Ritonavir toxicity

Therapies not recommended for initial treatment due to poor potency or significant toxicity include delavirdine, nevirapine in patients with moderate to high CD4+ T-cell counts, indinavir or saquinavir used without ritonavir ( unboosted ), ritonavir used without another protease inhibitor, and tenofovir plus didanosine with an NNRTI. 

Dose adjustment for combination therapy with saquinavir For serious toxicities that may be associated with saquinavir mesylate, the drug should be interrupted. Saquinavir mesylate at doses less than 1,000 mg with ritonavir 100 mg twice daily are not recommended since lower doses have not shown antiviral activity. For recipients of combination therapy with saquinavir mesylate and ritonavir, dose adjustments may be necessary. These adjustments should be based on the known toxicity profile of the individual agent and the pharmacokinetic interaction between saquinavir and the coadministered drug. Health care providers should refer the complete monographs for these drugs for comprehensive dose adjustment recommendations and drug-associated adverse reactions of nucleoside analogues. 

Hepatic toxicity Tipranavir coadministered with ritonavir 200 mg has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. 

Foscarnet should not be used in combination with drugs that cause renal toxicity (e.g., acyclovir, aminoglycosides, amphotericin B, NSAIDs). Abnormal renal function has been noted when foscarnet is used with ritonavir or ritonavir and saquinavir. Pentamidine may increase the risk of nephrotoxicity, hypocalcemia, and... 

Garlic bulb Ritonavir Two brief case reports describe gastrointestinal toxic effects in patients taking garlic and ritonavir. 

As an inhibitor of CYP3A4 and CYP2C9, the potential for drug-drug interactions with atazanavir is great (Tables 49-3 and 49-4). Atazanavir AUC is reduced by 76% when combined with omeprazole thus, the combination is to be avoided. In addition, co-administration of atazanavir with other drugs that inhibit UGT1A1, such as indinavir and irinotecan, is contraindicated because of enhanced toxicity. Tenofovir and efavirenz should not be -administered with atazanavir unless ritonavir is added to boost levels. 

Saquinavir should be taken within 2 hours after a fatty meal for enhanced absorption. Saquinavir is 97% protein-bound, and serum half-life is approximately 2 hours. Saquinavir has a large volume of distribution, but penetration into the cerebrospinal fluid is negligible. Excretion is primarily in the feces. Reported adverse effects include gastrointestinal discomfort (nausea, diarrhea, abdominal discomfort, dyspepsia) and rhinitis. When administered in combination with low-dose ritonavir, there appears to be less dyslipidemia or gastrointestinal toxicity than with some of the other boosted PI regimens. 

Drug-specific toxicities ritonavir, gastrointestinal distress saquinavir, hard gel capsules indinavir, renal colic nelfinavir, diarrhea amprenavir, nausea and vomiting. Increased risk of poor adherence with long-term treatment, leading to resistance... 

Piroxicam Piroxicam and ritonavir should not be administered concurrently due to potential toxicity. 

Disulfiram-like reaction with ritonavir, tipranavir, diazoxide Increases levels and toxicity of tacrolimus, cyclosporine, lithium, and phenytoin... 

DIGOXIN ANTIVIRALS-RITONAVIR (WITH OR WITHOUT LOPINAVIR) Plasma digoxin concentrations may be t by ritonavir Uncertain probably due to inhibition of P-gp-mediated renal excretion of digoxin and t intestinal absorption Monitor digoxin levels watch for digoxin toxicity... 

IMATINIB 1. ANTIBIOTICS - clarithromycin, erythromycin 2. ANTIFUNGALS -fluconazole, itraconazole, ketoconazole voriconazole 3. ANTIVIRALS -efavirenz, ritonavir 4. GRAPEFRUIT JUICE 5. H2 RECEPTOR BLOCKERS - cimetidine t imatinib levels with t risk of toxicity (e.g. abdominal pain, constipation, dyspnoea) and of neurotoxicity (e.g. taste disturbances, dizziness, headache, paraesthesia, peripheral neuropathy) Due to inhibition of CYP3A4-mediated metabolism of imatinib Monitor for clinical efficacy and for the signs of toxicity listed, along with convulsions, confusion and signs of oedema (including pulmonary oedema). Monitor electrolytes and liver function, and for cardiotoxicity... 

TOREMIFENE PROTEASE INHIBITORS -RITONAVIR t plasma concentrations of toremifene Due to inhibition of metabolism of toremifene by the CYP3A4 isoenzymes by ritonavir Clinical relevance is uncertain. Necessaiy to monitor for clinical toxicities... 

CORTICOSTEROIDS PROTEASE INHIBITORS-RITONAVIR t plasma levels of betamethasone, dexamethasone, hydrocortisone, prednisolone and both inhaled and intranasal budesonide and fluticasone with ritonavir (with or without lopinavir) Inhibition of CYP3A4-mediated metabolism Monitor closely for signs of corticosteroid toxicity and immunosupression, and i dose as necessaiy. Consider using inhaled bedometasone... 

RITONAVIR IRINOTECAN T plasma concentrations of SN-38 (>AUC by 100%) and t toxicity of irinotecan, e.g. diarrhoea, acute cholinergic syndrome, interstitial pulmonary disease Due to inhibition of the metabolism of irinotecan by CYP3A4 isoenzymes by ritonavir Peripheral blood counts should be checked before each course of treatment. Monitor lung function. Recommendation is to l dose of irinotecan by 25%... 

PROTEASE INHIBITORS ANTIDIARRHOEAL DRUGS-LOPERAMIDE t risk of adverse effects when loperamide is co-ingested with ritonavir Ritonavir inhibits P-gp and CYP3A4 Monitor for clinical effect, and consider 1 dose if necessaiy. Stop if there are signs of abdominal distension in HIV patients as toxic megacolon has been reported... 

TIPRANAVIR + RITONAVIR ATAZANAVIR Possibly 1 efficacy of atazanavir and t toxicity of tipranavir + ritonavir Significant i bioavailability Avoid co-administration... 

PROTEASE INHIBITORS PROGESTOGENS -NORETHISTERONE t adverse effects with amprenavir and atazanavir. Possibly 1 efficacy and risk of contraceptive failure with nelfinavir and ritonavir (with or without lopinavir) Uncertain Advise patients to use additional contraception for the period of intake and for 1 month after stopping coadministration with these drugs. Barrier methods are necessary to prevent transmission of infection from patients with HIV. Watch for early features of toxicity of amprenavir and atazanavir, and adjust the dose accordingly... 

AMPHETAMINES ANTIVIRALS-RITONAVIR t plasma concentrations of amphetamine, with risk of toxic effects Due to inhibition of CYP2D6-mediated metabolism of amphetamine Avoid concurrent use... 

Antivirals ritonavir may raise plasma concentration of piroxicam NSAIDs may increase haematological toxicity from zidovudine. 

Burman W, Orr L. Carbamazepine toxicity after starting combination antiretroviral therapy including ritonavir and efavirenz. AIDS 2000 14(17) 2793. ... 

Ritonavir is a very potent inhibitor of CYP3A4, which is responsible for the metabolism of ergotamine, and this interaction obviously led to toxic plasma concentrations of the alkaloid. 

Solas C, Basso S, Poizot-Martin I, Ravaux I, Gallais H, Gastaut JA, Durand A, Lacarelle B. High indinavir Cmin is associated with higher toxicity in patients on indinavir-ritonavir 800/100 mg twice-daily regimen. J Acquir Immune Defic Syndr 2002 29(4) 374-7. 

The adverse effects commonly observed with ritonavir in adults are reportedly similar in children (19). Of 51 children aged 6 months to 18 years who took escalating doses of a liquid formulation of ritonavir (from 250 up to 400 mg/m every 12 hours), seven withdrew because of gastrointestinal toxicity and four because of grade three hepatic transaminase rises. Both serum triglyceride and cholesterol concentrations increased significantly from baseline within 12 weeks of treatment. 

In a pilot, non-randomized study, HIV-infected patients with tuberculosis were treated with regimens containing rifampicin and ritonavir (31). Despite the effects on CYP3A4, there was no significant interaction plasma ritonavir concentrations remained sufficiently high and rifampicin concentrations did not rise to the toxic range. 

This class of agents affects a later part of the HIV cycle, by inhibiting the protease enzyme and leading to impaired assembly of mature HIV virions. Examples include amprenavir, atazanavir, darunavir, fosampre-navir indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir. There have been no published reports of AKI or other direct kidney toxicity due to amprenavir, darunavir, fosamprenavir, and lopinavir. 

Protease inhibitors are targeted towards the HIV proteases, which are essential to activate precursors of gag-pol. HIV protease is essential for infectivity and cleaves the viral polyprotein (gag-pol) into active viral enzymes and structural proteins. The mechanism of action of these drags is by binding reversibly to the active site of HIV protease and blocking subsequent viral maturation. This major class includes saquinavir, ritonavir, indinavir, and nelfi-navir. Toxicities of protease inhibitors include nausea, vomiting, and diarrhea. 

The two Pis used most in the last 5 to 6 years, nearly always in combination regimens with two NRTIs, are indinavir and ritonavir. Saquinavir, one of the least toxic, has very low (and variable) oral bioavailability that predisposes to resistance development. 

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