ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions are:TPOXX Capsules (incidence >= 2%): headache, nausea, abdominal pain, and vomiting. 6.1) TPOXX Injection (incidence >= 4%): administration site reactions and headache. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact SIGA Technologies Inc. at 1-888-899-3472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. TPOXX Capsules (incidence >= 2%): headache, nausea, abdominal pain, and vomiting. 6.1) TPOXX Injection (incidence >= 4%): administration site reactions and headache. 6.1) 6.1 Clinical 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.TPOXX Clinical Trial (Oral Administration)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 (every 12 hours) 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: Treatment-Related Adverse Reactions Reported in >= 2% of Healthy Adult Subjects Receiving at Least One Dose of TPOXX Capsules 600 mgaIncludes abdominal pain, abdominal pain upper, abdominal distension, abdominal discomfort, abdominal pain lower, epigastric pain Adverse ReactionTPOXX 600 mg = 359 (%) Placebo = 90 (%) Headache128Nausea54Abdominal pain 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, pruritusTPOXX 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 subjects received placebo. TPOXX injection was administered over 6 hour period via infusion pump twice daily (every 12 hours) for 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 ReactionsThe most frequently reported adverse reactions included infusion site pain, infusion site swelling, infusion site erythema, infusion site extravasation, and headache. Adverse reactions that occurred in at least 4% of subjects in the TPOXX treatment group are shown in Table 4. Table 4: Treatment-Related Adverse Reactions Reported in >= 4% of Healthy Adult Subjects Receiving at Least One Dose of TPOXX Injection 240 mgTPOXX 240 mg = 26 (%) Placebo = (%) Infusion Site Pain7367Infusion Site Swelling3967Infusion Site Erythema2367Infusion Site Extravasation1950Headache150Adverse Reactions Leading to Discontinuation of TPOXX InjectionThree subjects (12%) had their treatment with TPOXX injection discontinued due to adverse reactions. One subject had two adverse reactions. Each of these subjects adverse reactions (with severity) are listed below:Moderate Infusion site extravasationMild Infusion site extravasationMild Infusion site swelling and mild infusion site painLess Common Adverse ReactionsClinically 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 edemaMusculoskeletal and connective tissue: myalgia, arthritis, back pain, muscle tightnessGastrointestinal: diarrheaEye: photophobiaSkin and Subcutaneous Tissue: pruritus generalized. 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. Moderate Infusion site extravasation. Mild Infusion site extravasation. Mild Infusion site swelling and mild infusion site pain. 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.

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 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 AUC 0-24hr, max, and tau/troughare 29816 hrong/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 hours in healthy adults, the mean steady-state values of tecovirimat AUC 0-24hr, max, and minare 39405 hrong/mL (n, CV: 22, 23%), 2630 ng/mL (n, CV: 22, 22%), and 747 ng/mL (n, CV: 22, 29%). Refer to Table 7for pharmacokinetic parameters of tecovirimat. Tecovirimat steady-state is achieved by Day 4-6. Table 7: Pharmacokinetic Properties of TecovirimataValue reflects administration of drug with food. bValue refers to mean systemic exposure (AUC 24hr). Meal: 600 kcal, 25 fat. cTecovirimat 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[5.3.2.02,6.08,10]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) enzymes et 1/2value refers to mean terminal plasma half-life. fSingle dose administration of 14C]-tecovirimat in mass balance study. KEY: NA Not Applicable or Not AvailableAbsorption200 mg intravenous600 mg oral Median max(h) (Range) (6-6.5)6 (2-24) Effect of food (relative to fasting)NA39% Distribution Bound to human plasma proteins77-82 Blood-to-plasma ratio (drug or drug-related materials)0.62-0.90 Volume of distribution (Vz or Vz/F, L) (CV%)383 (46%)1030Metabolism Metabolic pathways Hydrolysis, UGT1A1 d, UGT1A4 Elimination Major route of eliminationMetabolism Clearance (CL or CL/F, L/hr) (CV%)13 (23%)31 1/2(h) e(CV%) 21 (45%)19 (29%) of dose excreted in urine NA73, predominantly as metabolites of dose excreted in feces NA23, 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 every 12 hours for treatment of smallpox disease in humans. Humans achieve greater systemic exposure (AUC, max, and min) of tecovirimat following dose of 600 mg every 12 hours 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 orally every 12 hours, the observed mean steady state values of AUC 0-24hr, max, and troughwere 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)] Hydroxypropyl--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 StudiesThe 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. Table 8: Drug Interactions Changes in Pharmacokinetic Parameters for Co-Administered Drug in the Presence of TPOXX aAll interaction studies conducted in healthy volunteers with tecovirimat 600 mg twice daily (every 12 hours). bComparison based on exposures when administered as flurbiprofen omeprazole midazolam. Co-Administered Drug Dose of Co-Administered Drug (mg) NMean Ratio (90% CI) of Co-Administered Drug PK With/Without TPOXX No Effect 1.00 max AUC inf Flurbiprofen omeprazole midazolam omeprazole 20, single dose241.87 (1.51, 2.31) 1.73 (1.36, 2.19) midazolam 2, 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.Table 9: Drug Interactions Changes in TPOXX Pharmacokinetic Parameters in the Presence of Co-Administered Drug aAll interaction studies conducted in healthy volunteers with tecovirimat 600 mg twice daily (every 12 hours) taken with meal (consisting of approximately 600 calories and 25 fat). bNumber of subjects with reportable PK values when TPOXX was co-administered with phosphate binder. Co-Administered Drug Dose of Co-Administered Drug (mg) b Mean Ratio (90% CI) of TPOXX PK With/Without Co-Administered Drug No Effect 1.00 max AUC0-24 hourPhosphate bindersSevelamer carbonate (1600 mg, single dose)391.16 (1.08, 1.26) 1.26 (1.17, 1.36) Sucroferric oxyhydroxide (500 mg, single dose)371.15 (1.06, 1.24) 1.20 (1.11, 1.29) Calcium acetate (1334 mg, single dose)371.09 (1.01, 1.18) 1.16 (1.07, 1.25) Lanthanum carbonate (500 mg, single dose)381.21 (1.12, 1.30) 1.22 (1.13, 1.32) The relative bioavailability indicated an increase in peak and total systemic exposure (Cmax and AUCs) when 600 mg TPOXX was orally administered with 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 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 (EC 50), 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 10 7plaque-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 10). Table 10: Survival Rates in Tecovirimat Treatment Studies in Cynomolgus Macaques and NZW Rabbits Exhibiting Clinical Signs of Orthopoxvirus DiseaseaDay post-challenge tecovirimat treatment was initiated bp-value is from 1-sided Boschloo Test (with Berger-Boos modification of gamma 0.000001) compared to placebo cSurvival percentage in tecovirimat treated animals minus survival percentage in placebo treated animals dExact 95% confidence interval based on the score statistic of difference in survival rates eA placebo control group was not included in this study. KEY:NA Not Applicable Treatment Initiation Survival Percentage (No. survived/n) p-value Survival Rate Difference (95% CI) 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 4NA 88% (7/8)NANA.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Pediatric and Adult Patientsweighing 40 kg or more 2.3) (Oral Dosing):40 kg to less than 120 kg: 600 mg of TPOXX every 12 hours for 14 days120 kg or more: 600 mg of TPOXX every hours for 14 daysPediatrics and adult patients weighing 13 kg or more and those who cannot swallow capsules( 2.3) (Oral Dosing):TPOXX Capsules can be administered by carefully opening the number of capsule noted below and mixing and administering the entire contents in 30 mL of liquid (e.g., milk, chocolate milk) or soft food (e.g., apple sauce, yogurt): 13 kg to less than 25 kg: 200 mg (1 Capsule) of TPOXX every 12 hours for 14 days25 kg to less than 40 kg: 400 mg (2 Capsules) of TPOXX every 12 hours for 14 days40 kg to less than 120 kg: 600 mg (3 Capsules) of TPOXX every 12 hours for 14 days120 kg or more: 600 mg (3 capsules) every hours for 14 daysPatients weighing kg and above( 2.5) (Intravenous Dosing):3 kg to less than 35 kg: mg/kg every 12 hours by intravenous infusion over hours for up to 14 days35 kg to less than 120 kg: 200 mg every 12 hours by intravenous infusion over hours for up to 14 days120 kg and above: 300 mg every 12 hours by intravenous infusion over hours for up to 14 daysPediatric patients weighing 13 kg or more should be switched to TPOXX Capsules to complete the 14-day treatment course as soon as oral therapy can be tolerated.Administration Instruction for TPOXX Capsules:Take within 30 minutes after full meal containing moderate or high fat. 2.1, 2.3) Administration Instructions for TPOXX Injection:Infuse over hours via infusion pump. 2.5) See Full Prescribing Information for additional information on the administration and preparation of TPOXX Capsules and Injection. 2) Pediatric and Adult Patientsweighing 40 kg or more 2.3) (Oral Dosing):40 kg to less than 120 kg: 600 mg of TPOXX every 12 hours for 14 days120 kg or more: 600 mg of TPOXX every hours for 14 days. 40 kg to less than 120 kg: 600 mg of TPOXX every 12 hours for 14 days. 120 kg or more: 600 mg of TPOXX every hours for 14 days. Pediatrics and adult patients weighing 13 kg or more and those who cannot swallow capsules( 2.3) (Oral Dosing):TPOXX Capsules can be administered by carefully opening the number of capsule noted below and mixing and administering the entire contents in 30 mL of liquid (e.g., milk, chocolate milk) or soft food (e.g., apple sauce, yogurt): 13 kg to less than 25 kg: 200 mg (1 Capsule) of TPOXX every 12 hours for 14 days25 kg to less than 40 kg: 400 mg (2 Capsules) of TPOXX every 12 hours for 14 days40 kg to less than 120 kg: 600 mg (3 Capsules) of TPOXX every 12 hours for 14 days120 kg or more: 600 mg (3 capsules) every hours for 14 days. 13 kg to less than 25 kg: 200 mg (1 Capsule) of TPOXX every 12 hours for 14 days. 25 kg to less than 40 kg: 400 mg (2 Capsules) of TPOXX every 12 hours for 14 days. 40 kg to less than 120 kg: 600 mg (3 Capsules) of TPOXX every 12 hours for 14 days. 120 kg or more: 600 mg (3 capsules) every hours for 14 days. Patients weighing kg and above( 2.5) (Intravenous Dosing):3 kg to less than 35 kg: mg/kg every 12 hours by intravenous infusion over hours for up to 14 days35 kg to less than 120 kg: 200 mg every 12 hours by intravenous infusion over hours for up to 14 days120 kg and above: 300 mg every 12 hours by intravenous infusion over hours for up to 14 days. kg to less than 35 kg: mg/kg every 12 hours by intravenous infusion over hours for up to 14 days. 35 kg to less than 120 kg: 200 mg every 12 hours by intravenous infusion over hours for up to 14 days. 120 kg and above: 300 mg every 12 hours by intravenous infusion over hours for up to 14 days. Pediatric patients weighing 13 kg or more should be switched to TPOXX Capsules to complete the 14-day treatment course as soon as oral therapy can be tolerated.. Administration Instruction for TPOXX Capsules:Take within 30 minutes after full meal containing moderate or high fat. 2.1, 2.3) Administration Instructions for TPOXX Injection:Infuse over hours via infusion pump. 2.5) See Full Prescribing Information for additional information on the administration and preparation of TPOXX Capsules and Injection. 2) 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 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 capsulesTake TPOXX capsules within 30 minutes after full meal containing moderate or high fat.Missed DoseIf dose of oral TPOXX is missed, the patient should take the dose as soon as possible and anytime up to hours prior to the next scheduled dose. If less than hours remain before the next scheduled dose, do not take the missed dose, and resume dosing at the next scheduled dose.TPOXX injectionAdminister TPOXX injection by IV infusion over 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 below.Table 1: Recommended Dosage and Preparation Instructions for TPOXX Capsules in Pediatric Patients Weighing at Least 13 kg and AdultsaTPOXX capsules should be taken within 30 minutes after full meal containing moderate or high fat [see Clinical Pharmacology 12.3)] Body WeightOral Dosage for 14 Days Dosage (Number of Capsules)Drug Food Preparation for Patients Who Cannot Swallow Capsules13 kg to less than 25 kg200 mg (1 capsule) every 12 hoursCarefully open the required number of capsules and mix contents of capsule(s) of TPOXX with 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.25 kg to less than 40 kg400 mg (2 capsules) every 12 hours40 kg to less than 120 kg600 mg (3 capsules) every 12 hours120 kg and above600 mg (3 capsules) every hours. 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 kg and adults is displayed in Table 2below. TPOXX injection is supplied in 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 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 (2C 8C) for up to 24 hours or at room temperature (15C 25C) for up to hours.Gently swirl the syringe of in-use solution prior to inserting into the syringe pump and infuse over hours every 12 hours for 14 days.Do not re-use the single-dose vial once it has been punctured.Table 2: Recommended Pediatric and Adult Dosage and Preparation Instructions TPOXX Injection for IV Infusion aPatients weighing at least 13 kg should be switched to TPOXX Capsules to complete the 14 day treatment course as soon as oral therapy can be tolerated. b10 mg/mL TPOXX solution containing 40% hydroxypropyl betadex (8 per vial) with water for injection [see Dosage Forms and Strengths 3)] cDiluent is either 0.9% (w/v) sodium chloride injection or 5% (w/v) dextrose injection solution. dDepending on size of syringe available with syringe pump system, two separate syringes may be needed for each hour administration. Body WeightDosage for up to 14 daysVolume of TPOXX Injection Volume of Diluent 3 kg to less than 35 kg6 mg/kg every 12 hours by intravenous infusion over hours 0.6 mL/kg1.2 mL/kg35 kg to less than 120 kg200 mg every 12 hours by intravenous infusion over hours20 mL40 mL120 kg and above 300 mg every 12 hours by intravenous infusion over hours30 mL60 mL. 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 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 (2C 8C) for up to 24 hours or at room temperature (15C 25C) for up to hours.. Gently swirl the syringe of in-use solution prior to inserting into the syringe pump and infuse over hours every 12 hours for 14 days.. Do not re-use the single-dose vial once it has been punctured.

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) 7.1 Effect 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.Table 5provides listing of established or significant drug interactions and clinical recommendations for select sensitive substrates [see Warnings and Precautions 5.1) and Clinical Pharmacology 12.3)] Table 5: Significant Drug Interactions with Effect of TPOXX on Other Drugsa decrease, increase bThese interactions have been studied in healthy adults. Concomitant Drug Class: Drug Name Effect on Concentration Clinical Effect/RecommendationBlood Glucose-Lowering Agent:Repaglinide 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:Midazolam midazolamMonitor for effectiveness of midazolam.. 7.2 Effect of Other drugs on TPOXX. Co-administration of phosphate binders with tecovirimat increases tecovirimat bioavailability. Table 6provides listing of established drug interactions and clinical recommendations for select phosphate binders [see Clinical Pharmacology 12.3)] Table 6: Significant Drug Interactions with Effect of Other Drugs on TPOXXa increase bThese interactions have been studied in healthy adults. Concomitant Drug Class: Drug Name Effect on Concentration Clinical Effect/RecommendationPhosphate Binders b: Calcium acetate Lanthanum carbonate Sevelamer carbonate Sucroferric oxyhydroxide tecovirimatMonitor for signs or symptoms of adverse effects when TPOXX is co-administered with phosphate binders [see Overdose 10)] . 7.3 Drugs Without Clinically Significant Interactions With TPOXX. Based on 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.

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 capsules as directed within 30 minutes of eating full meal containing moderate or high fat with 6-8 oz. of water [see Clinical Pharmacology 12.3)] Inform patients to take TPOXX for the entire duration without missing or skipping dose [see Dosage and Administration 2)] Inform patients who cannot swallow capsules to refer to the Instructions for Use [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 [see Drug Interactions 7)] Co-administration of TPOXX with repaglinide may cause hypoglycemia [see Warnings and Precautions 5.1) and Drug Interactions 7.1)] TPOXX injection: Hydroxypropyl--cyclodextrin, required component of TPOXX injection, is eliminated through glomerular filtration. Therefore, in patients with severe renal impairment (defined as creatinine clearance below 30 mL/min), the use of TPOXX injection is contraindicated [see Contraindications 4)] 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 [see Warnings and Precautions 5.2) and Use in Specific Populations 8.6)] LactationInstruct individuals with smallpox not to breastfeed their infant because of the risk of passing variola virus to the breastfed infant [see Use in Specific Populations 8.2)] TPOXX capsules Manufactured by: Catalent Pharma Solutions, LLC 1100 Enterprise Drive Winchester, KY 40391 TPOXX injection manufactured by: Patheon Manufacturing Services LLC 5900 Martin Luther King Jr. Highway Greenville, NC 27834 Distributed by: SIGA Technologies, Inc. 4575 SW Research Way, Suite 110 Corvallis, OR 97333.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USE TPOXX (Te-Pox or Tee-pahx) (tecovirimat) capsules, for oral use This Instructions for Use contains information on how to prepare and give dose of TPOXX capsules to children who weigh 28 pounds (13 kg) to less than 88 pounds (40 kg) or adults or children who have trouble swallowing TPOXX capsules whole.Read this Instructions for Use before taking TPOXX capsules. There may be new information. This Instructions for Use does not take the place of talking to your healthcare provider about your medicinal condition or treatment.Step 1:Gather the supplies you need to prepare dose of TPOXX: bottle of TPOXX (1 capsule 200 mg of medicine)1 tablespoon1 small bowl or cupYour 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 (see Figure A). Step 3:Find the prescribed dose in the same row as the weight of the person taking the medicine on the TPOXX Dosing Table (see Figure A). Step 4:Get small bowl or cup and place it on flat surface.Add tablespoons (30 mL) of liquid or soft food to the bowl or cup.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 (see Figure A).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 or cup 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 or cup. Repeat this for each capsule that is needed for the total prescribed 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 TPOXX medicine mixture is now ready to take.Step 8:Swallow the TPOXX medicine mixture. All the TPOXX medicine mixtureshould be swallowed to make sure the entire dose it taken. The TPOXX mixture must be taken within 30 minutes after meal containing approximately 25 grams of fat andwithin 30 minutes after mixing it. For people weighing 28 pounds (13 kg) to less than 264 pounds (120 kg), TPOXX medicine mixture should be given times day (every 12 hours), by mouth, for 14 days.For people weighing 264 pounds (120 kg) and above, TPOXX medicine mixture should be given 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 Table (Figure A)Body Weight Prescribed Dose Amount of Liquid or Soft Food Number of Capsules Food and Medicine Mixture Instructions 28 pounds (13 kg) to less than 55 pounds (25 kg) 200 mg (1 capsule) Every 12 hours tablespoons1 TPOXX capsule Mix entire contents of TPOXX capsule with tablespoons of liquid or soft food. 55 pounds (25 kg) to less than 88 pounds (40 kg) 400 mg (2 capsules) Every 12 hours tablespoons2 TPOXX capsules Mix entire contents of TPOXX capsules with tablespoons of liquid or soft food. 88 pounds (40 kg) to less than 265 pounds (120 kg) 600 mg (3 capsules) Every 12 hours tablespoons3 TPOXX capsules Mix entire contents of TPOXX capsules with tablespoons of liquid or soft food. 265 pounds (120 kg) and above 600 mg (3 capsules) Every hours tablespoons3 TPOXX capsules Mix entire contents of TPOXX capsules with tablespoons of liquid or soft food. How should store TPOXX CapsulesStore TPOXX at room temperature between 68F to 77F (20C to 25C).Keep TPOXX in its original container.Keep TPOXX and all medicines out of the reach of children.TPOXX capsules Manufactured by: Catalent Pharma Solutions 1100 Enterprise Drive Winchester, KY 40391 TPOXX injection manufactured by: Patheon Manufacturing Services LLC 5900 Martin Luther King Jr. Highway Greenville, NC 27834 Distributed by: SIGA Technologies, Inc. 4575 SW Research Way, Suite 110 Corvallis, OR 97333 This Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: 05/2022. bottle of TPOXX (1 capsule 200 mg of medicine). tablespoon. small bowl or cup. 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 or cup and place it on flat surface.. Add tablespoons (30 mL) of liquid or soft food to the bowl or cup.. 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 or cup. Repeat this for each capsule that is needed for the total prescribed dose.. Throw away the empty capsule shells.. The powder may not completely dissolve.. The TPOXX medicine mixture is now ready to take.. The TPOXX mixture must be taken within 30 minutes after meal containing approximately 25 grams of fat andwithin 30 minutes after mixing it. For people weighing 28 pounds (13 kg) to less than 264 pounds (120 kg), TPOXX medicine mixture should be given times day (every 12 hours), by mouth, for 14 days.. For people weighing 264 pounds (120 kg) and above, TPOXX medicine mixture should be given times day (every hours), by mouth, for 14 days.. Store TPOXX at room temperature between 68F to 77F (20C to 25C).. Keep TPOXX in its original container.

PHARMACOKINETICS SECTION.

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 AUC 0-24hr, max, and tau/troughare 29816 hrong/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 hours in healthy adults, the mean steady-state values of tecovirimat AUC 0-24hr, max, and minare 39405 hrong/mL (n, CV: 22, 23%), 2630 ng/mL (n, CV: 22, 22%), and 747 ng/mL (n, CV: 22, 29%). Refer to Table 7for pharmacokinetic parameters of tecovirimat. Tecovirimat steady-state is achieved by Day 4-6. Table 7: Pharmacokinetic Properties of TecovirimataValue reflects administration of drug with food. bValue refers to mean systemic exposure (AUC 24hr). Meal: 600 kcal, 25 fat. cTecovirimat 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[5.3.2.02,6.08,10]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) enzymes et 1/2value refers to mean terminal plasma half-life. fSingle dose administration of 14C]-tecovirimat in mass balance study. KEY: NA Not Applicable or Not AvailableAbsorption200 mg intravenous600 mg oral Median max(h) (Range) (6-6.5)6 (2-24) Effect of food (relative to fasting)NA39% Distribution Bound to human plasma proteins77-82 Blood-to-plasma ratio (drug or drug-related materials)0.62-0.90 Volume of distribution (Vz or Vz/F, L) (CV%)383 (46%)1030Metabolism Metabolic pathways Hydrolysis, UGT1A1 d, UGT1A4 Elimination Major route of eliminationMetabolism Clearance (CL or CL/F, L/hr) (CV%)13 (23%)31 1/2(h) e(CV%) 21 (45%)19 (29%) of dose excreted in urine NA73, predominantly as metabolites of dose excreted in feces NA23, 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 every 12 hours for treatment of smallpox disease in humans. Humans achieve greater systemic exposure (AUC, max, and min) of tecovirimat following dose of 600 mg every 12 hours 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 orally every 12 hours, the observed mean steady state values of AUC 0-24hr, max, and troughwere 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)] Hydroxypropyl--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 StudiesThe 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. Table 8: Drug Interactions Changes in Pharmacokinetic Parameters for Co-Administered Drug in the Presence of TPOXX aAll interaction studies conducted in healthy volunteers with tecovirimat 600 mg twice daily (every 12 hours). bComparison based on exposures when administered as flurbiprofen omeprazole midazolam. Co-Administered Drug Dose of Co-Administered Drug (mg) NMean Ratio (90% CI) of Co-Administered Drug PK With/Without TPOXX No Effect 1.00 max AUC inf Flurbiprofen omeprazole midazolam omeprazole 20, single dose241.87 (1.51, 2.31) 1.73 (1.36, 2.19) midazolam 2, 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.Table 9: Drug Interactions Changes in TPOXX Pharmacokinetic Parameters in the Presence of Co-Administered Drug aAll interaction studies conducted in healthy volunteers with tecovirimat 600 mg twice daily (every 12 hours) taken with meal (consisting of approximately 600 calories and 25 fat). bNumber of subjects with reportable PK values when TPOXX was co-administered with phosphate binder. Co-Administered Drug Dose of Co-Administered Drug (mg) b Mean Ratio (90% CI) of TPOXX PK With/Without Co-Administered Drug No Effect 1.00 max AUC0-24 hourPhosphate bindersSevelamer carbonate (1600 mg, single dose)391.16 (1.08, 1.26) 1.26 (1.17, 1.36) Sucroferric oxyhydroxide (500 mg, single dose)371.15 (1.06, 1.24) 1.20 (1.11, 1.29) Calcium acetate (1334 mg, single dose)371.09 (1.01, 1.18) 1.16 (1.07, 1.25) Lanthanum carbonate (500 mg, single dose)381.21 (1.12, 1.30) 1.22 (1.13, 1.32) The relative bioavailability indicated an increase in peak and total systemic exposure (Cmax and AUCs) when 600 mg TPOXX was orally administered with 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 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 SummaryThere are no available data on the use of tecovirimat in pregnant individuals to evaluate for 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 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 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.DataAnimal DataTecovirimat 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).

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 05/2022PATIENT INFORMATIONTPOXX (Te-Pox or Tee-pahx) (tecovirimat) capsules, for oral use TPOXX (Te-Pox or Tee-pahx) (tecovirimat) injection, for intravenous use What is TPOXX TPOXX is prescription medicine used to treat smallpox disease caused by type of virus called variola virus in adults and children who weigh at least pounds (3 kg). 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.TPOXX may not work well in people who have weakened immune system (immunocompromised). Who should not receive TPOXX injectionDo not receive TPOXX injection if you or your child have severe kidney problems.TPOXX injection contains an ingredient called hydroxypropyl -cyclodextrin which is cleared from your body through the kidneys. Tell your healthcare provider if you or your child have kidney problems because receiving TPOXX injection may not be right for you or your child. Before taking or receiving TPOXX, tell your healthcare provider about all of your or your childs medical conditions, including if you or your child:have diabetes.have kidney problems.are pregnant or plan to become pregnant. It is not known if TPOXX can harm the unborn baby. Tell your healthcare provider if you or your child become pregnant during treatment with TPOXX.are breastfeeding or plan to breastfeed. It is not known if TPOXX passes into your breast milk. You should not breastfeed during treatment with TPOXX. You should not breastfeed if you have smallpox because of the risk of passing variola virus to the breastfed infant.Talk to your healthcare provider about the best way to feed the baby during treatment with TPOXX. Tell your healthcare provider about all of the medicines you or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using TPOXX with certain other medicines may affect each other causing possible serious side effects. You can ask your healthcare provider or pharmacist for list of medications that interact with TPOXX. Especially tell your healthcare provider if you takea medicine used to treat type diabetes called repaglinide. Know the medicines you or your child take. Keep list of your medicines to show your healthcare provider and pharmacist when you get new medicine. 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 TPOXXStay under the care of your healthcare provider during treatment with TPOXX.TPOXX capsules:Take TPOXX capsules exactly as your healthcare provider tells you. Do not change the dose or stop taking TPOXX without talking to your healthcare provider.For adults and children who weigh at least 40 kg and less than 120 kg, take capsules of TPOXX times day (every 12 hours) by mouth for 14 days. For adults and children who weigh at least 120 kg, take capsules of TPOXX times day (every hours) by mouth for 14 days. TPOXX should be taken within 30 minutes after eating full meal of moderate or high fat (approximately 600 calories and 25 grams of fat). Swallow capsules whole with to ounces of water. 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 capsules for instructions on how to prepare and take dose of TPOXX if: your child weighs less than 88 pounds (40 kg), or you or your child have trouble swallowing TPOXX capsules. It is important to take TPOXX for the full 14 day course of treatment. Do not miss or skip dose of TPOXX.If you miss an oral dose of TPOXX, you should take the dose as soon as possible and anytime up to hours before the next scheduled dose. If less than hours remain before the next scheduled dose, do not take the missed dose, and take your next dose as scheduled.If you take too much TPOXX, call your healthcare provider or go to the nearest hospital emergency room right away.TPOXX Injection for Intravenous Infusion (IV)TPOXX injection is given to you or your child by intravenous (IV) infusion into vein slowly over hours using an infusion pump by health care provider.What are the possible side effects of TPOXX TPOXX may cause serious side effects, including: Low blood sugar (hypoglycemia).Low blood sugar can happen when TPOXX is taken or received 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 shaky dizziness confusion sweating weakness fast heartbeat irritability The most common side effects of TPOXX capsules include: headache nausea stomach pain vomiting The most common side effects of TPOXX injection include: reactions at the site of your IV infusion These 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. 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 TPOXXTPOXX capsules: 200 mgActive 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 No. 1, FD&C red No. 3, FD&C yellow No. 6, and titanium dioxide. TPOXX injection: 200 mg in each 20 mL vialActive ingredient:tecovirimat Inactive ingredients:hydroxypropyl -cyclodextrin and water for injection. TPOXX capsules manufactured by: Catalent Pharma Solutions 1100 Enterprise Drive Winchester, KY 40391 TPOXX injection manufactured by: Patheon Manufacturing Services LLC 5900 Martin Luther King Jr. Highway Greenville, NC 27834 Distributed By: SIGA Technologies, Inc. 4575 SW Research Way, Suite 110 Corvallis, OR 97333 For more information, go to www.SIGA.comor call 1-888-899-3472. 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.. TPOXX may not work well in people who have weakened immune system (immunocompromised).. have diabetes.. have kidney problems.. are pregnant or plan to become pregnant. It is not known if TPOXX can harm the unborn baby. Tell your healthcare provider if you or your child become pregnant during treatment with TPOXX.. are breastfeeding or plan to breastfeed. It is not known if TPOXX passes into your breast milk. You should not breastfeed during treatment with TPOXX. You should not breastfeed if you have smallpox because of the risk of passing variola virus to the breastfed infant.Talk to your healthcare provider about the best way to feed the baby during treatment with TPOXX. You should not breastfeed if you have smallpox because of the risk of passing variola virus to the breastfed infant.. Talk to your healthcare provider about the best way to feed the baby during treatment with TPOXX.. Stay under the care of your healthcare provider during treatment with TPOXX.. Take TPOXX capsules exactly as your healthcare provider tells you. Do not change the dose or stop taking TPOXX without talking to your healthcare provider.. For adults and children who weigh at least 40 kg and less than 120 kg, take capsules of TPOXX times day (every 12 hours) by mouth for 14 days. For adults and children who weigh at least 120 kg, take capsules of TPOXX times day (every hours) by mouth for 14 days. TPOXX should be taken within 30 minutes after eating full meal of moderate or high fat (approximately 600 calories and 25 grams of fat). Swallow capsules whole with to ounces of water. 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 capsules for instructions on how to prepare and take dose of TPOXX if: your child weighs less than 88 pounds (40 kg), or you or your child have trouble swallowing TPOXX capsules. your child weighs less than 88 pounds (40 kg), or you or your child have trouble swallowing TPOXX capsules.. It is important to take TPOXX for the full 14 day course of treatment. Do not miss or skip dose of TPOXX.. If you miss an oral dose of TPOXX, you should take the dose as soon as possible and anytime up to hours before the next scheduled dose. If less than hours remain before the next scheduled dose, do not take the missed dose, and take your next dose as scheduled.. 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 or received 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding is not recommended in patients with smallpox. 8.2) 8.1 Pregnancy. Risk SummaryThere are no available data on the use of tecovirimat in pregnant individuals to evaluate for 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 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 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.DataAnimal DataTecovirimat 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 SummaryBecause 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 drug is present in animal milk, it is likely to be present in human milk. 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 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--cyclodextrin, an ingredient in TPOXX injection, in pediatric patients less than years of age. Given the potential for drug accumulation due to renal immaturity in pediatric patients less than 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--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)].

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) 5.1 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 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--Cyclodextrin Excipient for Patients with Renal Insufficiency and Pediatric Patients 2 Years of Age. Patients with renal insufficiencyTPOXX Injection: In healthy patients and in patients with mild to severe renal insufficiency, the majority of an g dose of hydroxypropyl--cyclodextrin (per 200 mg tecovirimat/20 mL solution) is eliminated in the urine. It is known that clearance of hydroxypropyl--cyclodextrin is reduced in patients with mild, moderate, and severe renal impairment, resulting in higher exposure to hydroxypropyl--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--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 patientsTPOXX Injection: In pediatric patients less than years of age, there are limited data regarding the use of hydroxypropyl--cyclodextrin. Given that renal tubular function rapidly matures over the first few years of life, clearance of hydroxypropyl--cyclodextrin may be reduced in young pediatric patients, resulting in higher exposure to hydroxypropyl--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--cyclodextrin. Given the potential for drug accumulation due to renal immaturity in pediatric patients less than years, monitoring of renal function after treatment is recommended [see Use in Specific Populations 8.4) and Clinical Pharmacology 12.3)].