Lopinavir/ritonavir (Lopinavir/r) is a fixed dose combination of two HIV protease inhibitors (PIs).
Lopinavir, an inhibitor of the HIV protease, prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles. Ritonavir does not contribute directly to the antiviral activity but acts as a “pharmacokinetic enhancer” by increasing the concentration of lopinavir. Lopinavir/r tablets may be taken with or without food. Protein binding of lopinavir is 98% to 99%. Lopinavir is extensively metabolized by the hepatic cytochrome P450 system, almost exclusively by the CYP3A isoenzyme. Because ritonavir is a potent CYP3A inhibitor, it inhibits the metabolism of lopinavir and increases plasma levels of lopinavir. Serum half-life of lopinavir is 5 to 6 hours and is excreted through urine and feces.
Fixed-dose combination of Lopinavir/r tablet is indicated in combination with other antiretroviral agents for the treatment of HIV infection.
Lopinavir/r is contraindicated in patients with known hypersensitivity to any of its ingredients, including ritonavir. Co-administration of Lopinavir/r is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 1.
Table 1: Drugs that are contraindicated with Lopinavir/r
|Drug class||Drugs within class that are contraindicated with Lopinavir/ritonavir|
|Ergot Derivatives||Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine|
|GI Motility Agent||Cisapride|
Lopinavir/r tablets may be taken with or without food. Tablets should be swallowed whole and not chewed, broken, or crushed. The recommended oral dose of Lopinavir/r tablet is as follows:
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy (ART), including lopinavir/r.
Lopinavir/r tablets can be administered with or without food. The tablet formulation also does not require dose adjustments for concomitant use with certain NNRTIs and PIs in treatment-naive patients. Lopinavir/r tablets can be taken at the same time as didanosine without food. Lopinavir/r induces glucuronidation and has the potential to reduce plasma concentrations of zidovudine or abacavir concentrations if these drugs are taken concurrently. The clinical significance of this potential drug interaction is unknown. When taken concurrently, lopinavir/r increases tenofovir concentrations; the mechanism of this interaction is unknown. Patients taking both lopinavir/r and tenofovir should be monitored for tenofovir-associated adverse events. An increased rate of adverse events has also been observed when fosamprenavir is coadministered with lopinavir/r. Appropriate doses of both drugs with respect to safety have not been established. Lopinavir/r is an inhibitor of the P450 isoform CYP3A in vitro. Coadministration of lopinavir/r and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects. Lopinavir/r has also been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation. Lopinavir concentrations decrease in patients concurrently taking efavirenz, nevirapine, amprenavir, or nelfinavir, due to induction of CYP3A by these drugs; increased dosage of lopinavir/r may be required. Concentrations of antiarrhythmic drugs (amiodarone, bepridil, lidocaine, and quinidine) may be increased if taken concurrently with lopinavir/r; therapeutic monitoring of antiarrhythmic concentration may be necessary. Concomitant use of lopinavir/r with lipid lowering agents will result in an increase of concentrations of these agents. Levels of atorvastatin or cerivastatin should be lowered to the lowest possible level when used in combination with lopinavir/r. Pravastatin or fluvastatin should be considered as substitutes for atorvastatin or cerivastatin. Concomitant use of lovastatin or simvastatin with lopinavir/r is not recommended, as serious reactions such as myopathy, including rhabdomyolysis, may occur. Concurrent use of carbamazepine, dexamethasone, phenobarbital or phenytoin with lopinavir/r may decrease concentrations of lopinavir and lead to decreased effectiveness of lopinavir. Serum concentrations of clarithromycin may increase if administered concomitantly with lopinavir/r. In patients concurrently taking clarithromycin, doses of lopinavir/r should be decreased as necessary in patients with renal impairment. Concentrations of cyclosporine, sirolimus, and tacrolimus may increase if administered concomitantly with lopinavir/r. Therapeutic monitoring is recommended for patients taking any of these immunosuppressants concurrently with lopinavir/r. Concentrations of dihydropyridine calcium channel blockers (felodipine, nicardipine, and nifedipine) may also increase if taken concomitantly with lopinavir/r; clinical monitoring is recommended. Azole antifungals such as itraconazole and ketoconazole are not recommended to be taken concurrently with lopinavir/r because it may increase azole concentrations. Coadministration of voriconazole with lopinavir/r has not been studied. However, administration of voriconazole with ritonavir 400 mg every 12 hours decreased the voriconazole steady-state AUC by an average of 82%. The effect of lower ritonavir doses on voriconazole is not known at this time; until data are available, voriconazole should not be administered to patients receiving lopinavir/r. When rifabutin and lopinavir/r are administered concurrently, increased concentrations of rifabutin and rifabutin metabolite occur. A rifabutin dosage reduction by at least 75% is recommended, with further dose reduction possibly necessary. Concomitant use of ritonavir and St. John's wort (Hypericum perforatum) or products containing St. John's wort is not recommended as St. John's wort may substantially decrease lopinavir/r concentrations, resulting in suboptimal lopinavir concentrations, loss of virologic response, and possible resistance to lopinavir/r. Concomitant use of warfarin with lopinavir/r may affect warfarin serum concentrations; International Ratio Monitoring is recommended. Coadministration of lopinavir/r and the phosphodiesterase (PDE) inhibitors sildenafil, tadalafil, or vardenafil is expected to substantially increase PDE inhibitor concentration and risk of adverse effects, including hypotension, prolonged erection, syncope, and visual changes. These PDE inhibitors should be used with caution, at reduced doses, and with increased monitoring for adverse events. Because contraceptive steroid concentrations may be altered when lopinavir/r is coadministered with oral and topical contraceptives containing ethinyl estradiol, alternative methods of nonhormonal contraception are recommended while a patient is taking lopinavir/r.
The most common adverse event is diarrhoea, which was generally of mild to moderate severity. Other events that can occur are listed below by body system. Body as a Whole: Allergic reaction, back pain, chest pain, chest pain substernal, cyst, drug interaction, drug level increased, face oedema, flu syndrome, hypertrophy, infection bacterial, malaise, viral infection and redistribution/accumulation of body fat. Cardiovascular System: Atrial fibrillation, cerebral infarct, deep thrombophlebitis, deep vein thrombosis, migraine, palpitation, postural hypotension, thrombophlebitis, varicose vein, and vasculitis and bradyarrhythmias. Digestive System: Cholangitis, cholecystitis, constipation, dry mouth, enteritis, enterocolitis, eructation, oesophagitis, fecal incontinence, gastritis, gastroenteritis, hemorrhagic colitis, hepatitis, increased appetite, jaundice, mouth ulceration, pancreatitis, periodontitis, sialadenitis, stomatitis, and ulcerative stomatitis. Endocrine System: Cushing's syndrome, diabetes mellitus, and hypothyroidism. Hemic and Lymphatic System: Anaemia, leukopenia, and lymphadenopathy. Metabolic and Nutritional Disorders: Avitaminosis, dehydration, oedema, glucose tolerance decreased, lactic acidosis, obesity, peripheral oedema, and weight gain. Musculoskeletal System: Arthralgia, arthrosis and bone necrosis. Nervous System: Abnormal dreams, agitation, amnesia, anxiety, apathy, ataxia, confusion, convulsion, dizziness, dyskinesia, emotional lability, encephalopathy, facial paralysis, hypertonia, nervousness, neuropathy, peripheral neuritis, somnolence, thinking abnormal, tremor, and vertigo. Respiratory System: Asthma, dyspnoea, lung oedema, pharyngitis, rhinitis, and sinusitis. Skin and Appendages: Acne, alopecia, dry skin, eczema, exfoliative dermatitis, furunculosis, maculopapular rash, nail disorder, pruritis, seborrhoea, skin benign neoplasm, skin discoloration, skin ulcer, sweating and Stevens Johnson Syndrome and erythema multiforme. Special Senses: Abnormal vision, eye disorder, otitis media, taste loss, taste perversion, and tinnitus. Urogenital System: Abnormal ejaculation, amenorrhoea, breast enlargement, gynecomastia, kidney calculus, nephritis, and urine abnormality. Laboratory Abnormalities: Increase in blood glucose, total bilirubin SGOT, SGPT, GGT, total cholesterol, triglycerides, amylase,uric acid and decrease in neutrophil count.
Keep in a cool, dry and dark place.