Summary Basis of Decision for Nitisinone Tablets

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) documents provide information related to the original authorization of a product. The SBD for Nitisinone Tablets is located below.

Recent Activity for Nitisinone Tablets

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.

Post-Authorization Activity Table (PAAT) for Nitisinone Tablets

Updated: 2025-07-30

The following table describes post-authorization activity for Nitisinone Tablets, a product which contains the medicinal ingredient nitisinone. 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.

Drug Identification Numbers (DINs):

  • DIN 02458616 - 2 mg nitisinone, tablet, oral administration
  • DIN 02458624 - 5 mg nitisinone, tablet, oral administration
  • DIN 02458632 - 10 mg nitisinone, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 261089 2022-02-01 Issued NOC 2022-06-09 Submission filed as a Level I – Supplement to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration section of the PM. An NOC was issued.
SNDS # 224962 2019-03-04 Issued NOC 2019-10-11 Submission filed as a Level I – Supplement for a change in the specifications for the drug product involving test and acceptance criteria / analytical procedures, and to update the PM with pediatric data. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration section 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 (DINs 02458616, 02458624) market notification Not applicable Date of first sale:
2017-01-13		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Drug product (DIN 02458632) market notification Not applicable Date of first sale:
2016-12-19		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 193770 2016-03-31 Issued NOC
2016-11-04		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Nitisinone Tablets

Date SBD issued: 2017-02-17

The following information relates to the New Drug Submission for Nitisinone Tablets.

Nitisinone
2 mg, 5 mg, and 10 mg tablets, oral

Drug Identification Number (DIN):

  • DIN 02458616 - 2 mg tablet
  • DIN 02458624 - 5 mg tablet
  • DIN 02458632 - 10 mg tablet

Cycle Pharmaceuticals Ltd.

New Drug Submission Control Number: 193770

 

On November 4, 2016, Health Canada issued a Notice of Compliance to Cycle Pharmaceuticals Ltd. for the drug product, Nitisinone Tablets.

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 Nitisinone Tablets is favourable for the treatment of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

 

1 What was approved?

 

Nitisinone Tablets, a reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase, were authorized for the treatment of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

Treatment with Nitisinone Tablets should be initiated and supervised by a physician experienced in the treatment of HT-1.

Clinical studies of nitisinone did not include any subjects aged 65 and over.

Clinical studies of nitisinone were conducted in patients with HT-1, ranging in age from birth to 21 years of age.

Nitisinone Tablets are contraindicated for patients who are hypersensitive to nitisinone or to any ingredient in the formulation or component of the container. Mothers receiving Nitisinone Tablets should not breast feed. Nitisinone Tablets were approved for use under the conditions stated in the Nitisinone Tablets Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Nitisinone Tablets have three strengths: 2 mg, 5 mg, and 10 mg nitisinone. In addition to the medicinal ingredient, the tablets contain glyceryl dibehenate, and lactose monohydrate.

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 Nitisinone Tablets Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Nitisinone Tablets approved?

 

Health Canada considers that the benefit/risk profile of Nitisinone Tablets is favourable for the treatment of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.

Hereditary tyrosinemia type 1 (HT-1) is a genetic defect in the final enzyme of the tyrosine degradation pathway, fumarylacetoacetase. As a result of the defect in the enzyme, intermediate metabolites of the pathway accumulate, notably maleylacetoacetate and fumarylacetoacetate. These metabolites are unstable and are rapidly converted to the metabolites succinylacetone and succinylacetoacetate which are toxic, affecting the liver and kidney in particular. In addition, succinylacetone inhibits the porphyrin synthesis pathway, leading to the accumulation of 5-aminolevulinate which is neurotoxic.

Patients with untreated HT-1 have a substantially shortened lifespan, and may die of acute liver failure before their second year of life, or, in the less common chronic form, may die from liver failure or hepatocellular carcinoma by the end of their second decade. Globally, HT-1 is rare, with an incidence of approximately 1 case per 100,000 live births. The incidence can be higher in certain regions, such as a region in Canada where the carrier rate is approximately1 in 20 inhabitants and the incidence is estimated at 1 in 1,846 live births.

At the time of filing, the only nitisinone product available globally was manufactured by Swedish Orphan Biovitrum, under the brand name Orfadin, and released through the Health Canada Special Access Program since 1994. Nitisinone acts by inhibiting the second step in the tyrosine degradation pathway, the enzyme 4-hydroxy phenylpyruvate dioxygenase. Since nitisinone inhibits the tyrosine degradation pathway upstream from the formation of maleylacetoacetate and fumarylacetoacetate, it avoids accumulation of the toxic metabolites succinylacetoacetate and succinylacetone.

The efficacy of Nitisinone Tablets for the treatment of patients with HT-1 has been established based on demonstration of bioequivalence of Nitisinone Tablets to the foreign authorized nitisinone product, Orfadin. Demonstration of bioequivalence allowed bridging of the evidence for the efficacy and safety of the Orfadin formulation to the Nitisinone Tablets formulation, thereby supporting market authorization of Nitisinone Tablets. Evidence for the efficacy and safety of Orfadin was derived primarily from publically available results and analyses of the multinational NTBC Study, as well as published reports of other nitisinone clinical trials, particularly the Quebec NTBC study. This was supplemented by publically available post-marketing safety data.

The multinational NTBC Study was conducted by 96 investigators at 87 different hospitals in 25 countries. The study was open-label and uncontrolled. Due to dramatic clinical and biochemical improvements seen in an initial group of 5 Swedish HT-1 patients treated with nitisinone, it was concluded that it would be unethical to include a placebo group in subsequent studies of nitisinone in this life-threatening disease.

The main analysis of the NTBC Study included 207 patients, ranging in age from birth to 21.7 years of age at enrolment. The median duration of treatment with nitisinone was 22.2 months, and the starting dose of nitisinone was 0.6 to 1 mg/kg/day, which was increased to 2 mg/kg/day in some patients, based on weight, biochemical, and enzyme markers. The results of the study were compared with an historical control, consisting of clinical outcome data from a published international survey of 108 HT-1 patients who were treated solely with a tyrosine and phenylalanine restricted diet.

In the historical HT-1 population, for patients diagnosed at 0-2 months (77% of all patients) and treated with dietary tyrosine and phenylalanine restriction alone, 44% died within 6 months, and the 1 and 2 year survival rates were 38% and 29%, respectively. In contrast, in the NTBC study main analysis, the 1 and 2 year survival rates were 88% for patients initiating nitisinone therapy before 2 months of age. For untreated patients in the historical control group who were diagnosed from 2-6 months of age, 1 and 2 year survival was 74%, compared to 95% at 1 and 2 years for patients initiating nitisinone therapy in this age range. For the few patients diagnosed after 6 months of age in the historical control group, 1 and 2 year survival was 96%, compared to 1 and 2 year survival rates of 97% for patients starting nitisinone after 6 months of age in the NTBC study.

The results of the NTBC Study were supported by the results of the published Quebec NTBC Study. The study comprised 78 HT-1 patients, including 28 patients who were treated with diet alone prior to the availability of nitisinone and 50 patients treated prospectively with nitisinone. Among the untreated Quebec patients, 8/28 (29%) died prior to liver transplantation, at a mean age of 16 months. No deaths occurred prior to transplantation in the nitisinone-treated patients.

Clear clinical benefit was evident in both the international and Quebec NTBC Studies, when HT-1 patients treated with nitisinone and dietary restriction were compared to historical data for patients receiving dietary restriction alone. In addition to increased survival, patients treated with nitisinone displayed substantial decreases in liver failure (including death due to liver failure or major bleeding, and need for transplantation due to liver failure), risk of hepatocellular carcinoma, and risk of porphyric neurological crises. Consistent with these findings, nitisinone therapy resulted in normalization of biochemical abnormalities associated with HT-1, including plasma/urine succinylacetone and erythrocyte porphobilinogen-synthase levels, urine 5-aminolevulinic acid, and serum alpha-fetoprotein levels.

No serious safety concerns associated with nitisinone have been identified. Corneal tyrosine crystals and corneal opacities with related symptoms are a risk associated with the elevation in plasma tyrosine levels typically seen with nitisinone treatment; however, symptoms generally resolve with stricter dietary tyrosine restriction. In addition, occasional cases of thrombocytopenia and neutropenia were noted, although no associated serious sequelae were identified. These events are included as warnings in the Nitisinone Tablets Product Monograph.

No new concerns have been identified during the monitoring of nitisinone safety since the marketing of Orfadin in the United States, Europe, and other jurisdictions, as well as over the more than 20 years nitisinone have been accessed in Canada through the Special Access Program.

To date, the experience of chronic treatment of HT-1 with nitisinone is limited, as is the experience of treatment of older adults, since clinical trials only enrolled patients up to the age of 22 years. However, such data are accumulating due to continuing treatment of HT-1 patients whose nitisinone therapy began in infancy. The sponsor has committed to ongoing surveillance of patients receiving Nitisinone Tablets, post-marketing. No data are available regarding the use of nitisinone in geriatric patients. This is reflected in the Nitisinone Tablets Product Monograph.

Adequate data do not exist to assess the safety of nitisinone in pregnant women. The Nitisinone Tablets Product Monograph states that Nitisinone Tablets should be used in pregnancy only when the benefits of continued treatment are judged to outweigh the risks.

It is not known whether nitisinone is present in human milk; however, studies in rats suggest that nitisinone is present in rat milk and causes ocular toxicity and lower body weight in nursing pups. Consequently, due to the potential for adverse reactions in nursing infants, the Nitisinone Tablets Product Monograph includes a contraindication advising women not to breastfeed if they are taking Nitisinone Tablets.

A Risk Management Plan (RMP) for Nitisinone Tablets was considered acceptable by Health Canada. 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. Risk minimization includes ongoing post-marketing surveillance, creation of a Pan-Canadian Patient Registry to evaluate the long-term safety and adequate labelling of all identified safety issues, including the lack of data in some subpopulations, and the potential risk from use during pregnancy and lactation, along with the potential for risk to the fetus and mother from discontinuing nitisinone during pregnancy.

A Look-alike Sound-alike brand name assessment was performed and the proposed name has been deemed acceptable.

Nitisinone Tablets are a new formulation compared to the nitisinone capsules used in the nitisinone clinical trials and globally, post-approval. Nitisinone Tablets display better thermal stability than the capsule formulation and therefore do not require refrigeration, unlike the capsules. However, for administration to infants, the tablets require crushing before mixing with water, and cannot be administered using a baby bottle.

Overall, it is considered that the evidence of the benefit provided by nitisinone for the treatment of HT-1, a serious and often fatal disorder for which no approved treatment exists in Canada, clearly outweighs the associated risks, acknowledging the existing uncertainties. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Nitisinone Tablets 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 Nitisinone Tablets?

 

At the time of filing the drug submission for Nitisinone Tablets, the only nitisinone product available globally was manufactured by Swedish Orphan Biovitrum, under the brand name Orfadin. Orfadin capsules were approved for the treatment of HT-1 in combination with dietary tyrosine and phenylalanine restriction by the United States Food and Drug Administration (FDA) in 2002, and by the European Medicines Agency (EMA) in 2005. Orfadin has also been approved in Russia, Chile, Australia, Israel, South Korea, Mexico, Ukraine, and Japan. Orfadin is also available in other countries on a "named patient" basis. This includes Canada, where Orfadin has been released through the Special Access Program (SAP) since 1994.

The sponsor and Health Canada held pre-submission meetings on June 9, 2014 and November 13, 2015. The sponsor proposed filing a New Drug Submission (NDS) based on demonstration of bioequivalence of Nitisinone Tablets to the foreign authorized Orfadin product, combined with submitting evidence of safety and efficacy of Orfadin in the form of reviews from the Orfadin marketing authorization submissions of other major regulators, as well as studies in the literature and post-market safety data. Health Canada advised that this would be an acceptable option for the sponsor, taking into account Health Canada's existing guidance on Drug Submissions Relying on Third-Party Data and The Use of Foreign Reviews by Health Canada, and also considering the long-standing use of Orfadin in Canada through the SAP for a serious and life-threatening disease.

The New Drug Submission for Nitisinone Tablets was reviewed under the Priority Review Policy. The NDS was judged to meet the criteria for a priority review on the basis that the information provided by the sponsor suggested substantial evidence of efficacy of nitisinone for the treatment of a serious and life-threatening condition for which no approved treatment exists in Canada.

 

Submission Milestones: Nitisinone Tablets

Submission Milestone Date
Pre-submission meeting: 2014-06-09 - 2015-11-13
Request for priority status  
Filed: 2016-02-09
Approval issued by Director, Bureau of Metabolism, Oncology, and Reproductive Sciences: 2016-03-04
Submission filed: 2016-03-31
Screening  
Screening Acceptance Letter issued: 2016-05-09
Review  
Biopharmaceutics Evaluation complete: 2016-07-21
Quality Evaluation complete: 2016-10-31
Clinical Evaluation complete: 2016-11-03
Labelling Review complete: 2016-11-03
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2016-11-04

 

The Canadian regulatory decision of the clinical safety and efficacy of Nitisinone Tablets was based on a review and critical assessment of the Orfadin clinical review reports from the FDA, EMA, and Therapeutic Goods Administration of Australia (TGA), with reference to the data filed by the sponsor in Canada. The review reports were supplemented by published literature reports of the pivotal, multinational nitisinone trial, the NTBC study, and other nitisinone clinical trials, in particular the Quebec NTBC study, along with post-marketing safety data. This NDS review was therefore based on an assessment of the literature reports and foreign market experience for Orfadin, as well as reviews by foreign regulators, and complies with the relevant Health Canada guidance on submissions relying on third-party data and the use of foreign reviews.

The Canadian regulatory decision on the non-clinical component of the drug submission was also based on a critical assessment of the TGA, EMA, and FDA Orfadin non-clinical reviews.

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.

As part of the post-market commitments, Cycle Pharmaceuticals Ltd. proposed to develop a Pan-Canadian Patient Registry to evaluate the long-term safety of Nitisinone Tablets in the treatment of hereditary tyrosinaemia type 1.

 

5 What post-authorization activity has taken place for Nitisinone Tablets?

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 Nitisinone Tablets 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

Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1 (HT-1), nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible for the observed liver and kidney toxicity. In addition, succinylacetone inhibits the porphyrin synthesis pathway, leading to the accumulation of 5-aminolevulinate (5-ALA), which is neurotoxic.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies.

Formal drug interaction studies were not performed with nitisinone. In vitro studies demonstrated that nitisinone does not inhibit cytochrome P450 (CYP) enzyme, CYP3A4, CYP1A2 or CYP2C19 activity, but is a substrate of CYP3A4, and inhibits CYP2C9, CYP2D6 and CYP2E1 enzyme activity. Dose-adjustment may be required when nitisinone is co-administered with drugs that are inhibitors or inducers of CYP3A4, and monitoring is recommended when it is co-administered with drugs metabolized by CYP2C9, CYP2D6 and CYP2E1 enzymes.

The influence of renal or hepatic impairment, race, and genetic polymorphisms on the pharmacokinetics of Nitisinone Tablets is unknown.

A comparative bioavailability study satisfactorily bridged the 10 mg strength of the Nitisinone Tablets to the Orfadin 10 mg capsules (foreign authorized reference product manufactured by Swedish Orphan Biovitrum International). A waiver of the requirement to conduct clinical bioequivalence studies with the 2 mg and 5 mg Nitisinone Tablets was granted on the basis of in vitro (comparative dissolution) and in vivo (bioequivalence) evidence provided by the sponsor with this submission.

Another study evaluated the effects of a high-fat, high-calorie meal on the pharmacokinetics of a single 10 mg dose of the Nitisinone Tablets administered to healthy subjects. No significant differences were observed in the extent of absorption of nitisinone between fasting and fed conditions. It was observed that the fed state delays the median time to maximum concentration by approximately 3 hours, which is not expected to impact the safety or efficacy profile of the product in patients.

This drug submission is considered to meet the requirements of the Food and Drugs Act and Regulations insofar as the comparative bioavailability information is concerned.

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

 

Clinical Efficacy

Evidence of the clinical efficacy of Nitisinone Tablets for the treatment of HT-1 was demonstrated through the bioequivalence of Nitisinone Tablets with the foreign authorized Orfadin product, the nitisinone formulation that has been marketed internationally for this indication. The submitted evidence for the efficacy of the Orfadin formulation consisted of reviews of the NTBC study, conducted by the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Therapeutic Goods Administration of Australia (TGA), which led to market authorization of Orfadin in those jurisdictions. These reviews were supplemented by published literature reports of the NTBC study and other nitisinone clinical trials, in particular the Quebec NTBC study, along with post-marketing safety data. Therefore, this drug submission review relied on the assessment of literature reports and foreign market experience for the Orfadin nitisinone formulation, as well as reviews by foreign regulators, in compliance with the relevant Health Canada guidance on submissions relying on third party data (Drug Submissions Relying on Third Party Data) and the guidance on use of foreign reviews (The Use of Foreign Reviews by Health Canada).

The NTBC study was conducted by 96 investigators at 87 different hospitals in 25 countries. The study was open-label and uncontrolled. Due to dramatic clinical and biochemical improvements seen in an initial group of 5 Swedish HT-1 patients treated with nitisinone, it was concluded that it would be unethical to include a placebo group in subsequent studies of nitisinone in this life-threatening disease.

The EMA and TGA reviews of the NTBC study considered results from a main analysis, which included 207 patients over a 6-year period, and a complementary analysis, which included 250 patients over a 7-year period, using an initial daily dose of 1 mg/kg bodyweight. Due to the substantial overlap, the two analyses shared an estimated 150 patients. Based on the combined data, approximately 290 patients were enrolled from the beginning of the main analysis to the conclusion of the complementary analysis.

In the main analysis of the NTBC study, median duration of treatment with nitisinone was 22.2 months, and the starting dose of nitisinone was 0.6 to 1 mg/kg/day, which was increased to 2 mg/kg/day in some patients, based on weight, biochemical, and enzyme markers. The primary efficacy variables consisted of overall survival, survival without liver transplantation, death due to liver failure, transplantation due to liver failure and hepatocellular carcinoma (HCC). The results of the NTBC study were compared with an historical control, consisting of clinical outcome data from a published international survey of 108 HT-1 patients who were treated solely with a tyrosine and phenylalanine restricted diet.

In the historical control population of HT-1 patients diagnosed at 0-2 months and treated with dietary restriction alone, 44% died within 6 months. Survival at 1 and 2 years was 38% and 29% for patients whose symptoms manifested before the age of 2 months, 74% at 1 and 2 years for those diagnosed at 2 to 6 months, and 96% at 1 and 2 years for the relatively few patients diagnosed after 6 months of age. In contrast, in the NTBC study main analysis, 1 and 2 year survival rates (which were identical) were 88%, 95%, and 97%, for patients initiating nitisinone therapy before 2 months, at 2 to 6 months, and after 6 months of age, respectively.

In the historical control group, 6/108 (6.4%) patients underwent liver transplantation due to liver failure, compared with 7/207 (3.4%) patients in the NTBC study main analysis. In the historical cohort, the occurrence of HCC was 18% in patients older than 2 years, while in the NTBC study patients treated with nitisinone before the age of 2 years displayed a cumulative probability of HCC of 1% over 4 years of follow-up.

In the NTBC study, nitisinone treatment resulted in rapid improvement and normalization of urinary succinylacetone and 5-ALA levels, as well as plasma succinylacetone and erythrocyte PBG-synthase levels.

The results of the NTBC study were supported by the Quebec NTBC study, the second largest prospective study of nitisinone in the treatment of HT-1. This study comprised 78 HT-1 patients, of whom 50 were treated prospectively with nitisinone between 1994 and 2004. The remaining 28 patients, who were diagnosed with HT-1 from 1984 to 1994 and who did not receive nitisinone, served as an historical control group. Acute complications of HT-1 occurred frequently in the historical control group, assessed retrospectively through chart review. The untreated patients spent 56/784 months hospitalized, half of the time due to porphyric neurological crises, compared to no hospitalization due to complications of HT-1 in nitisinone-treated patients during the study period (mean nitisinone exposure of 9.5 years). Among the historical control patients, 8/28 (29%) died prior to liver transplantation, at a mean age of 16 months. No deaths occurred prior to transplantation in nitisinone-treated patients. Of the 28 untreated HT-1 patients, 20 of 28 (71%) underwent liver transplantation, for cirrhosis or cancer (13 patients), acute hepatic failure (2) or neurological crises (5 patients). In comparison, for the nitisinone-treated patients, liver transplantations were only performed in patients who initiated nitisinone after the age of 30 days (7/26, or 27%). All these patients displayed evidence of significant liver abnormalities prior to initiating nitisinone therapy. In the Quebec NTBC study, biochemical abnormalities associated with HT-1 normalized rapidly with nitisinone treatment, including plasma and urine succinylacetone levels, and plasma 5-ALA and α fetoprotein levels.

Overall, the bioequivalence of Nitisinone Tablets to the foreign authorized Orfadin product, together with the substantial evidence of efficacy of Orfadin as demonstrated in the NTBC Studies and documented in the review reports from other regulators and publications, combined with its history of clinical use, provided sufficient evidence to support the clinical efficacy of Nitisinone Tablets for the treatment of patients with HT-1.

For more information regarding the clinical efficacy of Nitisinone Tablets, refer to the Nitisinone Tablets Product Monograph, approved by Health Canada and available through the Drug Product Database.

Note: Bioequivalence data is not always included in the Canadian Product Monograph

Indication

The New Drug Submission for Nitisinone Tablets was filed with the following indication:

  • Nitisinone Tablets are indicated for the treatment of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.
  • The treatment with nitisinone together with dietary restriction results in a higher survival probability in all HT-1 phenotypes.
  • Clinical studies of nitisinone did not include any subjects aged 65 and over to determine whether they respond differently from younger subjects. There are no specific dose recommendations for elderly or patients that have renal or hepatic impairment.
  • The dose recommendation in mg/kg body weight is the same in children and adults.

Health Canada recommended the following:

  • Nitisinone Tablets are indicated for the treatment of patients with hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.
  • Treatment with nitisinone should be initiated and supervised by a physician experienced in the treatment of HT-1.
  • Clinical studies of nitisinone did not include any subjects aged 65 and over.
  • Clinical studies of nitisinone were conducted in patients with HT-1, ranging in age from birth to 21 years of age.

Clinical Safety

Evidence of clinical safety of Nitisinone Tablets for the treatment of HT-1 was based on demonstration of bioequivalence of Nitisinone Tablets to the foreign authorized Orfadin product, allowing bridging of Orfadin safety data. The submitted evidence for the safety of the Orfadin formulation consisted of reviews of the NTBC study, conducted by the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Therapeutic Goods Administration of Australia (TGA), which led to market authorization of Orfadin in those jurisdictions. These reviews were supplemented by published literature reports of the NTBC study and other nitisinone clinical trials, in particular the Quebec NTBC study, along with publically available post marketing safety data. Therefore, this drug submission review relied on the assessment of literature reports and foreign market experience for the Orfadin nitisinone formulation, as well as reviews by foreign regulators, in compliance with the relevant Health Canada guidance on submissions relying on third party data (Drug Submissions Relying on Third Party Data) and the guidance on use of foreign reviews (The Use of Foreign Reviews by Health Canada).

A combined analysis of the NTBC study and the Quebec NTBC study (see Clinical Efficacy section) along with post-market safety reports has not identified serious safety issues associated with nitisinone use in HT-1 patients. Corneal tyrosine crystals and corneal opacities with related eye pain and photophobia are associated with elevations in plasma tyrosine levels seen with nitisinone treatment; however, these symptoms generally resolved with strict dietary tyrosine restriction. In addition, occasional cases of thrombocytopenia and neutropenia were noted, although no associated serious sequelae, such as bleeding or infection were observed. These events are noted as warnings in the Nitisinone Tablets Product Monograph, including instructions regarding appropriate ophthalmological monitoring.

With the increasing survival of children with HT-1 since the advent of nitisinone therapy, there have been recent literature reports suggesting an increased risk of impaired cognitive function in patients with HT-1 treated with nitisinone and dietary restriction. It is uncertain whether the reported delays in neurocognitive development may be related to nitisinone exposure, high plasma tyrosine concentrations, low phenylalanine concentrations, the effect of acute liver disease in infancy, or an intrinsic effect of HT-1.

Although the majority of clinical trial data were obtained from pediatric patients, the international NTBC study enrolled patients up to an age of 21.7 years of age. The use of nitisinone in adults for the treatment of HT-1 is appropriate, as directed, with weight-based dosing and standard monitoring of biochemical and clinical parameters.

No data are available regarding the use of nitisinone in geriatric patients, and this is reflected in the Nitisinone Tablets Product Monograph.

There have been reports of women with HT-1 treated with nitisinone who became pregnant and continued taking nitisinone throughout pregnancy; however, adequate data do not exist to assess the safety of nitisinone in pregnant women. Reproductive toxicity has been seen in animal species at nitisinone levels comparable to human exposures; however, the risks posed to the fetus by untreated maternal HT-1 are considered substantial. As a result, the Nitisinone Tablets Product Monograph states that nitisinone should be used in pregnancy only when the benefits of continued treatment are judged to outweigh the risks.

It is not known whether nitisinone is present in human milk. Studies in rats suggest that nitisinone is present in rat milk and can cause ocular toxicity and lower body weight in nursing pups. Consequently, due to the potential for adverse reactions in infants breastfed by mothers taking nitisinone, the Nitisinone Tablets Product Monograph includes a contraindication advising that women with HT-1 taking nitisinone should not breast-feed.

Overall, despite the uncertainties associated with the abbreviated development program for nitisinone, the safety profile of Nitisinone Tablets is considered acceptable for the treatment of patients with HT-1. Appropriate warnings and precautions are in place in the approved Nitisinone Tablets Product Monograph to address and manage the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Review of non-clinical data by foreign regulators was endorsed by Health Canada. The TGA recommended that Orfadin could be approved from a non-clinical perspective, despite a number of deficiencies in the development program, which was in accord with the EMA and FDA recommendations.

Primary pharmacodynamic studies demonstrated inhibitory effects of nitisinone on 4 hydroxyphenylpyruvate dioxygenase activity in vitro in rat liver-preparations and in vivo activity in mice and rats following oral administration.

Following repeated oral dosing, nitisinone-related target organ toxicities in mice, rats, rabbits, dogs, and monkeys included corneal opacities and keratitis (rats and dogs), mild centrilobular hypertrophy of the liver (mice and rats), renal enlargement and impaired function (mice), increased sciatic nerve demyelination (mice, high dose), and clinical signs of neurotoxicity and gastrointestinal irritation in dogs.

Nitisinone was not mutagenic in bacterial cells, but was mutagenic in mammalian cells in vitro (mouse lymphoma forward mutation test) and produced a weakly positive mouse micronucleus test in vivo. An in vivo mouse liver deoxyribonucleic (DNA) synthesis assay performed at the request of the EMA did not show evidence of DNA damage in vivo. Therefore, nitisinone is regarded as having limited evidence of genotoxicity.

Long-term carcinogenicity studies and adequate non-rodent chronic toxicity studies were not completed with nitisinone, which constitutes a deficiency for a product intended for long-term human use.

In a study in rats given maternally toxic doses of 50 mg/kg/day (4 times the maximum clinical dose, based on body surface area), increased stillbirths and reduced live births, birth weights and survival after birth were observed, as well as increased rates of skeletal abnormalities.

In mice and rabbits, embryotoxicity (decreased fetal weights, early intra- uterine deaths and post-implantation loss) and fetal abnormalities (skeletal abnormalities in both species, and umbilical hernia, lung abnormalities in rabbits) were observed at oral nitisinone doses from 5 mg/kg/day (less than the maximum clinical dose, based on body surface area), following administration during organogenesis.

In mice, maternal treatment at oral doses from 5 mg/kg/day (less than the maximum clinical dose, based on body surface area) during organogenesis through weaning was associated with reduced pup survival, weight gain and developmental delays. In rats, exposure of drug-naïve pups to nitisinone through milk from treated dams given 100 mg/kg/day orally (9 times the maximum clinical dose, based on body surface area) was associated with reduced pup weight and development of corneal opacities.

Taking into account the non-clinical reproductive toxicity findings, nitisinone use during lactation should be avoided and therefore breastfeeding while taking nitisinone is contraindicated. Safety of nitisinone during pregnancy is uncertain, however the risks posed to the fetus by untreated maternal HT-1 are considered substantial.

Overall, the pre-clinical development program for nitisinone displayed a number of deficiencies. With the exception of the genotoxicity and reproduction toxicity tests, studies were not compliant with Good Laboratory Practices. However, considering the serious and life-threatening nature of HT-1, the lack of approved therapy, evidence of clinical efficacy, and the longstanding history of clinical use globally, the limitations of the non-clinical database do not preclude granting marketing authorization. Appropriate warnings and precautionary measures are in place in the Nitisinone Tablets Product Monograph to address the identified safety concerns.

For more information, refer to the Nitisinone Tablets 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 Nitisinone Tablets 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 one year for the 2 mg tablets, and 2 years for the 5 mg and 10 mg tablets is considered acceptable when the product is stored at 15-30oC.

Proposed limits of drug-related impurities are considered adequately qualified (i.e. within International Council for Harmonisation 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.

The excipient, lactose monohydrate, is of animal origin. Letters of attestation confirming that the materials are not from a bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) affected country/area have been provided for this product indicating that it is considered to be safe for human use.

 

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