Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Ritonavir Tablets USP, 100 mg are white to off-white, film-coated, ovaloid tablets, debossed with ‘Z’ on one side and ‘24’ on other side. Bottles of 3 NDC 68071-3898-3 Recommended Storage Store at or below 30°C (86°F). Exposure to temperatures up to 50°C (122°F) for seven days permitted. Dispense in original container or USP equivalent tight container (75 mL, 200 mL, 1300 mL and 2000 mL). For patient use: exposure of this product to high humidity outside the original or USP equivalent tight container (75 mL, 200 mL, 1300 mL and 2000 mL) for longer than 2 weeks is not recommended.; PACKAGE LABEL PRINCIPAL DISPLAY PANEL - 100 mg (30 Tablets Bottle) pdp
- 16 HOW SUPPLIED/STORAGE AND HANDLING Ritonavir Tablets USP, 100 mg are white to off-white, film-coated, ovaloid tablets, debossed with ‘Z’ on one side and ‘24’ on other side. Bottles of 3 NDC 68071-3898-3 Recommended Storage Store at or below 30°C (86°F). Exposure to temperatures up to 50°C (122°F) for seven days permitted. Dispense in original container or USP equivalent tight container (75 mL, 200 mL, 1300 mL and 2000 mL). For patient use: exposure of this product to high humidity outside the original or USP equivalent tight container (75 mL, 200 mL, 1300 mL and 2000 mL) for longer than 2 weeks is not recommended.
- PACKAGE LABEL PRINCIPAL DISPLAY PANEL - 100 mg (30 Tablets Bottle) pdp
Overview
Ritonavir is an inhibitor of HIV protease with activity against the Human Immunodeficiency Virus (HIV). Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C 37 H 48 N 6 O 5 S 2 , and its molecular weight is 720.95. Ritonavir has the following structural formula: Ritonavir USP is a white to light-tan, crystalline powder. Ritonavir has a bitter metallic taste. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. Ritonavir tablets USP are available for oral administration in a strength of 100 mg ritonavir with the following inactive ingredients: copovidone, corn starch, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, hypromellose, mannitol, microcrystalline cellulose, polyethylene glycol, polysorbate, powdered cellulose, silicified microcrystalline cellulose, sodium stearyl fumarate, sorbitan monolaurate, talc, and titanium dioxide. chemical structure
Indications & Usage
Ritonavir tablets are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Ritonavir tablets are HIV protease inhibitors indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection ( 1 )
Dosage & Administration
Adult patients: 600 mg twice-day with meals ( 2.3 ) Pediatrics patients: The recommended twice daily dose for children greater than one month of age is based on body surface area and should not exceed 600 mg twice daily with meals ( 2.4 ) Ritonavir oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 44 weeks has been attained ( 2.4 , 5.2 ) Ritonavir oral powder can only be used for dosing increments of 100 mg ( 2.4 ) Dose modification for ritonavir tablet is necessary when used with other protease inhibitors ( 2.6 ) 2.1 General Administration Recommendations Ritonavir tablets must be used in combination with other antiretroviral agents. Ritonavir tablets are administered orally. Ritonavir tablets should be swallowed whole, and not chewed, broken or crushed. Take ritonavir tablets with meals. General Dosing Guidelines Patients who take the 600 mg twice daily soft gel capsule ritonavir dose may experience more gastrointestinal side effects such as nausea, vomiting, abdominal pain or diarrhea when switching from the soft gel capsule to the tablet formulation because of greater maximum plasma concentration (C max ) achieved with the tablet formulation relative to the soft gel capsule [see Clinical Pharmacology (12.3) ] . Patients should also be aware that these adverse events (gastrointestinal or paresthesias) may diminish as therapy is continued. 2.3 Dosage Recommendations in Adults Recommended Dosage for Treatment of HIV-1: The recommended dosage of ritonavir is 600 mg twice daily by mouth to be taken with meals. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir tablets 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 should not be exceeded upon completion of the titration [see Dosage and Administration (2.6) ] . Pregnant Women Ritonavir oral solution is not recommended during pregnancy due to its ethanol content. Ritonavir oral solution contains the excipients ethanol and propylene glycol [see Use in Specific Populations (8.1) ] . 2.4 Dosage Recommendations in Pediatric Patients Ritonavir tablets must be used in combination with other antiretroviral agents [see Dosage and Administration (2) ] . The recommended dosage of ritonavir tablets in pediatric patients older than 1 month is 350 to 400 mg per m 2 twice daily by mouth to be taken with meals and should not exceed 600 mg twice daily. Ritonavir tablets should be started at 250 mg per m 2 twice daily and increased at 2 to 3 day intervals by 50 mg per m 2 twice daily. If patients do not tolerate 400 mg per m 2 twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered [see Dosage and Administration (2.6) ] . Pediatric Dosage Guidelines for Oral Solution Ritonavir oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 44 weeks has been attained [see Warnings and Precautions (5.2) ]. Ritonavir oral solution contains the excipients ethanol and propylene glycol. Special attention should be given to accurate calculation of the dose of ritonavir oral solution, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors, and overdose. This is especially important for young children. Total amounts of ethanol and propylene glycol from all medicines that are to be given to pediatric patients 1 to 6 months of age should be taken into account in order to avoid toxicity from these excipients [see Warnings and Precautions (5.2) and Overdosage (10) ]. When possible, dose should be administered using a calibrated dosing syringe. Table 1. Pediatric Dosage Guidelines for Oral Solution * Body Surface Area (m 2 ) Twice Daily Dose 250 mg per m 2 Twice Daily Dose 300 mg per m 2 Twice Daily Dose 350 mg per m 2 Twice Daily Dose 400 mg per m 2 0.20 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) 0.50 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) 1.00 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) 1.50 4.7 mL (375 mg) 5.6 mL (450 mg) 6.6 mL (525 mg) 7.5 mL (600 mg) *The concentration of the oral solution is 80 mg per mL. Body surface area (BSA) can be calculated as follows 1 : Pediatric Dosage Guidelines for Oral Powder Ritonavir oral powder should be used only for dosing increments of 100 mg. Ritonavir powder should not be used for doses less than 100 mg or for incremental doses between 100 mg intervals. Ritonavir oral solution is the preferred formulation for patients requiring doses less than 100 mg or incremental doses between 100 mg intervals. Figure1 2.6 Dose Modification due to Drug Interaction Dose reduction of ritonavir tablet is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir. Prescribers should consult the full prescribing information and clinical study information of these protease inhibitors if they are co-administered with a reduced dose of ritonavir [see Warnings and Precautions (5.1) , and Drug Interactions (7) ].
Warnings & Precautions
The following have been observed in patients receiving ritonavir: The concomitant use of ritonavir and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 5.1 , 7.2 ) Toxicity in preterm neonates: Ritonavir oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. A safe and effective dose of ritonavir oral solution in this patient population has not been established ( 2.4 , 5.2 ) Hepatotoxicity: Fatalities have occurred. Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis B and hepatitis C, or marked transaminase elevations (5.3 , 8.6) Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate (5.4) Allergic Reactions/Hypersensitivity: Allergic reactions have been reported and include anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson syndrome, bronchospasm and angioedema. Discontinue treatment if severe reactions develop (5.5 , 6.2) PR interval prolongation may occur in some patients. Cases of second and third degree heart block have been reported. Use with caution with patients with preexisting conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval (5.6 , 12.3) Total cholesterol and triglycerides elevations: Monitor prior to therapy and periodically thereafter (5.7) Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia (5.8) Patients may develop immune reconstitution syndrome (5.9) Patients may develop redistribution/accumulation of body fat (5.10) Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required (5.11) 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of ritonavir, respectively. These interactions may lead to: Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications. Clinically significant adverse reactions from greater exposures of ritonavir. Loss of therapeutic effect of ritonavir and possible development of resistance. When co-administering ritonavir with other protease inhibitors, see the full prescribing information for that protease inhibitor including important Warnings and Precautions. See Table 4 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7) ]. Consider the potential for drug interactions prior to and during ritonavir therapy; review concomitant medications during ritonavir therapy, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7) ]. 5.2 Toxicity in Preterm Neonates Ritonavir oral solution contains the excipients ethanol and propylene glycol. 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 ethanol and propylene glycol. Ritonavir oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. However, if the benefit of using ritonavir 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 ritonavir 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 ethanol 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 (2.4) and Overdosage (10) ]. 5.3 Hepatotoxicity Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretroviral drugs (see Table 3). There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering ritonavir 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 ritonavir 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 ritonavir 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 ritonavir 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. Ritonavir 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 ritonavir 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 ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with ritonavir 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. Consider monitoring for hyperglycemia, new onset diabetes mellitus, or an exacerbation of diabetes mellitus in patients treated with ritonavir. 5.9 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including ritonavir. 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 ritonavir therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.
Boxed Warning
DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONS Co-administration of ritonavir 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 ritonavir on the hepatic metabolism of certain drugs. Review medications taken by patients prior to prescribing ritonavir or when prescribing other medications to patients already taking ritonavir [see Contraindications (4) , Warnings and Precautions (5.1) ]. WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONS See full prescribing information for complete boxed warning Co-administration of ritonavir 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 ritonavir on the hepatic metabolism of certain drugs. Review medications taken by patients prior to prescribing ritonavir or when prescribing other medications to patients already taking ritonavir. ( 4 , 5.1 )
Contraindications
When co-administering ritonavir tablets with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information. Ritonavir tablets are contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients. Ritonavir tablets are contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . Alpha 1- Adrenoreceptor Antagonist : alfuzosin Antianginal: ranolazine Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine Antifungal: voriconazole Anti-gout: colchicine Antipsychotics: lurasidone, pimozide Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine GI Motility Agent: cisapride HMG-CoA Reductase Inhibitors: lovastatin, simvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide PDE5 Inhibitor: sildenafil (Revatio ® ) when used for the treatment of pulmonary arterial hypertension Sedative/Hypnotics: triazolam, orally administered midazolam Ritonavir tablets are contraindicated with drugs that are potent CYP3A inducers where significantly reduced ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ] . Anticancer Agents: apalutamide Herbal Products: St. John's Wort (hypericum perforatum) Ritonavir tablets are contraindicated in patients with known hypersensitivity to ritonavir (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) or any of its ingredients (4) Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations may be associated with serious and/or life-threatening events (4) Co-administration with drugs that significantly reduce ritonavir (4)
Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling. Drug Interactions [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] Pancreatitis [see Warnings and Precautions (5.4) ] Allergic Reactions/Hypersensitivity [see Warnings and Precautions (5.5) ] When co-administering ritonavir with other protease inhibitors, see the full prescribing information for that protease inhibitor including adverse reactions. The most frequently reported adverse drug reactions among patients receiving ritonavir 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 (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Adverse Reactions in Adults The safety of ritonavir alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table 2 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 ritonavir in combined Phase II/IV studies. The most frequently reported adverse drug reactions among patients receiving ritonavir 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. Table 2. Treatment-Emergent Adverse Reactions (With Possible or Probable Relationship to Study Drug) Occurring in greater than or equal to 1% of Adult Patients Receiving Ritonavir in Combined Phase II/IV Studies (N = 1,755) * Represents a medical concept including several similar MedDRA PTs Adverse Reactions n % Eye disorders Blurred vision 113 6.4 Gastrointestinal disorders Abdominal Pain (upper and lower)* 464 26.4 Diarrhea including severe with electrolyte imbalance* 1,192 67.9 Dyspepsia 201 11.5 Flatulence 142 8.1 Gastrointestinal hemorrhage* 41 2.3 Gastroesophageal reflux disease (GERD) 19 1.1 Nausea 1,007 57.4 Vomiting* 559 31.9 General disorders and administration site conditions Fatigue including asthenia* 811 46.2 Hepatobiliary disorders Blood bilirubin increased (including jaundice)* 25 1.4 Hepatitis (including increased AST, ALT, GGT)* 153 8.7 Immune system disorders Hypersensitivity including urticaria and face edema* 114 8.2 Metabolism and nutrition disorders Edema and peripheral edema* 110 6.3 Gout* 24 1.4 Hypercholesterolemia* 52 3.0 Hypertriglyceridemia* 158 9.0 Lipodystrophy acquired* 51 2.9 Musculoskeletal and connective tissue disorders Arthralgia and back pain* 326 18.6 Myopathy/creatine phosphokinase increased* 66 3.8 Myalgia 156 8.9 Nervous system disorders Dizziness* 274 15.6 Dysgeusia* 285 16.2 Paresthesia (including oral paresthesia)* 889 50.7 Peripheral neuropathy 178 10.1 Syncope* 58 3.3 Psychiatric disorders Confusion* 52 3.0 Disturbance in attention 44 2.5 Renal and urinary disorders Increased urination* 74 4.2 Respiratory, thoracic and mediastinal disorders Coughing* 380 21.7 Oropharyngeal Pain* 279 15.9 Skin and subcutaneous tissue disorders Acne* 67 3.8 Pruritus* 214 12.2 Rash (includes erythematous and maculopapular)* 475 27.1 Vascular disorders Flushing, feeling hot* 232 13.2 Hypertension* 58 3.3 Hypotension including orthostatic hypotension* 30 1.7 Peripheral coldness* 21 1.2 Laboratory Abnormalities in Adults Table 3 shows the percentage of adult patients who developed marked laboratory abnormalities. Table 3. Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and Hematology Abnormalities Occurring in greater than 3% of Patients Receiving Ritonavir - Indicates no events reported. Study 245 Naive Patients Study 247 Advanced Patients Study 462 PI-Naive Patients Variable Limit Ritonavir plus Zidovudine Ritonavir Zidovudine Ritonavir Placebo Ritonavir plus Saquinavir Chemistry High Cholesterol > 240 mg/dL 30.7 44.8 9.3 36.5 8.0 65.2 CPK > 1000 IU/L 9.6 12.1 11.0 9.1 6.3 9.9 GGT > 300 IU/L 1.8 5.2 1.7 19.6 11.3 9.2 SGOT (AST) > 180 IU/L 5.3 9.5 2.5 6.4 7.0 7.8 SGPT (ALT) > 215 IU/L 5.3 7.8 3.4 8.5 4.4 9.2 Triglycerides > 800 mg/dL 9.6 17.2 3.4 33.6 9.4 23.4 Triglycerides > 1500 mg/dL 1.8 2.6 - 12.6 0.4 11.3 Triglycerides Fasting > 1500 mg/dL 1.5 1.3 - 9.9 0.3 - Uric Acid > 12 mg/dL - - - 3.8 0.2 1.4 Hematology Low Hematocrit < 30% 2.6 - 0.8 17.3 22.0 0.7 Hemoglobin < 8.0 g/dL 0.9 - - 3.8 3.9 - Neutrophils ≤ 0.5 x 10 9 /L - - - 6.0 8.3 - RBC < 3.0 x 10 12 /L 1.8 - 5.9 18.6 24.4 - WBC < 2.5 x 10 9 /L - 0.9 6.8 36.9 59.4 3.5 Adverse Reactions in Pediatric Patients Ritonavir 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 ritonavir clinical trials. Laboratory Abnormalities in Pediatric Patients The following Grade 3 to 4 laboratory abnormalities occurred in greater than 3% of pediatric patients who received treatment with ritonavir either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%). 6.2 Postmarketing Experience The following adverse events (not previously mentioned in the labeling) have been reported during post-marketing use of ritonavir. 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 ritonavir 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. Renal and Urinary Disorders Nephrolithiasis Skin and subcutaneous tissue disorders Toxic epidermal necrolysis (TEN) has been reported.
Drug Interactions
When co-administering ritonavir 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. Co-administration of ritonavir can alter the concentrations of other drugs. The potential for drug-drug interactions must be considered prior to and during therapy (4 , 5.1 , 7 , 12.3) 7.1 Potential for Ritonavir to Affect Other Drugs Ritonavir is 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 ritonavir 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 4. 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. These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with ritonavir. The healthcare provider should consult appropriate references for comprehensive information. 7.2 Established and Other Potentially Significant Drug Interactions Table 4 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 Contraindications (4) , Warnings and Precautions (5.1) , and Clinical Pharmacology (12.3) ] for magnitude of interaction. Table 4. Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Ritonavir or Concomitant Drug Clinical Comment HIV-Antiviral Agents HIV-1 Protease Inhibitor: atazanavir darunavir fosamprenavir ↑ amprenavir ↑ atazanavir ↑ darunavir See the complete prescribing information for fosamprenavir, atazanavir, darunavir for details on co-administration with ritonavir. HIV-1 Protease Inhibitor: indinavir ↑ indinavir Appropriate doses for this combination, with respect to efficacy and safety, have not been established. HIV-1 Protease Inhibitor: saquinavir ↑ saquinavir See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir. Saquinavir/ritonavir in combination with rifampin is not recommended due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together. HIV-1 Protease Inhibitor: tipranavir ↑ tipranavir See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir. Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine ↑ ritonavir Appropriate doses of this combination with respect to safety and efficacy have not been established. HIV-1 CCR5 - antagonist: maraviroc ↑ maraviroc See the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors. Integrase Inhibitor: raltegravir ↓ raltegravir The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration. Other Agents Alpha 1-Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Contraindicated due to potential hypotension [see Contraindications (4) ]. Antianginal: ranolazine ↑ ranolazine Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4) ]. Analgesics, Narcotic: tramadol, propoxyphene, methadone, fentanyl ↑ analgesics ↓ methadone ↑ fentanyl A dose decrease may be needed for these drugs when co-administered with ritonavir. Dosage increase of methadone may be considered. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with ritonavir. Anesthetic: meperidine ↓ meperidine/ ↑ normeperidine (metabolite) Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures). Antialcoholics: disulfiram/ metronidazole Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine ↑ antiarrhythmics Contraindicated due to potential for cardiac arrhythmias [see Contraindications (4) ]. Antiarrhythmics: disopyramide, lidocaine, mexiletine ↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available. Anticancer Agents: abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓ ritonavir # Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to ritonavir or to the class of protease inhibitors [see Contraindications (4) ] . Avoid co-administration of encorafenib or ivosidenib with ritonavir due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with ritonavir cannot be avoided, modify dose as recommended in encorafenib USPI. If co-administration of ivosidenib with ritonavir cannot be avoided, reduce ivosidenib dose to 250 mg once daily. Avoid use of neratinib, venetoclax or ibrutinib with ritonavir. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as ritonavir. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. Anticoagulant: warfarin ↑↓ warfarin Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is recommended. Anticoagulant: rivaroxaban ↑ rivaroxaban Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding. Anticonvulsants: carbamazepine, clonazepam, ethosuximide ↑ anticonvulsants A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available. Anticonvulsants: divalproex, lamotrigine, phenytoin ↓ anticonvulsants A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available. Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g., fluoxetine, paroxetine, tricyclics: e.g., amitriptyline, nortriptyline ↑ antidepressants A dose decrease may be needed for these drugs when co-administered with ritonavir. Antidepressant: bupropion ↓ bupropion ↓ active metabolite, hydroxybupropion Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion. Antidepressant: desipramine ↑ desipramine Dosage reduction and concentration monitoring of desipramine is recommended. Antidepressant: trazodone ↑ trazodone Adverse events of nausea, dizziness, hypotension and syncope have been observed following co- administration of trazodone and ritonavir. A lower dose of trazodone should be considered. Antiemetic: dronabinol ↑ dronabinol A dose decrease of dronabinol may be needed when co-administered with ritonavir. Antifungals: ketoconazole itraconazole voriconazole ↑ ketoconazole ↑ itraconazole ↓ voriconazole High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended. Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated due to the potential for loss of antifungal response [see Contraindications (4) ] . Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Anti-gout: colchicine ↑ colchicine Contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications (4) ]. For patients with normal renal or hepatic function: Treatment of gout flares-co-administration of colchicine in patients on ritonavir: 0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days. Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Anti-infective: clarithromycin ↑ clarithromycin For patients with renal impairment, adjust clarithromycin dose as follows: For patients with CL CR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%. For patients with CL CR less than 30 mL per min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. Antimycobacterial: bedaquiline ↑ bedaquiline Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk. Antimycobacterial: rifabutin ↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary. Antimycobacterial: rifampin ↓ ritonavir May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered. Antiparasitic: atovaquone ↓ atovaquone Clinical significance is unknown; however, increase in atovaquone dose may be needed. Antiparasitic: quinine ↑ quinine A dose decrease of quinine may be needed when co-administered with ritonavir. Antipsychotics: lurasidone pimozide ↑ lurasidone ↑ pimozide Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4) ]. Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. Antipsychotics: perphenazine, risperidone, thioridazine ↑ antipsychotics A dose decrease may be needed for these drugs when co-administered with ritonavir. Antipsychotics: quetiapine ↑ quetiapine Initiation of ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. β-Blockers: metoprolol, timolol ↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir. Bronchodilator: theophylline ↓ theophylline Increased dosage of theophylline may be required; therapeutic monitoring should be considered. Calcium channel blockers: diltiazem, nifedipine, verapamil ↑ calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir. Digoxin ↑ digoxin Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels. Endothelin receptor antagonists: bosentan ↑ bosentan Co-administration of bosentan in patients on ritonavir: In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. GnRH Receptor Antagonists:elagolix ↑ elagolix ↓ ritonavir Concomitant use of elagolix 200 mg twice daily and ritonavir for more than 1 month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily and ritonavir to 6 months. Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine ↑ ergot derivatives Contraindicated due to potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4) ]. GI Motility Agent: cisapride ↑ cisapride Contraindicated due to potential for cardiac arrhythmias [see Contraindications (4) ]. Hepatitis C direct acting antiviral: glecaprevir/pibrentasvir simeprevir ↑ glecaprevir ↑ pibrentasvir ↑ simeprevir It is not recommended to co-administer ritonavir with glecaprevir/pibrentasvir, or simeprevir. Herbal Products: St. John's Wort (hypericum perforatum) ↓ ritonavir Contraindicated due to potential for loss of virologic response and possible resistance to ritonavir or to the class of protease inhibitors [see Contraindications (4) ]. Lipid-modifying agents HMG-CoA Reductase Inhibitor: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4) ]. Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose. If ritonavir is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co- administration with atorvastatin and rosuvastatin. Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity [see Contraindications (4) ]. Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin) ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir. Kinase Inhibitors: fostamatinib (also see anticancer agents above ) ↑ fostamatinib metabolite R406 Monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. Long-acting beta-adrenoceptor agonist: salmeterol ↑ salmeterol Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. Oral Contraceptives or Patch Contraceptives: ethinyl estradiol ↓ ethinyl estradiol Alternate methods of contraception should be considered. PDE5 Inhibitors: avanafil sildenafil, tadalafil, vardenafil ↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Sildenafil when used for the treatment of pulmonary arterial hypertension (Revatio ® ) is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Contraindications (4) ] . Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio ® ) is contraindicated [see Contraindications (4) ] . The following dose adjustments are recommended for use of tadalafil (Adcirca ® ) with ritonavir: Co-administration of ADCIRCA in patients on ritonavir: In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of ritonavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for the treatment of erectile dysfunction: It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem ↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir. Sedative/Hypnotics: triazolam, orally administered midazolam ↑ triazolam ↑ midazolam Contraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications (4) ] . Sedative/hypnotics: Parenteral midazolam ↑ midazolam Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Stimulant: methamphetamine ↑ methamphetamine Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir. Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone ↑ glucocorticoids Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use. # refers to interaction with apalutamide.
Similar Drugs
Related medications based on brand, generic name, substance, active ingredients.