New drugs approved in 2012

In 2012, the Food and Drug Administration approved 39 new molecular entities (i.e., drugs). This was the highest number of approvals in the 2003 to 2012 period. Of the 39, 2 have not yet come onto the market, 3 are highly unlikely to be used in women of reproductive age, and 1 is a four-drug combination for HIV-1 infection.

The remaining 33 agents are classified as anorexiant (1), anticoagulant (1), anticonvulsant (1), antidote (1), antilipemic (1), antineoplastic (11), antituberculosis (1), dermatologic (1), endocrine/metabolic (3), gastrointestinal (4), hematologic (1), immunologic (2), impotence (1), ophthalmic (2), respiratory (1), and urinary tract agent (1).

There is no reported human pregnancy experience for any of these agents. Consequently, the potential risk to the embryo and/or fetus must be estimated based on the indication, mechanism of action, other drugs with a similar mechanism, route of administration, molecular weight, elimination half-life, and animal reproduction data. Some of these drugs have been included in the quarterly updates to the 9th edition of my book "Drugs in Pregnancy and Lactation." The remainder will appear in the 10th edition, scheduled to be released in the spring of 2014.

Lorcaserin (Belviq) is an anorexiant. Because weight loss in pregnancy usually offers no benefit to a pregnant woman, the manufacturer classifies the drug as contraindicated in pregnancy.

A new anticoagulant, apixaban (Eliquis), is used to reduce the risk of stroke in patients with atrial fibrillation. The animal data suggest low risk and, when combined with the indication, the drug should not be withheld because of pregnancy.

The animal data for the anticonvulsant perampanel (Fycompa) suggest risk, but the absence of human pregnancy experience prevents a full assessment of the embryo-fetal risk. If the drug is used in pregnancy, physicians are encouraged to recommend that their patients enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334.

The antidote, glucarpidase (Voraxaze), is used to treat toxic levels of methotrexate. Because methotrexate is contraindicated in pregnancy, it appears that there will be few opportunities for use of this drug in a pregnant woman. The same can be said for the antilipemic agent, lomitapide (Juxtapid). Decreasing the levels of lipids and cholesterol offers no benefit in pregnancy. The manufacturer classifies the agent as contraindicated because of the toxicity observed in three animal species.

Among the new antineoplastic agents approved, six are kinase inhibitors. Of these, five are in the subclass of tyrosine kinase inhibitors (trade name; indication): Axitinib (Inlyta; renal cancer), bosutinib (Bosulif; leukemia), cabozantinib (Cometriq; thyroid cancer), ponatinib (Iclusig; leukemia), and ziv-aflibercept (Zaltrap; colorectal cancer). The sixth kinase inhibitor is a multikinase inhibitor: regorafenib (Stivarga; colorectal cancer).

Other new antineoplastics are the antiandrogen enzalutamide (Xtandi; prostate cancer but could be used for other cancers), the proteasome inhibitor carfilzomib (Kyprolis; multiple myeloma), and the protein synthesis inhibitor omacetaxine (Synribo; leukemia). Pertuzumab (Perjeta; breast cancer) is a monoclonal antibody that is given in combination with trastuzumab and docetaxel. Vismodegib (Erivedge; basal cell cancer) is a miscellaneous antineoplastic that has been associated with amenorrhea in clinical trials. Animal data suggest risk of embryo-fetal harm.

All of the above antineoplastics are contraindicated in pregnancy because their mechanisms suggest the potential for embryo-fetal harm. However, if a drug is the best choice for a woman with a severe or a potentially fatal disease, it should not be withheld because the maternal benefit should far outweigh the unknown embryo-fetal risk.

Bedaquiline (Sirturo) is a new antituberculosis agent that can be used in pregnancy because of the low risk in animal studies and its indication. The dermatologic agent, ingenol mebutate (Picato) is used topically for actinic keratosis and appears to be compatible in pregnancy, because blood levels of the drug and two of its metabolites were below the lower limit of quantification (0.1 ng/mL).

The three endocrine/metabolic agents are ivacaftor (Kalydeco; cystic fibrosis), taliglucerase alfa (Elelyso; Gaucher disease), and pasireotide (Signifor; Cushing’s disease). The animal data for ivacaftor suggest low risk. Taliglucerase alfa appears to be compatible in pregnancy because it might reduce the risk of spontaneous abortion and bleeding complications. However, based on animal data, if a pregnant woman takes pasireotide, she should be informed of the potential risk, including abortion, to her embryo and/or fetus.

There are four gastrointestinal agents: crofelemer (Fulyzaq; antidiarrheal), linaclotide (Linzess; laxative), teduglutide (Gattex; short bowel syndrome), and the combination of sodium picosulfate, magnesium oxide, and citric acid (Prepopik; osmotic laxative). All appear to be compatible in pregnancy because of limited, if any, absorption (crofelemer, linaclotide, and sodium picosulfate) or because it is an analogue of a naturally occurring peptide (teduglutide).

The animal data for the hematologic agent, peginesatide (Omontys; anemia in patients with chronic renal disease) suggest risk. The drug has a high molecular weightthat should limit its passage across the placenta, but it still might cross in the third trimester. Because it stimulates erythropoiesis in human red blood cell precursors, it could do the same in the fetus if it crosses.

The two immunologic drugs are teriflunomide (Aubagio; multiple sclerosis) and tofacitinib (Xeljanz; rheumatoid arthritis). Teriflunomide, the principal active metabolite of leflunomide and responsible for leflunomide’s activity, is contraindicated in pregnancy. If a woman conceives while taking this drug, an 11-day procedure for accelerated elimination is recommended because it takes an average of 8 months (and it may be as long as 2 years) to reach plasma concentrations that are considered minimal risk (see package insert for procedure). The animal data for tofacitinib suggest risk. It is contraindicated if combined with methotrexate.

At first glance, it does not appear that the vasodilator avanafil (Stendra; impotence agent) will be used in pregnancy. However, a similar agent, sildenafil, has been used for the treatment of pulmonary arterial hypertension, a high-risk condition in pregnancy. Based on its indication, mechanism of action, and low-risk animal data, avanafil can be used in pregnancy if indicated.

Aclidinium bromide (Tudorza Pressair; bronchodilator) is a respiratory agent used in chronic obstructive pulmonary disease, chronic bronchitis, and emphysema. The animal data suggest low risk. The low plasma concentrations suggest that the drug represents a low, if any, risk in pregnancy.

The two ophthalmic preparations are ocriplasmin (Jetrea; symptomatic vitreomacular adhesions) and tafluprost (Zioptan; glaucoma). Both are probably compatible in pregnancy because of the undetectable or very low systemic concentrations.

The animal data for mirabegron (Myrbetriq; antispasmodic for overactive bladder) suggest low risk. It is an adrenergic agonist that increases bladder capacity. Although there are no human data, it probably can be used in pregnancy, but avoiding the first trimester should be considered.

As with pregnancy, there are no reports involving the use of the above drugs during breast-feeding. When there are little or no human data, the risk to a nursing infant can be estimated by considering several factors: indication, duration of therapy, molecular weight, plasma protein binding, elimination half-life, presence of the drug in the systemic circulation, and the most common adverse effects observed in adults.

Using these criteria for the drugs discussed above, there are only 10 that are probably compatible with breast-feeding: glucarpidase, ingenol mebutate, sodium picosulfate, taliglucerase alfa, crofelemer, linaclotide, peginesatide, aclidinium bromide, tafluprost, and ocriplasmin. The remaining drugs are either contraindicated (most of the antineoplastics and tofacitinib if combined with methotrexate) or may cause toxicity in a nursing infant.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at obnews@frontlinemedcom.com.

In 2012, the Food and Drug Administration approved 39 new molecular entities (i.e., drugs). This was the highest number of approvals in the 2003 to 2012 period. Of the 39, 2 have not yet come onto the market, 3 are highly unlikely to be used in women of reproductive age, and 1 is a four-drug combination for HIV-1 infection.

The remaining 33 agents are classified as anorexiant (1), anticoagulant (1), anticonvulsant (1), antidote (1), antilipemic (1), antineoplastic (11), antituberculosis (1), dermatologic (1), endocrine/metabolic (3), gastrointestinal (4), hematologic (1), immunologic (2), impotence (1), ophthalmic (2), respiratory (1), and urinary tract agent (1).

There is no reported human pregnancy experience for any of these agents. Consequently, the potential risk to the embryo and/or fetus must be estimated based on the indication, mechanism of action, other drugs with a similar mechanism, route of administration, molecular weight, elimination half-life, and animal reproduction data. Some of these drugs have been included in the quarterly updates to the 9th edition of my book "Drugs in Pregnancy and Lactation." The remainder will appear in the 10th edition, scheduled to be released in the spring of 2014.

Lorcaserin (Belviq) is an anorexiant. Because weight loss in pregnancy usually offers no benefit to a pregnant woman, the manufacturer classifies the drug as contraindicated in pregnancy.

A new anticoagulant, apixaban (Eliquis), is used to reduce the risk of stroke in patients with atrial fibrillation. The animal data suggest low risk and, when combined with the indication, the drug should not be withheld because of pregnancy.

The animal data for the anticonvulsant perampanel (Fycompa) suggest risk, but the absence of human pregnancy experience prevents a full assessment of the embryo-fetal risk. If the drug is used in pregnancy, physicians are encouraged to recommend that their patients enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334.

The antidote, glucarpidase (Voraxaze), is used to treat toxic levels of methotrexate. Because methotrexate is contraindicated in pregnancy, it appears that there will be few opportunities for use of this drug in a pregnant woman. The same can be said for the antilipemic agent, lomitapide (Juxtapid). Decreasing the levels of lipids and cholesterol offers no benefit in pregnancy. The manufacturer classifies the agent as contraindicated because of the toxicity observed in three animal species.

Among the new antineoplastic agents approved, six are kinase inhibitors. Of these, five are in the subclass of tyrosine kinase inhibitors (trade name; indication): Axitinib (Inlyta; renal cancer), bosutinib (Bosulif; leukemia), cabozantinib (Cometriq; thyroid cancer), ponatinib (Iclusig; leukemia), and ziv-aflibercept (Zaltrap; colorectal cancer). The sixth kinase inhibitor is a multikinase inhibitor: regorafenib (Stivarga; colorectal cancer).

Other new antineoplastics are the antiandrogen enzalutamide (Xtandi; prostate cancer but could be used for other cancers), the proteasome inhibitor carfilzomib (Kyprolis; multiple myeloma), and the protein synthesis inhibitor omacetaxine (Synribo; leukemia). Pertuzumab (Perjeta; breast cancer) is a monoclonal antibody that is given in combination with trastuzumab and docetaxel. Vismodegib (Erivedge; basal cell cancer) is a miscellaneous antineoplastic that has been associated with amenorrhea in clinical trials. Animal data suggest risk of embryo-fetal harm.

All of the above antineoplastics are contraindicated in pregnancy because their mechanisms suggest the potential for embryo-fetal harm. However, if a drug is the best choice for a woman with a severe or a potentially fatal disease, it should not be withheld because the maternal benefit should far outweigh the unknown embryo-fetal risk.

Bedaquiline (Sirturo) is a new antituberculosis agent that can be used in pregnancy because of the low risk in animal studies and its indication. The dermatologic agent, ingenol mebutate (Picato) is used topically for actinic keratosis and appears to be compatible in pregnancy, because blood levels of the drug and two of its metabolites were below the lower limit of quantification (0.1 ng/mL).

The three endocrine/metabolic agents are ivacaftor (Kalydeco; cystic fibrosis), taliglucerase alfa (Elelyso; Gaucher disease), and pasireotide (Signifor; Cushing’s disease). The animal data for ivacaftor suggest low risk. Taliglucerase alfa appears to be compatible in pregnancy because it might reduce the risk of spontaneous abortion and bleeding complications. However, based on animal data, if a pregnant woman takes pasireotide, she should be informed of the potential risk, including abortion, to her embryo and/or fetus.

There are four gastrointestinal agents: crofelemer (Fulyzaq; antidiarrheal), linaclotide (Linzess; laxative), teduglutide (Gattex; short bowel syndrome), and the combination of sodium picosulfate, magnesium oxide, and citric acid (Prepopik; osmotic laxative). All appear to be compatible in pregnancy because of limited, if any, absorption (crofelemer, linaclotide, and sodium picosulfate) or because it is an analogue of a naturally occurring peptide (teduglutide).

The animal data for the hematologic agent, peginesatide (Omontys; anemia in patients with chronic renal disease) suggest risk. The drug has a high molecular weightthat should limit its passage across the placenta, but it still might cross in the third trimester. Because it stimulates erythropoiesis in human red blood cell precursors, it could do the same in the fetus if it crosses.

The two immunologic drugs are teriflunomide (Aubagio; multiple sclerosis) and tofacitinib (Xeljanz; rheumatoid arthritis). Teriflunomide, the principal active metabolite of leflunomide and responsible for leflunomide’s activity, is contraindicated in pregnancy. If a woman conceives while taking this drug, an 11-day procedure for accelerated elimination is recommended because it takes an average of 8 months (and it may be as long as 2 years) to reach plasma concentrations that are considered minimal risk (see package insert for procedure). The animal data for tofacitinib suggest risk. It is contraindicated if combined with methotrexate.

At first glance, it does not appear that the vasodilator avanafil (Stendra; impotence agent) will be used in pregnancy. However, a similar agent, sildenafil, has been used for the treatment of pulmonary arterial hypertension, a high-risk condition in pregnancy. Based on its indication, mechanism of action, and low-risk animal data, avanafil can be used in pregnancy if indicated.

Aclidinium bromide (Tudorza Pressair; bronchodilator) is a respiratory agent used in chronic obstructive pulmonary disease, chronic bronchitis, and emphysema. The animal data suggest low risk. The low plasma concentrations suggest that the drug represents a low, if any, risk in pregnancy.

The two ophthalmic preparations are ocriplasmin (Jetrea; symptomatic vitreomacular adhesions) and tafluprost (Zioptan; glaucoma). Both are probably compatible in pregnancy because of the undetectable or very low systemic concentrations.

The animal data for mirabegron (Myrbetriq; antispasmodic for overactive bladder) suggest low risk. It is an adrenergic agonist that increases bladder capacity. Although there are no human data, it probably can be used in pregnancy, but avoiding the first trimester should be considered.

As with pregnancy, there are no reports involving the use of the above drugs during breast-feeding. When there are little or no human data, the risk to a nursing infant can be estimated by considering several factors: indication, duration of therapy, molecular weight, plasma protein binding, elimination half-life, presence of the drug in the systemic circulation, and the most common adverse effects observed in adults.

Using these criteria for the drugs discussed above, there are only 10 that are probably compatible with breast-feeding: glucarpidase, ingenol mebutate, sodium picosulfate, taliglucerase alfa, crofelemer, linaclotide, peginesatide, aclidinium bromide, tafluprost, and ocriplasmin. The remaining drugs are either contraindicated (most of the antineoplastics and tofacitinib if combined with methotrexate) or may cause toxicity in a nursing infant.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at obnews@frontlinemedcom.com.

In 2012, the Food and Drug Administration approved 39 new molecular entities (i.e., drugs). This was the highest number of approvals in the 2003 to 2012 period. Of the 39, 2 have not yet come onto the market, 3 are highly unlikely to be used in women of reproductive age, and 1 is a four-drug combination for HIV-1 infection.

The remaining 33 agents are classified as anorexiant (1), anticoagulant (1), anticonvulsant (1), antidote (1), antilipemic (1), antineoplastic (11), antituberculosis (1), dermatologic (1), endocrine/metabolic (3), gastrointestinal (4), hematologic (1), immunologic (2), impotence (1), ophthalmic (2), respiratory (1), and urinary tract agent (1).

There is no reported human pregnancy experience for any of these agents. Consequently, the potential risk to the embryo and/or fetus must be estimated based on the indication, mechanism of action, other drugs with a similar mechanism, route of administration, molecular weight, elimination half-life, and animal reproduction data. Some of these drugs have been included in the quarterly updates to the 9th edition of my book "Drugs in Pregnancy and Lactation." The remainder will appear in the 10th edition, scheduled to be released in the spring of 2014.

Lorcaserin (Belviq) is an anorexiant. Because weight loss in pregnancy usually offers no benefit to a pregnant woman, the manufacturer classifies the drug as contraindicated in pregnancy.

A new anticoagulant, apixaban (Eliquis), is used to reduce the risk of stroke in patients with atrial fibrillation. The animal data suggest low risk and, when combined with the indication, the drug should not be withheld because of pregnancy.

The animal data for the anticonvulsant perampanel (Fycompa) suggest risk, but the absence of human pregnancy experience prevents a full assessment of the embryo-fetal risk. If the drug is used in pregnancy, physicians are encouraged to recommend that their patients enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334.

The antidote, glucarpidase (Voraxaze), is used to treat toxic levels of methotrexate. Because methotrexate is contraindicated in pregnancy, it appears that there will be few opportunities for use of this drug in a pregnant woman. The same can be said for the antilipemic agent, lomitapide (Juxtapid). Decreasing the levels of lipids and cholesterol offers no benefit in pregnancy. The manufacturer classifies the agent as contraindicated because of the toxicity observed in three animal species.

Among the new antineoplastic agents approved, six are kinase inhibitors. Of these, five are in the subclass of tyrosine kinase inhibitors (trade name; indication): Axitinib (Inlyta; renal cancer), bosutinib (Bosulif; leukemia), cabozantinib (Cometriq; thyroid cancer), ponatinib (Iclusig; leukemia), and ziv-aflibercept (Zaltrap; colorectal cancer). The sixth kinase inhibitor is a multikinase inhibitor: regorafenib (Stivarga; colorectal cancer).

Other new antineoplastics are the antiandrogen enzalutamide (Xtandi; prostate cancer but could be used for other cancers), the proteasome inhibitor carfilzomib (Kyprolis; multiple myeloma), and the protein synthesis inhibitor omacetaxine (Synribo; leukemia). Pertuzumab (Perjeta; breast cancer) is a monoclonal antibody that is given in combination with trastuzumab and docetaxel. Vismodegib (Erivedge; basal cell cancer) is a miscellaneous antineoplastic that has been associated with amenorrhea in clinical trials. Animal data suggest risk of embryo-fetal harm.

All of the above antineoplastics are contraindicated in pregnancy because their mechanisms suggest the potential for embryo-fetal harm. However, if a drug is the best choice for a woman with a severe or a potentially fatal disease, it should not be withheld because the maternal benefit should far outweigh the unknown embryo-fetal risk.

Bedaquiline (Sirturo) is a new antituberculosis agent that can be used in pregnancy because of the low risk in animal studies and its indication. The dermatologic agent, ingenol mebutate (Picato) is used topically for actinic keratosis and appears to be compatible in pregnancy, because blood levels of the drug and two of its metabolites were below the lower limit of quantification (0.1 ng/mL).

The three endocrine/metabolic agents are ivacaftor (Kalydeco; cystic fibrosis), taliglucerase alfa (Elelyso; Gaucher disease), and pasireotide (Signifor; Cushing’s disease). The animal data for ivacaftor suggest low risk. Taliglucerase alfa appears to be compatible in pregnancy because it might reduce the risk of spontaneous abortion and bleeding complications. However, based on animal data, if a pregnant woman takes pasireotide, she should be informed of the potential risk, including abortion, to her embryo and/or fetus.

There are four gastrointestinal agents: crofelemer (Fulyzaq; antidiarrheal), linaclotide (Linzess; laxative), teduglutide (Gattex; short bowel syndrome), and the combination of sodium picosulfate, magnesium oxide, and citric acid (Prepopik; osmotic laxative). All appear to be compatible in pregnancy because of limited, if any, absorption (crofelemer, linaclotide, and sodium picosulfate) or because it is an analogue of a naturally occurring peptide (teduglutide).

The animal data for the hematologic agent, peginesatide (Omontys; anemia in patients with chronic renal disease) suggest risk. The drug has a high molecular weightthat should limit its passage across the placenta, but it still might cross in the third trimester. Because it stimulates erythropoiesis in human red blood cell precursors, it could do the same in the fetus if it crosses.

The two immunologic drugs are teriflunomide (Aubagio; multiple sclerosis) and tofacitinib (Xeljanz; rheumatoid arthritis). Teriflunomide, the principal active metabolite of leflunomide and responsible for leflunomide’s activity, is contraindicated in pregnancy. If a woman conceives while taking this drug, an 11-day procedure for accelerated elimination is recommended because it takes an average of 8 months (and it may be as long as 2 years) to reach plasma concentrations that are considered minimal risk (see package insert for procedure). The animal data for tofacitinib suggest risk. It is contraindicated if combined with methotrexate.

At first glance, it does not appear that the vasodilator avanafil (Stendra; impotence agent) will be used in pregnancy. However, a similar agent, sildenafil, has been used for the treatment of pulmonary arterial hypertension, a high-risk condition in pregnancy. Based on its indication, mechanism of action, and low-risk animal data, avanafil can be used in pregnancy if indicated.

Aclidinium bromide (Tudorza Pressair; bronchodilator) is a respiratory agent used in chronic obstructive pulmonary disease, chronic bronchitis, and emphysema. The animal data suggest low risk. The low plasma concentrations suggest that the drug represents a low, if any, risk in pregnancy.

The two ophthalmic preparations are ocriplasmin (Jetrea; symptomatic vitreomacular adhesions) and tafluprost (Zioptan; glaucoma). Both are probably compatible in pregnancy because of the undetectable or very low systemic concentrations.

The animal data for mirabegron (Myrbetriq; antispasmodic for overactive bladder) suggest low risk. It is an adrenergic agonist that increases bladder capacity. Although there are no human data, it probably can be used in pregnancy, but avoiding the first trimester should be considered.

As with pregnancy, there are no reports involving the use of the above drugs during breast-feeding. When there are little or no human data, the risk to a nursing infant can be estimated by considering several factors: indication, duration of therapy, molecular weight, plasma protein binding, elimination half-life, presence of the drug in the systemic circulation, and the most common adverse effects observed in adults.

Using these criteria for the drugs discussed above, there are only 10 that are probably compatible with breast-feeding: glucarpidase, ingenol mebutate, sodium picosulfate, taliglucerase alfa, crofelemer, linaclotide, peginesatide, aclidinium bromide, tafluprost, and ocriplasmin. The remaining drugs are either contraindicated (most of the antineoplastics and tofacitinib if combined with methotrexate) or may cause toxicity in a nursing infant.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at obnews@frontlinemedcom.com.