brincidofovir 100 MG Oral Tablet [Tembexa]

INDICATIONS AND USAGE TEMBEXA is an orthopoxvirus nucleotide analog DNA polymerase inhibitor and is indicated for the treatment of human smallpox disease in adult and pediatric patients, including neonates. ( 1.1 ) Limitations of Use: • TEMBEXA is not indicated for the treatment of diseases other than human smallpox disease. ( 1.2 ) • The effectiveness of TEMBEXA 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 ) • TEMBEXA efficacy may be reduced in immunocompromised patients based on studies in immune deficient animals. ( 1.2 ) 1.1 Treatment of Human Smallpox Disease TEMBEXA ® is indicated for the treatment of human smallpox disease caused by variola virus in adult and pediatric patients, including neonates. 1.2 Limitations of Use TEMBEXA is not indicated for the treatment of diseases other than human smallpox disease [see Warnings and Precautions ( 5.1 , 5.2 )] . The effectiveness of TEMBEXA for the 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 )] . TEMBEXA efficacy may be reduced in immunocompromised patients based on studies in immune deficient animals.

DOSAGE AND ADMINISTRATION • Testing: Before initiation and during treatment with TEMBEXA perform hepatic laboratory testing and pregnancy testing. ( 2.1 ) • See full prescribing information for details on important administration instructions. ( 2.2 ) • Adult and pediatric patients weighing 48 kg or above: 200 mg (two 100 mg tablets or 20 mL oral suspension for patients who cannot swallow tablets) once weekly for 2 doses. ( 2.3 ) • Adult and pediatric patients weighing 10 kg to less than 48 kg: 4 mg/kg oral suspension once weekly for 2 doses. ( 2.3 ) • Pediatric patients weighing less than 10 kg: 6 mg/kg oral suspension once weekly for 2 doses. ( 2.3 ) 2.1 Testing Before Initiating and During Treatment with TEMBEXA Perform hepatic laboratory testing in all patients before starting TEMBEXA and while receiving TEMBEXA, as clinically appropriate [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.7 )] . Perform pregnancy testing before initiation of TEMBEXA in individuals of childbearing potential to inform risk [see Warnings and Precautions ( 5.5 ) and Use in Specific Populations ( 8.3 )] . 2.2 Important Administration Instructions Avoid direct contact with broken or crushed tablets or oral suspension. If contact with skin or mucous membranes occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with water [see Warnings and Precautions ( 5.6 )] . TEMBEXA Tablets TEMBEXA tablets can be taken on an empty stomach or with a low-fat meal (approximately 400 calories, with approximately 25% of calories from fat) [see Clinical Pharmacology ( 12.3 )] . Swallow TEMBEXA tablets whole. Do not crush or divide TEMBEXA tablets. TEMBEXA Oral Suspension Take TEMBEXA oral suspension on an empty stomach [see Clinical Pharmacology ( 12.3 )] . Shake oral suspension before use. Use an appropriate oral dosing syringe to correctly measure the total prescribed dose [see Patient Counseling Information ( 17 )] . Discard unused portion after completion of 2 prescribed doses. For patients who cannot swallow, TEMBEXA oral suspension can be administered by enteral tube (naso-gastric or gastrostomy tubes) as follows: • Draw up prescribed dose with a calibrated catheter-tip syringe, and utilize this syringe to administer the dose via the enteral tube. • Refill the catheter-tip syringe with 3 mL of water, shake, and administer the contents via the enteral tube. • Flush with water before and after enteral administration. 2.3 Recommended Dosage The recommended dosage of TEMBEXA in pediatric and adult patients is displayed in Table 1 [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )] . Table 1: Recommended Dosage in Pediatric and Adult Patients Patient’s Weight (kg) TEMBEXA Oral Suspension (10 mg/mL) TEMBEXA Tablet (100 mg) Less than 10 kg 6 mg/kg once weekly for 2 doses (on Days 1 and 8) N/A 10 kg to less than 48 kg 4 mg/kg once weekly for 2 doses (on Days 1 and 8) N/A 48 kg and above 200 mg (20 mL) once weekly for 2 doses (on Days 1 and 8) 200 mg (two 100 mg tablets) once weekly for 2 doses (on Days 1 and 8)

WARNINGS AND PRECAUTIONS • Elevations in Hepatic Transaminases and Bilirubin: May cause increases in serum transaminases (ALT or AST) and serum bilirubin. Monitor liver laboratory parameters before and during treatment. ( 5.2 ) • Diarrhea and Other Gastrointestinal Adverse Events: Diarrhea and additional gastrointestinal adverse events including nausea, vomiting, and abdominal pain may occur. Monitor patients, provide supportive care, and if necessary, do not give the second and final dose of TEMBEXA. ( 5.3 ) • Coadministration with Related Products: TEMBEXA should not be coadministered with intravenous cidofovir. ( 5.4 ) • Embryo-fetal Toxicity: May cause fetal harm. Advise individuals of childbearing potential of the potential risk to the fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 ) • Carcinogenicity: TEMBEXA should be considered a potential human carcinogen. Do not crush or divide TEMBEXA tablets. ( 5.6 , 13.1 ) • Male Infertility: Based on testicular toxicity in animal studies, TEMBEXA may irreversibly impair fertility in individuals of reproductive potential. ( 5.7 , 8.3 ) 5.1 Increased Risk for Mortality When Used for Longer Duration TEMBEXA is not indicated for use in diseases other than human smallpox. An increase in mortality was observed in a randomized, placebo-controlled Phase 3 trial when TEMBEXA was evaluated in another disease. An increased risk in mortality is possible if TEMBEXA is used for a duration longer than at the recommended dosage on Days 1 and 8 [see Indications and Usage ( 1.2 ) and Dosage and Administration ( 2.3 )] . Study 301 (CMX001-301) evaluated TEMBEXA versus placebo for the prevention of cytomegalovirus infection. A total of 303 subjects received TEMBEXA (100 mg twice weekly) and 149 subjects received matching placebo for up to 14 weeks. The primary endpoint was evaluated at Week 24. All-cause mortality at Week 24 was 16% in the TEMBEXA group compared to 10% in the placebo group. Safety and effectiveness of TEMBEXA have not been established for diseases other than human smallpox disease. 5.2 Elevations in Hepatic Transaminases and Bilirubin Elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin have been observed, including cases of concurrent increases in ALT and bilirubin. During the first 2 weeks of TEMBEXA therapy in 392 subjects, ALT elevations >3x the upper limit of normal were reported in 7% of subjects and bilirubin elevations >2x the upper limit of normal were reported in 2% of subjects; these elevations in hepatic laboratory tests were generally reversible and did not require discontinuation of TEMBEXA [see Adverse Reactions ( 6.1 ) and Nonclinical Toxicology ( 13.2 )] . Severe hepatobiliary adverse events including hyperbilirubinemia, acute hepatitis, hepatic steatosis, and venoocclusive liver disease have been reported in less than 1% of subjects. Perform hepatic laboratory testing in all patients before starting TEMBEXA and while receiving TEMBEXA, as clinically appropriate. Monitor patients who develop abnormal hepatic laboratory tests during TEMBEXA therapy for the development of more severe hepatic injury. Consider discontinuing TEMBEXA if ALT levels remain persistently >10x the upper limit of normal. Do not give the second and final dose of TEMBEXA on Day 8 if ALT elevation is accompanied by clinical signs and symptoms of liver inflammation or increasing direct bilirubin, alkaline phosphatase, or International Normalized Ratio (INR) [see Adverse Reactions ( 6.1 ) and Drug Interactions ( 7.1 )] . 5.3 Diarrhea and Other Gastrointestinal Adverse Events During the first 2 weeks of TEMBEXA therapy in 392 subjects, a composite term of diarrhea (all grade, all cause) occurred in 40% of TEMBEXA-treated subjects compared with 25% of subjects in the placebo control group. Treatment with TEMBEXA was discontinued in 5% of subjects for diarrhea (composite term) compared with 1% in the placebo control group. Additional gastrointestinal (GI) adverse events included nausea, vomiting, and abdominal pain; some of these adverse events required discontinuation of TEMBEXA [see Adverse Reactions ( 6.1 ) and Drug Interactions ( 7.1 ) and Nonclinical Toxicology ( 13.2 )] . Monitor patients for GI adverse events including diarrhea and dehydration, provide supportive care, and if necessary, do not give the second and final dose of TEMBEXA. 5.4 Coadministration with Related Products TEMBEXA should not be co-administered with intravenous cidofovir. Brincidofovir, a lipid-linked derivative of cidofovir, is intracellularly converted to cidofovir [see Clinical Pharmacology ( 12.3 )] . 5.5 Embryo-fetal Toxicity Based on findings from animal reproduction studies, TEMBEXA may cause fetal harm when administered to pregnant individuals. TEMBEXA administration to pregnant rats and rabbits resulted in embryotoxicity, decreased embryo-fetal survival and/or structural malformations. These effects occurred in animals at systemic exposures less than the expected human exposure based on the recommended dose of TEMBEXA. Use an alternative therapy to treat smallpox during pregnancy, if feasible. Perform pregnancy testing in individuals of childbearing potential before initiation of TEMBEXA. Advise individuals of childbearing potential to avoid becoming pregnant and to use effective contraception during treatment with TEMBEXA and for at least 2 months after the last dose. Advise individuals of reproductive potential with partners of childbearing potential to use condoms during treatment with TEMBEXA and for at least 4 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] . 5.6 Carcinogenicity TEMBEXA is considered a potential human carcinogen. Mammary adenocarcinomas and squamous cell carcinomas occurred in rats at systemic exposures less than the expected human exposure based on the recommended dose of TEMBEXA [see Nonclinical Toxicology ( 13.1 )] . Do not crush or divide TEMBEXA tablets. Avoid direct contact with broken or crushed tablets or oral suspension. If contact with skin or mucous membranes occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with water [see How Supplied/Storage and Handling ( 16 )] . 5.7 Male Infertility Based on testicular toxicity in animal studies, TEMBEXA may irreversibly impair fertility in individuals of reproductive potential [see Use in Specific Populations ( 8.3 ) and Nonclinical Toxicology ( 13.1 )] .

CONTRAINDICATIONS None. None. ( 4 )

Mechanism of Action Brincidofovir is an antiviral drug against variola (smallpox) virus [see Microbiology ( 12.4 )] .