Tecovirimat Monohydrate

7 DRUG INTERACTIONS Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 5.1 , 7 , 12.3 ) 7.1 Effect of TPOXX on Other Drugs Tecovirimat is a weak inducer of cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C8 and CYP2C19. However, the effects are not expected to be clinically relevant for most substrates of those enzymes based on the magnitude of interactions and the duration of treatment of TPOXX. Table 5 provides a listing of established or significant drug interactions and clinical recommendations for select sensitive substrates [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )] . Table 5: Significant Drug Interactions with Effect of TPOXX on Other Drugs a ↓ = decrease, ↑ = increase b These interactions have been studied in healthy adults. Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Effect/Recommendation Blood Glucose-Lowering Agent: Repaglinide b ↑ repaglinide Monitor blood glucose and monitor for hypoglycemic symptoms in patients when TPOXX is co-administered with repaglinide [see Warnings and Precautions ( 5.1 )] . CNS Depressant: Midazolam b ↓ midazolam Monitor for effectiveness of midazolam. 7.2 Effect of Other drugs on TPOXX Co-administration of phosphate binders with tecovirimat increases tecovirimat bioavailability. Table 6 provides a listing of established drug interactions and clinical recommendations for select phosphate binders [see Clinical Pharmacology ( 12.3 )] . Table 6: Significant Drug Interactions with Effect of Other Drugs on TPOXX a ↑ = increase b These interactions have been studied in healthy adults. Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Effect/Recommendation Phosphate Binders b : Calcium acetate Lanthanum carbonate Sevelamer carbonate Sucroferric oxyhydroxide ↑ tecovirimat Monitor for signs or symptoms of adverse effects when TPOXX is co-administered with phosphate binders [see Overdose ( 10 )] . 7.3 Drugs Without Clinically Significant Interactions With TPOXX Based on a drug interaction study, no clinically significant drug interactions have been observed when TPOXX is co-administered with bupropion, flurbiprofen, or omeprazole [see Clinical Pharmacology ( 12.3 )] . 7.4 Vaccine Interactions No vaccine-drug interaction studies have been performed in human subjects. Some animal studies have indicated that co-administration of TPOXX at the same time as live smallpox vaccine (vaccinia virus) may reduce the immune response to the vaccine. The clinical impact of this interaction on vaccine efficacy is unknown.

1 INDICATIONS AND USAGE TPOXX is an inhibitor of the orthopoxvirus VP37 envelope wrapping protein and is indicated for the treatment of human smallpox disease in adults and pediatric patients weighing at least 3 kg. ( 1.1 ) Limitations of Use: The effectiveness of TPOXX for treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical. ( 1.2 ) TPOXX efficacy may be reduced in immunocompromised patients based on studies demonstrating reduced efficacy in immunocompromised animal models. ( 1.2 ) 1.1 Treatment of Human Smallpox Disease TPOXX ® is indicated for the treatment of human smallpox disease caused by variola virus in adults and pediatric patients weighing at least 3 kg. 1.2 Limitations of Use The effectiveness of TPOXX for treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical [see Clinical Studies ( 14 )] . TPOXX efficacy may be reduced in immunocompromised patients based on studies demonstrating reduced efficacy in immunocompromised animal models.

2 DOSAGE AND ADMINISTRATION Pediatric and Adult Patients weighing 40 kg or more ( 2.3 ) (Oral Dosing): 40 kg to less than 120 kg: 600 mg of TPOXX every 12 hours for 14 days 120 kg or more: 600 mg of TPOXX every 8 hours for 14 days Pediatrics and adult patients weighing 13 kg or more and those who cannot swallow capsules ( 2.3 ) (Oral Dosing): TPOXX Capsules can be administered by carefully opening the number of capsule noted below and mixing and administering the entire contents in 30 mL of liquid (e.g., milk, chocolate milk) or soft food (e.g., apple sauce, yogurt): 13 kg to less than 25 kg: 200 mg (1 Capsule) of TPOXX every 12 hours for 14 days 25 kg to less than 40 kg: 400 mg (2 Capsules) of TPOXX every 12 hours for 14 days 40 kg to less than 120 kg: 600 mg (3 Capsules) of TPOXX every 12 hours for 14 days 120 kg or more: 600 mg (3 capsules) every 8 hours for 14 days Patients weighing 3 kg and above ( 2.5 ) (Intravenous Dosing): 3 kg to less than 35 kg: 6 mg/kg every 12 hours by intravenous infusion over 6 hours for up to 14 days 35 kg to less than 120 kg: 200 mg every 12 hours by intravenous infusion over 6 hours for up to 14 days 120 kg and above: 300 mg every 12 hours by intravenous infusion over 6 hours for up to 14 days Pediatric patients weighing 13 kg or more should be switched to TPOXX Capsules to complete the 14-day treatment course as soon as oral therapy can be tolerated. Administration Instruction for TPOXX Capsules: Take within 30 minutes after a full meal containing moderate or high fat. ( 2.1 , 2.3 ) Administration Instructions for TPOXX Injection: Infuse over 6 hours via infusion pump. ( 2.5 ) See Full Prescribing Information for additional information on the administration and preparation of TPOXX Capsules and Injection. ( 2 ) 2.1 Important Dosing Instructions It is recommended that patients 13 kg and above initiate oral treatment with TPOXX capsules if possible. If patients are unable to take oral TPOXX capsules or Drug-Food Preparation, treatment may be initiated with TPOXX injection as a 6 hour intravenous (IV) infusion. If IV treatment is necessary, conversion from IV to oral TPOXX is recommended as soon as oral treatment can be tolerated [see Dosage and Administration ( 2.3 )] . In patients receiving an IV infusion, the first dose of oral treatment should be given at the time of and in place of the next scheduled IV dosing. In patients receiving an oral treatment who subsequently require IV treatment, the first dose of IV infusion should be given at the time of and in place of the next scheduled oral dosing. TPOXX capsules Take TPOXX capsules within 30 minutes after a full meal containing moderate or high fat. Missed Dose If a dose of oral TPOXX is missed, the patient should take the dose as soon as possible and anytime up to 8 hours prior to the next scheduled dose. If less than 8 hours remain before the next scheduled dose, do not take the missed dose, and resume dosing at the next scheduled dose. TPOXX injection Administer TPOXX injection by IV infusion over 6 hours via an infusion pump. Must dilute TPOXX Injection prior to use [see Dosage and Administration ( 2.5 )] . 2.2 Testing Before Initiating and During Treatment with TPOXX Injection Determine creatinine clearance in all patients before starting TPOXX injection and monitor while receiving TPOXX injection as clinically appropriate [see Dosage and Administration ( 2.4 ), Contraindictions ( 4 ), Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.4 , 8.6 )] . 2.3 TPOXX Oral Dosage for Pediatric Patients Weighing at Least 13 kg and Adults The recommended dosage of TPOXX capsules in pediatric patients weighing at least 13 kg and adults is displayed in Table 1 below. Table 1: Recommended Dosage and Preparation Instructions for TPOXX Capsules in Pediatric Patients Weighing at Least 13 kg and Adults a TPOXX capsules should be taken within 30 minutes after a full meal containing moderate or high fat [see Clinical Pharmacology ( 12.3 )] Body Weight Oral Dosage for 14 Days a Dosage (Number of Capsules) Drug Food Preparation for Patients Who Cannot Swallow Capsules 13 kg to less than 25 kg 200 mg (1 capsule) every 12 hours Carefully open the required number of capsules and mix contents of capsule(s) of TPOXX with 30 mL of liquid (e.g., milk, chocolate milk) or soft food (e.g., apple sauce, yogurt). The entire mixture should be administered within 30 minutes of its preparation. 25 kg to less than 40 kg 400 mg (2 capsules) every 12 hours 40 kg to less than 120 kg 600 mg (3 capsules) every 12 hours 120 kg and above 600 mg (3 capsules) every 8 hours 2.4 Renal Impairment TPOXX injection is contraindicated in patients with creatinine clearance below 30 mL per minute [see Contraindictions ( 4 )] . 2.5 Dosage and Administration of TPOXX Injection for Intravenous Infusion The recommended dosage of TPOXX injection in pediatric patients weighing at least 3 kg and adults is displayed in Table 2 below. TPOXX injection is supplied in a single-dose clear glass vial containing 200 mg/20 mL (10 mg/mL). Parenteral drug products must be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. To administer: Use aseptic technique when preparing TPOXX injection. Withdraw the quantity of TPOXX injection (Table 2), add this volume to the syringe then dilute with two equal parts of either 0.9% (w/v) sodium chloride injection (normal saline) or 5% (w/v) dextrose injection in a syringe of suitable size. Injection with diluents other than 0.9% sodium chloride or 5% dextrose solution has not been studied. NOT FOR IV BOLUS INJECTION. Do not use prefilled infusion bags for product preparation and administration. The diluted TPOXX injection may be stored refrigerated (2°C - 8°C) for up to 24 hours or at room temperature (15°C - 25°C) for up to 4 hours. Gently swirl the syringe of in-use solution prior to inserting into the syringe pump and infuse over 6 hours every 12 hours for 14 days. Do not re-use the single-dose vial once it has been punctured. Table 2: Recommended Pediatric and Adult Dosage and Preparation Instructions TPOXX Injection for IV Infusion a a Patients weighing at least 13 kg should be switched to TPOXX Capsules to complete the 14 day treatment course as soon as oral therapy can be tolerated. b 10 mg/mL TPOXX solution containing 40% hydroxypropyl betadex (8 g per vial) with water for injection [see Dosage Forms and Strengths ( 3 )] c Diluent is either 0.9% (w/v) sodium chloride injection or 5% (w/v) dextrose injection solution. d Depending on size of syringe available with syringe pump system, two separate syringes may be needed for each 6 hour administration. Body Weight Dosage for up to 14 days Volume of TPOXX Injection b Volume of Diluent c 3 kg to less than 35 kg 6 mg/kg every 12 hours by intravenous infusion over 6 hours a 0.6 mL/kg 1.2 mL/kg 35 kg to less than 120 kg 200 mg every 12 hours by intravenous infusion over 6 hours 20 mL 40 mL 120 kg and above d 300 mg every 12 hours by intravenous infusion over 6 hours 30 mL 60 mL