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Tecovirimat Capsules

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Tecovirimat is an inhibitor of the orthopoxvirus VP37 envelope wrapping protein. Tecovirimat is available as immediate release capsules containing tecovirimat monohydrate equivalent to 200 mg of tecovirimat for oral administration. The capsules are imprinted in white ink with “SIGA” followed by the SIGA logo followed by “®” on an orange body, and a black cap imprinted in white ink with “ST-246®.” The capsules include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The capsule shell is composed of gelatin, FD&C blue #1, FD&C red #3, FD&C yellow #6, and titanium dioxide.

Tecovirimat monohydrate is a white to off-white crystalline solid with the chemical name Benzamide, N-[(3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6 ethenocycloprop[f]isoindol-2(1H)-yl]-4-(trifluoromethyl), rel-(monohydrate). The molecular structure is as follows:

Empirical formula: C19H15F3N2O3·H2O - Molecular weight: 394.35 g/mol

Tecovirimat monohydrate is practically insoluble in water and across the pH range of 2.0-6.5 (< 0.1 mg/mL).

2. INDICATIONS AND USAGE

2.1 Treatment of Human Smallpox Disease

Tecovirimat is indicated for the treatment of human smallpox disease caused by variola virus in adults and pediatric patients weighing at least 13 kg.

2.2 Limitations of Use

The effectiveness of tecovirimat 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].

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

3. DOSAGE AND ADMINISTRATION

3.1 Dosage for Adults and Pediatric Patients Weighing at Least 40 kg

The recommended dosage of tecovirimat in adults and pediatric patients weighing at least 40 kg is 600 mg (three 200 mg capsules) taken twice daily orally for 14 days. Tecovirimat should be taken within 30 minutes after a full meal of moderate or high fat [see Clinical Pharmacology].

3.2 Dosage for Pediatric Patients

The recommended dosage for pediatric patients is based on weight starting at 13 kg as shown in Table 1. The dose should be given twice daily orally for 14 days and should be taken within 30 minutes after a full meal of moderate or high fat [see Clinical Pharmacology].

3.3 Preparation for Administration to Pediatrics and Those Who Cannot Swallow Capsules

Tecovirimat capsules can be administered by carefully opening the capsule and mixing the entire contents in 30 mL of liquid (e.g., milk, chocolate milk) or soft food (e.g., apple sauce, yogurt). The entire mixture should be administered within 30 minutes of its preparation.

Table 1: Recommended Pediatric and Adult Dosage and Preparation Instructions

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

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 tecovirimat with repaglinide [see Drug Interactions (7) and Clinical Pharmacology].

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 tecovirimat. Symptoms resolved in all subjects after intake of food and/or oral glucose.

6. ADVERSE REACTIONS

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 tecovirimat has not been studied in patients with smallpox disease.

The safety of tecovirimat 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 tecovirimat, 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 tecovirimat in a twice daily 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 tecovirimat treatment group are shown in Table 2.

Table 2: Adverse Reactions Reported in ≥ 2% of Healthy Adult Subjects Receiving at Least One Dose of Tecovirimat 600 mg

a Includes abdominal pain, abdominal pain upper, abdominal distension, abdominal discomfort, abdominal pain lower, epigastric pain

Adverse Reactions Leading to Discontinuation of Tecovirimat

Six subjects (2%) had their treatment with tecovirimat 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 tecovirimat 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

7. DRUG INTERACTIONS

7.1 Effect of Tecovirimat 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 tecovirimat. See Table 3 for clinical recommendations for select sensitive substrates.

7.2 Established Drug Interactions

Table 3 provides a listing of established or significant drug interactions [see Warnings and Precautions (5.1) and Clinical Pharmacology].

Table 3: Significant Drug Interactions

a ↓ = decrease, ↑ = increase

b These interactions have been studied in healthy adults.

7.3 Drugs Without Clinically Significant Interactions With Tecovirimat

Based on a drug interaction study, no clinically significant drug interactions have been observed when tecovirimat is co-administered with bupropion, flurbiprofen, or omeprazole [see Clinical Pharmacology].

7.4 Vaccine Interactions

No vaccine-drug interaction studies have been performed in human subjects. Some animal studies have indicated that co-administration of tecovirimat 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.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

No adequate and well-controlled studies in pregnant women were conducted; therefore there are no human data to establish the presence or absence of tecovirimat associated risk.

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. 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

There are no data to assess the effect on milk production, the presence of the drug in human milk, and/or the effects on the breastfed child. When administered to lactating mice, tecovirimat was present in the milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tecovirimat and any potential adverse effects on the breastfed child from tecovirimat or from the underlying maternal condition.

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 female and male reproductive potential in humans. Decreased fertility due to testicular toxicity was observed in male mice [see Nonclinical Toxicology].

8.4 Pediatric Use

As in adults, the effectiveness of tecovirimat in pediatric patients is based solely on efficacy studies in animal models of orthopoxvirus disease. As exposure of healthy pediatric subjects to tecovirimat 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 twice daily. The dosage for pediatric patients is based on weight [see Dosage and Administration (3.2) and Clinical Pharmacology].

8.5 Geriatric Use

Clinical studies of tecovirimat did not include sufficient numbers of subjects aged 65 and over to determine whether the safety profile of tecovirimat is different in this population compared to younger subjects. Of the 359 subjects in the clinical study of tecovirimat, 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].

8.6 Renal Impairment

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].

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].

9. OVERDOSAGE

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

10. MECHANISM OF ACTION

Tecovirimat is an antiviral drug against variola (smallpox) virus.

Mechanism of Action

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.

Activity in Cell Culture

In cell culture assays, the effective concentrations of tecovirimat resulting in a 50% reduction in virus-induced cytopathic effect (EC50), were 0.016-0.067 μM, 0.014-0.039 μM, 0.015 μM, and 0.009 μM, for variola, monkeypox, rabbitpox, and vaccinia viruses, respectively. Ranges given for variola and monkeypox viruses are reflective of results from multiple strains assayed.

Resistance

There are no known instances of naturally occurring tecovirimat resistant orthopoxviruses, although tecovirimat resistance may develop under drug selection. Tecovirimat has a relatively low resistance barrier, and certain amino acid substitutions in the target VP37 protein can confer large reductions in tecovirimat antiviral activity. The possibility of resistance to tecovirimat should be considered in patients who either fail to respond to therapy or who develop recrudescence of disease after an initial period of responsiveness.

Cross Resistance: There are no other antiviral drugs approved for the treatment of variola (smallpox) virus infection.

11. PHARMACODYNAMICS

Cardiac Electrophysiology

Tecovirimat does not prolong the QT interval to any clinically relevant extent at the anticipated therapeutic exposure.

12. PHARMACOKINETICS

At the approved recommended dosage, the mean steady-state values of tecovirimat AUC0-24hr, Cmax, and Cmin are 28791 hr·ng/mL (CV: 35%), 2106 ng/mL (CV: 33%), and 587 ng/mL (CV: 38%), respectively. Tecovirimat steady-state AUC is achieved by Day 6. Refer to Table 4 for pharmacokinetic parameters of tecovirimat.

Table 4: Pharmacokinetic Properties of Tecovirimat

a Value reflects administration of drug with food.

b Value refers to mean systemic exposure (AUC24hr). Meal: ~ 600 kcal, ~ 25 g fat.

c Tecovirimat is metabolized by hydrolysis of the amide bond and glucuronidation. The following inactive metabolites were detected in plasma: M4 (N-{3,5-dioxo-4-azatetracyclo[5.3.2.0{2,6}.0{8,10}]dodec-11-en-4-yl}amine), M5 (3,5 dioxo-4-aminotetracyclo[5.3.2.0{2,6}.0{8,10}]dodec-11-ene), and TFMBA (4 (trifluoromethyl) benzoic acid)

d Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) enzymes

e t1/2 value refers to mean terminal plasma half-life.

f Single dose administration of [14C]-tecovirimat in mass balance study.

Comparison of Animal and Human PK Data to Support Effective Human Dose Selection

Because the effectiveness of tecovirimat cannot be tested in humans, a comparison of tecovirimat exposures achieved in healthy human subjects to those observed in animal models of orthopoxvirus infection (nonhuman primates and rabbits infected with monkeypox virus and rabbitpox virus, respectively) in therapeutic efficacy studies was necessary to support the dosage regimen of 600 mg twice daily for treatment of smallpox disease in humans. 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 these animal models.

Specific Populations

No clinically significant differences in the pharmacokinetics of tecovirimat were observed based on age, sex, ethnicity, renal impairment (based on estimated GFR), or hepatic impairment (Child Pugh Scores A, B or C).

Pediatric Patients

Tecovirimat pharmacokinetics has not been evaluated in pediatric patients. The recommended pediatric dosing regimen is expected to produce tecovirimat exposures that are comparable to those in adult subjects based on a population pharmacokinetic modeling and simulation approach [see Dosage and Administration (3.2) and Use in Specific Populations (8.4)].

Drug Interaction Studies

The effect of tecovirimat on the exposure of co-administered drugs are shown in Table 5.

Table 5: Drug Interactions – Changes in Pharmacokinetic Parameters for Co-Administered Drug in the Presence of Tecovirimata

a All interaction studies conducted in healthy volunteers with tecovirimat 600 mg twice daily.

b Comparison based on exposures when administered as flurbiprofen + omeprazole + midazolam.

No pharmacokinetic changes were observed for the following drug when co-administered with tecovirimat: flurbiprofen.

Cytochrome P450 (CYP) Enzymes: Tecovirimat is a weak inhibitor of CYP2C8 and CYP2C19, and a weak inducer of CYP3A4. Tecovirimat is not an inhibitor or an inducer of CYP2B6 or CYP2C9.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

CYP Enzymes: Tecovirimat is not an inhibitor of CYP1A2, CYP2D6, CYP2E1 or CYP3A4, and is not an inducer of CYP1A2. Tecovirimat is not a substrate for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4.

UGT Enzymes: Tecovirimat is a substrate of UGT1A1 and UGT1A4.

Transporter Systems: Tecovirimat inhibited Breast Cancer Resistance Protein (BCRP) in vitro.

Tecovirimat is not an inhibitor of P-glycoprotein (P-gp), organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), organic anion transporter 1 (OAT1), OAT3, and organic cation transporter 2 (OCT2). Tecovirimat is not a substrate for P-gp, BCRP, OATP1B1, and OATP1B3.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

Each TPOXX capsule contains 200 mg of tecovirimat. 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 bottle contains 42 capsules (NDC 50072-200-42) with an induction seal and child-resistant cap.

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Rx only

Rev 07/18