Summary Basis of Decision for Orfadin
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 Orfadin is located below.
Recent Activity for Orfadin
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 Orfadin
Updated:
The following table describes post-authorization activity for Orfadin, 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 that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Numbers (DINs):
- DIN 02459698 - 2 mg nitisinone capsule, oral
- DIN 02459701 - 5 mg nitisinone capsule, oral
- DIN 02459728 - 10 mg nitisinone capsule, oral
- DIN 02459736 - 20 mg nitisinone capsule, oral
- DIN 02469693 - 4 mg/mL, nitisinone, suspension, oral
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02469693) market notification | Not applicable | Date of first sale:2018-07-10 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NC # 215784 | 2018-04-26 | Issued NOL2018-10-11 | Submission filed as a Level II (120 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, Drug Interactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 207481 | 2017-07-13 | Issued NOC2018-03-27 | Submission filed as a Level I - Supplement to seek approval for for a new dosing regimen for Orfadin (nitisinone) for once a day use (except in patients with a body weight <20 kg). There were no significant changes to the overall benefit-harm-uncertainty profile of Orfadin when used once a day. The data were reviewed and considered acceptable, and an NOC was issued. |
| SNDS # 204557 | 2017-04-07 | Issued NOC2017-11-14 | Submission filed as a Level I - Supplement to seek approval for Orfadin (4 mg/mL nitisinone) oral suspension. The data were reviewed and considered acceptable, and an NOC was issued. A new DIN (02469693) was issued for the new dosage form. |
| Drug product (DINs 02459698, 02459701, 02459728, 02459736) market notification | Not applicable | Date of first sale:2017-02-17 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 193226 | 2016-03-30 | Issued NOC2016-12-13 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Orfadin
Date SBD issued: 2017-02-17
The following information relates to the new drug submission for Orfadin.
Nitisinone
2 mg, 5 mg, 10 mg, and 20 mg capsules, oral
Drug Identification Number (DIN):
- DIN 02459698 - 2 mg capsule
- DIN 02459701 - 5 mg capsule
- DIN 02459728 - 10 mg capsule
- DIN 02459736 - 20 mg capsule
Swedish Orphan Biovitrum AB (publ)
New Drug Submission Control Number: 193226
On December 13, 2016, Health Canada issued a Notice of Compliance to Swedish Orphan Biovitrum AB (publ) for the drug product, Orfadin. Based on Health Canada's review, the benefit/risk profile of Orfadin 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?
Orfadin (nitisinone), a reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase, was authorized for the treatment of 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.
Orfadin is contraindicated for patients who are hypersensitive to nitisinone or to any ingredient in the formulation or component of the container. Mothers receiving Orfadin must not breastfeed. Orfadin was approved for use under the conditions stated in the Orfadin Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Orfadin (2 mg, 5 mg, 10 mg, and 20 mg nitisinone) is presented as a capsule. In addition to the medicinal ingredient, the capsule contains ammonium hydroxide, gelatine, black iron oxide, pre-gelatinized starch (maize), propylene glycol, shellac, 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 Orfadin Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Orfadin approved?
Health Canada considers that the benefit/risk profile of Orfadin 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, fumarylacetoacetate hydrolase. 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 approximately 1 in 20 inhabitants and the incidence is estimated at 1 in 1,846 live births.
Evidence for the efficacy and safety of Orfadin (nitisinone) was based on evidence from the NTBC study, supported by the recently published report of the Quebec NTBC study, and post-market safety data.
The NTBC study was a Phase II/III multinational open-label uncontrolled study of 291 HT-1 patients in 30 countries, including Canada. 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. Porphyric neurological crises and normalization of biochemical abnormalities were also examined. The main analysis of the study included 207 patients (from birth to 21.7 years of age), who were treated for a median duration of 22.2 months. Combined data from a complementary analysis, which included 250 patients, indicated that 291 patients were enrolled from the beginning of the main analysis to the conclusion of the complementary analysis, with the two analyses sharing 166 patients. Since no placebo/diet-only control group was included in the study, for ethical reasons, the results were compared with a historical control group from a published survey of 108 HT-1 patients treated with a tyrosine- and phenylalanine-restricted diet only.
Survival analysis showed that, historically, of HT-1 patients diagnosed before the age of 2 months and treated with dietary restriction alone, 44% died within 6 months. In contrast, patients diagnosed before 2 months and treated with nitisinone in the NTBC study had a 2 year survival rate of 88%. Compared with the historical data for patients treated only with diet, in addition to increased survival at 1 and 2 years, nitisinone treated patients displayed decreased rates of liver failure (including death due to liver failure or major bleeding), need for transplantation due to liver failure, risk of hepatocellular carcinoma, and decreased porphyric neurological crises. Nitisinone treatment resulted in rapid normalization of the biochemical abnormalities associated with HT-1.
The Quebec NTBC study consisted of 78 HT-1 patients, of whom 50 were treated prospectively with nitisinone while the remaining 28 patients who did not receive nitisinone served as a historical control group. Acute complications of HT-1 occurred frequently in the historical control group, including death prior to liver transplantation. No such deaths were seen in the nitisinone treated patients, and there were no hospitalizations due to complications of HT-1 in nitisinone-treated patients during the study period.
A combined safety analysis of the NTBC study and the Quebec NTBC study, along with the monitoring of post-market safety reports did not identify serious or new safety issues associated with nitisinone use. 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 Orfadin Product Monograph.
A Risk Management Plan (RMP) for Orfadin 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 measures include ongoing post-marketing surveillance, commitment to a Canadian post-approval safety study, and adequate labelling of all identified safety issues, including the lack of data in some subpopulations, the potential risk from use during pregnancy and lactation, and the potential 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 Orfadin has been deemed acceptable.
Overall, the therapeutic benefits seen in the pivotal study are positive and the benefits of Orfadin therapy are considered to outweigh the potential risks. Orfadin has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and adequate monitoring. Appropriate warnings and precautions are in place in the Orfadin 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 Orfadin?
At the time of filing, Orfadin was the only nitisinone product available globally. Orfadin has been released through the Health Canada Special Access Program (SAP) for HT-1 patients since 1994.
The New Drug submission (NDS) for Orfadin 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: Orfadin
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2015-06-01 |
| Request for priority status | |
| Filed: | 2015-12-16 |
| Approval issued by Director, Bureau of Metabolism, Oncology, and Reproductive Sciences: | 2016-01-15 |
| Submission filed: | 2016-03-30 |
| Screening | |
| Screening Deficiency Notice issued: | 2016-04-29 |
| Response filed: | 2016-06-10 |
| Screening Acceptance Letter issued: | 2016-07-08 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2016-08-30 |
| Quality Evaluation complete: | 2016-11-30 |
| Clinical Evaluation complete: | 2016-12-13 |
| Labelling Review complete: | 2016-12-09 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2016-12-13 |
The Canadian regulatory decision on the clinical and quality sections of the review of Orfadin was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Medicines Agency (EMA), the United States Food and Drug Administration (FDA), and Therapeutic Goods Administration of Australia (TGA) were used as an added reference.
The Canadian regulatory decision on the non-clinical component of the drug submission was based on a critical assessment of the TGA, EMA, and FDA Orfadin non-clinical reviews, as well as assessment of a recently completed nitisinone mouse carcinogenicity study.
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, Swedish Orphan Biovitrum AB (publ) has agreed to monitor the long-term safety of Orfadin in the treatment of hereditary tyrosinemia type 1, and to conduct a Canadian post-approval safety study.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Nitisinone, the active ingredient in Orfadin, is a competitive inhibitor of 4-hydroxyphenylpyruvate 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, CYP2C9, CYP2D6 and CYP2E1 enzymes.
The influence of renal or hepatic impairment, race, and genetic polymorphisms on the pharmacokinetics of Orfadin is unknown.
The 2 mg, 5 mg and 10 mg nitisinone capsules were used in the Phase III clinical study demonstrating the safety and efficacy of Orfadin. The 20 mg capsule was developed at a later stage and was tested for comparative bioavailability against the 10 mg capsule strength in Study #Sobi.NTBC-004. Comparative bioavailability was successfully demonstrated between the 20 mg and the 10 mg strengths of Orfadin capsules; each strength administered as a 20 mg dose.
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.
Consistent with current clinical practice and Orfadin dosing instructions during studies in HT-1 patients, it is recommended that if nitisinone treatment is initiated with food, this should be maintained on a routine basis. In the case of pediatric patients, the capsules may be opened and the content suspended in a small amount of water or formula diet immediately before intake.
For further details, please refer to the Orfadin Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy and safety of Orfadin (nitisinone) for the treatment of HT-1 was demonstrated based on evidence from the international NTBC study, supported by the recently published results of the Quebec NTBC study.
The NTBC Study was a Phase II/III multinational, open-label, uncontrolled study conducted between 1991 and 2000 in 30 countries, including Canada. Results of the study were analyzed and presented as 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 body weight. Due to the substantial overlap, the two analyses shared 166 patients. A total of 291 patients were enrolled from the beginning of the main analysis to the end 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 results of the NTBC study were compared with a historical control, consisting of clinical outcome data from an international survey of 108 HT-1 patients who were treated with a tyrosine- and phenylalanine-restricted diet.
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.
In the main analysis, 1 and 2 year survival rates 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, compared with 38% and 29%, 74% and 96% in patients treated with dietary restriction alone in whom symptoms developed before 2 months, between 2 and 6 months, and after 6 months of age, respectively. Nitisinone treatment also resulted in rapid improvement and normalization of plasma and urinary succinylacetone, urine 5-aminolevulinic acid (5-ALA) levels, erythrocyte porphobilinogen synthase levels and serum alpha-fetoprotein levels.
In the historical control group, 6/108 (6.4%) of the 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 hepatocellular carcinoma (HCC) was 18% in patients older than 2 years, while in the NTBC study patients treated with nitisinone before the age of 2 years had a cumulative probability of HCC of 1% over 4 years of follow-up.
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.The study comprised 78 HT-1 patients, of whom 50 were treated prospectively with nitisinone between 1994 and 2004, and the remaining 28 patients, who were diagnosed with HT-1 from 1984 to 1994, did not receive nitisinone, and served as a historical control group. Acute complications of HT-1 occurred frequently in the historical control group, assessed retrospectively through chart review.
According to the published results of the Quebec NTBC study, 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, and 20 (71%) underwent liver transplantation, for cirrhosis or cancer (13 patients), acute hepatic failure (2) or neurological crises (5).
The nitisinone-treated patients in the Quebec NTBC study had no deaths prior to transplantation and liver transplantations were only performed in patients who initiated nitisinone after the age of 30 days (7/26, or 27%). All of these patients displayed evidence of significant liver abnormalities prior to initiating nitisinone therapy. In the study, biochemical abnormalities normalized rapidly with nitisinone treatment, including plasma and urine succinylacetone levels, plasma 5 ALA levels, and alpha fetoprotein levels.
For more information regarding the clinical efficacy of Orfadin refer to the Orfadin 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.
The submitted studies support the use of Orfadin for the treatment for adult and pediatric patients with confirmed diagnosis of HT-1, in combination with dietary restriction of tyrosine and phenylalanine. The recommended indication is the same as the indication filed with the submission. Text regarding the use in the geriatric and pediatric populations was revised.
Clinical Safety
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 Orfadin 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 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 Orfadin 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 Orfadin 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 Orfadin Product Monograph includes a contraindication advising that women with HT-1 taking nitisinone must not breast-feed.
Overall, the safety profile of Orfadin is considered acceptable for the treatment of patients with HT-1. Appropriate warnings and precautions are in place in the approved Orfadin Product Monograph to address and manage the identified safety concerns.
For more information, refer to the Orfadin 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 (nitisinone) 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. Health Canada also reviewed a 26-week mouse carcinogenicity study of nitisinone, which failed to show evidence of neoplastic effects.
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.
Longer-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 intrauterine 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 Orfadin Product Monograph to address the identified safety concerns.
For more information, refer to the Orfadin 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 Orfadin 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 18 months for the 2 mg, 5 mg, and 10 mg capsules, and 24 months for the 20 mg capsule is considered acceptable when Orfadin is stored refrigerated at +2 C to +8 C. For all strengths, during the shelf life, the patient may store the product at a temperature of not more than 25ºC for two months, after which the product must be discarded.
Proposed limits of drug-related impurities are considered adequately qualified i.e., within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies.
All sites involved in production are compliant with Good Manufacturing Practices.
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 gelatin in the capsule shell is of animal origin. A letter of attestation confirming that the material is not from a bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) affected country/area has been provided for this product indicating that it is considered to be safe for human use.