Pharmacy and Therapeutics - January 2008 - (Page 55) Pharmaceutical Approval Update not be taken with food. The capsules should be swallowed whole with water. Patients should be advised to take nilotinib on an empty stomach. Nilotinib should be taken at least two hours after a meal. No food should be consumed for at least one hour after the dose is taken. Patients should not consume grapefruit products and other foods known to inhibit CYP 3A4 at any time during nilotinib treatment. Commentar y: The effectiveness of nilotinib is based on hematological and cytogenetic (chromosome-related) response rates. So far, no controlled trials have shown a clinical benefit, such as improvement in disease-related symptoms or increased survival. Efficacy was demonstrated in one nonrandomized, multicenter study. Nilotinib improved outcomes in all three forms of CML, and it was most effective in treating chronic-phase CML. Of the 12 patients in this category, 11 experienced a complete hematological remission of cancer (i.e., a disappearance of all findings consistent with advanced-stage CML) and a return of their blood counts to normal. Thirteen of 33 patients with blastic-phase CML (the most advanced stage) had a hematological response (control of white blood cell counts), and nine patients had a cytogenetic response (elimination of cells with the cancer-causing defect). Of 46 patients with accelerated-phase CML, 33 had a hematological response and 22 had a cytogenetic response. Nilotonib showed less activity than expected in patients with acute lymphocytic leukemia (ALL). Nilotinib’s side effects were tolerable and differed from those observed with imatinib. Occasionally, patients experienced abnormally long QTcF intervals (i.e., a corrected QT interval using Fridericia’s formula). A prolonged QT interval is considered a marker of a cardiac arrhythmia. These findings indicate the need for careful monitoring for cardiac events and arrhythmias in all patients receiving nilotinib as well as a strict avoidance of medications that may prolong the QTcF interval. Sources: www.pharma.us.novartis.com; www.cancer.gov; www.medicalnewstoday Warnings and Precautions: Immune Reconstitution Syndrome: During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, Mycobacterium tuberculosis, or reactivation of varicella zoster virus). Such complications may necessitate further evaluation and treatment. Caution should be used when raltegravir is administered with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) because of reduced raltegravir plasma concentrations. Effect on Other Agents: In vitro, raltegravir does not inhibit CYP 1A2, CYP 2B6, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, or CYP 3A, and it does not induce CYP 3A4. A drug-interaction study of midazolam (Versed, Roche) confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP 3A4 in vivo by demonstrating a lack of effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP 3A4 substrate. Similarly, raltegravir does not inhibit the UDP-glucuronosyltransferases (UGTs) tested (UGT 1A1, UGT 2B7) or P-glycoprotein–mediated transport. Based on these data, raltegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein, such as protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), methadone, opioid analgesics, statins, azole antifungals, proton pump inhibitors, oral contraceptives, or drugs for erectile dysfunction. In drug-interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of lamivudine (Epivir, GlaxoSmithKline) or tenofovir (Viread, Gilead). Effect of Other Agents on Raltegravir: Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. In in vivo and in vitro studies, raltegravir was eliminated mainly by metabolism via a UGT 1A1–mediated glucuronidation pathway. Rifampin, a strong inducer of UGT 1A1, reduces plasma concentrations of raltegravir. Therefore, health care professionals should use caution when coadministering raltegravir with rifampin or other strong inducers of UGT 1A1. The impact of other inducers of drug-metabolizing enzymes, such as phenytoin (Dilantin, Pfizer) and phenobarbital, on UGT 1A1 is unknown. Other weaker inducers—efavirenz (Sustiva, BristolMyers Squibb), nevirapine (Viramune, Roxane/Boehringer Ingelheim), rifabutin (Mycobutin, Pharmacia & Upjohn/ Pfizer), and St. John’s wort—may be used with the recommended dose of raltegravir. Similar to rifampin, tipranavir (Aptivus, Boehringer Ingelheim) combined with ritonavir (Nor vir, Abbott) reduces plasma concentrations of raltegravir. Tipranavir/ritonavir may be coadministered with raltegravir without a dose adjustment of raltegravir. Atazanavir (Reyataz, Bristol-Myers Squibb), a strong inhibitor of UGT 1A1, and the combination of atazanavir/ritonavir increase plasma concentrations of raltegravir. Atazanavir/ ritonavir may be coadministered with raltegravir without a dose adjustment of raltegravir. Coadministration of raltegravir with other drugs that inhibit UGT1 A1 may increase plasma lev- Raltegravir (Isentress) Manufacturer: Merck & Co., White House Station, N.J. Indication: In combination with other antiretroviral agents, raltegravir is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in treatment-experienced adults with evidence of viral replication and with HIV-1 strains that are resistant to multiple antiretroviral agents. Drug Class: Raltegravir is an integrase inhibitor. Integrase is one of three viral enzymes necessary for HIV replication. Integrase blends HIV genetic material into the DNA of human CD4 cells. This integration of DNA makes it possible for the infected cell to make new copies of HIV. By interfering with integrase, the drug prevents HIV genetic material from integrating into the CD4 cell and thus stops HIV replication. Uniqueness of Drug: Integrase inhibitors are a new drug class that targets a new step in the life cycle of the virus. Because of this capability, even the most drug-experienced HIV patient should benefit. Integrase inhibitors target HIV in a way that differs from existing HIV medications. For patients with an extensive HIV medication history or HIV resistance, integrase inhibitors offer a new option. Vol. 33 No. 1 • January 2008 • P&T® 55 http://www.cancer.gov http://www.pharma.us.novartis.com http://www.medicalnewstoday.com
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