ritonavir 100 MG Oral Powder

INDICATIONS AND USAGE NORVIR tablets are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. NORVIR oral powder is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection. NORVIR tablets are HIV protease inhibitors indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection ( 1 ) NORVIR oral powder is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection ( 1 )

DOSAGE AND ADMINISTRATION Adult patients: 600 mg twice-daily 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 , 5.2 ) 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 is necessary when used with other protease inhibitors. ( 2.6 ) 2.1 General Administration Recommendations Ritonavir must be used in combination with other antiretroviral agents. Ritonavir is administered orally. Ritonavir tablets should be swallowed whole, and not chewed, broken or crushed. Take ritonavir 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 (Cmax) 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 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 (approx. 43% v/v) and propylene glycol (approx. 27% w/v) [see Use in Specific Populations ( 8.1 )] . 2.4 Dosage Recommendations in Pediatric Patients Ritonavir must be used in combination with other antiretroviral agents [see Dosage and Administration ( 2 )] . The recommended dosage of ritonavir 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 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 (approx. 43% v/v) and propylene glycol (approx. 27% w/v). Special attention should be given to accurate calculation of the dose of ritonavir, 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 * * The concentration of the oral solution is 80 mg per mL. 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) 1.0 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) 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 . 2.6 Dose Modification due to Drug Interaction Dose reduction of ritonavir 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 )] . Image

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 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 res

CONTRAINDICATIONS • When co-administering ritonavir with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information. • Ritonavir is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients. • Ritonavir is 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 )]. o Alpha 1- Adrenoreceptor Antagonist : alfuzosin o Antianginal: ranolazine o Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine o Antifungal: voriconazole o Anti-gout: colchicine o Antipsychotics: lurasidone, pimozide o Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine o GI Motility Agent: cisapride o HMG-CoA Reductase Inhibitors: lovastatin, simvastatin o Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide o PDE5 Inhibitor: sildenafil (Revatio®) when used for the treatment of pulmonary arterial hypertension o Sedative/Hypnotics: triazolam, orally administered midazolam • Ritonavir is 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)] . o Anticancer Agents: apalutamide o Herbal Products: St. John's Wort (hypericum perforatum) • Ritonavir is 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 )

Mechanism of Action Ritonavir is an antiretroviral drug [see Microbiology ( 12.4 ) ] .