Ritonavir

Pronunciation

Class: HIV 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

Warning(s)

  • Concomitant use with certain sedative hypnotics, antiarrhythmics, or ergot alkaloids may result in 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 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 Regimens containing low-dose ritonavir with certain other PIs (atazanavir, darunavir, fosamprenavir, lopinavir) are preferred or alternative PIs for initial therapy in adults, adolescents, and children.200 201

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Regimens containing ritonavir as the sole PI (full-dose ritonavir) are no longer recommended for initial treatment in adults, adolescents, or pediatric patients because of high pill burden and GI intolerance.200 201

Ritonavir Dosage and Administration

Administration

Oral Administration

Capsules

Administer orally, preferably with a meal.1 19 200 201

Solution

Administer orally, preferably with a meal.19 200 201 209

Recommended for children >1 month of age who cannot swallow capsules.1

Administer using calibrated dosing syringe when 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

Tablets

Administer orally with a meal.209 Swallow tablet whole; do not break, chew, or crush.209

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.1 200 209

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
Full-dose Ritonavir
Oral

>1 month of age: Initially, 250 mg/m2 twice daily, increase in increments of 50 mg/m2 every 12 hours (i.e., by 100 mg/m2 daily) at intervals of 2–3 days as tolerated up to 350–400 mg/m2 twice daily (not >600 mg twice daily).1 209

If a dosage of 400 mg/m2 twice daily is not tolerated (due to adverse effects), use highest dosage that is tolerated or consider use of an alternative PI.1 209

Table 1. Pediatric Dosage of Full-dose Ritonavir Using Oral Solution209

Body Surface Area (m2)

Twice daily dose of 250 mg/m2

Twice daily dose of 300 mg/m2

Twice daily dose of 350 mg/m2

Twice daily dose of 400 mg/m2

0.2

0.6 mL (50 mg)

0.75 mL (60 mg)

0.9 mL (70 mg)

1 mL (80 mg)

0.25

0.8 mL (62.5 mg)

0.9 mL (75 mg)

1.1 mL (87.5 mg)

1.25 mL (100 mg)

0.5

1.6 mL (125 mg)

1.9 mL (150 mg)

2.2 mL (175 mg)

2.5 mL (200 mg)

0.75

2.3 mL (187.5 mg)

2.8 mL (225 mg)

3.3 mL (262.5 mg)

3.75 mL (300 mg)

1

3.1 mL (250 mg)

3.75 mL (300 mg)

4.4 mL (350 mg)

5 mL (400 mg)

1.25

3.9 mL (312.5 mg)

4.7 mL (375 mg)

5.5 mL (437.5 mg)

6.25 mL (500 mg)

1.5

4.7 mL (375 mg)

5.6 mL (450 mg)

6.6 mL (525 mg)

7.5 ml (600 mg)

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

Adults

Treatment of HIV Infection
Full-dose Ritonavir
Oral

Initially 300 mg twice daily; increase dosage every 2–3 days by 100 mg twice daily up to a dosage of 600 mg twice daily.1 209

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

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection
Oral

600 mg twice daily.1 209

Special Populations

Hepatic Impairment

Dosage adjustment 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.1 209 200 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

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 jiroveci [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 800-258-4263 or .1 202 209

Only limited experience using full-dose ritonavir in pregnant women; low concentrations reported.202 Some experts state that ritonavir should only be given as low-dose ritonavir in conjunction with another PI (ritonavir-boosted PI regimens) 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 not 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

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

Interactions for Ritonavir

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 (warfarin)

Warfarin concentrations affected1 159 209

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 concentrations1 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 (rifabutin, rifampin, rifapentine)

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

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 AUC188

Do not use concomitantly188

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; the manufacturer of ritonavir states that a reduced midazolam dosage be considered, particularly if multiple doses administered1 200 209

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 (dexamethasone, fluticasone, prednisone)

Fluticasone nasal spray/oral inhalation: Increased fluticasone concentrations resulting in decreased cortisol concentrations; systemic corticosteroid effects (Cushing’s syndrome, adrenal suppression) reported with concomitant ritonavir1 175 176 177 178 179 180 181 182 200 209

Dexamethasone or prednisone: Possible increased corticosteroid concentrations1

Fluticasone nasal spray/oral inhalation: Concomitant use with ritonavir, including low-dose ritonavir, not recommended unless potential benefits outweigh risk of systemic corticosteroid adverse effects1 200 209

Dexamethasone: Use caution;200 reduced corticosteroid dosage may be needed;1 209 consider alternative corticosteroid for long-term therapy200

Prednisone: Reduced corticosteroid dosage may be needed1 209

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

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, ergonovine, 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 Clcr of 30–60 mL/minute and by 75% in patients with Clcr <30 mL/minute1 200 209

Maraviroc

Low-dose ritonavir (ritonavir 100 mg twice daily): Increased maraviroc concentrations and AUC1 209 224

No in vitro evidence of antagonistic antiretroviral effects224

Regimens that include low-dose ritonavir (except ritonavir-boosted tipranavir): Recommended dosage of maraviroc is 150 mg twice daily224

Ritonavir-boosted tipranavir: Recommended dosage of maraviroc is 300 mg twice daily224

Meperidine

Decreased meperidine concentration; increased normeperidine (meperidine metabolite) concentration1 152 209

Dosage increase and long-term concomitant use not recommended because normeperidine has analgesic and CNS stimulant activity (i.e., seizures)1 209

Methadone

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

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

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 AUC225

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

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

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

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

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, nortriptyline)

Concomitant use with some tricyclic antidepressants (e.g., amitriptyline, nortriptyline) may increase plasma concentrations of the tricyclic1 209

Desipramine: Increased desipramine concentrations1 30 70 209

Tricyclic dosage may need to be reduced1 209

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

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

20–25°C (may be exposed to 15–30°C).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

  • Pharmacologically related to other PIs (e.g., amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir); differs structurally from these drugs and also differs pharmacologically and structurally from other currently available antiretrovirals.1 6 8 12 209

  • 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

  • Cross-resistance between ritonavir and nucleoside reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs) unlikely since the drugs have different target enzymes and mechanisms of action.1 209

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.

Ritonavir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, liquid-filled

100 mg

Norvir

Abbott

Solution

80 mg/mL

Norvir

Abbott

Tablets, film-coated

100 mg

Norvir

Abbott

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Norvir 100MG Capsules (ABBOTT): 30/$290.98 or 90/$842.94

Norvir 100MG Tablets (ABBOTT): 30/$289.99 or 90/$825.91

Norvir 80MG/ML Solution (ABBOTT): 240/$1,508.58 or 720/$4,525.74

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 25, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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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.

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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. Abbott Laboratories. Norvir (ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2012 Feb.

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.

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

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