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Pharmaceutical Approval Update June 2011

Marvin M. Goldenberg PhD, RPh, MS

Abiraterone Acetate Tablets (Zytiga)

Manufacturer: Centocor Ortho Biotech Inc., Horsham, Pa./Patheon, Inc., Toronto, Canada

Indication: Abiraterone acetate, a cytochrome P450 (CYP) 17 inhibitor, is indicated in combination with prednisone for men with advanced castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel (Taxotere, Sanofi-aventis).

Biological Class: Abiraterone is an inhibitor of CYP 17 (17α-hydroxylase/C17,20-lyase). Each tablet contains 250 mg of abiraterone acetate, chemically designated as (3β17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate.

Uniqueness of Biological Agent: Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor that in turn blocks CYP 17. This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis. CYP 17 catalyzes two sequential reactions: (1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and (2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17,20-lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP 17 by abiraterone can also increase mineralocorticoid production by the adrenal glands. Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels.

Warnings and Precautions:

Adverse reactions caused by mineralocorticoid excess. Abiraterone should be used with caution in patients with cardiovascular disease. The drug may cause hypertension, hypokalemia, and fluid retention because of increased mineralocorticoid levels resulting from the inhibition of CYP 17. Coadministration of a corticosteroid suppresses adrenocorticotropic hormone, resulting in fewer, less severe adverse reactions.

Adrenocortical insufficiency. Adrenocortical insufficiency has been reported when abiraterone was given with prednisone following interruption of daily steroid therapy or when a concurrent infection or stress was present. Monitoring for symptoms and signs of adrenocortical insufficiency is recommended, particularly if patients have stopped using prednisone, if their prednisone dose has been reduced, or if they have been experiencing unusual stress.

Hepatotoxicity. Marked elevations in liver enzymes (ALT, AST, and bilirubin) have occurred, leading to drug discontinuation or dosage modifications.

Food effects. Abiraterone must be taken on an empty stomach. No food should be eaten for at least two hours before and for at least one hour after abiraterone is taken. The peak concentration (Cmax) and area-under-the time curve (AUC0-∞) concentration of abiraterone were increased upward to 17-fold and 10-fold higher, respectively, when a single dose of abiraterone was taken with a meal, compared with the fasted state.

Dosage and Administration: The recommended dose of abiraterone acetate is 1,000 mg orally once daily on an empty stomach along with oral prednisone 5 mg twice daily. No food should be consumed for at least two hours before and for at least one hour after the dose is taken. In patients with moderate hepatic impairment (Child–Pugh Class B) at baseline, the recommended dose of abiraterone should be reduced to 250 mg once daily. If hepatotoxicity occurs during abiraterone acetate therapy, treatment should be interrupted. Therapy may be restarted with a reduced dose of 750 mg once daily following the return of liver function test results to baseline values. When patients resume treatment, serum transaminases (ALT, AST) and bilirubin levels should be monitored at a minimum of every two weeks for three months and monthly thereafter.

Commentary: In patients with prostate cancer, the male sex hormone testosterone stimulates prostate tumors to grow. Surgery or medication is used to reduce testosterone production or to block the hormone’s effects. However, prostate cancer sometimes continues to grow even when testosterone levels are low. Abiraterone was approved to treat men with these castration-resistant cancers.

The company’s New Drug Application was evaluated under the FDA’s priority review program, and the drug was approved ahead of the scheduled date of June 20, 2011. The approval was based on results from a phase 3, randomized, placebo-controlled study showing that abiraterone plus prednisone resulted in a 35% reduction in the risk of death (14.8 months vs. 10.9 months, respectively) and a 3.9-month difference in median survival compared with placebo plus prednisone.

The drug is expected to cost about $5,000 per month, with a typical course of therapy taking about eight months.

Source: www.accessdata.fda.gov/drugsatfda_docs/label/2011/202379lbl.pdf

Linagliptin (Tradjenta)

Manufacturer: Boehringer Ingelheim, Ridgefield, Conn./Eli Lilly, Indianapolis, Ind.

Indication: Linagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus.

Drug Class: Linagliptin is an orally active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. The chemical name is 1H-purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]. The chemical formula is C25H26N8O2, and the molecular weight is 472.54 g/mol.

Uniqueness of Drug: DPP-4 is an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Linagliptin thus increases active incretin hormone levels, stimulating the release of insulin in a glucose-dependent manner and decreasing circulating glucagon levels. Both incretin hormones are involved in the physiological regulation of glucose homeostasis.

Incretin hormones are secreted at a low basal concentration throughout the day, and levels rise immediately after a meal. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose concentrations. GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in decreased hepatic glucose output.

Warnings and Precautions:

Using linagliptin with drugs causing hypoglycemia. Insulin secretagogues are known to cause hypoglycemia. In a clinical trial, linagliptin in combination with an insulin secretagogue (e.g., a sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo. Therefore, a lower dose of the insulin secretagogue, when used with linagliptin, may be required to reduce the risk of hypoglycemia.

Macrovascular outcomes. No clinical studies have established evidence of macrovascular risk reduction with linagliptin tablets or with any other antidiabetic drug.

Dosage and Administration: The recommended dose is 5 mg once daily. The tablets can be taken with or without food. When linagliptin is used with an insulin secretagogue (e.g., a sulfonylurea), a lower dose of the insulin secretagogue may be needed to decrease the risk of hypoglycemia.

Commentary: Linagliptin can be used along with diet and exercise to lower blood glucose levels in adults with type-2 diabetes. The medication lowers blood glucose levels by increasing incretin concentrations, which increase insulin values after meals and throughout the day. Linagliptin has been studied as a stand-alone therapy and in combination with other type-2 diabetes therapies, including metformin (Glucophage, Bristol-Myers Squibb), glimepiride (Amaryl, Sanofi-aventis), and pioglitazone (Actos, Takeda/Eli Lilly). It has not been studied in combination with insulin, and it should not be used to treat patients with type-1 diabetes or diabetic ketoacidosis.

Sources: www.fda.gov; www.tradjenta.com

Peginterferon alfa-2b (Sylatron)

Manufacturer: Schering Corp., Kenilworth, N.J.

Indication: Peginterferon alfa-2b, an alpha interferon, is indicated for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy.

Drug Class: Peginterferon alfa-2b is a covalent conjugate of recombinant alfa-2b interferon with monomethoxy polyethylene glycol (PEG). The average molecular weight of the peginterferon alfa-2b molecule is approximately 31,000 daltons. Interferon alfa-2b is a protein obtained from the bacterial fermentation of a strain of Escherichia coli bearing a genetically engineered plasmid containing an interferon gene from human leukocytes.

Uniqueness of Drug: Peginterferon alfa-2b is a pleiotropic cytokine. The mechanism by which it exerts its effects in patients with melanoma is unknown.

Boxed Warning: This product, as well as other interferon alfa products, increases the risk of neuropsychiatric disorders, including severe depression and suicidality.

Warnings and Precautions:

Depression and other neuropsychiatric adverse reactions. Peginterferon alfa-2b can cause life-threatening or fatal neuropsychiatric reactions, such as suicide, suicidal and homicidal ideation, depression, and an increased risk of relapse in recovering drug addicts. According to postmarketing reports with peginterferon alfa-2b and interferon alfa-2b, treatment may also result in aggressive behavior, psychoses, hallucinations, bipolar disorders, mania, and encephalopathy. If severe or worsening psychiatric symptoms or behaviors persist, peginterferon alfa-2b should be permanently discontinued and patients should be referred for psychiatric evaluation.

Cardiovascular reactions. In a clinical trial, adverse cardiac reactions, including myocardial infarction, bundle-branch block, ventricular tachycardia, and supraventricular arrhythmias, occurred in 4% of patients receiving peginterferon alfa-2b and in 2% of controls.

Retinopathy and other ocular reactions. Decreased visual acuity or blindness resulting from retinopathy can be associated with peginterferon alfa-2b. Ocular changes (macular edema, retinal artery or vein thrombosis, retinal hemorrhages, cotton-wool spots, optic neuritis, papilledema, and serous retinal detachment) may be induced or worsened by peginterferon alfa-2b or other alpha interferons. If new or worsening retinopathy develops, peginterferon alfa-2b should be discontinued.

Hepatic failure. Peginterferon alfa-2b is associated with an increased risk of hepatic decompensation and death in patients with cirrhosis. The medication should be discontinued if severe (grade 3) hepatic injury or hepatic decompensation—a Child–Pugh score above 6 (class B or C)—is present.

Endocrinopathies. Peginterferon alfa-2b can cause new-onset or worsening of hypothyroidism, hyperthyroidism, and diabetes mellitus. The drug should be permanently discontinued if these conditions develop and if they cannot be effectively managed.

Dosage and Administration: The recommended dose is 6 mcg/kg per week subcutaneously for eight doses, followed by 3 mcg/kg per week subcutaneously, for up to five years. Patients should receive premedication with acetaminophen 500 to 1,000 mg orally 30 minutes before the first dose of peginterferon alfa-2b and as needed for subsequent doses.

Contraindications: Peginterferon alfa-2b is not indicated for patients with a history of anaphylaxis to this drug or to interferon alfa-2b, those with autoimmune hepatitis, and those with hepatic decompensation.

Commentary: Peginterferon alfa-2b is a once-weekly subcutaneous injection that patients may self-inject to treat melanoma. Therapy must begin within 84 days after definitive surgical resection, including complete lymphadenectomy. This is the first approved therapy for the adjuvant treatment of melanoma by the FDA in more than 15 years. The approval was based on data from the European Organization for the Research and Treatment of Cancer (EORTC) clinical trial.

Source: www.accessdata.fda.gov/drugsatfda_docs/label/2011/103949s5153lbl.pdf