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.

2.1 Important Dosing Instructions

It is recommended that patients 13 kg and above initiate oral treatment with TPOXX capsules if possible. If patients are unable to take oral TPOXX capsules or Drug-Food Preparation, treatment may be initiated with TPOXX injection as a 6 hour intravenous (IV) infusion. If IV treatment is necessary, conversion from IV to oral TPOXX is recommended as soon as oral treatment can be tolerated [see Dosage and Administration (2.3)]. In patients receiving an IV infusion, the first dose of oral treatment should be given at the time of and in place of the next scheduled IV dosing.

In patients receiving an oral treatment who subsequently require IV treatment, the first dose of IV infusion should be given at the time of and in place of the next scheduled oral dosing.

TPOXX capsules

Take TPOXX capsules within 30 minutes after a full meal containing moderate or high fat.

Missed Dose

If a dose of oral TPOXX is missed, the patient should take the dose as soon as possible and anytime up to 8 hours prior to the next scheduled dose. If less than 8 hours remain before the next scheduled dose, do not take the missed dose, and resume dosing at the next scheduled dose.

TPOXX injection

Administer TPOXX injection by IV infusion over 6 hours via an infusion pump. Must dilute TPOXX Injection prior to use [see Dosage and Administration (2.5)].

2.2 Testing Before Initiating and During Treatment with TPOXX Injection

Determine creatinine clearance in all patients before starting TPOXX injection and monitor while receiving TPOXX injection as clinically appropriate [see Dosage and Administration (2.4), Contraindictions (4), Warnings and Precautions (5.2) and Use in Specific Populations (8.4, 8.6)].

2.3 TPOXX Oral Dosage for Pediatric Patients Weighing at Least 13 kg and Adults

The recommended dosage of TPOXX capsules in pediatric patients weighing at least 13 kg and adults is displayed in Table 1 below.

2.4 Renal Impairment

TPOXX injection is contraindicated in patients with creatinine clearance below 30 mL per minute [see Contraindictions (4)].

2.5 Dosage and Administration of TPOXX Injection for Intravenous Infusion

The recommended dosage of TPOXX injection in pediatric patients weighing at least 3 kg and adults is displayed in Table 2 below.

TPOXX injection is supplied in a single-dose clear glass vial containing 200 mg/20 mL (10 mg/mL). Parenteral drug products must be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. To administer:

• Use aseptic technique when preparing TPOXX injection.
• Withdraw the quantity of TPOXX injection (Table 2), add this volume to the syringe then dilute with two equal parts of either 0.9% (w/v) sodium chloride injection (normal saline) or 5% (w/v) dextrose injection in a syringe of suitable size. Injection with diluents other than 0.9% sodium chloride or 5% dextrose solution has not been studied. NOT FOR IV BOLUS INJECTION. Do not use prefilled infusion bags for product preparation and administration.
• The diluted TPOXX injection may be stored refrigerated (2°C - 8°C) for up to 24 hours or at room temperature (15°C - 25°C) for up to 4 hours.
• Gently swirl the syringe of in-use solution prior to inserting into the syringe pump and infuse over 6 hours every 12 hours for 14 days.
• Do not re-use the single-dose vial once it has been punctured.

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)].

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.

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.

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

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)].

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)].

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.

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)].

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Cardiac Electrophysiology

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

12.3 Pharmacokinetics

At the recommended oral dosage of 600 mg every 12 hours administered in healthy adults weighing less than 120 kg, the mean steady-state values of tecovirimat AUC0-24hr, Cmax, and Ctau/trough are 29816 hr•ng/mL (n, CV: 43, 34%), 2159 ng/mL (n, CV: 46, 32%), and 845 ng/mL (n, CV: 45, 47%), respectively. At the recommended intravenous dosage of 200 mg every 12 hours administered by IV infusion over 6 hours in healthy adults, the mean steady-state values of tecovirimat AUC0-24hr, Cmax, and Cmin are 39405 hr•ng/mL (n, CV: 22, 23%), 2630 ng/mL (n, CV: 22, 22%), and 747 ng/mL (n, CV: 22, 29%). Refer to Table 7 for pharmacokinetic parameters of tecovirimat. Tecovirimat steady-state is achieved by Day 4-6.

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

Because the effectiveness of TPOXX 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 every 12 hours for treatment of smallpox disease in humans. Humans achieve greater systemic exposure (AUC, Cmax, and Cmin) of tecovirimat following a dose of 600 mg every 12 hours 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). At the 600 mg twice-daily dosage, tecovirimat exposure was reduced in adult subjects weighing more than 120 kg compared to the exposures in adult subjects weighing less than 120 kg. Specifically, in 34 adult subjects weighing more than 120 kg who received 600 mg TPOXX orally every 12 hours, the observed mean steady state values of AUC0-24hr, Cmax, and Ctrough were 19500 hr•ng/mL (CV: 23%), 1300 ng/mL (CV: 29%), and 585 ng/mL (CV: 31%), respectively.

Pediatric Patients

TPOXX 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 (2.2) and Use in Specific Populations (8.4)].

Hydroxypropyl-β-cyclodextrin, when administered intravenously, is eliminated through glomerular filtration which may be reduced in pediatric patients with renal immaturity [see Warnings and Precautions (5.2) 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 8. The effect of co-administered drugs on the exposure of tecovirimat are shown in Table 9.

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.

The relative bioavailability indicated an increase in peak and total systemic exposure (Cmax and AUCs) when 600 mg TPOXX was orally administered with 4 different phosphate binders (1600 mg sevelamer carbonate, 500 mg sucroferric oxyhydroxide, 1334 mg calcium acetate, 500 mg lanthanum carbonate) compared to TPOXX administered alone.

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.

12.4 Microbiology

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.

Non-antagonistic antiviral activity of tecovirimat and brincidofovir against orthopoxviruses has been demonstrated in cell culture and animal models.

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

Cross-resistance between tecovirimat and brincidofovir is not expected based on their distinct mechanisms of action. Where tested, orthopoxvirus isolates resistant to cidofovir (the active metabolite of brincidofovir) have not been resistant to tecovirimat. Likewise, orthopoxvirus isolates resistant to tecovirimat retain their sensitivity to cidofovir.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Carcinogenicity studies have not been conducted with tecovirimat.

Tecovirimat was not genotoxic in in vitro or in vivo assays, including a bacterial reverse mutation assay, a mammalian mutagenicity assay in mouse lymphoma L5178Y/TK± cells, and in an in vivo mouse micronucleus study.

Impairment of Fertility

In a fertility and early embryonic development study in mice, no effects of tecovirimat on female fertility were observed at tecovirimat exposures (AUC) approximately 24 times higher than human exposure at the RHD. In male mice, decreased male fertility associated with testicular toxicity (increased percent abnormal sperm and decreased sperm motility) was observed at 1,000 mg/kg/day (approximately 24 times the human exposure at the RHD).

13.2 Animal Toxicology and/or Pharmacology

In a repeat-dose toxicology study in dogs, convulsions (tonic and clonic) were observed in one animal within 6 hours of a single dose of 300 mg/kg (approximately 4 times higher than the highest observed human exposure at the RHD based on Cmax). Electroencephalography (EEG) findings in this animal were consistent with seizure activity during the observed convulsions. Tremors, which were considered non-adverse, were observed at 100 mg/kg/dose (similar to the highest observed human exposure at the RHD based on Cmax), although no convulsions or EEG findings were observed at this dose.