FDA approves pasireotide for Cushing's, with postmarketing safety studies

Pasireotide, a somatostatin analogue, has been approved by the Food and Drug Administration as a treatment for Cushing’s disease in adults "for whom pituitary surgery is not an option or has not been curative."

Pasireotide, which will be marketed as Signifor by Novartis Pharmaceuticals, is administered subcutaneously twice a day. "Although surgery tends to be first-line therapy to treat Cushing’s disease, Signifor is a new treatment option for patients when surgery hasn’t worked or isn’t an option," Dr. Mary Parks, director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement announcing approval on Dec. 14.

t has been approved with a Medication Guide, which will be provided to patients with each filled prescription, describing the risks and adverse reactions associated with treatment, according to the statement.

In the study that was the basis of the approval, treatment was associated with hyperglycemia, detected as early as 2 weeks after patients started the drug, and resulted in exacerbations of diabetes with continued treatment in some patients. Hence, "patients need to be carefully monitored for this side effect and be treated appropriately with anti-diabetic therapies, including insulin," the FDA statement said. The recommended dosage is 600 mcg or 900 mcg twice a day, with a recommended dosage range of 300-900 mcg twice a day.

Approval was based on a phase III study of 162 people with Cushing’s disease, with mean urinary cortisol levels at least 1.5 times the upper limit of normal (ULN), who received one of two doses of pasireotide. At 6 months, 15% of the patients treated with 600 mcg twice a day and 26% of those treated with 900 mcg twice a day met the primary endpoint of a urinary free cortisol level at or below the ULN. Treatment was also associated with improvement in the clinical signs and symptoms of Cushing’s disease (N. Engl. J. Med. 2012;366:914-24).

The most common adverse events associated with the treatment reported in at least 20% of patients were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes; 25% of patients had a serious adverse event, and 17% of the patients in the study discontinued treatment because of an adverse event, according to the prescribing information.

In November, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously supported approval of pasireotide, based on the results of the study, although the committee members were concerned about the marked hyperglycemia and abnormal liver enzymes reported in some patients.

Reflecting the panel’s recommendations to further study the long-term adverse effects of hyperglycemia and diabetes associated with the drug after approval, the FDA is requiring the company to conduct three postmarketing studies: a study that evaluates the management of hyperglycemia in treated patients; a long-term registry study of people with Cushing’s disease treated with the drug; and a safety study that will monitor reports of serious hyperglycemia, acute liver injury, and adrenal insufficiency in treated patients.

The prescribing information includes the recommendation to monitor liver tests after 1-2 weeks of treatment, followed by once a month for 3 months and then every 6 months; and dosing recommendations for patients with hepatic impairment.

Pasireotide binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. Lanreotide and octreotide are the two somatostatin analogues that have been previously approved; they are approved for acromegaly, and bind primarily to somatostatin receptor 2. Pasireotide was studied in Cushing’s disease because of its broader binding profile, according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels.

The prescribing information for pasireotide is available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf. Serious adverse events associated with the drug should be reported to the FDA’s MedWatch program at 800-332-1088 or here.

Pasireotide, a somatostatin analogue, has been approved by the Food and Drug Administration as a treatment for Cushing’s disease in adults "for whom pituitary surgery is not an option or has not been curative."

Pasireotide, which will be marketed as Signifor by Novartis Pharmaceuticals, is administered subcutaneously twice a day. "Although surgery tends to be first-line therapy to treat Cushing’s disease, Signifor is a new treatment option for patients when surgery hasn’t worked or isn’t an option," Dr. Mary Parks, director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement announcing approval on Dec. 14.

t has been approved with a Medication Guide, which will be provided to patients with each filled prescription, describing the risks and adverse reactions associated with treatment, according to the statement.

In the study that was the basis of the approval, treatment was associated with hyperglycemia, detected as early as 2 weeks after patients started the drug, and resulted in exacerbations of diabetes with continued treatment in some patients. Hence, "patients need to be carefully monitored for this side effect and be treated appropriately with anti-diabetic therapies, including insulin," the FDA statement said. The recommended dosage is 600 mcg or 900 mcg twice a day, with a recommended dosage range of 300-900 mcg twice a day.

Approval was based on a phase III study of 162 people with Cushing’s disease, with mean urinary cortisol levels at least 1.5 times the upper limit of normal (ULN), who received one of two doses of pasireotide. At 6 months, 15% of the patients treated with 600 mcg twice a day and 26% of those treated with 900 mcg twice a day met the primary endpoint of a urinary free cortisol level at or below the ULN. Treatment was also associated with improvement in the clinical signs and symptoms of Cushing’s disease (N. Engl. J. Med. 2012;366:914-24).

The most common adverse events associated with the treatment reported in at least 20% of patients were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes; 25% of patients had a serious adverse event, and 17% of the patients in the study discontinued treatment because of an adverse event, according to the prescribing information.

In November, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously supported approval of pasireotide, based on the results of the study, although the committee members were concerned about the marked hyperglycemia and abnormal liver enzymes reported in some patients.

Reflecting the panel’s recommendations to further study the long-term adverse effects of hyperglycemia and diabetes associated with the drug after approval, the FDA is requiring the company to conduct three postmarketing studies: a study that evaluates the management of hyperglycemia in treated patients; a long-term registry study of people with Cushing’s disease treated with the drug; and a safety study that will monitor reports of serious hyperglycemia, acute liver injury, and adrenal insufficiency in treated patients.

The prescribing information includes the recommendation to monitor liver tests after 1-2 weeks of treatment, followed by once a month for 3 months and then every 6 months; and dosing recommendations for patients with hepatic impairment.

Pasireotide binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. Lanreotide and octreotide are the two somatostatin analogues that have been previously approved; they are approved for acromegaly, and bind primarily to somatostatin receptor 2. Pasireotide was studied in Cushing’s disease because of its broader binding profile, according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels.

The prescribing information for pasireotide is available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf. Serious adverse events associated with the drug should be reported to the FDA’s MedWatch program at 800-332-1088 or here.

Pasireotide, a somatostatin analogue, has been approved by the Food and Drug Administration as a treatment for Cushing’s disease in adults "for whom pituitary surgery is not an option or has not been curative."

Pasireotide, which will be marketed as Signifor by Novartis Pharmaceuticals, is administered subcutaneously twice a day. "Although surgery tends to be first-line therapy to treat Cushing’s disease, Signifor is a new treatment option for patients when surgery hasn’t worked or isn’t an option," Dr. Mary Parks, director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said in the FDA statement announcing approval on Dec. 14.

t has been approved with a Medication Guide, which will be provided to patients with each filled prescription, describing the risks and adverse reactions associated with treatment, according to the statement.

In the study that was the basis of the approval, treatment was associated with hyperglycemia, detected as early as 2 weeks after patients started the drug, and resulted in exacerbations of diabetes with continued treatment in some patients. Hence, "patients need to be carefully monitored for this side effect and be treated appropriately with anti-diabetic therapies, including insulin," the FDA statement said. The recommended dosage is 600 mcg or 900 mcg twice a day, with a recommended dosage range of 300-900 mcg twice a day.

Approval was based on a phase III study of 162 people with Cushing’s disease, with mean urinary cortisol levels at least 1.5 times the upper limit of normal (ULN), who received one of two doses of pasireotide. At 6 months, 15% of the patients treated with 600 mcg twice a day and 26% of those treated with 900 mcg twice a day met the primary endpoint of a urinary free cortisol level at or below the ULN. Treatment was also associated with improvement in the clinical signs and symptoms of Cushing’s disease (N. Engl. J. Med. 2012;366:914-24).

The most common adverse events associated with the treatment reported in at least 20% of patients were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes; 25% of patients had a serious adverse event, and 17% of the patients in the study discontinued treatment because of an adverse event, according to the prescribing information.

In November, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously supported approval of pasireotide, based on the results of the study, although the committee members were concerned about the marked hyperglycemia and abnormal liver enzymes reported in some patients.

Reflecting the panel’s recommendations to further study the long-term adverse effects of hyperglycemia and diabetes associated with the drug after approval, the FDA is requiring the company to conduct three postmarketing studies: a study that evaluates the management of hyperglycemia in treated patients; a long-term registry study of people with Cushing’s disease treated with the drug; and a safety study that will monitor reports of serious hyperglycemia, acute liver injury, and adrenal insufficiency in treated patients.

The prescribing information includes the recommendation to monitor liver tests after 1-2 weeks of treatment, followed by once a month for 3 months and then every 6 months; and dosing recommendations for patients with hepatic impairment.

Pasireotide binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. Lanreotide and octreotide are the two somatostatin analogues that have been previously approved; they are approved for acromegaly, and bind primarily to somatostatin receptor 2. Pasireotide was studied in Cushing’s disease because of its broader binding profile, according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels.

The prescribing information for pasireotide is available at www.accessdata.fda.gov/drugsatfda_docs/label/2012/200677lbl.pdf. Serious adverse events associated with the drug should be reported to the FDA’s MedWatch program at 800-332-1088 or here.