Brand name: Norvir
Drug class: HIV Protease Inhibitors

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Introduction

Antiretroviral; HIV protease inhibitor (PI).

Uses for Ritonavir

Treatment of HIV Infection

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

Regimens containing full-dose ritonavir or ritonavir as the sole PI are no longer recommended for initial treatment because of high pill burden, GI intolerance, and metabolic toxicity.

Low-dose ritonavir is commonly used in conjunction with other PIs as a pharmacokinetic enhancer (booster) to decrease metabolism of and increase plasma concentrations of the other PI; consult guidelines for the most current information on recommended regimens. Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

Postexposure prophylaxis of HIV infection following occupational exposure^{† [off-label]} (PEP) in health-care personnel and others exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

USPHS recommends 3-drug regimen of raltegravir in conjunction with emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) as the preferred regimen for PEP following occupational exposures to HIV. Several alternative regimens that include an integrase strand transfer inhibitor (INSTI), nonnucleoside reverse transcriptase inhibitor (NNRTI), or PI and 2 nucleoside reverse transcriptase inhibitors (NRTIs) also recommended. Recommended alternatives to raltegravir (to be given in conjunction with 2 NRTIs) include ritonavir-boosted darunavir, etravirine, rilpivirine, ritonavir-boosted atazanavir, and lopinavir/ritonavir.

Management of occupational exposures to HIV is complex and evolving; consult infectious diseases specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible. Do not delay initiation of PEP while waiting for expert consultation.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)

Postexposure prophylaxis of HIV infection following nonoccupational exposure^{† [off-label]} (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.

When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, CDC states preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (given as emtricitabine/tenofovir DF; Truvada); alternative recommended in these patients is ritonavir-boosteddarunavir used in conjunction with emtricitabine/tenofovir DF (Truvada).

Consult infectious diseases specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) if nPEP indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if considering a regimen not included in CDC guidelines, source virus is known or likely to be resistant to antiretrovirals, or healthcare provider is inexperienced in prescribing antiretrovirals. Do not delay initiation of nPEP while waiting for expert consultation.

Ritonavir Dosage and Administration

General

Pretreatment Screening

• Evaluate serum triglyceride and serum cholesterol concentrations prior to initiation of ritonavir therapy.

• Ritonavir use has been associated with changes in serum AST, ALT, γ-glutamyltransferase (GGT), creatine phosphokinase (CPK), and uric acid. Perform appropriate laboratory tests prior to initiation of therapy.

Patient Monitoring

• Consider monitoring for hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus in patients receiving ritonavir.

• Monitor serum triglyceride and serum cholesterol concentrations at periodic intervals during ritonavir therapy.

• Monitor appropriate laboratory tests (e.g., AST, ALT, GGT, CPK, uric acid) periodically after initiation of therapy, and when clinical signs and symptoms occur.

• Clinical monitoring recommended when ritonavir is used concomitantly with drugs that prolong the PR interval (including calcium channel blockers, β-adrenergic blockers, digoxin, atazanavir), particularly with drugs metabolized by cytochrome P-450 (CYP) isoenzyme 3A.

Dispensing and Administration Precautions

• The Institute for Safe Medication Practices (ISMP) list of error-prone abbreviations, symbols, and dose designations states that the use of abbreviations for antiretroviral medications (e.g., DOR, TAF, TDF) during the medication use process should be avoided as their use has been associated with serious medication errors.

Other General Considerations

• Use with caution in patients with preexisting liver disease, liver enzyme abnormalities, or coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Consider more frequent testing of serum AST and ALT concentrations in these patients, especially during the first 3 months of therapy.

• Use ritonavir with caution in patients with structural heart disease, cardiac conduction abnormalities, ischemic heart disease, and cardiomyopathies.

Administration

Ritonavir can be given orally as film-coated tablets or oral powder.

Must be given in combination with other antiretrovirals for treatment of HIV.

Oral Administration

Tablets

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

Oral Powder

Only indicated for use in pediatric patients.

Administer orally with a meal; may lessen bitter aftertaste of oral powder.

Only use for dosing increments of 100 mg; do not use for doses <100 mg or for dose increments between 100 mg intervals.

Mix oral powder with a soft food (e.g., applesauce, vanilla pudding) or liquid (e.g., water, chocolate milk, infant formula). After mixing, must be used within 2 hours; discard after this period.

May administer via feeding tube if mixed with water.

Dosage

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

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

Pediatric Patients

Treatment of HIV Infection

Low-dose Ritonavir for Ritonavir-boosted PI Regimens

Oral

When low-dose ritonavir is used with another HIV PI as a pharmacokinetic enhancer (ritonavir-boosted PI), dosage of ritonavir varies and is specific to the drug combination in use.

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 twice daily as tolerated up to 350–400 mg/m² twice daily (not >600 mg twice daily).

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 antiretroviral therapy.

Adults

Treatment of HIV Infection

Low-dose Ritonavir for Ritonavir-boosted PI Regimens

Oral

100–400 mg daily.

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.

Special Populations

Hepatic Impairment

Dosage adjustments not necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B); data not available for severe hepatic impairment (Child-Pugh class C).

Renal Impairment

Manufacturer states that clinically important decreases in ritonavir clearance not expected in renal impairment.

Geriatric Patients

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

Cautions for Ritonavir

Contraindications

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

• Concomitant use with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, amiodarone, cisapride, colchicine [in patients with hepatic or renal impairment], dronedarone, ergot alkaloids, flecainide, lomitapide, lovastatin, lurasidone, oral midazolam, pimozide, propafenone, quinidine, ranolazine, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, triazolam, voriconazole).

• Concomitant use with drugs that are potent CYP3A inducers where significantly reduced ritonavir plasma concentrations may be associated with a potential loss of virologic response and possible development of resistance and cross-resistance (e.g., apalutamide, St. John's wort [Hypericum perforatum]).

Warnings/Precautions

Warnings

Risk of Serious Adverse Reactions Due to Drug Interactions

Concomitant use with certain drugs contraindicated because of risk of life-threatening adverse events, significant interaction, or loss of virologic activity (see Boxed Warning). Concomitant use with other drugs may require caution, dosage adjustments, and/or increased monitoring. When ritonavir-boosted PI regimens are used, the usual cautions, precautions, and contraindications associated with the other PI should be considered.

Other Warnings and Precautions

Hepatic Effects

Elevated hepatic aminotransferase concentrations >5 times ULN, clinical hepatitis, and jaundice reported; risk may be increased in patients with HBV or HCV coinfection.

Use with caution in patients with preexisting liver disease, liver enzyme abnormalities, or hepatitis; consider more frequent testing of serum AST and ALT concentrations in these patients, especially during the first 3 months of therapy.

Hepatic dysfunction (including some fatalities) reported. Generally has occurred in patients with advanced HIV infection and/or receiving multiple concomitant drugs.

Pancreatitis

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

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

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

Allergic Reactions/Hypersensitivity

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

PR Interval Prolongation

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

Use with caution in patients with structural heart disease, cardiac conduction abnormalities, ischemic heart disease, or cardiomyopathies; these individuals may be at increased risk for cardiac conduction abnormalities.

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

Lipid Disorders

Substantial increases in total serum cholesterol and triglyceride concentrations have occurred. Determine serum triglyceride and cholesterol concentrations prior to and periodically during therapy; manage lipid disorders as clinically appropriate.

Diabetes Mellitus/Hyperglycemia

Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of PIs; diabetic ketoacidosis has occurred. Monitor blood glucose and initiate or adjust dosage of oral hypoglycemic agent or insulin as needed.

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have been reported to occur in the setting of immune reconstitution; the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Fat Redistribution

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement ("buffalo hump"), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance; causal relationship not established.

Patients with Hemophilia

Spontaneous bleeding noted with PIs; causal relationship not established.

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

Resistance/Cross-resistance

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

Laboratory Tests

Associated with alterations in certain laboratory tests (e.g., serum AST, ALT, γ-glutamyltransferase (GGT), CPK, uric acid). Perform appropriate clinical chemistry tests prior to and periodically after initiation of ritonavir, or when symptoms occur.

Specific Populations

Pregnancy

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

Data from the registry indicate that birth defects occurred in 2.3% of live births following first trimester exposures and in 2.9% of live births following second/third trimester exposures; the birth defect rate among pregnant women in the US reference population is 2.7%.

Lactation

Limited data indicate that ritonavir is distributed into human milk.

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.

Females and Males of Reproductive Potential

No evidence of effects on fertility when given to male or female rats at exposures equivalent to 40 and 60% of the human dosage, respectively. Because ritonavir may reduce the efficacy of combined hormonal contraceptives, advise patients to use an effective alternative contraceptive method or an additional barrier method of contraception.

Pediatric Use

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

Antiretroviral activity in children >1 month to 21 years of age similar to that in adults. Adverse effects in children >1 month to 21 years of age similar to those reported in adults; vomiting, diarrhea, skin rash/allergy reported in ≥2% of pediatric patients in clinical studies.

Geriatric Use

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

Select dosage with caution, usually starting at the lower end of the dosing range, because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Hepatic Impairment

Use with caution in patients with preexisting liver disease, liver enzyme abnormalities, or hepatitis; consider more frequent monitoring of AST and ALT, especially during the first 3 months.

There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C.

No dosage adjustment required for patients with mild (Child-Pugh Class A) or moderate hepatic impairment (Child-Pugh Class B). Not studied in those with severe hepatic impairment (Child-Pugh Class C); avoid use

Renal Impairment

Pharmacokinetics not evaluated in patients with renal impairment. Because ritonavir undergoes negligible renal excretion, reduced clearance in renal impairment not expected.

Common Adverse Effects

The most frequent adverse reactions occurring in ≥25% of patients receiving ritonavir alone or combined with other antiretrovirals include GI reactions (diarrhea, nausea, vomiting, upper and lower abdominal pain), neurologic disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia.

Drug Interactions

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

Strong inhibitor of CYP3A.

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

When used concomitantly with other PIs (i.e., atazanavir, darunavir, fosamprenavir), consult the prescribing information for that PI, including important drug interaction information.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A4 or CYP2D6 with possible alteration in metabolism of ritonavir and/or other drug.

Specific Drugs and Foods

Ritonavir Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained within 2 and 4 hours under fasting and non-fasting conditions, respectively.

Ritonavir tablets are not bioequivalent to ritonavir capsules (no longer marketed in US); similar AUC but higher peak plasma concentration with ritonavir tablets compared with capsules.

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

Compared with administration in the fasting state, extent of absorption was 21–23% lower when ritonavir tablets were administered with a moderate-fat or high-fat meal.

Compared with administration in the fasting state, extent of absorption was 23–49% lower when ritonavir oral powder was administered with a moderate-fat or high-fat meal.

Special Populations

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

Pediatric patients >2 years of age: Limited data indicate ritonavir dosages of 350–400 mg/m² twice daily in those >2 years of age result in plasma concentrations comparable to those reported in adults receiving 600 mg of ritonavir twice daily.

Infants 1–24 months of age: Ritonavir trough concentrations in infants receiving 350–450 mg/m² of ritonavir twice daily were lower than concentrations reported in adults receiving 600 mg of ritonavir twice daily. Higher ritonavir exposures not observed with 450 mg/m² twice daily compared with 350 mg/m² twice daily in these infants.

Distribution

Extent

Not fully characterized.

Low concentrations cross the placenta; has been detected in cord blood and neonatal hair.

Limited data indicate present in human milk.

Plasma Protein Binding

98–99%.

Special Populations

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

Elimination

Metabolism

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

Elimination Route

Excreted principally in feces (86.4%) as unchanged drug (33.8%) and metabolites; 11.3% excreted in urine (3.5% as unchanged drug).

Dialysis unlikely to remove substantial amounts of ritonavir.

Half-life

3–5 hours.

Stability

Storage

Oral

Tablets

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

Oral Powder

≤30°C.

Actions and Spectrum

• Active against HIV-1.

• Inhibits replication of HIV by interfering with HIV protease.

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

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

Advice to Patients

• Advise patients and/or caregivers to read and follow directions for preparation of ritonavir oral powder.

• Advise caregivers to update their healthcare provider when their child's weight changes so that their ritonavir dose may be adjusted as necessary.

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

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

• Stress importance of taking ritonavir with a meal.

• If a dose is missed, it should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time; if a dose is skipped, the next dose should not be doubled.

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

• Inform patients that pre-existing liver disease, including HBV or HCV infections, can worsen during use of ritonavir, therefore, liver function test monitoring is necessary during therapy. Advise patients to inform their healthcare providers if signs and symptoms of worsening liver dysfunction develop (e.g., loss of appetite, stomach pain, jaundice, skin itchiness).

• Advise patients to notify their healthcare provider if signs and symptoms suggestive of pancreatitis develop (e.g., nausea, vomiting, stomach pain).

• Advise patients to inform their healthcare provider if a rash develops during treatment.

• Inform patients that redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.

• Inform patients that hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus can occur. Patients should promptly notify their healthcare provider if signs and symptoms of diabetes develop (e.g., urinating frequently, excessive thirst or hunger, or excessive weight loss and/or increased blood glucose).

• Inform patients that cholesterol and triglyceride levels may increase with use of ritonavir.

• Inform patients with hemophilia that increased bleeding may occur when protease inhibitors such as ritonavir are used.

• Advise patients to inform their 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.

• Stress importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Inform patients that an antiretroviral pregnancy registry is available that monitors fetal outcomes of infants exposed to ritonavir. Providers can register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Inform patients using combined hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with ritonavir because hormone levels may be decreased.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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