Summary Basis of Decision for Panhematin
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 Panhematin is located below.
Recent Activity for Panhematin
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 Panhematin
Updated:
The following table describes post-authorization activity for Panhematin, a product which contains the medicinal ingredient hemin. 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 02476991 - 2% w/w crisaborole, ointment, topical
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02478765) market notification | Not applicable | Date of first sale:2018-12-05 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 212276 | 2017-12-20 | Issued NOC2018-07-13 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Panhematin
Date SBD issued: 2018-11-20
The following information relates to the new drug submission for Panhematin.
Hemin
268 mg/vial, powder for solution, intravenous
Drug Identification Number (DIN):
- 02478765
Recordati Rare Diseases Canada Inc.
New Drug Submission Control Number: 212276
On July 13, 2018, Health Canada issued a Notice of Compliance to Recordati Rare Diseases Canada Inc. for the drug product Panhematin.
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 Panhematin is favourable for the amelioration of recurrent attacks of acute intermittent porphyria temporally related to the menstrual cycle in susceptible women, after initial carbohydrate therapy is known or suspected to be inadequate.
1 What was approved?
Panhematin is an enzyme inhibitor derived from processed red blood cells. It was authorized for the amelioration of recurrent attacks of acute intermittent porphyria temporally related to the menstrual cycle in susceptible women, after initial carbohydrate therapy is known or suspected to be inadequate.
Based on the data submitted to and reviewed by Health Canada, the safety and efficacy of Panhematin in pediatric patients have not been established. Therefore, Health Canada has not authorized an indication for pediatric use.
Evidence from clinical data in the geriatric population (patients over 65 years of age) is not sufficient to determine whether they respond differently from younger subjects.
Panhematin is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Panhematin was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Panhematin (hemin, 268 mg/vial) is presented as a sterile, lyophilized powder for intravenous administration after reconstitution. In addition to the medicinal ingredient, each dispensing vial of Panhematin contains 240 mg sodium carbonate and 335 mg of sorbitol. The pH may have been adjusted with hydrochloric acid. When mixed as directed with Sterile Water for Injection, USP, each 48 mL provides the equivalent of approximately 261 mg hematin (5.4 mg/mL). The product contains no preservatives.
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 Panhematin Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Panhematin approved?
Health Canada considers that the benefit-risk profile of Panhematin is favourable for the amelioration of recurrent attacks of acute intermittent porphyria temporally related to the menstrual cycle in susceptible women, after initial carbohydrate therapy is known or suspected to be inadequate.
Acute intermittent porphyria is a rare autosomal dominant disorder resulting from a partial deficiency of the enzyme porphobilinogen deaminase (PBGD) in the heme biosynthesis pathway. The deficiency in PBGD leads to an accumulation of the precursors of porphyrins in the liver. The main clinical manifestations include abdominal pain, psychiatric symptoms, neurological manifestations and cardiovascular changes. Patients suffer intermittent neurovisceral attacks that can persist for several days and repeat over several weeks. On the basis of prevalence data from other countries, it is estimated that there would be between 360 to 720 Canadians with acute intermittent porphyria. One fifth of the patients present with symptoms requiring treatment.
Currently, there are no approved drug products for acute intermittent porphyria in Canada. The supportive care includes carbohydrate therapy and removal of triggering factors.
Panhematin contains hematin that has been prepared from large pools of human red blood cells. Hematin is an iron-containing metalloporphyrin complex that is bound to a hydroxide ion. Hematin is structurally similar to the endogenous substance, heme, which acts to limit the hepatic and/or marrow synthesis of porphyrin in a negative feedback manner. This action is likely due to the inhibition of δ-aminolevulinic acid synthase, the enzyme which limits the rate of the porphyrin/heme biosynthetic pathway.
Designing and conducting well-controlled clinical trials in patients with rare diseases face many challenges. Thus, controlled clinical trials have not been conducted with Panhematin. The market authorization of Panhematin was based on clinical evidence derived from published information and post-marketing experience data.
The effectiveness of Panhematin for the amelioration of recurrent attacks of acute intermittent porphyria was evaluated in five open-label studies, a compassionate-use study, case reports, and an observational study investigating patient-reported outcomes in patients with acute porphyrias. A total of 372 patients were treated with Panhematin for acute porphyria attacks. Of these patients, 369 were evaluable for efficacy whereas 248 were evaluable for safety.
Across all studies, patients with acute attacks of porphyria were treated with hemin at doses of 1 to 4 mg/kg/day once or twice daily for 1 to14 days based on clinical signs. A maximum dose of 6 mg/kg of hemin in any 24-hour period was used. For most studies, the doses of Panhematin administered intravenously to patients were 3 to 4 mg/kg. However, historical release data show that the content of the vials was typically about 76.6% of the 350 mg label claim and the actual amount of drug used in the studies published in the 1970s and 1980s is not available. Based on the new label claim of hemin content in a vial of Panhematin (268 mg hemin per vial), the proposed recommended dose in the Panhematin Product Monograph has been adjusted and is considered to be justified.
The five open-label studies included 99 patients with acute porphyria, 72 of whom had acute intermittent porphyria. Thirty (30) patients received prior or concomitant glucose treatment. Patients experienced a clinical response in 85.5% (141/165) of treatment courses of Panhematin. A clinical response was defined as improvement of symptoms and reduction in pain. In addition, all patients experienced a chemical response which was defined as normalization of urinary δ-aminolevulinic acid and porphobilinogen.
The compassionate-use, multicentre, open-label, non-comparative study enrolled 130 patients with a diagnosis of acute porphyria, including 90 patients (69%) treated for acute attacks, 19 patients (15%) treated for prophylaxis, and 21 patients (16%) treated for both acute attacks and prophylaxis. A clinical response was achieved if the physician determined that the admitting symptoms had resolved, there was a clinically acceptable response, or the patient went into remission. A physician-assessed clinical response was achieved for all acute attacks in 81 (73%) of 111 patients. Ninety-four patients (85%) of 111 had ≥1 clinical response and 17 patients (15%) of 111 had no response.
The observational study investigated patient-reported outcomes in 108 patients with acute porphyria, including 90 patients with acute intermittent porphyria. Fifty-five percent (55%) of patients reported having received hemin during acute attacks, and 74% of these patients assessed Panhematin therapy as very successful in the treatment of abdominal pain and other symptoms. Fifty percent (50%) reported having recveived treatment with opiates during an acute attack, and 44% of these patients reported that opiates were effective.
Panhematin is, generally, well tolerated. The identified safety concerns associated with Panhematin include the risk of phlebitis and the risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jacob disease (vCJD) agent and, theoretically, the CJD agent. The risk that Panhematin may transmit an infectious agent has been reduced by screening blood donors for prior exposure to certain viruses, by testing for the presence of certain virus infections, and by inactivating certain viruses. Despite these measures, Panhematin can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in the product.
Increased levels of iron and serum ferritin have been reported in post-marketing experience. In addition, a reversible renal shutdown was observed in a case where an excessive hematin dose (12.2 mg/kg) had been administered in a single infusion.
The identified safety concerns have been appropriately addressed in the Warnings and Precautions section and the Adverse Reactions section of the Panhematin Product Monograph.
A Risk Management Plan (RMP) for Panhematin was submitted by Recordati Rare Diseases Canada Inc. to Health Canada. Substantial deficiencies were identified in the RMP. Therefore, Health Canada requested that the sponsor submit a revised RMP within 90 days of the market authorization of Panhematin (see What follow-up measures will the company take?). The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Panhematin Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Panhematin was accepted.
Based on the data submitted, Health Canada considers that the benefits of Panhematin outweigh the potential risks in the target patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Panhematin 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 Panhematin?
The drug submission for Panhematin was reviewed under the Priority Review Policy. Substantial evidence was provided to demonstrate clinical effectiveness of Panhematin in the amelioration of recurrent attacks of acute intermittent porphyria, a serious, life-threatening condition for which no drug is presently marketed in Canada.
Submission Milestones: Panhematin
| Submission Milestone | Date |
|---|---|
| Request for priority status | |
| Filed: | 2017-10-31 |
| Approval issued by Director, Centre for Biologics Evaluation: | 2017-11-22 |
| Submission filed: | 2017-12-20 |
| Screening | |
| Screening Acceptance Letter issued: | 2018-01-16 |
| Review | |
| On-Site Evaluation: | 2018-06-13 - 2018-06-15 |
| Quality Evaluation complete: | 2018-07-12 |
| Clinical Evaluation complete: | 2018-07-13 |
| Review of Risk Management Plan complete: | 2018-04-27 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-07-12 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2018-07-13 |
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?
As part of the marketing authorization of Panhematin, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) submitting to Health Canada the following:
- a revised risk management plan (RMP) within 90 days of the market authorization; and
- within the revised RMP, a copy of the "Dear Health Care Professional" letter, regarding the new label claim and dose recommendations.
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
Hemin, the medicinal ingredient in Panhematin, is structurally similar to the endogenous compound, heme. The term hematin has been used to describe the chemical reaction product of hemin and sodium carbonate solution. Hemin and hematin are iron containing metalloporphyrin complexes with either bound chloride or hydroxide ions, respectively.
Heme acts to limit the hepatic and/or marrow synthesis of porphyrin. This action is likely due to the inhibition of δ-aminolevulinic acid synthase, the enzyme which limits the rate of the porphyrin/heme biosynthetic pathway. The exact mechanism by which Panhematin produces symptomatic improvement in patients with acute episodes of hepatic porphyrias has not been elucidated.
Following intravenous administration of hematin in non-jaundiced human patients, an increase in fecal urobilinogen can be observed which is roughly proportional to the amount of hematin administered. This suggests an enterohepatic pathway as at least one route of elimination. Bilirubin metabolites are also excreted in the urine following hematin injections. Other aspects of human pharmacokinetics have not been defined.
For further details, please refer to the Panhematin Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Given the rarity of acute intermittent porphyria, controlled clinical trials have not been conducted with Panhematin. Therefore, the effectiveness of Panhematin for the amelioration of recurrent attacks of acute intermittent porphyria was evaluated in five open-label studies (number of patients [n] = 99), one compassionate-use study (n = 130), case reports (n = 32), and one observational study (n = 108) investigating patient-reported outcomes in patients with acute porphyrias. A total of 372 patients were treated with Panhematin for acute porphyria attacks. Of these patients, 369 were evaluable for efficacy.
The five open-label studies included 99 patients with acute porphyria, 72 of whom had acute intermittent porphyria. Of the 99 patients, 30 received prior or concomitant glucose treatment. Patients experienced a clinical response in 85.5% (141/165) of treatment courses of hemin. The clinical response to treatment was defined by improvement of symptoms and reduction in pain. In addition, all patients experienced a chemical response which was defined as normalization of urinary δ-aminolevulinic acid and porphobilinogen.
The compassionate-use, multicentre, open-label, non-comparative study enrolled 130 patients with a diagnosis of acute porphyria, including 90 patients (69%) treated for acute attacks, 19 patients (15%) treated for prophylaxis and 21 patients (16%) treated for both acute attacks and prophylaxis. A clinical response to treatment was achieved if the physician determined that the admitting symptoms had resolved, there was a clinically acceptable response, or the patient went into remission. A physician-assessed clinical response was achieved for all acute attacks in 81 (73%) of 111 patients. Ninety-four patients (85%) of 111 had ≥1 clinical response and 17 patients (15%) of 111 had no response.
The observational study investigated patient-reported outcomes in 108 patients with acute porphyria, including 90 patients with acute intermittent porphyria. Fifty-five percent (55%) of patients reported having received hemin during acute attacks, and 74% of these patients assessed Panhematin therapy as very successful in the treatment of abdominal pain and other symptoms. Fifty percent (50%) reported having received treatment with opiates during an acute attack, and 44% of these patients reported that opiates were effective.
Overall, the published data support the effectiveness of Panhematin in the amelioration of recurrent attacks of acute intermittent porphyria in the target patient population.
For more information, refer to the Panhematin Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety evaluation of Panhematin was based on published information and post-marketing experience data.
Across one compassionate-use study, five open-label studies, and case reports, the safety profile of Panhematin was evaluated in 248 patients with acute porphyria. Of these patients, 220 had acute intermittent porphyria, 18 had variegate porphyria, and one had hereditary coproporphyria.
In the compassionate-use study (described in the Clinical Efficacy section), the most commonly reported adverse events included headache, nausea, fever, injection-site reaction (phlebitis) and vomiting. Twenty-five percent (25%) of the reported adverse events were considered possibly or probably related to treatment by the investigator. Five serious adverse events were reported as possibly or probably related to treatment, including "adverse drug reaction", "injection-site reaction", "phlebitis", "pyrexia, bacteremia" and "cellulitis".
In the five open-label studies including 99 patients with acute porphyria, a transitory renal failure was observed in one patient with acute intermittent porphyria, who had received an infusion of 1,000 mg hematin (12.2 mg/kg). Cases of phlebitis were also reported.
In the case reports, reported adverse events included phlebitis, thrombophlebitis, fever, irritation, Coombs-negative hemolytic anemia, transitory renal failure (one case), circulatory collapse (anaphylactoid reaction), coagulopathy and thrombocytopenia.
Post-marketing safety data have been collected since 1983, when Panhematin was approved by the United States Food and Drug Administration. According to the data reported as of July 31, 2017, the cumulative patient exposure collected since 2009 equaled to a total of 70,881 vials of Panhematin distributed to 8,338 patients. In Canada, Panhematin has been available since 2014, under the Health Canada Special Access Programme. During the reporting period of August 1, 2016 to July 3, 2017, 14 vials were distributed to two patients in Canada.
Since 1983, there have been 357 post-marketing spontaneous case reports received by the sponsor. These reports contained 776 adverse events (538 non-serious and 238 serious adverse events). Administration site conditions, such as extravasation, pain and pyrexia, accounted for one third of all adverse events reported. These were followed by vascular disorders such as phlebitis or thrombophlebitis, nausea, vomiting and increased serum ferritin.
Overall, the safety profile of Panhematin is considered acceptable for the amelioration of recurrent attacks of acute intermittent porphyria in the target patient population.
Appropriate warnings and precautions are in place in the approved Panhematin Product Monograph to address the identified safety concerns.
For more information, refer to the Panhematin Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Non-clinical data support the use of Panhematin for the specified indication.
Repeat-dose toxicity studies of Panhematin were conducted in rats and mice. The no-observed-adverse-effect level (NOAEL) for Panhematin following intermittent intravenous administration of 7 doses was established as 6 mg/kg in rats and 12 mg/kg in mice. The highest NOAEL dose was equivalent to 1.5 to 2 times the human dose in rats and to 3 to 4 times the human dose in mice.
Panhematin showed no genotoxic effects. Carcinogenicity studies, and reproductive and developmental toxicity studies have not been conducted with Panhematin.
In view of the intended use of Panhematin, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Panhematin Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Characterization of the Drug Substance
Hematin, the medicinal ingredient in Panhematin, is an enzyme inhibitor derived from processed human red blood cells. Hematin is a small molecule with a well-defined structure. It is an iron containing metalloporphyrin complex with a bound hydroxide ion.
Panhematin is manufactured with the drug substance hemin, which converts to hematin during drug product formulation.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Panhematin has been manufactured for more than 30 years and marketed in the United States. Over that time, several adjustments have been made to the manufacturing process and facilities as well as the product ownership.
The validation of the drug substance manufacturing process was carried out on three consecutive lots in 2008. The validation data showed that the process parameters were all well within their operating ranges although there were very few instances where operating limits were challenged. The parameters and ranges in the process validation are consistent with how the drug substance is manufactured today with a few minor exceptions. The sponsor provided a list of significant changes since the time of the process validation. None of these changes necessitated process revalidation for the drug substance.
The manufacturing process for Panhematin was originally validated in 2008 with partial revalidation conducted in 2015 and 2017 to support the increased fill weight (targetting a nominal 350 mg/vial presentation). Validation studies addressed the filling of the vials and the lyophilization process. Additional data were also available to support mixing validation, and to show consistency in manufacture across multiple commercial batches. It was clear from the data provided that there is a significant loss in product content across compounding and filling, and robust measures are in place to limit the time between compounding and start of lyophilization.
Additional data were provided from media fill studies that validated certain sterile processing steps and procedures. While limited data (approximately 10 years old) were provided in the submission, more recent results were reviewed during the on-site evaluation and found to be acceptable.
Results from process validation studies have demonstrated consistent, reproducible manufacturing and that the drug substance and Panhematin will meet their predetermined specifications. Also, the manufacturing steps have been shown to adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within acceptable limits.
The proposed routine process monitoring and in-process control parameters were those used for validation and are essentially unchanged from the historical controls. Overall, sufficient and acceptable data have been provided regarding the control of the process and the control regime is appropriate for this type of product.
Process validation data and results from comparability studies demonstrate that the process can reproducibly yield Panhematin drug product that is of acceptable quality, however, the process yields Panhematin containing around 80% of the originally proposed label claim. Therefore, the sponsor was requested to revise the content claim for Panhematin to accurately reflect vial content. The sponsor performed a statistical analysis of available data and determined that the more representative equivalent amount of hemin in finished product vials was 268 mg/vial (as opposed to the non-representative 350 mg/vial initially proposed) and that is what the accepted label will show.
Panhematin is provided as a sterile, lyophilized powder for intravenous administration after reconstitution. Each dispensing vial of Panhematin contains the equivalent of 268 mg hemin, 240 mg sodium carbonate and 335 mg of sorbitol. The pH may have been adjusted with hydrochloric acid. Panhematin contains no residual hydrochloric acid. When reconstituted as directed with Sterile Water for Injection, USP, each 48 mL provides approximately 261 mg hematin (5.4 mg/mL). The product contains no preservatives.
The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.
Control of the Drug Substance and Drug Product
The majority of the materials proposed for use in this submission are of compendial grade, except for the outdated red blood cells originally intended for transfusion. The drug substance specifications are unchanged since the beginning of the production. Information on the processes used for blood collection (e.g., donor selection, deferral procedures associated with reactive test results, donor re-entry algorithms, disposal of unsuitable material, and the system for maintaining donor information and for conducting lookback procedures) was provided and deemed acceptable. Overall, the raw materials were found to be acceptable.
Three lots of Panhematin were assessed by Health Canada as per the test plan requirements for reconstitution time and appearance. The test results and other information provided indicate consistent manufacture. The lots met test plan and manufacturer specifications.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life at 20ºC to 25ºC for Panhematin is considered acceptable.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured.
The facility involved in the manufacture of the drug substance was not available for an on-site evaluation due to a shutdown, but this facility had previously been approved to manufacture intermediates for other authorized products.
On-site evaluations were carried out at the facilities involved in the manufacture and testing of the drug product. All noted observations have been acceptably resolved.
All sites involved in production are compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
The drug substance, hemin, is a small molecule obtained in high purity as a dried crystalline solid. It is manufactured from outdated red blood cells accepted for transfusion (i.e., obtained from screened donors) by a chemical process which employs a strong acid, organic solvents, and high heat for extended periods. Data provided from viral clearance studies support three viral inactivation steps that contribute to the overall viral reduction capacity of the manufacturing process. The overall virus reduction (inactivation) capacity of the drug substance manufacturing process is deemed adequate.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| PANHEMATIN | 02478765 | RECORDATI RARE DISEASES CANADA INC | HEMIN 268 MG / VIAL |