FDA Approves TPOXX (Tecovirimat) for the Treatment of Human Smallpox Disease
On July 13, 2018, the U.S. Food and Drug Administration (FDA) approved TPOXX (tecovirimat) under the “Animal Efficacy Rule” (21 CFR Part 314, subpart I “Approval of New Drugs when Human Efficacy Studies are not Ethical or Feasible”) for the treatment of human smallpox disease in adults and pediatric patients weighing at least 13 kg. The effectiveness of TPOXX for treatment of smallpox disease has not been determined in humans (see below).
The approved recommended dosage of TPOXX for adults is 600 mg orally twice daily for 14 days. The approved recommended dosage of TPOXX for pediatric patients is based on weight as follows:
- 13 kg to < 25 kg: 200 mg orally twice daily for 14 days
- 25 kg to < 40 kg: 400 mg orally twice daily for 14 days
- ≥ 40 kg: 600 mg orally twice daily for 14 days
TPOXX should be taken within 30 minutes after a full meal (moderate or high fat). Additional instructions for administration for pediatrics and those who cannot swallow capsules can be found in the full prescribing information linked below. TPOXX efficacy may be reduced in immunocompromised patients based on studies demonstrating reduced efficacy in immunocompromised animal models.
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)
- MOA: Tecovirimat targets and inhibits the activity of the orthopoxvirus VP37 protein (encoded by and highly conserved in all members of the orthopoxvirus genus) and blocks its interaction with cellular Rab9 GTPase and TIP47, which prevents the formation of egress-competent enveloped virions necessary for cell-to-cell and long-range dissemination of virus.
- General PK: At the approved recommended dosage, TPOXX mean AUC0-24hr is 28791 hr·ng/mL (CV: 35%), Cmax is 2106 ng/mL (CV: 33%), and Cmin is 587 ng/mL (CV: 38%). Tecovirimat steady state AUC is achieved by Day 6.
- Comparison of Animal and Human PK Data: Humans achieve greater systemic exposure (AUC, Cmax, and Cmin) of tecovirimat following a twice daily dose of 600 mg when compared to the therapeutic exposures in animal models of orthopoxvirus infection, nonhuman primates and rabbits infected with monkeypox virus and rabbitpox virus, respectively.
- Absorption: Tmax is 4 to 6 hours.
- Effect of Food (relative to fasting): Meal (~ 600 calories, ~ 25 grams of fat) increased tecovirimat AUC24hr by 39%.
- Distribution: The volume of distribution (Vz/F) is 1030 L and plasma protein binding is 77 to 82%.
- Elimination: The mean terminal half-life is 20 hours and clearance (CL/F) is 31 L/hr.
- Metabolism: Tecovirimat is metabolized by hydrolysis of the amide bond and glucuronidation by UGT1A1 and UGT1A4.
- Excretion: In a mass balance study, 73% of a single [14C] tecovirimat dose was excreted in urine predominantly as metabolites and 23% in feces predominantly as tecovirimat.
- Cardiac Electrophysiology: TPOXX does not prolong the QT interval to any clinically relevant extent at the anticipated therapeutic exposure.
Drug Interactions
- Repaglinide: Co-administration with TPOXX increases the concentration of repaglinide (a blood glucose-lowering agent). Monitor blood glucose and monitor for hypoglycemic symptoms.
- Midazolam: Co-administration with TPOXX decreases the concentration of midazolam (a CNS depressant). Monitor for effectiveness of midazolam.
No clinically significant drug interactions have been observed when TPOXX is co-administered with bupropion, flurbiprofen, or omeprazole.
Use in Specific Populations
No clinically significant differences in the pharmacokinetics of tecovirimat were observed based on age, renal impairment, or hepatic impairment.
Efficacy and Safety
The effectiveness of TPOXX 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. Therefore, the effectiveness of TPOXX for treatment of smallpox disease was established based on results of animal efficacy studies of non-human primates and rabbits infected with non-variola orthopoxviruses. Treatment with tecovirimat for 14 days resulted in statistically significant improvement in survival relative to placebo in both animal models. Additional information regarding efficacy studies can be found in the full prescribing information linked below.
The safety of TPOXX has not been studied in patients with smallpox disease. The safety of TPOXX was evaluated in healthy adult subjects ages 18-79 years in a Phase 3 clinical trial. Common adverse reactions (≥ 2%) were headache, nausea, abdominal pain, and vomiting.
Full prescribing information is available at https://go.usa.gov/xUXmV.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.
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