Summary Basis of Decision for Velphoro

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 Velphoro is located below.

Recent Activity for Velphoro

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.

Summary Basis of Decision (SBD) for Velphoro

Date SBD issued: 2018-03-12

The following information relates to the new drug submission for Velphoro.

Iron (as sucroferric oxyhydroxide)
500 mg iron (equivalent to 2,500 mg sucroferric oxyhydroxide), tablet (chewable), oral

Drug Identification Number (DIN):

  • 02471574

Vifor Fresenius Medical Care Renal Pharma Ltd.

New Drug Submission Control Number: 201492

On January 5, 2018, Health Canada issued a Notice of Compliance to Vifor Fresenius Medical Care Renal Pharma Ltd. for the drug product Velphoro.

The market authorization was based on quality (chemistry and manufacturing), non clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit-risk profile of Velphoro is favourable for the control of serum phosphorus levels in adult patients with end-stage renal disease on dialysis.

1 What was approved?

Velphoro, a phosphate binder, was authorized for the control of serum phosphorus levels in adult patients with end-stage renal disease on dialysis.

Velphoro 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.
  • Patients with hemochromatosis or any other iron accumulation disorders.

No data are available to Health Canada regarding the use of Velphoro in patients under 18 years of age. Consequently, an indication for pediatric use has not been authorized.

In clinical trials of Velphoro, no overall differences in safety or efficacy were observed between subjects aged 65 years or over and younger subjects.

Velphoro 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.

Velphoro (500 mg iron, equivalent to 2,500 mg sucroferric oxyhydroxide) is presented as a chewable tablet. Sucroferric oxyhydroxide is a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, pregelatinized maize starch and potato starch. In addition to the medicinal ingredient, the tablet contains magnesium stearate, neohesperidin dihydrochalcone, silica (colloidal, anhydrous), and woodberry flavour.

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

2 Why was Velphoro approved?

Health Canada considers that the benefit-risk profile of Velphoro is favourable for the control of serum phosphorus levels in adult patients with end-stage renal disease on dialysis.

Chronic kidney disease affects 5% to 10% of the world population, and it is characterized by a gradual deterioration in renal function as measured by glomerular filtration rate. Chronic kidney disease is associated with multiple complications, including hypertension, anemia, malnutrition, secondary hyperparathyroidism, and bone disease. Declining kidney function is also associated with a progressive deterioration of mineral homeostasis, including that of phosphorus and calcium.

Hyperphosphatemia is common in patients with end-stage renal disease (Stage 5D [Dialysis] chronic kidney disease) regardless of the dialysis method employed. Failure to control hyperphosphatemia is associated with an increase in secondary hyperparathyroidism, renal bone disease (renal osteodystrophy, also referred to as chronic kidney disease - mineral and bone disorder), cardiovascular and other soft tissue calcification, and mortality.

Accordingly, adequate control of serum phosphorus in Stage 5D chronic kidney disease is a cornerstone of patient management. Dietary phosphate restriction and dialysis are usually insufficient to adequately control serum phosphorus levels. Therefore, phosphate binders are used by almost all dialysis patients as a component of their hyperphosphatemia management. The goal of phosphate binder therapy is to limit the intestinal absorption of dietary phosphorus to the point that dialytic clearance can maintain the serum phosphorus concentration between 1.13 and 1.78 mmol/L for Stage 5D chronic kidney disease patients.

Currently approved phosphate binders in Canada include sevelamer hydrochloride, sevelamer carbonate, and lanthanum carbonate. These drugs are effective in lowering serum phosphate, but their use has been associated with gastrointestinal symptoms.

Velphoro, an iron-based phosphate binder, has demonstrated significant reductions in serum phosphorus levels in patients with end-stage renal disease on dialysis. The market authorization of Velphoro was primarily based on data derived from two pivotal active-controlled studies conducted in end-stage renal disease patients on hemodialysis or peritoneal dialysis:

  • Study PA-CL-03A, a Phase II, 6-week, open-label, randomized, active-controlled (sevelamer hydrochloride), parallel group, dose-finding study; and
  • Study PA-CL-05A, a Phase III, 27-week, open-label, randomized, active-controlled (sevelamer carbonate), parallel group, safety and efficacy study, and its 28-week extension, Study PA-CL-05B, with a total duration of 55 weeks.

In Study-PA-CL-05A, the maintenance dose of Velphoro (1,000 to 3,000 mg iron/day, equivalent to 5 to 15 g/day sucroferric oxyhydroxide) demonstrated superiority (p<0.001) in maintaining the phosphorus lowering effect in hemodialysis patients at Week 27 compared with the non-effective low-dose control (250 mg iron/day, equivalent to 1.25 g/day sucroferric oxyhydroxide). The long-term maintenance of serum phosphorus levels with Velphoro treatment for up to 12 months was also demonstrated. The efficacy of Velphoro was consistent across all subgroups (sex, age, ethnicity and geographic region). Clinically relevant efficacy was shown in patients on hemodialysis and peritoneal dialysis, although the latter formed a minority of the total patient population.

Throughout the clinical development program, Velphoro was well tolerated at the proposed doses. The safety profile of Velphoro, as with other non-absorbed drugs, was primarily defined by gastrointestinal adverse events including diarrhea. The majority of the diarrhea adverse events occurred early after starting treatment, were mild in severity, and resolved with continued use of Velphoro. Although no marked differences in the severity of adverse events were noted in the pivotal studies when compared to sevelamer, a higher proportion of patients discontinued treatment due to gastrointestinal adverse events in the Velphoro group as compared to the sevelamer group. In the extension Study PA-CL-05B, discontinuation rates were markedly lower compared with the first 6 months of treatment but they remained higher among the Velphoro-treated patients compared to the sevelamer-treated patients.

No new or significant safety signals emerged with long-term treatment in the analysis of the safety extension study. Based upon a review of the post-marketing data, the safety profile of Velphoro remains unchanged and no issues have arisen that would recommend changes to prescribing information.

Velphoro is an iron-based phosphate binder. The non-clinical studies have shown minimal release of iron from Velphoro in the gastrointestinal tract. In the clinical studies, there were increases in iron parameters (ferritin and transferrin saturation) that occurred early in the treatment and stabilized thereafter. This observation indicates that minimal iron absorption during treatment with Velphoro cannot be excluded. Long-term data did not show an increased risk of iron accumulation or adverse events related to iron parameters. In current clinical practice, chronic kidney disease patients on dialysis are commonly administered intravenously significant amounts of iron averaging from 5 to 7 mg per day. These patients undergo regular assessment of their iron status (including hemoglobin), thus allowing for early detection of any increase in iron stores and appropriate adjustment of the intravenous iron treatment. Therefore, the risk of iron overload with long-term treatment with Velphoro in the target patient population is minimal. The risk of potential iron accumulation has been reflected in the Warnings and Precautions section of the Product Monograph.

Velphoro is presented as a 2.5 g sucroferric oxyhydroxide chewable tablet, but the labelling is based on the iron content rather than the quantity of sucroferric oxyhydroxide. Each chewable tablet contains 500 mg iron as 2,500 mg sucroferric oxyhydroxide.

A Risk Management Plan (RMP) for Velphoro was submitted by Vifor Fresenius Medical Care Renal Pharma Ltd. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look alike Sound alike brand name assessment was performed and the proposed name Velphoro was accepted.

Overall, Velphoro has been shown to have a favourable benefit-risk profile based on non-clinical and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Velphoro 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 Velphoro?

Submission Milestones: Velphoro

Submission MilestoneDate
Pre-submission meeting:2016-10-19
Submission filed:2016-12-22
Screening
Screening Acceptance Letter issued:2017-02-16
Review
Quality Evaluation complete:2018-01-03
Clinical Evaluation complete:2018-01-03
Review of Risk Management Plan complete:2017-10-19
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2017-10-12
Notice of Compliance issued by Director General, Therapeutic Products Directorate:2018-01-05

The Canadian regulatory decision on the non-clinical and clinical review of Velphoro was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

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.

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

Velphoro (sucroferric oxyhydroxide) is a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches. Phosphate binding takes place by ligand exchange between hydroxyl groups and/or water in sucroferric oxyhydroxide and the phosphate ions throughout the physiological pH range of the gastrointestinal tract. The bound phosphate is eliminated with feces. Both serum phosphorus levels and calcium-phosphorus product levels are reduced as a consequence of the reduced dietary phosphate absorption.

Given the insolubility and degradation characteristics of Velphoro, no classical pharmacokinetic studies can be carried out (e.g., determination of the distribution volume, area under the curve, etc.). The Phase I clinical program, therefore, focussed on measures of phosphate binding capacity, iron release and absorption, and drug-drug interactions.

A significant reduction in serum phosphorus levels was seen in chronic kidney disease patients treated with Velphoro 2,000 mg iron/day for 7 days, but not in healthy subjects. Similarly, no changes in serum phosphate were seen in a Phase I dose-ranging tolerability study in healthy subjects. Velphoro was well tolerated in both Phase I studies with mainly mild gastrointestinal adverse events reported (e.g., diarrhea and discoloured feces) and showed only minimal iron absorption.

Studies in healthy volunteers have shown a low risk of drug-drug interactions between Velphoro and some drugs commonly used in dialysis patients including losartan, furosemide, digoxin, warfarin, and omeprazole. However, a potential adsorption of levothyroxine, doxycycline and alendronate by Velphoro has been reported. Therefore, these potential drug-drug interactions have been highlighted in the Velphoro Product Monograph, with recommendations for administering alendronate, doxycycline and levothyroxine separately from Velphoro.

The clinical pharmacological data support the use of Velphoro for the specified indication.

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

Clinical Efficacy

The ability of Velphoro to lower serum phosphorus in end-stage renal disease patients on dialysis was demonstrated in two pivotal clinical trials:

  • Study PA-CL-03A, a Phase II, 6-week, open-label, randomized, active-controlled (sevelamer hydrochloride), parallel group, dose-finding study; and
  • Study PA-CL-05A, a Phase III, 27-week, open-label, randomized, active-controlled (sevelamer carbonate), parallel group, safety and efficacy study, and its 28-week extension, Study PA-CL-05B, with a total duration of 55 weeks.

The open-label design of the trials conducted with Velphoro was necessitated by the chewed or crushed ingestion of Velphoro as compared to the whole tablet ingestion of the active comparators. In addition, fecal discolouration with the iron-based Velphoro precluded double blinding.

A total of 835 patients have been treated with Velphoro in the pivotal clinical trials at doses up to 3,000 mg iron/day (15 g/day sucroferric oxyhydroxide).

The efficacy endpoints included change from baseline in serum phosphorus levels at the end of treatment and at various time points.

The dose-finding Study PA-CL-03A enrolled a total of 154 adult patients with end-stage renal disease on hemodialysis and with serum phosphorus levels ≥1.78 mmol/L. The primary objective of Study PA-CL-03A was to investigate the ability of different doses of Velphoro (250 mg iron/day to 2,500 mg iron/day, equivalent to 1.25 g/day to 12.5 g/day sucroferric oxyhydroxide, as hereafter referred to) to lower serum phosphorus levels in patients with chronic kidney disease on maintenance hemodialysis. A priori assumption was that the lowest dose group (1.25 g/day) would be an inactive control group. The study demonstrated that the two highest doses of Velphoro (12.5 g/day and 10.0 g/day) were significantly (p<0.05) superior to the Velphoro low-dose control group (1.25 g/day) in lowering serum phosphorus levels from baseline to end of treatment. The 1.25 g/day dose of Velphoro was found to be ineffective. The phosphorus lowering effect of Velphoro appeared dose-related. The maximum response and the clinically relevant change of 0.65 mmol/L were achieved with the dose of 10.0 g/day.

The efficacy of Velphoro in lowering serum phosphorus levels has been further demonstrated and confirmed in the pivotal Phase III trial (Study PA-CL-05A) and its extension (Study PA-CL-05B). Study PA-CL-05A enrolled a total of 1,055 chronic kidney disease patients on hemodialysis or peritoneal dialysis, whose serum phosphorus levels were ≥1.94 mmol/L.

In Stage 1 of the Study PA-CL-05A, Velphoro was shown to be non-inferior to sevelamer carbonate in lowering serum phosphorus in chronic kidney disease patients (undergoing hemodialysis or peritoneal dialysis) after 12 weeks of treatment. The treatment difference (Velphoro versus sevelamer carbonate) was 0.08 mmol/L with 97.5% confidence interval (CI) upper limit of 0.15 mmol/L, which was below the 0.19 mmol/L predefined non-inferiority margin. The mean dose used after 12 weeks of treatment was 10.0 g/day for Velphoro and 8.2 g/day for sevelamer carbonate.

Stage 2 of the study was structured to establish the superiority of the Velphoro maintenance dose identified in Stage 1 versus a Velphoro low-dose control in maintaining the phosphorus lowering effect in patients undergoing hemodialysis. The low-dose control used in Stage 2 was the Velphoro 1.25 g/day dose that was found to be ineffective in Study PA-CL-03A. Switching to the ineffective Velphoro low dose (in patients in whom the effective dose was withdrawn following re-randomization) resulted in a rapid rise in mean serum phosphorus levels, confirming the long-term efficacy of Velphoro.

Maintenance of effect has been demonstrated after 24 weeks of treatment. Mean serum phosphorus levels in both the Velphoro group and the sevelamer carbonate group remained steady throughout the maintenance phase of Study PA-CL-05A, and throughout the extension Study PA-CL-05B. The phosphorus lowering effect of Velphoro was consistent and similar to the effect observed with sevelamer carbonate across all subgroups (dialysis type, sex, age, region, and race) over 52 weeks of treatment. The decrease in serum phosphorus levels seen in Stage 1 of Study PA-CL-05A was similar across subjects undergoing peritoneal dialysis and hemodialysis, when compared both within Velphoro-treated subjects, and between the Velphoro and sevelamer treatment groups. This was in line with studies of other phosphate binders where the efficacy of the drugs was found to be consistent, irrespective of the modality of dialysis.

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

Clinical Safety

The clinical development program of Velphoro included 1,112 subjects (chronic kidney disease patients and healthy volunteers) treated with Velphoro for up to 55 weeks. In the integrated data from Study PA-CL-05A and its extension, Study PA-CL-05B (described in Clinical Efficacy section), over 500 subjects treated with Velphoro have completed at least 24 weeks of treatment, and over 300 subjects have completed at least 52 weeks of treatment, with a total of 470.5 person-years of exposure. A total of 610 subjects (86.3%) were exposed to more than 7.5 g/day (1,500 mg iron/day), the proposed starting dose for Velphoro, for an average duration of 223.7 days.

The safety profile of Velphoro is primarily defined by gastrointestinal adverse events, which is to be expected, since the drug is practically insoluble and hardly absorbed. Most commonly reported gastrointestinal adverse events were diarrhea (23.6%) and discoloured feces (16.1%). The laxative action of Velphoro has been noted in all studies, including those conducted in healthy volunteers. In most subjects, diarrhea occurred early after starting treatment, it was mild in severity, and resolved with continued use of Velphoro. Diarrhea was the most common treatment-related adverse event causing discontinuation in the Velphoro group. The incidence of diarrhea in the Velphoro group was substantially lower in the extension Study PA-CL-05B, providing further support for the early onset and transient nature of these events. Discoloured feces is an expected event for an oral iron-based compound. The relatively low incidence of discoloured feces reported in the clinical program suggests that many patients do not consider this event to be of concern.

Constipation is a concern in chronic kidney disease patients on dialysis, occurring in over 60% of patients, and it is also commonly reported with the use of oral iron medications. Throughout the clinical development program, there has been no indication that constipation is a concern with the use of Velphoro. The incidence of constipation with Velphoro was low (5.1%) over 52 weeks in Studies PA-CL-05A and PA-CL-05B, and the majority of reported events were mild in severity.

Very few serious adverse events were related to treatment, and they were generally attributed to the gastrointestinal disorders. Although the incidence of serious adverse events was similar between Velphoro and sevelamer, a higher proportion of patients discontinued treatment due to treatment-emergent adverse events in the Velphoro group compared to the sevelamer group (number of patients [n] = 148; 20.9% versus n = 36; 10.3%, respectively, in the integrated data from Studies PA-CL-05A and PA-CL-05B). Gastrointestinal adverse events were the most common adverse events leading to withdrawal in both groups, accounting for 70 of 148 withdrawals (47.3%) in the Velphoro group and 11 of 36 (30.6%) in the sevelamer group. In the extension Study PA-CL-05B, discontinuation rates were markedly lower among the Velphoro-treated patients, but they remained higher compared to the sevelamer group.

Overall, there were 21 deaths in subjects treated with Velphoro during the Phase II and Phase III studies, none of which were considered related to treatment. In keeping with the end-stage renal disease patient population, most of the deaths involved cardiac or cardiorespiratory events, and the overall death rate was similar between the two treatment groups.

Velphoro is an iron-based phosphate binder and non-clinical studies have shown minimal release of iron from Velphoro in the gastrointestinal tract. No significant changes in iron parameters were noted in the Phase I studies or in the short-term Study PA-CL-03A. In Studies PA-CL-05A and PA-CL-05B, serum ferritin, serum iron and transferrin saturation for subjects receiving Velphoro showed increases, which occurred early during treatment and stabilized thereafter. No clinically meaningful changes in hemoglobin or hematocrit were noted. In current clinical practice, chronic kidney disease patients on dialysis are commonly administered intravenously significant amounts of iron averaging 5 to 7 mg per day. In a Phase I study, subjects on hemodialysis had a median uptake of 0.02% of iron from Velphoro. This would equate to absorption of 0.6 mg iron/day following administration of the maximum proposed daily dose of 1.5 g iron/day Velphoro. The iron status, including hemoglobin is regularly assessed in the chronic kidney disease patients on dialysis. Consequently, any increase in iron stores will be detected early, and adjustments to their intravenous iron treatment made accordingly. Therefore, the risk of potential iron accumulation with long-term treatment with Velphoro is minimal, and an appropriate wording has been included in the Warnings and Precautions section of the Velphoro Product Monograph.

No safety signals were detected with respect to clinical chemistry, hematological, or vitamin levels. Post hoc analyses from clinical studies demonstrated that Velphoro did not impact the intact parathyroid hormone lowering effect of oral vitamin D analogues. Vitamin D and 1,25-hydroxy vitamin D levels remained unchanged. No changes in electrocardiogram parameters or vital signs were seen. In Study PA-CL-05A and its extension, Study PA-CL-05B, there were significant decreases in fibroblast growth factor 23 (FGF-23) (responsible for phosphate and vitamin D metabolism) in both treatment groups, with no significant difference between treatment groups. Significant increases in bone-specific alkaline phosphatase were observed in both treatment groups, with a significantly higher increase in the sevelamer group. However, given that serum intact parathyroid hormone, calcium, and vitamin D levels remained relatively stable, the small changes in bone-specific alkaline phosphatase which occurred concurrently with the control of serum phosphorus levels during long-term treatment with Velphoro were not considered clinically relevant.

Overall, Velphoro has a comparable safety profile to sevelamer. No signs of increased numbers of adverse events related to Velphoro were seen in the post-marketing experience.

Appropriate warnings and precautions are in place in the approved Velphoro Product Monograph to address the identified safety concerns.

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

7.2 Non-Clinical Basis for Decision

Velphoro is a mixture of polynuclear iron(III)-oxyhydroxide, sucrose and starches. The iron content of Velphoro is about 21% w/w.

Non-clinical studies have demonstrated that Velphoro is an effective and well-tolerated oral phosphate binder. Under acidic conditions, mainly iron phosphate is formed, whereas under slightly alkaline conditions, iron(III)-oxyhydroxide is the favoured chemical species. In vitro studies showed high phosphate binding capacity of Velphoro especially at pH values higher than 2.5 and up to 8.1. The maximum iron release (6.3%) from Velphoro occurred at very low pH values of 1.2 to 1.5 (i.e., under the fasting state of the stomach). Therefore, Velphoro should be taken with food, to maximize adsorption of phosphate from the diet and minimize iron release from Velphoro. Regular monitoring of iron levels should follow standard clinical practice in end-stage renal disease patients on dialysis.

Velphoro is insoluble and therefore not absorbed. No classical pharmacokinetic studies were carried out. Velphoro is not metabolized. However, the degradation product mononuclear iron species can be released from the surface of Velphoro and absorbed. Data from rats and dogs indicated that there was very little absorption of iron from sucroferric oxyhydroxide (<1.5% of the administered dose) during passage through the gastrointestinal tract. The absorbed iron was recovered in the typical tissues of iron storage or utilization (red blood cells, liver, spleen, bone marrow). Velphoro was excreted in feces only.

The toxicity profile of Velphoro largely reflects the intended pharmacological activity of Velphoro. Local effects observed in the rodent gastrointestinal tract (mucosal hyperplasia, and diverticulum/cyst formation in the colon and caecum of mice) were considered species-specific and not relevant for human use. There was an increased incidence (21.9%) of benign C-cell adenoma in the thyroid of male rats at the highest dose (12.5 times the maximum intended human clinical dose) of sucroferric oxyhydroxide. This is thought to be most likely an adaptive response to the pharmacological effect of the drug, and not clinically relevant.

Velphoro is not genotoxic, and no specific adverse effects were observed in animal reproductive and developmental toxicity studies.

In conclusion, the non-clinical data provided support for the use of Velphoro as an oral phosphate binder for the control of serum phosphorus levels. The results of the non-clinical studies as well as the potential risks to humans have been included in the Velphoro Product Monograph. In view of the intended use of Velphoro, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Velphoro 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 Velphoro has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15ºC to 30ºC).

Proposed limits of drug-related impurities are considered adequately qualified, i.e., within the 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.