Ritonavir dosing

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. 

Ritonavir dose adjustment when fosamprenavir plus ritonavir are administered with efavirenz An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with fosamprenavir plus ritonavir once daily. 

Space ritonavir doses evenly around the clock and continue taking the drug for the full course of treatment... 

NNRTIs LOPINAVIR AND RITONAVIR Possible 1 efficacy of lopinavir/ritonavir Uncertain 1 bioavailability Consider t lopinavir/ritonavir dose (by 33% with efavirenz and to 53 mg/133 mg twice daily, and monitor drug concentrations, with nevirapine). Monitor viral load closely as this dose t may be insufficient. Monitor LFTs closely... 

Ritonavir (dose not stated) was given to 11 healthy subjects for 14 days, with a single 5-mg dose of methadone on day 11. Ritonavir reduced the maximum serum levels of methadone by 37.8% and the AUC by 36.3%. However, in another study in 15 healthy subjects receiving methadone, ritonavir 100 mg twice daily for 7 days had no significant effect on methadone pharmacokinetics. "... 

Ritonavir Ritonavir dose reductions might be appropriate No dose adjustments required, but not well tolerated. Monitor liver function No dose adjustments required... 

A 30-year-old woman taking nevirapine, saquinavir 1.2 g daily and ritonavir 600 mg daily with undeteetable viral load had her epilepsy med-ieation ehanged from gabapentin and lorazepam to lamotrigine and phenytoin beeause of inereased frequeney and severity of seizures. She required phenytoin 8 mg/kg daily to maintain therapeutie serum levels. The ritonavir dose was doubled and the saquinavir dose inereased to 2 g daily to eompensate for the enzyme-indueing efifeets of phenytoin. The patient s viral load remained undeteetable, and her seizures deereased over the next 6 months but she died suddenly of unexplained causes following a tonic-elonie seizure (autopsy not performed). ... 

When ritonavir is given as a pharmacokinetic booster the recommended dose is saquinavir/ritonavir 1000/100 mg twice daily. Higher ritonavir doses are associated with increased adverse effects. ... 

Ritonavir alone Rifabutin dose reduced by at least 75% (150 mg every other day or three times per week). Further dose reductions may be necessary. Ritonavir dose unchanged. May be used at usual doses, although limited data (ritonavir levels reduced). May lead to loss of virologic response. 3, 11... 

Condon SM, LaPorte MG, Herbertz T (2005) Allosteric inhibitors of hepatitis C NS5B RNA-dependent RNA polymerase, Curr Med Chem Anti-Infect Agents 4 99-110 Cooper CL, van Heeswijk RP, Gallicano K, Cameron DW (2003) A review of low-dose ritonavir in protease inhibitor combination therapy, Clin Infect Dis 36 1585-1592 Courcambeck J, Bouzidi M, Perbost R, Jouirou B, Amrani N, Cacoub P, Pepe G, Sabatier JM, Halfon P (2006) Resistance of hepatitis C vims to NS3 A protease inhibitors mechanisms... 

Lalezari JP, DeJesus E, Northfelt DW, Richmond G, Wolfe P, Haubrich R, Henry D, Powderly W, Becker S, Thompson M, Valentine E, Wright D, Carlson M, Riddler S, Haas FF, DeMasi R, Sista PR, Salgo M, Delehanty J (2003a) A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in nonnucleoside reverse transcriptase inhibitor-naive HIV-infected adults. Antivir Ther 8 279-287... 

NRTIs (based on resistance testing) + PI (with or without low-dose ritonavir)... 

Fosamprenavir (fAPV) Lexiva 700-mg tabs ARV-na ive pts fAPV 1,400 mg bid or fAPV 700 mg + RTV 1 00 mg bid PS-experienced pts fAPV 700 mg + RTV 1 00 mg bid Co-admin is tra tion w/EFV fAPV 700 mg + RTV 1 00 mg bid or fAPV 1400 mg + RTV 300 mg qday Child-Pugh Dose Class 5-8 700 mg bid 9-12 Not recommended Ritonavir should not be used in patients with hepatic impairment None Skin rash diarrhea, nausea and vomiting headache hyperlipidemia LFT elevation hyperglycemia fat maldistribution increased bleeding episodes in patients with hemophilia CYP3A4 inhibitor, inducer, and substrate... 

Sildenafil doses should be decreased when any potent cytochrome P450 3A4 inhibitor is used (e g., cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and saquinavir). Vardenafil doses vary accordingto which agent is used (2.5 mg q 72 h for ritonavir, 2.5 mg q 24 h for indinavir, ketoconazole 400 mg daily, and itraconazole 400 mg daily and 5 mg q 24 h for ketoconazole 200 mg daily, itraconazole200 mg daily, and erythromycin). Tadalafil doses are reduced only when it is used with the most potent cytochrome P450 3A4 inhibitors (e g., ketoconazole or ritonavir). 

Exhibit 6.6 Phase III Study A Study of Lopinavir/Ritonavir Tablets Comparing Once-Daily Versus Twice-Daily Dosing in Antiretroviral-Experienced, HIV-1 Infected Subjects... 

The purpose of this study is to determine whether once-daily dosing of the lopinavir/ritonavir (Kaletra) tablet in combination with investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors will reduce HIV viral load to very low levels in patients who have detectable viral loads with their current antiretroviral therapy. 

Concomitant medications - For patients taking concomitant potent inhibitors of CYP3A4 (eg, ketoconazole, ritonavir), the maximum recommended dose of tadalafil is 10 mg, not to exceed once every 72 hours. 

Concomitant mecf/caf/ons - The dosage of vardenafil may require adjustment in patients receiving certain CYP3A4 inhibitors. For ritonavir, do not exceed a single dose of 2.5 mg vardenafil in a 72-hour period. For indinavir, ketoconazole 400 mg/day, and itraconazole 400 mg/day, do not exceed a single dose of 2.5 mg vardenafil in a 24-hour period. For ketoconazole 200 mg/day, itraconazole 200 mg/day, and erythromycin, do not exceed a single dose of 5 mg vardenafil in a 24-hour period. 

Coadministration with CYP450 inhibitors- Nhen coadministered with potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, nefazodone), do not exceed a daily dose of darifenacin 7.5 mg. 

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