Summary Basis of Decision for Pantoloc M ™
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:
Pantoloc MTM
Pantoprazole magnesium, 40 mg, Enteric-coated tablets, Oral
ALTANA Pharma Inc.
Submission control no: 091462
Date issued: 2006-06-22
Health Products and Food Branch
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Health Canada
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrPANTOLOC MMD, Pantoprazole magnésique, 40 mg, comprimés entéro-solubles, ALTANA Pharma Inc., N° de contrôle de la présentation 091462
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02267233
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
™ is used under license from ALTANA Pharma Inc.
2 Notice of decision
On April 22, 2005, Health Canada issued a Notice of Compliance to ALTANA Pharma Inc. for the drug product Pantoloc M™. Pantoloc M™ contains the medicinal ingredient pantoprazole magnesium which is an H+, K+-ATPase inhibitor. The sponsor submitted this application as a newly developed formulation of the currently authorized proton pump inhibitor pantoprazole sodium (Pantoloc).
Pantoloc M™ is indicated for the treatment of conditions where a reduction of gastric acid secretion is required such as gastric and duodenal ulcers, reflux esophagitis, symptomatic gastro-esophageal reflux disease (sGERD), and Helicobacter pylori associated duodenal ulcers. Pantoloc M™ is a specific inhibitor of the gastric H+, K+-ATPase enzyme (the proton pump) that is responsible for acid secretion by the parietal cells of the stomach.
The market authorization was based on data from quality control studies, pre-clinical, and clinical studies. Efficacy and safety were examined in a clinical trial involving 636 patients with GERD; 322 were given pantoprazole magnesium while 314 were given the currently approved pantoprazole sodium. Separate pharmacokinetic studies showed that pantoprazole magnesium and pantoprazole sodium were not kinetically equivalent. However, pantoprazole magnesium was found to be non-inferior in healing reflux disease and had a comparable safety profile relative to pantoprazole sodium. Furthermore, pharmacodynamic studies have shown that the effect of both formulations on gastric acidity (pH) was equivalent.
Pantoloc M™ (pantoprazole magnesium) is presented in enteric-coated tablets. The recommended adult dosage is 40 mg given orally once or twice daily depending on the type of condition being treated. In the case of H. pylori associated duodenal ulcers, Pantoloc M™ administration should be taken in combination with either clarithromycin and metronidazole, or clarithromycin and amoxicillin. Dosing guidelines are available in the Product Monograph.
Pantoloc M™ is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, please see the Dosage Forms, Composition and Packaging section of the Product Monograph. Detailed conditions for the use of Pantoloc M™ are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Pantoloc M™ is favourable for the treatment of conditions where a reduction of gastric acid secretion is required.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Manufacturing Process and Process Controls
Pantoprazole magnesium is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterisation
Pantoprazole magnesium is a white to beige powder dihydrate only slightly soluble in water which possesses a chiral centre at the sulfur atom. The structure of pantoprazole magnesium has been adequately explained and the representative spectra have been provided. Physical and chemical properties have been described and found to be satisfactory. There is no evidence of polymorphism for the manufacturing of this drug substance.
The sponsor has provided a summary of all drug-related impurities. Impurities that arose from manufacturing were reported, characterized, and were found to be within ICH established limits, and therefore considered to be acceptable.
Control of Drug Substance
Validation reports were satisfactorily submitted for all analytical procedures used for in-process and release testing of the drug substance, and to justify the specification of the drug substance.
Data from batch analyses were reviewed and considered to be acceptable according to the specification of the drug substance.
Stability
Based upon the real-time and accelerated stability study data submitted, the proposed shelf-life, storage and shipping conditions for pantoprazole magnesium were supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Pantoloc M™ has been authorized in one strength, 40 mg. The tablets are round, yellow, biconvex, and film-coated with "40" printed in brown ink on one side reflecting the strength. Tablets are available in bottles of 100. Bottles for marketing are made of white HDPE and have grey LDPE screw caps and milky transparent LDPE spacers.
All excipients found in the drug product are acceptable for use in drugs by the Canadian Food and Drug Regulations. The compatibility of pantoprazole magnesium with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Pantoprazole magnesium tablets were developed in a stepwise process by increasing the batch sizes from lab scale to the final production process which was then validated. Particle size distribution was monitored and was considered acceptable.
Studies were also undertaken to evaluate the container closure system and microbiological attributes of the dosage form, the results of which were considered acceptable.
Manufacturing Process and Process Controls
All equipment, operating parameters, in-process tests and detailed instructions are adequately defined in the documentation. The manufacturing process for commercial production is well-controlled and yields tablets that meet all relevant specifications. The manufacturing process was considered to be adequately controlled within justified limits.
Control of Drug Product
Pantoloc M™ is tested to verify its identity, appearance, content uniformity, dissolution, capsule markings, and the presence of degradation products and microbiological impurities. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
The validation process is considered to be complete. Validation reports were submitted for in-process and release testing of the drug product, and no anomalies were present. The results for all of the batches were within the proposed specification limits.
Stability
Based upon real-time and accelerated stability study data submitted, the proposed 18 month shelf-life at 15-30°C for the drug product is considered to be acceptable.
The container proposed for use with pantoprazole magnesium tablets is identical to that currently used for the authorized and marketed pantoprazole sodium and has proved acceptable to support both the safety and stability of the product. Health Canada thus considers the proposed container/closure system acceptable for use with Pantoloc M™ tablets.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and the equipment are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Pantoloc M™ has demonstrated that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for the commercial process.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
To support the original submission of the sodium salt, single and repeat-dose pharmacodynamics and pharmacokinetics were studied in mice, rats, dogs, and monkeys. No animal data were presented to demonstrate the pharmacodynamic equivalence of pantoprazole-Mg and pantoprazole-Na as the active compound itself (pantoprazole) is unchanged, and as such, further studies were deemed unnecessary.
3.2.2 Pharmacokinetics
A study to investigate the bioavailability of the pantoprazole-Mg tablet core relative to the pantoprazole-Na tablet core was conducted in Beagle dogs. Uncoated tablets were administered orally as a single dose. The bioavailability of the magnesium core relative to the sodium core was 86.2% and the corresponding Cmax was 61.8%. The apparent terminal half-life (t1/2) of pantoprazole is increased by approximately 23% with the magnesium tablets as compared to the sodium tablets. The difference in pharmacokinetic parameters of the Mg salt and the Na salt was likely due to the very slow dissolution of the Mg tablets in the stomach/duodenum which is a result of its significantly reduced solubility. This also results in more degradation of the drug contributing to lower plasma levels.
Toxicokinetic data measured in a newly-submitted repeat-dose toxicity study in rats was consistent with the above results though t1/2 was not increased.
3.2.3 Toxicology
Studies of pantoprazole in animals were submitted to support the original submission of the sodium salt and included single- and repeat-dose toxicity, carcinogenicity, reproductive toxicity, and special studies on pulmonary effects, local tolerance, antigenicity, and effects on red blood cells. These studies showed that pantoprazole has a safety profile comparable to that of other proton pump inhibitors and does not present a safety concern for human use. As the toxicity of pantoprazole has been well characterized by these previous studies and as the chemical nature of the drug and its mechanism show no grounds for any differences in the action between pantoprazole-Mg and pantoprazole-Na, the pre-clinical information previously submitted supports the use of the magnesium salt as well.
Two additional pre-clinical studies were submitted for pantoprazole-Mg; a single-dose study in rats and mice and a repeat-dose study in rats. In the single-dose study, the drug substance was given orally by gavage at 3 dose levels and it was found that doses up to 1000 mg/kg induced no changes in behaviour or body weight. In the repeat-dose study, the Mg and Na salts were administered once daily by the oral route for 4 weeks. There were no indications of any differences in the pattern of toxic changes between the two drugs. Compound-related effects were noted on red blood cells and the target organs were the stomach, liver and thyroid. No qualitative or quantitative differences in the toxic response were apparent between the two forms of pantoprazole.
3.2.4 Summary and Conclusion
The pre-clinical studies demonstrated that pantoprazole magnesium did differ from pantoprazole sodium, the present formulation (Pantoloc), in terms of PK parameters. The PK parameters (AUC and Cmax) were lower in animals treated with the magnesium salt than those treated with the sodium salt. The magnesium salt is less water-soluble than the sodium salt. Once absorbed, pantoprazole magnesium elicits the same toxicological effect in rats as those found in animals treated with the sodium salt. Compound-related effects were noted on red blood cells and the target organs were the stomach, liver and thyroid. No qualitative or quantitative differences in the toxicological response were apparent between the two forms of pantoprazole. Thus, from these studies, pantoprazole magnesium does not appear to elicit new or unpredictable toxicological effects.
The amount of magnesium ion ingested with a daily dose of a 40 mg pantoprazole magnesium tablet (approximately 1.3 mg magnesium) is far lower than that found in many foods, beverages, dietary mineral supplements and than the recommended daily allowance (approximately 280-300 mg). Thus exchanging sodium for magnesium does not place humans at risk of excessive magnesium intake.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
One Phase II, two-centre, randomized, two-way crossover, comparative pharmacodynamic study was conducted to compare the 24-hour intragastric pH profile under steady-state conditions following administration of pantoprazole magnesium versus pantoprazole sodium once daily for seven days in GERD patients. No serious adverse events were reported and pantoprazole magnesium was found to demonstrate comparative efficacy to pantoprazole sodium in patients with GERD having either H. pylori positive or negative status. Large differences were found when variables are compared between H. pylori positive and negative subjects, which is supported by the literature. Proton pump inhibitors appear to be more effective in patients with H. pylori. Pharmacodynamic equivalence was shown for pantoprazole magnesium 40 mg versus pantoprazole sodium 40 mg in H. pylori negative and H. pylori positive patients.
3.3.2 Pharmacokinetics
Two single-centre, double-blind, double-dummy, randomized, two-way crossover bioequivalence studies were conducted in healthy adult males. Patients received a single dose of either pantoprazole magnesium or pantoprazole sodium under fasting conditions for the first study while the second study was conducted under fed conditions. Pantoprazole magnesium was not shown to be bioequivalent to pantoprazole sodium in either study. The Cmax values during both fed and fasted state were about 67% of the value for pantoprazole sodium.
3.3.3 Clinical Efficacy (analysis of main studies)
One multi-centre, randomized, double-blind, parallel group comparison study was conducted to compare the efficacy and tolerability of pantoprazole-Na and the new developed pantoprazole-Mg in patients with reflux esophagitis (GERD I to III according to Savary Miller Classification modified by Siewert) with respect to the healing of mucosal lesions after an 8-week treatment period. The aim of the study was to demonstrate that pantoprazole-Mg was non-inferior to pantoprazole-Na, the commercial formulation. A total of 322 patients were treated with pantoprazole-Mg 40 mg and 314 patients were treated with pantoprazole-Na. From the results of the study, healing rates were dependent on the initial GERD grade I, II, or III after 4 and 8 weeks. The proportion of patients healed decreased with increasing GERD grades in both treatment groups. Of note is the finding that healing rates of H. pylori positive patients were rather similar to that in H. pylori negative patients treated with both pantoprazole salts in contrast with the pharmacodynamic findings. The percent time pH>4 in H. pylori positive patients was 2- fold higher than in H. pylori negative patients. With respect to endoscopic healing after 4 and 8 weeks of treatment in GERD patients, pantoprazole-Mg was found to be non-inferior to pantoprazole-Na.
3.3.4 Clinical Safety
Adverse events (AEs) reported by the patients were documented at each visit in the above clinical study; intensity and causality were assessed. Both pantoprazole salts were well tolerated; the total number of patients reporting an AE was less than 20% in each group.
No specific risks which might be related to pantoprazole-Mg were identified. Analysis of all data raised during the course of the healing study revealed that the safety profile of pantoprazole-Mg is comparable to pantoprazole-Na.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The data in this submission confirm that pantoprazole-Mg is non-inferior to pantoprazole-Na in healing reflux disease. Pharmacodynamic equivalence was shown for pantoprazole-Mg 40 mg vs pantoprazole-Na 40 mg in H. pylori negative and H. pylori positive patients. The pharmacodynamic trial revealed no difference in acid inhibitory potency between the substances. Moreover, plasma levels (AUC and Cmax) for pantoprazole-Mg were not higher than that for pantoprazole-Na. The magnesium content of a 40 mg tablet is negligibly low, 1.268 mg, and thus far below the amount of magnesium taken with food or dietary supplements therefore the magnesium content in the pantoprazole magnesium tablet is not a cause of concern.
Toxicity data established no apparent qualitative or quantitative differences in the toxicological response between pantoprazole-Mg and the well characterized pantoprazole-Na. In healthy male subjects, kinetic studies comparing the two salts show that AUC and Cmax of pantoprazole-Mg is almost 100% and about 65% relative to that of pantoprazole-Na, respectively, under both fed and fasted conditions. Neither adverse events nor other specific risks, which might be related to treatment with pantoprazole-Mg, were identified. The safety profile of pantoprazole-Mg is comparable to pantoprazole-Na and considered acceptable.
In summary, the benefit to risk ratio for pantoprazole-Mg is considered favourable thus pantoprazole-Mg can be used as pantoprazole-Na for the same indications.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Pantoloc M™ is favourable in the treatment of conditions where a reduction of gastric acid secretion is required such as stomach and duodenal ulcers, reflux esophagitis, and symptoms of gastro-esophageal reflux disease (GERD). The 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.
4 Submission Milestones
Submission Milestones: Pantoloc MTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2003-07-29 |
| Submission filed | 2004-05-04 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2004-06-28 |
| Review 1 | |
| Quality Evaluation Complete | 2005-03-31 |
| Clinical Evaluation Complete | 2005-04-03 |
| Labelling Review Complete | 2005-04-22 |
| NOC issued by Director General | 2005-04-22 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| TECTA | 02267233 | TAKEDA CANADA INC | PANTOPRAZOLE (PANTOPRAZOLE MAGNESIUM) 40 MG |