FDA

Tembexa

Approved 4 Jun 2021OralTablet

The FDA lists this product in 2 strengths and forms.

Indications

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 )

1.1Treatment 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.

1.2Limitations 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.

Contraindications

None. None. ( 4 )

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 )

At a glance

Brand name: Tembexa
Active substance: brincidofovir
Route: Oral
Dosage form: Tablet
Applicant: Emergent Biodefense
Status: Prescription
FDA approval: 4 Jun 2021
Application: NDA214461-001

Indications

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 )

1.1Treatment 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.

1.2Limitations of Use

TEMBEXA efficacy may be reduced in immunocompromised patients based on studies in immune deficient animals.

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 )

Pregnancy and breastfeeding

8.1Pregnancy 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.

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 .

6.1Clinical 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 )] .

Tembexa

Indications

1.1Treatment of Human Smallpox Disease

1.2Limitations of Use

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Tembexa

Indications

1.1Treatment of Human Smallpox Disease

1.2Limitations of Use

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Increased Risk for Mortality When Used for Longer Duration

5.2Elevations in Hepatic Transaminases and Bilirubin Elevations

5.4Coadministration with Related Products

5.5Embryo-fetal Toxicity Based

5.6Carcinogenicity

5.7Male Infertility Based

Interactions

7.1Effect of Other Drugs on

7.2Vaccine Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

Adverse reactions

6.1Clinical Trials Experience

Composition

Strengths and forms

Official product information