Summary Basis of Decision for Xofluza
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 Xofluza is located below.
Recent Activity for Xofluza
SBDs written for eligible drugs 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. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
The following table describes post-authorization activity for Xofluza, a product which contains the medicinal ingredient baloxavir marboxil. 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 that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Updated: 2023-08-29
Drug Identification Number (DIN):
- DIN 02496364 – 20 mg baloxavir marboxil, tablet, oral administration
- DIN 02496372 – 40 mg baloxavir marboxil, tablet, oral administration
- DIN 02524163 – 80 mg baloxavir marboxil, tablet, oral administration
Post-Authorization Activity Table (PAAT)
Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
---|---|---|---|
SNDS # 267547 | 2022-09-01 | Issued NOC 2023-03-27 | Submission filed as a Level I – Supplement for the addition of a drug product manufacturing site and change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued. |
SNDS # 266521 | 2022-07-28 | Issued NOC 2023-02-27 | Submission filed as a Level I – Supplement for the addition of a manufacturing site involving starting material, intermediates, and drug substance. The submission was reviewed and considered acceptable, and an NOC was issued. |
SNDS # 253245 | 2021-05-31 | Issued NOC 2022-01-13 | Submission filed as a Level I – Supplement for the addition of a new strength (80 mg). The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02524163) was issued for the new presentation. A Regulatory Decision Summary was published. |
SNDS # 253190 | 2021-05-28 | Issued NOC 2021-09-02 | Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Drug Interactions and Microbiology sections of the PM. An NOC was issued. |
SNDS # 244963 | 2020-10-06 | Issued NOC 2021-05-06 | Submission filed as a Level I – Supplement for the addition of a drug product manufacturing facility and a primary and secondary packaging site. The submission was reviewed and considered acceptable, and an NOC was issued. |
NDS # 227361 | 2019-04-30 | Issued NOC 2020-02-19 | NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Xofluza
Date SBD issued: 2020-05-05
The following information relates to the New Drug Submission for Xofluza.
Baloxavir marboxil
Drug Identification Number (DIN):
- DIN 02496364 - 20 mg tablet, oral administration
- DIN 02496372 - 40 mg tablet, oral administration
Hoffmann-La Roche Ltd.
New Drug Submission Control Number: 227361
On February 19, 2020, Health Canada issued a Notice of Compliance to Hoffmann-La Roche Limited for the drug product Xofluza.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-harm-uncertainty profile of Xofluza is favourable for the treatment of uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours and who are otherwise healthy or at high risk of developing influenza complications.
A recommendation was included reminding health professionals to consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use Xofluza.
Health professionals were also informed that efficacy is based on significant reduction in the time to alleviation or improvement of influenza symptoms with Xofluza compared with placebo.
1 What was approved?
Xofluza, an antiviral, was authorized for the treatment of uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours and who are otherwise healthy or at high risk of developing influenza complications.
A recommendation was included reminding health professionals to consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use Xofluza.
Efficacy is based on significant reduction in the time to alleviation or improvement of influenza symptoms with Xofluza compared with placebo.
The safety and efficacy of Xofluza have been established in pediatric patients with acute uncomplicated influenza who are at least 12 years of age and who weigh at least 40 kg. Health Canada has therefore authorized an indication for pediatric use in patients meeting these criteria. However, the safety and efficacy of Xofluza in pediatric patients with acute uncomplicated influenza who are less than 12 years of age or who weigh less than 40 kg have not been established.
Evidence from one pivotal clinical study in patients with influenza at high risk of developing complications suggests that use in geriatric patients, at least 65 years of age and weighing at least 40 kg, is not associated with relevant differences in safety or effectiveness compared with patients less than 65 years of age. The safety and efficacy of Xofluza in geriatric patients with acute uncomplicated influenza who weigh less than 40 kg has not been established.
Xofluza 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.
Xofluza was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Xofluza (20 mg and 40 mg baloxavir marboxil) is presented as tablets. In addition to the medicinal ingredient, the tablets contain croscarmellose sodium, lactose monohydrate, povidone, microcrystalline cellulose, sodium stearyl fumarate, hypromellose, talc, and titanium dioxide.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Xofluza Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Xofluza approved?
Health Canada considers that the benefit-harm-uncertainty profile of Xofluza is favourable for the treatment of uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours and who are otherwise healthy or at high risk of developing influenza complications.
A recommendation was included reminding health professionals to consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use Xofluza.
Efficacy is based on significant reduction in the time to alleviation or improvement of influenza symptoms with Xofluza compared with placebo.
Influenza is an acute, febrile respiratory illness, primarily caused by the influenza virus types A and B. In an average influenza season, an estimated 10-20% of the Canadian population becomes infected with influenza, which causes approximately 12,200 hospitalizations and 3,500 deaths annually.
Management of influenza remains a significant public health challenge due to the annual antigenic variation of influenza strains, the highly contagious nature of the disease, and increased susceptibility to severe complications among vulnerable subpopulations. Typically, symptomatic disease begins 48 hours after exposure and most patients recover in seven to ten days. However, complications related to influenza can lead to severe illnesses including primary viral pneumonia, bacterial superinfection, and decompensation of pre-existing medical conditions.
Annual vaccination is an important component of prevention and control. Other drugs currently used to treat influenza include the neuraminidase inhibitors (NAIs) oseltamivir and zanamivir. Approval for the NAIs was based on studies conducted in the outpatient setting, and mainly with otherwise healthy patients. Resistance to NAIs has been observed.
Baloxavir marboxil, the medicinal ingredient in Xofluza, is a prodrug with a novel mechanism of action. It is converted to baloxavir, the active metabolite, through hydrolysis. Baloxavir selectively inhibits cap-dependent endonuclease (CEN), an enzyme specific to the influenza virus, which is a component of the viral ribonucleic acid (RNA) polymerase complex. This inhibits transcription of influenza virus messenger RNA, thereby preventing viral replication.
The clinical efficacy of Xofluza was evaluated primarily in two pivotal Phase III studies, the first conducted in otherwise healthy patients (CAPSTONE-1) and the second conducted in patients at high risk for developing complications related to influenza infection (CAPSTONE-2). In each of these studies, patients were given a single oral dose of Xofluza within 48 hours of the onset of symptoms. The dose administered to each patient was dependent on body weight.
Statistically significant improvements were observed with respect to the primary efficacy endpoints in both pivotal studies. In CAPSTONE-1, the primary endpoint was the median time to alleviation of influenza symptoms (TTAS). The TTAS endpoint has been commonly used as a measure of the efficacy of anti-influenza virus drugs, with a reduction of 24 hours accepted as a clinically meaningful benefit for the approved NAIs. In CAPSTONE-2, the primary endpoint was the median time to improvement of influenza symptoms (TTIS).
A supportive Phase II study, Study 1518T0821, was conducted for dose-finding purposes and to demonstrate proof-of-concept. Patients enrolled in this study had uncomplicated influenza infection, and were otherwise healthy. The outcomes of this study were supportive of those from the pivotal study, CAPSTONE-1.
Overall, Xofluza was determined to be effective against influenza viruses A and B based on the clinical data. Treatment-emergent mutations have been identified in influenza virus isolates from the clinical studies, which have been associated with reduced susceptibility to the active metabolite, baloxavir. The fitness of these mutations remains unclear. Potential risks were mitigated through the communication of available results pertinent to resistance monitoring in the Xofluza Product Monograph. A recommendation was issued to health professionals to consider the available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use Xofluza.
A Risk Management Plan (RMP) for Xofluza was submitted by Hoffmann-La Roche Limited 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.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Xofluza Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Xofluza was accepted.
Xofluza has an acceptable safety profile based on the non-clinical and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Xofluza Product Monograph to address the identified safety concerns.
This 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. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Xofluza?
The New Drug Submission (NDS) for Xofluza was reviewed as part of the New Chemical Entities Work Sharing Trial (NCEWST), a work-sharing initiative between Canada, Australia, Singapore, and Switzerland. This partnership aims to promote collaboration between regulatory agencies, optimize the use of resources, reduce duplication, and enhance each agency's ability to ensure consumers have timely access to safe, effective, and high-quality therapeutic products.
This submission was simultaneously filed with Health Canada, Australia's Therapeutic Goods Administration (TGA), and Swissmedic, Switzerland's regulatory agency for medical products. The review was jointly conducted. Health Canada completed the quality review of Xofluza. The TGA completed the clinical review, and Swissmedic completed the non-clinical review. Although the review of the submission was collaborative, each jurisdiction made their regulatory decision independently of the others.
Submission Milestones: Xofluza
Submission Milestone | Date |
---|---|
Pre-submission meeting: | 2019-02-19 |
Submission filed: | 2019-04-30 |
Screening | |
Screening Acceptance Letter issued: | 2019-05-31 |
Review | |
Review of Risk Management Plan complete: | 2020-02-14 |
Quality Evaluation complete: | 2020-02-19 |
Clinical/Medical Evaluation complete: | 2020-02-19 |
Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2020-02-19 |
Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2020-02-19 |
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
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
The clinical review of Xofluza was completed by Australia's Therapeutic Goods Administration (TGA) as part of a work-sharing initiative with Canada, Switzerland, and Singapore. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.
Clinical Pharmacology
Baloxavir marboxil (the medicinal ingredient in Xofluza) is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts anti-influenza virus activity. Baloxavir acts on the cap-dependent endonuclease (CEN), an influenza virus-specific enzyme, which is a component of the viral ribonucleic acid (RNA) polymerase complex. This inhibits the transcription of influenza virus genomes, thereby inhibiting replication of the influenza virus.
After oral administration of a single 40 mg dose, baloxavir marboxil is extensively converted to its active metabolite, baloxavir. In a human mass balance study, baloxavir accounted for 82.2% of the total exposure (as measured by the area under the concentration-time curve [AUC]) to baloxavir marboxil and its metabolites.
The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Xofluza have been well characterized in influenza patients and in healthy volunteers. In the pivotal studies, no differences were observed between otherwise healthy influenza patients (CAPSTONE-1) and those at high risk of developing complications (CAPSTONE-2) with respect to the pharmacokinetic parameters examined.
Body weight and race were identified as covariates in the oral clearance (CL/F) of baloxavir through a population pharmacokinetic analysis. Dose adjustment is required based on body weight, because exposure to baloxavir decreases as body weight increases, and the observed effects were significant. A single 40 mg dose is recommended for patients weighing 40 kg to <80 kg, and a single 80 mg dose is recommended for patients weighing ≥80 kg. Additionally, exposure to baloxavir was lower in non-Asian patients than in Asian patients. However, this difference was not considered clinically significant when the recommended dose was administered to patients.
At twice the expected exposure from recommended dosing, Xofluza did not prolong the corrected QT (QTc) interval in healthy subjects.
No dose adjustment is required due to mild or moderate hepatic impairment, based on the results of a clinical study in this patient population. However, the pharmacokinetics of Xofluza in patients with severe hepatic impairment has not been evaluated.
Renal excretion is a minor pathway for the elimination of both baloxavir marboxil and its active metabolite, baloxavir. Although there were no studies dedicated to examining the effects of renal impairment on the pharmacokinetics of Xofluza, some insights were obtained through the population pharmacokinetic analysis. The results of the population pharmacokinetic analysis did not reveal any clinically meaningful effect of renal function on the pharmacokinetics of baloxavir in patients with a creatinine clearance (CrCl) of 50 ml/min and above. Based on this information, no dose adjustment is required in patients with renal impairment.
The potential of both baloxavir marboxil and baloxavir for drug-drug interactions was appropriately characterized in vitro and in vivo. No clinically meaningful drug-drug interactions were identified with a strong cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) inhibitor; the substrates of CYP 3A4, P-gp, and breast cancer resistance protein (BCRP), or the neuraminidase inhibitor oseltamivir. However, non-clinical data indicate that products containing polyvalent cations may decrease the plasma concentration of baloxavir. Therefore, Xofluza should not be taken with polyvalent cation-containing laxatives or antacids, or oral supplements containing iron, zinc, selenium, calcium, or magnesium. Additionally, Xofluza should not be taken with dairy products.
For further details, please refer to the Xofluza Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Xofluza was evaluated in otherwise healthy patients as well as in patients at high risk for developing complications related to influenza infection. The studies described were all randomized, double-blind, and placebo-controlled.
The pivotal studies (CAPSTONE-1 and CAPSTONE-2) evaluated the safety and efficacy of a single oral dose of Xofluza administered within 48 hours of the onset of symptoms, without regard to meals. The dose administered to each patient was dependent on body weight. Patients weighing 40 kg to <80 kg were given a single 40 mg dose, and patients weighing ≥80 kg were given a single 80 mg dose. Both pivotal studies also included a third treatment group (in addition to the groups receiving Xofluza or a placebo) in which patients received a 75 mg dose of oseltamivir, an active comparator, twice daily for five days.
CAPSTONE-1 (Pivotal Phase III study in otherwise healthy patients)
CAPSTONE-1 (Study 1601T0831) was a pivotal Phase III study in patients 12-64 years of age. Patients enrolled in this study had uncomplicated influenza infection, and were otherwise healthy.
The primary efficacy endpoint of this study was the median time to alleviation of influenza symptoms (TTAS). The TTAS endpoint has been commonly used as a measure of the efficacy of anti-influenza virus drugs, with a reduction of 24 hours accepted as a clinically meaningful benefit for the approved NAIs.
A statistically significant improvement was observed in the median TTAS in patients who received Xofluza (number of patients [n] = 455) compared to those who received the placebo (n = 230). In the intent-to-treat infected (ITTI) population, the median TTAS was 54 hours in patients who received Xofluza (95% confidence interval [CI]: 50, 59) and 80 hours in patients who received the placebo (95% CI: 73, 87; p<0.0001).
The primary endpoint was further supported by a faster resolution of fever in patients treated with Xofluza compared to those who received the placebo, which was considered clinically relevant.
Study 1518T0821 (Supportive Phase II study in otherwise healthy patients)
Study 1518T0821 was a supportive proof-of-concept and dose-finding Phase II study conducted in Japanese adults. Patients enrolled in this study had uncomplicated influenza infection, and were otherwise healthy.
The results from this supportive study were supportive of the results from the pivotal study, CAPSTONE-1. The median TTAS was 50 hours in patients who were treated with 40 mg Xofluza (95% CI: 45, 64), and 78 hours in patients who received the placebo (95% CI: 68, 89).
CAPSTONE-2 (Pivotal Phase III study in high-risk patients)
In the high-risk patient population, evidence of clinical efficacy came primarily from the results of CAPSTONE-2 (Study 1602T0832); a pivotal, randomized, double-blind and placebo-controlled Phase III study. This study enrolled patients 12 years of age and older with uncomplicated influenza infection, who were at high risk for developing influenza-related complications.
The primary efficacy endpoint of this study was the median time to improvement of influenza symptoms (TTIS), a novel efficacy endpoint which includes both the alleviation of new symptoms and the improvement of any pre-existing symptoms that had worsened in patients with influenza due to the infection. A statistically significant improvement was observed in the median TTIS in patients who received Xofluza (n = 385) compared to those who received the placebo (n = 385).
In the intent-to-treat infected (ITTI) population, the median TTIS was 73 hours in patients who received Xofluza (95% CI: 68, 85) and 102 hours in patients who received the placebo (95% CI: 93, 113; p<0.0001). The primary endpoint was supported by a faster resolution of fever, as well as a reduction in the overall incidence of influenza-related complications. However, the overall incidence of complications was low, and the lower overall incidence in patients who received Xofluza was mainly driven by lower incidences of bronchitis and sinusitis. There were no significant treatment differences for the other complications of death, hospitalization, otitis media and pneumonia.
Overall Efficacy Analysis
Xofluza was determined to be effective against influenza viruses A and B based on the clinical data. There is no clinical evidence for efficacy of Xofluza in any illness caused by agents other than influenza viruses A and B.
Influenza virus types and subtypes characteristically vary from one season to the next, and the efficacy of anti-influenza virus drugs may vary based on the strain. In CAPSTONE-1 subgroup analyses, efficacy was observed for Xofluza compared with placebo for type A/H3 virus, detected in the vast majority of patients, but not for type B virus, detected in less than 10% of patients. In CAPSTONE-2, in which type A/H3 (predominant strain) and type B viruses were more evenly represented, the median TTIS was observed to be shorter with Xofluza compared with placebo in both subgroups.
The potential for the emergence and dissemination of viral resistance generally depends on both the incidence of treatment-emergent resistance mutations and the ability of the resistant strains to transmit resistance. Treatment-emergent mutations have been identified in influenza virus isolates from the clinical studies, which have been associated with reduced susceptibility to the active metabolite, baloxavir. The fitness of these mutations remains unclear. Potential risks were mitigated through the communication of available results pertinent to resistance monitoring in the Xofluza Product Monograph. Additionally, a recommendation was included reminding health professionals to consider the available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use Xofluza.
In each of the pivotal studies, no statistically significant differences were identified (in a secondary analysis) between Xofluza and oseltamivir with respect to the primary endpoints. However, the pivotal studies have not demonstrated that Xofluza and oseltamivir are equivalent to one another.
While significant reductions in the median time to cessation of viral shedding by virus titer and by reverse transcription polymerase chain reaction were observed, reduced transmission of influenza virus, a clinically relevant measure of efficacy, has not been established.
Efficacy has not been established in the following settings:
- Pediatric patients with acute uncomplicated influenza who are <12 years of age or who weigh <40 kg;
- Geriatric patients with acute uncomplicated influenza who weigh <40 kg;
- Patients who begin treatment after 48 hours of symptoms;
- For the treatment of complicated influenza (i.e. patients requiring hospitalization); or
- For the prevention of influenza.
Indication
Sponsor's proposed indication | Health Canada-approved indication |
Xofluza (baloxavir marboxil) is indicated for:
|
Xofluza (baloxavir marboxil tablets) is indicated for the treatment of uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours and who are otherwise healthy or at high risk of developing influenza complications. Health professionals should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use Xofluza. Efficacy is based on significant reduction in the time to alleviation or improvement of influenza symptoms with Xofluza compared with placebo. |
Patients with certain conditions associated with high risk for the development of influenza-related complications were excluded from CAPSTONE-2 in order to prevent exposure in utero or unnecessary potential risk to patients from receiving the placebo rather than an active antiviral drug. This rationale is acceptable in the context of a clinical trial. Additionally, the size of some high-risk groups was too small for statistical comparisons. However, some patients meeting the exclusion criteria are also considered to be among those at highest risk for developing influenza-related complications. It was determined that generalizing the available data from the study in high-risk patients to the wider high-risk population is reasonable. The authorized indication of Xofluza is therefore broad enough to encompass all high-risk conditions.
For more information, refer to the Xofluza Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The overall safety profile of Xofluza was based on data from 2,109 patients who had been exposed to at least one dose of Xofluza in the completed Phase I, II, and III studies. This patient group included 1,640 adults and adolescents (12 years of age and older) with acute uncomplicated influenza who received Xofluza in CAPSTONE-1, CAPSTONE-2, or Study 1518T0821, which are described in detail in the Clinical Efficacy section. Approximately 81% of patients were 18-64 years of age, 13% were 65 years of age and older, and 6% were adolescents 12 to 17 years of age. All patients enrolled in the pivotal studies (CAPSTONE-1 and CAPSTONE-2) weighed 40 kg or more, and the vast majority of patients in the supportive study (1518T0821) weighed 45 kg or more.
Xofluza was generally well-tolerated, and the safety profile was similar in high-risk and otherwise healthy patients. There were no apparent safety concerns in either group of patients, and no relevant differences in safety were observed based on age.
The incidence of treatment-related adverse events in patients treated with Xofluza was consistent between the pooled studies in otherwise healthy patients (CAPSTONE-1 and Study 1518T0821) and the study in patients at high risk of developing influenza-related complications (CAPSTONE-2), 5% and 6%, respectively. The incidence of treatment-related adverse events was also consistent between patients who were treated with Xofluza (5% and 6%, respectively) and patients who received placebo in the pooled otherwise healthy studies and the high risk study (5% and 8%, respectively).
The incidence of serious adverse events in patients treated with Xofluza was low across CAPSTONE-1, CAPSTONE-2, and Study 1518T0821 (0.7% in total). No treatment-related serious adverse events were identified, and no fatalities occurred among Xofluza-treated patients across all three studies.
Overdoses with Xofluza have been reported from clinical trials and in the post-market setting. Adverse events of vomiting, some of which may be clinically significant, have been reported following overdoses of Xofluza. However, no adverse events were reported following overdose in the majority of cases.
A safety signal was identified during the review of the Xofluza submission related to prescribing and dispensing errors associated with different dose packs. This led to medication errors, including overdosage and underdosage. This risk was mitigated by limiting the number of packaging configurations and clearly communicating the dosing instructions and available packaging configurations in the Xofluza Product Monograph.
Influenza infection is associated with neuropsychiatric adverse events (NPAEs), with a relative risk of NPAEs approximately twice that of the general population within 30 days of infection. Post-marketing data for NPAEs in Xofluza-treated patients appear consistent with the complications of influenza, and the incidence of NPAEs in the three clinical studies was generally similar across treatment groups, including the placebo group. Baloxavir marboxil does not cross the blood-brain barrier, which limits the potential for NPAEs. Additionally, it is a substrate for the drug transporter P-glycoprotein (expressed at the blood-brain barrier), which would further restrict brain penetration.
A Serious Warnings and Precautions box is included in the Xofluza Product Monograph to highlight the risk of clinically significant hypersensitivity reactions. Xofluza has been associated with Type I immediate hypersensitivity reactions, based on the review of post-marketing data. Clinically significant hypersensitivity reactions to Xofluza have included anaphylaxis, urticaria, and angioedema. There were some reports of erythema multiforme (EM) and one case of acute generalized exanthematous pustulosis (AGEP). However, these reports were considered to be actually more consistent with an acute allergic-like reaction characterized by urticaria and rash, and these events have been communicated in the Xofluza Product Monograph.
A warning was included in the Xofluza Product Monograph to recommend that health professionals should be alert to the potential for secondary bacterial infections and treat with antibiotics as appropriate. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza.
Events of bloody diarrhea, melena, and ischemic colitis were reported during post-marketing use of Xofluza. While the evidence reviewed to date does not provide compelling evidence of an association between Xofluza and these gastrointestinal events, the establishment of causality is not a pre-requisite to inclusion within Post-Market Adverse Reactions. The communication of these events was considered a risk mitigation measure.
For more information, refer to the Xofluza Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical review of Xofluza was completed by the Swiss regulator Swissmedic as part of a work-sharing initiative with Canada, Australia, and Singapore. The non-clinical package complied with International Council for Harmonisation (ICH) guidelines. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.
Baloxavir marboxil, the medicinal ingredient in Xofluza, is a prodrug which is converted by hydrolysis to the active metabolite, baloxavir. In vitro data indicate that baloxavir inhibits the cap-dependent endonuclease (CEN), an influenza virus-specific enzyme in the viral RNA polymerase complex. The inhibition of CEN by baloxavir prevents transcription of influenza virus genomes, thereby inhibiting replication of the influenza virus.
Overall, baloxavir was found to be more potent against strains of influenza A than strains of influenza B. No evidence of cross-resistance was found with strains resistant to neuraminidase inhibitors. Additionally, in vitro assays did not identify any off-target pharmacodynamic effects of baloxavir.
The non-clinical toxicology evaluation of baloxavir marboxil also included repeat-dose studies in rats and cynomolgus monkeys, reproductive developmental studies in rats and rabbits, juvenile toxicity studies in rats, and in vitro and in vivo genotoxicity studies. Signs of toxicity were identified in the gastrointestinal tract, liver, and thyroid in rats and monkeys. The effects observed in these organs are considered to be of low clinical risk, as they occurred after repeat doses of baloxavir marboxil, whereas Xofluza is administered as a single dose. Additionally, these effects were generally of low or moderate severity and reversed after cessation of treatment with baloxavir marboxil.
Maternal toxicity was observed when baloxavir marboxil was administered to pregnant rabbits at doses resulting in approximately six times the expected human exposure based on the recommended dose. This resulted in miscarriages as well as an increase in the incidence rates of minor skeletal abnormalities in fetuses. Based on observations from non-clinical studies, Xofluza should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.
No carcinogenicity studies were conducted with baloxavir marboxil. This is considered acceptable because Xofluza is administered as a single dose, and the non-clinical evidence did not indicate any carcinogenicity risk.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Xofluza Product Monograph. Considering the intended use of Xofluza, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Xofluza Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The quality review of Xofluza was completed by Health Canada as part of a work-sharing initiative with Australia, Switzerland, and Singapore. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.
The Chemistry and Manufacturing information submitted for Xofluza 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 36 months is acceptable when the drug product is stored at room temperature (15ºC to 30ºC) in its original packaging, in order to protect from moisture. Xofluza should not be used after the expiry date shown on the package. Disposal of unused medicine or waste material should be carried out according to local requirements, and should not be disposed of via wastewater or with household waste.
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
Lactose monohydrate, an excipient in Xofluza capsules, is of animal origin. Lactose monohydrate used in the production of Xofluza is sourced from healthy animals, in the same conditions as milk collected for human consumption. The sponsor has provided documentation confirming that it is not considered a risk for transmitting bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE).
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Product name | DIN | Company name | Active ingredient(s) & strength |
---|---|---|---|
XOFLUZA | 02496364 | HOFFMANN-LA ROCHE LIMITED | BALOXAVIR MARBOXIL 20 MG |
XOFLUZA | 02524163 | HOFFMANN-LA ROCHE LIMITED | BALOXAVIR MARBOXIL 80 MG |
XOFLUZA | 02496372 | HOFFMANN-LA ROCHE LIMITED | BALOXAVIR MARBOXIL 40 MG |