U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  21

______________ ______________ DOSAGE FORMS AND STRENGTHS Capsule: 200 mg. (3) ___________________ CONTRAINDICATIONS____________________ None (4) _______________ WARNINGS AND PRECAUTIONS _______________ Hypoglycemia: Co-administration with repaglinide may cause hypoglycemia. Monitor blood glucose and monitor for hypoglycemic symptoms during coadministration. (5.1) ____________________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 1-541-753-2000 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ____________________DRUG INTERACTIONS____________________ Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.1, 7, 12.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). 13 Reference ID: 4291064 Efficacy Based on Animal Models Alone Inform patients that the efficacy of TPOXX is based solely on efficacy studies demonstrating a 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 Information Advise patients to take TPOXX as directed within 30 minutes of eating a full meal of moderate or high fat [see Clinical Pharmacology (12.3)]. Inform patients to take TPOXX for the entire duration without missing or skipping a dose [see Dosage and Administration (2)]. Drug Interactions Inform 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 1100 Enterprise Drive Winchester, KY 40391 Distributed by: SIGA Technologies, Inc. 4575 SW Research Way Corvallis, OR 97333

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tecovirimat is an antiviral drug against variola (smallpox) virus [see Microbiology (12.4)]. 12.2 Pharmacodynamics Cardiac Electrophysiology TPOXX does not prolong the QT interval to any clinically relevant extent at the anticipated therapeutic exposure. 12.3 Pharmacokinetics At the approved recommended dosage, the mean steady-state values of TPOXX AUC0-24hr, Cmax, and Cmin are 28791 hr·ng/mL (CV: 35%), 2106 ng/mL (CV: 33%), and 587 ng/mL (CV: 38%), 8 Reference ID: 4291064 respectively. Tecovirimat steady-state AUC is achieved by Day 6. Refer to Table 4 for pharmacokinetic parameters of tecovirimat. Table 4: Pharmacokinetic Properties of Tecovirimat Absorption Tmax (h)a 4-6 Effect of food (relative to fasting)b ?39% Distribution % Bound to human plasma proteins 77-82 Blood-to-plasma ratio (drug or drug-related materials) 0.62-0.90 Volume of distribution (Vz/F, L) 1030 Metabolism Metabolic pathwaysc Hydrolysis, UGT1A1d , UGT1A4 Elimination Major route of elimination Metabolism 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 tecovirimat a Value reflects administration of drug with food. b Value refers to mean systemic exposure (AUC24hr). Meal: ~ 600 kcal, ~ 25 g fat. c Tecovirimat is metabolized by hydrolysis of the amide bond and glucuronidation. The following inactive metabolites were detected in plasma: M4 (N-{3,5-dioxo-4-azatetracyclo[5.3.2.0{2,6}.0{8,10}]dodec-11-en-4­ yl}amine), M5 (3,5 dioxo-4-aminotetracyclo[5.3.2.0{2,6}.0{8,10}]dodec-11-ene), and TFMBA (4 (trifluoromethyl) benzoic acid) d Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) enzymes e t1/2 value refers to mean terminal plasma half-life. f Single dose administration of [14C]-tecovirimat in mass balance study. Comparison of Animal and Human PK Data to Support Effective Human Dose Selection Because the effectiveness of TPOXX cannot be tested in humans, a comparison of tecovirimat exposures achieved in healthy human subjects to those observed in animal models of orthopoxvirus infection (nonhuman primates and rabbits infected with monkeypox virus and rabbitpox virus, respectively) in therapeutic efficacy studies was necessary to support the dosage regimen of 600 mg twice daily for treatment of smallpox disease in humans. Humans achieve greater systemic exposure (AUC, Cmax, and Cmin) of tecovirimat following a twice daily dose of 600 mg when compared to the therapeutic exposures in these animal models. 9 Reference ID: 4291064 Specific Populations No clinically significant differences in the pharmacokinetics of tecovirimat were observed based on age, sex, ethnicity, renal impairment (based on estimated GFR), or hepatic impairment (Child Pugh Scores A, B or C). Pediatric Patients TPOXX pharmacokinetics has not been evaluated in pediatric patients. The recommended pediatric dosing regimen is expected to produce tecovirimat exposures that are comparable to those in adult subjects based on a population pharmacokinetic modeling and simulation approach [see Dosage and Administration (2.2) and Use in Specific Populations (8.4)]. Drug Interaction Studies The effect of tecovirimat on the exposure of co-administered drugs are shown in Table 5. Table 5: Drug Interactions – Changes in Pharmacokinetic Parameters for Co-Administered Drug in the Presence of TPOXXa Co-Administered Drug Dose of Co-Administered Drug (mg) N Mean Ratio (90% CI) of Co-Administered Drug PK With/Without TPOXX No Effect = 1.00 Cmax AUCinf Flurbiprofen + omeprazole + midazolamb omeprazole 20 single dose 24 1.87 (1.51, 2.31) 1.73 (1.36, 2.19) midazolam 2 single dose 0.61 (0.54, 0.68) 0.68 (0.63, 0.73) Repaglinide 2 single dose 30 1.27 (1.12, 1.44) 1.29 (1.19, 1.40) Bupropion 150 single dose 24 0.86 (0.79, 0.93) 0.84 (0.78, 0.89) a All interaction studies conducted in healthy volunteers with tecovirimat 600 mg twice daily. b Comparison based on exposures when administered as flurbiprofen + omeprazole + midazolam. No pharmacokinetic changes were observed for the following drug when co-administered with tecovirimat: flurbiprofen. Cytochrome P450 (CYP) Enzymes: Tecovirimat is a weak inhibitor of CYP2C8 and CYP2C19, and a weak inducer of CYP3A4. Tecovirimat is not an inhibitor or an inducer of CYP2B6 or CYP2C9. In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically CYP Enzymes: Tecovirimat is not an inhibitor of CYP1A2, CYP2D6, CYP2E1 or CYP3A4, and is not an inducer of CYP1A2. Tecovirimat is not a substrate for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. UGT Enzymes: Tecovirimat is a substrate of UGT1A1 and UGT1A4. 10 Reference ID: 4291064 Transporter Systems: Tecovirimat inhibited Breast Cancer Resistance Protein (BCRP) in vitro. Tecovirimat is not an inhibitor of P-glycoprotein (P-gp), organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), organic anion transporter 1 (OAT1), OAT3, and organic cation transporter 2 (OCT2). Tecovirimat is not a substrate for P-gp, BCRP, OATP1B1, and OATP1B3.

12.4 Microbiology Mechanism of Action Tecovirimat targets and inhibits the activity of the orthopoxvirus VP37 protein (encoded by and highly conserved in all members of the orthopoxvirus genus) and blocks its interaction with cellular Rab9 GTPase and TIP47, which prevents the formation of egress-competent enveloped virions necessary for cell-to-cell and long-range dissemination of virus. Activity in Cell Culture In cell culture assays, the ef

USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary No adequate and well-controlled studies in pregnant women were conducted; therefore there are no human data to establish the presence or absence of 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 a mouse pre-/post-natal development study, no toxicities were observed at maternal tecovirimat exposures up to 24 times higher than human exposure at the RHD (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data: Tecovirimat was administered orally to pregnant mice at doses up to 1,000 mg/kg/day from gestation Days 6-15. No embryofetal toxicities were observed at doses up to 1,000 mg/kg/day (approximately 23 times higher than human exposure at the RHD). Tecovirimat was administered orally to pregnant rabbits at doses up to 100 mg/kg/day from gestation Days 6-19. No embryofetal toxicities were observed at doses up to 100 mg/kg/day (0.4 times the human exposure at the RHD). In the pre-/post-natal development study, tecovirimat was administered orally to pregnant mice at doses up to 1,000 mg/kg/day from gestation Day 6 to post-natal Day 20. No toxicities were observed at doses up to 1,000 mg/kg/day (approximately 24 times higher than human exposure at the RHD). 8.2 Lactation Risk Summary There are no data to assess the effect on milk production, the presence of the drug in human milk, and/or the effects on the breastfed child. When administered to lactating mice, tecovirimat was present in the milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TPOXX and any potential adverse effects on the breastfed child from TPOXX or from the underlying maternal condition. 6 Reference ID: 4291064 Data In a lactation study at doses up to 1,000 mg/kg/day, mean tecovirimat milk to plasma ratios up to approximately 0.8 were observed at 6 and 24 hours post-dose when administered orally to mice on lactation Day 10 or 11. 8.3 Females and Males of Reproductive Potential Infertility There are no data on the effect of tecovirimat on female and male reproductive potential in humans. Decreased fertility due to testicular toxicity was observed in male mice [see Nonclinical Toxicology (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)]. 8.6 Renal Impairment No dosage adjustment is required for patients with mild, moderate or severe renal impairment or patients with end stage renal

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. 7 Reference ID: 4291064 11