Summary of Product Characteristics (SmPC) - Tecovirimat Siga 200 mg hard capsules
1 NAME OF THE MEDICINAL PRODUCT
Tecovirimat SIGA 200 mg hard capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains tecovirimat monohydrate equivalent to 200 mg tecovirimat.
Excipient(s) with known effect
Each capsule contains 31.5 mg lactose (as monohydrate) and 0.41 mg sunset yellow (E110).
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Hard capsule (capsule)
Opaque gelatin capsules with an orange body and black cap, containing white to off-white powder. The body is printed with “SIGA” and the SIGA logo (a curved triangle with letters in it) followed by “®” in white ink. The cap is printed with “ST-246®” in white ink. The capsules are 21.7 millimeters long and 7.64 millimeters around the centre.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Tecovirimat SIGA is indicated for the treatment of the following viral infections in adults and children with body weight at least 13 kg:
- Smallpox
- Cowpox
Tecovirimat SIGA is also indicated to treat complications due to replication of vaccinia virus following vaccination against smallpox in adults and children with body weight at least 13 kg (see sections 4.4 and 5.1).
Tecovirimat SIGA should be used in accordance with official recommendations.
4.2 Posology and method of administration
Posology
Tecovirimat treatment should be initiated as soon as possible after diagnosis (see section 4.1).
Adults and children of at least 13 kg
The recommended doses are described in Table 1.
Table 1: Recommended Dose by Body Weight
| Body Weight | Dosage | Number of Capsules |
| 13 kg to less than 25 kg | 200 mg every 12 hours for 14 days | One Tecovirimat 200 mg capsule |
| 25 kg to less than 40 kg | 400 mg every 12 hours for 14 days | Two Tecovirimat 200 mg capsules |
| 40 kg to less than 120 kg | 600 mg every 12 hours for 14 days | Three Tecovirimat 200 mg capsules |
| 120 kg and above | 600 mg every 8 hours for 14 days | Three Tecovirimat 200 mg capsules |
Re-dosing in case of vomiting
If vomiting occurs within 30 minutes of taking tecovirimat hard capsules, another dose may be administered immediately. If vomiting occurs more than 30 minutes after taking tecovirimat hard capsules, no additional dose should be given and dosing should resume as usual after 12 hours.
Special populations
Elderly
No dosage adjustment is required (see section 5.2).
Renal impairment
No dosage adjustment is required (see section 5.2).
Hepatic impairment
No dosage adjustment is required (see section 5.2).
Paediatric population
Tecovirimat should not be administered to children of less than 13 kg body weight. No dose recommendations for children less than 13 kg body weight have been established.
Method of administration
Oral use.
Tecovirimat hard capsules should be taken within 30 minutes after a meal of moderate or high fat (see section 5.2).
For patients who cannot swallow tecovirimat hard capsules, the capsules may be opened and the contents may be mixed with approximately 30 mL of liquid (e.g. milk) or soft food (e.g. yogurt) and swallowed within 30 minutes of completing a meal (see sections 5.2 and 6.3).
Wash and dry your hands before and after preparation. Carefully open the capsule so that the contents do not spill or escape into the air. Hold the capsule with the cap facing up and pull the cap away from the body of the capsule. Use a small container for mixing. Mix the entire contents of the capsule with 30 mL of liquid (e.g. milk) or soft food (e.g. yogurt). The mixture should be taken within 30 minutes after mixing and within 30 minutes of eating a meal.
The recommended paediatric and adult dosage and preparation instructions are given in the table below.
Table 2: Recommended Dosage and Preparation Instructions
Body weight | Tecovirimat dose | Amount of liquid or soft food | Number of capsules | Food and tecovirimat mixture instructions |
| 13 kg to less than 25 kg | 200 mg | 2 tablespoons | 1 Tecovirimat capsule | Mix entire contents of 1 Tecovirimat capsule with 2 tablespoons of liquid or soft food. |
| 25 kg to less than 40 kg | 400 mg | 2 tablespoons | 2 Tecovirimat capsules | Mix entire contents of 2 Tecovirimat capsules with 2 tablespoons of liquid or soft food. |
| 40 kg to less than 120 kg | 600 mg | 2 tablespoons | 3 Tecovirimat capsules | Mix entire contents of 3 Tecovirimat capsules with 2 tablespoons of liquid or soft food. |
120 kg and above | 600 mg | 2 tablespoons | 3 Tecovirimat capsules | Mix entire contents of 3 Tecovirimat capsules with 2 tablespoons of liquid or soft food. |
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Co-administration of other medicinal products
Co-administration of repaglinide and tecovirimat may cause mild to moderate hypoglycaemia, (see section 4.5). Blood glucose and hypoglycaemic symptoms should be monitored when administering tecovirimat with repaglinide.
Co-administration of midazolam and tecovirimat may reduce the effectiveness of midazolam (see section 4.5). Effectiveness of midazolam should be monitored when administering tecovirimat with midazolam.
Use in people with epilepsy and concomitant use with drugs that can lower seizure threshold
Although no cases of seizures in humans were observed in the clinical development programme, due to the uncertainty of the effect of tecovirimat on potentiating epileptic seizures (see section 5.3 for non-clinical findings), caution is recommended for use in people with epilepsy and for concomitant use with drugs that can lower seizure threshold.
Renal impairment
Tecovirimat should be used with caution in patients with severe renal impairment as there is limited clinical data in this population and higher unbound drug and metabolites levels may be observed. (see sections 4.2 and 5.2).
Hepatic impairment
Tecovirimat should be used with caution in patients with severe hepatic impairment as there is limited clinical data in this population and higher unbound drug and metabolite levels may be observed (see sections 4.2 and 5.2).
Immunocompromised population
The safety and efficacy of tecovirimat has not been evaluated in immunocompromised individuals. Nonclinical studies using animal models indicate that tecovirimat may have reduced efficacy in immunocompromised individuals. See section 5.1.
Excipients
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine contains sunset yellow (E110). May cause allergic reactions.
4.5 Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on tecovirimat
Tecovirimat is a substrate of UGT1A1, 1A3 and 1A4. Co-administration of tecovirimat with strong inhibitors or inducers of these UGTs is not expected to have a clinically important effect on tecovirimat exposures.
Tecovirimat was studied in people against phosphate binders with the results indicating a slight increase in exposure of tecovirimat. See Table 3 for results.
Table 3: Interactions and dose recommendations with tecovirimat
Medicinal Product by therapeutic areaa | Effect on tecovirimat levels. Mean percent change in AUC, Cmax | Recommendation concerning co-administration with Tecovirimat |
| Phosphate Bindersa: | ||
| Calcium acetate | Tecovirimat: AUC: ↑ 16% Cmax: ↑ 9% | A risk for increase in tecovirimat plasma concentrations cannot be excluded when co-administered with phosphate binders. Monitor for signs or symptoms of adverse effects when Tecovirimat SIGA is co-administered with phosphate binders. |
| Lanthanum carbonate | Tecovirimat: AUC: ↑ 23% Cmax: ↑ 21% | |
| Sevelamer carbonate | Tecovirimat: AUC: ↑ 27% Cmax: ↑ 16% | |
| Sucroferric oxyhydroxide | Tecovirimat: AUC: ↑ 21% Cmax: ↑ 15% | |
aThese interactions have been studied in healthy adults.
Effect of tecovirimat on other medicinal products
Tecovirimat and its M4 metabolite are inducers of cytochrome P450 (CYP)3A and CYP2B6. Co-administration with tecovirimat may lead to reduced plasma exposures of sensitive substrates of CYP3A4 or CYP2B6, potentially leading to reduced effects. Monitoring is advised during co-administration of tecovirimat with CYP3A4 and CYP2B6 substrates that have narrow therapeutic windows. See Table 3 for some examples.
Tecovirimat is a weak inhibitor of CYP2C8 and CYP2C19. Co-administration with tecovirimat may lead to increased plasma exposures of sensitive substrates of CYP2C8 or CYP2C19, potentially leading to increased adverse effects. Monitoring is advised during co-administration of tecovirimat with CYP2C8 and CYP2C19 substrates that have narrow therapeutic windows. See Table 4 for some examples.
Table 4: Interactions and Dose Recommendations with Other Medicinal Products
| Medicinal Product by therapeutic areaa | Effect on medicinal product levels. Mean percent change in AUC, Cmax, | Recommendation concerning co-administration with Tecovirimat |
| Antidepressant: | ||
| Bupropiona (150 mg) | Decreased Bupropion AUC: ↓ 15% Cmax: ↓ 14% | No dose adjustment is required. The effectiveness of bupropion should be monitored. |
| Antidiabetics: | ||
| Repaglinidea (2 mg) | Repaglinide: AUC: ↑ 27% Cmax: ↑ 27% | Tecovirimat is a weak inhibitor of CYP2C8 and caused an increase in repaglinide plasma concentrations. Co-administration of repaglinide and tecovirimat may cause mild to moderate hypoglycemia. Blood glucose and hypoglycemic symptoms should be monitored in patients when tecovirimat is co-administered with repaglinide. |
| Antifungals | ||
| Voriconazole | Interactions not studied Expected AUC: ↑ Cmax: ↑ | A risk for increase in voriconazole plasma concentrations cannot be excluded (CYP2C19 substrate). The combination of tecovirimat and voriconazole should be used with caution. |
| Antiviral - non-nucleoside reverse transcriptase inhibitor | ||
| Rilpivirine | Interactions not studied Expected AUC: ↓ Cmax: ↓ | A risk for decreases in rilpivirine plasma concentrations cannot be excluded (CYP3A4 substrate). The combination of tecovirimat and rilpivirine should be used with caution. |
| CCR5 antagonists | ||
| Maraviroc | Interactions not studied Expected AUC: ↓ Cmax: ↓ | A risk for decreases in maraviroc plasma concentrations cannot be excluded (CYP3A4 substrate). The combination of tecovirimat and maraviroc should be used with caution. |
| CNS Depressant: | ||
| Midazolama (2 mg) | Midazolam: AUC: ↓ 32% Cmax: ↓ 39% | Tecovirimat is a weak inducer of CYP3A4 and caused a decrease in plasma conncentrations of midazolam. The effectiveness of midazolam should be monitored and the dose adjusted as necessary. |
| HMG CO-A Reductase Inhibitors | ||
| Atorvastatin | Interactions not studied Expected AUC: ↓ Cmax: ↓ | A risk for decreases in atorvastatin plasma concentrations cannot be excluded (CYP3A4 substrate). The combination of tecovirimat and atorvastatin should be used with caution. |
| Immunosuppressants | ||
| Tacrolimus | Interactions not studied Expected AUC: ↓ Cmax: ↓ | A risk for decreases in tacrolimus plasma concentrations cannot be excluded (CYP3A4 substrate). The combination of tecovirimat and tacrolimus should be used with caution. |
| Narcotic Analgesics | ||
| Methadone | Interactions not studied Expected AUC: ↓ Cmax: ↓ | A risk for decreases in methadone plasma concentrations cannot be excluded (CYP2B6 substrate). The combination of tecovirimat and methadone should be used with caution. |
| Nonsteoidal anti-inflammatory | ||
| Flurbiprofena (50 mg) | Flurbiprofen: AUC: ↔ Cmax: ↔ | No dose adjustment is required. |
| PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS | ||
| Sildenafil Tadalafil Vardenafil | Interactions not studied Expected AUC: ↓ Cmax: ↓ | A risk for decreases in PDE-5 inhibitor plasma concentrations cannot be excluded (CYP3A4 substrate). The combination of tecovirimat and PDE-5 inhibitors should be used with caution. |
| Protease inhibitors (PIs) | ||
| Darunavir | Interactions not studied Expected AUC: ↓ Cmax: ↓ | A risk for decreases in darunavir plasma concentrations cannot be excluded (CYP3A4 substrate). The combination of tecovirimat and darunavir should be used with caution. |
| Proton Pump Inhibitors: | ||
| Omeprazolea (20 mg) | Omeprazole AUC: ↑ 73% Cmax: ↑ 83% | Tecovirimat is a weak inhibitor of CYP2C19 and caused an increase in plasma centrations of omeprazole. The combination of tecovirimat and proton pump inhibitors should be used with caution. |
| Lansoprazole Rabeprazole | Interactions not studied Expected AUC: ↑ Cmax: ↑ | |
aThese interactions have been studied in healthy adults to evaluate the effect of repeated doses of tecovirimat 600 mg twice daily on the single-dose PK of probe substrates.
Vaccine
No vaccine-drug interaction studies have been performed in human subjects. Some animal studies have indicated that co-administration of tecovirimat at the same time as live smallpox vaccine (vaccinia virus) may reduce the immune response to the vaccine.
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no data from the use of tecovirimat in pregnant women.
Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).
Tecovirimat is not recommended during pregnancy, unless the benefits are considered to outweigh the risks.
Breast-feeding
It is unknown whether tecovirimat/metabolites are excreted in human milk.
Available toxicological/safety data in animals have shown excretion of tecovirimat in milk (see section 5.3).
A risk to the newborns/infants cannot be excluded.
Breast-feeding should be discontinued during treatment with tecovirimat.
Fertility
The effects of tecovirimat on fertility in humans have not been studied.
Tecovirimat caused decreased fertility due to testicular toxicity in male mice (see section 5.3).
4.7 Effects on ability to drive and use machines
Tecovirimat has minor influence on the ability to drive and use machines. Patients should be informed about the possible occurrence of dizziness and should be cautioned about driving or operating machines until they know how tecovirimat will affect them.
4.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse drug reactions were headache (12.3%) and nausea (4.5%).
Tabulated summary of adverse reactions
The following adverse reactions have been identified during the Phase 3 clinical trial. Adverse reactions are classified according to System Organ Class and frequency. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
Table 5: Frequency of Adverse Reactions by System Organ Class from Clinical Trials
| System organ class | Very Common | Common | Uncommon |
| Blood and lyphatic system disorders | Haematocrit Decreased Haemoglobin Decreased Leucopoenia Thrombocytopenia | ||
| Metabolism and nutrician disorders | Decreased appetite | ||
| Hepatobiliary disorders | Elevated LFT | ||
| Psychiatric disorders | Anxiety Depression Dysphoria Irritability Panic attack | ||
| Nervous system disorders | Headache | Dizziness | Disturbance in attention Dysgeusia Electroencephalogram abnormal Insomnia Migraine Somnolence Paraesthesia |
| Cardiac disorders | Heart Rate Increased Palpitations | ||
| Respiratory, thoracic and mediastinal disorders | Oropharyngeal pain | ||
| Gastrointestinal disorders | Abdominal pain upper Abdominal discomfort Diarrhoea Nausea Vomiting | Abdominal distention Aphthous ulcer Chapped lips Constipation Dry mouth Dyspepsia Eructation Flatulence Gastrooesophageal reflux disease Infrequent bowel movements Paraesthesia oral | |
| Skin and subcutaneous tissue disorders | Palpable purpura Pruritus generalised Rash Rash pruritic | ||
| Musculoskeletal and connective tissue disorders | Arthralgia Osteoarthritis | ||
| System organ class | Very Common | Common | Uncommon |
General disorders and administration site conditions | Chills Fatigue Feeling jittery Malaise Pain Pyrexia Thirst |
Paediatric population
Tecovirimat has not been studied in the paediatric population.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
In case of overdose, patients should be monitored for any signs or symptoms of adverse reactions. Haemodialysis will not significantly remove tecovirimat in overdosed patients.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiviral for systemic use, other antivirals, ATC code: J05AX24.
Mechanism of action
Tecovirimat inhibits the activity of the orthopoxvirus VP37 protein, which is encoded by a highly conserved gene in all members of the orthopoxvirus genus. Tecovirimat blocks the interaction of VP37 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 effective concentrations of tecovirimat resulting in a 50% reduction in virus induced cytopathic effect (EC50), were 0.016-0.067 µM, 0.015 µM and 0.009 µM, for smallpox, rabbitpox and vaccinia viruses, respectively.
Resistance
Current virologic assessment of mpox shows only rare evidence of resistance, with resistance documented in <1% of isolates. Tecovirimat has a relatively low resistance barrier, and certain amino acid substitutions in the target VP37 protein can confer large reductions in tecovirimat antiviral activity. Resistance mutations have arisen in patients receiving prolonged tecovirimat treatment for mpox, particularly in immunocompromised patients, such as HIV patients with low CD4 T-cell counts. The possibility of resistance to tecovirimat should be considered in patients either who fail to respond to therapy or who develop recrudescence of disease after an initial period of responsiveness.
Clinical efficacy
There is no human efficacy data available for the treatment of smallpox, cowpox or complications due to replication of vaccinia virus following vaccination against smallpox.
Nonclinical efficacy
Efficacy studies were conducted in cynomolgus macaques infected with mpox 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 5 x 107 plaque-forming units of mpox virus. Tecovirimat was administered orally once daily at a dose level of 10 mg/kg for 14 days, starting at Day 4, 5 or 6 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 a dose level of 40 mg/kg, starting at Day 4 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 4 post-challenge. Survival was monitored for 3-6 times the mean time to death for untreated animals in each model.
Treatment with tecovirimat for 14 days resulted in statistically significant improvement in survival relative to placebo, except when given to cynomolgus macaques starting at Day 6 post-challenge (Table 6).
Table 6: Survival Rates in Tecovirimat Treatment Studies in Cynomolgus
Macaques and NZW Rabbits Exhibiting Clinical Signs of Orthopoxvirus Disease
| Treatment Initiationa | Survival Percentage (No. survived/n) | p-valueb | Survival Rate Differencec (95% CI)d | ||
| Placebo | Tecovirimat | ||||
| Cynomolgus Macaques | |||||
| Study 1 | Day 4 | 0% (0/7) | 80% (4/5) | 0.0038 | 80% (20.8%, 99.5%) |
| Study 2 | Day 4 | 0% (0/6) | 100% (6/6) | 0.0002 | 100% (47.1%, 100%) |
| Study 3 | Day 4 | 0% (0/3) | 83% (5/6) | 0.0151 | 83% (7.5%, 99.6%) |
| Day 5 | 83% (5/6) | 0.0151 | 83% (7.5%, 99.6%) | ||
| Day 6 | 50% (3/6) | 0.1231 | 50% (-28.3%, 90.2%) | ||
| NZW Rabbits | |||||
| Study 4 | Day 4 | 0% (0/10) | 90% (9/10) | < 0.0001 | 90% (50.3%, 99.8%) |
| Study 5 | Day 4 | NAe | 88% (7/8) | NA | NA |
aDay 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
Pharmacokinetic/pharmacodynamic relationship
The non-human primate (NHP) and rabbit PK/PD models were developed in order to establish the exposure-response relationship between tecovirimat treatment and survival. The dose and regimen for humans were subsequently selected to provide exposures that exceed those associated with the fully effective dose in animals. Analysis of PK/PD models indicates that Cmin and AUC are the most predictive PK parameters for drug efficacy.
Paediatric population
The MHRA has deferred the obligation to submit the results of studies with tecovirimat in one or more subsets of the paediatric population in the treatment of orthopoxvirus disease (smallpox, cowpox and vaccinia) (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under ‘exceptional circumstances’. This means that for ethical reasons it has not been possible to obtain complete information on this medicinal product.
The benefits of tecovirimat have thus far only been shown in animal studies.
5.2 Pharmacokinetic properties
Absorption
Tecovirimat reaches maximum plasma concentrations 4 to 6 hours after oral administration with food.
The administration of tecovirimat with a meal of moderate fat and calories (~ 600 calories and ~ 25 grams of fat), as compared to tecovirimat taken in the fasted (unfed) state, increased the drug exposure (AUC) by 39%.
Distribution
Tecovirimat is 77.3-82.2% bound to human plasma proteins. After a single 600 mg dose of [14C]-tecovirimat in healthy subjects, concentrations of total radioactivity were lower in whole blood compared to plasma at all time points, with ratios of whole blood to plasma ranging from 0.62-0.90 across all time points. Tecovirimat has a high volume of distribution (1356 L).
Biotransformation
Based on human studies, tecovirimat is metabolized to form metabolites 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).
None of the metabolites is pharmacologically active.
Tecovirimat is a substrate of UGT1A1 and UGT1A4. In urine, primary tecovirimat glucuronide conjugate and M4 glucuronide conjugate were the most abundant components accounting for means of 24.4% and 30.3% of dose, respectively. However, none of the glucuronide conjugates was found as a major metabolite in plasma.
Elimination
After a single dose of [14C]-tecovirimat in healthy subjects, approximately 95% of the [14C]-radioactivity was recovered in urine and faeces over the 192-hour post-dose period, with approximately 73% of the [14C]-radioactivity administered being recovered in urine and 23% being recovered in faeces, indicating that the renal pathway is the major route of excretion. The renal excretion of parent compound was minimal, accounting for less than 0.02%. The majority of drug excreted by the renal system is in a glucuronidated form. In faeces, the excretion was mainly of unchanged tecovirimat. The terminal half-life of tecovirimat was 19.3 hr.
Linearity/non-linearity
Tecovirimat exhibits linear pharmacokinetics over a dose range of 100-600 mg.
Special populations
No clinically significant differences in the pharmacokinetics of tecovirimat were observed in healthy subjects based on age, gender or race.
Renal impairment
In subjects with renal impairment (based on estimated GFR), no clinically significant differences in the pharmacokinetics of tecovirimat were observed.
Hepatic impairment
In subjects with with mild, moderate or severe hepatic impairment (based on Child Pugh Scores A, B or C), no clinically significant differences in the pharmacokinetics of tecovirimat were observed.
Paediatric patients
The pharmacokinetics of tecovirimat has not been evaluated in paediatric patients as it is considered unethical to treat healthy peadiatric subjects. The recommended paediatric dosing regimen for subjects at least 13 kg body weight is expected to produce tecovirimat exposures that are comparable to those in adult subjects ages 18 to 50 based on a population pharmacokinetic modeling and a simulation approach.
5.3 Preclinical safety data
Effects in non-clinical studies were observed only at exposures considered in excess of the maximum human exposure indicating little relevance to clinical use.
The non-clinical safety was evaluated in 28-day and 3-month studies in mice and monkeys, respectively. Cmax exposures at the no observed adverse effect level in the toxicology studies compared to the human Cmax at the recommended human dose (RHD) have safety margins of 23 based on the mouse and 2.5 based on the monkey. The dog is a more sensitive species to tecovirimat and was tested after a single dose or repeated doses. Six hours after a single dose of 300 mg/kg, one dog experienced convulsions (tonic and clonic) with electroencephalography (EEG) consistent with seizure activity. This dose produce a Cmax in the dog that was approximately 4 times higher than the highest human Cmax at the RHD. In the dog, the no observe adverse effect level was determined to be 30 mg/kg with a Cmax safety margin at the RHD of
1.
Carcinogenicity studies have not been conducted with tecovirimat.
Tecovirimat was not genotoxic in in vitro or in vivo assays.
In a fertility and early embryonic development study in mice, no effects of tecovirimat on female fertility were observed at tecovirimat exposures (AUC) approximately 24 times higher than human exposure at the RHD. In a fertility and early embryonic development study in mice, no biologically meaningful effects of tecovirimat on male or female fertility were observed at tecovirimat exposures (AUC) approximately 24 times higher than human exposure at the RHD.
Reproductive toxicity studies have been performed in mice and rabbits. Based on pilot studies, the highest dose selected for the definitive study in rabbit was 100 mg/kg and in mice was 1,000 mg/kg. No embryo-foetal toxicities were observed in rabbit at doses up to 100 mg/kg/day (0.4 times the human exposure at the RHD) and no embryo-foetal toxicities were observed at doses up to 1,000 mg/kg/day in mice (approximately 23 times higher than human exposure at the RHD).
No embryo-foetal toxicities were observed at doses up to 100 mg/kg/day in rabbits (0.4 times the human exposure at the RHD). Maternal toxicity was detected in rabbits at 100 mg/kg/day, which included decreases in body weight and mortality.
Available toxicological/safety data in animals have shown excretion of tecovirimat in milk. 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule content
Silica, colloidal anhydrous
Croscarmellose sodium (E468)
Hypromellose (E464)
Lactose monohydrate
Magnesium stearate
Cellulose, microcrystalline (E460)
Sodium laurilsulfate (E487)
Capsule shell
Gelatin
Brilliant blue FCF (E133)
Erythrosine (E127)
Sunset yellow (E110)
Titanium dioxide (E171)
Printing ink
Shellac (E904)
Titanium dioxide (E171)
Isopropyl alcohol
Ammonium hydroxide (E527)
Butyl alcohol
Propylene glycol
Simeticone
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years.
Capsules that have been opened and mixed with food or liquids, should be consumed within 30 minutes (see section 6.6).
6.4 Special precautions for storage
Store below 25°C.
Store in the original package in order to protect from light.
For storage conditions after mixing the medicinal product, see section 6.3.
6.5 Nature and contents of container
High-density polyethylene (HDPE) bottles with a polypropylene child-resistant cap.
Pack-size of 84 (2 bottles of 42) hard capsules.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
SIGA Technologies Netherlands B.V.
Prinsenhil 29,
Breda 4825 AX,
The Netherlands
8 MARKETING AUTHORISATION NUMBER(S)
PLGB 56708/0001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
30/06/2022
10 DATE OF REVISION OF THE TEXT
18/06/2026