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)

 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.

 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).

U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  21

ADVERSE REACTIONS

 Common adverse reactions in healthy adult subjects (= 2%) were headache, nausea, abdominal pain, and vomiting.

CONTRAINDICATIONS-                                                                                                       None

WARNINGS AND PRECAUTIONS-                                                                                     Hypoglycemia:  Co-administration with repaglinide may cause hypoglycemia.  Monitor blood glucose and monitor for hypoglycemic symptoms during coadministration.

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labelling

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.

 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. Inform patients to take TPOXX for the entire duration without missing or skipping a dose.

 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

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

1 Mechanism of Action-                                                                                                     Tecovirimat is an antiviral drug against variola (smallpox) virus

 2. Pharmacodynamics Cardiac Electrophysiology-                                                      TPOXX does not prolong the QT interval to any clinically relevant extent at the anticipated therapeutic exposure.

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%), respectively. Tecovirimat steady-state AUC is achieved by Day 6. 

 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 aValue reflects administration of drug with food.

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.

Drug Interaction Studies-                                                                                                   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)

All interaction studies conducted in healthy volunteers with tecovirimat 600 mg twice daily. 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.

 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).

 USE IN SPECIFIC POPULATIONS                                                                                   

 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. 

 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.

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 

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.

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.

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

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

6. Renal 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

7. Hepatic Impairment-                                                                                                      No dosage adjustment is required for patients with mild, moderate or severe hepatic impairment (Child Pugh Class A, B, or C)

 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.