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Ritonavir

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
Brands: Norvir

Medically reviewed by Drugs.com on Feb 8, 2021. Written by ASHP.

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. (See Specific Drugs and Foods under Interactions.)

Introduction

Antiretroviral; HIV protease inhibitor (PI).

Uses for Ritonavir

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients >1 month of age; used in conjunction with other antiretrovirals.

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).

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).

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.

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.

Ritonavir Dosage and Administration

Administration

Oral Administration

Capsules

Administer orally, preferably with a meal.

Tablets

Administer orally with a meal. Swallow tablet whole; do not break, chew, or crush.

Solution

Administer orally, preferably with a meal.

Administer using calibrated dosing syringe whenever possible. Agitate solution prior to each dose.

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.

Contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol; 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). (See Pediatric Use under Cautions.)

Dosage

Must be given in conjunction with other antiretrovirals. Low-dose ritonavir is used with certain PIs (atazanavir, darunavir, fosamprenavir, indinavir, saquinavir, tipranavir) in ritonavir-boosted regimens.

If using full-dose ritonavir, initiate therapy using a dose escalation schedule to minimize nausea.

Tablets are not bioequivalent to capsules. 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. Adverse effects (e.g., GI, paresthesias) may lessen with continued therapy.

Pediatric Patients

Treatment of HIV Infection
Low-dose Ritonavir for Ritonavir-boosted PI Regimens
Oral

4–6 mg/kg daily (80–400 mg daily). Specific dosage varies depending on which PI is used (e.g., atazanavir, darunavir, fosamprenavir, tipranavir).

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).

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.

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.

Adults

Treatment of HIV Infection
Low-dose Ritonavir for Ritonavir-boosted PI Regimens
Oral

100–400 mg daily. Specific dosage varies depending on which PI is used (e.g., atazanavir, darunavir, fosamprenavir, indinavir, saquinavir, tipranavir).

Full-dose Ritonavir
Oral

Initially 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.

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Oral

600 mg twice daily.

Adults

Oral

600 mg twice daily.

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).

Renal Impairment

Dosage adjustments not necessary.

Geriatric Patients

Select dosage carefully; initiate therapy at the low end of the dosing range.

Cautions for Ritonavir

Contraindications

  • Known hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) to ritonavir or any ingredient in the formulation.

  • 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). (See Specific Drugs and Foods under Interactions.)

  • Concomitant use with St. John’s wort [Hypericum perforatum] or voriconazole. (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. Concomitant use with other drugs may require caution, dosage adjustments, and/or increased monitoring. (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.

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.

Hepatic dysfunction (including some fatalities) reported; causal relationship not established. Generally has occurred in patients with advanced HIV infection and/or receiving multiple concomitant drugs.

Pancreatitis

Pancreatitis (sometimes fatal) with or without marked elevations in triglycerides has occurred.

Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis.

Consider pancreatitis in patients who develop abdominal pain, nausea, and vomiting or elevated serum amylase or lipase concentrations. Discontinue ritonavir if a diagnosis of pancreatitis is made.

Sensitivity Reactions

Urticaria, mild skin eruptions, bronchospasm, and angioedema have occurred. Anaphylaxis or Stevens-Johnson syndrome reported rarely. Discontinue ritonavir if severe reactions occur.

Cardiovascular Effects

Prolongation of PR interval reported. Second- or third-degree AV block reported during postmarketing monitoring.

Dose-dependent prolongation of QT and PR intervals reported with ritonavir-boosted saquinavir; torsades de pointes and second- or third- degree AV block reported rarely.

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.

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.

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.

Preterm neonates 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.

Life-threatening toxicity reported in neonates, predominantly preterm neonates receiving lopinavir/ritonavir oral solution, which also contains alcohol and propylene glycol. (See Pediatric Use under Cautions.)

Lipid Effects

Substantial increases in total serum cholesterol and triglyceride concentrations have occurred.

Determine serum triglyceride and cholesterol concentrations prior to and periodically during therapy; manage lipid disorders as clinically appropriate. (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.

Monitor blood glucose and initiate or adjust dosage of oral hypoglycemic agent or insulin as needed.

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]); this may necessitate further evaluation and treatment.

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.

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.

Hemophilia A and B

Spontaneous bleeding noted with PIs; causal relationship not established.

Caution in patients with a history of hemophilia type A or B. Increased hemostatic (e.g., antihemophilic factor) therapy may be needed.

HIV Resistance

Possibility of HIV resistant to ritonavir and possible cross-resistance to other PIs. Continued full-dose ritonavir therapy after loss of viral suppression may increase likelihood of cross-resistance to other PIs.

Specific Populations

Pregnancy

Category B.

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].

Experts state that ritonavir should only be given as low-dose ritonavir in conjunction with another PI (ritonavir-boosted PI) in pregnant women.

Lactation

Distributed into milk in rats; not known whether distributed into human milk.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Safety and efficacy established in infants >1 month of age.

Antiretroviral activity in children >1 month to 21 years of age similar to that in adults. 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.

Oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol. Inadvertent ingestion of the oral solution or overdosage in an infant or young child may result in substantial toxicity and is potentially lethal. (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 receiving lopinavir/ritonavir oral solution, which also contains alcohol and propylene glycol.

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.

If the oral solution is used in preterm neonates 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.

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

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.

Extra vigilance warranted in HIV patients with HBV or HCV coinfection because of increased risk of hepatotoxicity. Concomitant administration of low-dose ritonavir and tipranavir associated with clinical hepatitis and hepatic decompensation, including some fatalities.

Potential for decreased ritonavir concentrations in patients with moderate hepatic impairment; monitor carefully. Not studied in severe hepatic impairment.

Common Adverse Effects

GI effects (nausea, diarrhea, vomiting, anorexia, abdominal pain, taste perversion), asthenia, circumoral and peripheral paresthesia.

Interactions for Ritonavir

Metabolized by CYP3A and, to a lesser extent, by CYP2D6.

Inhibits CYP3A and, to a lesser extent, CYP2D6.

Induces CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6; increases activity of glucuronosyl transferase.

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.

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Alfuzosin

Possible pharmacokinetic interaction; may result in hypotension

Concomitant use contraindicated

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)

Amiodarone, flecainide, propafenone, quinidine: Concomitant use contraindicated

Disopyramide, mexiletine, systemic lidocaine: Use caution; monitor concentrations of the antiarrhythmic agent

Anticoagulants, oral

Rivaroxaban: Increased rivaroxaban concentrations and AUC; may increase bleeding risk

Warfarin: Possible altered warfarin concentrations

Rivaroxaban: Avoid concomitant use

Warfarin: Monitor INR, particularly when starting or stopping ritonavir

Anticonvulsants

Carbamazepine, clonazepam, ethosuximide: Possible increased anticonvulsant concentrations

Divalproex, lamotrigine, phenytoin: Possible decreased anticonvulsant concentrations

Phenobarbital: Potential for decreased concentrations of ritonavir or active PI in ritonavir-boosted regimens

Carbamazepine, clonazepam, ethosuximide: Use concomitantly with caution; reduced anticonvulsant dosage may be necessary; monitor anticonvulsant concentrations

Divalproex, lamotrigine, phenytoin: Use concomitantly with caution; increased anticonvulsant dosage may be needed; monitor anticonvulsant concentrations

Phenobarbital: Consider other anticonvulsants; alternatively, monitor virologic response and concentrations of the active PI and phenobarbital

Antifungals, azoles

Fluconazole: No important changes in ritonavir pharmacokinetics

Itraconazole: Potentially increased itraconazole and ritonavir concentrations

Ketoconazole: Increased ritonavir and ketoconazole concentrations

Voriconazole: Decreased voriconazole AUC (by 82% with ritonavir 400 mg twice daily and by 39% with ritonavir 100 mg twice daily)

Fluconazole: Dosage adjustment not needed

Itraconazole: Avoid itraconazole dosages >200 mg daily; consider monitoring itraconazole concentrations

Ketoconazole: Avoid ketoconazole dosages >200 mg daily

Voriconazole: Concomitant use with ritonavir 400 mg twice daily contraindicated

Voriconazole: Concomitant use with low-dose ritonavir (100 mg) not recommended unless benefit outweighs risk; consider monitoring voriconazole concentrations if used concurrently with ritonavir-boosted regimens

Antimycobacterials (bedaquiline, rifabutin, rifampin, rifapentine)

Bedaquiline: Possible increased bedaquiline concentrations; clinical importance unknown

Rifabutin: Increased rifabutin concentrations; possible decreased ritonavir concentrations

Rifampin: Decreased ritonavir concentrations may lead to loss of virologic response

Rifapentine: Possible decreased ritonavir concentrations

Bedaquiline: Use concomitantly with ritonavir-boosted PIs with caution and only if potential benefits outweigh risks; monitor for corrected QT (QTc) interval prolongation and liver dysfunction

Rifabutin: Reduce rifabutin dosage to 150 mg every other day or 150 mg 3 times weekly; further dosage reduction may be needed; 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; use another antimycobacterial agent

Rifapentine: Concomitant use not recommended

Atazanavir

Increased atazanavir concentrations; concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted atazanavir)

Prolonged PR interval reported with both atazanavir and ritonavir

No in vitro evidence of antagonistic antiretroviral effects

Recommended dosage is ritonavir 100 mg once daily and atazanavir 300 mg once daily with food; safety and efficacy of concomitant use of atazanavir and ritonavir dosage >100 mg once daily not established

Use concomitantly with caution and clinical monitoring

Concomitant use of ritonavir-boosted atazanavir with other PIs not recommended

Atovaquone

Possible atovaquone concentrations

Clinical importance unknown; increased atovaquone dosage may be needed

Avanafil

Increased avanafil concentrations and AUC

Do not use concomitantly; safe and effective avanafil dosage for concomitant use with ritonavir not established

Benzodiazepines

Oral midazolam or triazolam: Possible increased benzodiazepine concentrations; potential for prolonged or increased sedation or respiratory depression

Clorazepate, diazepam, estazolam, flurazepam: Possible increased concentrations of the benzodiazepine

Alprazolam: Decreased alprazolam clearance; increased risk of sedative effects

Oral midazolam or triazolam: Concomitant use contraindicated

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; the manufacturer of ritonavir states that a reduced midazolam dosage be considered, particularly if multiple doses administered

Clorazepate, diazepam, estazolam, flurazepam: Use with caution; reduced benzodiazepine dosage may be needed

Alprazolam or diazepam: Consider alternative benzodiazepines (e.g., lorazepam, oxazepam, temazepam)

β-Adrenergic blocking agents (metoprolol, timolol)

Possible increase in concentrations of the β-adrenergic blocking agent

Adverse cardiac and neurologic effects reported with β-adrenergic blocking agents

Monitor patient; caution advised; reduced dosage of the β-adrenergic blocking agent may be necessary

Boceprevir

Low-dose ritonavir: Decreased boceprevir concentrations and AUC

Ritonavir-boosted PIs (e.g., ritonavir-boosted atazanavir, ritonavir-boosted darunavir, lopinavir/ritonavir): Decreased concentrations and AUC of boceprevir and the HIV PIs; possible reduced efficacy of HCV and HIV treatment regimens

Concomitant use with ritonavir-boosted HIV PIs (e.g., ritonavir-boosted atazanavir, ritonavir-boosted darunavir, lopinavir/ritonavir) not recommended

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 rebound

Bosentan

Possible increased bosentan concentrations

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 tolerability

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 tolerability

Calcium-channel blocking agents (diltiazem, nifedipine, verapamil)

Possible increased concentrations of the calcium-channel blocking agent

Monitor patient; caution advised; reduced dosage of the calcium-channel blocking agent may be necessary

Cisapride

Pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)

Concomitant use contraindicated

Co-trimoxazole

Interaction unlikely

Dosage adjustment not necessary

Colchicine

Possible increased colchicine concentrations

Patients with renal or hepatic impairment: Avoid concomitant use of colchicine and ritonavir

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 later

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 daily

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)

Corticosteroids (beclomethasone, budesonide, dexamethasone, fluticasone, methylprednisolone, prednisolone, prednisone, triamcinolone)

Beclomethasone (orally inhaled, intranasal): Clinically important pharmacokinetic interactions not expected

Budesonide or fluticasone (orally inhaled, intranasal): Increased corticosteroid concentrations; Cushing’s syndrome and adrenal suppression reported when ritonavir used concomitantly with budesonide or fluticasone

Methylprednisolone, prednisolone, triamcinolone (intra-articular or other local injections): Increased corticosteroid concentrations; may result in adrenal insufficiency or Cushing's syndrome

Budesonide or prednisone (systemic): Increased corticosteroid concentrations; may result in adrenal insufficiency or Cushing's syndrome; budesonide (systemic) may decrease ritonavir concentrations

Dexamethasone (systemic): Possible increased corticosteroid concentrations; possible decreased ritonavir concentrations

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; consider alternative (e.g., beclomethasone),

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)

Budesonide or prednisone (systemic): Do not use concomitantly with ritonavir unless potential benefits outweigh risks of systemic corticosteroid adverse effects

Dexamethasone (systemic): Use concomitantly with caution; consider alternative corticosteroid for long-term use

Darunavir

Increased darunavir concentrations and AUC; concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted darunavir)

Dasatinib

Increased dasatinib concentrations

Dasatinib dosage may need to be decreased or dosing interval adjusted

Delavirdine

Increased ritonavir concentrations

Appropriate dosage for concomitant use with respect to safety and efficacy not established

Didanosine

Decreased didanosine concentrations and AUC; no effect on ritonavir concentrations

In vitro evidence of additive antiretroviral effects

If ritonavir and didanosine used concomitantly, administer the drugs at least 2.5 hours apart; dosage adjustment generally not necessary

Digoxin

Increased digoxin concentrations and prolonged digoxin half-life with concomitant low-dose ritonavir

Caution advised; monitor digoxin concentrations; reduced digoxin dosage may be necessary

Disulfiram

Possible disulfiram-like reaction with ritonavir capsules or oral solution because of alcohol content

Dronabinol

Possible increased dronabinol concentrations

Use concomitantly with caution; decreased dronabinol dosage may be needed

Ecstasy (methylenedioxymethamphetamine, MDMA), Liquid ecstasy (γ-hydroxybutyrate, GHB)

Life-threatening reactions reported

Elvitegravir and cobicistat

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/COBI/TDF/FTC): Possible altered concentrations of elvitegravir or cobicistat; ritonavir and cobicistat have similar effects on CYP3A4

EVG/COBI/TDF/FTC: Do not use concomitantly

Efavirenz

Increased ritonavir AUC and increased efavirenz AUC

Higher incidence of dizziness, nausea, paresthesia, and elevated hepatic enzyme concentrations with regimens that include full-dose ritonavir (500 mg twice daily) and efavirenz

Monitor hepatic enzymes

Emtricitabine

In vitro evidence of additive or synergistic antiretroviral effects

Enfuvirtide

Low-dose ritonavir (200 mg twice daily): Increased enfuvirtide concentrations and AUC

Not considered clinically important

Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

Possibility of pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., acute ergot toxicity)

Concomitant use contraindicated

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 possible

Estrogens/Progestins

Hormonal contraceptives: Decreased peak plasma concentrations of ethinyl estradiol with oral or transdermal contraceptive preparations

Use alternative or additional contraceptive measures

Etravirine

Full-dose ritonavir (600 mg twice daily): Substantial decrease in etravirine concentrations and possible decreased antiretroviral efficacy

No in vitro evidence of antagonism

Full-dose ritonavir (600 mg twice daily): Concomitant use not recommended

Fentanyl

Possible increased fentanyl concentrations

Carefully monitor for fentanyl therapeutic effects and adverse effects, including potentially fatal respiratory depression

Fosamprenavir

Increased amprenavir concentrations and AUC; concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted fosamprenavir)

Increased potential for drug interactions since ritonavir is a potent inhibitor of CYP3A4 and also inhibits CYP2D6

In vitro evidence of additive antiretroviral effects

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 daily

Garlic

Interaction unlikely

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 rhabdomyolysis

Atorvastatin: Use lowest necessary atorvastatin dosage with careful monitoring

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; avoid concomitant use with some other ritonavir-boosted PI regimens (e.g., ritonavir-boosted tipranavir)

Lovastatin: Concomitant use contraindicated

Pitavastatin: Dosage adjustments not necessary if pitavastatin used concomitantly with ritonavir-boosted PI regimens

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 effects

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 daily

Simvastatin: Concomitant use contraindicated

Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)

Potential for increased concentrations of cyclosporine, sirolimus, or tacrolimus

Monitor concentrations of the immunosuppressive agent

Indinavir

Increased concentrations of indinavir and ritonavir; concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted indinavir)

Incidence of renal effects (nephrolithiasis) may be higher when ritonavir and indinavir used concomitantly compared with usual dosage of indinavir alone

Manufacturers of indinavir and ritonavir state that appropriate dosages with respect to safety and efficacy not established

When ritonavir-boosted indinavir is used, some experts suggest indinavir 800 mg twice daily with ritonavir 100 or 200 mg twice daily

Lopinavir/ritonavir

Increased lopinavir concentrations and AUC; used to therapeutic advantage (commercially available as Kaletra; lopinavir in fixed combination with ritonavir [lopinavir/ritonavir])

In patients receiving lopinavir/ritonavir, appropriate dosages of additional ritonavir not established with respect to safety and efficacy

Macrolides (clarithromycin)

Clarithromycin: Increased AUC of ritonavir and clarithromycin; decreased AUC of 14-hydroxyclarithromycin

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/minute

Maraviroc

Low-dose ritonavir (ritonavir 100 mg twice daily): Increased maraviroc concentrations and AUC

No in vitro evidence of antagonistic antiretroviral effects

Regimens that include low-dose ritonavir (except ritonavir-boosted tipranavir): Recommended dosage of maraviroc is 150 mg twice daily

Ritonavir-boosted tipranavir: Recommended dosage of maraviroc is 300 mg twice daily

Meperidine

Decreased meperidine concentration; increased normeperidine (meperidine metabolite) concentration

Dosage increase and long-term concomitant use not recommended because normeperidine has analgesic and CNS stimulant activity (i.e., seizures)

Methadone

Decreased methadone concentrations and AUC

Consider need to increase methadone dosage

Methamphetamine

Possible increased methamphetamine concentrations

Use concomitantly with caution; decreased methamphetamine dosage may be needed

Metronidazole

Possible disulfiram-like reaction with ritonavir capsules or oral solution because of alcohol content

Nelfinavir

Increased nelfinavir concentrations; no change in ritonavir concentrations

Appropriate dosages for concomitant use with respect to safety and efficacy not established

Nevirapine

Clinically important pharmacokinetic interaction with full-dose ritonavir unlikely

Nilotinib

Increased nilotinib concentrations

Nilotinib dosage may need to be decreased or dosing interval adjusted

Propoxyphene

Use concomitantly with caution; decreased propoxyphene dosage may be needed

Psychotherapeutic agents

Pimozide: Pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)

Quetiapine: Increased quetiapine concentrations expected

Trazodone: Increased trazodone concentrations and AUC; adverse effects (nausea, dizziness, hypotension, syncope) reported with concomitant trazodone and ritonavir

Bupropion: Possible decreased bupropion and hydroxybupropion (active metabolite) concentrations

Other psychotherapeutics: Possible increased plasma concentrations of buspirone, nefazodone, perphenazine, risperidone, thioridazine

Adverse cardiac and neurologic effects reported with nefazodone or trazodone

Pimozide: Concomitant use contraindicated

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 quetiapine

Trazodone: Use concomitantly with caution; consider decreased trazodone dosage

Bupropion: Monitor for response to bupropion

Amitriptyline, imipramine, nortriptyline: Some experts recommend using lowest antidepressant dosage and titrating dosage based on clinical response and/or antidepressant concentrations

Other psychotherapeutics: Use concomitantly with caution; dosage reduction of the psychotherapeutic agent (buspirone, nefazodone, perphenazine, risperidone, thioridazine) may be necessary

Quinine

Possible increased quinine concentrations

Decreased quinine dosage may be necessary

Quinupristin and dalfopristin

Possible increased ritonavir concentrations

Raltegravir

Low-dose ritonavir (100 mg twice daily): Decreased raltegravir concentrations and AUC; data not available regarding concomitant use of raltegravir and higher ritonavir dosage, but raltegravir concentrations may be decreased

In vitro evidence of additive to synergistic antiretroviral effects

Dosage adjustments not necessary; when low-dose ritonavir used to boost PI concentrations, consider possibility of drug interactions between raltegravir and the other PI

Rilpivirine

Ritonavir-boosted PIs: Possible increased rilpivirine concentrations; not expected to affect PI concentrations

No in vitro evidence of antagonistic antiretroviral effects

St. John’s wort (Hypericum perforatum)

Decreased ritonavir concentrations; possible loss of virologic response and increased risk of ritonavir resistance

Concomitant use contraindicated

Salmeterol

Increased salmeterol concentrations; may increase risk of QT interval prolongation, palpitations, or sinus tachycardia

Concomitant use not recommended

Saquinavir

Increased saquinavir concentrations; concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted saquinavir)

Ritonavir-boosted saquinavir causes dose-dependent prolongation of QT and PR intervals; torsades de pointes and complete heart block reported

Recommended dosage is saquinavir 1 g twice daily and ritonavir 100 mg twice daily

Concomitant use of ritonavir-boosted saquinavir with rifampin not recommended; risk of severe hepatotoxicity

Monitor ECG and electrolytes prior to and during therapy with ritonavir-boosted saquinavir

Selective serotonin-reuptake inhibitors (SSRIs)

Concomitant use with some SSRIs (e.g., fluoxetine, paroxetine) may increase plasma concentrations of the SSRI

Fluoxetine: Adverse cardiac and neurologic effects reported

Escitalopram: Pharmacokinetic interaction unlikely

SSRI dosage may need to be reduced

Sildenafil

Increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection)

Sildenafil (Revatio) for treatment of PAH: Concomitant use with ritonavir (including low-dose ritonavir) contraindicated; ritonavir manufacturer states that a safe and effective dose for concomitant use not established

Sildenafil for treatment of erectile dysfunction: Use caution and reduced sildenafil dosage (25 mg repeated no more frequently than every 48 hours); closely monitor for adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)

Simeprevir

Low-dose ritonavir (100 mg twice daily): Increased simeprevir AUC

Concomitant use not recommended

Tadalafil

Increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection)

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 tolerability

Avoid use of tadalafil (Adcirca) for treatment of PAH during initiation of PI therapy; 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 tolerability

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 hours

Tadalafil for treatment of benign prostatic hyperplasia: Do not exceed tadalafil dosage of 2.5 mg once daily

Telaprevir

Low-dose ritonavir: Decreased telaprevir concentrations and AUC

Ritonavir-boosted atazanavir: Decreased telaprevir concentrations and AUC; increased atazanavir trough concentrations and AUC

Ritonavir-boosted darunavir: Decreased telaprevir and darunavir concentrations and AUC

Ritonavir-boosted fosamprenavir: Decreased concentrations and AUCs of telaprevir and amprenavir (active metabolite of fosamprenavir)

Lopinavir/ritonavir: Decreased telaprevir concentrations and AUC; no clinically important effect on lopinavir concentrations and AUC

Concomitant use of telaprevir and ritonavir-boosted HIV PIs (e.g., ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, lopinavir/ritonavir) not recommended

Theophylline

Decreased theophylline concentrations

Increased theophylline dosage may be necessary; monitor theophylline concentrations

Tipranavir

Increased tipranavir concentrations and AUC; concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted tipranavir)

Ritonavir-boosted tipranavir: Hepatotoxicity, including deaths, reported

Recommended dosage is ritonavir 200 mg twice daily with tipranavir 500 mg twice daily

Ritonavir-boosted tipranavir: Monitor closely, including assessment of liver function tests prior to and periodically during therapy

Tramadol

Use concomitantly with caution; decreased tramadol dosage may be needed

Tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline)

Concomitant use with some tricyclic antidepressants (e.g., amitriptyline, imipramine, nortriptyline) expected to increase plasma concentrations of the antidepressant

Desipramine: Increased desipramine concentrations

Decreased tricyclic antidepressant dosage may be needed; experts state use lowest possible dosage of the antidepressant in patients receiving ritonavir-boosted PIs; titrate dosage based on clinical assessment and/or plasma concentrations of the antidepressant

Desipramine: Decrease desipramine dosage and monitor desipramine concentrations

Vardenafil

Increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, visual disturbances, prolonged erection)

Use caution and initial vardenafil dose of 2.5 mg; do not exceed dosage of 2.5 mg once every 72 hours

Vinblastine

Possible increased vinblastine concentrations

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 inhibitor

Vincristine

Possible increased vincristine concentrations

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 inhibitor

Zidovudine

No effect on ritonavir pharmacokinetics; decreased zidovudine peak concentrations and AUC

In vitro evidence of additive antiretroviral effects

Dosage adjustment generally not needed

Zolpidem

Possible increased zolpidem concentrations

Use concomitantly with caution; decreased zolpidem dosage may be necessary

Ritonavir Pharmacokinetics

Absorption

Bioavailability

Well absorbed from GI tract; peak plasma concentrations attained within 2–4 hours (fasting).

Ritonavir tablets are not bioequivalent to ritonavir capsules; similar AUC but higher peak plasma concentration with ritonavir tablets compared with capsules.

Food

Administration with food delays time to peak plasma concentrations by 2 hours.

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).

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.

Compared with administration in the fasting state, extent of absorption was decreased 7% when ritonavir oral solution was administered with a meal.

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.

Special Populations

Hepatic impairment: Decreased ritonavir concentrations in patients with moderate hepatic impairment compared with individuals with normal hepatic function.

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.

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. Higher ritonavir exposures not observed with 450 mg/m2 twice daily compared with 350 mg/m2 twice daily in these infants.

Distribution

Extent

Not fully characterized.

Low concentrations cross the placenta.

Distributed into milk in rats; not known if distributed into human milk.

Plasma Protein Binding

98–99%.

Special Populations

Mild to moderate hepatic impairment does not result in clinically important changes in protein binding.

Elimination

Metabolism

Metabolized by CYP3A and, to a lesser extent, by CYP2D6.

Elimination Route

Excreted principally in feces (86.4%) as unchanged drug (33.8%) and metabolites.

Dialysis unlikely to remove substantial amounts of ritonavir; dialysis can remove alcohol and propylene glycol if overdosage of the oral solution occurs.

Half-life

3–5 hours.

Stability

Storage

Oral

Capsules

2–8°C until dispensed. Once dispensed, capsules should be refrigerated at 2–8°C, but may be stored at <25°C for up to 30 days. Protect from light. Avoid exposure to excessive heat.

Tablets

≤30°C; exposure to temperatures up to 50°C for 7 days permitted. Dispense in original container or USP equivalent tight container (≤60 mL); avoid prolonged exposure (>2 weeks) to high humidity outside such containers.

Oral Solution

20–25°C; store and dispense in original container. Do not refrigerate; avoid exposure to excessive heat.

Actions and Spectrum

  • Active against HIV-1; has some in vitro activity against HIV type 2 (HIV-2).

  • Inhibits replication of HIV by interfering with HIV protease.

  • HIV-1 with reduced susceptibility to ritonavir have been selected in vitro and have emerged during therapy with the drug.

  • Varying degrees of cross-resistance occur among HIV PIs.

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.

  • Importance of using in conjunction with other antiretrovirals—not for monotherapy.

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.

  • Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency syndrome (AIDS) and death.

  • 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. 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.

  • When tablets are used, importance of taking with a meal. When capsules or oral solution are used, take with a meal if possible.

  • 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.

  • Advise patients that ECG changes (PR prolongation) have occurred; importance of consulting clinician if dizziness, lightheadedness, abnormal heart beats, or loss of consciousness occurs.

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.

  • 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.

  • 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. Should not be used in patients receiving avanafil for treatment of erectile dysfunction or sildenafil for treatment of PAH.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise HIV-infected women not to breast-feed.

  • Importance of advising patients of other important precautionary information. (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.

Ritonavir

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 2022, Selected Revisions February 17, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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