Treatment of HIV-1 infection in combination with other antiviral agents.
|•||PO (Adults and Children >40 kg): 400/100 mg (3 capsules or 5 ml oral solution) twice daily ormay be given as a single daily dose of 800/200 mg (6 capsules or 10 ml oral solution); single dose approved for adults only.|
|•||PO (Children 15–40 kg): 10 mg/kg lopinavir content twice daily.|
|•||PO (Children 7–15 kg): 12 mg/kg lopinavir content twice daily.|
|•||PO (Adults and Children >40 kg): 533/133 mg (4 capsules or 6.5 ml oral solution) twice daily.|
|•||PO (Children 15–50 kg): 11 mg/kg lopinavir content twice daily.|
|•||PO (Children 7–15 kg): 13 mg/kg lopinavir content twice daily.|
|•||Inhibits HIV viral protease.|
|•||Concurrent use of dihydroergotamine, ergotamine, ergonovine, flecainide, methylergonovine, midazolam, pimozide, propafenone, amiodaroneand triazolam, which are highly dependent on CY P3A or CY P2D6 for metabolism and for which increased blood levels may result in serious and/or life-threatening events.|
|•||Concurrent use with simastatin, lovastatin, St. John’s wort (hypericum perforatum) is not recommended.|
|•||Hypersensitivity or intolerance to alcohol or castor oil (present in capsules and liquid).|
Use Cautiously in:
|•||Known alcohol intolerance (oral solution contains alcohol).|
|•||Concurrent use with atorvastatin (may increase risk of rhabdomyolysis).|
|•||Concurrent use of antiarrhythmics including lidocaine and quinidine (therapeutic blood level monitoring recommended) .|
|•||Concurrent use of anticonvulsants including carbamazepine, phenobarbital or phenytoin (may decrease effectiveness of lopinavir).|
|•||Concurrent use of dihydropyridine calcium channel blockers including felodipine, nifedipine and nicardipine (clinical monitoring recommended due to increased levels of calcium channel blocker).|
|•||Impaired hepatic function, history of hepatitis (for ritonavir content).|
|•||OB: Pregnancy or lactation (safety not established; breastfeeding not recommended in HIV-infected patients).|
Exercise Extreme Caution in:
|•||Concurrent use with sildenafil, vardenafil or tadalafil should be undertaken with extreme caution and may result in hypotension, syncope, visual changes and prolonged erection.|
CV: Vasodilation (3%); hypertension (2%); angina pectoris, atrial fibrillation, AV block, cerebral infarct, deep vein thrombosis, MI, palpitation, postural hypotension, thrombophlebitis, tricuspid valve incompetence, varicose vein, vasculitis (less than 2%); bradyarrhythmias, first-degree AV block, QTc interval prolongation, second-degree AV block, third-degree AV block, torsades de pointes (postmarketing).
CNS: Asthenia (9%); headache (6%); depression, insomnia (3%); decreased libido, paraesthesia (2%); abnormal dreams, abnormal thinking, affect lability, agitation, amnesia, anxiety, apathy, ataxia, balance disorder, confusion, convulsion, disorientation, dizziness, dyskinesia, encephalopathy, extrapyramidal syndrome, facial palsy, fatigue, hypertonia, malaise, migraine, mood swings, nervousness, peripheral neuropathy, somnolence, tremor, vertigo (less than 2%).
DERM: Rash (12%); acne, allergic dermatitis, alopecia, benign neoplasm of the skin, cellulitis, dermatitis acneiform, dry skin, eczema, exfoliative dermatitis, face swelling, folliculitis, furuncle, idiopathic capillaritis, maculopapular rash, nail disorder, pruritus, seborrhea, skin discoloration, skin hypertrophy, skin striae, skin ulcer, sweating (less than 2%); erythema multiforme, Stevens-Johnson syndrome (postmarketing).
EENT: Ageusia, eye disorder, hyperacusis, otitis media, tinnitus, visual disturbance (less than 2%).
ENDO: Cushing syndrome, diabetes mellitus, hypothyroidism (less than 2%).
GI: Diarrhea (60%); dysgeusia (22%); vomiting (21%); nausea (16%); abdominal pain (11%); dyspepsia (6%); flatulence (4%); anorexia, dysphagia, upper abdominal pain (2%); abdominal discomfort, abdominal distension, cholangitis, constipation, decreased appetite, dry mouth, duodenitis, enteritis, enterocolitis, eructation, esophagitis, fecal incontinence, gastric disorder, gastric ulcer, gastritis, gastroenteritis, gastroesophageal reflux disease, hemorrhagic enterocolitis, hemorrhoids, increased appetite, lower abdominal pain, mouth ulceration, pancreatitis, periodontitis, rectal hemorrhage, sialadenitis, stomach discomfort, stomatitis (less than 2%).
GU: Hypogonadism (2%); breast enlargement, ejaculation disorder, erectile dysfunction, gynecomastia, hematuria, menorrhagia, nephritis, nephrolithiasis, perineal abscess, renal disorder, urine abnormality, urine odor abnormal (less than 2%).
HEMA/LYMPH: Anemia, leukopenia, lymphadenopathy, neutropenia, splenomegaly (less than 2%).
HEPA: Cholecystitis, cytolytic hepatitis, hepatic steatosis, hepatitis, hepatomegaly, jaundice, liver tenderness (less than 2%).
HYPERSEN: Drug hypersensitivity, hypersensitivity (less than 2%).
LABTESTABS: Increased total cholesterol (39%); increased triglycerides (36%); increased GGT (29%); increased ALT (11%); increased AST (10%); increased amylase (8%); decreased neutrophils, increased CPK, increased glucose, increased lipase, increased uric acid (5%); decreased platelet count (4%); decreased CrCl, decreased sodium, increased sodium, increased total bilirubin (3%); decreased Hgb, decreased inorganic phosphorous (2%).
M/N: Weight decreased (3%); decreased glucose tolerance, dehydration, edema, facial edema, hypovitaminosis, lactic acidosis, lipomatosis, obesity, peripheral edema, weight increased (less than 2%).
MUSC: Myalgia (2%); arthralgia, arthropathy, back pain, muscular weakness, osteoarthritis, osteonecrosis, pain in extremity (less than 2%).
RESP: Bronchitis (2%); asthma, bronchopneumonia, cough, dyspnea, pharyngitis, pulmonary edema, rhinitis, sinusitis (less than 2%).
OTHER: Chills, pyrexia (2%); bacterial infection, chest pain, cyst, drug level increased, hypertrophy, immune reconstitution syndrome, influenza, lipoma, neoplasm, viral infection (less than 2%); accumulation/redistribution of body fat (postmarketing).
Abacavir, atovaquone, bupropion, (fos)amprenavir, lamotrigine, methadone, olanzapine, phenytoin, theophylline, zidovudine
Levels of these agents may be reduced, decreasing the efficacy. Monitor the clinical response of the patient and adjust the dose of these agents as needed.
Lopinavir concentrations may be elevated, increasing the pharmacologic and adverse reactions. Monitor the clinical response of the patient when one of these agents is started or stopped. Adjust the lopinavir/ritonavir dose as needed.
Antiarrhythmics (eg, amiodarone, bepridil, lidocaine [systemic], quinidine)
Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when coadministered with lopinavir/ritonavir.
Aripiprazole plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Consider reducing the aripiprazole dose by 50% when used in combination with lopinavir/ritonavir.
Atorvastatin, beta-blockers (eg, metoprolol), buspirone, calcium channel blockers (eg, amlodipine), cilostazol, cyclosporine, desipramine, digoxin, dronabinol, erlotinib, eszopiclone, methamphetamine, nefazodone, phenothiazines (eg, perphenazine), protease inhibitors (eg, nelfinavir), quetiapine, quinine, rapamycin, risperidone, rosuvastatin, tacrolimus, tenofovir, trazodone, tyrosine kinase receptor inhibitors (eg, dasatinib)
Levels of these agents may be elevated, increasing the pharmacologic and adverse reactions. Use with caution and monitor the patient and drug concentrations (when available). A dose reduction in these agents may be needed.
Azole antifungals (eg, itraconazole, ketoconazole, voriconazole)
Ketoconazole and itraconazole levels may be increased. High dosages of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended. Voriconazole levels may be decreased when coadministered with ritonavir; therefore, voriconazole coadministered with ritonavir is contraindicated. Plasma ritonavir concentrations may be elevated, increasing the risk of toxicity. Consider using an alternative antifungal agent.
Benzodiazepines (eg, alprazolam, flurazepam), buprenorphine, fentanyl, zolpidem
Plasma levels of these agents, including parenteral midazolam, may be increased. Closely monitor for respiratory depression and prolonged sedation. Adjust the dose of these agents as needed. Coadministration of oral midazolam or triazolam and lopinavir/ritonavir is contraindicated.
Bosentan plasma concentrations may be elevated, increasing the pharmacologic effect and risk of adverse reactions. Discontinue bosentan at least 36 hours prior to starting lopinavir/ritonavir therapy. Bosentan 62.5 mg once daily or every other day can be resumed 10 days or more after starting lopinavir/ritonavir.
Cabazitaxel plasma concentrations may be elevated, increasing the risk of adverse reactions. Avoid coadministration.
Carbamazepine, phenobarbital, phenytoin, protease inhibitors (amprenavir, fosamprenavir, tipranavir)
Lopinavir concentrations may be reduced, decreasing efficacy. Monitor the clinical response of the patient when one of these agents is started or stopped. Adjust the lopinavir/ritonavir dose as needed. Avoid coadministration of tipranavir and lopinavir/ritonavir.
Cat’s claw ( Uncaria tomentosa )
Ritonavir plasma concentrations may be elevated, increasing the risk of toxicity. Advise patients receiving lopinavir/ritonavir to avoid use of the herbal product cat’s claw.
Cisapride, conivaptan, dronedarone, eplerenone, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin), meperidine, midazolam (oral), pimozide, propoxyphene, ranolazine, rifampin, St. John’s wort, tolvaptan, triazolam
Contraindicated because of potentially serious or life-threatening reactions or loss of virologic response.
Ritonavir and clarithromycin plasma levels may be increased. For patients with renal impairment, consider the following dosage adjustments: for patients with CrCl 30 to 60 mL/min, reduce the dose of clarithromycin by 50%; for patients with CrCl less than 30 mL/min, reduce the dose of clarithromycin by 75%.
Colchicine plasma concentrations may be elevated, increasing the risk of toxicity. Coadministration of colchicine and lopinavir/ritonavir is contraindicated in patients with hepatic or renal function impairment. In patients with healthy renal and hepatic function, coadminister lopinavir/ritonavir and colchicine with caution, using a max colchicine dosage of 0.3 mg twice daily. Carefully monitor for colchicine-related adverse reactions.
Contraceptives, hormonal (eg, ethinyl estradiol)
Loss of hormonal contraceptive effectiveness, possibly leading to unintended pregnancy, may occur. Use alternative or additional nonhormonal contraceptive measures when estrogen-based oral contraceptives or the contraceptive patch and lopinavir/ritonavir are coadministered.
Corticosteroids (eg, dexamethasone, fluticasone propionate [inhaled], prednisone, triamcinolone)
Lopinavir/ritonavir may be less effective when coadministered with corticosteroids because of decreased lopinavir plasma concentrations. Corticosteroid plasma concentrations may be elevated, increasing the pharmacologic and toxic effects (eg, Cushing syndrome with secondary adrenal insufficiency). Coadministration of inhaled fluticasone and lopinavir/ritonavir is not recommended unless the potential benefit outweighs the risk of adverse reactions. Use the lowest effective dose of triamcinolone when coadministered with lopinavir/ritonavir. Close clinical monitoring for signs and symptoms of adrenal suppression and Cushing syndrome is recommended.
Darunavir plasma concentrations may be reduced, decreasing the pharmacologic effects. Lopinavir/ritonavir plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Coadministration is not recommended.
Deferasirox plasma concentrations may be reduced, decreasing the pharmacologic effect. If coadministration cannot be avoided, consider an initial dosage of deferasirox 30 mg/kg/day. Adjust the deferasirox dosages according to serum ferritin concentrations and clinical response.
Because didanosine should be given on an empty stomach and lopinavir/ritonavir oral solution should be taken with food, give didanosine 1 h before or 2 h after lopinavir/ritonavir oral solution.
A disulfiram-like reaction may occur when coadministered with the lopinavir/ritonavir oral solution, which contains alcohol. Avoid lopinavir/ritonavir solution in patients taking disulfiram or metronidazole.
Plasma concentrations and pharmacologic effects of docetaxel may be increased. Use of lopinavir/ritonavir with docetaxel may increase the risk of neutropenia. If coadministration cannot be avoided, close clinical and laboratory monitoring are indicated. A docetaxel dosage reduction may be needed.
Plasma concentrations and pharmacologic effects of eletriptan may be increased by lopinavir/ritonavir. Do not use eletriptan within 72 h of lopinavir/ritonavir.
Erythromycin plasma concentration may be elevated, increasing the risk of sudden death from cardiac causes. Avoid concurrent use of erythromycin and lopinavir/ritonavir.
Ritonavir plasma concentrations may be elevated, increasing the risk of toxicity. Advise patients receiving lopinavir/ritonavir to avoid use of the herbal product evening primrose.
Relative to fasting, administration of oral solution with a moderate- or high-fat meal increased lopinavir AUC and Cmax . To enhance bioavailability and minimize pharmacokinetic variability, administer the oral solution with food.
Plasma concentrations and pharmacologic activity of lopinavir/ritonavir may be decreased by garlic, reducing the efficacy. Avoid coadministration of garlic and lopinavir/ritonavir. If combination use cannot be avoided, closely monitor for signs of therapeutic failure of lopinavir/ritonavir.
Grapefruit juice may increase the plasma concentrations of lopinavir/ritonavir. If grapefruit juice cannot be avoided, closely monitor the clinical response of the patient and adjust the lopinavir/ritonavir dose as needed.
Iloperidone plasma concentrations and pharmacologic effects may be increased. Reduce the dose of iloperidone by one-half when coadministered with lopinavir/ritonavir. If therapy with lopinavir/ritonavir is discontinued, increase the dose of iloperidone to the original dose.
Indinavir plasma levels may be elevated, increasing the pharmacologic and adverse reactions. Decrease indinavir dosage to 600 mg twice daily when coadministered with lopinavir 400 mg/ritonavir 100 mg twice daily.
Irinotecan plasma levels may be elevated, increasing the pharmacologic effects and risk of toxicity (eg, diarrhea, neutropenia). Closely monitor for irinotecan toxicity.
Ixabepilone plasma levels may be elevated, increasing the pharmacologic and adverse reactions. If coadministration cannot be avoided, consider a reduction in ixabepilone dose. Consult the package labeling for ixabepilone for the specific recommendations.
Thyroxine serum concentrations may be increased or decreased. Monitor thyroid function status when lopinavir/ritonavir is started or stopped. Adjust the levothyroxine dose as needed.
Maraviroc plasma concentrations may be increased. When coadministered with lopinavir/ritonavir, patients should receive maraviroc 150 mg twice daily.
mTOR inhibitors (eg, everolimus, temsirolimus)
mTOR plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. If coadministration of lopinavir/ritonavir is necessary, monitor the clinical response of the patient and adjust the mTOR dose as needed.
Muscarinic receptor antagonists (eg, darifenacin, fesoterodine, solifenacin, tolterodine)
Muscarinic receptor antagonist plasma concentrations may be increased by lopinavir/ritonavir. When lopinavir/ritonavir is coadministered, the dose of darifenacin should not exceed 7.5 mg daily, the dose of fesoterodine should not exceed 4 mg daily, the dose of solifenacin should not exceed 5 mg daily, and the dose of tolterodine should not exceed 2 mg daily.
Lopinavir concentrations may be reduced, decreasing the efficacy. Consider a dosage increase of lopinavir/ritonavir in treatment-experienced patients when decreased susceptibility to lopinavir is clinically suspected. Nelfinavir concentrations may be increased. Do not administer lopinavir/ritonavir once daily in combination with nelfinavir.
Plasma concentrations and pharmacologic effects of nilotinib may be increased, including life-threatening cardiac arrhythmias. If coadministration cannot be avoided, closely monitor for adverse reactions, including QT prolongation. Nilotinib dosage adjustments may be needed when lopinavir/ritonavir is started or stopped.
NNRTIs (eg, delavirdine, efavirenz, nevirapine)
Lopinavir and ritonavir plasma concentrations and clinical efficacy may be reduced when coadministered with efavirenz and nevirapine. Consider a dosage increase of lopinavir/ritonavir when used in combination with efavirenz or nevirapine. Delavirdine may increase lopinavir and ritonavir concentrations. Appropriate doses of this combination have not been established.
Phosphodiesterase type 5 inhibitors (eg, sildenafil, tadalafil, vardenafil)
Coadministration of lopinavir/ritonavir with sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension. When used for erectile dysfunction, coadminister with caution and increase monitoring for adverse reactions. In patients receiving lopinavir/ritonavir, the phosphodiesterase type 5 dosage should not exceed the following: sildenafil 25 mg every 48 h, tadalafil 10 mg every 72 h, or vardenafil 2.5 mg every 72 h.
QT prolonging drugs (eg, antiarrhythmic agents [amiodarone], cisapride, pimozide)
Postmarketing cases of QT interval prolongation and torsade de pointes have been reported, although causality of lopinavir/ritonavir could not be established. An additive effect of lopinavir/ritonavir with other drugs that prolong the QT interval cannot be excluded.
Quinazolines (eg, alfuzosin, silodosin, tamsulosin)
Quinazoline plasma concentrations may be elevated. Coadministration of alfuzosin or silodosin and ritonavir is contraindicated. Similarly, tamsulosin should not be coadministered with lopinavir/ritonavir.
Rifamycins (rifabutin, rifampin, rifapentine)
Coadministration may lead to loss of virologic response and possible resistance to lopinavir/ritonavir, or to the class of protease inhibitors or other coadministered antiretroviral agents when administered with rifampin. Ritonavir may elevate serum rifabutin concentrations; therefore, dosage reduction of rifabutin by at least 75% of the usual dosage of 300 mg/day is recommended (ie, a max dosage of 150 mg every other day or 3 times per wk). Monitor for adverse reactions. Coadministration with rifampin is contraindicated.
Romidepsin plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions (including QT prolongation). If coadministration cannot be avoided, close clinical, laboratory, and ECG monitoring are indicated. Adjust the romidepsin dose as needed.
The risk of CV adverse reactions associated with salmeterol, including QT prolongation, palpitation, and sinus tachycardia may be increased. Coadministration is not recommended.
SSRIs (eg, fluoxetine, paroxetine)
The AUC of ritonavir may be increased. SSRI levels may be increased. Serotonin syndrome may occur; closely monitor for adverse reactions. A dose decrease may be needed. Lopinavir/ritonavir decreased plasma levels of paroxetine with coadministration. Guide any dose adjustment by clinical effect.
Vinblastine or vincristine concentrations may be elevated, increasing the risk of adverse reactions. Consider temporarily withholding lopinavir/ritonavir in patients who develop hematologic or GI side effects. If lopinavir/ritonavir must be withheld for a prolonged period, consider initiating a revised regimen that does not include a CYP3A or P-glycoprotein inhibitor.
Because warfarin concentrations may be altered, monitor INR when starting or stopping lopinavir/ritonavir. Adjust the warfarin dose as needed.
Therapeutic Classification: antiretrovirals
Pharmacologic Classification: protease inhibitors, metabolic inhibitors
Absorption: Well absorbed following oral administration; food enhances absorption.
Protein Binding:—98–99 % bound to plasma proteins.
Metabolism/Excretion: completely metabolized in the liver by cytochrome P450 P3A (CY P450 P3A); ritonavir is a potent inhibitor of this enzyme.
Half-life: 5–6 hr
|ORAL||RAPID||4 HOUR||12 HOUR|