Pharmacy and Therapeutics - January 2008 - (Page 56) Pharmaceutical Approval Update els of raltegravir. Dosage and Administration: For patients with HIV-1 infection, raltegravir 400 mg is administered orally, twice daily with or without food. Commentar y: Raltegravir is the first agent of an HIV drug class called integrase inhibitors. It blocks the insertion of HIV’s genetic material into human DNA, preventing the virus from replicating. Raltegravir is active against HIV that is resistant to other previously approved drug classes for this infection. Raltegravir is indicated, along with other antiretroviral drugs, for patients who have not responded to therapy. According to the available safety data, the benefits of raltegravir in HIV-1 treatment-experienced subjects outweigh the currently identified risks. However, potential risks include liver damage and cancer. In clinical studies, a higher number of cancers was noted among treated patients than those taking a placebo, but the increase might have been a result of a low rate of cancer in the placebo patients. Source: www.merck.com tions, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Patients experiencing new or worsening symptoms may require a reduced dose of ixabepilone or a delay in the dose. In clinical studies, peripheral neuropathy was managed through dose reductions, dose delays, and discontinuation of treatment. Neuropathy was the most frequent cause of treatment cessation resulting from drug toxicity. A pooled analysis of 945 cancer patients treated with ixabepilone indicated that patients with diabetes mellitus might be at an increased risk of severe neuropathy. The presence of grade 1 neuropathy and prior therapy with neurotoxic chemotherapy agents did not predict either the development or worsening of neuropathy. Patients with moderate-to-severe neuropathy (grade 2 or greater) were excluded from studies with ixabepilone. Caution should be used in patients with diabetes who have moderate-to-severe neuropathy. Myelosuppression: Myelosuppression is dose-dependent and is manifested primarily as neutropenia. In clinical studies, grade 4 neutropenia (fewer than 500 cells/mm3) occurred in 36% of patients receiving ixabepilone/capecitabine and in 23% of patients receiving ixabepilone alone. Neutropenia-related deaths occurred in 1.9% of 414 patients with normal hepatic function or with mild hepatic impairment who received the combination. Neutropenia-related deaths occurred in 0.4% of 240 patients treated with ixabepilone alone. To monitor for myelosuppression, the company recommends frequent peripheral blood cell counts for all patients receiving ixabepilone. For patients who experience severe neutropenia or thrombocytopenia, the dose should be reduced. Hypersensitivity Reactions: Patients with a history of a sever e hypersensitivity reaction to agents containing polyoxyethylated castor oil (Cremophor EL, BASF) or its derivatives should not use ixabepilone. All patients should receive premedication with a histamine H1 and an H2 antagonist approximately one hour before the ixabepilone infusion, and they should be observed for hypersensitivity reactions (flushing, rash, dyspnea, bronchospasm). For patients with severe hypersensitivity reactions, the ixabepilone infusion should be stopped and aggressive supportive treatment with epinephrine or corticosteroids should be started. Patients who experience a hypersensitivity reaction after one cycle of ixabepilone must receive premedication in subsequent cycles with a corticosteroid, in addition to the H1 and H2 antagonists, and an extension of the infusion time should be considered. Dosage and Administration: The recommended dose of ixabepilone is 40 mg/m2, administered intravenously over three hours every three weeks. Doses for patients with a body surface area greater than 2.2 m2 should be calculated based on 2.2 m2. Dose Adjustments during Treatment: During treatment, patients should undergo periodic clinical observation and laboratory tests, including complete blood cell counts. If toxicities are present, treatment should be delayed to allow recovery. Dosing-adjustment guidelines for monotherapy and combination therapy are available in the package insert. If toxicities recur, the dose should be reduced by an additional 20%. Ixabepilone (Ixempra) Manufacturer: Bristol-Myers Squibb, Princeton, N.J. Indication: Ixabepilone is indicated in combination with capecitabine (Xeloda, Roche) for patients with metastatic or locally advanced breast cancer that is resistant to treatment with an anthracycline plus a taxane or whose cancer is taxane-resistant and for whom further anthracycline therapy is contraindicated. As monotherapy, ixabepilone is indicated for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. Drug Class: Ixabepilone is a microtubule inhibitor belonging to a class of antineoplastic agents, the epothilones and their analogues. The epothilones are isolated from the mycobacterium Sorangium cellulosum. As a semisynthetic analogue of epothilone B, ixabepilone a 16-member polypetide macrolide, with a chemically modified lactam substitution for the naturally existing lactone. Uniqueness of Product: Ixabepilone binds directly to beta-tubulin subunits on microtubules, leading to suppression of microtubule dynamics. Ixabepilone suppresses the dynamic instability of αβ-II and αβ-III microtubules. Ixabepilone possesses low in vitro susceptibility to multiple tumor resistance mechanisms, including efflux transporters, such as motilityrelated protein-1 (MRP-1) and P-glycoprotein (P-gp). Ixabepilone blocks cells in the mitotic phase of the cell division cycle, leading to cell death. Boxed Warning: Toxicity in Hepatic Impairment: Ixabepilone in combination with capecitabine is contraindicated in patients with elevations in AST or ALT above 2.5 times the ULN or bilirubin above 1 times the ULN because of an increased risk of toxicity and neutropenia-related death. Warnings and Precautions: Neuropathy: In trials, peripheral neuropathy was common and occurred early during treatment; approximately 75% of new-onset or worsening neuropathy occurred during the first three cycles. Patients treated with ixabepilone should be monitored for symptoms of neuropathy, such as burning sensa- 56 P&T® • January 2008 • Vol. 33 No. 1 http://www.merck.com
For optimal viewing of this digital publication, please enable JavaScript and then refresh the page. If you would like to try to load the digital publication without using Flash Player detection, please click here.