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

Medically reviewed by Drugs.com on Feb 7, 2024. 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.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

Oral

4–6 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

Oral

100–400 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

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.¹ ²⁰⁹

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection

Oral

600 mg twice daily.¹ ²⁰⁹

Adults

Oral

600 mg twice daily.¹ ²⁰⁹

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

Category B.¹ ²⁰⁹

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 S_cr 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	Concomitant use contraindicated¹ ²⁰⁰ ²⁰⁹
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 Warfarin: Possible altered warfarin concentrations¹ ¹⁵⁹ ²⁰⁹	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 (QT_c) 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	Possible atovaquone concentrations¹ ²⁰⁹	Clinical importance unknown; increased atovaquone dosage may be needed¹ ²⁰⁹
Avanafil	Increased avanafil concentrations and AUC¹ ¹⁸⁸ ²⁰⁹	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	Possible increased bosentan concentrations¹ ²⁰⁹	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	Concomitant use contraindicated¹ ²⁰⁰ ²⁰⁹
Co-trimoxazole	Interaction unlikely¹ ⁶⁰ ²⁰⁹	Dosage adjustment not necessary³⁰
Colchicine	Possible increased colchicine concentrations¹ ²⁰⁹	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	Increased dasatinib concentrations¹ ²⁰⁹	Dasatinib dosage may need to be decreased or dosing interval adjusted¹ ²⁰⁹
Delavirdine	Increased ritonavir concentrations¹ ¹²⁶ ²⁰⁹	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 In vitro evidence of additive antiretroviral effects¹ 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	Possible increased dronabinol concentrations¹ ²⁰⁹	Use concomitantly with caution; decreased dronabinol dosage may be needed¹ ²⁰⁹
Ecstasy (methylenedioxymethamphetamine, MDMA), Liquid ecstasy (γ-hydroxybutyrate, GHB)	Life-threatening reactions reported¹⁷⁰ ¹⁷¹ ¹⁷²
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	Monitor hepatic enzymes¹⁴² 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	Possible increased fentanyl concentrations¹ ²⁰⁹	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 Simvastatin: Concomitant use contraindicated¹ ²⁰⁰ ²⁰⁹
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)	Potential for increased concentrations of cyclosporine, sirolimus, or tacrolimus¹ ²⁰⁹	Monitor concentrations of the immunosuppressive agent¹ 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 Cl_cr of 30–60 mL/minute and by 75% in patients with Cl_cr <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	Decreased methadone concentrations and AUC¹ ²⁰⁹	Consider need to increase methadone dosage¹ ³⁰ ⁹⁵ ²⁰⁹
Methamphetamine	Possible increased methamphetamine concentrations¹ ²⁰⁹	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	Increased nilotinib concentrations¹ ²⁰⁹	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	Possible increased quinine concentrations¹ ²⁰⁹	Decreased quinine dosage may be necessary¹ ²⁰⁹
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	Concomitant use contraindicated¹ ²⁰⁰ ²⁰⁹
Salmeterol	Increased salmeterol concentrations; may increase risk of QT interval prolongation, palpitations, or sinus tachycardia¹ ²⁰⁹	Concomitant use not recommended¹ ²⁰⁰ ²⁰⁹
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	SSRI dosage may need to be reduced¹ ²⁰⁹
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	Decreased theophylline concentrations¹ ⁶⁸ ²⁰⁹	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	Possible increased vinblastine concentrations¹ ²⁰⁹	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	Possible increased vincristine concentrations¹ ²⁰⁹	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 In vitro evidence of additive antiretroviral effects¹ ²⁰⁹	Dosage adjustment generally not needed³⁰ ⁵⁷
Zolpidem	Possible increased zolpidem concentrations¹ ²⁰⁹	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

Not fully characterized.¹ ²⁰⁹

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

98–99%.¹ ²⁰⁹

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

3–5 hours.¹ ²⁰⁹

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.

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

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

References

1. AbbVie Inv. Norvir (ritonavir) soft gelatin capsules prescribing information. North Chicago, IL; 2013 Nov.

2. Danner SA, Carr A, Leonard JM et al et al. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. N Engl J Med. 1995; 333:1528-33. http://www.ncbi.nlm.nih.gov/pubmed/7477167?dopt=AbstractPlus

3. Markowitz M, Saag M, Powderly WG et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med. 1995; 333:1534-9. http://www.ncbi.nlm.nih.gov/pubmed/7477168?dopt=AbstractPlus

4. Erickson J, Neidhart DJ, VanDrie J et al. Design, activity, and 2.8 A crystal structure of a C₂ symmetric inhibitor complexed to HIV-1 protease. Science. 1990; 249:527-33. http://www.ncbi.nlm.nih.gov/pubmed/2200122?dopt=AbstractPlus

5. Kempf DJ, Marsh KC, Denissen JF et al. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc Natl Acad Sci USA. 1995; 92:2484-8. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=42242&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/7708670?dopt=AbstractPlus

6. Vella S. Rationale and experience with reverse transcriptase inhibitors and protease inhibitors. J Acquir Immune Defic Syndr Hum Retrovirol. 1995; 10(Suppl 1):S58-61.

7. Markowitz M, Mo H, Kempf DJ et al. Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor. J Virol. 1995; 69:701-6. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=188631&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/7815532?dopt=AbstractPlus

8. Molla A, Korneyeva M, Gao Q et al. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat Mat. 1996; 2:760-6.

9. Tisdale M, Myers RE, Maschera B et al. Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors. Antimicrob Agents Chemother. 1995; 39:1704-10. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=162812&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/7486905?dopt=AbstractPlus

10. Carrillo A, Stewart KD, Sham HL et al. In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor. J Virol. 1998; 72:7532-41. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=109995&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/9696850?dopt=AbstractPlus

11. Ridky T, Leis J. Development of drug resistance to HIV-1 protease inhibitors. J Biol Chem. 1995; 270:29621-3. http://www.ncbi.nlm.nih.gov/pubmed/8530341?dopt=AbstractPlus

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66. Sun E, Heath-Chiozzi M, Cameron DW et al. Concurrent ritonavir and rifabutin increases risk of rifabutin-associated adverse effects. In: XI International Conference on AIDS, 1996: Abstracts-on-disk. Vancouver, BC, 1996 Jul 7–12. Abstract No. Mo.B.171.

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166. Scara L (Novartis Pharmaceuticals, East Hanover, NJ): Personal communication; 2000 Aug 1.

168. American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC). Targeted tuberculin testing and treatment of latent tuberculosis infections. Am J Respir Crit Care Med. 2000; 161:S221-47.

170. Antonious T, Tsang AL. Interactions between recreational drugs and antiretroviral agents. Ann Pharmacol. 2002; 38:1598-613.

171. Harrington RD. Life-threatening interactions between HIV-1 protease inhibitors and the illicit drugs MDMA and γ-hydroxybutyrate. Arch Intern Med. 1999; 159:2221-4. http://www.ncbi.nlm.nih.gov/pubmed/10527300?dopt=AbstractPlus

172. Henry JA, Hill IR. Fatal interaction between ritonavir and MDMA. Lancet. 1998; 352:1751-2. http://www.ncbi.nlm.nih.gov/pubmed/9848354?dopt=AbstractPlus

173. Lewis-Hall FD. Dear healthcare professional letter: Change in labeling for Deseryl (trazodone hydrochloride) tablets. Princeton, NJ: Bristol-Myers Squibb Company 2004. From the FDA website; accessed 2004 Sep 24. http://www.fda.gov/medwatch/SAFETY/2004/Desyrel_DHCP.pdf

175. Gupta SK, Dubé MP. Exogenous Cushing syndrome mimicking human immunodeficiency virus lipodystrophy. Clin Infect Dis. 2002; 35:e69-71. http://www.ncbi.nlm.nih.gov/pubmed/12203188?dopt=AbstractPlus

176. Rouanet I, Peyrière H, Mauboussin JM, Vincent D. Cushing’s syndrome in a patient treated by ritonavir/lopinavir and inhaled fluticasone. HIV Medicine. 2003; 4:140-150. Letter

177. Clevenbergh P, Corcostegui M, Gérard D et al. Iatrogenic Cushing’s syndrome in an HIV-infected patient treated with inhaled corticosteroids (fluticasone propionate) and low dose ritonavir enhanced PI containing regimens. J Infect. 2002; 44:194-5. http://www.ncbi.nlm.nih.gov/pubmed/12099750?dopt=AbstractPlus

178. Samaras K, Pett S, Gowers A et al. Iatrogenic Cushing’s syndrome with osteoporosis and secondary adrenal failure in human immunodeficiency virus-infected patients receiving inhaled corticosteroids and ritonavir-boosted protease inhibitors: six cases. J Clin Endocrinol Metab. 2005; 90:4394-8. http://www.ncbi.nlm.nih.gov/pubmed/15755851?dopt=AbstractPlus

179. Hillebrand-Haverkort ME, Prummel MF, ten Veen JH. Ritonavir-induced Cushing’s syndrome in a patient treated with nasal fluticasone. AIDS. 1999; 10:1803. Letter

180. Chen F, Kearney T, Robinson S et al. Cushing’s syndrome and severe adrenal suppression in patients treated with ritonavir and inhaled nasal fluticasone. Sex Transm Infect. 1999; 75:274. Letter http://www.ncbi.nlm.nih.gov/pubmed/10615321?dopt=AbstractPlus

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184. Vertex Pharmaceuticals Incorporated. Incivek (telaprevir) film-coated tablets prescribing information. Cambridge, MA; 2012 Jun.

185. Merck & Co. Victrelis (boceprevir) capsules prescribing information. Whitehouse Station, NJ; 2012 Apr.

186. Food and Drug Administration. FDA drug safety communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increse the risk of muscle injury. 2012 Mar 1. From FDA website. Accessed 2012 Apr 23. http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm

188. Vivus. Stendra (avanafil) tablets prescribing information. Mountain View, CA; 2012 Apr.

192. Forest Pharmaceuticals, Inc. Lexapro (escitalopram oxalate) tablets and oral solution prescribing information. St. Louis, MO; 2009 Mar.

193. Food and Drug Administration. FDA drug safety communication: Invirase (saquinavir) labels now contain updated risk information on abnormal heart rhythms. From FDA website. http://www.fda.gov/Drugs/DrugSafety/ucm230096.htm

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202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (March 28, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

203. Bristol-Myers Squibb. Reyataz (atazanavir sulfate) capsules prescribing information. Princeton, NJ; 2012 Mar.

204. Janssen. Prezista (darunavir) oral suspension and tablets prescribing information. Titusville, NJ; 2012 Jun.

205. ViiV Healthcare. Lexiva (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2012 Feb.

206. Merck Sharp & Dohme. Crixivan (indinavir sulfate) capsules prescribing information. Whitehouse Station, NJ; 2012 Apr.

207. Abbott Laboratories. Kaletra (lopinavir/ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2012 Feb.

208. ViiV Healthcare. Viracept (nelfinavir mesylate) tablets and oral powder prescribing information. Research Triangle Park, NC; 2012 Apr.

209. AbbVie Inc. Norvir (ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2013 Nov.

210. Genentech USA. Invirase (saquinavir mesylate) capsules and tablets prescribing information. South San Francisco, CA; 2012 Feb.

211. Boehringer Ingelheim. Aptivus (tipranavir) capsules and oral solution prescribing information. Ridgefield, CT; 2012 Apr.

213. Bristol-Myers Squibb. Sustiva (efavirenz) capsules and tablets prescribing information. Princeton, NJ; 2012 Jun.

214. Janssen. Intelence (etravirine) tablets prescribing information. Raritan, NJ; 2012 Mar.

215. Boehringer Ingelheim. Viramune (nevirapine) tablets and oral suspension prescribing information. Ridgefield, CT; 2011 Nov.

218. Gilead Sciences. Emtriva (emtricitabine) capsules and oral solution prescribing information. Foster City, CA; 2012 Jul.

223. Genentech USA. Fuzeon (enfuvirtide) for injection prescribing information. South San Francisco, CA; 2011 Aug.

224. ViiV Healthcare. Selzentry (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2011 Nov.

225. Merck Sharp & Dohme. Isentress (raltegravir) film-coated tablets and chewable tablets prescribing information. Whitehouse Station, NJ; 2012 Apr.

226. Tibotec Therapeutics. Edurant (rilpivirine) tablets prescribing information. Raritan, NJ; 2011 May.

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Pill H R9 is Ritonavir 100 mg — Ritonavir 100 mg (H R9)