Trade Names:Norvir- Capsules, soft gelatin 100 mg- Solution, oral 80 mg/mLNorvir SEC (Canada)
Inhibits HIV protease, rendering the enzyme incapable of processing the gag-pol polyprotein precursor, which leads to production of noninfectious immature HIV particles.
T max after administration of the oral solution is 2 h (fasting) or 4 h (nonfasting). Under nonfasting conditions, the oral solution C max decreased 23% and the extent of absorption decreased 7%. C max is approximately 11.2 mcg/mL.
Vd is 0.41 L/kg. Protein binding is 98% to 99%, mainly to albumin and alpha-1 acid glycoprotein.
Liver via CYP3A is the major isoform involved in metabolism; CYP2D6 also contributes. Five metabolites have been identified. The major metabolite is isopropylthiazole oxidation metabolite (M-2), which has antiviral activity similar to that of the parent drug.
Eliminated in the urine (approximately 11.3% with approximately 3.5% excreted as unchanged drug) and feces (approximately 86.4% with 33.8% as unchanged drug). The half-life is 3 to 5 h. Systemic Cl is approximately 8.8 L/h (multiple dose) and approximately 4.6 L/h (single dose). Renal Cl is less than 0.1 L/h.
Pharmacokinetics have not been studied in patients with renal function impairment; however, a decrease in renal Cl is not expected.Hepatic Function Impairment
Potential for lower ritonavir concentration in moderate hepatic function impairment. Not studied in severe impairment. No dosage adjustment required for mild to moderate impairment.Elderly
Pharmacokinetics have not been studied in older patients.Children
Steady-state oral Cl for children was about 1.5 to 1.7 times faster. In children younger than 2 years of age, trough concentrations were lower than those obtained in adults; AUC and C min were approximately 16% and 60% lower, respectively, than in adults.Gender
Pharmacokinetic studies show no differences between men and women.Race
Pharmacokinetic differences have not been identified.
Treatment of HIV infection in combination with other antiretroviral agents.
Hypersensitivity to product; concomitant therapy with alfuzosin, amiodarone, bepridil, cisapride, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), flecainide, midazolam, pimozide, propafenone, quinidine, triazolam, or voriconazole.
PO 600 mg twice daily. Dosage titration may reduce adverse reactions; 300 mg twice daily and increased at 2- to 3-day intervals by 100 mg twice daily.Children older than 1 mo of age
PO Start with 250 mg/m 2 twice daily and increase dosage at 2- to 3-day intervals by 50 mg/m 2 twice daily up to the highest tolerated dose (max, 600 mg twice daily).In Combination With Protease InhibitorsAdults
PO Decrease ritonavir dosage to 100 mg once daily when given with atazanavir (300 mg daily); decrease ritonavir dosage to 100 mg twice daily when given with darunavir (600 mg twice daily), fosamprenavir (700 mg twice daily), or saquinavir; decrease ritonavir dosage to 200 mg once daily when given with fosamprenavir (1,400 mg once daily); decrease ritonavir dosage to 200 mg twice daily when given with tipranavir.
Store soft gelatin capsules in the refrigerator at 36° to 46°F until dispensed. Refrigeration of soft gelatin capsules by the patient is recommended but not required if used within 30 days and stored below 77°F. Protect from light. Avoid exposure to excessive heat.Solution
Store oral solution at 68° to 77°F. Do not refrigerate. Store and dispense in original container. Avoid exposure to excessive heat. Keep cap tightly closed.
Ritonavir plasma concentrations may be elevated, increasing the risk of adverse reactions. Adjust the ritonavir dose as needed.Anticonvulsants (ie, carbamazepine, clonazepam, ethosuximide)
Use with caution. Plasma levels may be elevated by ritonavir; adjust dose as needed.Anticonvulsants (ie, divalproex, lamotrigine, phenytoin)
Use with caution. Plasma levels may be reduced by ritonavir; adjust dose as needed.Antidepressants (eg, bupropion, nefazodone, SSRIs [eg, fluoxetine], trazodone, tricyclic antidepressants [eg, desipramine]), aripiprazole, atorvastatin, azole antifungal agents (ie, itraconazole, ketoconazole), benzodiazepines (eg, diazepam, estazolam, flurazepam), beta-blockers (eg, metoprolol, timolol), buspirone, calcium channel blockers (eg, amlodipine, diltiazem, nifedipine, verapamil), clarithromycin, clorazepate, cyclosporine, digoxin, disopyramide, dronabinol, eszopiclone, itraconazole, ketoconazole, lidocaine (systemic), methamphetamine, mexiletine, phenothiazines (eg, perphenazine, thioridazine), phosphodiesterase type 5 inhibitors (eg, sildenafil, tadalafil, vardenafil), protease inhibitors (eg, atazanavir, darunavir, fosamprenavir, tipranavir), quetiapine, quinine, rifabutin, risperidone, rosuvastatin, sirolimus, steroids (eg, dexamethasone, fluticasone, prednisone), tacrolimus, vinblastine, vincristine, zolpidem
Plasma levels may be elevated by ritonavir, increasing the risk of adverse reactions; careful monitoring and/or dosage adjustment are warranted.Atovaquone, methadone, olanzapine, pravastatin, theophylline, zidovudine
Plasma levels may be reduced by ritonavir, decreasing the efficacy; adjust dose as needed.Carbamazepine, efavirenz, mefloquine, nevirapine, rifampin, rifapentine
Ritonavir plasma levels may be decreased, resulting in a loss of virologic response.Colchicine
Colchicine plasma concentrations may be elevated, increasing the risk of toxicity. Coadministration of colchicine and ritonavir is contraindicated in patients with hepatic or renal function impairment. In patients with healthy renal and hepatic function, coadminister ritonavir and colchicine with caution, using a maximum colchicine dosage of 0.3 mg twice daily. Carefully monitor for colchicine-related adverse reactions.Didanosine
Didanosine plasma concentrations may be reduced, decreasing the efficacy. Separate administration times by 2.5 h to avoid formulation incompatibilities.Disulfiram, metronidazole
Because ritonavir formulations contain alcohol, a disulfiram-like reaction can occur.Drugs that are highly dependent on CYP3A for clearance, have a narrow therapeutic index, or that may result in a potentially serious adverse reaction because of the expected magnitude of an interaction (eg, alfuzosin, amiodarone, astemizole, bepridil, bosentan, cisapride, conivaptan, dihydroergotamine, disopyramide, dronedarone, eplerenone, ergonovine, ergotamine, flecainide, lidocaine, methylergonovine, mexiletine, midazolam, pimozide, propafenone, quinidine, ranolazine, terfenadine, triazolam, voriconazole)
Coadministration with ritonavir is contraindicated.Ethinyl estradiol
Plasma levels may be reduced by ritonavir, decreasing the efficacy. Consider alternative methods of contraception.HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin)
Risk of myopathy, including rhabdomyolysis, may be increased. Coadministration with ritonavir is not recommended.Indinavir
Indinavir plasma levels may be elevated; however, the appropriate dose when coadministered with ritonavir has not been established.Ixabepilone, nilotinib
Plasma concentrations may be elevated by ritonavir, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration with ritonavir.Levothyroxine
Thyroxine serum concentrations may be increased or decreased, resulting in hyperthyroidism or hypothyroidism. Monitor patients when starting or stopping ritonavir. Adjust the levothyroxine dose as needed.Maraviroc
Maraviroc plasma concentrations may be increased. When coadministered with ritonavir, give maraviroc 150 mg twice daily.Meperidine
Meperidine plasma levels may be decreased while levels of the active metabolite, normeperidine, may be increased; coadministration is not recommended.Muscarinic receptor antagonists (eg, darifenacin, fesoterodine, solifenacin, tolterodine)
Muscarinic receptor antagonist plasma concentrations may be increased by ritonavir. When ritonavir is coadministered, the dosage of darifenacin should not exceed 7.5 mg daily, the dosage of solifenacin should not exceed 5 mg daily, the dosage of tolterodine should not exceed 2 mg daily, and the dosage of fesoterodine should not exceed 4 mg daily.Opioid analgesics (eg, alfentanil, buprenorphine, fentanyl, propoxyphene, sufentanil, tramadol)
Dose reduction of these agents may be needed with ritonavir administration.Rifabutin
Plasma concentrations of rifabutin and its metabolite may be elevated. Reduce the rifabutin dose by at least 75%.Salmeterol
Pharmacologic effects of salmeterol may be increased by ritonavir, increasing the risk of cardiovascular toxicity (eg, QT prolongation). Coadministration is not recommended.Saquinavir
Saquinavir plasma levels may be elevated, increasing the risk of adverse reactions.Selective 5-HT 1 receptor agonists (eg, eletriptan)
Ritonavir may increase plasma concentrations and pharmacologic effects of these agents. It is recommended that eletriptan not be given within 72 h of ritonavir.St. John's wort
May lead to loss of ritonavir virologic response and possible resistance to ritonavir or the class of protease inhibitors.Tyrosine kinase receptor inhibitors (eg, dasatinib)
Ritonavir may elevate plasma concentrations of these agents, increasing the pharmacologic effects and risk of adverse reactions. Closely monitor the clinical response of the patient. Adjust the dose of tyrosine kinase receptor inhibitor as needed.Warfarin
Warfarin plasma levels may be decreased; INR monitoring is recommended.
None well documented.
Syncope, vasodilation (2%); cerebral ischemia, cerebral venous thrombosis, CV disorder, hypertension, hypotension, migraine, MI, palpitation, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia, vasospasm (less than 2%); first-degree, second-degree, or third-degree heart block, orthostatic hypotension, right bundle branch block (postmarketing).
Asthenia (15%); circumoral paresthesia, headache (7%); peripheral paresthesia (6%); dizziness (4%); insomnia, paresthesia, somnolence (3%); anxiety, depression, malaise (2%); abnormal thinking, confusion (1%); abnormal dreams, abnormal gait, agitation, amnesia, aphasia, ataxia, coma, convulsion, decreased libido, dementia, depersonalization, diplopia, emotional lability, euphoria, hallucinations, hyperesthesia, hyperkinesia, hypesthesia, incoordination, manic reaction, nervousness, neuralgia, neuropathy, paralysis, peripheral neuropathic pain, peripheral neuropathy, peripheral sensory neuropathy, personality disorder, sleep disorder, speech disorder, stupor, subdural hematoma, tonic-clonic seizures, tremor, urinary retention, vertigo, vestibular disorder (less than 2%); seizures (postmarketing).
Rash (4%); sweating (3%); acne, contact dermatitis, dry skin, eczema, erythema multiforme, exfoliative dermatitis, folliculitis, fungal dermatitis, furunculosis, maculopapular rash, molluscum contagiosum, onychomycosis, pruritus, psoriasis, pustular rash, seborrhea, skin discoloration, skin disorder, skin hypertrophy, skin melanoma, urticaria, vesiculobullous rash (less than 2%).
Pharyngitis, throat irritation (3%); abnormal electro-oculogram, abnormal electroretinogram, abnormal vision, amblyopia/blurred vision, blepharitis, conjunctivitis, ear pain, eye disorder, eye pain, hearing impairment, increased cerumen, iritis, parosmia, photophobia, taste loss, tinnitus, uveitis, visual field defect, vitreous disorder (less than 2%).
Adrenal cortex insufficiency, diabetes mellitus (less than 2%).
Nausea (30%); diarrhea (23%); vomiting (17%); taste perversion (11%); anorexia (8%); dyspepsia (6%); flatulence (2%); abnormal stools, bloody diarrhea, cheilitis, colitis, dry mouth, dysphagia, eructation, esophageal ulcer, esophagitis, gastritis, gastroenteritis, GI disorder, GI hemorrhage, gingivitis, ileus, melena, mouth ulcer, pancreatitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, sialadenitis, stomatitis, tenesmus, thirst, tongue edema, ulcerative colitis (less than 2%).
Abnormal kidney function, acute kidney failure, breast pain, cystitis, dysuria, hematuria, impotence, kidney calculus, kidney failure, kidney pain, menorrhagia, penis disorder, polyuria, urethritis, urinary frequency, UTI, vaginitis (less than 2%); renal function impairment (postmarketing).
Neutropenia (9%); hyperamylasemia (7%); thrombocytopenia (5%); anemia (4%); acute myeloblastic leukemia, anemia, ecchymosis, leukopenia, lymphadenopathy, lymphocytosis, myeloproliferative disorder, thrombocytopenia (less than 2%); increased bleeding in patients with hemophilia A or B (postmarketing).
Cholestatic jaundice, hepatic coma, hepatitis, hepatomegaly, hepatosplenomegaly, liver damage (less than 2%).
Elevated cholesterol (45%); decreased WBC (37%); triglycerides more than 800 mg/dL (34%); elevated GGT (20%); decreased RBC (19%); decreased Hct (17%); triglycerides more than 1,500 mg/dL (13%); elevated CPK (12%); elevated AST (10%); elevated ALT (9%); decreased neutrophils (6%); elevated uric acid, decreased Hgb (4%).
Weight loss (2%); albuminuria, alcohol intolerance, avitaminosis, dehydration, edema, enzymatic abnormality, glycosuria, gout, hypercholesterolemia, increased BUN, peripheral edema, xanthomatosis (less than 2%); redistribution/accumulation of body fat (postmarketing).
Arthralgia, myalgia (2%); arthritis, arthrosis, back pain, bone disorder, bone pain, extraocular palsy, joint disorder, leg cramps, muscle cramps, muscle weakness, myositis, neck pain, neck rigidity, twitching (less than 2%).
Asthma, bronchitis, dyspnea, epistaxis, hiccup, hypoventilation, increased cough, interstitial pneumonia, larynx edema, lung disorder, rhinitis, sinusitis (less than 2%).
Abdominal pain (8%); fever (5%); pain (2%); accidental injury, allergic reaction, altered hormone level, cachexia, chest pain, chills, enlarged abdomen, facial edema, facial pain, flu syndrome, hypothermia, pelvic pain, photosensitivity reaction, substernal chest pain (less than 2%); dehydration usually with GI symptoms and sometimes resulting in hypotension, syncope, or renal function impairment (postmarketing).
Drug interactions with certain nonsedating antihistamines (astemizole and terfenadine [no longer available in the US]), sedative hypnotics, antiarrhythmic agents, or ergot derivatives may result in serious and/or life-threatening adverse reactions (eg, cardiac arrhythmias, prolonged or increased sedation, respiratory depression).
Because ritonavir can increase triglycerides, cholesterol, AST, ALT, GGT, CPK, and uric acid concentrations, perform appropriate lab testing prior to initiating therapy and periodically during therapy or if any clinical signs/symptoms occur during therapy. Monitor blood glucose closely.
Category B .
Undetermined. HIV-infected mothers should not breast-feed their infants.
Not recommended for children younger than 1 mo of age.
Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.
Mild skin eruptions, urticaria, bronchospasm, angioedema, anaphylaxis, and Stevens-Johnson syndrome have been reported.
Use caution. Increased hepatic transaminase levels (5 × ULN), hepatitis, and jaundice have been reported. Ritonavir concentration may be lower.
Varying degrees of cross-resistance among protease inhibitors have been observed; continued administration following loss of viral suppression may increase likelihood of cross-resistance to other protease inhibitors.
Ritonavir may prolong the PR interval. Use with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, or cardiomyopathies.
New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia may occur.
Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy.
There have been reports of increased bleeding, including skin hematomas and hemarthrosis, in patients with hemophilia type A and B.
Has been reported in patients receiving combination antiretroviral therapy.
Substantial increases in total triglycerides and cholesterol can occur.
Major toxicity; may be fatal. Consider if patient develops abdominal pain, nausea, vomiting, or lab test abnormalities.
Paresthesia, renal failure with eosinophilia.
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