Tembexa Drug Information

• 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 )] .

Effect of Other Drugs on

TEMBEXA Inhibitors for Organic Anion Transporting Polypeptide (OATP) 1B1 and 1B3 Concomitant use of TEMBEXA with OATP1B1 and 1B3 inhibitors (clarithromycin, cyclosporine, erythromycin, gemfibrozil, human immunodeficiency virus and hepatitis C virus protease inhibitors, rifampin ) increase brincidofovir AUC and C max which may increase TEMBEXA-associated adverse reactions . Where possible, consider alternative medications that are not OATP1B1 or 1B3 inhibitors. If concomitant use with TEMBEXA is necessary, increase monitoring for adverse reactions associated with TEMBEXA (elevations in transaminases and bilirubin, diarrhea, or other GI adverse events) and postpone the dosing of OATP1B1 or 1B3 inhibitors for at least 3 hours after TEMBEXA administration.

Vaccine Interactions No vaccine-drug interaction studies have been performed in human subjects.

Animal studies have indicated that coadministration of TEMBEXA at the same time as live smallpox vaccine (vaccinia virus) may reduce the immune response to the vaccine. It is also possible that TEMBEXA may reduce the immune response to replication-defective smallpox vaccine (modified vaccinia virus Ankara). The clinical impacts of these potential interactions on vaccine efficacy are unknown.

Pregnancy Risk Summary Based on findings from animal reproduction studies, TEMBEXA may cause fetal harm when administered to pregnant individuals. Use an alternative therapy to treat smallpox during pregnancy, if feasible. There are no available data on the use of brincidofovir in pregnant individuals to evaluate for a drug-associated risk of major birth defects, miscarriage, and other adverse maternal and fetal outcomes.

In animal reproduction studies, oral administration of brincidofovir to pregnant rats and rabbits during the period of organogenesis resulted in embryotoxicity and structural malformations. These effects occurred in animals at systemic exposures less than the expected human exposure based on the recommended dose of TEMBEXA ( see Data ). The estimated background risk of major birth defects for the indicated population is unknown, and the estimated background risk of miscarriage for the indicated population is higher than the general population. All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals were administered oral doses of brincidofovir up to 4.5 mg/kg/day from gestation days 7 to 20. Maternal toxicity in rats, characterized by decreases in food consumption and decreased body weight gain, was observed at doses of 1.5 and 4.5 mg/kg/day. These effects correlated with decreased fetal weights in rats given 4.5 mg/kg/day.

Brincidofovir administration in rats was not associated with effects on intrauterine growth or survival at any dose, and there were no external malformations or developmental variations. In rabbits, 4.5 mg/kg/day brincidofovir was associated with decreased maternal body weight and food consumption, decreased fetal body weight, increased late resorptions and morphological changes which included external, visceral and skeletal malformations and variations. In the pre-/post-natal development study, administration of brincidofovir at doses of 0, 0.25, 1, and 4 mg/kg/day and 15 mg/kg twice weekly to pregnant rats from gestation day 7 to lactation day 20 resulted in pup toxicity at maternally toxic doses (4 mg/kg/day and 15 mg/kg twice weekly). Pup body weight and viability were decreased, and reproductive function of the pups was impaired as evidenced by a delay in sexual maturation, decreased testes and epididymal size, reduced mating and an increase in the number of days to mating as well as preimplantation loss.

All effects were observed at systemic exposures less than the expected human exposure based on the recommended dose of TEMBEXA.

Pediatric Use As in adults, the effectiveness of TEMBEXA in smallpox infected pediatric patients, including neonates, is based solely on efficacy studies in animal models of orthopoxvirus disease. The recommended pediatric dosing regimen is expected to produce brincidofovir exposures that are comparable to those in adults based on a population pharmacokinetic modeling and simulation approach. The dosage for pediatric patients is based on weight . There have been 23 pediatric subjects aged 7 months to 17 years who received TEMBEXA in a randomized, placebo-controlled clinical trial.

The safety in adult and pediatric subjects treated with TEMBEXA were similar . An additional 166 pediatric subjects aged 3 months to 18 years of age received TEMBEXA from uncontrolled studies and expanded access. The dosage of TEMBEXA in pediatric patients <3 months of age was based on modeling and simulations .

There is no clinical experience with overdosage of TEMBEXA. In the event of an overdose, monitor patients for adverse effects and provide appropriate supportive care.