Lopinavir dosing

Excretion - Less than 3% of the lopinavir dose is excreted unchanged in the urine. The half-life of lopinavir over a 12-hour dosing interval averaged 5 to 6 hours the apparent oral clearance (CL/F) of lopinavir is 6 to 7 L/h. 

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. 

HIV treatment In combination with other antiretroviral agents for the treatment of HIV infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in a controlled study of lopinavir/ritonavir combination of 24 weeks duration and in smaller uncontrolled dose-ranging studies of 72 weeks duration. At present, there are no results from controlled trials evaluating the effect on clinical progression of HIV. 

Concomitant therapy with efavirenz, nevirapine, fosamprenavir, or nelfinavir-Consider a dose increase to 533/133 mg lopinavir/ritonavir (4 capsules or 6.5 mL) twice daily taken with food when used in combination with efavirenz, nevirapine, amprenavir, or nelfinavir, or 600/150 mg (3 tablets) twice daily with or without food when used in combination with efavirenz, nevirapine, fosamprenavir without ritonavir, or nelfinavir in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). 

Children (6 months to 12 years of age) The recommended dosage of lopinavir/ritonavir oral solution is 12/3 mg/kg for those weighing 7 to less than 15 kg and 10/2.5 mg/kg for those 15 to 40 kg (approximately equivalent to 230/57.5 mg/m ) twice daily with food, up to a maximum dose of 400/100 mg in children greater than 40 kg (5 mL or 3 capsules, or 2 tablets) twice daily. It is preferred that the prescriber calculate the appropriate milligram dose for each individual child 12 years of age and younger and determine the corresponding volume of solution or number of capsules or tablets. 

Dosing based on the lopinavir component of lopinavir/ritonavir solution (80 mg/20 mg per ml). 

Absorption - Administration of a single 400/100 mg dose of lopinavir/ritonavir... 

Lopinavir/Ritonavir (Kaletra) [Antiretroviral/Protease Inhibitor] Uses HIV Infxn Action Protease inhibitor Dose Adults. Tx... 

Included in the WHO 14th Model List of Essential Medicines (2006), lopinavir only in the combination with low dose ritonavir. 

Lopinavir is available in the United States only as a fixed-dose combination with ritonavir (Kaletra). In this regimen, a low dose of ritonavir is used to inhibit the rapid inactivation of lopinavir by CYP3A4. Side effects, which are generally mild, include diarrhea, nausea, asthenia, and headache. Pancreatitis occurs rarely. Ritonavir is a potent inhibitor of CYP3A4 and also inhibits CYP2D6. In addition to the drugs contraindicated for all protease inhibitors, fiecainide, propafenone, pimozide, and rifampin should not be given with lopinavir-ritonavir combination therapy. 

A hxed-dose combination of lopinavir and ritonavir is used to treat HIV infection in the United States. This combination is particularly effective because... 

B. Ritonavir is a potent inhibitor of CYP3A4, the enzyme that rapidly inactivates lopinavir. This combination includes a low dose of ritonavir that is not likely to cause serious side effects but instead inhibits lopinavir metabolism. Ritonavir and lopinavir are HIV protease inhibitors and do not affect reverse transcriptase. Lopinavir is almost completely eliminated by metabolism to inactive metabolites little is eliminated unchanged by the kidney. Lopinavir is not known to inhibit the ability of HIV to mutate. Lopinavir inhibits the enzyme HIV protease, not a structural protein. 

HIV infection (in combination with other antiretrovirals) PO 800 mg (two 400-mg capsules) q8h. Dosage adjustments when given concomitantly Delavirdine, itraconazole, ketoconazok Reduce dose to 600 mg q8h. Efavirenz-. Increase dose to 1,000 mg q8h. Lopinavir/ritonavir Reduce dose to 600 mg twice a day. Nevirapine-. Increase dose to 1,000 mgqSh. Rifabutin-. Reduce rifabutin by lA and increase indinavir to 1,000 mg q8h. Ritonavir 100-200 mg twice a day and indinavir 800 mg twice a day or ritonavir 400 mg twice a day and indinavir 400 mg twice a day. 

Fosamprenavir PI2 1400 mg bid or 700 mg bid with ritonavir 100 bid or 1400 mg daily with ritonavir 100-200 mg daily. Adjust dose in hepatic insufficiency Separate dosing from antacids by 2 h. Avoid concurrent high-fat meals Diarrhea, nausea, vomiting, hypertriglyceridemia, rash, headache, perioral paresthesias, t liver enzymes See footnote 4 for contraindicated medications. Do not administer with lopinavir/ritonavir or in severe hepatic insufficiency. Also avoid cimetidine, disulfiram, metronidazole, vitamin E, ritonavir oral solution, and alcohol when using the oral solution... 

Lopinavir/ritonavir PI/PI2 400 mg/100 mg bid or 800 mg/200 mg daily. May need dose adjustment in hepatic insufficiency Take with food. Separate dosing from ddl by 1 h. Store capsules and solution in refrigerator Diarrhea, abdominal pain, nausea, hypertriglyceridemia, headache, t liver enzymes, See footnote 4 for contraindicated medications. Also avoid fosamprenavir. Avoid disulfiram and metronidazole with oral solution... 

The U.S. has consistently opposed compulsory licensing by other countries. In January 2001, the U.S. requested a WTO panel against Brazil to prevent Brazilian "local manufacture" of AIDS drugs (WTO 2001). Under international pressure, the U.S. withdrew the panel request in the months leading up to the Fourth WTO Ministerial Conference in Doha (Thomas 2001 t Hoen 2002). More recently, U.S. groups attacked Brazil in July 2005 over a proposed compulsory license of Kaletra (lopinavir and ritonavir), an AIDS fixed-dose combination drug. The patent owner, Abbott Laboratories, reached a voluntary price reduction agreement with Brazil which made the formal compulsory license unnecessary, another demonstration of the power of compulsory licenses to improve access (Benson 2005). 

Lopinavir/Ritonavir (Kaletra) [Anrirelroviral/Protease Inhibitor] Uses HIV Infxn Action Protease inhibitor Dose Adults. Tx naive 2 tab PO daily or 1 tab PO bid Tx experiencedpt 1 tab PO bid (T dose if w/ amprenavir, efavirenz, fosamprenavir, nelfinavir, nevirapine) Peds. 7-15 kg 12/3 mg/kg PO bid 15-40 kg 10/2.5 mg/kg PO bid >40 kg Adult dose w/ food Caution [C, /-] Numerous interactions Contra w/drugs dependent on CYP3A/CYP2D6 (Table VI-8) Disp Tab, soln SE Avoid disulfiram (soln has EtOH), metronidazole GI upset, asthenia, T cholesterol/triglycerides, pancreatitis protease metabolic synd Interactions T Effects Wl clarithromycin, erythromycin T effects OF amiodarone, amprenavir, azole andfungals, bepridil, cisapride, cyclosporine, CCBs, ergot alkaloids, flecainide, flurazepam, HMG-CoA reductase inhibitors, indinavir, lidocaine, meperidine, midazolam, pimozide, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, tacrolimus, terfenadine, triazolam, zolpidem 1 effects Wl barbiturates, carbamazepine, dexamethasone, didanosine, efavirenz, nevirapine, phenytoin, rifabutin, rifampin, St. John s wort 1 effects OF OCPs, warfarin EMS Use andarrhythmics and benzodiazepines... 

Trade name for a combination of lopinavir and low-dose ritonavir. ... 

Lopinavir/ritonav ir PI/PI 400 mg/100 mg bid With food. Separate dosing with didanosine by 1 hour. Diarrhea, abdominal pain, nausea The oral solution contains alcohol store capsules and solution in refrigerator see footnote 2 for concurrent drug contraindication s. 

PHENYTOIN PROTEASE INHIBITORS Possibly 1 efficacy of phenytoin, with a risk of fits when coadministered with indinavir, nelfinavir and ritonavir (with or without lopinavir) Uncertain 1 plasma levels of phenytoin Use with caution. Monitor phenytoin levels weekly. Adjust doses at 7-10-day intervals. Maximum suggested dose adjustment each time is 25 mg... 

SOLIFENACIN PROTEASE INHIBITORS t adverse effects with nelfinavir and ritonavir (with or without lopinavir) Inhibition of CYP3A4-mediated metabolism of solifenacin Limit maximum dose of solifenacin to 5 mg daily... 

ALFENTANIL, BUPRENORPHINE, FENTANYL, TRAMADOL PROTEASE INHIBITORS Possibly t adverse effects when buprenorphine is co administered with indinavir, ritonavir (with or without lopinavir) or saquinavir Inhibition of CYP3A4 (CYP2D6 in the case of tramadol) Halve the starting dose and titrate to effect. For single injection of fentanyl, monitor sedation and respiratoiy function closely. If continued use of fentanyl, i dose may be required. Concomitant use of ritonavir and transdermal fentanyl is not recommended... 

METHADONE, PETHIDINE PROTEASE INHIBITORS 1 efficacy of methadone, with risk of withdrawal, when coadministered with amprenavir, nelfinavir, ritonavir (with or without lopinavir) or saquinavir Uncertain possibly due to induction of CYP3A4 and CYP2D6 Monitor closely for opioid withdrawal, and t dose of methadone as necessary. This advice includes co-administration of methadone with low-dose ritonavir. Short-term use of pethidine is unlikely to cause a problem... 

CLARITHROMYCIN, ERYTHROMYCIN PROTEASE INHIBITORS Possibly t adverse effects of macrolide with atazanavir, ritonavir (with or without lopinavir) and saquinavir Inhibition of CYP3A4- and possibly CYP1 A2-mediated metabolism. Altered transport via P-gp may be involved. Amprenavir and indinavir are also possibly t by erythromycin Consider alternatives unless there is Mycobacterium avium intracellulare infection if combined, 1 dose by 50% (75% in the presence of renal failure with a creatinine clearance of <30mL/min)... 

RIFABUTIN PROTEASE INHIBITORS t efficacy and t adverse effects of rifabutin Inhibition of CYP3A4-mediated metabolism. Nelfinavir also competitively inhibits 2C19 1 rifabutin dose by at least 50% when given with amprenavir, indinavir or nelfinavir, and by 75% with atazanavir, ritonavir (with or without lopinavir) or tipranavir... 

ITRACONAZOLE, KETOCONAZOLE PROTEASE INHIBITORS Possibly t levels of ketoconazole by amprenavir, indinavir and ritonavir (with or without lopinavir). Conversely, indinavir, ritonavir and saquinavir levels t by itraconazole and ketoconazole Inhibition of, or competition for, CYP3A4-mediated metabolism Use itraconazole with caution and monitor for adverse effects. No dose adjustment is recommended for doses <400 mg/day of ketoconazole... 

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... 

PROTEASE INHIBITORS SSRIs t adverse effects of fluoxetine, paroxetine and sertraline when co-administered with ritonavir (with or without lopinavir). Cardiac and neurological events have been reported, including serotonin syndrome Ritonavir is associated with the most significant interaction of the protease inhibitors due to potent inhibition of CYP3A, CYP2D6, CYP2C9 and CYP2C19 isoenzymes Warn patients to watch for t side-effects of SSRIs and consider 1 dose ofSSRI... 

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