Norvir

Generic Name: Ritonavir
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

Special Alerts:

[Posted 10/21/2010] ISSUE: FDA notified healthcare professionals of new risk information added to the Warnings and Precautions, Contraindications, and Clinical Pharmacology sections of the antiviral drug saquinavir (Invirase), describing a potential change in the electrical activity of the heart when saquinavir is used with another antiviral medication, ritonavir (Norvir). Changes in the electrical activity of the heart may lead to abnormal heart rhythms, known as prolonged QT or PR intervals. A prolonged QT interval can lead to a serious abnormal rhythm called torsades de pointes, which can be fatal. A prolonged PR interval can lead to a serious abnormal rhythm called complete heart block. Torsades de pointes and complete heart block have been reported in patients taking saquinavir with ritonavir

BACKGROUND: The medications saquinavir and ritonavir are given together to treat HIV infection. Ritonavir must be given at a low dose with saquinavir in order to increase the level of saquinavir in the body. In February 2010, FDA announced it was reviewing clinical trial data about a potentially serious effect on the heart from the use of saquinavir in combination with ritonavir. This new information was derived from a clinical study designed to study a drug’s impact on the electrical activity of the heart.

RECOMMENDATION: Patients at particular risk are those with underlying heart conditions or those who have existing heart rate or rhythm problems. An electrocardiogram should be performed prior to initiation of treatment. Physicians consider whether ongoing EKG monitoring is appropriate for patients and when it should be done. The Data Summary in the Drug Safety Communication provides more details.

FDA will require that a Medication Guide be given to patients when picking up a prescription for Invirase. The Medication Guide will include information on the risk of abnormal heart rhythms. For more information visit the FDA website at: and .

[Posted 02/23/2010] FDA notified healthcare professionals and patients that it is reviewing clinical trial data about a potentially serious effect on the heart from the use of saquinavir (Invirase) in combination with ritonavir (Norvir), antiviral medications given together to treat HIV infection.

The data suggest that together the two drugs may affect the electrical activity of the heart, known as prolonged QT or PR intervals. A prolonged QT interval can increase the risk for a serious abnormal rhythm called torsades de pointes. A prolonged PR interval can cause the electrical signal responsible for generating a heart beat to slow or even stop, known as heart block.

FDA's analysis of these data is ongoing. The agency will update the public as soon as this review is complete. However, healthcare professionals should be aware of this potential risk for changes to the electrical activity of the heart. Saquinavir and ritonavir should not be used in patients already taking medications known to cause QT interval prolongation such as Class IA (such as quinidine,) or Class III (such as amiodarone) antiarrhythmic drugs, or in patients with a history of QT interval prolongation.

Patients should not stop taking their prescribed antiviral medications. Patients who are concerned about possible risks associated with using saquinavir and ritonavir should talk to their healthcare professional.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:

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  Online:

  
  


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  Phone: 1-800-332-1088

  
  


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  Mail: return the postage-paid FDA form 3500, which may be downloaded from the MedWatch “Download Forms” page (), to address on the pre-addressed form

  
  

For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for ritonavir to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

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  Concomitant use with certain nonsedating antihistamines, 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 (See Specific Drugs and Foods under Interactions.)

  
  

Introduction

Antiretroviral; HIV protease inhibitor (PI).^{1 2 3 4 5 6 7 12}

Uses for Norvir

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Treatment of HIV Infection

Treatment of HIV infection in conjunction with other antiretrovirals.¹ Regimens containing ritonavir as the sole HIV protease inhibitor (PI) no longer recommended for initial treatment in adults because of high pill burden and GI intolerance.¹⁰⁸

Low-dose ritonavir used in conjunction with other PIs to decrease metabolism of and increase plasma concentrations of the other PI (ritonavir pharmacokinetic enhancement or ritonavir-boosted regimens).^{108 143} Regimens containing low-dose ritonavir with other PIs (atazanavir, darunavir, fosamprenavir, lopinavir, saquinavir) are preferred or alternative PIs for initial therapy in adults.¹⁰⁸

Norvir Dosage and Administration

Administration

Oral Administration

Administer orally preferably with a meal.^{1 19 108 143}

Administer oral solution using the calibrated dosing syringe provided by the manufacturer.^{1 90} Agitate the solution prior to each dose.¹

The taste of the oral solution can be improved by mixing with up to 240 mL of chocolate milk, Ensure, or Advera; these diluted oral solutions should be used within 1 hour of preparation.¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Must be given in conjunction with other antiretrovirals.¹ Low-dose ritonavir used with atazanavir, darunavir, fosamprenavir, indinavir, saquinavir, or tipranavir in ritonavir-boosted regimens. If used with didanosine, adjustment in the treatment regimen recommended.^{1 108} (See Specific Drugs and Foods under Interactions.)

To minimize nausea associated with initiation of standard-dosage ritonavir therapy, initiate therapy using a dose escalation schedule.¹

Pediatric Patients

Treatment of HIV Infection

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).^{1 143}

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.^{1 143}

Table 1. Pediatric Dosage Using Oral Solution1

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)

Adults

Treatment of HIV Infection

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 Alternatively, some experts recommend 300 mg twice daily initially, then increase over 5 days to 600 mg twice daily.¹⁴³

Low-dose Ritonavir for Ritonavir-boosted Regimens

Oral

100–400 mg daily, given once daily or in 2 divided doses.¹⁰⁸

Prescribing Limits

Pediatric Patients

Treatment of HIV Infection

Oral

600 mg twice daily.^{1 143}

Special Populations

Hepatic Impairment

Dosage adjustment not necessary in patients with mild^{1 108} to moderate hepatic impairment;¹ data not available for severe hepatic impairment.^{1 108}

Renal Impairment

Dosage adjustments not necessary.¹⁰⁸

Geriatric Patients

Select dosage carefully; initiate therapy at the low end of the dosing range.¹

Cautions for Norvir

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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  Known hypersensitivity to ritonavir or any ingredient in the formulation.¹

  
  


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  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, astemizole or terfenadine [drugs no longer commercially available in the US], cisapride, ergot alkaloids, flecainide, midazolam, pimozide, propafenone, quinidine, triazolam).¹ (See Specific Drugs and Foods under Interactions.)

  
  


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  Concomitant use with voriconazole.¹ (See Specific Drugs and Foods under Interactions.)

  
  

Warnings/Precautions

Warnings

Interactions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Concomitant use with certain drugs not recommended (e.g., fluticasone, lovastatin, simvastatin, St. John’s wort) or requires particular concern (e.g., sildenafil, tadalafil, vardenafil).^{1 108} (See Specific Drugs and Foods under Interactions.)

Cardiac and neurologic events reported with certain antiarrhythmic agents (e.g., disopyramide, mexiletine), psychotherapeutic agents (e.g., nefazodone, fluoxetine), and β-adrenergic blocking agents.¹ (See Specific Drugs and Foods under Interactions.)

Hepatic Effects

Elevated hepatic aminotransferase concentrations >5 times ULN, clinical hepatitis, and jaundice reported; risk may be increased in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.¹

Hepatic dysfunction (including some fatalities) reported; causal relationship not established.¹ Generally has occurred in patients with advanced HIV infection and/or receiving multiple concomitant drugs.¹

Pancreatitis

Pancreatitis (sometimes fatal) with or without marked elevations in triglycerides has occurred.¹

Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis.¹

Consider pancreatitis in patients who develop abdominal pain, nausea, and vomiting or elevated serum amylase or lipase concentrations.¹ Discontinue ritonavir if a diagnosis of pancreatitis is made.¹

Hyperglycemic Effects

Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of PIs; diabetic ketoacidosis has occurred.¹

Monitor blood glucose and initiate or adjust dosage of oral hypoglycemic agent or insulin as needed.¹

Sensitivity Reactions

Urticaria, mild skin eruptions, bronchospasm, and angioedema have occurred.¹ Anaphylaxis or Stevens-Johnson syndrome reported rarely.¹

General Precautions

HIV Resistance

Possibility of HIV resistant to ritonavir and possible cross-resistance to other PIs.¹ Effect of ritonavir therapy on subsequent therapy with other PIs under investigation.¹

Hemophilia A and B

Spontaneous bleeding noted with PIs; causal relationship not established.^{1 48 75 119}

Caution in patients with a history of hemophilia type A or B.^{1 48 119} Increased hemostatic (e.g., antihemophilic factor) therapy may be needed.^{1 80 118}

Cardiovascular Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Prolongation of the PR interval reported.¹ Second- or third-degree AV block reported during postmarketing surveillance.¹

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

Caution if ritonavir is used with other drugs that prolong the PR interval (e.g., some β-adrenergic blocking agents, digoxin, calcium-channel blockers, atazanavir), especially drugs metabolized by CYP3A.¹

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 this may necessitate further evaluation and treatment.¹

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}

Lipid Effects

Substantial increases in total serum cholesterol and triglyceride concentrations have occurred.¹

Determine serum triglyceride and cholesterol concentrations prior to and periodically during therapy; manage lipid disorders as clinically appropriate.¹ (See Specific Drugs and Food under Interactions.)

Specific Populations

Pregnancy

Category B.¹

Antiretroviral Pregnancy Registry at 800-258-4263.¹

Low-dose ritonavir used in conjunction with other PIs in ritonavir-boosted regimens.¹⁶⁰

Lactation

Not known whether distributed into human milk.¹

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.¹

Pediatric Use

Safety and efficacy not established in infants <1 month of age.¹

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

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

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.¹

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

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

Extra vigilance warranted in HIV patients with HBV or HCV coinfection because of increased risk of hepatotoxicity.¹ Concomitant administration of tipranavir and low-dose ritonavir associated with clinical hepatitis and hepatic decompensation, including some fatalities.¹

Potential for decreased ritonavir concentrations in patients with moderate hepatic impairment; monitor carefully.¹ Not studied in severe hepatic impairment.¹

Common Adverse Effects

GI effects (nausea,^{1 2 3 75 76} diarrhea,^{1 3 15 75 76} vomiting,^{1 3 15 75 76} anorexia,^{1 3 75} abdominal pain,^{1 3 75} taste perversion);^{1 3 15 75} asthenia;^{1 3 75} circumoral^{1 2 3 15 75} and peripheral paresthesia.^{1 2 15 75}

Interactions for Norvir

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Metabolized by CYP3A and, to a lesser extent, by CYP2D6.^{1 29}

Inhibits CYP3A and, to a lesser extent, CYP2D6.¹

Induces CYP3A, CYP1A2, and possibly CYP2C9; increases activity of glucuronosyl transferase.¹

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

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Alfuzosin	Pharmacokinetic interaction; potential for serious or life-threatening reactions1	Concomitant use contraindicated1 108
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	Concomitant use with amiodarone, flecainide, propafenone, or quinidine contraindicated1 108 Caution if given with disopyramide, mexiletine, or systemic lidocaine; monitor concentrations of the antiarrhythmic agent 1
Anticoagulants, oral	Warfarin concentrations affected1 159	Use with caution; monitor INR1
Anticonvulsants	Possible increased concentrations of carbamazepine, clonazepam, or ethosuximide1	Caution if given with carbamazepine, clonazepam, or ethosuximide; reduction in dosage of the anticonvulsant may be necessary; monitor anticonvulsant concentrations1
	Possible decreased concentrations of divalproex, lamotrigine, or phenytoin 1	Caution if given with divalproex, lamotrigine, or phenytoin; increase in anticonvulsant dosage may be needed; monitor anticonvulsant concentrations1
Antifungals, azoles (fluconazole, itraconazole, ketoconazole, voriconazole)	Fluconazole: No important changes in ritonavir pharmacokinetics1 28	Fluconazole: Dosage adjustment not needed28 57 58
	Itraconazole: Increased itraconazole concentrations1	Itraconazole: Avoid itraconazole dosages >200 mg daily1
	Ketoconazole: Increased ritonavir and ketoconazole concentrations1	Ketoconazole: Avoid ketoconazole dosages >200 mg daily1
	Voriconazole: Decreased voriconazole AUC (by 82% with ritonavir 400 mg twice daily1 108 and by 39% with ritonavir 100 mg twice daily)108	Voriconazole: Concomitant use with ritonavir 400 mg twice daily contraindicated108 Voriconazole: Concomitant use with low-dose ritonavir (100 mg) not recommended unless benefit outweighs risk108
Antimycobacterials (rifabutin, rifampin, rifapentine)	Rifabutin: Increased rifabutin concentrations; possible decreased ritonavir concentrations1 30 65 141	Rifabutin: Reduce rifabutin dosage to 150 mg every other day or 150 mg 3 times weekly; further dosage reduction may be needed 1 163
	Rifampin: Decreased ritonavir concentrations1 58	Rifampin: Concomitant use not recommended;108 use another antimycobacterial agent1
		Rifapentine: Concomitant use not recommended108
Atazanavir	Increased atazanavir concentrations; concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted atazanavir)108 169 In vitro evidence of additive antiretroviral effects169	When used with atazanavir in adults, use ritonavir 100 mg once daily with atazanavir 300 mg once daily with food;108 169 safety and efficacy of concomitant use of atazanavir and ritonavir dosage >100 mg once daily not established169 Concomitant use of ritonavir-boosted atazanavir with other PIs not recommended169
Atovaquone	Possible decreased concentrations of atovaquone1	Clinical importance unknown; increase in atovaquone dosage may be needed1
Benzodiazepines	Pharmacokinetic interactions with midazolam or triazolam; potential for prolonged or increased sedation or respiratory depression1 Possible increase in clorazepate, diazepam, estazolam, or flurazepam concentrations1 Decreased clearance of alprazolam162	Manufacturer of ritonavir states that concomitant use with midazolam or triazolam contraindicated;1 108 however, some experts state a single parenteral dose of midazolam can be used with caution in a monitored situation for procedural sedation108 Caution if used with clorazepate, diazepam, estazolam, or flurazepam; reduced benzodiazepine dosage may be needed1 Increased risk of sedative effects with alprazolam162
β-Adrenergic blocking agents (metoprolol, timolol)	Possible increase in concentrations of the β-adrenergic blocking agent1 Adverse cardiac and neurologic effects reported with β-adrenergic blocking agents 1	Monitor patient; caution advised; reduced dosage of the β-adrenergic blocking agent may be necessary1
Calcium-channel blocking agents (diltiazem, nifedipine, verapamil)	Possible increased concentrations of the calcium-channel blocking agent1	Monitor patient; caution advised; reduced dosage of the calcium-channel blocking agent may be necessary1
Cisapride	Pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1 78	Concomitant use contraindicated1 108
Co-trimoxazole	Interaction unlikely1 60	Dosage adjustment not necessary30
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 ritonavir and fluticasone (oral inhalation, intranasal)1 108 175 176 177 178 179 180 181 182 Dexamethasone or prednisone: Possible increase in concentrations of the corticosteroid1	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 108 If considering use with other corticosteroids, caution advised; decreased corticosteroid dosage may be needed1
Darunavir	Increased darunavir concentrations and AUC1 108 184	Ritonavir 100 mg twice daily with darunavir 600 mg twice daily recommended1 184
Delavirdine	Increased ritonavir concentrations1 126	Appropriate dosage for concomitant use with respect to safety and efficacy not established1 108
Didanosine	In vitro evidence of additive antiretroviral effects1	If ritonavir and didanosine used concomitantly, administer the drugs at least 2.5 hours apart;1 dosage adjustment not necessary1
Digoxin	Possible increased digoxin concentrations1	Caution advised; monitor digoxin concentrations1
Disulfiram	Possible disulfiram-like reaction with ritonavir capsules or oral solution because of alcohol content1
Dronabinol	Possible increased dronabinol concentrations1	Use with caution; decreased dronabinol dosage may be needed1
Ecstasy (methylenedioxymethamphetamine, MDMA), Liquid ecstasy (γ-hydroxybutyrate, GHB)	Life-threatening reactions reported170 171 172
Efavirenz	Increased ritonavir AUC and increased efavirenz AUC31 108 142 Higher incidence of dizziness, nausea, paresthesia, and elevated hepatic enzyme concentrations with regimens that include both drugs31 142	Monitor hepatic enzymes31 142 no change in dosage needed108
Emtricitabine	In vitro evidence of additive or synergistic antiretroviral effectsf
Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)	Possibility of pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., acute ergot toxicity)1	Concomitant use contraindicated1 108 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 possible160
Estrogens/Progestins	Hormonal contraceptives: Decreased peak plasma concentrations of ethinyl estradiol with oral contraceptive preparations1 79	Use alternative or additional contraceptive measures1 78 79
Etravirine	Full-dose ritonavir: Substantial decrease in etravirine concentrations and possible decreased antiretroviral efficacy187 No in vitro evidence of antagonistic antiretroviral effects 187	When etravirine is used in conjunction with a PI, regimen must include low-dose ritonavir 187 Full-dose ritonavir (600 mg twice daily): Concomitant use not recommended108 187
Fosamprenavir	Increased amprenavir plasma concentrations and AUC1 108 185 Concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted fosamprenavir);108 185 increased potential for drug interactions since ritonavir is a potent inhibitor of CYP3A4 and also inhibits CYP2D6185 In vitro evidence of additive antiretroviral effects185	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 daily108 185 Once-daily regimen of ritonavir-boosted fosamprenavir not recommended in PI-experienced patients185 If ritonavir-boosted fosamprenavir used once daily with efavirenz, an additional 100 mg/day (300 mg total) of ritonavir is recommended185 If ritonavir-boosted fosamprenavir used, concomitant use of flecainide or propafenone contraindicated185
Garlic	Interaction unlikely102
HMG-CoA reductase inhibitors	Decreased clearance and increased concentrations of some HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin, atorvastatin) with potential for increased risk of myopathy (including rhabdomyolysis)1 Decreased concentrations of pravastatin with ritonavir-boosted saquinavir108	Concomitant use with lovastatin or simvastatin contraindicated1 108 If used with atorvastatin or rosuvastatin, use lowest possible dosage of the HMG-CoA reductase inhibitor1 Consider using HMG-CoA reductase inhibitors with a low potential for interaction (e.g., pravastatin, fluvastatin)1 165 166
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)	Potential for increased concentrations of cyclosporine, sirolimus, or tacrolimus1	Monitor concentrations of the immunosuppressive agent1
Indinavir	Increased indinavir concentrations and increased ritonavir concentrations;1 26 43 108 concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted indinavir)108 Incidence of renal effects (nephrolithiasis) may be higher when ritonavir and indinavir used concomitantly compared with usual dosage of indinavir alone43 108	Limited data support use of ritonavir 400 mg twice daily with indinavir 400 mg twice daily or ritonavir 100 or 200 mg twice daily with indinavir 800 mg twice daily17 108 164
Lopinavir	Increased lopinavir peak plasma concentrations and AUC;108 167 used to therapeutic advantage (commercially available as Kaletra; lopinavir in fixed combination with ritonavir)108 167	Additional ritonavir not recommended with lopinavir/ritonavir; appropriate dosages for such concomitant use with respect to safety and efficacy not established167
Macrolides (clarithromycin)	Increased AUC of ritonavir and clarithromycin; decreased AUC of 14-hydroxyclarithromycin1 58 130	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
Maraviroc	Low-dose ritonavir (ritonavir 100 mg twice daily): Increased concentrations of maraviroc1 108 186	Regimens that include low-dose ritonavir (except ritonavir-boosted tipranavir): Recommended dosage of maraviroc is 150 mg twice daily1 186 108
Meperidine	Decreased meperidine concentration; increased normeperidine (meperidine metabolite) concentration1 152	Dosage increase and long-term concomitant use not recommended because normeperidine has analgesic and CNS stimulant activity (i.e., seizures)1
Methadone	Decreased methadone concentrations and AUC1	Consider need to increase methadone dosage1 30 95
Methamphetamine	Possible increased methamphetamine concentrations1	Use with caution; decreased methamphetamine dosage may be needed1
Metronidazole	Possible disulfiram-like reaction with ritonavir capsules or oral solution because of alcohol content1
Nelfinavir	Increased nelfinavir concentrations; no change in ritonavir concentrations105 108 126	Appropriate dosages for concomitant use with respect to safety and efficacy not established 105 108
Nevirapine	Clinically important pharmacokinetic interactions unlikely56 108	Dosage adjustment not needed108
Propoxyphene		Use with caution; decreased propoxyphene dosage may be needed1
Psychotherapeutic agents	Pimozide: Pharmacokinetic interaction; potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1	Pimozide: Concomitant use contraindicated1 108
	Desipramine: Increased desipramine concentrations1 30 70	Desipramine: Decrease desipramine dosage and monitor desipramine concentrations1 30 70
	Trazodone: Increased trazodone concentrations and AUC;adverse effects (nausea, dizziness, hypotension, syncope) reported with concomitant trazodone and ritonavir1	Trazodone: Use with caution and consider decreased trazodone dosage1
	Bupropion: Possible decreased bupropion and hydroxybupropion (active metabolite) concentrations1	Bupropion: Monitor for response to bupropion1
	Other psychotherapeutics: Possible increased plasma concentrations of buspirone, nefazodone, perphenazine, risperidone, SSRIs, tricyclic antidepressants, thioridazine1 173	Other psychotherapeutics: Use with caution; dosage reduction of the psychotherapeutic agent (buspirone, nefazodone, perphenazine, risperidone, SSRIs, tricyclic antidepressants, thioridazine) may be necessary1 108 173
	Adverse cardiac and neurologic effects reported with fluoxetine, nefazodone, and trazodone1 173
Quinine	Possible increased quinine concentrations1	Use with caution; decreased quinine dosage may be necessary1
Quinupristin and dalfopristin	Possible increased ritonavir concentrations151
Saquinavir	Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph. Increased saquinavir concentrations1 52 75 78 84 Concomitant low-dose ritonavir used to therapeutic advantage (ritonavir-boosted saquinavir)108	Ritonavir 100 mg twice daily with saquinavir 1 g twice daily recommended1 108 110 Concomitant use of ritonavir-boosted saquinavir with rifampin not recommended; risk of severe hepatotoxicity1
St. John’s wort (Hypericum perforatum)	Decreased ritonavir concentrations; possible loss of virologic response and increased risk of ritonavir resistance43 154 155