FDA News: FDA Approves TEMBEXA (Brincidofovir) for the Treatment of Human Smallpox Disease in Adult and Pediatric Patients Including Neonates

Author: [AUTHOR] Published on 6/21/2021 2:34:00 PM

FDA Approves TEMBEXA (Brincidofovir) for the Treatment of Human Smallpox Disease in Adult and Pediatric Patients Including Neonates

On June 4, 2021, the US Food and Drug Administration (FDA) approved TEMBEXA (brincidofovir) tablets and suspension for the treatment of human smallpox disease in adult and pediatric patients, including neonates. TEMBEXA is not indicated for the treatment of diseases other than human smallpox disease. 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. In addition, TEMBEXA efficacy may be reduced in immunocompromised patients based on studies in immune deficient animals.
The recommended dosage of TEMEXA is listed below:
  • 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.
  • Adult and pediatric patients weighing 10 kg to less than 48 kg: 4 mg/kg oral suspension once weekly for 2 doses.
  • Pediatric patients weighing less than 10 kg: 6 mg/kg oral suspension once weekly for 2 doses.
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). Swallow tablet whole. TEMBEXA oral suspension should be taken on an empty stomach. Shake oral suspension before use. For patients who cannot swallow, TEMBEXA oral suspension can be administered by enteral tube (ET). Specific instructions for ET administration can be found in the full prescribing information linked below.

All patients should receive hepatic laboratory testing before starting TEMBEXA and while receiving TEMBEXA as clinically appropriate. Furthermore, individuals of childbearing potential should receive pregnancy testing to inform risk before initiation of TEMBEXA.

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.

Additional information regarding dosage and administration as well as warnings and precautions about increased risk for mortality when used for longer duration, elevations in hepatic transaminases and bilirubin, diarrhea and other gastrointestinal (GI) events adverse events, embryo-fetal toxicity, cardiotoxicity, and male infertility can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)
  • MOA: Brincidofovir is an orthopoxvirus nucleotide analog DNA polymerase inhibitor against variola (smallpox) virus.
  • General PK: Brincidofovir is a prodrug that is converted intracellularly to cidofovir, which is subsequently phosphorylated to cidofovir diphosphate, the active antiviral moiety, following oral administration. Brincidofovir plasma exposures do not accumulate after repeat doses. The metabolite cidofovir diphosphate reaches maximum concentration at 47 hours (23 to 311 hours) following administration of the recommended dose, with a mean (CV%) half-life of 113 hours (34.2%). The PK properties of brincidofovir following administration of TEMBEXA are provided in Table 1. The exposure parameters of brincidofovir and cidofovir diphosphate following administration of TEMBEXA at the recommended dose are provided in Table 2.
Table 1: PK Properties of Brincidofovir in Healthy Adults



Oral suspension





3 hours (2 to 8 hours)

Effect of food on TEMBEXA Tablet (relative to fasting)b

  • AUCinf decreased by 31%
  • Cmax decreased by 49%


% Bound to human plasma proteins


Blood-to-plasma ratio (drug or drug-related materials)c

0.48 to 0.61

Apparent Volume of distribution, L



Apparent Clearance, L/hr


Mean terminal half-life (t1/2), hr



Metabolic pathways

hydrolysis, CYP4F2


cidofovir and cidofovir diphosphate (active)


% of dose excreted in urinec

51%, as metabolites

% of dose excreted in fecesc

40%, as metabolites

a. Administered under fasted conditions.
b. Low-fat meal: ~400 calories, with ~25% calories from fat. No clinically meaningful change in intracellular concentrations of cidofovir diphosphate were seen when TEMBEXA Tablet was administered with a low-fat meal. The effect of food on TEMBEXA oral suspension has not been studied.
c. Following administration of radiolabeled brincidofovir.

Table 2: Single-Dose Exposure Parameters of Brincidofovir and Cidofovir Diphosphate in Healthy Adults

PK Parameter

Geometric Mean (%CV)


Cidofovir diphosphate


480 ng/mL (70%)

9.7 pg/106 cells (75%)


3400 ng·hr/mL (58%)

1200 pg·hr/106 cells (75%)

Drug Interactions
Inhibitors for Organic Anion Transporting Polypeptide (OATP) 1B1 and 1B3: 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. Some examples of OATP1B1 or 1B3 inhibitors include clarithromycin, cyclosporine, erythromycin, gemfibrozil, human immunodeficiency virus [HIV] and hepatitis C virus [HCV] protease inhibitors, rifampin [single dose]. Concomitant use of TEMBEXA with OATP1B1 and 1B3 inhibitors increase brincidofovir AUC and Cmax which may increase TEMBEXA associated adverse reactions.

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.

Use in Specific Populations
No clinically meaningful differences in the PK of brincidofovir were observed based on age, sex, race, reduced activity in the CYP4F2 enzyme, renal impairment including ESRD with or without dialysis (based on estimated glomerular filtration rate [GFR]), or hepatic impairment (Child Pugh Class B, C).

Pediatric Patients: The PK of TEMBEXA suspension has been evaluated in pediatric individuals. PK simulation was used to derive dosing regimens that are predicted to provide pediatric patients, including neonates, with exposures comparable to the observed exposure in adults receiving TEMBEXA tablets.

Efficacy and Safety
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 efficacy of the drug is not ethical. Therefore, the effectiveness of TEMBEXA for treatment of smallpox disease was established based on results of adequate and well-controlled animal efficacy studies of rabbits and mice infected with species specific non-variola orthopoxviruses. Survival rates observed in the animal studies may not be predictive of survival rates in clinical practice.

Efficacy studies were conducted in the rabbitpox model (New Zealand White rabbits infected with rabbitpox virus) and the mousepox model (BALB/c mice infected with ectromelia virus). The primary efficacy endpoint for these studies was survival. Survival was monitored for 4 to 5 times the mean time to death for untreated animals in each model. Additional information regarding the efficacy trial(s) can be found in the full prescribing information linked below.

Common adverse reactions (occurring in at least 2% of TEMBEXA treated subjects) were diarrhea, nausea, vomiting, and abdominal pain.

Full prescribing information is available at https://go.usa.gov/x69cb.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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