Summary Basis of Decision for Vyvanse ™
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:
VyvanseTM
Lisdexamfetamine dimesylate, 30 mg and 50 mg, Capsule, Oral
Shire Canada Inc.
Submission control no: 120534
Date issued: 2010-06-10
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):
- 02322951 - 30 mg
- 02322978 - 50 mg
Therapeutic Classification:
Non-medicinal ingredients:
Capsule shell:
Gelatin, titanium dioxide, and one or more of the following: D and C Red number 28, D and C Yellow number 10, FD and C Blue number 1, and FD and C Red number 40.
Submission type and control no:
Date of Submission:
Date of authorization:
VYVANSE™ is a trademark used under a licence from Shire LLC
2 Notice of decision
On February 19, 2009, Health Canada issued a Notice of Compliance to Shire Canada Inc. for the drug product Vyvanse™.
Vyvanse™ is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children aged 6 to 12 years.
Vyvanse™ contains the medicinal ingredient lisdexamfetamine dimesylate which is a pro-drug of dextroamphetamine, a central nervous system (CNS) stimulant. After oral administration, lisdexamfetamine dimesylate is rapidly absorbed from the gastrointestinal tract and converted to dextroamphetamine which is responsible for the effect of Vyvanse™ in ADHD. The mode of therapeutic action of dextroamphetamine in ADHD is not fully established; however, it is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron thereby promoting the release of these monoamines into the extraneuronal space.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Vyvanse™ were evaluated in two, 4-week, clinical studies in children aged 6-12 years with ADHD. One study was a Phase III, randomized, double-blind, parallel-group, placebo-controlled study (n=285). Patients received doses of 30, 50, or 70 mg of Vyvanse™ once daily for 4 weeks. The other study was a Phase II, randomized, double-blind, placebo- and active-controlled, multi-dose, 3-period and 3-treatment crossover study (n=50). In this study, all patients received a 3-week open-label dose titration with mixed salts amphetamine extended-release capsules, and were then randomized with respect to treatment sequence for the same dose of mixed salts amphetamine extended-release capsules (10, 20, or 30 mg), Vyvanse™ (30, 50, and 70 mg), or placebo; once daily in the morning for 1 week. In both clinical studies, significant improvements in ADHD symptoms were observed in patients who received Vyvanse™ compared to patients who received placebo. Vyvanse™ was generally well-tolerated. Adverse drug reactions observed with Vyvanse™ treatment reflected side effects commonly associated with amphetamine use.
Vyvanse™ (30 mg and 50 mg, lisdexamfetamine dimesylate) is presented in capsule form. The recommended dose for children with ADHD who are 6 to 12 years of age and are either starting treatment for the first time or switching from another medication is 30 mg once daily in the morning. If the physician, based on clinical judgment, decides a dose increase above 30 mg/day is warranted, the maximum recommended dose is 50 mg/day; dosage adjustment should occur after approximately one week. Dosing guidelines are available in the Product Monograph.
Vyvanse™ is contraindicated for patients who have advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma, allergy to amphetamines or to any of the components of Vyvanse™ or its container. Vyvanse™ is also contraindicated in patients that are in an agitated state or that have a history of drug abuse. Administration of Vyvanse™ during or within 14 days following the administration of monoamine oxidase inhibitors may result in hypertensive crises. Vyvanse™ 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 Vyvanse™ 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 Vyvanse™ is favourable for the treatment of ADHD in children aged 6 to 12 years.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Lisdexamfetamine dimesylate, the medicinal ingredient of Vyvanse™, is a pro-drug of dextroamphetamine, a central nervous system stimulant. After oral administration, lisdexamfetamine dimesylate is converted to active dextroamphetamine (d-amphetamine) which is responsible for the effect of Vyvanse™ in Attention Deficit Hyperactivity Disorder (ADHD). The mode of therapeutic action of d-amphetamine in ADHD is not fully established; however, it is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron thereby promoting the release of these monoamines into the extraneuronal space.
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 lisdexamfetamine dimesylate has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within International Conference on Harmonisation (ICH) established limits and/or were qualified from batch analysis, and therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications are considered acceptable.
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 lisdexamfetamine dimesylate.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed retest period for the drug substance was supported and is considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Vyvanse™ (lisdexamfetamine dimesylate) capsules are presented in two strengths: 30 mg and 50 mg of lisdexamfetamine dimesylate. The capsule fill consists of a white to light-tan powder. The colour and markings on the capsule are dependent on the dosage of the formulation.
- Vyvanse™ 30 mg capsules have a white body with an orange cap. The capsules are imprinted with NRP104 30 mg.
- Vyvanse™ 50 mg capsules have a white body with a blue cap. The capsules are imprinted with NRP104 50 mg.
Both strengths are packaged in high density polyethylene (HDPE) bottles of 100 capsules per bottle, with polypropylene (PP) caps.
The capsule fill has the following non-medicinal ingredients: microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The capsule shell contains gelatin, titanium dioxide, and one or more of the following: D and C Red number 28, D and C Yellow number 10, FD and C Blue number 1, and FD and C Red number 40.
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 lisdexamfetamine dimesylate with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Vyvanse™ is tested to verify that its identity, appearance, content uniformity, assay, dissolution, moisture content, and levels of degradation products, drug-related impurities, and microbiological impurities are within acceptance criteria. The test specifications are considered acceptable.
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 Vyvanse™.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Stability
Based on the long-term and accelerated stability data submitted, Vyvanse™ is considered acceptable when stored at 15-30°C in HDPE bottles with PP caps.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment that are involved in the production of Vyvanse™ are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
The excipient gelatin, a component of the capsule shell is of animal origin. A letter of attestation confirming that the material is not from a bovine spongiform encephalopathy/ transmissible spongiform encephalopathy (BSE/TSE) affected country/area has been provided for this product indicating that it is considered to be safe for human use.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Vyvanse™ 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
3.2.1 Pharmacology
Vyvanse™ (lisdexamfetamine dimesylate) is a prodrug of d-amphetamine. After oral administration, Vyvanse™ is converted to d-amphetamine, the compound responsible for the drug's therapeutic activity in the treatment of ADHD; and L-lysine, a naturally occurring essential amino acid.
A series of non-clinical studies were conducted to evaluate the pharmacology and safety of lisdexamfetamine dimesylate as compared to d-amphetamine. In binding studies, there appear to be no direct interaction by lisdexamfetamine dimesylate with active sites considered to be critical for the pharmacological effects of d-amphetamine. In the pharmacodynamic studies, the effects of orally administered lisdexamfetamine dimesylate were generally comparable to d-amphetamine.
3.2.2 Pharmacokinetics
Following oral administration, absorption of lisdexamfetamine dimesylate increased non-linearly with increasing dose. Lisdexamfetamine dimesylate was not detected in rat brain tissue after oral administration.
The major metabolites observed in plasma, urine, bile, and feces following oral administration were glucuronidated amphetamine and amphetamine. These two moieties comprised >90% of the total metabolites in plasma after oral dosing. Urinary excretion was the primary route of elimination. Elimination of radiolabelled lisdexamfetamine dimesylate in urine and feces occurred largely in the first 48 hours post-dose.
3.2.3 Toxicology
One-month toxicology studies in rats and dogs demonstrated pharmacological effects similar to those of an equimolar dose of d-amphetamine sulphate at the mid doses. No chronic toxicity, carcinogenicity, or reproductive studies were conducted, since lisdexamfetamine dimesylate is a prodrug for d-amphetamine which has been previously evaluated for these toxicity endpoints.
Mutagenicity, teratogenicity, and juvenile toxicity studies did not reveal any unexpected toxicity.
In animal drug dependence studies, lisdexamfetamine produced behavioral effects qualitatively similar to those of the central nervous system (CNS) stimulant d-amphetamine.
In juvenile rats and dogs, significant decreases in bodyweight gain were observed. In rats, dose-related decreases in food consumption, and crown-rump length were also seen. The doses tested in both species approximated the recommended therapeutic doses in humans.
3.2.4 Conclusion
Based on the findings from the non-clinical studies, the pharmacological and toxicological profiles of lisdexamfetamine dimesylate are consistent with d-amphetamine.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Vyvanse™ (lisdexamfetamine dimesylate), is a prodrug of d-amphetamine. After oral administration, Vyvanse™ is converted to d-amphetamine, the compound responsible for the drug's therapeutic activity. The mode of therapeutic action of dextroamphetamine in ADHD is not fully established; however, it is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron thereby promoting the release of these monoamines into the extraneuronal space.
3.3.2 Pharmacokinetics
After oral administration, lisdexamfetamine dimesylate is converted to d-amphetamine and L-lysine, which is believed to occur by first-pass intestinal and/or hepatic metabolism. In children aged 6-12 years, the time to reach maximum plasma concentration (Tmax) of d-amphetamine was approximately 3.5 hours following single-dose oral administration of lisdexamfetamine dimesylate (30 mg, 50 mg, or 70 mg) after an 8-hour overnight fast. The Tmax of lisdexamfetamine dimesylate was approximately 1 hour. Linear pharmacokinetics of d-amphetamine after single-dose oral administration of lisdexamfetamine dimesylate were established over the dose range of 30 mg to 70 mg in children aged 6 to 12 years. There was no unexpected accumulation of d-amphetamine at steady-state in healthy adults and no accumulation of lisdexamfetamine dimesylate after once-daily dosing for seven consecutive days.
Lisdexamfetamine is not metabolized by cytochrome P450 enzymes. Following the oral administration of radiolabelled lisdexamfetamine dimesylate, approximately 96% of the oral dose radioactivity was recovered in the urine, and only 0.3% was recovered in the feces over a period of 120 hours.
3.3.3 Clinical Efficacy
The efficacy and safety of Vyvanse™ (lisdexamfetamine dimesylate) were evaluated in two, 4-week, clinical studies in children aged 6-12 years with ADHD. One of the studies was a Phase III study (NRP104.301) and the other one was a Phase II study (NRP104.201). The effectiveness of Vyvanse™ for long-term use, that is (i.e.), for more than 4 weeks, has not been systematically evaluated in controlled trials.
The Phase III study was a randomized, double-blind, parallel-group, placebo-controlled fixed dose titration study (n=285). Patients received doses of 30 mg, 50 mg, or 70 mg of Vyvanse™ once daily for 4 weeks. The primary endpoint was change from baseline on the ADHD Rating Scale at week 4. Statistically significant improvements in ADHD symptoms were reported in all three Vyvanse™ dose groups compared to placebo.
The Phase II study was a randomized, double-blind, placebo- and active-controlled, multi-dose, 3-period and 3-treatment crossover study (n=50). In this study, all patients received a 3-week open-label dose titration with mixed salts amphetamine extended-release capsules, and were then randomized with respect to treatment sequence for the same dose of mixed salts amphetamine extended-release capsules (10 mg, 20 mg, or 30 mg), Vyvanse™ (30 mg, 50 mg, or 70 mg), or placebo; once daily in the morning for 1 week. The primary efficacy endpoint was the average of investigator ratings from the Swanson, Kotkin, Agler, M.Flynn and Pelham (SKAMP)-Deportment scores across eight sessions of a 12-hour treatment day. Both Vyvanse™ and the mixed salts amphetamine extended-release capsules had statistically favourable effects on ADHD symptomatology compared with placebo.
Both studies were well-controlled and demonstrated that Vyvanse™ was effective in the treatment of ADHD in children 6-12 years of age. No well-controlled studies in patients younger than 6 and older than 12 years were available; therefore, Vyvanse™ can be authorized for use only in children between the ages of 6 and 12 years.
The effectiveness of Vyvanse™ for long-term use, i.e., for more than 4 weeks, has not been systematically evaluated in controlled trials. Available dose response data suggest that doses over 30 mg/day do not confer additional efficacy, but the incidence of adverse events increases with dose. Therefore, the recommended therapeutic dose is 30 mg/day once daily in the morning. Higher doses may be used at the discretion of the treating physician, up to maximum recommended dose of 50 mg/day. Detailed conditions for the use of Vyvanse™ are described in the Vyvanse™ Product Monograph.
3.3.4 Clinical Safety
A total of 401 subjects were exposed to Vyvanse™ (lisdexamfetamine dimesylate) during the course of the clinical development program. Since lisdexamfetamine is a prodrug of d-amphetamine, a well-known pharmacological entity, and the parent drug itself has very low or no pharmacological activity, the exposure data is deemed to be adequate.
The adverse event profiles of Vyvanse™ seen in the Phase III study (NRP104.301) and the Phase II study (NRP104.201), described in section 3.3.3 Clinical Efficacy, are consistent with those of an amphetamine-like sympathomimetic agent. The most common adverse drug reactions were decreased appetite, insomnia, upper abdominal pain, headache, irritability, vomiting, decreased weight, and nausea.
Drug Abuse and Dependence Studies
In a human abuse liability study, when equivalent oral doses of 100 mg Vyvanse™ and 40 mg immediate release d-amphetamine sulfate were administered to individuals with a history of drug abuse, Vyvanse™ 100 mg produced subjective responses on a scale of "Drug Liking Effects" (primary endpoint) that were significantly less than d-amphetamine immediate release 40 mg. However, oral administration of 150 mg Vyvanse™ produced increases in positive subjective responses on this scale that were statistically indistinguishable from the positive subjective responses produced by 40 mg of oral immediate-release d-amphetamine and 200 mg of diethylpropion.
Intravenous administration of 50 mg lisdexamfetamine to individuals with a history of drug abuse produced positive subjective responses on scales measuring "Drug Liking", "Euphoria", "Amphetamine Effects", and "Benzedrine Effects" that were not significantly different from placebo. Administration of a dose of 20 mg of intravenous d-amphetamine produced significant positive subjective responses on these scales.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Vyvanse™ is a pro-drug of d-amphetamine. Therefore, after absorption and conversion of lisdexamfetamine to d-amphetamine and l-lysine, pharmacological effects and adverse events are qualitatively similar to those of d-amphetamine. All the class statements that apply to amphetamine-like drugs are present in the Vyvanse™ Product Monograph.
The sponsor has submitted sufficient data to demonstrate that Vyvanse™ is effective in the treatment of ADHD in the pediatric population (6-12 yrs of age). Therefore, Vyvanse™ can be approved for use only in children between the ages of 6 and 12 years.
Available dose response data suggest that doses over the 30 mg/day do not confer additional efficacy, but the incidence of adverse events increases with dose. Therefore, the recommend therapeutic dose is 30 mg/day once daily in the morning. Higher doses may be used at the discretion of the treating physician, up to maximum recommended dose of 50 mg/day.
Vyvanse™ is a Schedule III drug under the Controlled Drugs and Substances Act and may produce physical and psychological dependence.
Amphetamines have been extensively abused. Tolerance, extreme psychological dependence, and severe social disability have occurred. There are reports of patients who have increased the dosage to levels many times higher than recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression. Careful supervision is therefore recommended during drug withdrawal. Manifestations of chronic intoxication with amphetamines may include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.
In conclusion, the benefits of Vyvanse™ therapy for the treatment ADHD in children aged 6 to 12 years outweigh the risks. Restrictions to manage risks associated with this drug have been incorporated into the labelling and Vyvanse™ Product Monograph to manage the use of this product.
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 Vyvanse™ is favourable in the treatment of ADHD in children aged 6 to 12 years. 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: VyvanseTM
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2008-03-07 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2008-04-25 |
| Review | |
| Quality Evaluation complete: | 2009-02-17 |
| Clinical Evaluation complete: | 2009-02-18 |
| Labelling Review complete: | 2009-02-18 |
| Notice of Compliance (NOC) issued by Director General: | 2009-02-19 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| VYVANSE | 02322951 | TAKEDA CANADA INC | LISDEXAMFETAMINE DIMESYLATE 30 MG |
| VYVANSE | 02322978 | TAKEDA CANADA INC | LISDEXAMFETAMINE DIMESYLATE 50 MG |