Ritonavir (Monograph)
Brand name: Norvir
Drug class: HIV Protease Inhibitors
- Protease Inhibitors
VA class: AM800
Chemical name: [5S-(5R*,8R*,10R*,11R*)]10-(Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-di oxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid,5-thiazolylmethyl ester
Molecular formula: C37H48N6O5S2
CAS number: 155213-67-5
Warning
-
Concomitant use with certain classes of drugs, including sedative hypnotics, antiarrhythmics, or ergot alkaloids may result in potentially serious and/or life-threatening events due to possible effects of ritonavir on hepatic metabolism of the drugs.1 209 (See Specific Drugs and Foods under Interactions.)
Introduction
Antiretroviral; HIV protease inhibitor (PI).1 2 3 4 5 6 7 12 200 209
Uses for Ritonavir
Treatment of HIV Infection
Treatment of HIV-1 infection in adults, adolescents, and pediatric patients >1 month of age;1 209 used in conjunction with other antiretrovirals.1 209
Low-dose ritonavir is used in conjunction with other PIs to decrease metabolism of and increase plasma concentrations of the other PI (ritonavir-boosted regimens).200 201
For initial treatment in antiretroviral-naive adults and adolescents, several recommended or alternative antiretroviral regimens include certain ritonavir-boosted PIs (i.e., ritonavir-boosted atazanavir, ritonavir-boosted darunavir, fixed combination of lopinavir/ritonavir) and 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).200
For initial treatment in antiretroviral-naive pediatric patients, experts recommend several preferred and alternative regimens that include certain ritonavir-boosted PIs (i.e., ritonavir-boosted atazanavir, ritonavir-boosted darunavir, lopinavir/ritonavir) and 2 NRTIs.201
Regimens containing full-dose ritonavir or ritonavir as the sole PI are no longer recommended for initial treatment in adults, adolescents, or pediatric patients because of high pill burden, GI intolerance, and metabolic toxicity.200 201
Ritonavir Dosage and Administration
Administration
Oral Administration
Capsules
Administer orally, preferably with a meal.1 19 200 201
Tablets
Administer orally with a meal.209 Swallow tablet whole; do not break, chew, or crush.209
Solution
Administer orally, preferably with a meal.19 200 201 209
Administer using calibrated dosing syringe whenever possible.209 Agitate solution prior to each dose.209
Taste of the oral solution can be improved by mixing with up to 240 mL of chocolate milk, Ensure, or Advera; use these diluted oral solutions within 1 hour of preparation.209
Contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol;209 do not use in neonates with postmenstrual age <44 weeks (i.e., time elapsed since first day of the mother’s last menstrual period to birth plus time elapsed after birth).209 (See Pediatric Use under Cautions.)
Dosage
Must be given in conjunction with other antiretrovirals.1 Low-dose ritonavir is used with certain PIs (atazanavir, darunavir, fosamprenavir, indinavir, saquinavir, tipranavir) in ritonavir-boosted regimens.1 200 201 209
If using full-dose ritonavir, initiate therapy using a dose escalation schedule to minimize nausea.1 209
Tablets are not bioequivalent to capsules.209 Tablets may result in higher peak plasma ritonavir concentrations; patients may experience more adverse GI effects (e.g., nausea, vomiting, abdominal pain, diarrhea) when switching from capsules to tablets.209 Adverse effects (e.g., GI, paresthesias) may lessen with continued therapy.209
Pediatric Patients
Treatment of HIV Infection
Low-dose Ritonavir for Ritonavir-boosted PI Regimens
Oral4–6 mg/kg daily (80–400 mg daily).203 204 205 211 Specific dosage varies depending on which PI is used (e.g., atazanavir, darunavir, fosamprenavir, tipranavir).203 204 205 211
Full-dose Ritonavir
Oral>1 month of age: Manufacturer recommends 250 mg/m2 twice daily initially; at 2- or 3-day intervals, increase in increments of 50 mg/m2 every 12 hours as tolerated up to 350–400 mg/m2 twice daily (not >600 mg twice daily).1 209
Consult manufacturer’s product information for recommendations regarding volume of ritonavir oral solution to use for each dosage level when the dose escalation schedule is used in pediatric patients ≥1 month of age.209
If dosage of 400 mg/m2 twice daily not tolerated (due to adverse effects), highest dosage that is tolerated may be used for maintenance therapy in conjunction with other antiretrovirals; however, consider use of an alternative PI.1 209
Adults
Treatment of HIV Infection
Low-dose Ritonavir for Ritonavir-boosted PI Regimens
Oral100–400 mg daily.200 203 204 205 210 211 Specific dosage varies depending on which PI is used (e.g., atazanavir, darunavir, fosamprenavir, indinavir, saquinavir, tipranavir).200 203 204 205 210 211
Full-dose Ritonavir
OralInitially 300 mg twice daily; at 2- to 3-day intervals, increase dosage by 100 mg twice daily up to a dosage of 600 mg twice daily.1 209
Prescribing Limits
Pediatric Patients
Treatment of HIV Infection
Oral
Adults
Oral
Special Populations
Hepatic Impairment
Dosage adjustments not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B); data not available for severe hepatic impairment (Child-Pugh class C).1 209
Renal Impairment
Dosage adjustments not necessary.200
Geriatric Patients
Select dosage carefully; initiate therapy at the low end of the dosing range.1 209
Cautions for Ritonavir
Contraindications
-
Known hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) to ritonavir or any ingredient in the formulation.1 209
-
Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, amiodarone, cisapride, ergot alkaloids, flecainide, lovastatin, oral midazolam, pimozide, propafenone, quinidine, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, triazolam).1 209 (See Specific Drugs and Foods under Interactions.)
-
Concomitant use with St. John’s wort [Hypericum perforatum] or voriconazole.1 209 (See Specific Drugs and Foods under Interactions.)
Warnings/Precautions
Interactions
Concomitant use with certain drugs is contraindicated because of risk of life-threatening adverse events, significant interaction, or loss of virologic activity.1 200 209 Concomitant use with other drugs may require caution, dosage adjustments, and/or increased monitoring.1 200 209 (See Specific Drugs and Foods under Interactions.)
When ritonavir-boosted PI regimens are used, the usual cautions, precautions, and contraindications associated with the other PI should be considered.1 209
Hepatic Effects
Elevated hepatic aminotransferase concentrations >5 times ULN, clinical hepatitis, and jaundice reported; risk may be increased in patients with HBV or HCV infection.1 209
Hepatic dysfunction (including some fatalities) reported; causal relationship not established.1 209 Generally has occurred in patients with advanced HIV infection and/or receiving multiple concomitant drugs.1 209
Pancreatitis
Pancreatitis (sometimes fatal) with or without marked elevations in triglycerides has occurred.1 209
Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis.1 209
Consider pancreatitis in patients who develop abdominal pain, nausea, and vomiting or elevated serum amylase or lipase concentrations.1 209 Discontinue ritonavir if a diagnosis of pancreatitis is made.1 209
Sensitivity Reactions
Urticaria, mild skin eruptions, bronchospasm, and angioedema have occurred.1 209 Anaphylaxis or Stevens-Johnson syndrome reported rarely.1 209 Discontinue ritonavir if severe reactions occur.209
Cardiovascular Effects
Prolongation of PR interval reported.1 209 Second- or third-degree AV block reported during postmarketing monitoring.1 209
Dose-dependent prolongation of QT and PR intervals reported with ritonavir-boosted saquinavir;193 210 torsades de pointes and second- or third- degree AV block reported rarely.193 210
Use with caution in patients with structural heart disease, cardiac conduction abnormalities, ischemic heart disease, or cardiomyopathies; these individuals may be at increased risk for cardiac conduction abnormalities.1 209
Caution advised if used with other drugs that prolong PR interval (e.g., some β-adrenergic blocking agents, some calcium-channel blockers, digoxin, atazanavir), especially drugs metabolized by CYP3A.1 209
Precautions Associated with Alcohol and Propylene Glycol in the Oral Solution
Ritonavir oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol.209
Preterm neonates† [off-label] may be at increased risk of propylene glycol-associated adverse effects due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events.209
Life-threatening toxicity reported in neonates, predominantly preterm neonates receiving lopinavir/ritonavir oral solution, which also contains alcohol and propylene glycol.209 (See Pediatric Use under Cautions.)
Lipid Effects
Substantial increases in total serum cholesterol and triglyceride concentrations have occurred.1 209
Determine serum triglyceride and cholesterol concentrations prior to and periodically during therapy; manage lipid disorders as clinically appropriate.1 209 (See Specific Drugs and Food under Interactions.)
Hyperglycemic and Diabetogenic Effects
Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of PIs; diabetic ketoacidosis has occurred.1 209
Monitor blood glucose and initiate or adjust dosage of oral hypoglycemic agent or insulin as needed.1 209
Immune Reconstitution Syndrome
During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]);1 209 this may necessitate further evaluation and treatment.1 209
Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have been reported to occur in the setting of immune reconstitution; the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1 209
Adipogenic Effects
Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.1 120 121 122 123 209
Hemophilia A and B
Spontaneous bleeding noted with PIs; causal relationship not established.1 48 75 119 209
Caution in patients with a history of hemophilia type A or B.1 48 119 209 Increased hemostatic (e.g., antihemophilic factor) therapy may be needed.1 80 209
HIV Resistance
Possibility of HIV resistant to ritonavir and possible cross-resistance to other PIs.1 209 Continued full-dose ritonavir therapy after loss of viral suppression may increase likelihood of cross-resistance to other PIs.1 209
Specific Populations
Pregnancy
Antiretroviral Pregnancy Registry at 209 202 1 .[Web]800-258-4263 or
Experts state that ritonavir should only be given as low-dose ritonavir in conjunction with another PI (ritonavir-boosted PI) in pregnant women.202
Lactation
Distributed into milk in rats;202 not known whether distributed into human milk.1 209
Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 209
Pediatric Use
Safety and efficacy established in infants >1 month of age.1 209
Antiretroviral activity in children >1 month to 21 years of age similar to that in adults.1 209 Adverse effects in children >1 month to 21 years of age similar to those reported in adults; vomiting, diarrhea, skin rash/allergy reported in ≥2% of pediatric patients in clinical studies.1 209
Oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol.209 Inadvertent ingestion of the oral solution or overdosage in an infant or young child may result in substantial toxicity and is potentially lethal.209 (See Precautions Associated with Alcohol and Propylene Glycol in the Oral Solution under Cautions.)
Life-threatening cardiac toxicity (including complete AV block, bradycardia, cardiomyopathy), lactic acidosis, acute renal failure, CNS depression, and respiratory complications leading to death have been reported, predominantly in preterm neonates† [off-label] receiving lopinavir/ritonavir oral solution, which also contains alcohol and propylene glycol.209
If benefits of ritonavir oral solution for treatment of HIV infection in an infant immediately after birth are judged to outweigh potential risks, monitor the infant closely for increases in serum osmolality and Scr and other signs of toxicity, including hyperosmolality with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, apnea), seizures, hypotonia, cardiac arrhythmias, ECG changes, and hemolysis.209
If the oral solution is used in preterm neonates† [off-label] or pediatric patients 1–6 months of age, take into account the total amounts of alcohol and propylene glycol from all drugs the child is receiving to avoid toxicity associated with these excipients.209
Geriatric Use
Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1 209
Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 209
Hepatic Impairment
Use with caution in patients with preexisting liver disease, liver enzyme abnormalities, or hepatitis; consider more frequent monitoring of AST and ALT, especially during the first 3 months.1 209
Extra vigilance warranted in HIV patients with HBV or HCV coinfection because of increased risk of hepatotoxicity.1 209 Concomitant administration of low-dose ritonavir and tipranavir associated with clinical hepatitis and hepatic decompensation, including some fatalities.1 209
Potential for decreased ritonavir concentrations in patients with moderate hepatic impairment; monitor carefully.1 209 Not studied in severe hepatic impairment.1 209
Common Adverse Effects
GI effects (nausea,1 2 3 75 209 diarrhea,1 3 15 75 209 vomiting,1 3 15 75 209 anorexia,1 3 75 209 abdominal pain,1 3 75 209 taste perversion),1 3 15 75 209 asthenia,1 3 75 209 circumoral1 2 3 15 75 209 and peripheral paresthesia.1 2 15 75 209
Drug Interactions
Metabolized by CYP3A and, to a lesser extent, by CYP2D6.1 29 209
Inhibits CYP3A and, to a lesser extent, CYP2D6.1 209
Induces CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6; increases activity of glucuronosyl transferase.1 209
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A or CYP2D6 with possible alteration in metabolism of ritonavir and/or other drug.1 209
Specific Drugs and Foods
Drug or Food |
Interaction |
Comments |
---|---|---|
Alfuzosin |
Possible pharmacokinetic interaction; may result in hypotension1 209 |
|
Antiarrhythmic agents (amiodarone, disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine) |
Possible increased antiarrhythmic agent concentrations; potential for serious or life-threatening effects (e.g., cardiac arrhythmias)1 209 |
Amiodarone, flecainide, propafenone, quinidine: Concomitant use contraindicated1 200 209 Disopyramide, mexiletine, systemic lidocaine: Use caution; monitor concentrations of the antiarrhythmic agent 1 209 |
Anticoagulants, oral |
Rivaroxaban: Increased rivaroxaban concentrations and AUC; may increase bleeding risk1 200 209 |
Rivaroxaban: Avoid concomitant use1 200 209 Warfarin: Monitor INR, particularly when starting or stopping ritonavir1 200 209 |
Anticonvulsants |
Carbamazepine, clonazepam, ethosuximide: Possible increased anticonvulsant concentrations1 209 Divalproex, lamotrigine, phenytoin: Possible decreased anticonvulsant concentrations1 209 Phenobarbital: Potential for decreased concentrations of ritonavir or active PI in ritonavir-boosted regimens200 |
Carbamazepine, clonazepam, ethosuximide: Use concomitantly with caution; reduced anticonvulsant dosage may be necessary; monitor anticonvulsant concentrations1 209 Divalproex, lamotrigine, phenytoin: Use concomitantly with caution; increased anticonvulsant dosage may be needed; monitor anticonvulsant concentrations1 209 Phenobarbital: Consider other anticonvulsants; alternatively, monitor virologic response and concentrations of the active PI and phenobarbital200 |
Antifungals, azoles |
Fluconazole: No important changes in ritonavir pharmacokinetics1 28 209 Itraconazole: Potentially increased itraconazole and ritonavir concentrations1 200 209 Ketoconazole: Increased ritonavir and ketoconazole concentrations1 209 Voriconazole: Decreased voriconazole AUC (by 82% with ritonavir 400 mg twice daily1 200 209 and by 39% with ritonavir 100 mg twice daily)200 209 |
Fluconazole: Dosage adjustment not needed28 57 58 Itraconazole: Avoid itraconazole dosages >200 mg daily;1 209 consider monitoring itraconazole concentrations200 Ketoconazole: Avoid ketoconazole dosages >200 mg daily1 209 Voriconazole: Concomitant use with ritonavir 400 mg twice daily contraindicated1 209 Voriconazole: Concomitant use with low-dose ritonavir (100 mg) not recommended unless benefit outweighs risk;1 209 consider monitoring voriconazole concentrations if used concurrently with ritonavir-boosted regimens200 |
Antimycobacterials (bedaquiline, rifabutin, rifampin, rifapentine) |
Bedaquiline: Possible increased bedaquiline concentrations;200 clinical importance unknown200 Rifabutin: Increased rifabutin concentrations; possible decreased ritonavir concentrations1 30 65 141 209 Rifampin: Decreased ritonavir concentrations may lead to loss of virologic response1 58 209 Rifapentine: Possible decreased ritonavir concentrations200 |
Bedaquiline: Use concomitantly with ritonavir-boosted PIs with caution and only if potential benefits outweigh risks;200 monitor for corrected QT (QTc) interval prolongation and liver dysfunction200 Rifabutin: Reduce rifabutin dosage to 150 mg every other day or 150 mg 3 times weekly; further dosage reduction may be needed; 1 163 209 in patients receiving ritonavir-boosted PIs, some experts recommend rifabutin 150 mg daily or 300 mg 3 times weekly and plasma rifabutin concentrations and antimycobacterial activity monitoring Rifampin: Concomitant use not recommended;200 use another antimycobacterial agent1 200 209 Rifapentine: Concomitant use not recommended200 |
Atazanavir |
Increased atazanavir concentrations; concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted atazanavir) 200 203 Prolonged PR interval reported with both atazanavir and ritonavir1 209 No in vitro evidence of antagonistic antiretroviral effects203 |
Recommended dosage is ritonavir 100 mg once daily and atazanavir 300 mg once daily with food;200 203 safety and efficacy of concomitant use of atazanavir and ritonavir dosage >100 mg once daily not established203 Use concomitantly with caution and clinical monitoring1 209 Concomitant use of ritonavir-boosted atazanavir with other PIs not recommended203 |
Atovaquone |
Clinical importance unknown; increased atovaquone dosage may be needed1 209 |
|
Avanafil |
Do not use concomitantly;1 188 209 safe and effective avanafil dosage for concomitant use with ritonavir not established1 209 |
|
Benzodiazepines |
Oral midazolam or triazolam: Possible increased benzodiazepine concentrations; potential for prolonged or increased sedation or respiratory depression1 209 Clorazepate, diazepam, estazolam, flurazepam: Possible increased concentrations of the benzodiazepine1 209 Alprazolam: Decreased alprazolam clearance;1 162 209 increased risk of sedative effects162 |
Oral midazolam or triazolam: Concomitant use contraindicated1 200 209 Parenteral midazolam: Some experts state that a single parenteral dose of midazolam can be used with caution in a monitored situation for procedural sedation where respiratory depression and/or prolonged sedation can be managed;200 the manufacturer of ritonavir states that a reduced midazolam dosage be considered, particularly if multiple doses administered1 209 Clorazepate, diazepam, estazolam, flurazepam: Use with caution; reduced benzodiazepine dosage may be needed1 209 Alprazolam or diazepam: Consider alternative benzodiazepines (e.g., lorazepam, oxazepam, temazepam)200 |
β-Adrenergic blocking agents (metoprolol, timolol) |
Possible increase in concentrations of the β-adrenergic blocking agent1 209 Adverse cardiac and neurologic effects reported with β-adrenergic blocking agents 1 209 |
Monitor patient; caution advised; reduced dosage of the β-adrenergic blocking agent may be necessary1 209 |
Boceprevir |
Low-dose ritonavir: Decreased boceprevir concentrations and AUC185 Ritonavir-boosted PIs (e.g., ritonavir-boosted atazanavir, ritonavir-boosted darunavir, lopinavir/ritonavir): Decreased concentrations and AUC of boceprevir and the HIV PIs;117 185 200 possible reduced efficacy of HCV and HIV treatment regimens117 118 |
Concomitant use with ritonavir-boosted HIV PIs (e.g., ritonavir-boosted atazanavir, ritonavir-boosted darunavir, lopinavir/ritonavir) not recommended112 185 200 If boceprevir was initiated for treatment of chronic HCV in a patient coinfected with HIV receiving a suppressive antiretroviral regimen containing a ritonavir-boosted HIV PI, inform patient of possible drug interaction and closely monitor for HCV treatment response and potential HCV and HIV virologic rebound112 117 118 200 |
Bosentan |
In patients already receiving ritonavir (including low-dose ritonavir) for ≥10 days, initiate bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1 200 209 In patients already receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating ritonavir (including low-dose ritonavir); after ≥10 days of ritonavir, resume bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1 200 209 |
|
Calcium-channel blocking agents (diltiazem, nifedipine, verapamil) |
Possible increased concentrations of the calcium-channel blocking agent1 209 |
Monitor patient; caution advised; reduced dosage of the calcium-channel blocking agent may be necessary1 209 |
Cisapride |
Pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1 78 209 |
|
Co-trimoxazole |
Dosage adjustment not necessary30 |
|
Colchicine |
Patients with renal or hepatic impairment: Avoid concomitant use of colchicine and ritonavir1 200 209 Colchicine for treatment of gout flares: In those receiving ritonavir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later1 200 209 Colchicine for prophylaxis of gout flares: In those receiving ritonavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 mg once daily1 200 209 Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving ritonavir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)1 200 209 |
|
Corticosteroids (beclomethasone, budesonide, dexamethasone, fluticasone, methylprednisolone, prednisolone, prednisone, triamcinolone) |
Beclomethasone (orally inhaled, intranasal): Clinically important pharmacokinetic interactions not expected200 Budesonide or fluticasone (orally inhaled, intranasal): Increased corticosteroid concentrations;1 200 209 Cushing’s syndrome and adrenal suppression reported when ritonavir used concomitantly with budesonide or fluticasone1 175 176 177 178 179 180 181 182 200 209 Methylprednisolone, prednisolone, triamcinolone (intra-articular or other local injections): Increased corticosteroid concentrations;200 may result in adrenal insufficiency or Cushing's syndrome200 Budesonide or prednisone (systemic): Increased corticosteroid concentrations;1 200 209 may result in adrenal insufficiency or Cushing's syndrome;1 200 209 budesonide (systemic) may decrease ritonavir concentrations200 Dexamethasone (systemic): Possible increased corticosteroid concentrations;1 209 possible decreased ritonavir concentrations200 |
Budesonide or fluticasone (orally inhaled, intranasal): Do not use concomitantly unless potential benefits of inhaled or intranasal corticosteroid outweigh risks of systemic corticosteroid adverse effects;1 200 209 consider alternative (e.g., beclomethasone),200 Methylprednisolone, prednisolone, triamcinolone (intra-articular or other local injections): Do not use concomitantly; consider alternative nonsteroidal therapies; if intra-articular corticosteroid required, use alternative antiretroviral that does not alter CYP3A4 activity (e.g., dolutegravir, raltegravir)200 Budesonide or prednisone (systemic): Do not use concomitantly with ritonavir unless potential benefits outweigh risks of systemic corticosteroid adverse effects1 200 209 Dexamethasone (systemic): Use concomitantly with caution;1 200 209 consider alternative corticosteroid for long-term use200 |
Darunavir |
Increased darunavir concentrations and AUC;1 200 204 concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted darunavir)204 |
|
Dasatinib |
Dasatinib dosage may need to be decreased or dosing interval adjusted1 209 |
|
Delavirdine |
Appropriate dosage for concomitant use with respect to safety and efficacy not established1 209 |
|
Didanosine |
Decreased didanosine concentrations and AUC; no effect on ritonavir concentrations1 209 |
If ritonavir and didanosine used concomitantly, administer the drugs at least 2.5 hours apart;1 dosage adjustment generally not necessary30 57 |
Digoxin |
Increased digoxin concentrations1 209 and prolonged digoxin half-life with concomitant low-dose ritonavir200 |
Caution advised; monitor digoxin concentrations;1 209 reduced digoxin dosage may be necessary200 |
Disulfiram |
Possible disulfiram-like reaction with ritonavir capsules or oral solution because of alcohol content1 209 |
|
Dronabinol |
Use concomitantly with caution; decreased dronabinol dosage may be needed1 209 |
|
Ecstasy (methylenedioxymethamphetamine, MDMA), Liquid ecstasy (γ-hydroxybutyrate, GHB) |
||
Elvitegravir and cobicistat |
Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/COBI/TDF/FTC): Possible altered concentrations of elvitegravir or cobicistat;200 ritonavir and cobicistat have similar effects on CYP3A4200 |
EVG/COBI/TDF/FTC: Do not use concomitantly200 |
Efavirenz |
Increased ritonavir AUC and increased efavirenz AUC142 213 Higher incidence of dizziness, nausea, paresthesia, and elevated hepatic enzyme concentrations with regimens that include full-dose ritonavir (500 mg twice daily) and efavirenz142 213 |
|
Emtricitabine |
In vitro evidence of additive or synergistic antiretroviral effects218 |
|
Enfuvirtide |
Low-dose ritonavir (200 mg twice daily): Increased enfuvirtide concentrations and AUC223 |
Not considered clinically important223 |
Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine) |
Possibility of pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., acute ergot toxicity)1 209 |
Concomitant use contraindicated1 200 209 If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving ritonavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible202 |
Estrogens/Progestins |
Hormonal contraceptives: Decreased peak plasma concentrations of ethinyl estradiol with oral or transdermal contraceptive preparations1 79 209 |
Use alternative or additional contraceptive measures1 78 79 209 |
Etravirine |
Full-dose ritonavir (600 mg twice daily): Substantial decrease in etravirine concentrations and possible decreased antiretroviral efficacy214 No in vitro evidence of antagonism214 |
Full-dose ritonavir (600 mg twice daily): Concomitant use not recommended214 |
Fentanyl |
Carefully monitor for fentanyl therapeutic effects and adverse effects, including potentially fatal respiratory depression1 209 |
|
Fosamprenavir |
Increased amprenavir concentrations and AUC;1 200 209 concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted fosamprenavir)200 205 Increased potential for drug interactions since ritonavir is a potent inhibitor of CYP3A4 and also inhibits CYP2D6205 In vitro evidence of additive antiretroviral effects205 |
When ritonavir-boosted fosamprenavir is used in a once-daily regimen, recommended dosage is fosamprenavir 1.4 g once daily with ritonavir 100 or 200 mg once daily; when used in a twice-daily regimen, recommended dosage is fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily1 200 209 |
Garlic |
Interaction unlikely102 |
|
HMG-CoA reductase inhibitors (statins) |
Atorvastatin, lovastatin, rosuvastatin, pitavastatin, pravastatin, simvastatin: Decreased clearance and increased concentrations of the statin with potential for increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis1 186 209 |
Atorvastatin: Use lowest necessary atorvastatin dosage with careful monitoring1 Atorvastatin: If used concomitantly with certain ritonavir-boosted PI regimens (e.g., ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, ritonavir-boosted saquinavir), use lowest necessary atorvastatin dosage and do not exceed dosage of 20 mg daily;186 200 avoid concomitant use with some other ritonavir-boosted PI regimens (e.g., ritonavir-boosted tipranavir)186 200 Lovastatin: Concomitant use contraindicated1 200 209 Pitavastatin: Dosage adjustments not necessary if pitavastatin used concomitantly with ritonavir-boosted PI regimens200 Pravastatin: If used concomitantly with certain ritonavir-boosted PI regimens (e.g., ritonavir-boosted darunavir), titrate statin dosage using lowest possible starting dosage and closely monitor for adverse effects200 Rosuvastatin: If used concomitantly with certain ritonavir-boosted PI regimens (e.g., ritonavir-boosted atazanavir, lopinavir/ritonavir), use lowest necessary rosuvastatin dosage and do not exceed dosage of 10 mg once daily186 200 |
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus) |
Potential for increased concentrations of cyclosporine, sirolimus, or tacrolimus1 209 |
|
Indinavir |
Increased concentrations of indinavir and ritonavir;1 26 206 concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted indinavir)200 Incidence of renal effects (nephrolithiasis) may be higher when ritonavir and indinavir used concomitantly compared with usual dosage of indinavir alone200 206 |
Manufacturers of indinavir and ritonavir state that appropriate dosages with respect to safety and efficacy not established1 206 209 When ritonavir-boosted indinavir is used, some experts suggest indinavir 800 mg twice daily with ritonavir 100 or 200 mg twice daily200 |
Lopinavir/ritonavir |
Increased lopinavir concentrations and AUC;200 207 used to therapeutic advantage (commercially available as Kaletra; lopinavir in fixed combination with ritonavir [lopinavir/ritonavir])200 207 |
In patients receiving lopinavir/ritonavir, appropriate dosages of additional ritonavir not established with respect to safety and efficacy207 |
Macrolides (clarithromycin) |
Clarithromycin: Increased AUC of ritonavir and clarithromycin; decreased AUC of 14-hydroxyclarithromycin1 58 130 209 |
Clarithromycin: Dosage adjustment not needed in patients with normal renal function; reduce clarithromycin dosage by 50% in patients with Clcr of 30–60 mL/minute and by 75% in patients with Clcr <30 mL/minute1 200 209 |
Maraviroc |
Low-dose ritonavir (ritonavir 100 mg twice daily): Increased maraviroc concentrations and AUC1 209 224 No in vitro evidence of antagonistic antiretroviral effects224 |
Regimens that include low-dose ritonavir (except ritonavir-boosted tipranavir): Recommended dosage of maraviroc is 150 mg twice daily224 Ritonavir-boosted tipranavir: Recommended dosage of maraviroc is 300 mg twice daily224 |
Meperidine |
Decreased meperidine concentration; increased normeperidine (meperidine metabolite) concentration1 152 209 |
Dosage increase and long-term concomitant use not recommended because normeperidine has analgesic and CNS stimulant activity (i.e., seizures)1 209 |
Methadone |
||
Methamphetamine |
Use concomitantly with caution; decreased methamphetamine dosage may be needed1 209 |
|
Metronidazole |
Possible disulfiram-like reaction with ritonavir capsules or oral solution because of alcohol content1 209 |
|
Nelfinavir |
Increased nelfinavir concentrations; no change in ritonavir concentrations126 208 |
Appropriate dosages for concomitant use with respect to safety and efficacy not established 208 |
Nevirapine |
Clinically important pharmacokinetic interaction with full-dose ritonavir unlikely215 |
|
Nilotinib |
Nilotinib dosage may need to be decreased or dosing interval adjusted1 209 |
|
Propoxyphene |
Use concomitantly with caution; decreased propoxyphene dosage may be needed1 209 |
|
Psychotherapeutic agents |
Pimozide: Pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1 209 Quetiapine: Increased quetiapine concentrations expected200 Trazodone: Increased trazodone concentrations and AUC; adverse effects (nausea, dizziness, hypotension, syncope) reported with concomitant trazodone and ritonavir1 209 Bupropion: Possible decreased bupropion and hydroxybupropion (active metabolite) concentrations1 209 Other psychotherapeutics: Possible increased plasma concentrations of buspirone, nefazodone, perphenazine, risperidone, thioridazine1 173 209 Adverse cardiac and neurologic effects reported with nefazodone or trazodone1 173 209 |
Pimozide: Concomitant use contraindicated1 200 209 Quetiapine: Initiate quetiapine at lowest dosage and titrate as needed; if initiating ritonavir in patients receiving quetiapine, reduce quetiapine to one-sixth of original dosage; monitor for efficacy and adverse effects of quetiapine200 Trazodone: Use concomitantly with caution; consider decreased trazodone dosage1 209 Bupropion: Monitor for response to bupropion1 209 Amitriptyline, imipramine, nortriptyline: Some experts recommend using lowest antidepressant dosage and titrating dosage based on clinical response and/or antidepressant concentrations200 Other psychotherapeutics: Use concomitantly with caution; dosage reduction of the psychotherapeutic agent (buspirone, nefazodone, perphenazine, risperidone, thioridazine) may be necessary1 173 200 209 |
Quinine |
||
Quinupristin and dalfopristin |
Possible increased ritonavir concentrations151 |
|
Raltegravir |
Low-dose ritonavir (100 mg twice daily): Decreased raltegravir concentrations and AUC;1 209 225 data not available regarding concomitant use of raltegravir and higher ritonavir dosage, but raltegravir concentrations may be decreased1 209 In vitro evidence of additive to synergistic antiretroviral effects225 |
Dosage adjustments not necessary; when low-dose ritonavir used to boost PI concentrations, consider possibility of drug interactions between raltegravir and the other PI200 |
Rilpivirine |
Ritonavir-boosted PIs: Possible increased rilpivirine concentrations; not expected to affect PI concentrations226 No in vitro evidence of antagonistic antiretroviral effects226 |
|
St. John’s wort (Hypericum perforatum) |
Decreased ritonavir concentrations; possible loss of virologic response and increased risk of ritonavir resistance1 154 155 209 |
|
Salmeterol |
Increased salmeterol concentrations; may increase risk of QT interval prolongation, palpitations, or sinus tachycardia1 209 |
|
Saquinavir |
Increased saquinavir concentrations;1 52 75 78 84 209 concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted saquinavir)200 Ritonavir-boosted saquinavir causes dose-dependent prolongation of QT and PR intervals; torsades de pointes and complete heart block reported193 210 |
Recommended dosage is saquinavir 1 g twice daily and ritonavir 100 mg twice daily1 200 209 Concomitant use of ritonavir-boosted saquinavir with rifampin not recommended; risk of severe hepatotoxicity1 209 Monitor ECG and electrolytes prior to and during therapy with ritonavir-boosted saquinavir193 210 |
Selective serotonin-reuptake inhibitors (SSRIs) |
Concomitant use with some SSRIs (e.g., fluoxetine, paroxetine) may increase plasma concentrations of the SSRI1 209 Fluoxetine: Adverse cardiac and neurologic effects reported1 209 Escitalopram: Pharmacokinetic interaction unlikely192 |
|
Sildenafil |
Increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection)1 200 209 |
Sildenafil (Revatio) for treatment of PAH: Concomitant use with ritonavir (including low-dose ritonavir) contraindicated;1 200 209 ritonavir manufacturer states that a safe and effective dose for concomitant use not established1 209 Sildenafil for treatment of erectile dysfunction: Use caution and reduced sildenafil dosage (25 mg repeated no more frequently than every 48 hours);1 200 209 closely monitor for adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)1 200 209 |
Simeprevir |
Low-dose ritonavir (100 mg twice daily): Increased simeprevir AUC200 |
Concomitant use not recommended200 |
Tadalafil |
Increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection)1 200 209 |
Tadalafil (Adcirca) for treatment of PAH: In patients already receiving ritonavir for ≥1 week, use initial tadalafil dosage of 20 mg once daily and increase to 40 mg once daily based on individual tolerability1 200 209 Avoid use of tadalafil (Adcirca) for treatment of PAH during initiation of PI therapy;1 209 in a patient already receiving tadalafil (Adcirca) for treatment of PAH, discontinue tadalafil for at least 24 hours before starting ritonavir; tadalafil can be restarted after ≥1 week of ritonavir therapy using initial tadalafil dosage of 20 mg once daily and increasing dosage to 40 mg once daily based on individual tolerability1 200 209 Tadalafil for treatment of erectile dysfunction: Use caution and initial tadalafil dose of 5 mg and do not exceed a single dose of 10 mg in 72 hours1 200 209 Tadalafil for treatment of benign prostatic hyperplasia: Do not exceed tadalafil dosage of 2.5 mg once daily200 |
Telaprevir |
Low-dose ritonavir: Decreased telaprevir concentrations and AUC184 Ritonavir-boosted atazanavir: Decreased telaprevir concentrations and AUC; increased atazanavir trough concentrations and AUC184 200 Ritonavir-boosted darunavir: Decreased telaprevir and darunavir concentrations and AUC184 200 Ritonavir-boosted fosamprenavir: Decreased concentrations and AUCs of telaprevir and amprenavir (active metabolite of fosamprenavir)184 200 Lopinavir/ritonavir: Decreased telaprevir concentrations and AUC; no clinically important effect on lopinavir concentrations and AUC184 200 |
Concomitant use of telaprevir and ritonavir-boosted HIV PIs (e.g., ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, lopinavir/ritonavir) not recommended184 200 |
Theophylline |
Increased theophylline dosage may be necessary;1 209 monitor theophylline concentrations1 209 |
|
Tipranavir |
Increased tipranavir concentrations and AUC;1 200 209 concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted tipranavir)200 Ritonavir-boosted tipranavir: Hepatotoxicity, including deaths, reported1 209 211 |
Recommended dosage is ritonavir 200 mg twice daily with tipranavir 500 mg twice daily1 209 Ritonavir-boosted tipranavir: Monitor closely, including assessment of liver function tests prior to and periodically during therapy1 200 209 |
Tramadol |
Use concomitantly with caution; decreased tramadol dosage may be needed1 209 |
|
Tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline) |
Concomitant use with some tricyclic antidepressants (e.g., amitriptyline, imipramine, nortriptyline) expected to increase plasma concentrations of the antidepressant1 200 209 Desipramine: Increased desipramine concentrations1 30 70 209 |
Decreased tricyclic antidepressant dosage may be needed;1 209 experts state use lowest possible dosage of the antidepressant in patients receiving ritonavir-boosted PIs;200 titrate dosage based on clinical assessment and/or plasma concentrations of the antidepressant200 Desipramine: Decrease desipramine dosage and monitor desipramine concentrations1 30 70 209 |
Vardenafil |
Increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection)1 200 209 |
Use caution and initial vardenafil dose of 2.5 mg; do not exceed dosage of 2.5 mg once every 72 hours1 200 209 |
Vinblastine |
Manufacturer of ritonavir recommends considering temporarily withholding ritonavir-containing antiretroviral regimens in patients who develop substantial hematologic or GI toxicity: alternatively, consider using a regimen that does not include CYP3A or P-glycoprotein transport system inhibitor1 209 |
|
Vincristine |
Manufacturer of ritonavir recommends considering temporarily withholding ritonavir-containing antiretroviral regimens in patients who develop substantial hematologic or Gl toxicity: alternatively, consider using a regimen that does not include CYP3A or P-glycoprotein transport system inhibitor1 209 |
|
Zidovudine |
No effect on ritonavir pharmacokinetics; decreased zidovudine peak concentrations and AUC1 209 |
|
Zolpidem |
Use concomitantly with caution; decreased zolpidem dosage may be necessary1 209 |
Ritonavir Pharmacokinetics
Absorption
Bioavailability
Well absorbed from GI tract; peak plasma concentrations attained within 2–4 hours (fasting).1 2 3 75 209
Ritonavir tablets are not bioequivalent to ritonavir capsules; similar AUC but higher peak plasma concentration with ritonavir tablets compared with capsules.209
Food
Administration with food delays time to peak plasma concentrations by 2 hours.1
Compared with administration in the fasting state, extent of absorption was increased 13% when ritonavir capsules were administered with a meal (615 kcal, 14.5% fat, 9% protein, 76% carbohydrate).1
Compared with administration in the fasting state, extent of absorption was 21–23% lower when ritonavir tablets were administered with a moderate-fat or high-fat meal.209
Compared with administration in the fasting state, extent of absorption was decreased 7% when ritonavir oral solution was administered with a meal.209
Dilution of ritonavir oral solution with 240 mL of chocolate milk, Advera, or Ensure not associated with clinically important changes in rate or extent of absorption.209
Special Populations
Hepatic impairment: Decreased ritonavir concentrations in patients with moderate hepatic impairment compared with individuals with normal hepatic function.1 209
Pediatric patients >2 years of age: Limited data indicate ritonavir dosages of 350–400 mg/m2 twice daily in those >2 years of age result in plasma concentrations comparable to those reported in adults receiving 600 mg of ritonavir twice daily.1 209
Infants 1–24 months of age: Ritonavir trough concentrations in infants receiving 350–450 mg/m2 of ritonavir twice daily were lower than concentrations reported in adults receiving 600 mg of ritonavir twice daily.1 183 209 Higher ritonavir exposures not observed with 450 mg/m2 twice daily compared with 350 mg/m2 twice daily in these infants.1 183 209
Distribution
Extent
Low concentrations cross the placenta.202
Distributed into milk in rats;202 not known if distributed into human milk.1 202 209
Plasma Protein Binding
Special Populations
Mild to moderate hepatic impairment does not result in clinically important changes in protein binding.1 209
Elimination
Metabolism
Metabolized by CYP3A and, to a lesser extent, by CYP2D6.1 209
Elimination Route
Excreted principally in feces (86.4%) as unchanged drug (33.8%) and metabolites.1 209
Dialysis unlikely to remove substantial amounts of ritonavir;1 209 dialysis can remove alcohol and propylene glycol if overdosage of the oral solution occurs.209
Half-life
Stability
Storage
Oral
Capsules
2–8°C until dispensed.1 Once dispensed, capsules should be refrigerated at 2–8°C, but may be stored at <25°C for up to 30 days.1 Protect from light.1 Avoid exposure to excessive heat.1
Tablets
≤30°C; exposure to temperatures up to 50°C for 7 days permitted.209 Dispense in original container or USP equivalent tight container (≤60 mL); avoid prolonged exposure (>2 weeks) to high humidity outside such containers.209
Oral Solution
20–25°C; store and dispense in original container.209 Do not refrigerate; avoid exposure to excessive heat.209
Actions and Spectrum
-
Active against HIV-1;1 2 3 5 6 7 209 has some in vitro activity against HIV type 2 (HIV-2).113
-
Inhibits replication of HIV by interfering with HIV protease.1 2 3 4 5 6 7 8 9 10 11 12 209
-
HIV-1 with reduced susceptibility to ritonavir have been selected in vitro and have emerged during therapy with the drug.1 2 3 5 7 8 9 10 11 209
-
Varying degrees of cross-resistance occur among HIV PIs.1 7 9 11
Advice to Patients
-
Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 209 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 209
-
Importance of using in conjunction with other antiretrovirals—not for monotherapy.1 209
-
Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 209
-
Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency syndrome (AIDS) and death.1 209
-
Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200
-
When tablets are used, importance of taking with a meal.209 When capsules or oral solution are used, take with a meal if possible.1 209
-
If a dose is missed, it should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time; if a dose is skipped, the next dose should not be doubled.1 209
-
Advise patients that ECG changes (PR prolongation) have occurred; importance of consulting clinician if dizziness, lightheadedness, abnormal heart beats, or loss of consciousness occurs.1 209
-
Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1 209
-
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), and any concomitant illnesses.1 209
-
Advise patients receiving a selective PDE5 inhibitor (e.g., sildenafil, tadalafil, vardenafil) that they may be at increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual changes, prolonged penile erection) and that any symptoms should be promptly reported to clinician.1 209 Should not be used in patients receiving avanafil for treatment of erectile dysfunction188 or sildenafil for treatment of PAH.1 209
-
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 209 Advise HIV-infected women not to breast-feed.1 209
-
Importance of advising patients of other important precautionary information.1 209 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Capsules, liquid-filled |
100 mg |
Norvir |
AbbVie |
Solution |
80 mg/mL |
Norvir |
AbbVie |
|
Tablets, film-coated |
100 mg |
Norvir |
AbbVie |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions February 17, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
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