotrexate and other immunosuppressive agents, and biologics. “In fact, many of these agents are specifically referred to as steroid-sparing,” Dr. High said.

Nor does he experience much pressure from patients to prescribe these drugs. “While occasionally I may encounter a patient who places pressure on me for oral steroids, it’s probably not nearly as frequently as providers in other fields are pressured to prescribe antibiotics or narcotics,” he said.

According to the Taiwanese researchers, the next step is to conduct more studies, including clinical trials, to determine optimal use of corticosteroids by monitoring adverse events. In the meantime, for practitioners such as Dr. Wallace and Dr. High, there is ample evidence from several recent studies of the harms of short-term corticosteroids, whereas the benefits for patients with self-limiting conditions remain uncertain. “This and other studies like it quite appropriately remind providers to avoid oral steroids when they’re not necessary and to seek alternatives where possible,” Dr. High said.

The study was supported by the National Health Research Institutes of Taiwan, the Ministry of Science and Technology of Taiwan, the Chang Gung Medical Foundation, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Dr. Yao has disclosed no relevant financial relationships. Dr. Wu has received grants from GlaxoSmithKline outside the submitted work. The editorialists and Dr. High have disclosed no relevant financial relationships. Dr. Wallace received an NIH grant during the writing of the editorial.
 

A version of this article originally appeared on Medscape.com.

Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosis, cataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated with serious risks.

Most recently, a population-based study of more than 2.6 million people found that taking corticosteroids for 14 days or less was associated with a substantially greater risk for gastrointestinal (GI) bleeding, sepsis, and heart failure, particularly within the first 30 days after therapy.

In the study, Tsung-Chieh Yao, MD, PhD, a professor in the division of allergy, asthma, and rheumatology in the department of pediatrics at Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues used a self-controlled case series to analyze data from Taiwan’s National Health Insurance Research Database of medical claims. They compared patients’ conditions in the period from 5 to 90 days before treatment to conditions from the periods from 5 to 30 days and from 31 to 90 days after therapy.

With a median duration of 3 days of treatment, the incidence rate ratios (IRRs) were 1.80 (95% confidence interval, 1.75-1.84) for GI bleeding, 1.99 (95% CI, 1.70-2.32) for sepsis, and 2.37 (95% CI, 2.13-2.63) for heart failure.

Given the findings, physicians should weigh the benefits against the risks of rare but potentially serious consequences of these anti-inflammatory drugs, according to the authors.

“After initiating patients on oral steroid bursts, physicians should be on the lookout for these severe adverse events, particularly within the first month after initiation of steroid therapy,” Dr. Yao said in an interview.

The findings were published online July 6 in Annals of Internal Medicine.

Of the 15,859,129 adult Asians in the Taiwanese database, the study included 2,623,327 adults aged 20-64 years who received single steroid bursts (14 days or less) between Jan. 1, 2013, and Dec. 31, 2015.

Almost 60% of the indications were for skin disorders, such as eczema and urticaria, and for respiratory tract infections, such as sinusitis and acute pharyngitis. Among specialties, dermatology, otolaryngology, family practice, internal medicine, and pediatrics accounted for 88% of prescriptions.

“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the authors wrote. They acknowledged that the database did not provide information on such potential confounders as disease severity and lifestyle factors, nor did it include children and vulnerable individuals, which may limit the generalizability of the results.

The findings echo those of a 2017 cohort study conducted by researchers at the University of Michigan in Ann Arbor. That study, by Akbar K. Waljee, MD, assistant professor of gastroenterology, University of Michigan, Ann Arbor, and colleagues, included data on more than 1.5 million privately insured U.S. adults. The researchers included somewhat longer steroid bursts of up to 30 days’ duration and found that use of the drugs was associated with a greater than fivefold increased risk for sepsis, a more than threefold increased risk for venous thromboembolism, and a nearly twofold increased risk for fracture within 30 days of starting treatment.

Furthermore, the elevated risk persisted at prednisone-equivalent doses of less than 20 mg/d (IRR, 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P < .001).

The U.S. study also found that during the 3-year period from 2012 to 2014, more than 20% of patients were prescribed short-term oral corticosteroids.

“Both studies indicate that these short-term regimens are more common in the real world than was previously thought and are not risk free,” Dr. Yao said.

Recognition that corticosteroids are associated with adverse events has been building for decades, according to the authors of an editorial that accompanies the new study.

“However, we commonly use short corticosteroid ‘bursts’ for minor ailments despite a lack of evidence for meaningful benefit. We are now learning that bursts as short as 3 days may increase risk for serious AEs, even in young and healthy people,” wrote editorialists Beth I. Wallace, MD, of the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and the Institute for Healthcare Policy and Innovation at Michigan Medicine, Ann Arbor, and Dr. Waljee, who led the 2017 study.

Dr. Wallace and Dr. Waljee drew parallels between corticosteroid bursts and other short-term regimens, such as of antibiotics and opiates, in which prescriber preference and sometimes patient pressure play a role. “All of these treatments have well-defined indications but can cause net harm when used. We can thus conceive of a corticosteroid stewardship model of targeted interventions that aims to reduce inappropriate prescribing,” they wrote.

In an interview, Dr. Wallace, a rheumatologist who prescribes oral steroids fairly frequently, noted that the Taiwan study is the first to investigate steroid bursts. “Up till now, these very short courses have flown under the radar. Clinicians very commonly prescribe short courses to help relieve symptoms of self-limited conditions like bronchitis, and we assume that because the exposure duration is short, the risks are low, especially for patients who are otherwise healthy.”

She warned that the data in the current study indicate that these short bursts – even at the lower end of the 1- to 2-week courses American physicians prescribe most often – carry small but real increases in risk for serious AEs. “And these increases were seen in young, healthy people, not just in people with preexisting conditions,” she said. “So, we might need to start thinking harder about how we are prescribing even these very short courses of steroids and try to use steroids only when their meaningful benefits really outweigh the risk.”

She noted that a patient with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. In that specific case, the benefits of short-term steroids may outweigh the risks, Dr. Wallace said.

But not everyone thinks a new strategy is needed. For Whitney A. High, MD, associate professor of dermatology and pathology at the University of Colorado at Denver, Aurora, the overprescribing of short-term corticosteroids is not a problem, and dermatologists are already exercising caution.

Bruce Jancin/MDedge News

“I only prescribe these drugs short term to, at a guess, about 1 in 40 patients and only when a patient is miserable and quality of life is being seriously affected,” he said in an interview. “And that’s something that can’t be measured in a database study like the one from Taiwan but only in a risk-benefit analysis,” he said.

Furthermore, dermatologists have other drugs and technologies in their armamentarium, including topical steroids with occlusion or with wet wraps, phototherapy, phosphodiesterase inhibitors, calcipotriene, methotrexate and other immunosuppressive agents, and biologics. “In fact, many of these agents are specifically referred to as steroid-sparing,” Dr. High said.

Nor does he experience much pressure from patients to prescribe these drugs. “While occasionally I may encounter a patient who places pressure on me for oral steroids, it’s probably not nearly as frequently as providers in other fields are pressured to prescribe antibiotics or narcotics,” he said.

According to the Taiwanese researchers, the next step is to conduct more studies, including clinical trials, to determine optimal use of corticosteroids by monitoring adverse events. In the meantime, for practitioners such as Dr. Wallace and Dr. High, there is ample evidence from several recent studies of the harms of short-term corticosteroids, whereas the benefits for patients with self-limiting conditions remain uncertain. “This and other studies like it quite appropriately remind providers to avoid oral steroids when they’re not necessary and to seek alternatives where possible,” Dr. High said.

The study was supported by the National Health Research Institutes of Taiwan, the Ministry of Science and Technology of Taiwan, the Chang Gung Medical Foundation, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Dr. Yao has disclosed no relevant financial relationships. Dr. Wu has received grants from GlaxoSmithKline outside the submitted work. The editorialists and Dr. High have disclosed no relevant financial relationships. Dr. Wallace received an NIH grant during the writing of the editorial.
 

A version of this article originally appeared on Medscape.com.

Consolidated mail outpatient pharmacy (CMOP) is an automated prescription order processing and delivery system developed by the US Department of Veterans Affairs (VA) in 1994 to provide medications to VA patients.¹ In fiscal year (FY) 2016, CMOP filled about 80% of VA outpatient prescriptions.²

Formalized by the 2010 Memorandum of Understanding between Indian Health Service (IHS) and VA, CMOP is a partnership undertaken to improve the delivery of care to patients by both agencies.³ The number of prescriptions filled by CMOP for IHS patients increased from 1,972 in FY 2010 to 840,109 in FY 2018.⁴ In the fourth quarter of FY 2018, there were 94 CMOP-enrolled IHS federal and tribal sites.⁵ It is only appropriate that a growing number of IHS sites are adopting CMOP considering the evidence for mail-order pharmacy on better patient adherence, improved health outcomes, and potential cost savings.^6-9 Furthermore, using a centralized pharmacy operation, such as CMOP, can lead to better quality services.¹⁰

Crownpoint Health Care Facility (CHCF) serves > 30,000 American Indians and is in Crownpoint, New Mexico, a small community of about 3,000 people.¹¹ Most of the patients served by the facility live in distant places. Many of these underserved patients do not have a stable means of transportation.¹² Therefore, these patients may have difficulty traveling to the facility for their health care needs, including medication pickups. More than 2.5 million American Indians and Alaska Natives IHS beneficiaries face similar challenges due to the rurality of their communities.¹³ CMOP can be a method to increase access to care for this vulnerable population. However, the utilization of CMOP varies significantly among IHS facilities. While some IHS facilities process large numbers of prescriptions through CMOP, other facilities process few, if any. There also are IHS facilities, such as CHCF, which are at the initial stage of implementing CMOP or trying to increase the volume of prescriptions processed through CMOP. Although the utilization of CMOP has grown exponentially among IHS facilities, there is currently no available resource that summarizes the relative advantages and disadvantages, the challenges and opportunities, and the strengths and weaknesses of implementing CMOP for IHS facilities

Methods

A questionnaire encompassing various aspects of CMOP prescription processing was developed and distributed to the primary CMOP contacts for IHS facilities. The questionnaire was first distributed by e-mail on December 19, 2018. It was e-mailed for a second time on January 16, 2019, and the questionnaire was open for responses until the end of January 2019 (Table).

Results

Forty-four of 94 CMOP-enrolled IHS sites responded to the questionnaire. Most sites train the majority of their pharmacists in CMOP prescription processing. Overall, 310 of 347 pharmacists (89%) in these 44 IHS sites can process prescriptions through CMOP. Thirty-one sites have all their pharmacists trained in CMOP prescription processing. Only 1 facility had less than half (2 of 17 pharmacists) of its pharmacists trained in CMOP prescription processing. More than half the total number of pharmacists, 185 out of 347 (53%), check electronic messages via Resource and Patient Management System (RPMS) MailMan to get information about prescriptions rejected by CMOP. Twenty sites have all their pharmacists check messages about CMOP rejections. However, 2 facilities reported that they do not check the rejection messages at all. Twenty-six of the 44 responding sites (59%) transmit prescriptions to CMOP manually in the electronic system. The rest (18 of 44) rely on the auto-transmission (AT) setup to transmit the CMOP-suspended prescriptions at specified times of the day.

Half the sites (8 of 16) that rely on patients asking for prescriptions to be mailed at the time of refill request do not use any method to designate a CMOP patient. Twenty-four sites use the narrative field on the patient’s profile in RPMS, the health information system used by most IHS facilities, to designate CMOP patients. Eighteen sites use pop-up messages on ScriptPro, a pharmacy automation system, as a designation method. Most of the sites (12 of 15) that use both RPMS and ScriptPro designation methods do not require patients to ask for prescriptions to be mailed at the time of refill request; prescriptions for these patients are routed through CMOP unless patients request otherwise. Only 3 of 44 sites use both methods and rely on patients asking for prescriptions to be mailed at the time of refill request. Some other reported designation methods were using the electronic health record (EHR) posting box, keeping a manual list of CMOP patients, and solely utilizing the Prescription Mail Delivery field in RPMS. Three sites also noted that they keep manual lists to auto-refill prescriptions through CMOP.

Thirty sites (68%) reported that they process every prescription through CMOP even if the patient had prescriptions with specified CMOP quantities. Only 8 sites (18%) said that they used the local mail-out program to keep the same days’ supply for all medication orders. For patients with CMOP-ineligible prescriptions, 34 of the 44 sites (77%) process the eligible prescriptions through CMOP and refill the rest of the prescriptions locally. Six sites (14%) process all medication orders locally for patients with any CMOP-ineligible prescriptions.

Only 12 of 44 sites (27%) involve pharmacy technicians in CMOP prescription processing. Five sites have technicians process prescription refills through CMOP. Two of these sites mentioned the strategy of technicians suspending the prescriptions to be sent to CMOP on the refill due date. Other technician roles included tracking CMOP packages, checking electronic messages for CMOP rejections, and signing up patients for CMOP.

Only 3 of the 44 sites (7%) have measured patient satisfaction with the CMOP program. One of these 3 sites reported that the overall satisfaction was high with CMOP. This site administered the survey to patients who came to the clinic for appointments. The second facility called patients and asked for their feedback. The third site conducted the survey by using student pharmacists. Two sites reported that they use the survey results from the CMOP-conducted patient satisfaction surveys, although they have not measured patient satisfaction at their specific facilities.

Most sites have not assessed CMOP’s impact on their insurance (point of sale) collections. However, 13 sites (30%) reported that they believe they are losing on collections by utilizing CMOP. The use of repackaged products by CMOP, which are usually nonreimbursable, is an issue that was mentioned multiple times. In contrast, 2 sites mentioned that CMOP has led to increased insurance collections for their facilities.

Discussion

The utility of CMOP among the responding IHS sites varies quite significantly. Some sites appreciate the convenience of CMOP while acknowledging its limitations, such as the possible decrease in insurance collections, lengthy prescription processing time, or medication backorders. However, some sites have reserved CMOP for special circumstances (eg, mailing refrigerated items to the patient’s street address) due to various complexities that may come with CMOP. One site reported that it compares IHS contract drug prices with VA contract drug prices quarterly to determine which prescriptions should be sent through CMOP.

Most of the IHS pharmacists (89%) are trained in CMOP prescription processing. If an IHS site wants to increase its volume of CMOP prescriptions, it is sensible to train as many pharmacists as possible so that the responsibility does not fall on a few pharmacists. Newly hired pharmacists can receive guidance from trained pharmacists. Designation methods for CMOP patients can be beneficial for these pharmacists to identify CMOP-enrolled patients, especially if the site does not require patients to ask for prescriptions to be mailed at the time of refill request. Only 3 sites (7%) use multiple designation methods in addition to relying on patients to ask for prescriptions to be mailed. Proper implementation of designation methods can remove this extra burden on patients. Conversely, requiring patients to ask for prescriptions to be sent through CMOP can prevent spontaneous mail-outs if a CMOP-designated patient wants to pick up prescriptions locally. Overall, 16 sites (36%) rely on patients asking for prescriptions to be mailed.

One of the main benefits of CMOP is the ability to mail refrigerated items. Local pharmacy mail-out programs may not have this ability. Patients at rural locations often use post office (PO) boxes because they are unable to receive postal services at their physical addresses; however, they may receive packages through United Parcel Service (UPS) at their physical addresses. CMOP uses UPS to send refrigerated items, but UPS does not deliver to PO boxes. Therefore, remotely located sites like CHCF have difficulty in fully optimizing this benefit. One solution is documenting both the physical and mailing addresses on the patient’s EHR, which enables CMOP to send refrigerated items to the patient’s home address via UPS and mail the rest of the prescriptions to the patient’s PO box address with the US Postal Service. The physical address must be listed above the PO box address to ensure that refrigerated items are not rejected by CMOP. Furthermore, both the physical address and the PO box address must be in the same city for this method to work. Two sites noted mailing refrigerated items as one of the major challenges in CMOP prescription processing.

CMOP-enrolled patients must be educated about requesting medications 7 to 10 days before they run out. There is no standard time line for prescriptions filled by CMOP. However, 1 site reported that it may take up to “10 days from time requested to mailbox.” This delay leads to pharmacies facing a dilemma as processing prescriptions too early can lead to insurance rejections, but processing them too late can lead to the patient not receiving the medication by the time they run out of their current supply. However, CMOP provides the ability to track prescriptions sent through CMOP. Pharmacists and technicians need to have access to BestWay Parcel Services Client Portal (genco-mms.bestwayparcel.com) to track CMOP packages. Tracking CMOP prescriptions is a way pharmacy technicians can be involved in CMOP prescription processing. Technicians seem to be underutilized, as only 27% of the responding sites utilize them to some degree in the CMOP process. One site delegated the responsibility of checking CMOP rejection messages to pharmacy technicians. Since 2 of the responding sites do not check CMOP rejection messages at all, this is an excellent opportunity to get pharmacy technicians involved.

A CMOP auto-refill program can potentially be utilized to avoid missed or late medications. In an auto-refill program, a pharmacist can refill prescriptions through CMOP on the due date without a patient request. They may get rejected by insurance the first time they are processed through CMOP for refilling too early if the processing time is taken into account. However, the subsequent refills do not have to consider the CMOP processing time as they would already be synchronized based on the last refill date. Though, if CMOP is out of stock on a medication and it is expected to be available soon, CMOP may take a few extra days to either fill the prescription or reject it if the drug stays unavailable. One of the sites reported “the amount of time [CMOP] holds medications if they are out of stock” as “the hardest thing to work around.” A couple of sites also mentioned the longer than usual delay in processing prescriptions by CMOP during the holidays as one of the major challenges.

CMOP use of repackaged products also may lead insurance companies to deny reimbursement. Repackaged products are usually cheaper to buy.¹⁴ However, most insurances do not reimburse for prescriptions filled with these products.¹⁵ The local drug file on RPMS may have a national drug code (NDC) that is reimbursable by insurance, but CMOP will change it to the repackaged NDC if they are filling the prescription with a repackaged product. One potential solution to this problem would be filling these prescriptions locally. Furthermore, insurance claims are processed when the prescriptions are filled by CMOP. Sites cannot return/cancel the prescription anymore at that point. Therefore, the inability to see real-time rejections as the medication orders are processed on-site makes it challenging to prevent avoidable insurance rejections, such as a refill too soon. One site calculated that it lost $26,386.45 by utilizing CMOP from January 9, 2018 to December 12, 2018. However, it is unclear whether this loss was representative of other sites. It is also worth noting that IHS sites can save a substantial amount of money on certain products by utilizing CMOP because VA buys these products at a reduced price.¹⁶

CMOP-transmitted prescriptions can be rejected for various reasons, such as CMOP manufacturer’s backorder, a different quantity from CMOP stock size, etc. Information about these rejected prescriptions is accessed through electronic messages on RPMS. CMOP does not dispense less than a full, unopened package for most over-the-counter (OTC) medications. The quantity on these prescriptions must be equal to or multiples of the package size for them to be filled by CMOP. This can lead to a patient having prescriptions with different days’ supplies, which results in various refill due dates. If a site has a local mail-out program available, it can potentially keep the same days’ supply for all prescriptions by mailing these OTC medications locally rather than utilizing CMOP. However, this can partially negate CMOP’s benefit of reduced workload.

CMOP also has specified quantities on some prescription medications. One survey respondent viewed “the quantity and day supply required by CMOP” as a negative influence on the site’s insurance collection. It is possible that CMOP does not carry all the medications that a CMOP-enrolled patient is prescribed. Most sites (77%) still send eligible prescriptions through CMOP for the patients who also have CMOP-ineligible prescriptions. There are a small number of sites (14%) that utilize local mail-out program for the patients with any CMOP-ineligible prescriptions, possibly to simplify the process. Schedule II controlled substances cannot be processed through CMOP either; however, facilities may have local policies that prohibit mailing any controlled substances.

Prescriptions can be manually transmitted to CMOP, or they can be automatically transmitted based on the run time and frequency of the auto-transmission setup. The prescriptions that are waiting to be transmitted to CMOP must be in the “suspended” status. The apparent advantage of relying on auto-transmission is that you do not have to complete the steps manually to transmit suspended CMOP prescriptions, thereby making the process more convenient. However, the manual transmission can be utilized as a checkpoint to verify that prescriptions were properly suspended for CMOP, as the prescription status changes from “S” (suspended) to “AT” once the transmission is completed. If a prescription is not properly suspended for CMOP, the status will remain as S even after manual transmission. More than half (59%) of the responding sites must find the manual transmission feature useful as they use it either over or in addition to the auto-transmission setup.

Despite the challenges, many IHS sites process thousands of monthly prescriptions through CMOP. Of the 94 CMOP-enrolled IHS sites, 17 processed > 1,000 prescriptions from March 27, 2019 to April 25, 2019.¹⁷ Five sites processed > 5,000 prescriptions.¹⁷ At the rate of > 5,000 prescriptions per month, the yearly CMOP prescription count will be > 60,000. That is more than one-third of the prescriptions processed by CHCF in 2018. By handling these prescriptions through CMOP, it can decrease pharmacy filling and dispensing workload, thereby freeing pharmacists to participate in other services.¹⁸ Furthermore, implementing CMOP does not incur any cost for the IHS site. There is a nondrug cost for each prescription that is filled through CMOP. This cost was $2.67 during FY 2016.¹⁹ The fee covers prescription vial, label, packaging for mail, postage, personnel, building overhead, and equipment capitalization.¹⁹ The nondrug cost of filling a prescription locally at the site can potentially exceed the cost charged by CMOP.¹⁹

A lack of objective data exists to assess the net impact of CMOP on patients. Different theoretical assumptions can be made, such as CMOP resulting in better patient adherence. However, there is no objective information about how much CMOP improves patient adherence if it does at all. Though J.D. Power US Pharmacy Study ranks CMOP as “among the best” mail-order pharmacies in customer satisfaction, only 3 of the 44 responding sites have measured patient satisfaction locally.²⁰ Only 1 site had objective data about CMOP’s impact on the point of sale. Therefore, it is currently difficult to perform a cost-benefit analysis of the CMOP program. There are opportunities for further studies on these topics.

Limitations

One limitation of this study is that < 50% of the CMOP-enrolled sites (44 of 94) responded to the questionnaire. It is possible that the facilities that had a significantly positive or negative experience with CMOP were more inclined to share their views. Therefore, it is difficult to conclude whether the responding sites are an accurate representative sample. Another limitation of the study was the questionnaire design and the reliance on free-text responses as opposed to structured data. The free-text responses had to be analyzed manually to determine whether they fall in the same category, thereby increasing the risk of interpretation error.

Conclusion

CMOP has its unique challenges but provides many benefits that local pharmacy mail-out programs may not possess, such as the abilities to mail refrigerated items and track packages. One must be familiar with CMOP’s various idiosyncrasies to make the best use of the program. Extensive staff education and orientation for new staff members must be done to familiarize them with the program. Nevertheless, the successful implementation of CMOP can lead to reduced pharmacy workload while increasing access to care for patients with transportation issues.

Acknowledgments
The authors thank LCDR Karsten Smith, PharmD, BCGP, the IHS CMOP Coordinator for providing the list of primary CMOP contacts and CDR Kendall Van Tyle, PharmD, BCPS, for proofreading the article.

Consolidated mail outpatient pharmacy (CMOP) is an automated prescription order processing and delivery system developed by the US Department of Veterans Affairs (VA) in 1994 to provide medications to VA patients.¹ In fiscal year (FY) 2016, CMOP filled about 80% of VA outpatient prescriptions.²

Formalized by the 2010 Memorandum of Understanding between Indian Health Service (IHS) and VA, CMOP is a partnership undertaken to improve the delivery of care to patients by both agencies.³ The number of prescriptions filled by CMOP for IHS patients increased from 1,972 in FY 2010 to 840,109 in FY 2018.⁴ In the fourth quarter of FY 2018, there were 94 CMOP-enrolled IHS federal and tribal sites.⁵ It is only appropriate that a growing number of IHS sites are adopting CMOP considering the evidence for mail-order pharmacy on better patient adherence, improved health outcomes, and potential cost savings.^6-9 Furthermore, using a centralized pharmacy operation, such as CMOP, can lead to better quality services.¹⁰

Crownpoint Health Care Facility (CHCF) serves > 30,000 American Indians and is in Crownpoint, New Mexico, a small community of about 3,000 people.¹¹ Most of the patients served by the facility live in distant places. Many of these underserved patients do not have a stable means of transportation.¹² Therefore, these patients may have difficulty traveling to the facility for their health care needs, including medication pickups. More than 2.5 million American Indians and Alaska Natives IHS beneficiaries face similar challenges due to the rurality of their communities.¹³ CMOP can be a method to increase access to care for this vulnerable population. However, the utilization of CMOP varies significantly among IHS facilities. While some IHS facilities process large numbers of prescriptions through CMOP, other facilities process few, if any. There also are IHS facilities, such as CHCF, which are at the initial stage of implementing CMOP or trying to increase the volume of prescriptions processed through CMOP. Although the utilization of CMOP has grown exponentially among IHS facilities, there is currently no available resource that summarizes the relative advantages and disadvantages, the challenges and opportunities, and the strengths and weaknesses of implementing CMOP for IHS facilities

Methods

A questionnaire encompassing various aspects of CMOP prescription processing was developed and distributed to the primary CMOP contacts for IHS facilities. The questionnaire was first distributed by e-mail on December 19, 2018. It was e-mailed for a second time on January 16, 2019, and the questionnaire was open for responses until the end of January 2019 (Table).

Results

Forty-four of 94 CMOP-enrolled IHS sites responded to the questionnaire. Most sites train the majority of their pharmacists in CMOP prescription processing. Overall, 310 of 347 pharmacists (89%) in these 44 IHS sites can process prescriptions through CMOP. Thirty-one sites have all their pharmacists trained in CMOP prescription processing. Only 1 facility had less than half (2 of 17 pharmacists) of its pharmacists trained in CMOP prescription processing. More than half the total number of pharmacists, 185 out of 347 (53%), check electronic messages via Resource and Patient Management System (RPMS) MailMan to get information about prescriptions rejected by CMOP. Twenty sites have all their pharmacists check messages about CMOP rejections. However, 2 facilities reported that they do not check the rejection messages at all. Twenty-six of the 44 responding sites (59%) transmit prescriptions to CMOP manually in the electronic system. The rest (18 of 44) rely on the auto-transmission (AT) setup to transmit the CMOP-suspended prescriptions at specified times of the day.

Half the sites (8 of 16) that rely on patients asking for prescriptions to be mailed at the time of refill request do not use any method to designate a CMOP patient. Twenty-four sites use the narrative field on the patient’s profile in RPMS, the health information system used by most IHS facilities, to designate CMOP patients. Eighteen sites use pop-up messages on ScriptPro, a pharmacy automation system, as a designation method. Most of the sites (12 of 15) that use both RPMS and ScriptPro designation methods do not require patients to ask for prescriptions to be mailed at the time of refill request; prescriptions for these patients are routed through CMOP unless patients request otherwise. Only 3 of 44 sites use both methods and rely on patients asking for prescriptions to be mailed at the time of refill request. Some other reported designation methods were using the electronic health record (EHR) posting box, keeping a manual list of CMOP patients, and solely utilizing the Prescription Mail Delivery field in RPMS. Three sites also noted that they keep manual lists to auto-refill prescriptions through CMOP.

Thirty sites (68%) reported that they process every prescription through CMOP even if the patient had prescriptions with specified CMOP quantities. Only 8 sites (18%) said that they used the local mail-out program to keep the same days’ supply for all medication orders. For patients with CMOP-ineligible prescriptions, 34 of the 44 sites (77%) process the eligible prescriptions through CMOP and refill the rest of the prescriptions locally. Six sites (14%) process all medication orders locally for patients with any CMOP-ineligible prescriptions.

Only 12 of 44 sites (27%) involve pharmacy technicians in CMOP prescription processing. Five sites have technicians process prescription refills through CMOP. Two of these sites mentioned the strategy of technicians suspending the prescriptions to be sent to CMOP on the refill due date. Other technician roles included tracking CMOP packages, checking electronic messages for CMOP rejections, and signing up patients for CMOP.

Only 3 of the 44 sites (7%) have measured patient satisfaction with the CMOP program. One of these 3 sites reported that the overall satisfaction was high with CMOP. This site administered the survey to patients who came to the clinic for appointments. The second facility called patients and asked for their feedback. The third site conducted the survey by using student pharmacists. Two sites reported that they use the survey results from the CMOP-conducted patient satisfaction surveys, although they have not measured patient satisfaction at their specific facilities.

Most sites have not assessed CMOP’s impact on their insurance (point of sale) collections. However, 13 sites (30%) reported that they believe they are losing on collections by utilizing CMOP. The use of repackaged products by CMOP, which are usually nonreimbursable, is an issue that was mentioned multiple times. In contrast, 2 sites mentioned that CMOP has led to increased insurance collections for their facilities.

Discussion

The utility of CMOP among the responding IHS sites varies quite significantly. Some sites appreciate the convenience of CMOP while acknowledging its limitations, such as the possible decrease in insurance collections, lengthy prescription processing time, or medication backorders. However, some sites have reserved CMOP for special circumstances (eg, mailing refrigerated items to the patient’s street address) due to various complexities that may come with CMOP. One site reported that it compares IHS contract drug prices with VA contract drug prices quarterly to determine which prescriptions should be sent through CMOP.

Most of the IHS pharmacists (89%) are trained in CMOP prescription processing. If an IHS site wants to increase its volume of CMOP prescriptions, it is sensible to train as many pharmacists as possible so that the responsibility does not fall on a few pharmacists. Newly hired pharmacists can receive guidance from trained pharmacists. Designation methods for CMOP patients can be beneficial for these pharmacists to identify CMOP-enrolled patients, especially if the site does not require patients to ask for prescriptions to be mailed at the time of refill request. Only 3 sites (7%) use multiple designation methods in addition to relying on patients to ask for prescriptions to be mailed. Proper implementation of designation methods can remove this extra burden on patients. Conversely, requiring patients to ask for prescriptions to be sent through CMOP can prevent spontaneous mail-outs if a CMOP-designated patient wants to pick up prescriptions locally. Overall, 16 sites (36%) rely on patients asking for prescriptions to be mailed.

One of the main benefits of CMOP is the ability to mail refrigerated items. Local pharmacy mail-out programs may not have this ability. Patients at rural locations often use post office (PO) boxes because they are unable to receive postal services at their physical addresses; however, they may receive packages through United Parcel Service (UPS) at their physical addresses. CMOP uses UPS to send refrigerated items, but UPS does not deliver to PO boxes. Therefore, remotely located sites like CHCF have difficulty in fully optimizing this benefit. One solution is documenting both the physical and mailing addresses on the patient’s EHR, which enables CMOP to send refrigerated items to the patient’s home address via UPS and mail the rest of the prescriptions to the patient’s PO box address with the US Postal Service. The physical address must be listed above the PO box address to ensure that refrigerated items are not rejected by CMOP. Furthermore, both the physical address and the PO box address must be in the same city for this method to work. Two sites noted mailing refrigerated items as one of the major challenges in CMOP prescription processing.

CMOP-enrolled patients must be educated about requesting medications 7 to 10 days before they run out. There is no standard time line for prescriptions filled by CMOP. However, 1 site reported that it may take up to “10 days from time requested to mailbox.” This delay leads to pharmacies facing a dilemma as processing prescriptions too early can lead to insurance rejections, but processing them too late can lead to the patient not receiving the medication by the time they run out of their current supply. However, CMOP provides the ability to track prescriptions sent through CMOP. Pharmacists and technicians need to have access to BestWay Parcel Services Client Portal (genco-mms.bestwayparcel.com) to track CMOP packages. Tracking CMOP prescriptions is a way pharmacy technicians can be involved in CMOP prescription processing. Technicians seem to be underutilized, as only 27% of the responding sites utilize them to some degree in the CMOP process. One site delegated the responsibility of checking CMOP rejection messages to pharmacy technicians. Since 2 of the responding sites do not check CMOP rejection messages at all, this is an excellent opportunity to get pharmacy technicians involved.

A CMOP auto-refill program can potentially be utilized to avoid missed or late medications. In an auto-refill program, a pharmacist can refill prescriptions through CMOP on the due date without a patient request. They may get rejected by insurance the first time they are processed through CMOP for refilling too early if the processing time is taken into account. However, the subsequent refills do not have to consider the CMOP processing time as they would already be synchronized based on the last refill date. Though, if CMOP is out of stock on a medication and it is expected to be available soon, CMOP may take a few extra days to either fill the prescription or reject it if the drug stays unavailable. One of the sites reported “the amount of time [CMOP] holds medications if they are out of stock” as “the hardest thing to work around.” A couple of sites also mentioned the longer than usual delay in processing prescriptions by CMOP during the holidays as one of the major challenges.

CMOP use of repackaged products also may lead insurance companies to deny reimbursement. Repackaged products are usually cheaper to buy.¹⁴ However, most insurances do not reimburse for prescriptions filled with these products.¹⁵ The local drug file on RPMS may have a national drug code (NDC) that is reimbursable by insurance, but CMOP will change it to the repackaged NDC if they are filling the prescription with a repackaged product. One potential solution to this problem would be filling these prescriptions locally. Furthermore, insurance claims are processed when the prescriptions are filled by CMOP. Sites cannot return/cancel the prescription anymore at that point. Therefore, the inability to see real-time rejections as the medication orders are processed on-site makes it challenging to prevent avoidable insurance rejections, such as a refill too soon. One site calculated that it lost $26,386.45 by utilizing CMOP from January 9, 2018 to December 12, 2018. However, it is unclear whether this loss was representative of other sites. It is also worth noting that IHS sites can save a substantial amount of money on certain products by utilizing CMOP because VA buys these products at a reduced price.¹⁶

CMOP-transmitted prescriptions can be rejected for various reasons, such as CMOP manufacturer’s backorder, a different quantity from CMOP stock size, etc. Information about these rejected prescriptions is accessed through electronic messages on RPMS. CMOP does not dispense less than a full, unopened package for most over-the-counter (OTC) medications. The quantity on these prescriptions must be equal to or multiples of the package size for them to be filled by CMOP. This can lead to a patient having prescriptions with different days’ supplies, which results in various refill due dates. If a site has a local mail-out program available, it can potentially keep the same days’ supply for all prescriptions by mailing these OTC medications locally rather than utilizing CMOP. However, this can partially negate CMOP’s benefit of reduced workload.

CMOP also has specified quantities on some prescription medications. One survey respondent viewed “the quantity and day supply required by CMOP” as a negative influence on the site’s insurance collection. It is possible that CMOP does not carry all the medications that a CMOP-enrolled patient is prescribed. Most sites (77%) still send eligible prescriptions through CMOP for the patients who also have CMOP-ineligible prescriptions. There are a small number of sites (14%) that utilize local mail-out program for the patients with any CMOP-ineligible prescriptions, possibly to simplify the process. Schedule II controlled substances cannot be processed through CMOP either; however, facilities may have local policies that prohibit mailing any controlled substances.

Prescriptions can be manually transmitted to CMOP, or they can be automatically transmitted based on the run time and frequency of the auto-transmission setup. The prescriptions that are waiting to be transmitted to CMOP must be in the “suspended” status. The apparent advantage of relying on auto-transmission is that you do not have to complete the steps manually to transmit suspended CMOP prescriptions, thereby making the process more convenient. However, the manual transmission can be utilized as a checkpoint to verify that prescriptions were properly suspended for CMOP, as the prescription status changes from “S” (suspended) to “AT” once the transmission is completed. If a prescription is not properly suspended for CMOP, the status will remain as S even after manual transmission. More than half (59%) of the responding sites must find the manual transmission feature useful as they use it either over or in addition to the auto-transmission setup.

Despite the challenges, many IHS sites process thousands of monthly prescriptions through CMOP. Of the 94 CMOP-enrolled IHS sites, 17 processed > 1,000 prescriptions from March 27, 2019 to April 25, 2019.¹⁷ Five sites processed > 5,000 prescriptions.¹⁷ At the rate of > 5,000 prescriptions per month, the yearly CMOP prescription count will be > 60,000. That is more than one-third of the prescriptions processed by CHCF in 2018. By handling these prescriptions through CMOP, it can decrease pharmacy filling and dispensing workload, thereby freeing pharmacists to participate in other services.¹⁸ Furthermore, implementing CMOP does not incur any cost for the IHS site. There is a nondrug cost for each prescription that is filled through CMOP. This cost was $2.67 during FY 2016.¹⁹ The fee covers prescription vial, label, packaging for mail, postage, personnel, building overhead, and equipment capitalization.¹⁹ The nondrug cost of filling a prescription locally at the site can potentially exceed the cost charged by CMOP.¹⁹

A lack of objective data exists to assess the net impact of CMOP on patients. Different theoretical assumptions can be made, such as CMOP resulting in better patient adherence. However, there is no objective information about how much CMOP improves patient adherence if it does at all. Though J.D. Power US Pharmacy Study ranks CMOP as “among the best” mail-order pharmacies in customer satisfaction, only 3 of the 44 responding sites have measured patient satisfaction locally.²⁰ Only 1 site had objective data about CMOP’s impact on the point of sale. Therefore, it is currently difficult to perform a cost-benefit analysis of the CMOP program. There are opportunities for further studies on these topics.

Limitations

One limitation of this study is that < 50% of the CMOP-enrolled sites (44 of 94) responded to the questionnaire. It is possible that the facilities that had a significantly positive or negative experience with CMOP were more inclined to share their views. Therefore, it is difficult to conclude whether the responding sites are an accurate representative sample. Another limitation of the study was the questionnaire design and the reliance on free-text responses as opposed to structured data. The free-text responses had to be analyzed manually to determine whether they fall in the same category, thereby increasing the risk of interpretation error.

Conclusion

CMOP has its unique challenges but provides many benefits that local pharmacy mail-out programs may not possess, such as the abilities to mail refrigerated items and track packages. One must be familiar with CMOP’s various idiosyncrasies to make the best use of the program. Extensive staff education and orientation for new staff members must be done to familiarize them with the program. Nevertheless, the successful implementation of CMOP can lead to reduced pharmacy workload while increasing access to care for patients with transportation issues.

Acknowledgments
The authors thank LCDR Karsten Smith, PharmD, BCGP, the IHS CMOP Coordinator for providing the list of primary CMOP contacts and CDR Kendall Van Tyle, PharmD, BCPS, for proofreading the article.

Consolidated mail outpatient pharmacy (CMOP) is an automated prescription order processing and delivery system developed by the US Department of Veterans Affairs (VA) in 1994 to provide medications to VA patients.¹ In fiscal year (FY) 2016, CMOP filled about 80% of VA outpatient prescriptions.²

Formalized by the 2010 Memorandum of Understanding between Indian Health Service (IHS) and VA, CMOP is a partnership undertaken to improve the delivery of care to patients by both agencies.³ The number of prescriptions filled by CMOP for IHS patients increased from 1,972 in FY 2010 to 840,109 in FY 2018.⁴ In the fourth quarter of FY 2018, there were 94 CMOP-enrolled IHS federal and tribal sites.⁵ It is only appropriate that a growing number of IHS sites are adopting CMOP considering the evidence for mail-order pharmacy on better patient adherence, improved health outcomes, and potential cost savings.^6-9 Furthermore, using a centralized pharmacy operation, such as CMOP, can lead to better quality services.¹⁰

Crownpoint Health Care Facility (CHCF) serves > 30,000 American Indians and is in Crownpoint, New Mexico, a small community of about 3,000 people.¹¹ Most of the patients served by the facility live in distant places. Many of these underserved patients do not have a stable means of transportation.¹² Therefore, these patients may have difficulty traveling to the facility for their health care needs, including medication pickups. More than 2.5 million American Indians and Alaska Natives IHS beneficiaries face similar challenges due to the rurality of their communities.¹³ CMOP can be a method to increase access to care for this vulnerable population. However, the utilization of CMOP varies significantly among IHS facilities. While some IHS facilities process large numbers of prescriptions through CMOP, other facilities process few, if any. There also are IHS facilities, such as CHCF, which are at the initial stage of implementing CMOP or trying to increase the volume of prescriptions processed through CMOP. Although the utilization of CMOP has grown exponentially among IHS facilities, there is currently no available resource that summarizes the relative advantages and disadvantages, the challenges and opportunities, and the strengths and weaknesses of implementing CMOP for IHS facilities

Methods

A questionnaire encompassing various aspects of CMOP prescription processing was developed and distributed to the primary CMOP contacts for IHS facilities. The questionnaire was first distributed by e-mail on December 19, 2018. It was e-mailed for a second time on January 16, 2019, and the questionnaire was open for responses until the end of January 2019 (Table).

Results

Forty-four of 94 CMOP-enrolled IHS sites responded to the questionnaire. Most sites train the majority of their pharmacists in CMOP prescription processing. Overall, 310 of 347 pharmacists (89%) in these 44 IHS sites can process prescriptions through CMOP. Thirty-one sites have all their pharmacists trained in CMOP prescription processing. Only 1 facility had less than half (2 of 17 pharmacists) of its pharmacists trained in CMOP prescription processing. More than half the total number of pharmacists, 185 out of 347 (53%), check electronic messages via Resource and Patient Management System (RPMS) MailMan to get information about prescriptions rejected by CMOP. Twenty sites have all their pharmacists check messages about CMOP rejections. However, 2 facilities reported that they do not check the rejection messages at all. Twenty-six of the 44 responding sites (59%) transmit prescriptions to CMOP manually in the electronic system. The rest (18 of 44) rely on the auto-transmission (AT) setup to transmit the CMOP-suspended prescriptions at specified times of the day.

Half the sites (8 of 16) that rely on patients asking for prescriptions to be mailed at the time of refill request do not use any method to designate a CMOP patient. Twenty-four sites use the narrative field on the patient’s profile in RPMS, the health information system used by most IHS facilities, to designate CMOP patients. Eighteen sites use pop-up messages on ScriptPro, a pharmacy automation system, as a designation method. Most of the sites (12 of 15) that use both RPMS and ScriptPro designation methods do not require patients to ask for prescriptions to be mailed at the time of refill request; prescriptions for these patients are routed through CMOP unless patients request otherwise. Only 3 of 44 sites use both methods and rely on patients asking for prescriptions to be mailed at the time of refill request. Some other reported designation methods were using the electronic health record (EHR) posting box, keeping a manual list of CMOP patients, and solely utilizing the Prescription Mail Delivery field in RPMS. Three sites also noted that they keep manual lists to auto-refill prescriptions through CMOP.

Thirty sites (68%) reported that they process every prescription through CMOP even if the patient had prescriptions with specified CMOP quantities. Only 8 sites (18%) said that they used the local mail-out program to keep the same days’ supply for all medication orders. For patients with CMOP-ineligible prescriptions, 34 of the 44 sites (77%) process the eligible prescriptions through CMOP and refill the rest of the prescriptions locally. Six sites (14%) process all medication orders locally for patients with any CMOP-ineligible prescriptions.

Only 12 of 44 sites (27%) involve pharmacy technicians in CMOP prescription processing. Five sites have technicians process prescription refills through CMOP. Two of these sites mentioned the strategy of technicians suspending the prescriptions to be sent to CMOP on the refill due date. Other technician roles included tracking CMOP packages, checking electronic messages for CMOP rejections, and signing up patients for CMOP.

Only 3 of the 44 sites (7%) have measured patient satisfaction with the CMOP program. One of these 3 sites reported that the overall satisfaction was high with CMOP. This site administered the survey to patients who came to the clinic for appointments. The second facility called patients and asked for their feedback. The third site conducted the survey by using student pharmacists. Two sites reported that they use the survey results from the CMOP-conducted patient satisfaction surveys, although they have not measured patient satisfaction at their specific facilities.

Most sites have not assessed CMOP’s impact on their insurance (point of sale) collections. However, 13 sites (30%) reported that they believe they are losing on collections by utilizing CMOP. The use of repackaged products by CMOP, which are usually nonreimbursable, is an issue that was mentioned multiple times. In contrast, 2 sites mentioned that CMOP has led to increased insurance collections for their facilities.

Discussion

The utility of CMOP among the responding IHS sites varies quite significantly. Some sites appreciate the convenience of CMOP while acknowledging its limitations, such as the possible decrease in insurance collections, lengthy prescription processing time, or medication backorders. However, some sites have reserved CMOP for special circumstances (eg, mailing refrigerated items to the patient’s street address) due to various complexities that may come with CMOP. One site reported that it compares IHS contract drug prices with VA contract drug prices quarterly to determine which prescriptions should be sent through CMOP.

Most of the IHS pharmacists (89%) are trained in CMOP prescription processing. If an IHS site wants to increase its volume of CMOP prescriptions, it is sensible to train as many pharmacists as possible so that the responsibility does not fall on a few pharmacists. Newly hired pharmacists can receive guidance from trained pharmacists. Designation methods for CMOP patients can be beneficial for these pharmacists to identify CMOP-enrolled patients, especially if the site does not require patients to ask for prescriptions to be mailed at the time of refill request. Only 3 sites (7%) use multiple designation methods in addition to relying on patients to ask for prescriptions to be mailed. Proper implementation of designation methods can remove this extra burden on patients. Conversely, requiring patients to ask for prescriptions to be sent through CMOP can prevent spontaneous mail-outs if a CMOP-designated patient wants to pick up prescriptions locally. Overall, 16 sites (36%) rely on patients asking for prescriptions to be mailed.

One of the main benefits of CMOP is the ability to mail refrigerated items. Local pharmacy mail-out programs may not have this ability. Patients at rural locations often use post office (PO) boxes because they are unable to receive postal services at their physical addresses; however, they may receive packages through United Parcel Service (UPS) at their physical addresses. CMOP uses UPS to send refrigerated items, but UPS does not deliver to PO boxes. Therefore, remotely located sites like CHCF have difficulty in fully optimizing this benefit. One solution is documenting both the physical and mailing addresses on the patient’s EHR, which enables CMOP to send refrigerated items to the patient’s home address via UPS and mail the rest of the prescriptions to the patient’s PO box address with the US Postal Service. The physical address must be listed above the PO box address to ensure that refrigerated items are not rejected by CMOP. Furthermore, both the physical address and the PO box address must be in the same city for this method to work. Two sites noted mailing refrigerated items as one of the major challenges in CMOP prescription processing.

CMOP-enrolled patients must be educated about requesting medications 7 to 10 days before they run out. There is no standard time line for prescriptions filled by CMOP. However, 1 site reported that it may take up to “10 days from time requested to mailbox.” This delay leads to pharmacies facing a dilemma as processing prescriptions too early can lead to insurance rejections, but processing them too late can lead to the patient not receiving the medication by the time they run out of their current supply. However, CMOP provides the ability to track prescriptions sent through CMOP. Pharmacists and technicians need to have access to BestWay Parcel Services Client Portal (genco-mms.bestwayparcel.com) to track CMOP packages. Tracking CMOP prescriptions is a way pharmacy technicians can be involved in CMOP prescription processing. Technicians seem to be underutilized, as only 27% of the responding sites utilize them to some degree in the CMOP process. One site delegated the responsibility of checking CMOP rejection messages to pharmacy technicians. Since 2 of the responding sites do not check CMOP rejection messages at all, this is an excellent opportunity to get pharmacy technicians involved.

A CMOP auto-refill program can potentially be utilized to avoid missed or late medications. In an auto-refill program, a pharmacist can refill prescriptions through CMOP on the due date without a patient request. They may get rejected by insurance the first time they are processed through CMOP for refilling too early if the processing time is taken into account. However, the subsequent refills do not have to consider the CMOP processing time as they would already be synchronized based on the last refill date. Though, if CMOP is out of stock on a medication and it is expected to be available soon, CMOP may take a few extra days to either fill the prescription or reject it if the drug stays unavailable. One of the sites reported “the amount of time [CMOP] holds medications if they are out of stock” as “the hardest thing to work around.” A couple of sites also mentioned the longer than usual delay in processing prescriptions by CMOP during the holidays as one of the major challenges.

CMOP use of repackaged products also may lead insurance companies to deny reimbursement. Repackaged products are usually cheaper to buy.¹⁴ However, most insurances do not reimburse for prescriptions filled with these products.¹⁵ The local drug file on RPMS may have a national drug code (NDC) that is reimbursable by insurance, but CMOP will change it to the repackaged NDC if they are filling the prescription with a repackaged product. One potential solution to this problem would be filling these prescriptions locally. Furthermore, insurance claims are processed when the prescriptions are filled by CMOP. Sites cannot return/cancel the prescription anymore at that point. Therefore, the inability to see real-time rejections as the medication orders are processed on-site makes it challenging to prevent avoidable insurance rejections, such as a refill too soon. One site calculated that it lost $26,386.45 by utilizing CMOP from January 9, 2018 to December 12, 2018. However, it is unclear whether this loss was representative of other sites. It is also worth noting that IHS sites can save a substantial amount of money on certain products by utilizing CMOP because VA buys these products at a reduced price.¹⁶

CMOP-transmitted prescriptions can be rejected for various reasons, such as CMOP manufacturer’s backorder, a different quantity from CMOP stock size, etc. Information about these rejected prescriptions is accessed through electronic messages on RPMS. CMOP does not dispense less than a full, unopened package for most over-the-counter (OTC) medications. The quantity on these prescriptions must be equal to or multiples of the package size for them to be filled by CMOP. This can lead to a patient having prescriptions with different days’ supplies, which results in various refill due dates. If a site has a local mail-out program available, it can potentially keep the same days’ supply for all prescriptions by mailing these OTC medications locally rather than utilizing CMOP. However, this can partially negate CMOP’s benefit of reduced workload.

CMOP also has specified quantities on some prescription medications. One survey respondent viewed “the quantity and day supply required by CMOP” as a negative influence on the site’s insurance collection. It is possible that CMOP does not carry all the medications that a CMOP-enrolled patient is prescribed. Most sites (77%) still send eligible prescriptions through CMOP for the patients who also have CMOP-ineligible prescriptions. There are a small number of sites (14%) that utilize local mail-out program for the patients with any CMOP-ineligible prescriptions, possibly to simplify the process. Schedule II controlled substances cannot be processed through CMOP either; however, facilities may have local policies that prohibit mailing any controlled substances.

Prescriptions can be manually transmitted to CMOP, or they can be automatically transmitted based on the run time and frequency of the auto-transmission setup. The prescriptions that are waiting to be transmitted to CMOP must be in the “suspended” status. The apparent advantage of relying on auto-transmission is that you do not have to complete the steps manually to transmit suspended CMOP prescriptions, thereby making the process more convenient. However, the manual transmission can be utilized as a checkpoint to verify that prescriptions were properly suspended for CMOP, as the prescription status changes from “S” (suspended) to “AT” once the transmission is completed. If a prescription is not properly suspended for CMOP, the status will remain as S even after manual transmission. More than half (59%) of the responding sites must find the manual transmission feature useful as they use it either over or in addition to the auto-transmission setup.

Despite the challenges, many IHS sites process thousands of monthly prescriptions through CMOP. Of the 94 CMOP-enrolled IHS sites, 17 processed > 1,000 prescriptions from March 27, 2019 to April 25, 2019.¹⁷ Five sites processed > 5,000 prescriptions.¹⁷ At the rate of > 5,000 prescriptions per month, the yearly CMOP prescription count will be > 60,000. That is more than one-third of the prescriptions processed by CHCF in 2018. By handling these prescriptions through CMOP, it can decrease pharmacy filling and dispensing workload, thereby freeing pharmacists to participate in other services.¹⁸ Furthermore, implementing CMOP does not incur any cost for the IHS site. There is a nondrug cost for each prescription that is filled through CMOP. This cost was $2.67 during FY 2016.¹⁹ The fee covers prescription vial, label, packaging for mail, postage, personnel, building overhead, and equipment capitalization.¹⁹ The nondrug cost of filling a prescription locally at the site can potentially exceed the cost charged by CMOP.¹⁹

A lack of objective data exists to assess the net impact of CMOP on patients. Different theoretical assumptions can be made, such as CMOP resulting in better patient adherence. However, there is no objective information about how much CMOP improves patient adherence if it does at all. Though J.D. Power US Pharmacy Study ranks CMOP as “among the best” mail-order pharmacies in customer satisfaction, only 3 of the 44 responding sites have measured patient satisfaction locally.²⁰ Only 1 site had objective data about CMOP’s impact on the point of sale. Therefore, it is currently difficult to perform a cost-benefit analysis of the CMOP program. There are opportunities for further studies on these topics.

Limitations

One limitation of this study is that < 50% of the CMOP-enrolled sites (44 of 94) responded to the questionnaire. It is possible that the facilities that had a significantly positive or negative experience with CMOP were more inclined to share their views. Therefore, it is difficult to conclude whether the responding sites are an accurate representative sample. Another limitation of the study was the questionnaire design and the reliance on free-text responses as opposed to structured data. The free-text responses had to be analyzed manually to determine whether they fall in the same category, thereby increasing the risk of interpretation error.

Conclusion

CMOP has its unique challenges but provides many benefits that local pharmacy mail-out programs may not possess, such as the abilities to mail refrigerated items and track packages. One must be familiar with CMOP’s various idiosyncrasies to make the best use of the program. Extensive staff education and orientation for new staff members must be done to familiarize them with the program. Nevertheless, the successful implementation of CMOP can lead to reduced pharmacy workload while increasing access to care for patients with transportation issues.

Acknowledgments
The authors thank LCDR Karsten Smith, PharmD, BCGP, the IHS CMOP Coordinator for providing the list of primary CMOP contacts and CDR Kendall Van Tyle, PharmD, BCPS, for proofreading the article.

The US Food and Drug Administration has approved fostemsavir (Rukobia, ViiV Healthcare), a first-in-class attachment inhibitor for the treatment of HIV-1 infection in adults.

Fostemsavir is indicated for use in combination with other antiretroviral (ARV) agents in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection who fail to achieve viral suppression on other regimens due to resistance, intolerance, or safety considerations.

“This approval marks a new class of antiretroviral medications that may benefit patients who have run out of HIV treatment options,” Jeff Murray, MD, deputy director of the Division of Antivirals in the FDA’s Center for Drug Evaluation and Research, said in a statement.

“The availability of new classes of antiretroviral drugs is critical for heavily treatment-experienced patients living with multidrug resistant HIV infection — helping people living with hard-to-treat HIV who are at greater risk for HIV-related complications to potentially live longer, healthier lives,” he said.

Fostemsavir 600 mg extended-release tablets are taken twice daily.

In the phase 3 BRIGHTE study, 60% of adults who added fostemsavir to optimized background ARV therapy achieved and maintained viral suppression through 96 weeks and saw clinically meaningful improvements in CD4+ T cells.

Most of the 371 participants in the study had been on anti-HIV therapy for more than 15 years (71%), had been exposed to five or more different HIV treatment regimens (85%), and/or had a history of AIDS (86%).

The most common adverse reactions with fostemsavir are nausea, fatigue, and diarrhea. Serious drug reactions included liver enzyme elevations in patients co-infected with hepatitis B or C virus and three cases of severe immune reconstitution inflammatory syndrome. 

“Exciting” Advance

“There is a small group of heavily treatment-experienced adults living with HIV who are not able to maintain viral suppression with currently available medication and, without effective new options, are at great risk of progressing to AIDS,” Deborah Waterhouse, CEO of ViiV Healthcare, said in a news release.

“The approval of Rukobia is a culmination of incredibly complex research, development, and manufacturing efforts to ensure we leave no person living with HIV behind,” she said.

“As a novel HIV attachment inhibitor, fostemsavir targets the first step of the viral lifecycle offering a new mechanism of action to treat people living with HIV,” Jacob P. Lalezari, MD, chief executive officer and director of Quest Clinical Research, commented in the release.

Fostemsavir is an “exciting” advance for the heavily treatment-experienced population and “an advancement the HIV community has long been waiting for. As an activist as well as researcher, I am very grateful to ViiV Healthcare for their commitment to heavily-treatment experienced people living with HIV,” he added.

Fostemsavir was reviewed and approved under the FDA’s fast track and breakthrough therapy designations, which are intended to facilitate and expedite the development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening condition.

Full prescribing information is available online.
 

This article first appeared on Medscape.com.

The US Food and Drug Administration has approved fostemsavir (Rukobia, ViiV Healthcare), a first-in-class attachment inhibitor for the treatment of HIV-1 infection in adults.

Fostemsavir is indicated for use in combination with other antiretroviral (ARV) agents in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection who fail to achieve viral suppression on other regimens due to resistance, intolerance, or safety considerations.

“This approval marks a new class of antiretroviral medications that may benefit patients who have run out of HIV treatment options,” Jeff Murray, MD, deputy director of the Division of Antivirals in the FDA’s Center for Drug Evaluation and Research, said in a statement.

“The availability of new classes of antiretroviral drugs is critical for heavily treatment-experienced patients living with multidrug resistant HIV infection — helping people living with hard-to-treat HIV who are at greater risk for HIV-related complications to potentially live longer, healthier lives,” he said.

Fostemsavir 600 mg extended-release tablets are taken twice daily.

In the phase 3 BRIGHTE study, 60% of adults who added fostemsavir to optimized background ARV therapy achieved and maintained viral suppression through 96 weeks and saw clinically meaningful improvements in CD4+ T cells.

Most of the 371 participants in the study had been on anti-HIV therapy for more than 15 years (71%), had been exposed to five or more different HIV treatment regimens (85%), and/or had a history of AIDS (86%).

The most common adverse reactions with fostemsavir are nausea, fatigue, and diarrhea. Serious drug reactions included liver enzyme elevations in patients co-infected with hepatitis B or C virus and three cases of severe immune reconstitution inflammatory syndrome. 

“Exciting” Advance

“There is a small group of heavily treatment-experienced adults living with HIV who are not able to maintain viral suppression with currently available medication and, without effective new options, are at great risk of progressing to AIDS,” Deborah Waterhouse, CEO of ViiV Healthcare, said in a news release.

“The approval of Rukobia is a culmination of incredibly complex research, development, and manufacturing efforts to ensure we leave no person living with HIV behind,” she said.

“As a novel HIV attachment inhibitor, fostemsavir targets the first step of the viral lifecycle offering a new mechanism of action to treat people living with HIV,” Jacob P. Lalezari, MD, chief executive officer and director of Quest Clinical Research, commented in the release.

Fostemsavir is an “exciting” advance for the heavily treatment-experienced population and “an advancement the HIV community has long been waiting for. As an activist as well as researcher, I am very grateful to ViiV Healthcare for their commitment to heavily-treatment experienced people living with HIV,” he added.

Fostemsavir was reviewed and approved under the FDA’s fast track and breakthrough therapy designations, which are intended to facilitate and expedite the development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening condition.

Full prescribing information is available online.
 

This article first appeared on Medscape.com.

The US Food and Drug Administration has approved fostemsavir (Rukobia, ViiV Healthcare), a first-in-class attachment inhibitor for the treatment of HIV-1 infection in adults.

Fostemsavir is indicated for use in combination with other antiretroviral (ARV) agents in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection who fail to achieve viral suppression on other regimens due to resistance, intolerance, or safety considerations.

“This approval marks a new class of antiretroviral medications that may benefit patients who have run out of HIV treatment options,” Jeff Murray, MD, deputy director of the Division of Antivirals in the FDA’s Center for Drug Evaluation and Research, said in a statement.

“The availability of new classes of antiretroviral drugs is critical for heavily treatment-experienced patients living with multidrug resistant HIV infection — helping people living with hard-to-treat HIV who are at greater risk for HIV-related complications to potentially live longer, healthier lives,” he said.

Fostemsavir 600 mg extended-release tablets are taken twice daily.

In the phase 3 BRIGHTE study, 60% of adults who added fostemsavir to optimized background ARV therapy achieved and maintained viral suppression through 96 weeks and saw clinically meaningful improvements in CD4+ T cells.

Most of the 371 participants in the study had been on anti-HIV therapy for more than 15 years (71%), had been exposed to five or more different HIV treatment regimens (85%), and/or had a history of AIDS (86%).

The most common adverse reactions with fostemsavir are nausea, fatigue, and diarrhea. Serious drug reactions included liver enzyme elevations in patients co-infected with hepatitis B or C virus and three cases of severe immune reconstitution inflammatory syndrome. 

“Exciting” Advance

“There is a small group of heavily treatment-experienced adults living with HIV who are not able to maintain viral suppression with currently available medication and, without effective new options, are at great risk of progressing to AIDS,” Deborah Waterhouse, CEO of ViiV Healthcare, said in a news release.

“The approval of Rukobia is a culmination of incredibly complex research, development, and manufacturing efforts to ensure we leave no person living with HIV behind,” she said.

“As a novel HIV attachment inhibitor, fostemsavir targets the first step of the viral lifecycle offering a new mechanism of action to treat people living with HIV,” Jacob P. Lalezari, MD, chief executive officer and director of Quest Clinical Research, commented in the release.

Fostemsavir is an “exciting” advance for the heavily treatment-experienced population and “an advancement the HIV community has long been waiting for. As an activist as well as researcher, I am very grateful to ViiV Healthcare for their commitment to heavily-treatment experienced people living with HIV,” he added.

Fostemsavir was reviewed and approved under the FDA’s fast track and breakthrough therapy designations, which are intended to facilitate and expedite the development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening condition.

Full prescribing information is available online.
 

This article first appeared on Medscape.com.

Captopril appears to be associated with a higher rate of pulmonary adverse reactions in patients with diabetes than that of other ACE inhibitors or angiotensin receptor blockers (ARBs) and therefore may not be the best choice for patients with diabetes and COVID-19, a new study suggests.

The study was published online in the Journal of the American Pharmacists Association.

The authors, led by Emma G. Stafford, PharmD, University of Missouri-Kansas City School of Pharmacy, note that diabetes seems to confer a higher risk of adverse outcomes in COVID-19 infection and there is conflicting data on the contribution of ACE inhibitors and ARBs, commonly used medications in diabetes, on the mortality and morbidity of COVID-19.

“In light of the recent COVID-19 outbreak, more research is needed to understand the effects that diabetes (and its medications) may have on the respiratory system and how that could affect the management of diseases such as COVID-19,” they say.

“Although ACE inhibitors and ARBs are generally considered to have similar adverse event profiles, evaluation of postmarketing adverse events may shed light on minute differences that could have important clinical impacts,” they add.

For the current study, the researchers analyzed data from multiple publicly available data sources on adverse drug reactions in patients with diabetes taking ACE inhibitors or ARBs. The data included all adverse drug events (ADEs) reported nationally to the US Food and Drug Administration and internationally to the Medical Dictionary for Regulatory Activities (MedDRA).

Results showed that captopril, the first ACE inhibitor approved back in 1981, has a higher incidence of pulmonary ADEs in patients with diabetes as compared with other ACE-inhibitor drugs (P = .005) as well as a statistically significant difference in pulmonary events compared with ARBs (P = .012).

“These analyses suggest that pharmacists and clinicians will need to consider the specific medication’s adverse event profile, particularly captopril, on how it may affect infections and other acute disease states that alter pulmonary function, such as COVID-19,” the authors conclude.

They say that the high incidence of pulmonary adverse drug effects with captopril “highlights the fact that the drugs belonging in one class are not identical and that its pharmacokinetics and pharmacodynamics can affect the patients’ health especially during acute processes like COVID-19.”

“This is especially important as current observational studies of COVID-19 patients tend to group drugs within a class and are not analyzing the potential differences within each class,” they add.

They note that ACE inhibitors can be broadly classified into 3 structural classes: sulfhydryl-, dicarboxyl-, and phosphorous- containing molecules. Notably, captopril is the only currently available ACE inhibitor belonging to the sulfhydryl-containing class and may explain the higher incidence of adverse drug effects observed, they comment.

“Health care providers have been left with many questions when treating patients with COVID-19, including how ACE inhibitors or ARBs may affect their clinical course. Results from this study may be helpful when prescribing or continuing ACE inhibitors or ARBs for patients with diabetes and infections or illnesses that may affect pulmonary function, such as COVID-19,” they conclude.

Questioning safety in COVID-19 an “overreach”

Commenting for Medscape Medical News, Michael A. Weber, MD, professor of medicine at State University of New York, said he thought the current article appears to overreach in questioning captopril’s safety in the COVID-19 setting.

“Captopril was the first ACE inhibitor available for clinical use. In early prescribing its dosage was not well understood and it might have been administered in excessive amounts,” Weber notes.

“There were some renal and other adverse effects reported that at first were attributed to the fact that captopril, unlike any other popular ACE inhibitors, contained a sulfhydryl (SH) group in its molecule,” he said. “It is not clear whether this feature could be responsible for the increased pulmonary side effects and potential danger to COVID-19 patients now reported with captopril in this new pharmacy article.”

But he adds: “The article contains no evidence that the effect of captopril or any other ACE inhibitor on the pulmonary ACE-2 enzyme has a deleterious effect on outcomes of COVID-19 disease. In any case, captopril — which should be prescribed in a twice-daily dose — is not frequently prescribed these days since newer ACE inhibitors are effective with just once-daily dosing.”

This article first appeared on Medscape.com.

Captopril appears to be associated with a higher rate of pulmonary adverse reactions in patients with diabetes than that of other ACE inhibitors or angiotensin receptor blockers (ARBs) and therefore may not be the best choice for patients with diabetes and COVID-19, a new study suggests.

The study was published online in the Journal of the American Pharmacists Association.

The authors, led by Emma G. Stafford, PharmD, University of Missouri-Kansas City School of Pharmacy, note that diabetes seems to confer a higher risk of adverse outcomes in COVID-19 infection and there is conflicting data on the contribution of ACE inhibitors and ARBs, commonly used medications in diabetes, on the mortality and morbidity of COVID-19.

“In light of the recent COVID-19 outbreak, more research is needed to understand the effects that diabetes (and its medications) may have on the respiratory system and how that could affect the management of diseases such as COVID-19,” they say.

“Although ACE inhibitors and ARBs are generally considered to have similar adverse event profiles, evaluation of postmarketing adverse events may shed light on minute differences that could have important clinical impacts,” they add.

For the current study, the researchers analyzed data from multiple publicly available data sources on adverse drug reactions in patients with diabetes taking ACE inhibitors or ARBs. The data included all adverse drug events (ADEs) reported nationally to the US Food and Drug Administration and internationally to the Medical Dictionary for Regulatory Activities (MedDRA).

Results showed that captopril, the first ACE inhibitor approved back in 1981, has a higher incidence of pulmonary ADEs in patients with diabetes as compared with other ACE-inhibitor drugs (P = .005) as well as a statistically significant difference in pulmonary events compared with ARBs (P = .012).

“These analyses suggest that pharmacists and clinicians will need to consider the specific medication’s adverse event profile, particularly captopril, on how it may affect infections and other acute disease states that alter pulmonary function, such as COVID-19,” the authors conclude.

They say that the high incidence of pulmonary adverse drug effects with captopril “highlights the fact that the drugs belonging in one class are not identical and that its pharmacokinetics and pharmacodynamics can affect the patients’ health especially during acute processes like COVID-19.”

“This is especially important as current observational studies of COVID-19 patients tend to group drugs within a class and are not analyzing the potential differences within each class,” they add.

They note that ACE inhibitors can be broadly classified into 3 structural classes: sulfhydryl-, dicarboxyl-, and phosphorous- containing molecules. Notably, captopril is the only currently available ACE inhibitor belonging to the sulfhydryl-containing class and may explain the higher incidence of adverse drug effects observed, they comment.

“Health care providers have been left with many questions when treating patients with COVID-19, including how ACE inhibitors or ARBs may affect their clinical course. Results from this study may be helpful when prescribing or continuing ACE inhibitors or ARBs for patients with diabetes and infections or illnesses that may affect pulmonary function, such as COVID-19,” they conclude.

Questioning safety in COVID-19 an “overreach”

Commenting for Medscape Medical News, Michael A. Weber, MD, professor of medicine at State University of New York, said he thought the current article appears to overreach in questioning captopril’s safety in the COVID-19 setting.

“Captopril was the first ACE inhibitor available for clinical use. In early prescribing its dosage was not well understood and it might have been administered in excessive amounts,” Weber notes.

“There were some renal and other adverse effects reported that at first were attributed to the fact that captopril, unlike any other popular ACE inhibitors, contained a sulfhydryl (SH) group in its molecule,” he said. “It is not clear whether this feature could be responsible for the increased pulmonary side effects and potential danger to COVID-19 patients now reported with captopril in this new pharmacy article.”

But he adds: “The article contains no evidence that the effect of captopril or any other ACE inhibitor on the pulmonary ACE-2 enzyme has a deleterious effect on outcomes of COVID-19 disease. In any case, captopril — which should be prescribed in a twice-daily dose — is not frequently prescribed these days since newer ACE inhibitors are effective with just once-daily dosing.”

This article first appeared on Medscape.com.

Captopril appears to be associated with a higher rate of pulmonary adverse reactions in patients with diabetes than that of other ACE inhibitors or angiotensin receptor blockers (ARBs) and therefore may not be the best choice for patients with diabetes and COVID-19, a new study suggests.

The study was published online in the Journal of the American Pharmacists Association.

The authors, led by Emma G. Stafford, PharmD, University of Missouri-Kansas City School of Pharmacy, note that diabetes seems to confer a higher risk of adverse outcomes in COVID-19 infection and there is conflicting data on the contribution of ACE inhibitors and ARBs, commonly used medications in diabetes, on the mortality and morbidity of COVID-19.

“In light of the recent COVID-19 outbreak, more research is needed to understand the effects that diabetes (and its medications) may have on the respiratory system and how that could affect the management of diseases such as COVID-19,” they say.

“Although ACE inhibitors and ARBs are generally considered to have similar adverse event profiles, evaluation of postmarketing adverse events may shed light on minute differences that could have important clinical impacts,” they add.

For the current study, the researchers analyzed data from multiple publicly available data sources on adverse drug reactions in patients with diabetes taking ACE inhibitors or ARBs. The data included all adverse drug events (ADEs) reported nationally to the US Food and Drug Administration and internationally to the Medical Dictionary for Regulatory Activities (MedDRA).

Results showed that captopril, the first ACE inhibitor approved back in 1981, has a higher incidence of pulmonary ADEs in patients with diabetes as compared with other ACE-inhibitor drugs (P = .005) as well as a statistically significant difference in pulmonary events compared with ARBs (P = .012).

“These analyses suggest that pharmacists and clinicians will need to consider the specific medication’s adverse event profile, particularly captopril, on how it may affect infections and other acute disease states that alter pulmonary function, such as COVID-19,” the authors conclude.

They say that the high incidence of pulmonary adverse drug effects with captopril “highlights the fact that the drugs belonging in one class are not identical and that its pharmacokinetics and pharmacodynamics can affect the patients’ health especially during acute processes like COVID-19.”

“This is especially important as current observational studies of COVID-19 patients tend to group drugs within a class and are not analyzing the potential differences within each class,” they add.

They note that ACE inhibitors can be broadly classified into 3 structural classes: sulfhydryl-, dicarboxyl-, and phosphorous- containing molecules. Notably, captopril is the only currently available ACE inhibitor belonging to the sulfhydryl-containing class and may explain the higher incidence of adverse drug effects observed, they comment.

“Health care providers have been left with many questions when treating patients with COVID-19, including how ACE inhibitors or ARBs may affect their clinical course. Results from this study may be helpful when prescribing or continuing ACE inhibitors or ARBs for patients with diabetes and infections or illnesses that may affect pulmonary function, such as COVID-19,” they conclude.

Questioning safety in COVID-19 an “overreach”

Commenting for Medscape Medical News, Michael A. Weber, MD, professor of medicine at State University of New York, said he thought the current article appears to overreach in questioning captopril’s safety in the COVID-19 setting.

“Captopril was the first ACE inhibitor available for clinical use. In early prescribing its dosage was not well understood and it might have been administered in excessive amounts,” Weber notes.

“There were some renal and other adverse effects reported that at first were attributed to the fact that captopril, unlike any other popular ACE inhibitors, contained a sulfhydryl (SH) group in its molecule,” he said. “It is not clear whether this feature could be responsible for the increased pulmonary side effects and potential danger to COVID-19 patients now reported with captopril in this new pharmacy article.”

But he adds: “The article contains no evidence that the effect of captopril or any other ACE inhibitor on the pulmonary ACE-2 enzyme has a deleterious effect on outcomes of COVID-19 disease. In any case, captopril — which should be prescribed in a twice-daily dose — is not frequently prescribed these days since newer ACE inhibitors are effective with just once-daily dosing.”

This article first appeared on Medscape.com.

The Food and Drug Administration approved a combination of pertuzumab (Perjeta, Genentech/Roche), trastuzumab (Herceptin, Genentech/Roche) and hyaluronidase (Phesgo, Genentech/Roche) that is administered subcutaneously – rather than intravenously – for the treatment of early and metastatic HER2-positive breast cancers.

Phesgo is initially used in combination with chemotherapy at an infusion center but could continue to be administered in a patient’s home by a qualified health care professional once chemotherapy is complete, according to the FDA.

Administration takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for maintenance doses, according to a Genentech press statement. This compares favorably with the 150 minutes needed for the combined loading dose of intravenous pertuzumab and trastuzumab, and the 60-150 minutes for intravenous maintenance infusions, the company said.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in an agency press release.

“The fixed-dose combination of trastuzumab and pertuzumab offers a simpler, faster, and easier treatment experience for patients with HER2-positive breast cancer,” said Antoinette Tan, MD, MHSc, chief of breast medical oncology at Levine Cancer Institute, Charlotte, N.C., in the company statement.

Dr. Tan also said that home administration “can be advantageous for patients and infusion centers.”

However, in April, the Community Oncology Alliance strenuously objected to this type of treatment in a patient’s home, as reported by Medscape Medical News.

The group, which represents U.S. community-based practices, said it “fundamentally opposes home infusion of chemotherapy, cancer immunotherapy, and cancer treatment supportive drugs because of serious patient safety concerns.”

The FDA’s approval was based on the results of the pivotal phase 3 FeDeriCa trial, a noninferiority study in patients with HER2-positive early breast cancer, which demonstrated that the new product had comparable efficacy and safety as intravenous pertuzumab and intravenous trastuzumab.

In terms of efficacy, the subcutaneous product demonstrated noninferior plasma levels of pertuzumab, which was the primary endpoint, when compared with IV administration of pertuzumab.

Safety was comparable between the two approaches, with no new safety signals using the subcutaneous delivery method, including no “meaningful difference” in cardiac toxicity, according to Genentech. However, there were more administration-related reactions with the new product. The most common adverse events in both groups were alopecia, nausea, diarrhea, and anemia.

The new product uses a drug delivery technology (Enhanze, Halozyme Therapeutics) that employs a proprietary enzyme that temporarily degrades hyaluronan, a glycosaminoglycan or chain of natural sugars in the body, to facilitate the dispersion and absorption of injected therapeutic drugs, according to Genentech.

In May, at the European Society for Medical Oncology Breast Cancer Virtual Meeting 2020, investigators of the phase 2 PHranceSCa study reported that “more than 80%” of patients preferred subcutaneous to intravenous administration of pertuzumab and trastuzumab.

This article first appeared on Medscape.com.

The Food and Drug Administration approved a combination of pertuzumab (Perjeta, Genentech/Roche), trastuzumab (Herceptin, Genentech/Roche) and hyaluronidase (Phesgo, Genentech/Roche) that is administered subcutaneously – rather than intravenously – for the treatment of early and metastatic HER2-positive breast cancers.

Phesgo is initially used in combination with chemotherapy at an infusion center but could continue to be administered in a patient’s home by a qualified health care professional once chemotherapy is complete, according to the FDA.

Administration takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for maintenance doses, according to a Genentech press statement. This compares favorably with the 150 minutes needed for the combined loading dose of intravenous pertuzumab and trastuzumab, and the 60-150 minutes for intravenous maintenance infusions, the company said.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in an agency press release.

“The fixed-dose combination of trastuzumab and pertuzumab offers a simpler, faster, and easier treatment experience for patients with HER2-positive breast cancer,” said Antoinette Tan, MD, MHSc, chief of breast medical oncology at Levine Cancer Institute, Charlotte, N.C., in the company statement.

Dr. Tan also said that home administration “can be advantageous for patients and infusion centers.”

However, in April, the Community Oncology Alliance strenuously objected to this type of treatment in a patient’s home, as reported by Medscape Medical News.

The group, which represents U.S. community-based practices, said it “fundamentally opposes home infusion of chemotherapy, cancer immunotherapy, and cancer treatment supportive drugs because of serious patient safety concerns.”

The FDA’s approval was based on the results of the pivotal phase 3 FeDeriCa trial, a noninferiority study in patients with HER2-positive early breast cancer, which demonstrated that the new product had comparable efficacy and safety as intravenous pertuzumab and intravenous trastuzumab.

In terms of efficacy, the subcutaneous product demonstrated noninferior plasma levels of pertuzumab, which was the primary endpoint, when compared with IV administration of pertuzumab.

Safety was comparable between the two approaches, with no new safety signals using the subcutaneous delivery method, including no “meaningful difference” in cardiac toxicity, according to Genentech. However, there were more administration-related reactions with the new product. The most common adverse events in both groups were alopecia, nausea, diarrhea, and anemia.

The new product uses a drug delivery technology (Enhanze, Halozyme Therapeutics) that employs a proprietary enzyme that temporarily degrades hyaluronan, a glycosaminoglycan or chain of natural sugars in the body, to facilitate the dispersion and absorption of injected therapeutic drugs, according to Genentech.

In May, at the European Society for Medical Oncology Breast Cancer Virtual Meeting 2020, investigators of the phase 2 PHranceSCa study reported that “more than 80%” of patients preferred subcutaneous to intravenous administration of pertuzumab and trastuzumab.

This article first appeared on Medscape.com.

The Food and Drug Administration approved a combination of pertuzumab (Perjeta, Genentech/Roche), trastuzumab (Herceptin, Genentech/Roche) and hyaluronidase (Phesgo, Genentech/Roche) that is administered subcutaneously – rather than intravenously – for the treatment of early and metastatic HER2-positive breast cancers.

Phesgo is initially used in combination with chemotherapy at an infusion center but could continue to be administered in a patient’s home by a qualified health care professional once chemotherapy is complete, according to the FDA.

Administration takes approximately 8 minutes for the initial loading dose and approximately 5 minutes for maintenance doses, according to a Genentech press statement. This compares favorably with the 150 minutes needed for the combined loading dose of intravenous pertuzumab and trastuzumab, and the 60-150 minutes for intravenous maintenance infusions, the company said.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, Phesgo offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in an agency press release.

“The fixed-dose combination of trastuzumab and pertuzumab offers a simpler, faster, and easier treatment experience for patients with HER2-positive breast cancer,” said Antoinette Tan, MD, MHSc, chief of breast medical oncology at Levine Cancer Institute, Charlotte, N.C., in the company statement.

Dr. Tan also said that home administration “can be advantageous for patients and infusion centers.”

However, in April, the Community Oncology Alliance strenuously objected to this type of treatment in a patient’s home, as reported by Medscape Medical News.

The group, which represents U.S. community-based practices, said it “fundamentally opposes home infusion of chemotherapy, cancer immunotherapy, and cancer treatment supportive drugs because of serious patient safety concerns.”

The FDA’s approval was based on the results of the pivotal phase 3 FeDeriCa trial, a noninferiority study in patients with HER2-positive early breast cancer, which demonstrated that the new product had comparable efficacy and safety as intravenous pertuzumab and intravenous trastuzumab.

In terms of efficacy, the subcutaneous product demonstrated noninferior plasma levels of pertuzumab, which was the primary endpoint, when compared with IV administration of pertuzumab.

Safety was comparable between the two approaches, with no new safety signals using the subcutaneous delivery method, including no “meaningful difference” in cardiac toxicity, according to Genentech. However, there were more administration-related reactions with the new product. The most common adverse events in both groups were alopecia, nausea, diarrhea, and anemia.

The new product uses a drug delivery technology (Enhanze, Halozyme Therapeutics) that employs a proprietary enzyme that temporarily degrades hyaluronan, a glycosaminoglycan or chain of natural sugars in the body, to facilitate the dispersion and absorption of injected therapeutic drugs, according to Genentech.

In May, at the European Society for Medical Oncology Breast Cancer Virtual Meeting 2020, investigators of the phase 2 PHranceSCa study reported that “more than 80%” of patients preferred subcutaneous to intravenous administration of pertuzumab and trastuzumab.

This article first appeared on Medscape.com.