Summary Basis of Decision for Tpoxx
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Tpoxx is located below.
Recent Activity for Tpoxx
The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.
The following table describes post-authorization activity for Tpoxx, a product which contains the medicinal ingredient tecovirimat (supplied as tecovirimat monohydrate). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).
For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.
Updated: 2025-09-18
Drug Identification Number (DIN):
DIN 02522772 - 200 mg tecovirimat, capsule, oral administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
Extraordinary Use SNDS # 289138 |
2024-07-31 |
Issued NOC 2025-07-17 |
Submission filed as a Level I – Supplement to update the PM with new safety information from the post-market clinical study SIGA-246-023. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Drug Interactions section of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued. |
|
Extraordinary Use SNDS # 269158 |
2022-11-02 |
Issued NOC 2023-10-18 |
Submission filed as a Level I – Supplement to change the dosing regimen. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration and Clinical Pharmacology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued. |
|
Drug product (DIN 02522772) market notification (restricted sale) |
Not applicable |
Date of first sale 2022-04-07 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
Extraordinary Use NDS # 247561 |
2020-12-22 |
Issued NOC 2021-11-29 |
NOC issued for Extraordinary Use New Drug Submission. |
Summary Basis of Decision (SBD) for Tpoxx
Date SBD issued: 2022-02-21
The following information relates to the New Drug Submission for Tpoxx.
Tecovirimat (supplied as tecovirimat monohydrate)
Drug Identification Number (DIN):
- DIN 02522772 - 200 mg tecovirimat, capsule, oral administration
SIGA Technologies, Inc.
New Drug Submission Control Number: 247561
On November 29, 2021, Health Canada issued a Notice of Compliance to SIGA Technologies, Inc. for the drug product Tpoxx.
Health Canada recognizes that there are extraordinary circumstances in which sponsors cannot reasonably provide substantial evidence demonstrating the efficacy and safety of a therapeutic product in humans as there are logistical or ethical challenges in conducting the appropriate human clinical trials. The Extraordinary Use New Drugs regulatory pathway was developed to authorize these drugs based on quality, non-clinical and limited clinical information (see Guidance Document - Submission and Information Requirements for Extraordinary Use New Drugs [EUNDs]). Tpoxx was authorized using this pathway.
Based on Health Canada's review, the benefit-harm-uncertainty profile of Tpoxx is favourable for the treatment of human smallpox disease in adults and pediatric patients weighing at least 13 kg.
The indication is accompanied by the important caveat statement that the sale of this extraordinary use new drug was authorized based on limited clinical testing in humans.
1 What was approved?
Tpoxx, an antiviral agent, was authorized for the treatment of human smallpox disease in adults and pediatric patients weighing at least 13 kg.
The indication is accompanied by the important caveat statement that the sale of this extraordinary use new drug was authorized based on limited clinical testing in humans.
Health Canada has authorized an extraordinary use indication for pediatric patients (<18 years of age) weighing ≥13 kg. No clinical studies in pediatric patients are available. Pharmacokinetic simulation was used to derive the dosing regimens of Tpoxx in pediatric patients that are predicted to be comparable to adult exposure from the recommended dose of Tpoxx. No data are available to Health Canada with respect to pediatric patients weighing <13 kg. Therefore, Health Canada has not authorized an indication for use in this population.
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.
Tpoxx (200 mg tecovirimat, supplied as tecovirimat monohydrate) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains ammonium hydroxide, colloidal silicon dioxide, croscarmellose sodium, FD&C Blue No. 1, FD&C Red No. 3, FD&C Yellow No. 6, gelatin, hydroxypropyl methylcellulose, isopropyl alcohol, lactose monohydrate, magnesium stearate, microcrystalline cellulose, n-butyl alcohol, propylene glycol, shellac, simethicone, sodium lauryl sulfate, and titanium dioxide.
The use of Tpoxx is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Tpoxx Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
2 Why was Tpoxx approved?
Health Canada considers that the benefit-harm-uncertainty profile of Tpoxx is favourable for the treatment of human smallpox disease in adults and pediatric patients weighing at least 13 kg.
The indication is accompanied by the important caveat statement that the sale of this extraordinary use new drug was authorized based on limited clinical testing in humans.
Smallpox, which is caused by the variola virus, is one of the most important human pathogens in history. Smallpox is a highly communicable disease and carries exceptionally high morbidity. Mortality rates range from 1% for variola minor to 30% for variola major. Aside from early vaccination, no therapies are currently available that can alter the outcome of disease or potentially prevent disease in a population that has been exposed.
Tpoxx (tecovirimat) is a novel therapeutic agent developed for the treatment of smallpox disease. Tecovirimat targets and inhibits the activity of the orthopoxvirus peripheral membrane protein VP37, which is encoded by a highly conserved gene in all members of the orthopoxvirus genus. Tecovirimat blocks the interaction of VP37 with two proteins: the cellular rat sarcoma virus (Ras)-associated binding (Rab) 9 guanosine triphosphate hydrolase (GTPase) and the 47 kDa tail-interacting protein (TIP47). The interaction of tecovirimat with the Rab9 GTPase and TIP47 proteins prevents the formation of egress competent enveloped virions necessary for cell-to-cell and long-range dissemination of virus.
For ethical and logistical reasons, it is not possible to conduct well-controlled clinical studies for treatments for smallpox. Therefore, Health Canada reviewed and authorized the sale of Tpoxx through the Extraordinary Use New Drugs (EUNDs) pathway, which was developed to allow a mechanism for the authorization of these drugs based on non-clinical and limited clinical information. The efficacy of Tpoxx was evaluated in cynomolgus monkeys and New Zealand White rabbits. Safety was evaluated in clinical studies in healthy human volunteers, as well as in non-clinical studies.
In vivo efficacy studies were conducted in cynomolgus macaques infected with monkeypox virus and New Zealand White rabbits infected with rabbitpox virus. The primary endpoint for these studies was survival. Tecovirimat was administered to the animals once daily for 14 days, and the timing of dosing was selected in order to evaluate the efficacy of treatment when it is initiated after the animals have developed clinical signs of disease. Statistically significant improvements in survival were observed in animals treated with tecovirimat for 14 days relative to placebo, except when given to cynomolgus macaques starting at Day 6 post-challenge (versus starting treatment on Day 4 or 5).
The safety of Tpoxx was evaluated in a Phase III clinical study in which 359 healthy adult subjects were given a 600 mg dose of Tpoxx twice daily for 14 days. The majority of these subjects (336 out of 359) received at least 23 of the 28 doses. The most frequently reported adverse reactions were headache and nausea. Adverse reactions that occurred in at least 1% of subjects that received at least one 600 mg dose of Tpoxx were headache (12%), nausea (5%), abdominal pain (2%), and vomiting (2%). In subjects that received the placebo, these adverse events were reported at frequencies of 8%, 4%, 1%, and 0%, respectively. Six subjects (2%) receiving Tpoxx discontinued due to adverse reactions.
As part of the marketing authorization for Tpoxx, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. The sponsor is expected to test certain impurities for mutagenicity in accordance with International Council for Harmonisation guidelines. Additionally, the sponsor will evaluate the efficacy and safety of tecovirimat in humans by conducting a Phase IV observational study which will start once a first case of smallpox is noted, and continue enrolment for 5 years or until 100 patients have completed the study, whichever comes first.
A Risk Management Plan (RMP) for Tpoxx was submitted by SIGA Technologies, Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
As indicated by Health Canada’s guidance document for Extraordinary Use New Drugs (EUNDs), Tpoxx is only available through a restricted distribution system under which only authorized entities such as the federal, provincial, territorial, and municipal government(s) have access to and can dispense the product.
The submitted inner and outer labels, package insert, and Patient Medication Information section of the Tpoxx Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
The sponsor submitted a brand name assessment that included testing for look-alike sound-alike attributes. Upon review, the proposed name Tpoxx was accepted.
Overall, the therapeutic benefit of Tpoxx, as inferred from the submitted animal efficacy studies, outweighs the known and expected risks of the product. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Tpoxx Product Monograph to address the identified safety concerns.
This Extraordinary Use New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. The sale of Tpoxx, as an authorized extraordinary use new drug, is restricted to authorized entities such as the federal, provincial, territorial, and municipal government(s).
For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Tpoxx?
The Canadian regulatory decision on the review of Tpoxx was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was consulted for relevant supplementary information.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Tpoxx
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2020-03-20 |
| New Drug Submission filed | 2020-12-22 |
| Screening | |
| Screening Acceptance Letter issued | 2021-02-02 |
| Review | |
| Review of Risk Management Plan completed | 2021-11-15 |
| Non-clinical evaluation completed | 2021-11-19 |
| Quality evaluation completed | 2021-11-24 |
| Labelling review completed | 2021-11-25 |
| Clinical/medical evaluation completed | 2021-11-26 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate | 2021-11-29 |
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
Tecovirimat, the medicinal ingredient in Tpoxx, targets and inhibits the activity of the orthopoxvirus peripheral membrane protein VP37, which is encoded by a highly conserved gene in all members of the orthopoxvirus genus. Tecovirimat blocks the interaction of VP37 with two proteins: the cellular rat sarcoma virus (Ras)-associated binding (Rab) 9 guanosine triphosphate hydrolase (GTPase) and the 47 kDa tail-interacting protein (TIP47). The interaction of tecovirimat with the Rab9 GTPase and TIP47 proteins prevents the formation of egress competent enveloped virions necessary for cell-to-cell and long-range dissemination of virus.
Because the effectiveness of Tpoxx cannot be tested in humans, tecovirimat exposures achieved in healthy human subjects were compared to exposure levels observed in animal models of orthopoxvirus infection (nonhuman primates infected with monkeypox virus and rabbits infected with rabbitpox virus). Humans achieved greater systemic exposure of tecovirimat (as measured by the area under the plasma concentration-time curve [AUC], maximum plasma concentration [Cmax], and minimum plasma concentration [Cmin]) following doses of 600 mg administered twice daily, compared to the therapeutic exposures in animal models.
The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Tpoxx have been characterized in healthy adult subjects. Human pharmacokinetic data was obtained through a Phase III safety study conducted in healthy and fed adult subjects (18 to 72 years of age) who received 600 mg Tpoxx twice daily for 14 days.
Tecovirimat reaches Cmax 4 to 6 hours after administration. At concentrations of 0.03 to 50 μM, tecovirimat is 77.3% to 82.2% bound to human plasma proteins. A single 600 mg dose of radioactively labelled tecovirimat ([14C]-tecovirimat) was administered to healthy subjects and the observed concentrations of total radioactivity were lower in whole blood compared to plasma at all time points. Tecovirimat is metabolized by hydrolysis of the amide bond and by glucuronidation. Three metabolites were detected in plasma and found to be inactive. The renal pathway was the major route of excretion. Over the 192-hour post-dose period, approximately 73% of the radioactively labelled dose was recovered in the urine, mainly in a glucuronidated form of the drug and metabolites, with only 0.02% of the dose excreted as the unchanged drug. Approximately 23% of the dose was recovered in the feces, mainly as unchanged tecovirimat. The terminal half-life of the drug was 19.3 hours.
No clinically significant differences were observed in the pharmacokinetics of tecovirimat in dedicated studies conducted in subjects with mild, moderate, or severe hepatic or renal insufficiency. No dosage adjustments are required for individuals with these conditions, or for patients with end-stage renal disease requiring hemodialysis.
Food increased the absorption of tecovirimat. A 40% to 50% increase in absorption was observed when Tpoxx was administered with a full meal with a moderate or high fat content (containing approximately 25 g of fat), compared to administration in the fasted state. Based on this observation, all studies (non-clinical and clinical) were designed to administer the drug with food. This information has been included in the Tpoxx Product Monograph along with instructions to take the recommended dose within 30 minutes after a moderate or high fat content meal in order to ensure the proper absorption of tecovirimat.
For further details, please refer to the Tpoxx Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Health Canada recognizes that there are circumstances in which sponsors cannot reasonably provide substantial evidence demonstrating the efficacy and safety of a therapeutic product in humans as there are logistical or ethical challenges in conducting the appropriate human clinical trials. The Extraordinary Use New Drugs (EUNDs) submission pathway was developed to allow a mechanism for authorization of these products based on non-clinical and limited clinical information (see Guidance Document - Submission and Information Requirements for Extraordinary Use New Drugs [EUNDs]).
The efficacy of Tpoxx was evaluated in well-controlled non-clinical studies in cynomolgus macaques and New Zealand White rabbits infected with non-variola orthopoxviruses. The survival rates observed in the animal studies may not be predictive of survival rates in clinical practice. Clinical safety studies of Tpoxx have only been conducted in healthy adult subjects, and are described in the Clinical Safety section.
Indication
| Sponsor's proposed indication | Health Canada-approved indication |
| Tpoxx capsules are indicated for: Treatment of orthopoxvirus disease (smallpox, monkeypox, cowpox, and vaccinia complications) in adults 18 years of age and older and pediatric and adolescent patients weighing at least 13 kg. | Tpoxx (tecovirimat capsules) is indicated for the treatment of human smallpox disease in adults and pediatric patients weighing at least 13 kg. |
The approved indication specifies that Tpoxx is authorized for the treatment of human smallpox disease, rather than orthopoxvirus disease. No clinical studies are available in pediatric patients. The dosing regimen recommended for pediatric patients is based on pharmacokinetic simulation using data from healthy adult subjects, and is predicted to result in exposures comparable to those observed in adults.
For more information, refer to the Tpoxx Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Tpoxx was evaluated in a Phase III clinical study in healthy adult subjects between the ages of 18 and 79 years. Ten percent of the subjects were 65 years of age or older. In the treatment group, 359 subjects received a 600 mg dose of Tpoxx twice daily for 14 days. Of these 359 subjects, 336 received at least 23 of the 28 doses. There were 90 subjects in the placebo group.
The most frequently reported adverse reactions were headache and nausea. Adverse reactions that occurred in at least 1% of subjects who received at least one 600 mg dose of Tpoxx were headache (12%), nausea (5%), abdominal pain (2%), and vomiting (2%). In subjects who received the placebo, these adverse events were reported at frequencies of 8%, 4%, 1%, and 0%, respectively. Six subjects (2%) receiving Tpoxx discontinued due to adverse reactions.
For more information, refer to the Tpoxx Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Due to the severe and life-threatening nature of smallpox, it is not ethical or feasible to conduct human clinical studies to evaluate the efficacy of the drug. Evidence of the efficacy of Tpoxx comes from non-clinical studies. A safety study was conducted in healthy adult human volunteers, which is described in the Clinical Safety section.
In vivo efficacy studies were conducted in cynomolgus macaques infected with monkeypox virus and New Zealand White rabbits infected with rabbitpox virus. The primary endpoint for these studies was survival.
Cynomolgus macaques were lethally challenged intravenously with 5 × 107 plaque-forming units of monkeypox virus. A 10 mg/kg dose of tecovirimat was administered orally once daily for 14 days, starting at Day 4, 5, or 6 post-challenge. New Zealand White rabbits were lethally challenged intradermally with 1,000 plaque-forming units of rabbitpox virus. A 40 mg/kg dose of tecovirimat was administered orally once daily for 14 days, starting at Day 4 post-challenge. The timing of tecovirimat dosing in these studies was selected in order to evaluate the efficacy of treatment when it was initiated after the animals had developed clinical signs of disease. Survival was monitored for 3- to 6-times the mean time to death for untreated animals in each species. Statistically significant improvements in survival were observed in animals treated with tecovirimat for 14 days relative to placebo, except when given to cynomolgus macaques starting at Day 6 post-challenge.
Additional non-clinical studies conducted with tecovirimat included a repeat-dose toxicology study in dogs, in vitro and in vivo genotoxicity assays, and reproductive and developmental toxicology studies in mice and rabbits. The available toxicology data for Tpoxx comply with regulatory requirements and support the proposed indication.
In a repeat-dose toxicology study in dogs, convulsions (tonic and clonic) were observed in one animal within 6 hours of a single 300 mg/kg dose of tecovirimat. This dose is approximately 4-times higher than the highest observed exposure at the recommended human dose (RHD) (based on Cmax). Electroencephalography (EEG) findings in this animal were consistent with seizure activity during the observed convulsions. Tremors, which were considered non-adverse, were observed in 2 out of 3 animals and 1 out of 2 animals at 100 mg/kg/dose (similar to the highest observed human exposure at the RHD based on Cmax), in two separate studies. These findings were specific to dogs and were not observed in other animal species or humans.
Tecovirimat was not genotoxic in in vitro or in vivo assays, including a bacterial reverse mutation assay, a mammalian mutagenicity assay in mouse lymphoma cells, and an in vivo mouse micronucleus study. Carcinogenicity studies have not been conducted with tecovirimat. This is acceptable based on the lack of carcinogenicity signals in the general toxicology studies, the negative genotoxicity studies, and the short duration of Tpoxx treatment in humans.
A fertility and early embryonic development study was conducted in male and female mice. At doses approximately 24-times higher than human exposure at the RHD, decreased fertility associated with testicular toxicity was observed in male mice, and no effects were observed on female fertility.
No signs of embryo-fetal developmental toxicity were detected in mice or rabbits during the period of organogenesis. Tecovirimat exposures were up to 23-times higher than the human exposure at the RHD in mice, and less than human exposures at the RHD in rabbits. No toxicities were observed in a pre- and postnatal development study in mice at maternal tecovirimat exposures up to 24-times higher than the human exposure at the RHD. As Tpoxx has not been studied in pregnant women, it should not be used during pregnancy unless the benefits outweigh the risks. Additionally, when administered to lactating mice, tecovirimat was present in the milk. Although it is unknown whether Tpoxx is excreted in human milk, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Tpoxx. Any potential adverse effects on the breastfed child from Tpoxx or from the underlying maternal condition should also be considered.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Tpoxx Product Monograph. Considering the intended use of Tpoxx, there were no pharmacological or toxicological issues within this submission which precluded authorization of the product.
For more information, refer to the Tpoxx Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The chemistry and manufacturing information submitted for Tpoxx has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 84 months is acceptable when the drug product is stored at room temperature (15 ºC to 25 ºC).
Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).
All sites involved in production are compliant with good manufacturing practices.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.
Raw materials used in the manufacture of Tpoxx are controlled throughout their life cycle (from procurement to disposal) to ensure that potential sources of impurities or adventitious agents can be identified. The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.