Tpoxx Drug Information

Treatment of Human Smallpox Disease

TPOXX ® is indicated for the treatment of human smallpox disease caused by variola virus in adults and pediatric patients weighing at least 3 kg.

Limitations of Use

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 . TPOXX efficacy may be reduced in immunocompromised patients based on studies demonstrating reduced efficacy in immunocompromised animal models.

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 TPOXX has not been studied in patients with smallpox disease. TPOXX Clinical Trial (Oral Administration) The safety of TPOXX was evaluated in 359 healthy adult subjects ages 18-79 years in a Phase 3 clinical trial.

Of the subjects who received at least one 600 mg dose of TPOXX, 59% were female, 69% were White, 28% were Black/African American, 1% were Asian, and 12% were Hispanic or Latino. Ten percent of the subjects who participated in the study were age 65 or older. Of these 359 subjects, 336 subjects received at least 23 of 28 doses of 600 mg TPOXX in a twice daily (every 12 hours) regimen for 14 days.

Most Frequently Reported Adverse Reactions The most frequently reported adverse reactions were headache and nausea. Adverse reactions that occurred in at least 2% of subjects in the TPOXX treatment group are shown in Table 3. Table 3: Treatment-Related Adverse Reactions Reported in ≥ 2% of Healthy Adult Subjects Receiving at Least One Dose of TPOXX Capsules 600 mg a Includes abdominal pain, abdominal pain upper, abdominal distension, abdominal discomfort, abdominal pain lower, epigastric pain Adverse Reaction TPOXX 600 mg N = 359 (%) Placebo N = 90 (%) Headache 12 8 Nausea 5 4 Abdominal pain a 2 1 Vomiting 2 0 Adverse Reactions Leading to Discontinuation of TPOXX Six subjects (2%) had their treatment with TPOXX discontinued due to adverse reactions. Each of these subject’s adverse reactions (with severity) is listed below: EEG change, abnormal Mild upset stomach, dry mouth, decreased concentration and dysphoria Mild nausea and fever, moderate diarrhea, severe headache Mild palpable purpura Mild nausea, fever and chills Mild facial redness, facial swelling and pruritus Less Common Adverse Reactions Clinically significant adverse reactions that were reported in <2% of subjects exposed to TPOXX and at rates higher than subjects who received placebo are listed below: Gastrointestinal: dry mouth, chapped lips, dyspepsia, eructation, oral paresthesia General and administration site: pyrexia, pain, chills, malaise, thirst Investigations: abnormal electroencephalogram, hematocrit decreased, hemoglobin decreased, heart rate increased Musculoskeletal and connective tissue: arthralgia, osteoarthritis Nervous system: migraine, disturbance in attention, dysgeusia, paresthesia Psychiatric: depression, dysphoria, irritability, panic attack Respiratory, Thoracic and Mediastinal Disorders: oropharyngeal pain Skin and subcutaneous tissue: palpable purpura, rash, pruritic rash, facial redness, facial swelling, pruritus TPOXX Clinical Trial (Intravenous Administration) The safety of multiple doses of 240 mg of TPOXX injection for IV infusion was evaluated in 26 healthy adult subjects ages 23-62 years, inclusive.

An additional 6 subjects received placebo. TPOXX injection was administered over a 6 hour period via infusion pump twice daily (every 12 hours) for 7 days. Of the 26 subjects administered TPOXX, 42% were female, 69% were White, 23% were Black/African American, and 42% were Hispanic or Latino.

Most Frequently Reported Adverse Reactions The most frequently reported adverse reactions included infusion site pain, infusion site swelling, infusion site erythema, infusion site extravasation, and headache. Adverse reactions that occurred in at least 4% of subjects in the TPOXX treatment group are shown in Table 4. Table 4: Treatment-Related Adverse Reactions Reported in ≥ 4% of Healthy Adult Subjects Receiving at Least One Dose of TPOXX Injection 240 mg TPOXX 240 mg N = 26 (%) Placebo N = 6 (%) Infusion Site Pain 73 67 Infusion Site Swelling 39 67 Infusion Site Erythema 23 67 Infusion Site Extravasation 19 50 Headache 15 0 Adverse Reactions Leading to Discontinuation of TPOXX Injection Three subjects (12%) had their treatment with TPOXX injection discontinued due to adverse reactions. One subject had two adverse reactions.

Each of these subject’s adverse reactions (with severity) are listed below: Moderate Infusion site extravasation Mild Infusion site extravasation Mild Infusion site swelling and mild infusion site pain Less Common Adverse Reactions Clinically significant adverse reactions that were reported in <4% of subjects exposed to TPOXX injection and at rates higher than subjects who received placebo are listed below: General and administration site: infusion site discomfort, infusion site edema Musculoskeletal and connective tissue: myalgia, arthritis, back pain, muscle tightness Gastrointestinal: diarrhea Eye: photophobia Skin and Subcutaneous Tissue: pruritus generalized

Effect of

TPOXX on Other Drugs Tecovirimat is a weak inducer of cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C8 and CYP2C19. However, the effects are not expected to be clinically relevant for most substrates of those enzymes based on the magnitude of interactions and the duration of treatment of TPOXX. Table 5 provides a listing of established or significant drug interactions and clinical recommendations for select sensitive substrates . Table 5: Significant Drug Interactions with Effect of TPOXX on Other Drugs a ↓ = decrease, ↑ = increase b These interactions have been studied in healthy adults. Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Effect/Recommendation Blood Glucose-Lowering Agent: Repaglinide b ↑ repaglinide Monitor blood glucose and monitor for hypoglycemic symptoms in patients when TPOXX is co-administered with repaglinide . CNS Depressant: Midazolam b ↓ midazolam Monitor for effectiveness of midazolam.

Effect of Other drugs on

TPOXX Co-administration of phosphate binders with tecovirimat increases tecovirimat bioavailability. Table 6 provides a listing of established drug interactions and clinical recommendations for select phosphate binders . Table 6: Significant Drug Interactions with Effect of Other Drugs on TPOXX a ↑ = increase b These interactions have been studied in healthy adults. Concomitant Drug Class: Drug Name Effect on Concentration a Clinical Effect/Recommendation Phosphate Binders b : Calcium acetate Lanthanum carbonate Sevelamer carbonate Sucroferric oxyhydroxide ↑ tecovirimat Monitor for signs or symptoms of adverse effects when TPOXX is co-administered with phosphate binders .

Drugs Without Clinically Significant Interactions With

TPOXX Based on a drug interaction study, no clinically significant drug interactions have been observed when TPOXX is co-administered with bupropion, flurbiprofen, or omeprazole .

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

Some animal studies have indicated that co-administration of TPOXX at the same time as live smallpox vaccine (vaccinia virus) may reduce the immune response to the vaccine. The clinical impact of this interaction on vaccine efficacy is unknown.

Pregnancy Risk Summary There are no available data on the use of tecovirimat 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, no embryofetal developmental toxicity was observed in mice during the period of organogenesis at tecovirimat exposures (area under the curve ) up to 23 times higher than human exposure at the recommended human dose (RHD). In rabbits, no embryofetal developmental toxicity was observed during organogenesis at tecovirimat exposures (AUC) less than human exposures at the RHD. In a mouse pre-/post-natal development study, no toxicities were observed at maternal tecovirimat exposures up to 24 times higher than human exposure at the RHD (see Data). The background risk of major birth defects and miscarriage 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 2-4% and 15-20%, respectively. Data Animal Data Tecovirimat was administered orally to pregnant mice at doses up to 1,000 mg/kg/day from gestation Days 6-15. No embryofetal toxicities were observed at doses up to 1,000 mg/kg/day (approximately 23 times higher than human exposure at the RHD). Tecovirimat was administered orally to pregnant rabbits at doses up to 100 mg/kg/day from gestation Days 6-19. No embryofetal toxicities were observed at doses up to 100 mg/kg/day (0.4 times the human exposure at the RHD). In the pre-/post-natal development study, tecovirimat was administered orally to pregnant mice at doses up to 1,000 mg/kg/day from gestation Day 6 to post-natal Day 20. No toxicities were observed at doses up to 1,000 mg/kg/day (approximately 24 times higher than human exposure at the RHD).

Pediatric Use As in adults, the effectiveness of TPOXX in pediatric patients is based solely on efficacy studies in animal models of orthopoxvirus disease. As exposure of healthy pediatric subjects to TPOXX with no potential for direct clinical benefit is not ethical, pharmacokinetic simulation was used to derive dosing regimens that are predicted to provide pediatric patients with exposures comparable to the observed exposure in adults receiving 600 mg orally twice daily (every 12 hours) or 200 mg intravenously twice daily (every 12 hours). The dosage for pediatric patients is based on weight . TPOXX Injection: There are limited data regarding the use of hydroxypropyl-β-cyclodextrin, an ingredient in TPOXX injection, in pediatric patients less than 2 years of age. Given the potential for drug accumulation due to renal immaturity in pediatric patients less than 2 years, monitoring of renal function after treatment is recommended .

• Capsules: None.
• TPOXX Injection: The excipient hydroxypropyl-β-cyclodextrin is eliminated through glomerular filtration. Therefore, TPOXX Injection is contraindicated in patients with severe renal impairment (defined as creatinine clearance below 30 mL/min) .
• TPOXX capsules: None TPOXX injection: TPOXX Injection is contraindicated in patients with severe renal impairment (defined as creatinine clearance below 30 mL/min)

There is no clinical experience with overdosage of TPOXX. In case of overdosage, monitor patients for any signs or symptoms of adverse effects. Hemodialysis will not significantly remove TPOXX in overdosed patients.