TPOXX

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 a drug interaction study, 10 of 30 healthy subjects experienced mild (6 subjects) or moderate (4 subjects) hypoglycemia following co-administration of repaglinide (2 mg) and TPOXX. Symptoms resolved in all subjects after intake of food and/or oral glucose. 5.2 Risks of Hydroxypropyl-β-Cyclodextrin Excipient for Patients with Renal Insufficiency and Pediatric Patients < 2 Years of Age Patients with renal insufficiency TPOXX Injection: In healthy patients and in patients with mild to severe renal insufficiency, the majority of an 8 g dose of hydroxypropyl-β-cyclodextrin (per 200 mg tecovirimat/20 mL solution) is eliminated in the urine. It is known that clearance of hydroxypropyl-β-cyclodextrin is reduced in patients with mild, moderate, and severe renal impairment, resulting in higher exposure to hydroxypropyl-β-cyclodextrin; in these patients, half-life values are increased over normal values by approximately two-, four-, and six-fold, respectively. In these patients, successive infusions may result in accumulation of hydroxypropyl-β-cyclodextrin until steady state is reached. In patients with mild (defined as creatinine clearance 60-89 mL/min) and moderate (defined as creatinine clearance 30-59 mL/min) renal impairment, TPOXX Injection should be used with caution. Creatinine clearance should be closely monitored and, if renal toxicity is suspected, consideration should be given to administering TPOXX orally if possible or to using an alternative medication. TPOXX Injection is contraindicated in patients with severe renal impairment (creatinine clearance 30 mL/min) [see Contraindictions ( 4 ) and Clinical Pharmacology ( 12.3 )] . Pediatric patients TPOXX Injection: In pediatric patients less than 2 years of age, there are limited data regarding the use of hydroxypropyl-β-cyclodextrin. Given that renal tubular function rapidly matures over the first few years of life, clearance of hydroxypropyl-β-cyclodextrin may be reduced in young pediatric patients, resulting in higher exposure to hydroxypropyl-β-cyclodextrin. TPOXX Injection should be used with caution in this population given that animal studies have shown potential for nephrotoxicity at very high exposure levels of hydroxypropyl-β-cyclodextrin. Given the potential for drug accumulation due to renal immaturity in pediatric patients less than 2 years, monitoring of renal function after treatment is recommended [see Use in Specific Populations ( 8.4 ) and Clinical Pharmacology ( 12.3 )] .

6 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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of TPOXX has not been studied in patients with smallpox disease. TPOXX Clinical Trial (Oral Administration) The safety of TPOXX was evaluated in 359 healthy adult subjects ages 18-79 years in a Phase 3 clinical trial. Of the subjects who received at least one 600 mg dose of TPOXX, 59% were female, 69% were White, 28% were Black/African American, 1% were Asian, and 12% were Hispanic or Latino. Ten percent of the subjects who participated in the study were age 65 or older. Of these 359 subjects, 336 subjects received at least 23 of 28 doses of 600 mg TPOXX in a twice daily (every 12 hours) regimen for 14 days. Most Frequently Reported Adverse Reactions The most frequently reported adverse reactions were headache and nausea. Adverse reactions that occurred in at least 2% of subjects in the TPOXX treatment group are shown in Table 3 . Table 3: Treatment-Related Adverse Reactions Reported in ≥ 2% of Healthy Adult Subjects Receiving at Least One Dose of TPOXX Capsules 600 mg a Includes abdominal pain, abdominal pain upper, abdominal distension, abdominal discomfort, abdominal pain lower, epigastric pain Adverse Reaction TPOXX 600 mg N = 359 (%) Placebo N = 90 (%) Headache 12 8 Nausea 5 4 Abdominal pain a 2 1 Vomiting 2 0 Adverse Reactions Leading to Discontinuation of TPOXX Six subjects (2%) had their treatment with TPOXX discontinued due to adverse reactions. Each of these subject’s adverse reactions (with severity) is listed below: EEG change, abnormal Mild upset stomach, dry mouth, decreased concentration and dysphoria Mild nausea and fever, moderate diarrhea, severe headache Mild palpable purpura Mild nausea, fever and chills Mild facial redness, facial swelling and pruritus Less Common Adverse Reactions Clinically significant adverse reactions that were reported in <2% of subjects exposed to TPOXX and at rates higher than subjects who received placebo are listed below: Gastrointestinal: dry mouth, chapped lips, dyspepsia, eructation, oral paresthesia General and administration site: pyrexia, pain, chills, malaise, thirst Investigations: abnormal electroencephalogram, hematocrit decreased, hemoglobin decreased, heart rate increased Musculoskeletal and connective tissue: arthralgia, osteoarthritis Nervous system: migraine, disturbance in attention, dysgeusia, paresthesia Psychiatric: depression, dysphoria, irritability, panic attack Respiratory, Thoracic and Mediastinal Disorders: oropharyngeal pain Skin and subcutaneous tissue: palpable purpura, rash, pruritic rash, facial redness, facial swelling, pruritus TPOXX Clinical Trial (Intravenous Administration) The safety of multiple doses of 240 mg of TPOXX injection for IV infusion was evaluated in 26 healthy adult subjects ages 23-62 years, inclusive. An additional 6 subjects received placebo. TPOXX injection was administered over a 6 hour period via infusion pump twice daily (every 12 hours) for 7 days. Of the 26 subjects administered TPOXX, 42% were female, 69% were White, 23% were Black/African American, and 42% were Hispanic or Latino. Most Frequently Reported Adverse Reactions The most frequently reported adverse reactions included infusion site pain, infusion site swelling, infusion site erythema, infusion site extravasation, and headache. Adverse reactions that occurred in at least 4% of subjects in the TPOXX treatment group are shown in Table 4 . Table 4: Treatment-Related Adverse Reactions Reported in ≥ 4% of Healthy Adult Subjects Receiving at Least One Dose of TPOXX Injection 240 mg TPOXX 240 mg N = 26 (%) Placebo N = 6 (%) Infusion Site Pain 73 67 Infusion Site Swelling 39 67 Infusion Site Erythema 23 67 Infusion Site Extravasation 19 50 Headache 15 0 Adverse Reactions Leading to Discontinuation of TPOXX Injection Three subjects (12%) had their treatment with TPOXX injection discontinued due to adverse reactions. One subject had two adverse reactions. Each of these subject’s adverse reactions (with severity) are listed below: Moderate Infusion site extravasation Mild Infusion site extravasation Mild Infusion site swelling and mild infusion site pain Less Common Adverse Reactions Clinically significant adverse reactions that were reported in <4% of subjects exposed to TPOXX injection and at rates higher than subjects who received placebo are listed below: General and administration site: infusion site discomfort, infusion site edema Musculoskeletal and connective tissue: myalgia, arthritis, back pain, muscle tightness Gastrointestinal: diarrhea Eye: photophobia Skin and Subcutaneous Tissue: pruritus generalized

<table ID="table3" width="700" styleCode="Noautorules"><caption>Table 3: Treatment-Related Adverse Reactions Reported in &#x2265; 2% of Healthy Adult Subjects Receiving at Least One Dose of TPOXX Capsules 600 mg</caption><col width="35%" align="left"/><col width="35%" align="left"/><col width="30%" align="left"/><tfoot><tr valign="top"><td colspan="3"><paragraph styleCode="footnote">^aIncludes abdominal pain, abdominal pain upper, abdominal distension, abdominal discomfort, abdominal pain lower, epigastric pain </paragraph></td></tr></tfoot><tbody><tr valign="top"><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Reaction</content></td><td styleCode="Toprule Botrule Rrule"><content styleCode="bold">TPOXX 600 mg N = 359 (%) </content></td><td styleCode="Toprule Botrule Rrule"><content styleCode="bold">Placebo N = 90 (%) </content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Headache</td><td styleCode="Botrule Rrule">12</td><td styleCode="Botrule Rrule">8</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Nausea</td><td styleCode="Botrule Rrule">5</td><td styleCode="Botrule Rrule">4</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Abdominal pain ^a</td><td styleCode="Botrule Rrule">2</td><td styleCode="Botrule Rrule">1</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Vomiting</td><td styleCode="Botrule Rrule">2</td><td styleCode="Botrule Rrule">0</td></tr></tbody></table>

<table ID="table4" width="700" styleCode="Noautorules"><caption>Table 4: Treatment-Related Adverse Reactions Reported in &#x2265; 4% of Healthy Adult Subjects Receiving at Least One Dose of TPOXX Injection 240 mg</caption><col width="35%" align="left"/><col width="35%" align="left"/><col width="30%" align="left"/><tbody><tr valign="top"><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold"/></td><td styleCode="Toprule Botrule Rrule"><content styleCode="bold">TPOXX 240 mg N = 26 (%) </content></td><td styleCode="Toprule Botrule Rrule"><content styleCode="bold">Placebo N = 6 (%) </content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Infusion Site Pain</td><td styleCode="Botrule Rrule">73</td><td styleCode="Botrule Rrule">67</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Infusion Site Swelling</td><td styleCode="Botrule Rrule">39</td><td styleCode="Botrule Rrule">67</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Infusion Site Erythema</td><td styleCode="Botrule Rrule">23</td><td styleCode="Botrule Rrule">67</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Infusion Site Extravasation</td><td styleCode="Botrule Rrule">19</td><td styleCode="Botrule Rrule">50</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Headache</td><td styleCode="Botrule Rrule">15</td><td styleCode="Botrule Rrule">0</td></tr></tbody></table>