Summary Basis of Decision for Zaxine

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:

Drug
 

 

Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Zaxine is located below.

Recent Activity for Zaxine

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.

Post-Authorization Activity Table (PAAT) for Zaxine

Updated:  2023-04-05

The following table describes post-authorization activity for Zaxine, a product which contains the medicinal ingredient rifaximin. 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 Guidance.

Drug Identification Number (DIN):

  • DIN 02410702 - 550 mg rifaximin, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 250527 2021-03-12 Cancellation Letter Received 2021-07-14 Submission filed as a Level I – Supplement to remove the package insert. The sponsor cancelled the submission administratively.
NC # 216973 2018-08-24 Issued NOL 2019-02-12 Submission filed as a Level II (120 day) Notifiable Change to update the PM. The changes were in response to Advisement Letters issued by Health Canada, dated 2017-10-19 and 2018-06-11, requesting revisions related to strategies to combat the development of resistance to prescription antimicrobial drugs. As a result of the NC, modifications were made to the Indications and Clinical Use, and Warnings and Precautions sections of the PM, and corresponding changes were made to Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 209230 2017-10-05 Issued NOC 2018-12-03 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. The submission was reviewed and considered acceptable, and an NOC was issued.
Drug product (DIN 02410702) market notification Not applicable Date of first sale:
2013-11-07		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 161256 2013-01-14 Issued NOC
2013-08-13		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Zaxine

AnchorAnchorDate SBD issued: 2013-10-31

The following information relates to the New Drug Submission for Zaxine.

Rifaximin, 550 mg, tablets, oral

Drug Identification Number (DIN): 02410702

Salix Pharmaceuticals Inc.

New Drug Submission Control Number: 161256

 

On August 13, 2013, Health Canada issued a Notice of Compliance to Salix Pharmaceuticals Inc. for the drug product Zaxine.

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/risk profile of Zaxine is favourable to support the indication for the reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥18 years of age.

1 What was approved?

Zaxine, an antibacterial agent, was authorized for the reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥18 years of age. The recommended dose of Zaxine is one 550 mg table taken orally two times a day without food.

In the trials of Zaxine for HE, 91% of the patients were using lactulose concomitantly. Differences in the treatment effect of those patients not using lactulose concomitantly could not be assessed.

Zaxine has not been studied in patients with MELD (Model for End-Stage Liver Disease) scores >25, and only 8.6% of patients in the controlled trial had MELD scores over 19.

Studies specifically designed to determine the dose in elderly patients have not been performed. In the controlled trial with Zaxine, 19.4% of subjects were aged 65 years and over, while 2.3% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

The safety and effectiveness of Zaxine in the prevention of overt hepatic encephalopathy (HE) recurrence has not been investigated in children and adolescents under 18 years of age.

Zaxine is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the ingredients in Zaxine.

Zaxine was approved for use under the conditions stated in the Zaxine Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Zaxine (500 mg, rifaximin) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains colloidal silicon dioxide, glyceryl distearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, red iron oxide, sodium starch glycolate, 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 Zaxine Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Zaxine approved?

Health Canada considers that the benefit/risk profile of Zaxine is favourable for the reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥18 years of age.

Hepatic encephalopathy (HE) is a serious, complex, episodic, neuropsychiatric syndrome that is often associated with advanced liver disease.

The definitive treatment of recurrent HE is liver transplantation. While waiting for transplant, the mainstay of prevention and treatment of HE is supportive care through identification and treatment of precipitating factors, and by the reduction in gut-derived nitrogenous products by use of lactulose and/or antibiotics.

Antibiotics appear to act indirectly by inhibiting the splitting of urea by deaminating bacteria in the gut, thus reducing the production of ammonia and other potential neurotoxins.

In this New Drug Submission (NDS), Zaxine (rifaximin) has been shown to be efficacious in decreasing the risk of overt hepatic encephalopathy recurrence in patients ≥18 years of age based on two Phase III studies, RFHE3001 (double-blind, placebo controlled 6 month pivotal study), and RFHE3002 (open-label extension study for up to 2 years). The efficacy and safety analyses from both studies demonstrated adequate support for the use of rifaximin in the prevention of HE recurrence. However, 91% of patients enrolled in these studies were taking lactulose concomitantly, and differences in the treatment effect of those patients not using lactulose concomitantly could not be assessed. In addition, the data supporting use in patients with severe hepatic impairment (Child-Pugh C) is limited and there are no data in patients with MELD scores >25.

The most common adverse events reported in both clinical studies included anemia, ascites, peripheral edema, pyrexia, muscle spasms, arthralgia, dizziness, depression, dyspnea, pruritus and rash, which were all seen at an incidence of ≥5% and at a higher frequency than in the placebo group.

Adverse events of special interest and seen in a higher proportion of rifaximin-treated subjects than in placebo-treated subjects in study RFHE3001 include Clostridium difficile (C. difficile) associated disease (CDAD).

Low systemic absorption of rifaximin has been noted in healthy individuals, but absorption is significantly increased in subjects with impaired hepatic function. In addition, there is the potential for increased systemic exposure to rifaximin in disease states in which intestinal barrier function or gut motility is altered.

A Risk Management Plan (RMP) for Zaxine was submitted by Salix Pharmaceuticals 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.

Overall, the therapeutic benefits observed in the two Phase III studies are positive and the benefits of Zaxine treatment are considered to outweigh the risks. Zaxine has an acceptable safety profile based on the non-clinical data and on the clinical studies. Risk management is achieved through appropriate labelling informing the prescriber of the potential safety issues observed with Zaxine treatment in the indicated patient population, in addition to an acceptable RMP. Appropriate warnings and precautions are in place in the Zaxine 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 Zaxine?

The drug submission for Zaxine was reviewed under the Priority Review Policy. Zaxine addressed an unmet medical need for an additional effective, safe, and well-tolerated therapy for HE.

Zaxine is a rifamycin derivative and is a new active substance within this class. Currently rifaximin may be obtained in Canada via the Special Access Program. Following a pre-New Drug Submission (NDS) meeting with Salix Pharmaceuticals Inc. on October 4, 2012, the sponsor submitted a priority review request for rifaximin (at that time the drug product name was Xifaxan) under control number 159822. The priority review request was granted on December 5, 2012.

Rifaximin is available on the market in other regulatory jurisdictions for indications including for prevention of HE recurrence. Rifaximin at a dose of 550 mg taken orally twice daily was approved by the United States Food and Drug Administeration (FDA) for reduction in risk of overt hepatic encephalopathy recurrence in patients 18 years of age and older. Rifaximin has also been approved by the Australian Therapeutic Goods Administration for the prevention of the recurrence of hepatic encephalopathy where other treatments have failed or are contraindicated. The HE indication was given a priority review in both jurisdictions. An application to the European Medicines Agency (EMEA) was submitted in September 2011 for the HE indication and approval was given in December 2012.

 

Submission Milestones: Zaxine

Submission Milestone Date
Pre-submission meeting: 2012-10-04
Request for priority status  
Filed: 2012-11-01
Approval issued by Director: 2012-12-05
Submission filed: 2013-01-14
Screening  
Screening Acceptance Letter issued: 2013-02-14
Review  
Quality Evaluation complete: 2013-07-03
Clinical Evaluation complete: 2013-08-12
Labelling Review complete: 2013-08-07
Notice of Compliance issued by Director General: 2013-08-13

The Canadian regulatory decision on the clinical review of Zaxine was based on a critical assessment of the Canadian data package. The foreign reviews completed by the United States Food and Drug Administration (FDA) and by the Therapeutics Goods Directorate of Australia (TGA) were used as an added reference.

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?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for Zaxine?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Zaxine is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Rafaximin, the active ingredient in Zaxine, is a non-systemic, broad-spectrum oral antibiotic agent that acts on the bacteria in the gastrointestinal tract by binding to the beta-subunit of bacterial deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase resulting in inhibition of bacterial RNA synthesis. Rifaximin has a broad antimicrobial spectrum against many Gram-positive, Gram-negative, aerobic and anaerobic bacteria, including ammonia-producing species. Rifaximin may inhibit the division of urea-deaminating bacteria, thereby reducing the production of ammonia and other compounds that are believed to be important in the pathogenesis of hepatic encephalopathy.

Following the administration of Zaxine 550 mg twice daily to patients with a history of HE, the systemic exposure to rifaximin was increased with increasing hepatic impairment. The area under the curve (AUC)tau was about 10-, 13-, and 20-fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively, compared to that in healthy patients. The highest systemic exposure to rifaximin was seen in patients with severe hepatic impairment.

Rifaximin is a substrate and a weak inducer of CYP3A4 in vitro. No clinically significant effects on the pharmacokinetics of CYP3A4 substrates were found in healthy subjects; however, the effect of rifaximin on CYP3A4 substrates in subjects with hepatic impairment has not been evaluated. The drug could have an effect on the pharmacokinetics of concomitant CYP3A4 substrates [for example (e.g.) warfarin, antiepileptics, antiarrhythmics] in hepatically impaired subjects who have elevated systemic levels of rifaximin.

An in vitro study suggested that rifaximin is a substrate of, and a weak inhibitor of P-glycoprotein (P-gp). Concomitant drugs that inhibit P-gp could significantly increase the systemic exposure of rifaximin. The potential to cause greater increases in hepatically impaired subjects has not been evaluated.

Rifaximin is almost exclusively excreted in feces. Systemically absorbed rifaximin is metabolized through hepatic (CYP3A4) and intestinal processes.

For further details, please refer to the Zaxine Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

For this New Drug Submission (NDS), evaluation of the efficacy of Zaxine for the prevention of hepatic encephalopathy (HE) recurrence in adult patients was assessed in two Phase III studies, RFHE3001 and RFHE3002.

Study RFHE3001 was a Phase III, multicenter, randomized, double-blind, placebo-controlled, six month study which evaluated the efficacy of Zaxine in adult patients in remission from overt HE associated with chronic hepatic cirrhosis. A total of 299 patients were randomized in a 1:1 ratio to receive either Zaxine 550 mg twice daily or placebo for up to 6 months. During the study, 140 patients received Zaxine and 159 patients received a placebo.

The primary endpoint for this study was the time to first breakthrough overt HE episode, defined as a marked, clinically significant deterioration in neurological function. Breakthrough overt HE episodes were measured by using the Conn score (assessment of mental status) and the asterixis grade (measure of neuromotor symptoms). Breakthrough overt HE was measured as an increase in the Conn score of Grade ≥2 [that is (i.e.) 0 or 1 to ≥2] or an increase in Conn and Asterixis score of one grade each for those patients who entered the study with a Conn score of 0. This evaluation was performed at Screening/Baseline, at Months 1 and 3, and every 3 months thereafter through end of treatment, at any unscheduled visits, and at follow-up. The tests were performed in the same location (i.e., study environment), and by study personnel who were trained to assess the patients.

The Conn Score and Asterixis Grade are defined as follow:

Conn Score

  • Grade 0 = No personality or behavioral abnormality detected.
  • Grade 1 = Trivial lack of awareness, euphoria or anxiety; shortened attention span; impairment of addition or subtraction.
  • Grade 2 = Lethargy; disorientation for time; obvious personality change; inappropriate behavior.
  • Grade 3 = Somnolence to semi-stupor, responsive to stimuli; confused; gross disorientation; bizarre behavior.
  • Grade 4 = Coma; unable to test mental state.

Asterixis Grade:

Asterixis (flapping tremor) was determined with the patient holding both arms and forearms extended with wrists dorsiflexed and fingers open for ≥30 seconds per standard practice.

Asterixis was measured on a continuum of five grades as shown below:

  • Grade 0 = No tremors.
  • Grade 1 = Rare flapping motions.
  • Grade 2 = Occasional, irregular flaps.
  • Grade 3 = Frequent flaps.
  • Grade 4 = Almost continuous flapping motions.

Patients were withdrawn from the RFHE3001 study upon experiencing a breakthrough overt HE episode.

Results from RFHE3001 study demonstrated that breakthrough overt HE episodes were experienced by 31 of 140 patients (22%) in the Zaxine treatment group and by 73 of 159 patients (46%) in the placebo treatment group during the 6-month treatment period. Zaxine significantly reduced the risk of overt HE breakthrough by 58% (p<0.0001), when compared to placebo.

A key secondary endpoint included in the RFHE3001 study was time to first HE-related hospitalization. Hepatic encephalopathy related hospitalizations (hospitalizations directly resulting from HE, or hospitalizations complicated by HE) were reported for 19 of 140 patients (14%) and 36 of 159 patients (23%) in the Zaxine and placebo groups, respectively. Zaxine significantly reduced the risk of overt HE-related hospitalizations by 50% (p<0.0129) during the 6-month treatment period.

Following successful participation in study RFHE3001, patients then had the opportunity to enroll in the open-label extension study, RFHE3002. Study RFHE3002 was a Phase III, multicenter, open-label, treatment-extension study which evaluated the long-term safety of Zaxine 550 mg twice daily for up to 24 months. A total of 322 patients in remission from overt HE with Conn scores of 0, 1 or 2 were eligible for participation. Patients enrolled had either successfully participated in a previous HE study (RFHE3001), or were new patients enrolled with more than one verifiable episode of HE within 12 months prior to screening. Patients were not required to withdrawn from this study after experiencing a breakthrough overt HE episode.

The primary endpoint for study RFHE3002 was the same as that of the RFHE3001 study, with the exception that breakthrough HE was an increase to Conn score of ≥3 for patients who had Conn score 2 at baseline.

Results from the RFHE3002 long-term study supported those results observed in the RFHE3001 study. Data from study RFHE3002 demonstrated that treatment with Zaxine for periods up to 24 months did not result in any loss of effect regarding protection from breakthrough overt HE episodes and the reduction in the burden of hospitalization. The time to first breakthrough overt HE episode profiles demonstrated long-term maintenance of remission in new Zaxine patients in RFHE3002 (including placebo crossover patients from RFHE3001) and continuing Zaxine patients in RFHE3002 (i.e., Zaxine rollover patients from RFHE3001).

Of note, 91% of the patients enrolled in the two clinical studies were taking concomitant lactulose. Given the large number of patients using lactulose concomitantly, differences in the treatment effect of those patients not using lactulose concomitantly could not be assessed.

Zaxine has not been studied in patients with MELD (Model for End-Stage Liver Disease) scores >25, and only 8.6% of patients in the controlled trial had MELD scores over 19. This information has been included in the indications section of the Product Monograph.

On initial filing of the submission, the following indication was proposed by the sponsor: Zaxine (rifaximin) is indicated for prevention of hepatic encephalopathy (HE) recurrence in patients ≥18 years of age.

Upon review of the data submitted, the approved indication by Health Canada is as follows: Zaxine (rifaximin) is indicated for the reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥18 years of age.

In conclusion, adequate clinical data was provided to support the proposed dose in the target population specified. However, in terms of sub-populations, the data for patients with severe hepatic impairment (Child-Pugh C) are limited and there are no data in patients with MELD score >25. There are also no data to support use in patients younger than 18 years of age.

For more information, refer to the Zaxine Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety evaluation of Zaxine in patients in remission from hepatic encephalopathy (HE) was based primarily on data from two clinical studies, RFHE3001 and RFHE3002, previously described in the Clinical Efficacy section.

In study RFHE3001, the most common treatment-emergent adverse events (TEAE) reported included nausea, ascites, peripheral edema, dizziness, muscle spasms, pruritis, depression, upper abdominal pain, dyspnea, rash, anemia, pyrexia and arthralgia. These TEAEs were all seen at an incidence ≥5% and at a higher frequency than in the placebo group.

In study RFHE3002, the most common TEAEs experienced by 10% of the total patients included hepatic encephalopathy (30%), urinary tract infection (23%), nausea (21%), peripheral edema (20%), anemia (16%), ascites (16%), abdominal pain (14%), renal failure acute (14%), hypokalemia (14%), vomiting (14%), dyspnea (13%), diarrhea (12%), constipation (12%), fatigue (12%), muscle spasms (12%), depression (12%), insomnia (11%), cellulitis (10%), pneumonia (10%) and dizziness (10%).

The drug-related TEAE observed in the two clinical studies with an incidence ≥1% included nausea, diarrhea, dizziness, abdominal pain, flatulence and vomiting. GI-related TEAE included diarrhea (2.3 %), nausea (2.6%), abdominal distension (1.0%), abdominal pain upper (1.0%), abdominal pain (1.5%), flatulence (1.3%), vomiting (1.3%) and constipation (0.5%). The most serious GI-related TEAE reported with the use of Zaxine is Clostridium difficile-associated disease (CDAD), which can occur more than two months after administration of rifaximin.

Post-market adverse drug reactions (reported voluntarily from a population of unknown size, causality unknown) to date include C. difficile-associated colitis and hypersensitivity reactions - including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis.

For more information, refer to the Zaxine Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

Rifaximin is currently available on the market in other regulatory jurisdictions, for the indication in prevention of hepatic encephalopathy recurrences in adults. Substantial portions of the non-clinical review was based on the foreign review submitted; in addition to performing an in-depth assessment on any new non-clinical studies provided.

In toxicology data package, in a two year rat study, increased malignant schwannomas were observed in the heart of male rats receiving rifaximin alfa at at doses of 150 to 250 mg/kg/day (doses equivalent to 1.3 to 2.2 times the recommended human dose, based on relative body surface area comparisons). This finding was not observed in the female rat. Yet, given this observation, a possible relationship between Zaxine treatment and carcinogenicity cannot be fully ruled out.

In animal embryo-fetal development study fetal malformations were reported. In rats slight and transient delay in ossification that did not affect the normal development of the offspring, was observed at rifaximin 300 mg/kg/day dose (equivalent to 2.6 times the clinical dose for hepatic encephalopathy, adjusted for body surface area), and in the rabbit, following oral administration of rifaximin during gestation, an increased incidence of skeletal variations was observed (at doses similar to clinical dose). The clinical relevance of these findings is not known. Yet, given this observation, a possible relationship between Zaxine treatment and teratogenicity cannot be fully ruled out.

Zaxine contains rifaximin in the polymorphic form alfa. The oral absorption of rifaximin polymorphic form alfa is limited, yet once absorbed rifaximin may undergo extensive metabolism.

In dogs administered with 2.4 mg/kg 14C-rifaximin by intravenous (IV) route, the majority of the dose was recovered from faeces (83-93%) while 0.45% from urine suggesting the faecal radioactivity from the IV dose is probably initially excreted in bile.

In vitro pharmacokinetic studies from various cell lines demonstrated interspecies differences in rifaximin metabolic rate and major differences in metabolites formed. The major human metabolite (25 desacetyl rifaximin) was not detected in rat and was demonstrated as minor metabolite in rabbits and dogs.

In vitro studies from human hepatocytes demonstrated that rifaximin is metabolized by CYP3A4. Multiple rifaximin metabolism pathways including deacetylation, demethylation, mono-oxidation, and desaturation were identified. The major metabolite observed was 25-desacetyl rifaximin. Rifaximin did not inhibit cytochrome P450 isozymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 at concentrations up to 200 ng/mL.

For more information, refer to the Zaxine 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 Zaxine 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.

Proposed limits of drug-related impurities are considered adequately qualified (that is within International Conference on Harmonisation (ICH) limits and/or qualified from toxicological studies.

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. None of the excipients used in the manufacture of the drug product are of human or animal origin.

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