tembexa

Important safety information

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 )] .