Ritonavir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]
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Black Box Warning
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WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONS
See full prescribing information for complete Boxed Warning.
Co-administration with other drugs: Co-administration of NORVIR with several classes of drugs including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs. Review medications taken by patients prior to prescribing NORVIR or when prescribing other medications to patients already taking NORVIR
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Overview
Ritonavir is an antiretroviral agents that is FDA approved for the treatment of HIV-1 infection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, nausea, vomiting, abdominal pain, paresthesia, rash, and fatigue/asthenia.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
HIV-1 infection
- 600 mg twice daily
- Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ritonavir in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ritonavir in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
HIV-1 Infection
- Children greater than 1 month is 350 to 400 mg per m2 twice daily.
- In combination with other antiretroviral agents.
- Not exceed 600 mg twice daily.
- Ritonavir should be started at 250 mg per m2 twice daily and increased at 2 to 3 day intervals by 50 mg per m2 twice daily.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ritonavir in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ritonavir in pediatric patients.
Contraindications
- When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.
- NORVIR is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients.
- Co-administration of NORVIR with several classes of drugs (including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations) is contraindicated and may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of these drugs (see TABLE 2).
- Voriconazole and St. John’s Wort are exceptions in that co-administration of NORVIR and voriconazole results in a significant decrease in plasma concentrations of voriconazole, and co-administration of NORVIR with St. John’s Wort may result in decreased ritonavir plasma concentrations.
Warnings
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WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONS
See full prescribing information for complete Boxed Warning.
Co-administration with other drugs: Co-administration of NORVIR with several classes of drugs including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs. Review medications taken by patients prior to prescribing NORVIR or when prescribing other medications to patients already taking NORVIR
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When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including important Warnings and Precautions.
5.1 Drug Interactions NORVIR is a CYP3A inhibitor. Initiating treatment with NORVIR in patients receiving medications metabolized by CYP3A or initiating medications metabolized by CYP3A in patients already maintained on NORVIR may result in increased plasma concentrations of concomitant medications. Higher plasma concentrations of concomitant medications can result in increased or prolonged therapeutic or adverse effects, potentially leading to severe, life-threatening or fatal events. The potential for drug-drug interactions must be considered prior to and during therapy with NORVIR. Review of other medications taken by patients and monitoring of patients for adverse effects is recommended during therapy with NORVIR.
See Table 2 for a listing of drugs that are contraindicated with NORVIR due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity. Also, see Table 5 for a listing of drugs with established and other significant drug interactions [see Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3)].
5.2 Toxicity in Preterm Neonates NORVIR oral solution contains the excipients alcohol (43.2% v/v) and propylene glycol (26.57% w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at an increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving lopinavir/ritonavir oral solution which also contains the excipients alcohol and propylene glycol.
NORVIR oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. However, if the benefit of using NORVIR oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to NORVIR oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients [see Dosage and Administration (2.2) and Overdosage (10)].
5.3 Hepatic Reactions Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving NORVIR alone or in combination with other antiretroviral drugs (see Table 4). There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering NORVIR to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of NORVIR treatment [see Use in Specific Populations (8.6)].
There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS.
5.4 Pancreatitis Pancreatitis has been observed in patients receiving NORVIR therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis [see Warnings and Precautions (5.7)]. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and NORVIR therapy should be discontinued if a diagnosis of pancreatitis is made.
5.5 Allergic Reactions/Hypersensitivity Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported. Cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome have also been reported. Discontinue treatment if severe reactions develop.
5.6 PR Interval Prolongation Ritonavir prolongs the PR interval in some patients. Post marketing cases of second or third degree atrioventricular block have been reported in patients.
NORVIR should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.
The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended [see Drug Interactions (7), and Clinical Pharmacology (12.3)].
5.7 Lipid Disorders Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6.1)]. Triglyceride and cholesterol testing should be performed prior to initiating NORVIR therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with NORVIR and HMG CoA reductase inhibitors [see Contraindications (4)and Drug Interactions (7)].
5.8 Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
5.9 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including NORVIR. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.10 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
5.11 Patients with Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.
5.12 Resistance/Cross-resistance Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors [see Microbiology (12.4)].
5.13 Laboratory Tests Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating NORVIR therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.
Adverse Reactions
Clinical Trials Experience
When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including adverse reactions.
6.1 Adult Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of NORVIR alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table 3 lists treatment-emergent Adverse Reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving NORVIR in combined Phase II/IV studies.
The most frequently reported adverse drug reactions among patients receiving NORVIR alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia.
Pediatric Clinical Trial Experience NORVIR has been studied in 265 pediatric patients greater than 1 month to 21 years of age. The adverse event profile observed during pediatric clinical trials was similar to that for adult patients.
Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in greater than or equal to 2% of pediatric patients enrolled in NORVIR clinical trials.
Laboratory Abnormalities
The following Grade 3-4 laboratory abnormalities occurred in greater than 3% of pediatric patients who received treatment with NORVIR either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%).
Postmarketing Experience
The following adverse events (not previously mentioned in the labeling) have been reported during post-marketing use of NORVIR. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to NORVIR exposure.
Body as a Whole
Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration.
Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.
Cardiovascular System
First-degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported [see Warnings and Precautions (5.6)].
Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded.
Endocrine System
Cushing's syndrome and adrenal suppression have been reported when ritonavir has been co-administered with fluticasone propionate or budesonide.
Nervous System
There have been postmarketing reports of seizure. Also, see Cardiovascular System.
Skin and subcutaneous tissue disorders
Toxic epidermal necrolysis (TEN) has been reported.
Drug Interactions
When co-administering NORVIR with other protease inhibitors (atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions.
7.1 Potential for NORVIR to Affect Other Drugs Ritonavir has been found to be an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when co-administered with ritonavir. Thus, co-administration of NORVIR with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 5.
Ritonavir also inhibits CYP2D6 to a lesser extent. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.
7.2 Established and Other Potentially Significant Drug Interactions Table 5 provides a list of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see Clinical Pharmacology (12.3) for magnitude of interaction].
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): B Human Data: There are no adequate and well-controlled studies in pregnant women. NORVIR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data No treatment related malformations were observed when ritonavir was administered to pregnant rats or rabbits. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dosage at an exposure equivalent to approximately 30% of that achieved with the proposed therapeutic dose. A slight increase in the incidence of cryptorchidism was also noted in rats at an exposure approximately 22% of that achieved with the proposed therapeutic dose.
Developmental toxicity observed in rabbits (resorptions, decreased litter size and decreased fetal weights) also occurred at a maternally toxic dosage equivalent to 1.8 times the proposed therapeutic dose based on a body surface area conversion factor.
Pregnancy Category (AUS): B3
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ritonavir in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Ritonavir during labor and delivery.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. It is not known whether ritonavir is secreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving NORVIR.
Pediatric Use
In HIV-infected patients age greater than 1 month to 21 years, the antiviral activity and adverse event profile seen during clinical trials and through postmarketing experience were similar to that for adult patients.
Geriatic Use
Clinical studies of NORVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
Gender
There is no FDA guidance on the use of Ritonavir with respect to specific gender populations.
Race
There is no FDA guidance on the use of Ritonavir with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Ritonavir in patients with renal impairment.
Hepatic Impairment
No dose adjustment of ritonavir is necessary for patients with either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C), therefore, ritonavir is not recommended for use in patients with severe hepatic impairment [see Warnings and Precautions (5.3), Clinical Pharmacology (12.3)].
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ritonavir in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Ritonavir in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Ritonavir Administration in the drug label.
Monitoring
There is limited information regarding Ritonavir Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Ritonavir and IV administrations.
Overdosage
10.1 Acute Overdosage - Human Overdose Experience Human experience of acute overdose with NORVIR is limited. One patient in clinical trials took NORVIR 1500 mg per day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose.
The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice.
10.2 Management of Overdosage NORVIR oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol. Ingestion of the product over the recommended dose by a young child could result in significant toxicity and could potentially be lethal.
Treatment of overdose with NORVIR consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with NORVIR. If indicated, elimination of unabsorbed drug should be achieved by gastric lavage; usual precautions should be observed to maintain the airway. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since ritonavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug. However, dialysis can remove both alcohol and propylene glycol in the case of overdose with ritonavir oral solution. A Certified Poison Control Center should be consulted for up-to-date information on the management of overdose with NORVIR
Pharmacology
There is limited information regarding Ritonavir Pharmacology in the drug label.
Mechanism of Action
Ritonavir is a peptidomimetic inhibitor of the HIV-1 protease. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of non-infectious immature HIV particles.
Structure
There is limited information regarding Ritonavir Structure in the drug label.
Pharmacodynamics
There is limited information regarding Ritonavir Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Ritonavir Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Ritonavir Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Ritonavir Clinical Studies in the drug label.
How Supplied
There is limited information regarding Ritonavir How Supplied in the drug label.
Storage
There is limited information regarding Ritonavir Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Ritonavir Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Ritonavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Ritonavir Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Ritonavir Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [4]
Overview
Ritonavir, with trade name Norvir (AbbVie, Inc.), is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS.
Ritonavir is frequently prescribed with HAART, not for its antiviral action, but as it inhibits the same host enzyme that metabolizes other protease inhibitors. This inhibition leads to higher plasma concentrations of these latter drugs, allowing the clinician to lower their dose and frequency and improving their clinical efficacy.
Category
Protease inhibitor
US Brand Names
NORVIR®
FDA Package Insert
Description | Clinical Pharmacology | Microbiology | Indications and Usage | Contraindications | Warnings and Precautions | Adverse Reactions | Drug Interactions | Overdosage | Clinical Studies | Dosage and Administration | How Supplied | Labels and Packages
Mechanism of Action
Ritonavir was originally developed as an inhibitor of HIV protease. It is one of the most complex inhibitors. It is now rarely used for its own antiviral activity, but remains widely used as a booster of other protease inhibitors. More specifically, ritonavir is used to inhibit a particular liver enzyme that normally metabolizes protease inhibitors, cytochrome P450-3A4 (CYP3A4).[1] The drug's molecular structure inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors. This discovery, which has drastically reduced the adverse effects and improved the efficacy of protease inhibitors and HAART, was first communicated in an article published in the journal AIDS in 1997 by researchers at the University of Liverpool.[2] This effect does come with a price: it also affects the efficacy of numerous other medications, making it difficult to know how to administer them concurrently. In addition it can cause a large number of side-effects on its own.
References
- ↑ Zeldin RK, Petruschke RA (2004). "Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients". Journal of Antimicrobial Chemotherapy. 53 (1): 4–9. doi:10.1093/jac/dkh029. PMID 14657084.
- ↑ Merry, Concepta; Barry, Michael G.; Mulcahy, Fiona; Ryan, Mairin; Heavey, Jane; Tjia, John F.; Gibbons, Sara E.; Breckenridge, Alasdair M.; Back, David J. (1997). "Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients". AIDS. 11 (4): F29–F33. doi:10.1097/00002030-199704000-00001. PMID 9084785.