Tecovirimat Monohydrate

TPOXX is an inhibitor of the orthopoxvirus VP37 envelope wrapping protein and is indicated for the treatment of human smallpox disease in adults and pediatric patients weighing at least 3 kg. ( 1.1 ) 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. ( 1.2 ) TPOXX efficacy may be reduced in immunocompromised patients based on studies demonstrating reduced efficacy in immunocompromised animal models. ( 1.2 )

1.1 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.

1.2 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 [see Clinical Studies ( 14 )] . TPOXX efficacy may be reduced in immunocompromised patients based on studies demonstrating reduced efficacy in immunocompromised animal models.

TPOXX Capsules TPOXX capsules are hard gelatin with an opaque orange body imprinted in white ink with “SIGA” followed by the SIGA logo followed by “®”, and an opaque black cap imprinted in white ink with “ST-246 ® ”, containing white to off-white powder. Each capsule contains 200 mg of tecovirimat. TPOXX Injection TPOXX injection: 200 mg/20 mL (10 mg/mL) of tecovirimat as a clear, colorless to pale yellow solution in a single-dose vial for further dilution. Capsules 200 mg of tecovirimat ( 2.4 ) Injection A single-dose vial containing 200 mg of tecovirimat in 20 mL for further dilution prior to intravenous infusion. ( 3 )

TPOXX 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) [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.6 )] . TPOXX capsules: None TPOXX injection: TPOXX Injection is contraindicated in patients with severe renal impairment (defined as creatinine clearance below 30 mL/min) ( 4 , 5.2 )

Hypoglycemia: Co-administration with repaglinide may cause hypoglycemia. Monitor blood glucose and monitor for hypoglycemic symptoms during co-administration. ( 5.1 )

5.1 Hypoglycemia When Co-Administered with Repaglinide Co-administration of repaglinide and tecovirimat may cause mild to moderate hypoglycemia. Monitor blood glucose and monitor for hypoglycemic symptoms when administering TPOXX with repaglinide [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . In a drug interaction study, 10 of 30 healthy subjects experienced mild (6 subjects) or moderate (4 subjects) hypoglycemia following co-administration of repaglinide (2 mg) and TPOXX. Symptoms resolved in all subjects after intake of food and/or oral glucose.

5.2 Risks of Hydroxypropyl-β-Cyclodextrin Excipient for Patients with Renal Insufficiency and Pediatric Patients < 2 Years of Age Patients with renal insufficiency TPOXX Injection: In healthy patients and in patients with mild to severe renal insufficiency, the majority of an 8 g dose of hydroxypropyl-β-cyclodextrin (per 200 mg tecovirimat/20 mL solution) is eliminated in the urine. It is known that clearance of hydroxypropyl-β-cyclodextrin is reduced in patients with mild, moderate, and severe renal impairment, resulting in higher exposure to hydroxypropyl-β-cyclodextrin; in these patients, half-life values are increased over normal values by approximately two-, four-, and six-fold, respectively. In these patients, successive infusions may result in accumulation of hydroxypropyl-β-cyclodextrin until steady state is reached. In patients with mild (defined as creatinine clearance 60-89 mL/min) and moderate (defined as creatinine clearance 30-59 mL/min) renal impairment, TPOXX Injection should be used with caution. Creatinine clearance should be closely monitored and, if renal toxicity is suspected, consideration should be given to administering TPOXX orally if possible or to using an alternative medication. TPOXX Injection is contraindicated in patients with severe renal impairment (creatinine clearance 30 mL/min) [see Contraindictions ( 4 ) and Clinical Pharmacology ( 12.3 )] . Pediatric patients TPOXX Injection: In pediatric patients less than 2 years of age, there are limited data regarding the use of hydroxypropyl-β-cyclodextrin. Given that renal tubular function rapidly matures over the first few years of life, clearance of hydroxypropyl-β-cyclodextrin may be reduced in young pediatric patients, resulting in higher exposure to hydroxypropyl-β-cyclodextrin. TPOXX Injection should be used with caution in this population given that animal studies have shown potential for nephrotoxicity at very high exposure levels of hydroxypropyl-β-cyclodextrin. 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 [see Use in Specific Populations ( 8.4 ) and Clinical Pharmacology ( 12.3 )] .

The most common adverse reactions are: TPOXX Capsules (incidence ≥ 2%): headache, nausea, abdominal pain, and vomiting. ( 6.1 ) TPOXX Injection (incidence ≥ 4%): administration site reactions and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact SIGA Technologies Inc. at 1-888-899-3472 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 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

Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 5.1 , 7 , 12.3 )

7.1 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 [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )] . 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 [see Warnings and Precautions ( 5.1 )] . CNS Depressant: Midazolam b ↓ midazolam Monitor for effectiveness of midazolam.

7.2 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 [see Clinical Pharmacology ( 12.3 )] . 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 [see Overdose ( 10 )] .

7.3 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 [see Clinical Pharmacology ( 12.3 )] .

7.4 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.

Lactation: Breastfeeding is not recommended in patients with smallpox. ( 8.2 )

8.1 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 [AUC]) 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).

8.2 Lactation Risk Summary Because of the potential for variola virus transmission through direct contact with the breastfed infant, breastfeeding is not recommended in patients with smallpox. There are no data on the presence of tecovirimat in human milk, the effects of the drug on the breastfed infant, or on milk production. Tecovirimat was present in animal milk (see Data) . When a drug is present in animal milk, it is likely to be present in human milk. Data In a lactation study at doses up to 1,000 mg/kg/day, mean tecovirimat milk to plasma ratios up to approximately 0.8 were observed at 6 and 24 hours post-dose when administered orally to mice on lactation Day 10 or 11.

8.3 Females and Males of Reproductive Potential Infertility There are no data on the effect of tecovirimat on human fertility. Decreased fertility due to testicular toxicity was observed in male mice [see Nonclinical Toxicology ( 13.1 )] .

8.4 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 [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )] . 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 [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )] .

8.5 Geriatric Use Clinical studies of TPOXX did not include sufficient numbers of subjects aged 65 and over to determine whether the safety profile of TPOXX is different in this population compared to younger subjects. Of the 359 subjects in the clinical study of TPOXX, 10% (36/359) were ≥ 65 years of age, and 1% (4/359) were ≥ 75 years of age. No alteration of dosing is needed for patients ≥ 65 years of age [see Clinical Pharmacology ( 12.3 )] .

8.6 Renal Impairment TPOXX Capsules: No dosage adjustment is required for patients with mild, moderate or severe renal impairment or patients with end stage renal disease (ESRD) requiring hemodialysis [see Clinical Pharmacology ( 12.3 )] . TPOXX Injection: Hydroxypropyl-β-cyclodextrin, an ingredient in TPOXX injection, when administered intravenously, is eliminated through glomerular filtration. No dosage adjustment is required for patients with mild (creatinine clearance 60-89 mL/min) or moderate (creatinine clearance 30-59 mL/min) renal impairment. TPOXX Injection is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min) [see Contraindictions ( 4 )] .

8.7 Hepatic Impairment No dosage adjustment is required for patients with mild, moderate or severe hepatic impairment (Child Pugh Class A, B, or C) [see Clinical Pharmacology ( 12.3 )] .

Tecovirimat is an antiviral drug against variola (smallpox) virus [see Microbiology ( 12.4 )] .