ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Common adverse reactions in healthy adult subjects (>= 2%) were headache, nausea, abdominal pain, and vomiting. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact SIGA Technologies at 1-888-899-3472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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.The safety of TPOXX was evaluated in 359 healthy adult subjects ages 18-79 years in Phase 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 twice daily regimen for 14 days.Most Frequently Reported Adverse ReactionsThe 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: Adverse Reactions Reported in >= 2% of Healthy Adult Subjects Receiving at Least One Dose of TPOXX 600 mga Includes abdominal pain, abdominal pain upper, abdominal distension, abdominal discomfort, abdominal painlower, epigastric painAdverse ReactionTPOXX 600 mgN 359(%)PlaceboN 90(%)Headache128Nausea54Abdominal paina 21Vomiting20Adverse Reactions Leading to Discontinuation of TPOXXSix subjects (2%) had their treatment with TPOXX discontinued due to adverse reactions. Each of these subjects adverse reactions (with severity) is listed below:EEG change, abnormalMild upset stomach, dry mouth, decreased concentration and dysphoriaMild nausea and fever, moderate diarrhea, severe headacheMild palpable purpuraMild nausea, fever and chillsMild facial redness, facial swelling and pruritusLess Common Adverse ReactionsClinically 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 paresthesiaGeneral and administration site: pyrexia, pain, chills, malaise, thirstInvestigations: abnormal electroencephalogram, hematocrit decreased, hemoglobin decreased, heart rate increasedMusculoskeletal and connective tissue: arthralgia, osteoarthritisNervous system: migraine, disturbance in attention, dysgeusia, paresthesiaPsychiatric: depression, dysphoria, irritability, panic attackRespiratory, Thoracic and Mediastinal Disorders: oropharyngeal painSkin and subcutaneous tissue: palpable purpura, rash, pruritic rash, facial redness, facial swelling, pruritus. 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. 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.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. In repeat-dose toxicology study in dogs, convulsions (tonic and clonic) were observed in one animal within hours of single dose of 300 mg/kg (approximately 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis and MutagenesisCarcinogenicity studies have not been conducted with tecovirimat.Tecovirimat was not genotoxic in in vitro or in vivo assays, including bacterial reverse mutation assay, mammalian mutagenicity assay in mouse lymphoma L5178Y/TK+- cells, and in an in vivo mouse micronucleus study.Impairment of FertilityIn 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tecovirimat is an antiviral drug against variola (smallpox) virus [see Microbiology (12.4)].. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyTPOXX does not prolong the QT interval to any clinically relevant extent at the anticipated therapeutic exposure.. 12.3 Pharmacokinetics. At the approved recommended dosage in healthy adults weighing less than 120 kg, the mean steady-state values of TPOXX AUC0-24hr, Cmax, and Ctau/trough are 29816 hrong/mL (n, CV: 43, 34%), 2159 ng/mL (n, CV: 46, 32%), and 845 ng/mL (n, CV: 45, 47%), respectively. Tecovirimat steady-state AUC is achieved by Day 6. Refer to Table for pharmacokinetic parameters of tecovirimat.Table 5:Pharmacokinetic Properties of TecovirimataValue reflects administration of drug with food.bValue refers to mean systemic exposure (AUC24hr). Meal: 600 kcal, 25 fat.cTecovirimat is metabolized by hydrolysis of the amide bond and glucuronidation. The following inactivemetabolites were detected in plasma: M4 (N-3,5-dioxo-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-en-4-ylamine), M5 (3,5 dioxo-4-aminotetracyclo[5.3.2.02,6.08,10]dodec-11-ene), and TFMBA (4 (trifluoromethyl) benzoic acid)dUridine diphosphate (UDP)-glucuronosyl transferase (UGT) enzymeset1/2 value refers to mean terminal plasma half-life.fSingle dose administration of [14C]-tecovirimat in mass balance study.Absorption Tmax (h)a 4-6 Effect of food (relative to fasting)b 39%Distribution Bound to human plasma proteins77-82 Blood-to-plasma ratio (drug or drug-related materials)0.62-0.90 Volume of distribution (Vz/F, L)1030Metabolism Metabolic pathwaysc Hydrolysis, UGT1A1d, UGT1A4Elimination Major route of eliminationMetabolism Clearance (CL/F, L/hr)31 t1/2 (h)e 20 of dose excreted in urinef 73, predominantly as metabolites of dose excreted in fecesf 23, predominantly as tecovirimatComparison of Animal and Human PK Data to Support Effective Human Dose SelectionBecause the effectiveness of TPOXX cannot be tested in humans, 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 twice daily dose of 600 mg when compared to the therapeutic exposures in these animal models.Specific PopulationsNo 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, 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 twice daily, the observed mean steady state values of AUC0-24hr, Cmax, and Ctrough were 19500 hrong/mL (CV: 23%), 1300 ng/mL (CV: 29%), and 585 ng/mL (CV: 31%), respectively.Pediatric PatientsTPOXX 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 population pharmacokinetic modeling and simulation approach [see Dosage and Administration (2.2) and Use in Specific Populations (8.4)].Drug Interaction StudiesThe effect of tecovirimat on the exposure of co-administered drugs are shown in Table 6.Table 6:Drug Interactions Changes in Pharmacokinetic Parameters for Co-Administered Drug in the Presence of TPOXXa aAll interaction studies conducted in healthy volunteers with tecovirimat 600 mg twice daily.bComparison based on exposures when administered as flurbiprofen omeprazole midazolam.Co-Administered DrugDose of Co-Administered Drug (mg)NMean Ratio (90% CI) of Co-Administered Drug PK With/Without TPOXX No Effect 1.00Cmax AUCinf Flurbiprofen omeprazole midazolamb omeprazole 20 single dose241.87(1.51, 2.31)1.73(1.36, 2.19)midazolam single dose0.61(0.54, 0.68)0.68(0.63, 0.73)Repaglinide2 single dose301.27(1.12, 1.44)1.29(1.19, 1.40)Bupropion150 single dose240.86(0.79, 0.93)0.84(0.78, 0.89)No pharmacokinetic changes were observed for the following drug when co-administered with tecovirimat: flurbiprofen.Cytochrome P450 (CYP) Enzymes: Tecovirimat is weak inhibitor of CYP2C8 and CYP2C19, and 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 ClinicallyCYP Enzymes: Tecovirimat is not an inhibitor of CYP1A2, CYP2D6, CYP2E1 or CYP3A4, and is not an inducer of CYP1A2. Tecovirimat is not substrate for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4.UGT Enzymes: Tecovirimat is 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 (OAT1), OAT3, and organic cation transporter (OCT2). Tecovirimat is not substrate for P-gp, BCRP, OATP1B1, and OATP1B3.. 12.4 Microbiology. Mechanism of ActionTecovirimat 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 CultureIn cell culture assays, the effective concentrations of tecovirimat resulting in 50% reduction in virus-induced cytopathic effect (EC50), were 0.016-0.067 uM, 0.014-0.039 uM, 0.015 uM, and 0.009 uM, 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.ResistanceThere are no known instances of naturally occurring tecovirimat resistant orthopoxviruses, although tecovirimat resistance may develop under drug selection. Tecovirimat has 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 ResistanceCross-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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. OverviewThe 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 drugs efficacy is not ethical. Therefore, the effectiveness of TPOXX for treatment of smallpox disease was established based on results of adequate and well-controlled animal efficacy studies of non-human primates and rabbits infected with non-variola orthopoxviruses. Survival rates observed in the animal studies may not be predictive of survival rates in clinical practice.Study DesignEfficacy studies were conducted in cynomolgus macaques infected with monkeypox virus, and New Zealand white (NZW) rabbits infected with rabbitpox virus. The primary efficacy endpoint for these studies was survival. In non-human primate studies, cynomolgus macaques were lethally challenged intravenously with x 107 plaque-forming units of monkeypox virus; tecovirimat was administered orally once daily at dose level of 10 mg/kg for 14 days, starting at Day 4, or post-challenge. In rabbit studies, NZW rabbits were lethally challenged intradermally with 1,000 plaque-forming units of rabbitpox virus; tecovirimat was administered orally once daily for 14 days at dose level of 40 mg/kg, starting at Day post-challenge. The timing of tecovirimat dosing in these studies was intended to assess efficacy when treatment is initiated after animals have developed clinical signs of disease, specifically dermal pox lesions in cynomolgus macaques, and fever in rabbits. Clinical signs of disease were evident in some animals at Day 2-3 post-challenge but were evident in all animals by Day post-challenge. Survival was monitored for 3-6 times the mean time to death for untreated animals in each model.Study ResultsTreatment with tecovirimat for 14 days resulted in statistically significant improvement in survival relative to placebo, except when given to cynomolgus macaques starting at Day post-challenge (Table 7).Table 7:Survival Rates in Tecovirimat Treatment Studies in Cynomolgus Macaques and NZW Rabbits Exhibiting Clinical Signs of Orthopoxvirus DiseaseaDay post-challenge tecovirimat treatment was initiatedbp-value is from 1-sided Boschloo Test (with Berger-Boos modification of gamma 0.000001) compared to placebocSurvival percentage in tecovirimat treated animals minus survival percentage in placebo treated animalsdExact 95% confidence interval based on the score statistic of difference in survival rateseA placebo control group was not included in this study.KEY: NA Not ApplicableTreatment Initiationa Survival Percentage(No. survived/n)p-valueb Survival RateDifferencec (95% CI)d PlaceboTecovirimatCynomolgus MacaquesStudy 1Day 40% (0/7)80% (4/5)0.003880% (20.8%, 99.5%)Study 2Day 40% (0/6)100% (6/6)0.0002100% (47.1%, 100%)Study 3Day 40% (0/3)83% (5/6)0.015183% (7.5%, 99.6%)Day 583% (5/6)0.015183% (7.5%, 99.6%)Day 650% (3/6)0.123150% (-28.3%, 90.2%)NZW RabbitsStudy 4Day 40% (0/10)90% (9/10)< 0.000190% (50.3%, 99.8%)Study 5Day 4NAe 88% (7/8)NANA.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None (4).

DESCRIPTION SECTION.

11 DESCRIPTION. TPOXX (tecovirimat) is an inhibitor of the orthopoxvirus VP37 envelope wrapping protein. TPOXX 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 (R) on an orange body, and black cap imprinted in white ink with ST-246(R). 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 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 chemical formula is C19H15F3N2O3.H2O representing molecular weight of 394.35 g/moL. The molecular structure is as follows:Tecovirimat monohydrate is practically insoluble in water and across the pH range of 2.0-6.5 (< 0.1 mg/mL).. Tecovirimat Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. TPOXX should be taken within 30 minutes after full meal containing moderate or high fat. (2.1, 2.2)Adults: and pediatric patients weighting at least 40 kg (2.1)- 40 kg to less than 120 kg: 600 mg of TPOXX twice daily for 14 days- 120 kg or more: 600 mg of TPOXX three times day for 14 daysPediatrics patients weighing 13 kg or more and those who cannot swallow capsules (2.2, 2.3):- 13 kg to less than 25 kg: 200 mg of TPOXX twice daily for 14 days- 25 kg to less than 40 kg: 400 mg of TPOXX twice daily for 14 days- 40 kg to less than 120 kg: 600 mg of TPOXX twice daily for 14 days- 120 kg or more: 600 mg of TPOXX three times daily for 14 days. TPOXX should be taken within 30 minutes after full meal containing moderate or high fat. (2.1, 2.2). Adults: and pediatric patients weighting at least 40 kg (2.1)- 40 kg to less than 120 kg: 600 mg of TPOXX twice daily for 14 days- 120 kg or more: 600 mg of TPOXX three times day for 14 days. Pediatrics patients weighing 13 kg or more and those who cannot swallow capsules (2.2, 2.3):- 13 kg to less than 25 kg: 200 mg of TPOXX twice daily for 14 days- 25 kg to less than 40 kg: 400 mg of TPOXX twice daily for 14 days- 40 kg to less than 120 kg: 600 mg of TPOXX twice daily for 14 days- 120 kg or more: 600 mg of TPOXX three times daily for 14 days. 2.1Dosage for Adults and Pediatric Patients Weighing at Least 40 kg. The recommended dosage of TPOXX in adults and pediatric patients weighing at least 40 kg is as shown in Table 1. The dose should be taken orally for 14 days. TPOXX should be taken within 30 minutes after full meal containing moderate or high fat [see Clinical Pharmacology (12.3)].Table 1:Recommended Dosage for Pediatric and Adult Patients Weighing at Least 40 kg Body Weight Dosage Number of Capsules 40 kg to less than 120 kg 600 mg twice daily Capsules twice daily 120 kg or more 600 mg three times day Capsules three times day. 2.2Dosage for Pediatric Patients. The recommended dosage for pediatric patients is based on weight starting at 13 kg as shown in Table 2. The dose should be given orally for 14 days and should be taken within 30 minutes after full meal containing moderate or high fat [see Clinical Pharmacology (12.3)].. 2.3Preparation for Administration to Pediatrics and Those Who Cannot Swallow Capsules. TPOXX 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 2: Recommended Pediatric and Adult Dosage and Preparation InstructionsBody WeightDosageNumber of CapsulesDrug-Food Preparation13 kg to less than 25 kg200 mg twice dailyContents of Capsule twice dailyMix capsule of TPOXX with 30 mL of liquid or soft food. Administer the whole mixture.25 kg to less than 40 kg400 mg twice dailyContents of Capsules twice dailyMix capsules of TPOXX with 30 mL of liquid or soft food. Administer the whole mixture.40 kg to less than 120 kg600 mg twice dailyContents of Capsules twice dailyMix capsules of TPOXX with 30 mL of liquid or soft food. Administer the whole mixture.120 kg and above600 mg three times dailyContents of Capsules three times dailyMix capsules of TPOXX with 30 mL of liquid or soft food. Administer the whole mixture.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. TPOXX capsules are hard gelatin with an opaque orange body imprinted in white ink with SIGA followed by the SIGA logo followed by (R), and an opaque black cap imprinted in white ink with ST-246(R), containing white to off-white powder. Each capsule contains 200 mg of tecovirimat.. Capsule: 200 mg. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.1, 7, 12.3). 7.1Effect of TPOXX on Other Drugs. Tecovirimat is weak inducer of cytochrome P450 (CYP)3A and 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. See Table for clinical recommendations for select sensitive substrates.. 7.2Established Drug Interactions. Table provides listing of established or significant drug interactions [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].Table 4:Significant Drug Interactionsa decrease, increaseb These interactions have been studied in healthy adults.Concomitant Drug Class: Drug NameEffect on Concentrationa Clinical Effect/RecommendationBlood Glucose-Lowering Agent:Repaglinideb repaglinideMonitor blood glucose and monitor for hypoglycemic symptoms in patients when TPOXX is co-administered with repaglinide [see Warnings and Precautions (5.1)].CNS Depressant:Midazolamb midazolamMonitor for effectiveness of midazolam.. 7.3Drugs Without Clinically Significant Interactions With TPOXX. Based on 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)].. 7.4Vaccine 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.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. InfertilityThere 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 (13.1)].

GERIATRIC USE SECTION.

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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 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 (R), and an opaque black cap imprinted in white ink with ST-246(R), containing white to off-white powder. Each bottle contains 42 capsules (NDC 50072-200-42) with an induction seal and child-resistant cap.Store capsules in the original bottle at 20C to 25C (68F to 77F); excursions permitted 15C to 30C (59F to 86F) [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. 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 13 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 drugs 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). 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 drugs 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). 1.1Treatment of Human Smallpox Disease. TPOXX(R) is indicated for the treatment of human smallpox disease caused by variola virus in adults and pediatric patients weighing at least 13 kg.. 1.2Limitations 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 drugs 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Efficacy Based on Animal Models AloneInform patients that the efficacy of TPOXX is based solely on efficacy studies demonstrating survival benefit in animals and that the effectiveness of TPOXX has not been tested in humans with smallpox disease [see Clinical Studies (14)].Important Dosage and Administration InformationAdvise patients to take TPOXX as directed within 30 minutes of eating full meal containing moderate or high fat [see Clinical Pharmacology (12.3)]. Inform patients to take TPOXX for the entire duration without missing or skipping dose [see Dosage and Administration (2)].Drug InteractionsInform patients that TPOXX may interact with other drugs. Advise patients to report to their healthcare provider the use of other prescription drugs. Co-administration of TPOXX with repaglinide may cause hypoglycemia [see Warnings and Precautions (5.1) and Drug Interactions (7.2)].Manufactured by:Catalent Pharma Solutions, LLC1100 Enterprise DriveWinchester, KY 40391Distributed by:SIGA Technologies, Inc.4575 SW Research WayCorvallis, OR 97333.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USETPOXX (Te-Pox or Tee-pahx)(tecovirimat)capsulesRead this Instructions for Use before taking TPOXX and follow the steps below to prepare and give dose of TPOXX to adults or children who have trouble swallowing TPOXX capsules.Step 1: Gather the supplies you need to prepare dose of TPOXX:1 bottle of TPOXX (1 capsule 200 mg of medicine)1 tablespoon small bowlYour choice of liquid or soft food:Liquid such as milk, chocolate milk or infant formulaSoft food such as applesauce or yogurt Step 2: Find the weight of the person taking the medicine on the TPOXX Dosing Table.Step 3: Find the prescribed dose in the same row as the weight of the person taking the medicine on the TPOXX Dosing Table below.Step 4: Find the amount of liquid or soft food needed in the same row as the weight of the person taking the medicine on the TPOXX Dosing Table below.Get small bowl and place it on flat surface.Add the correct amount of liquid or soft food to the bowl. Step 5: Find the number of TPOXX capsules needed in the same row as the weight of the person taking the medicine on the TPOXX Dosing Table below.Take out the correct number of TPOXX capsules from the bottle. Step 6: Hold the TPOXX capsule in sideways (horizontal) position directly over the bowl to make sure none of the medicine is lost.Hold the ends of the TPOXX capsule between the thumb and index (pointer) finger of both hands.Gently and slowly twist the ends of the capsule and pull it apart. Empty the contents of the capsule into the bowl. Repeat this for each capsule that is needed for your total dose.Throw away the empty capsule shells. Step 7: Use the tablespoon to mix together the capsule contents and the liquid or soft food.The powder may not completely dissolve.The food and medicine mixture is now ready to take. Step 8: The food and medicine mixture must be taken within 30 minutes after meal containing approximately 25 grams of fat AND within 30 minutes after mixing it.The ENTIRE food and medicine mixture should be swallowed to make sure the entire dose is taken.For patients weighing 13 kg to less than 120 kg, this food and medicine mixture should be given twice daily every 12 hours, by mouth, for 14 days.For patients weighing 120 kg and above, this food and medicine mixture should be given three times day every hours, by mouth, for 14 days. aGiven twice daily every 12 hours, by mouth, for 14 days.bGiven three times day every hours, by mouth, for 14 days.TPOXX Dosing TableBody WeightPrescribed DoseAmount of Liquid or Soft FoodNumber of CapsulesFood and Medicine Mixture Instructions13 kg to less than 25 kga 200 mg2 tablespoons1 TPOXX capsuleMix entire contents of TPOXX capsule with tablespoons of liquid or soft food.25 kg to less than 40 kga 400 mg2 tablespoons2 TPOXX capsuleMix entire contents of TPOXX capsules with tablespoons of liquid or soft food.40 kg to less than 120 kga 600 mg2 tablespoons3 TPOXX capsuleMix entire contents of TPOXX capsules with tablespoons of liquid or soft food.120 kg and aboveb 600 mg2 tablespoons3 TPOXX capsulesMix entire contents of TPOXX capsules with tablespoons of liquid or soft food.Keep TPOXX and all medicines out of the reach of children.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by:Catalent Pharma Solutions1100 Enterprise DriveWinchester, KY 40391Distributed by:SIGA Technologies, Inc.4575 SW Research Way, Suite 110Corvallis, OR 97333Issued: 11/2021. bottle of TPOXX (1 capsule 200 mg of medicine). tablespoon 1 small bowl. Your choice of liquid or soft food:Liquid such as milk, chocolate milk or infant formulaSoft food such as applesauce or yogurt Liquid such as milk, chocolate milk or infant formula. Soft food such as applesauce or yogurt. Get small bowl and place it on flat surface.. Add the correct amount of liquid or soft food to the bowl.. Take out the correct number of TPOXX capsules from the bottle.. Hold the ends of the TPOXX capsule between the thumb and index (pointer) finger of both hands.. Gently and slowly twist the ends of the capsule and pull it apart. Empty the contents of the capsule into the bowl. Repeat this for each capsule that is needed for your total dose.. Throw away the empty capsule shells.. The powder may not completely dissolve.. The food and medicine mixture is now ready to take.. The ENTIRE food and medicine mixture should be swallowed to make sure the entire dose is taken.. For patients weighing 13 kg to less than 120 kg, this food and medicine mixture should be given twice daily every 12 hours, by mouth, for 14 days.. For patients weighing 120 kg and above, this food and medicine mixture should be given three times day every hours, by mouth, for 14 days.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers clinical need for TPOXX and any potential adverse effects on the breastfed child from TPOXX or from the underlying maternal condition.DataIn 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 and 24 hours post-dose when administered orally to mice on lactation Day 10 or 11.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis and MutagenesisCarcinogenicity studies have not been conducted with tecovirimat.Tecovirimat was not genotoxic in in vitro or in vivo assays, including bacterial reverse mutation assay, mammalian mutagenicity assay in mouse lymphoma L5178Y/TK+- cells, and in an in vivo mouse micronucleus study.Impairment of FertilityIn 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 repeat-dose toxicology study in dogs, convulsions (tonic and clonic) were observed in one animal within hours of single dose of 300 mg/kg (approximately 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE. 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL NDC: 50072-200-42 200 mg Capsule 42-count Bottle Label. 200 mg Capsule 42-count Bottle Label.

PEDIATRIC USE SECTION.

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 twice daily. The dosage for pediatric patients is based on weight [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyTPOXX does not prolong the QT interval to any clinically relevant extent at the anticipated therapeutic exposure.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. At the approved recommended dosage in healthy adults weighing less than 120 kg, the mean steady-state values of TPOXX AUC0-24hr, Cmax, and Ctau/trough are 29816 hrong/mL (n, CV: 43, 34%), 2159 ng/mL (n, CV: 46, 32%), and 845 ng/mL (n, CV: 45, 47%), respectively. Tecovirimat steady-state AUC is achieved by Day 6. Refer to Table for pharmacokinetic parameters of tecovirimat.Table 5:Pharmacokinetic Properties of TecovirimataValue reflects administration of drug with food.bValue refers to mean systemic exposure (AUC24hr). Meal: 600 kcal, 25 fat.cTecovirimat is metabolized by hydrolysis of the amide bond and glucuronidation. The following inactivemetabolites were detected in plasma: M4 (N-3,5-dioxo-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-en-4-ylamine), M5 (3,5 dioxo-4-aminotetracyclo[5.3.2.02,6.08,10]dodec-11-ene), and TFMBA (4 (trifluoromethyl) benzoic acid)dUridine diphosphate (UDP)-glucuronosyl transferase (UGT) enzymeset1/2 value refers to mean terminal plasma half-life.fSingle dose administration of [14C]-tecovirimat in mass balance study.Absorption Tmax (h)a 4-6 Effect of food (relative to fasting)b 39%Distribution Bound to human plasma proteins77-82 Blood-to-plasma ratio (drug or drug-related materials)0.62-0.90 Volume of distribution (Vz/F, L)1030Metabolism Metabolic pathwaysc Hydrolysis, UGT1A1d, UGT1A4Elimination Major route of eliminationMetabolism Clearance (CL/F, L/hr)31 t1/2 (h)e 20 of dose excreted in urinef 73, predominantly as metabolites of dose excreted in fecesf 23, predominantly as tecovirimatComparison of Animal and Human PK Data to Support Effective Human Dose SelectionBecause the effectiveness of TPOXX cannot be tested in humans, 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 twice daily dose of 600 mg when compared to the therapeutic exposures in these animal models.Specific PopulationsNo 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, 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 twice daily, the observed mean steady state values of AUC0-24hr, Cmax, and Ctrough were 19500 hrong/mL (CV: 23%), 1300 ng/mL (CV: 29%), and 585 ng/mL (CV: 31%), respectively.Pediatric PatientsTPOXX 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 population pharmacokinetic modeling and simulation approach [see Dosage and Administration (2.2) and Use in Specific Populations (8.4)].Drug Interaction StudiesThe effect of tecovirimat on the exposure of co-administered drugs are shown in Table 6.Table 6:Drug Interactions Changes in Pharmacokinetic Parameters for Co-Administered Drug in the Presence of TPOXXa aAll interaction studies conducted in healthy volunteers with tecovirimat 600 mg twice daily.bComparison based on exposures when administered as flurbiprofen omeprazole midazolam.Co-Administered DrugDose of Co-Administered Drug (mg)NMean Ratio (90% CI) of Co-Administered Drug PK With/Without TPOXX No Effect 1.00Cmax AUCinf Flurbiprofen omeprazole midazolamb omeprazole 20 single dose241.87(1.51, 2.31)1.73(1.36, 2.19)midazolam single dose0.61(0.54, 0.68)0.68(0.63, 0.73)Repaglinide2 single dose301.27(1.12, 1.44)1.29(1.19, 1.40)Bupropion150 single dose240.86(0.79, 0.93)0.84(0.78, 0.89)No pharmacokinetic changes were observed for the following drug when co-administered with tecovirimat: flurbiprofen.Cytochrome P450 (CYP) Enzymes: Tecovirimat is weak inhibitor of CYP2C8 and CYP2C19, and 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 ClinicallyCYP Enzymes: Tecovirimat is not an inhibitor of CYP1A2, CYP2D6, CYP2E1 or CYP3A4, and is not an inducer of CYP1A2. Tecovirimat is not substrate for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4.UGT Enzymes: Tecovirimat is 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 (OAT1), OAT3, and organic cation transporter (OCT2). Tecovirimat is not substrate for P-gp, BCRP, OATP1B1, and OATP1B3.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryNo adequate and well-controlled studies in pregnant women were conducted; therefore there are no human data to establish the presence or absence of TPOXX 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 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.DataAnimal 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 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).

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Dosage for Adults and Pediatric Patients Weighing at Least 40 kg (2.1)11/2021Dosage and Administration, Preparation for Administration to Pediatrics and Those Who Cannot Swallow Capsules (2.3)11/2021.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 11/2021PATIENT INFORMATIONTPOXX (Te-Pox or Tee-pahx)(tecovirimat)capsulesWhat is TPOXXTPOXX is prescription medicine used to treat smallpox disease caused by type of virus called variola virus in adults and children who weigh at least 13 kg.TPOXX may not work well in people who have weakened immune system.The effectiveness of TPOXX has been studied only in animals with orthopoxvirus diseases. There have been no human studies in people who have smallpox disease. The safety of TPOXX was studied in adults. There have been no studies of TPOXX in children 17 years of age and younger.Before taking TPOXX, tell your healthcare provider about all of your medical conditions, including if you:have diabetes.are pregnant or plan to become pregnant. It is not known if TPOXX can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with TPOXX.are breastfeeding or plan to breastfeed. It is not known if TPOXX passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with TPOXX. Keep list of your medicines to show your healthcare provider and pharmacist.You can ask your healthcare provider or pharmacist for list of medications that interact with TPOXX.Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TPOXX with other medicines.How should take TPOXXTake TPOXX exactly as your healthcare provider tells you.For adults and children who weigh at least 40 kg and no more than 120 kg, take capsules of TPOXX twice day by mouth for 14 days.For adults and children who weigh at least 120 kg, take capsules of TPOXX three times day by mouth for 14 days.TPOXX should be taken within 30 minutes after eating full, fatty meal. Talk to your healthcare provider about examples of foods that you can eat that contain about 25 grams of fat. Always take TPOXX with food.See the Instructions for Use that comes with your TPOXX for instructions on how to prepare and take dose of TPOXX if:your child weighs less than 40 kg, OR you or your child have trouble swallowing TPOXX capsules. Stay under the care of your healthcare provider during treatment with TPOXX.Do not change your dose or stop taking TPOXX without talking to your healthcare provider.It is important to take TPOXX for the full 14 day course of treatment. Do not miss or skip dose of TPOXX.If you take too much TPOXX, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of TPOXXTPOXX may cause serious side effects, including:Low blood sugar (hypoglycemia). Low blood sugar can happen when TPOXX is taken with repaglinide, medicine used to treat type diabetes. Tell your healthcare provider if you get any of the following symptoms of low blood sugar: headache drowsiness hunger feeling jittery or shakyo dizzinesso confusiono sweatingo weaknesso fast heartbeato irritabilityThe most common side effects of TPOXX include: headache nauseao stomach paino vomitingThese are not all the possible side effects of TPOXX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or to SIGA at 1-888-899-3472.How should store TPOXXStore TPOXX at room temperature between 68F to 77F (20C to 25C).Keep TPOXX in its original container.Keep TPOXX and all other medicines out of the reach of children.General information about the safe and effective use of TPOXX.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use TPOXX for condition for which it was not prescribed. Do not give TPOXX to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TPOXX that is written for health professionals.What are the ingredients in TPOXXActive ingredient: tecovirimat Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The capsule shell is made of gelatin, FD&C blue 1, FD&C red 3, FD&C yellow 6, and titanium dioxide. Manufactured by: Catalent Pharma Solutions 1100 Enterprise Drive Winchester, KY 40391 Distributed By: SIGA Technologies, Inc. 4575 SW Research Way Corvallis, OR 97333 For more information, go to www.SIGA.com or call 1-888-899-3472. You can ask your healthcare provider or pharmacist for list of medications that interact with TPOXX.. Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TPOXX with other medicines.. See the Instructions for Use that comes with your TPOXX for instructions on how to prepare and take dose of TPOXX if:your child weighs less than 40 kg, OR you or your child have trouble swallowing TPOXX capsules. your child weighs less than 40 kg, OR you or your child have trouble swallowing TPOXX capsules.. Stay under the care of your healthcare provider during treatment with TPOXX.. Do not change your dose or stop taking TPOXX without talking to your healthcare provider.. It is important to take TPOXX for the full 14 day course of treatment. Do not miss or skip dose of TPOXX.. If you take too much TPOXX, call your healthcare provider or go to the nearest hospital emergency room right away.. Low blood sugar (hypoglycemia). Low blood sugar can happen when TPOXX is taken with repaglinide, medicine used to treat type diabetes. Tell your healthcare provider if you get any of the following symptoms of low blood sugar:. Store TPOXX at room temperature between 68F to 77F (20C to 25C).. Keep TPOXX in its original container.

SPL UNCLASSIFIED SECTION.

1.1Treatment of Human Smallpox Disease. TPOXX(R) is indicated for the treatment of human smallpox disease caused by variola virus in adults and pediatric patients weighing at least 13 kg.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryNo adequate and well-controlled studies in pregnant women were conducted; therefore there are no human data to establish the presence or absence of TPOXX 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 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.DataAnimal 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 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 SummaryThere 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 mothers clinical need for TPOXX and any potential adverse effects on the breastfed child from TPOXX or from the underlying maternal condition.DataIn 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 and 24 hours post-dose when administered orally to mice on lactation Day 10 or 11.. 8.3 Females and Males of Reproductive Potential. InfertilityThere 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 (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 twice daily. The dosage for pediatric patients is based on weight [see Dosage and Administration (2.2) 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)].. 8.6Renal 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 (12.3)].. 8.7Hepatic 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypoglycemia: Co-administration with repaglinide may cause hypoglycemia. Monitor blood glucose and monitor for hypoglycemic symptoms during co-administration. (5.1). 5.1Hypoglycemia 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) and Clinical Pharmacology (12.3)].In 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.