Ritonavir

1 INDICATIONS AND 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 )

2 DOSAGE AND 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 Precautio…

5 WARNINGS AND 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 fa…

4 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)

7 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 Contraindic…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ritonavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1–800–258–4263. Risk Summary Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Available data from the APR show no difference in the rate of overall birth defects for ritonavir compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data]. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with oral administration of ritonavir to pregnant rats and rabbits. During organogenesis in the rat and rabbit, systemic exposure (AUC) was approximately 1/3 lower than human exposure at the recommended daily dose. In the rat pre- and post-natal developmental study, maternal systemic exposure to ritonavir was approximately 1/2 of the exposure in humans at the recommended daily dose, based on a body surface area conversion factor [see Data]. Ritonavir oral solution is not recommended during pregnancy because there is no known safe level of ethanol exposure during pregnancy [see Clinical Considerations, Dosage and Administration (2.3) and Warnings and Precautions (5.2) ] . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Dose Adjustments During Pregnancy and the Postpartum Period Ritonavir oral solution contains ethanol and propylene glycol and is not recommended during pregnancy because there is no known safe level of ethanol exposure during pregnancy [see Dosage and Administration (2.3) and Warnings and Precautions (5.2) ]. Data Human Data Based on prospective reports to the APR of approximately 6100 live births following exposure to ritonavir-containing regimens (including over 2800 live births exposed in the first trimester and over 3200 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7% to 2.9%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.3% to 3.5%) following second and third trimester exposure to ritonavir-containing regimens. While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair. Animal Data Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on gestation days 6 through 17 and 6 through 19, respectively). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at doses producing systemic exposures (AUC) equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dose, at an exposure equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. A slight increase in the incidence of cryptorchidism was also noted in rats (at a maternally toxic dose) at an exposure approximately 1/5 lower than human exposure at the recommended dail…

8.3 Females and Males of Reproductive Potential Contraception Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.2) ] .

6 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 percenta…