WARNING: INCREASED RISK FOR MORTALITY WHEN USED FOR LONGER DURATION An increased incidence of mortality was seen in TEMBEXA-treated subjects compared to placebo-treated subjects in a 24-week clinical trial when TEMBEXA was evaluated in another disease [see Warnings and Precautions ( 5.1 )] . WARNING: INCREASED RISK FOR MORTALITY WHEN USED FOR LONGER DURATION See full prescribing information for complete boxed warning. An increased incidence of mortality was seen in TEMBEXA-treated subjects compared to placebo-treated subjects in a 24-week clinical trial when TEMBEXA was evaluated in another disease [see Warnings and Precautions ( 5.1 )] .
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warnings and cautions
5 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 )] .
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Elevations in hepatic transaminases and bilirubin [see Warnings and Precautions ( 5.2 )] • Diarrhea and other GI adverse events [see Warnings and Precautions ( 5.3 )] Common adverse reactions (occurring in at least 2% of TEMBEXA-treated subjects) were diarrhea, nausea, vomiting, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Emergent BioDefense Operations Lansing LLC at 1-877-246-8472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction 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. The safety of TEMBEXA has not been studied in patients with smallpox disease. The safety of TEMBEXA was evaluated in 392 adult subjects aged 18 to 77 years in Phase 2 and 3 randomized, placebo-controlled clinical trials. Of the subjects who received a 200 mg total weekly dose of TEMBEXA, 54% were male, 85% were White, 7% were Black/African American, 6% were Asian, and 10% were Hispanic or Latino. Twenty-one percent of subjects in the studies were age 65 or older. Of these 392 subjects, 85% received a 200 mg total weekly dose of TEMBEXA for at least 2 weeks. Common Adverse Reactions The most common adverse reactions (adverse events assessed as causally related by the investigator) experienced in the first 2 weeks of dosing with TEMBEXA were diarrhea and nausea. Adverse reactions that occurred in at least 2% of subjects in the TEMBEXA treatment group are shown in Table 2 . Table 2: Adverse Reactions (All Grades) Reported in ≥2% of Subjects Note: Only adverse reactions with onset in the first 2 weeks of treatment are presented. a. Composite term includes: bowel movement irregularity, defecation urgency, diarrhea, fecal incontinence, and frequent bowel movements. b. Composite term includes: vomiting and retching. c. Composite term includes: abdominal discomfort, abdominal distention, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain. Adverse Reaction TEMBEXA 200 mg N=392 % Placebo N=208 % Diarrhea a 8 3 Nausea 5 1 Vomiting b 4 1 Abdominal pain c 3 2 Adverse Reactions Leading to Discontinuation of TEMBEXA Fifteen subjects (4%) had their treatment with TEMBEXA discontinued due to adverse reactions. One subject had two adverse reactions; the other subjects had one reaction each. These adverse reactions were: • Diarrhea (n=9) • Nausea (n=3) • Vomiting (n=1) • Enteritis (n=1) • ALT increased (n=1) • Dyspepsia (n=1) These adverse reactions were mild (Grade 1, n=1), moderate (Grade 2, n=7) or severe (Grade 3, n=8) in severity and resolved upon discontinuation of TEMBEXA. Less Common Adverse Reactions Clinically significant adverse reactions that were reported in <2% of subjects (and also occurred in 2 or more subjects) exposed to TEMBEXA and at rates higher than in subjects who received placebo are listed below: • General and administration site: peripheral edema • Metabolism and nutrition: decreased appetite • Musculoskeletal and connective tissue: muscular weakness • Nervous system: dysgeusia • Skin and subcutaneous tissue: rash (includes rash, maculo-papular rash, pruritic rash) Selected treatment-emergent laboratory values occurring during the first 2 weeks of treatment with TEMBEXA are presented in Table 3 . Table 3: Frequencies of Selected Laboratory Abnormalities ULN = upper limit of normal a. Frequencies are based on treatment-emergent laboratory abnormalities. Graded per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 toxicity grading criteria. b. ALT >10x ULN occurred in one subject in the TEMBEXA group and no subjects in the placebo group. c. No subjects reported AST >10x ULN. Laboratory Parameter Abnormality a TEMBEXA 200 mg N=392 Placebo N=208 Alanine aminotransferase (ALT) b n 382 203 Grade 2 (>3 to 5x ULN), (%) 3 2 Grade 3 (>5 to 20x ULN), (%) 2 1 Grade 4 (>20x ULN), (%) 0 0 Aspartate aminotransferase (AST) c n 380 201 Grade 2 (>3 to 5x ULN), (%) 2 1 Grade 3 (>5 to 20x ULN), (%) 1 0 Grade 4 (>20x ULN), (%) 0 0 Total bilirubin n 382 203 Grade 2 (>1.5 to 3x ULN), (%) 3 2 Grade 3 (>3 to 10x ULN), (%) 1 <1 Grade 4 (>10x ULN), (%) 0 0 Serum creatinine n 383 205 Grade 2 (>1.5 to 3x ULN), (%) 4 4 Grade 3 (>3 to 6x ULN), (%) <1 0 Grade 4 (>6x ULN), (%) 0 0 Adverse Reactions in Pediatric Subjects In 23 pediatric subjects aged 7 months to 17 years who received TEMBEXA in a randomized, placebo-controlled clinical trial, the adverse reactions and laboratory abnormalities observed with TEMBEXA were similar to adults [see Use in Specific Populations ( 8.4 )] .