Methadone Zidovudine

With the introduction of RiF in 1967, the duration of combination therapy for the treatment of TB was significantiy reduced (from 18 to 9 months). Rifampin is nearly always used in combination with one or more other antitubercuiin agents. The drug is potentially hepatotoxic and may produce Gl disturbances, rash, and thrombocytopenic purpura. Rifampin is known to induce hepatic microsomai enzymes (cytochrome P450) and may decrease the effectiveness of oral contraceptives, corticosteroids, warfarin, quinidine, methadone, zidovudine, clarithromycin, and the azoie antifungai agents (see Chapter 10) (33). 

Drugs that may affect nelfinavir include anticonvulsants, azithromycin, azole antifungals, efavirenz, delavirdine, HMG-CoA reductase inhibitors, indinavir, interleukins, nevirapine, rifabutin, rifampin, ritonavir, saquinavir, St. John s wort. Drugs that may be affected by nelfinavir include amiodarone, antiarrhythmics (amiodarone, quinidine), azithromycin, benzodiazepines, efavirenz, ergot alkaloids, delavirdine, didanosine, fentanyl, indinavir, lamivudine methadone, nonsedating antihistamines, oral contraceptives, phenytoin, pimozide, quinidine, rifabutin, saquinavir, sildenafil, sirolimus, tacrolimus, zidovudine. 

Drugs that might affect amprenavir include abacavir, aldesleukin, antacids, anticonvulsants, azole antifungals, clarithromycin, cyclosporine, dexamethasone, buffered didanosine, disulfiram, ethanol, indinavir, methadone, metronidazole, nelfinavir, nonnucleoside reverse transcriptase inhibitors, oral contraceptives, rifamycins, ritonavir, saquinavir, St. John s wort, tacrolimus, and zidovudine. 

Drugs that might be affected by amprenavir include antiarrhythmics, anticonvulsants, azole antifungals, benzodiazepines, calcium channel blockers, cisapride, clarithromycin, cyclosporine, ergot alkaloids, fentanyl, HMG-CoA reductase inhibitors, indinavir, methadone, nelfinavir, oral contraceptives, pimozide, rifabutin, ritonavir, saquinavir, sildenafil, tacrolimus, trazodone, tricyclic antidepressants, warfarin, and zidovudine. 

Drugs that may interact with stavudine include didanosine, doxorubicin, hydroxyurea, methadone, ribavirin, and zidovudine. 

Drugs that may affect zidovudine include acetaminophen, atovaquone, bone marrow suppressive/cytotoxic agents (eg, adriamycin, dapsone), clarithromycin, doxorubicin, fluconazole, ganciclovir, methadone, nelfinavir/ritonavir, phenytoin, probenecid, ribavirin, rifamycins, stavudine, trimethoprim, and valproic acid. 

Drugs that may be affected by nevirapine include rifamycins, clarithromycin, oral contraceptives, efavirenz, ketoconazole, methadone, protease inhibitors, warfarin, zidovudine. 

Drugs that may be affected by peginterferon alfa-2a include theophylline, methadone, and NRTIs (eg, didanosine, zidovudine, stavudine). 

Contraindications to interferon alfa therapy include hepatic decompensation, autoimmune disease, and history of cardiac arrhythmia. Caution is advised in the setting of psychiatric disease, epilepsy, thyroid disease, ischemic cardiac disease, severe renal insufficiency, and cytopenia. Alfa interferons are abortifacient in primates and should not be administered in pregnancy. Potential drug-drug interactions include increased theophylline levels and increased methadone levels. Co-administration with didanosine is not recommended because of a risk of hepatic failure, and co-administration with zidovudine may exacerbate cytopenias. 

Besides being affected by medications and substances that affect the liver s metabolism, methadone itself affects the liver s metabolism of certain substances. A significant number of people who are taking methadone for heroin addiction also are HIV positive and are taking anti-HIV medications such as Desipramine (DMI) and zidovudine (AZT). Through its actions on the liver, methadone decreases the metabolism of these medications. Because of this, certain troublesome side effects of DMI and AZT, including nausea,... 

Trapnell CB, Klecker RW, Jamis-Dow C, et al. Glucuronidation of 3 -azido-3 -deoxythymidine (zidovudine) by human liver microsomes relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and val-proic acid. Antimicrob Agents Chemother 1998 42 1592-1596. 

McCance-Katz EF, Rainey PM, Jatlow P, Friedland G. Methadone effects on zidovudine disposition (AIDS Clinical Trials Group 262). J Acquir Immune Defic Syndr Hum Retrovirol 1998 18(5) 435 13. 

A 35-year old Caucasian man with AIDS and multiple opportunistic infections, including Mycobacterium kansasii and Mycobacterium avium complex (MAC) disease developed moderate to severe primary sensorineural hearing loss after 4—5 months of therapy with oral azithromycin 500 mg/day. Other medications included ethambutol, isoniazid, rifabutin, ciprofloxacin, co-trimoxazole, fluconazole, zidovudine (later switched to stavudine), lamivudine, indinavir, methadone, mod-ified-release oral morphine, pseudoephedrine, diphenhydramine, megestrol acetate, trazodone, sorbitol, salbutamol by metered-dose inhaler and nebulizer, ipratropium, and oral morphine solution as needed. Significant improvement of the hearing impairment was documented 3 weeks after drug withdrawal. 

Zidovudine glucuronidation in human hepatic micro-somes in vitro was inhibited more by the combination of fluconazole with valproic acid than with other drngs, snch as atovaquone and methadone (117). 

Clinically important, potentially hazardous interactions with abacavir, atorvastatin, bepridil, bupropion, carbamazepine, clarithromycin, cyclosporine, dexamethasone, digoxin, felodipine, fluticasone propionate, fosamprenavir, itraconazole, ketoconazole, lovastatin, methadone, midazolam, nicardipine, nifedipine, phenobarbital, phenytoin, rifabutin, simvastatin, sirolimus, St John s wort, systemic lidocaine, tacrolimus, tenofovir, trazodone, vinblastine, vincristine, voriconazole, warfarin, zidovudine... 

Noninterfering acetaminophen, amphotericin B, brotizolam, ceftazidime, ciprofloxacin, codeine, diclofenac, didanosine, domperidone, fluoxetine, foscarnet, gangiclovir, methadone, metoclopramide, mianserin, nystatin, pyrimethamine, ranitidine, sulfamethoxazole, temazepam, trimethoprim, zidovudine... 

Zidovudine (AZT) is an HIV reverse transcriptase inhibitor and chain terminator that is extensively glucuronidated (70% of the dose) primarily by UGT2B7. Metabolism of AZT is induced by rifampin (PXR), ritonavir, tipranavir, and efavirenz. Zidovudine clearance is inhibited by methadone (McCance-Katz, 1998) (opiates like codeine and morphine are UGT2B7 substrates), fluconazole Trapnell, 1998, atovaquone (Lee, 1996), and valproate (Lertora, 1994). Rifampin increased the formation clearance to AZT-glucuronide by twofold (Gallicano, 1999). 

Zidovudine had no effect on methadone levels in one study, but there is one report of a patient requiring a modest increase in methadone dose after starting zidovudine. Similarly case reports describe patients requiring a modest increase in methadone dose after starting abacavir. Methadone can increase zidovudine serum levels, and reduce levels of abacavir, stavudine, and didano-sine from the tablet formulation, but not the enteric-coated capsule preparation. Tenofovir, and a single dose of zidovu-dine/lamivudine had no effect on methadone pharmacokinetics. 

Methadone effects reduced or unaffected. A drug abuser with AIDS needed an increase in his levomethadone (7 -methadone) dosage from 40 to 60 mg daily, within a month of starting to take zidovudine 1 g daily. ... 

In contrast, a study found no evidence of any change in the pharmacokinetics of methadone in HIV-positive patients taking methadone 14 days after they started zidovudine 200 mg every 4 hours. No methadone withdrawal symptoms occurred. Another study in 16 patients taking methadone found that a single-dose of a fixed combination of zidovudine 300 mg with lamivudine 150 mg (Combivir) had no effect on the pharmacokinetics of methadone, and there was no evidence of withdrawal or toxicity. ... 

Zidovudine effects increased. In one study the mean AUC of zidovudine was increased by 43% by methadone, and in 4 of 9 patients it was doubled. In another study, 8 HIV-positive patients starting methadone found a 29% increase in the AUC of oral zidovudine and a 41% increase in the AUC of intravenous zidovudine. Three of the 8 patients stopped zidovudine because of adverse effects or haematologic toxicity." Decreased zidovudine clearance in patients taking methadone is described in another report. ... 

Uncertain. It appears that methadone reduces the bioavailability of dida-nosine, and to a lesser extent, stavudine, possibly because it delays gastric emptying. Thus, the enteric-coated didanosine preparation appears not to be affected. Conversely, methadone apparently reduces the glucuroni-dation of the zidovudine by the liver, resulting in an increase in its serum levels. Methadone may also reduce renal clearance of zidovudine."... 

The increase in zidovudine levels with methadone is established, although the clinical relevance is uncertain. Be alert for any increase in zidovudine adverse effects. The balance of evidence suggests that zidovudine is unlikely to reduce methadone levels, and the one case reported remains unexplained, although note that some of the adverse effects of zidovudine may be mistaken for opioid withdrawal effects. 

A patient taking lamivudine and zidovudine had a marked decrease in methadone serum levels when ritonavir was added." Another patient receiving methadone experienced an opioid withdrawal syndrome when ritonavir was added to a similar antiretroviral regimen. ... 

An HIV-positive patient taking methadone 90 mg daily with indinavir, lamivudine and zidovudine, developed withdravral symptoms and was hospitalised within a week of stopping these HIV drugs and starting ritonavir 400 mg, saquinavir 400 mg and stavudine 40 mg twice daily. The patient was eventually re-stabilised taking methadone 130 mg daily. ... 

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