Summary Basis of Decision for Emend ® IV
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:
Emend® IV
Fosaprepitant dimeglumine, 115 mg/vial, Powder for solution, Intravenous (IV)
Merck Frosst Canada Ltd.
Submission control no: 120374
Date issued: 2010-03-05
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):
- 02324679
Therapeutic Classification:
Non-medicinal ingredients:
lactose anhydrous, sodium hydroxide and/or
hydrochloric acid (for pH adjustment)
Submission type and control no:
Control Number: 120374
Date of Submission:
Date of authorization:
2 Notice of decision
On April 1, 2009, Health Canada issued a Notice of Compliance to Merck Frost Canada Ltd. for the drug product Emend® IV.
Emend® IV contains the medicinal ingredient fosaprepitant, as fosaprepitant dimeglumine, which is a substance P neurokinin 1 (NK1) receptor antagonist. NK1-receptor antagonists have been shown pre-clinically to inhibit emesis induced by cytotoxic chemotherapeutic agents via central actions.
Emend® IV, in combination with a 5-HT3 antagonist class of antiemetics and dexamethasone, is indicated for the:
- prevention of acute and delayed nausea and vomiting due to highly emetogenic cancer chemotherapy; and
- prevention of nausea and vomiting in women due to treatment with moderately emetogenic cancer chemotherapy (consisting of cyclophosphamide and anthracycline).
F osaprepitant is a prodrug of aprepitant. Preclinical and human Positron Emission Tomography (PET) studies have shown aprepitant to be brain penetrant and to occupy brain NK1 receptors. Preclinical studies show that aprepitant has a long duration of central activity, inhibits both the acute and delayed phases of cisplatin-induced emesis, and augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone against cisplatin-induced emesis.
The market authorization of Emend® IV was based on the bioequivalence study indicating that 115 mg of the prodrug, fosaprepitant, is equivalent to 125 mg oral aprepitant in regard to aprepitant exposure. No clinical studies that involved the use of fosaprepitant and both dexamethasone and a 5-HT3 antagonist class of antiemetics have been submitted. The safety and efficacy of Emend® IV were based on three studies previously submitted for the market authorization of oral aprepitant, currently marketed under the brand name Emend®. Two clinical studies evaluated oral aprepitant in 1103 patients with highly emetogenic chemotherapy. All patients received a chemotherapy regimen that included cisplatin ≥70 mg/m2 and most patients received additional chemotherapeutic agents. In both studies, a statistically significantly higher proportion of patients receiving the aprepitant regimen had a complete response (defined as no emetic episodes and no use of rescue therapy) compared to patients receiving standard therapy. Similar results were reported for a study that evaluated 866 breast cancer patients receiving moderately emetogenic chemotherapy regimens that included cyclophosphamide.
Emend® IV (115 mg fosaprepitant/vial) is presented as a powder for IV infusion only, upon reconstitution and dilution. The 3-day chemotherapy-induced nausea and vomiting (CINV) regimen includes Emend® IV (115 mg) 30 minutes prior to chemotherapy or Emend® (125 mg orally) 1 hour prior to chemotherapy on Day 1; Emend® (80 mg orally) on Days 2 and 3; in addition to a corticosteroid and a 5-HT3 antagonist. Dosing guidelines are available in the Product Monograph.
Emend® IV is contraindicated for patients who are hypersensitive to this drug, polysorbate 80, or to any ingredient in the formulation, and should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Precautions should be taken with patients receiving (a) medicinal products that are metabolized through CYP3A4, (b) warfarin, and (c) hormonal contraception. Emend® IV should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Emend® IV are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Emend® IV is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
Emend® IV contains the medicinal ingredient fosaprepitant, as fosaprepitant dimeglumine. Fosaprepitant is a prodrug of aprepitant which is currently marketed under the brand name Emend® (80 mg and 125 mg aprepitant). On August 24, 2007, Health Canada issued a Notice of Compliance (NOC) to Merck Frosst Canada Ltd. for the drug product, Emend®. Health Canada considers that the benefit/risk profile of Emend® in combination with a 5-hydroxytryptamine 3 (5-HT3) antagonist class of antiemetics and dexamethasone, is favourable for the prevention of acute and delayed nausea and vomiting due to highly emetogenic cancer chemotherapy; and the prevention of nausea and vomiting in women due to treatment with moderately emetogenic cancer chemotherapy consisting of cyclophosphamide and anthracycline. The indication for Emend® IV is the same as for Emend®.
The market authorization for Emend® IV was based on the bioequivalence study indicating that 115 mg of the prodrug, fosaprepitant, is equivalent to 125 mg oral aprepitant in regard to aprepitant exposure. The IV administration of fosaprepitant (115 mg) is to be used on the first day only of a three-day treatment regimen. On the second and third day, the recommended dose is 80 mg aprepitant administered orally. The safety and efficacy of Emend® IV were based on the three studies previously submitted for the market authorization of Emend®.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Fosaprepitant, as fosaprepitant dimeglumine, is the medicinal ingredient of Emend® IV. Fosaprepitant is a prodrug of aprepitant, a Neurokinin 1 (NK1) receptor antagonist. NK1-receptor antagonists have been shown pre-clinically to inhibit emesis induced by highly emetogenic chemotherapeutic agents, such as cisplatin, through their actions on the central nervous system.
Manufacturing Process and Process Controls
The drug substance is synthetically derived.
The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of fosaprepitant dimeglumine has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of fosaprepitant dimeglumine.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
Stability
Stability study results based on accelerated, long-term, and stress testing show that fosaprepitant dimeglumine is a stable compound when packaged as proposed over the proposed storage period and storage conditions.
3.1.2 Drug Product
Description and Composition
Emend® IV (fosaprepitant dimeglumine) is to be administered as an IV infusion. Emend® IV is a white to off-white lyophilized solid presented in a 10 mL glass vial closed by a rubber stopper and capped with an aluminum seal and a flip-off plastic cap. One vial is packaged in a carton.
Each vial of Emend® IV contains 188 mg of fosaprepitant dimeglumine equivalent to 115 mg of fosaprepitant. The non-medicinal ingredients are edetate disodium, PS80, lactose anhydrous, sodium hydroxide and/or hydrochloric acid (for pH adjustment).
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of fosaprepitant dimeglumine with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
The validated process is capable of consistently manufacturing product that meets release specifications.
Control of Drug Product
Emend® IV is tested to verify that its identity, appearance, content uniformity, weight, moisture content, assay, pH, completeness and clarity of solution, particulate matter, sterility, levels of degradation products, drug-related impurities, and bacterial endotoxins are within acceptance criteria. 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.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the long-term and accelerated stability data submitted, the proposed 24-month shelf-life for Emend® IV is considered acceptable in the proposed packaging when stored between 2-8°C.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Emend® IV are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
Among the excipients, only lactose is from animal origin. A supplier's certificate states that the milk is sourced from healthy animals in the same conditions as milk is used for human consumption. Therefore, the lactose does not present any risk of transmissible spongiform encephalopathy (TSE) contamination.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Emend® IV 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.
3.2 Non-Clinical Basis for Decision
The non-clinical pharmacology studies that support the New Drug Submission (NDS) for Emend® IV (fosaprepitant, as fosaprepitant dimeglumine) were previously reviewed for the Emend® (aprepitant) NDS. The medicinal ingredient of Emend® IV, fosaprepitant, is a prodrug of the medicinal ingredient of Emend®, aprepitant. Fosaprepitant rapidly converts to aprepitant in vivo following intravenous (IV) administration, therefore both products (Emend® IV and Emend®) have the same pharmacologic activity. Both products, Emend® IV and Emend®, in combination with other antiemetic agents, are indicated for the prevention of acute and delayed nausea and vomiting due to highly emetogenic and moderately emetogenic cancer chemotherapy. Health Canada issued an NOC to Merck Frosst Canada Ltd. for Emend® on August 24, 2007. For more information regarding Health Canada's review of aprepitant, refer to the Summary Basis of Decision (SBD) for Emend®. Some additional studies were conducted and will be discussed in this SBD.
3.2.1 Pharmacodynamics
No new pharmacodynamic (PD) studies were submitted for this drug submission.
In the development of the clinical formulation of fosaprepitant, several formulations were evaluated in the non-clinical IV vascular irritation/tolerability studies. Polysorbate 80 was chosen to be included in the market formulation.
3.2.2 Pharmacokinetics
The pharmacokinetic (PK) studies following IV administration of fosaprepitant to rats and dogs indicated that the prodrug, fosaprepitant, converted rapidly to the pharmacologically active entity, aprepitant, such that maximal plasma concentrations of the latter compound were observed as early as the first sampling time post-dose (2 to 3 min). Furthermore, the systemic exposure to the prodrug was relatively transient as compared to aprepitant.
Following IV administration of radiolabelled fosaprepitant to rats, radioactivity distributed rapidly and extensively throughout the body. Since fosaprepitant is rapidly converted to aprepitant, the tissue distribution observed reflects that of aprepitant.
The metabolism and excretion of the prodrug, including drug interactions, also mimicked the PK properties of aprepitant.
The potential of PS80 to act as an inhibitor of P-glycoprotein (P-gp) was assessed in vitro and in vivo.
3.2.3 Toxicology
The toxicology studies (single-dose, repeat-dose, genotoxicity, carcinogenicity, and reproductive and developmental toxicity) for fosaprepitant were largely those of aprepitant which were reviewed with the NDS for Emend®. No new toxicology studies of aprepitant were provided in this submission.
Additional toxicology studies were conducted with fosaprepitant and confirmed the acceptability of the formulation.
3.2.4 Conclusion
The non-clinical studies for the Emend® IV drug submission are considered acceptable. Most of the non-clinical studies submitted in the NDS for Emend® IV were previously submitted and reviewed for the market authorization of Emend®. The medicinal ingredient of Emend® IV, fosaprepitant, is a prodrug of the medicinal ingredient of Emend®, aprepitant. Fosaprepitant is rapidly converted to aprepitant and subsequently follows the pharmacology and toxicity findings of aprepitant. The pharamacology and toxicology studies support the use of Emend® IV for the proposed indication.
3.3 Clinical basis for decision
The medicinal ingredient of Emend® IV, fosaprepitant, is a prodrug of the medicinal ingredient of Emend®, aprepitant. The market authorization of Emend® IV was based on a bioequivalence study indicating that 115 mg of fosaprepitant, is equivalent to 125 mg oral aprepitant in regard to aprepitant exposure. No clinical studies that involved the combined use of fosaprepitant with dexamethasone and a 5-HT3 antagonist class of antiemetics have been submitted.
The safety and efficacy of aprepitant were based on three studies submitted for the market authorization of Emend®. Both products, Emend® IV and Emend®, in combination with other antiemetic agents, are indicated for the prevention of acute and delayed nausea and vomiting due to highly emetogenic and moderately emetogenic cancer chemotherapy. Health Canada issued an NOC to Merck Frosst Canada Ltd. for Emend® on August 24, 2007. For more information regarding Health Canada's review of aprepitant, refer to the Summary Basis of Decision (SBD) for Emend®.
3.3.1 Pharmacodynamics
Fosaprepitant is a prodrug of aprepitant and accordingly its PD properties are attributed to aprepitant. Non-clinical studies have shown that aprepitant has a high affinity for NK1 receptors. As an NK1-receptor antagonist, aprepitant inhibits emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via actions on the central nervous system.
3.3.2 Pharmacokinetics
The in vivo conversion of fosaprepitant to aprepitant appeared to be rapid and extensive. The fosaprepitant concentrations dropped below or near the level of quantitation within 15 minutes of the end of the fosaprepitant infusion. Over the single IV dose range of 25 to 200 mg fosaprepitant, the drug exposure [area under the curve (AUC)] of aprepitant increased slightly greater than proportionally with the dose of fosaprepitant, and the maximum drug concentration in plasma (Cmax) of aprepitant increased proportionally with the dose. The apparent volume of distribution at steady state (Vss) was less in women than in men. Over the multiple IV dose range of 25 to 100 mg/day fosaprepitant for 4 days, the accumulation ratio and the terminal half-life (t1/2) were dose-dependent. The apparent plasma clearance of aprepitant decreased as the dosing of fosaprepitant increased. There were no clinically important gender-related differences in aprepitant exposure (AUC) or apparent aprepitant plasma clearance. After the conversion of fosaprepitant to aprepitant, the metabolism follows that observed with the oral preparation of aprepitant (Emend®).
Single IV infusions of 100 mg fosaprepitant were generally well-tolerated. Single and multiple doses of fosaprepitant did not result in clinically significant decreases in systolic and diastolic blood pressure. The studies also demonstrated that supra-therapeutic doses of fosaprepitant were administered without a particular safety signal. Safety concerns regarding drug interactions with aprepitant in the Emend® Product Monograph also apply to fosaprepitant.
Bioequivalence
The bioequivance study was the "pivotal" study for this drug submission. The objective was to demonstrate single-dose bioequivalence (aprepitant AUC) between 115 mg fosaprepitant (Emend® IV) administered intravenously over 15 minutes and the currently marketed 125 mg aprepitant capsule (Emend®) administered orally. This equivalence is the basis for bridging the extensive safety and efficacy data with the oral 125 mg and 80 mg aprepitant regimen and the proposed regimen with the substitution of intravenous 115 mg fosaprepitant for the 125 mg oral dose on Day 1 of the chemotherapy-induced nausea and vomiting (CINV) regimen.
In a randomized, open-label crossover, bioequivalence study, 66 healthy subjects were dosed with 115 mg of Emend® IV intravenously and 125 mg of aprepitant orally. The systemic exposure (aprepitant AUC) of 115 mg of intravenous Emend® IV was equivalent to the systemic exposure following the oral administration of 125 mg aprepitant. As expected from an IV preparation, the Cmax increased and the tmax decreased with the administration of Emend® IV.
3.3.3 Clinical Efficacy
Emend® IV contains the medicinal ingredient fosaprepitant, as fosaprepitant dimeglumine. Fosaprepitant when administered intravenously is rapidly converted to aprepitant, the medicinal ingredient of Emend®. Both products, Emend® IV and Emend®, in combination with other antiemetic agents, are indicated for the prevention of acute and delayed nausea and vomiting due to highly emetogenic and moderately emetogenic cancer chemotherapy. Health Canada issued an NOC to Merck Frosst Canada Ltd. for Emend® on August 24, 2007.
The clinical efficacy of Emend® IV was based on the bioequivalence of Emend® IV to Emend® (oral aprepitant). The bioequivalence study demonstrated that 115 mg of the prodrug, fosaprepitant, is equivalent to 125 mg oral aprepitant in regard to aprepitant exposure. This equivalence was the basis for bridging the extensive efficacy and safety data with the oral 125 mg and 80 mg aprepitant regimen and the proposed regimen with the substitution of intravenous 115 mg fosaprepitant for the 125 mg oral dose on Day 1 of the CINV regimen. No clinical studies that involved the use of fosaprepitant and both dexamethasone and a 5-HT3 antagonist class of antiemetics were submitted.
For more information regarding Health Canada's review of aprepitant, refer to the Summary Basis of Decision (SBD) for Emend®.
3.3.4 Clinical Safety
Emend® IV contains the medicinal ingredient fosaprepitant, as fosaprepitant dimeglumine. Fosaprepitant when administered intravenously is rapidly converted to aprepitant, the medicinal ingredient of Emend®.
The clinical safety of Emend® IV was based on the bioequivalence of Emend® IV to Emend® (oral aprepitant). The bioequivalence study demonstrated that 115 mg of the prodrug, fosaprepitant, is equivalent to 125 mg oral aprepitant in regard to aprepitant exposure. This equivalence was the basis for bridging the extensive efficacy and safety data with the oral 125 mg and 80 mg aprepitant regimen and the proposed regimen with the substitution of intravenous 115 mg fosaprepitant for the 125 mg oral dose on Day 1 of the CINV regimen. No clinical studies that involved the use of fosaprepitant and both dexamethasone and a 5-HT3 antagonist class of antiemetics were submitted.
The clinical safety assessment of Emend® was primarily based on three pivotal studies. The profile of AEs and their incidence were similar between the aprepitant regimen and standard therapy. The AEs observed with aprepitant can be expected with fosaprepitant.
Drug interactions following administration of Emend® IV are likely to occur with drugs that interact with oral aprepitant. The warnings and precautions in the Product Monograph for Emend® IV are the same as those stated in the Product Monograph for Emend®. In the PK studies, Emend® IV was generally well-tolerated. With the exception of injection site events (erythema, induration, and pain), the AEs resulting from the IV prodrug (Emend® IV) were similar to those seen with the oral preparation (Emend®). For more information regarding Health Canada's review of aprepitant, refer to the Summary Basis of Decision (SBD) for Emend®.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Most chemotherapeutic treatments are associated with nausea and vomiting. These side effects may be quite incapacitating and seriously compromise the patient's quality of life of patients. NK1-receptor antagonists have been shown non-clinically to inhibit emesis induced by highly emetogenic chemotherapeutic agents, such as cisplatin, through their actions on the central nervous system. Emend® IV (fosaprepitant dimeglumine) is the prodrug of aprepitant, a NK1-receptor antagonist. The benefit/risk assessment of Emend® IV is similar to that of Emend® (aprepitant).
In the Emend® pivotal studies with patients receiving highly emetogenic chemotherapy, a statistically significantly higher proportion of patients receiving the Emend® regimen had a complete response (defined as no emetic episodes and no use of rescue therapy) compared to patients receiving standard therapy. Similar results were reported with another pivotal study that evaluated breast cancer patients receiving moderately emetogenic chemotherapy regimens that included cyclophosphamide.
The risk of potential drug interactions with Emend® also applies to Emend® IV. A prepitant is a substrate, a moderate inhibitor, an inducer of CYP3A4, and an inducer of CYP2C9. Due to the fact that cancer patients are often on multiple medications, the concomitant use of Emend® or Emend® IV increases their risk of experiencing drug interactions. Fortunately, the dosing regimen is only used for 3 days during each chemotherapy cycle, usually 3-4 weeks apart. This reduces the potential risk, as long as the treating physician follows the recommended drug dosage and duration. Drug interaction warnings have been clearly stated in the Product Monograph.
A prepitant may also have an immunosuppressive effect on patients, although the data collected to date suggest that this effect is small. Similar to the risk for drug interactions, if aprepitant is indicated for longer use, the immunosuppressive potential may be greater and immunotoxicity studies should be undertaken.
In conclusion, the benefits of aprepitant for the proposed indication outweigh the risks. The benefit/risk assessment of Emend® IV is similar to that of Emend® (aprepitant).
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Emend® IV in combination with a 5-HT3 antagonist class of antiemetics and dexamethasone is favourable for the prevention of acute and delayed nausea and vomiting due to highly emetogenic cancer chemotherapy, and the prevention of nausea and vomiting in women due to treatment with moderately emetogenic cancer chemotherapy consisting of cyclophosphamide and anthracycline. 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 NOC pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Emend® IV
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2008-04-18 |
| Screening | |
| Screening Acceptance Letter issued: | 2008-06-05 |
| Review | |
| Biostatistics Evaluation complete | 2007-02-16 |
| Quality Evaluation complete: | 2009-04-01 |
| Clinical Evaluation complete: | 2009-03-31 |
| Labelling Review complete: | 2009-04-01 |
| Notice of Decision issued by Director General: | 2009-04-01 |