Summary Basis of Decision for Pristiq ™
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:
PristiqTM
Desvenlafaxine succinate, 50 mg and 100 mg, Extended-release tablets, Oral
Wyeth Canada
Submission control no: 115439
Date issued: 2009-05-29
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):
- 02321092 - 50 mg
- 02321106 - 100 mg
Therapeutic Classification:
Non-medicinal ingredients:
Film coating: dextrose, maltodextrin, sodium carboxymethylcellulose, stearic acid, iron oxides and titanium dioxide.
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On February 4, 2009, Health Canada issued a Notice of Compliance to Wyeth Canada for the drug product, Pristiq.
Pristiq contains the medicinal ingredient desvenlafaxine (as desvenlafaxine succinate), an antidepressant that belongs to the class of dual-acting serotonin and norepinephrine reuptake inhibitors (SNRIs). Desvenlafaxine is the major metabolite of venlafaxine, which has had market authorization in Canada for the treatment of major depressive disorder since 1994.
Pristiq is indicated for the symptomatic relief of major depressive disorder. Desvenlafaxine succinate affects the levels of serotonin and norepinephrine, which are neurotransmitters in the central nervous system.
The market authorization was based on quality, non-clinical, and clinical information submitted. Four pivotal, 8-week, randomized, double-blind, placebo-controlled, fixed-dose studies (at doses of 50-400 mg/day) were conducted in adult outpatients with major depressive disorder. Pristiq showed superiority over placebo in all four studies. The adverse events observed with Pristiq were consistent with the pharmacology of SNRIs, and show a similar safety profile to that of venlafaxine.
Pristiq (50 mg and 100 mg desvenlafaxine succinate) is presented as extended-release tablets. Pristiq is not indicated for use in children under 18 years of age. For initial treatment, the recommended dose of Pristiq is 50 mg once daily, with or without food. It is recommended that Pristiq be taken at approximately the same time each day. Dosing guidelines are available in the Product Monograph.
Pristiq is contraindicated for patients who are taking monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with selective serotonin reuptake inhibitor (SSRI) or SNRI treatment or with other serotonergic drugs. Pristiq is also contraindicated for patients who are hypersensitive to desvenlafaxine succinate, venlafaxine hydrochloride, or to any of the excipients in the desvenlafaxine formulation. Pristiq 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 Pristiq 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 Pristiq is favourable for the symptomatic relief of major depressive disorder.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Desvenlafaxine (as desvenlafaxine succinate) is the medicinal ingredient of Pristiq. This drug substance is an antidepressant that belongs to the class of dual-acting serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs). Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of venlafaxine which has been marketed in Canada for treatment of depression since 1994. The succinate salt of desvenlafaxine, an extended-release formulation, was developed with an intended indication for the treatment of major depressive disorder (MDD).
Manufacturing Process and Process Controls
Desvenlafaxine succinate 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 International Conference on Harmonisation (ICH) requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of desvenlafaxine succinate has been adequately elucidated and the representative spectra have been provided. Confirmation of the chemical structure was provided by elemental analysis and spectroscopic analysis.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and therefore, are considered to be acceptable.
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 desvenlafaxine succinate.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the stability data submitted, the proposed re-test period and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Pristiq (desvenlafaxine succinate ) extended-release tablets are presented in two strengths: 50 mg and 100 mg of desvenlafaxine base. The 50 mg tablets are light pink, square pyramid tablets debossed with "W" over "50" on the flat side. The 100 mg tablets are reddish-orange, square pyramid tablets debossed with "W" over "100" on the flat side. Both strengths are packaged in high density polyethylene (HDPE) bottles of 14, 30, and 90 tablets, as well as unit-dose blister packages of 7, 14, and 28 tablets.
The inactive ingredients in the tablet core are hypromellose, magnesium stearate, microcrystalline cellulose, and talc. The film-coating consists of dextrose, maltodextrin, sodium carboxymethylcellulose, stearic acid, iron oxides and titanium dioxide.
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 desvenlafaxine succinate 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
Pristiq is tested to verify that its identity, appearance, uniformity of dosage units, assay, dissolution, and degradation products are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life limits, for individual and total degradation products, are within acceptable limits.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
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 Pristiq.
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 stability data submitted, the proposed 24-month shelf-life is considered acceptable when Pristiq tablets are packaged in the proposed packaging, and stored at 15-30°C, with excursions permitted to 40°C.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Pristiq are considered suitable for the activities and products manufactured.
The sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Pristiq 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 Pharmacodynamics
The medicinal ingredient of Pristiq, desvenlafaxine (as desvenlafaxine succinate), is a dual-acting SNRI. Characterization of the activity of desvenlafaxine for the human 5-HT transporter and human NE transporter was performed in cells expressing these human protein transporters. In addition, neurochemical and behavioral studies were performed to support the actions of desvenlafaxine to block the 5-HT and NE transporters in vivo. Various other assays were conducted to determine the binding selectivity of desvenlafaxine. Desvenlafaxine was also evaluated in a variety of animal models of depression.
The in vitro findings regarding inhibitory action at the 5-HT and NE transporters were consistent with the increased levels of 5-HT and NE found in vivo. Additionally, desvenlafaxine as an SNRI was shown to be efficacious in non-clinical models used to predict antidepressant activity. Further characterization of desvenlafaxine was done using in vitro assays to determine if it had other potential targets that would lead to clinical liabilities. No targets were identified with the exception of the 5-HT and NE monoamine transporters, confirming the mechanism of action identified in the in vitro and in vivo studies. The pharmacologic activities and known mode of action of desvenlafaxine do not suggest a potential for dependence or abuse. Overall, the non-clinical studies showed that the pharmacological profile of desvenlafaxine (the major metabolite of venlafaxine) was similar to venlafaxine, which is currently marketed for major depression.
3.2.2 Pharmacokinetics
Absorption
In rats, mice, and dogs, desvenlafaxine was rapidly absorbed after oral administration. Greater than proportional increases in plasma concentrations of desvenlafaxine were observed as the dosage increased in rats and dogs. Higher drug exposures were observed in female rats compared to male rats, whereas little or no gender differences were observed in mice and dogs. In general, there was no accumulation of desvenlafaxine in rats and dogs after multiple dosing, with the exception of the chronic (9-month) study in dogs, in which a low-to-moderate accumulation was observed.
Distribution
Desvenlafaxine protein binding was low in the plasma of all species studied. After absorption took place, desvenlafaxine was rapidly distributed to the tissues and then rapidly eliminated.
Even though the relative tissue:plasma radioactivity ratios in the brain were low after a radioactive dose in rats, desvenlafaxine concentrations in the brain and hypothalamus were higher than in plasma, indicating that the active moiety desvenlafaxine was distributed to the brain, which is the pharmacologic site of action. After the administration of radiolabelled desvenlafaxine, relatively low amounts of radioactivity were found in the placenta, amniotic fluid, and fetuses of gravid rats; however, radioactivity was excreted readily into the milk of lactating rats.
Metabolism
After a single oral (gavage) dosage of radiolabelled desvenlafaxine in mice, rats, and dogs, desvenlafaxine was rapidly and extensively metabolized. The major pathway of desvenlafaxine metabolism was by glucuronidation to form O-glucuronide. Oxidative metabolism to form the N-desmethyl metabolite was a minor pathway, and this was mediated primarily by the cytochrome P450 isozyme, CYP3A4.
Excretion
After a single oral (gavage) dosage of radiolabelled desvenlafaxine in mice, rats, and dogs, recovery of radioactivity was rapid and nearly complete. Urine was the predominant route of excretion in all three species, with essentially complete recovery of the radioactive dose within 24 hours after dosing in mice; 94.3% of the radioactive dose within 120 hours in rats; and 86.7% of the radioactive dose within 168 hours in dogs.
Drug Interactions
Desvenlafaxine is not a substrate or an inhibitor of P-glycoprotein (P-gp). Desvenlafaxine did not inhibit the following cytochrome P450 (CYP) isozymes: CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4, in human liver microsomes. Desvenlafaxine was a weak inhibitor for the CYP2D6 isozyme. Desvenlafaxine did not induce CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 isozymes in primary cultures of human hepatocytes. Based on these pharmacokinetic and metabolic characteristics, desvenlafaxine is not likely to have any clinically significant drug-drug interaction with other therapeutic drugs.
3.2.3 Toxicology
Single-Dose Toxicity
Desvenlafaxine-related mortality was observed in mice (at doses >1800 mg/kg) and rats (at doses >2500 mg/kg) following a single oral dose; and in mice (at doses >250 mg/kg) and rats (at doses >700 mg/kg) following a single intraperitoneal dose. No mortality was observed in dogs following a single oral dosage up to 500 mg/kg. The clinical signs of overdosage observed in these studies were ataxia, decreased motor activity, and tremors.
Repeat-Dose Toxicity
Repeat-dose toxicity studies revealed severe central nervous system (CNS) clinical signs (including convulsions and death) that were dose-limiting for desvenlafaxine in both rats and dogs. The CNS was considered to be the target organ for desvenlafaxine based on the severity of the clinical signs. Convulsions occurred in dog toxicity studies at 200 and 300 mg/kg/day (immediate release dosage form). No convulsions occurred in dogs at desvenlafaxine dosages up to 50 mg/kg/day for 9 months and 100 mg/kg/day for 3 months, and no convulsions occurred in dogs after administration of desvenlafaxine slow-reacting tablets at a dosage of 200 mg/kg/day for 3 months. None of the non-clinical studies suggest that desvenlafaxine possesses proconvulsant or anticonvulsant activity at therapeutically relevant dosages.
Exposure ratios for desvenlafaxine at the no observable adverse effect (NOAEL) from the 6-month rat and 9-month dog studies relative to a human dose of 50 mg were 3.3 and 22.8 in male and female rats, respectively, and 4.6 in dogs. When compared to a human dose of 200 mg, the exposure ratios were 0.8 in male rats, 5.7 in female rats and 1.1 in dogs.
Cardiovascular toxicity was limited to increases in blood pressure and heart rate. QTc prolongation and ventricular arrhythmias were not observed.
A transient increase in alanine transaminase and alkaline phosphatase was observed within the first few days of dosing in one 3-month toxicity study in dogs, but there were no microscopic changes at the end of the study. This increase was not seen later in the study nor in other repeat-dose studies of 3 or 9 months.
Genotoxicity
Desvenlafaxine is not considered to be genotoxic. A signal for clastogenicity was observed following a single dose at a single timepoint in the rat bone marrow chromosomal aberration assay. However, the weight of evidence from other genetic toxicology assays and the results of 2-year carcinogenicity bioassays, which revealed no carcinogenic potential of desvenlafaxine, indicate that desvenlafaxine is not genotoxic.
Carcinogenicity
No desvenlafaxine-related neoplasms occurred in mice or rats following 2 years of desvenlafaxine administration. Fibro-osseous lesions seen in female mice in the 2-year carcinogenicity study were considered mouse-specific, morphologically distinct from osteoporosis, and without a counterpart in humans.
Ocular Toxicity
In the 2-year carcinogenicity studies conducted in mice and rats, there was an increased incidence of retinal degeneration attributed to increased light exposure of the retina resulting from desvenlafaxine-induced mydriasis. Non-pigmented rodents are highly susceptible to retinal degeneration as a result of light exposure and this condition is exacerbated by mydriasis. The albino rodent is a poor model for retinal toxicity because of its high susceptibility to phototoxic retinopathy, the absence of pigment within the retinal pigment epithelial layer, and the high incidence of spontaneous retinal pathologies. There is no evidence that desvenlafaxine causes degenerative retinal effects in animals with pigmented eyes, such as dogs.
Reproductive and Developmental Toxicity
Administration of desvenlafaxine resulted in decreases in prolactin and estrogen in female rats during diestrus. These hormonal changes were considered to be the cause of sporadic effects on estrous cyclicity, decreased fertility, and the female contribution to a decreased number of live embryos per litter, when both males and females were given desvenlafaxine. The effect on the number of live fetuses per litter was consistently observed only when both males and females were administered desvenlafaxine. The human relevance of this finding is unknown.
Desvenlafaxine produced no embryo or fetal toxicity and was not teratogenic in the studies conducted. However, there were a decreased number of rat fetuses available for analysis at the highest dose of desvenlafaxine, resulting from the effects of desvenlafaxine on fertility. Consequently, the sponsor has agreed to conduct further embryo-fetal toxicity studies in rats with dosing only conducted during the period of organogenesis to avoid the reduced fertility effects of desvenlafaxine.
Desvenlafaxine produced no effects on peri- or post-natal development.
3.2.4 Conclusion
The data from the non-clinical pharmacology and toxicology program for desvenlafaxine show that the preclinical profile of desvenlafaxine is similar to that of venlafaxine. The toxicity findings were related to exaggerated pharmacology. Several potential safety issues were identified. However, they are not considered to be serious issues in terms of human safety, as most are considered manageable or potentially species specific.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The medicinal ingredient of Pristiq, desvenlafaxine, is the major active metabolite of venlafaxine, a drug currently marketed in Canada for the treatment of depression. Venlafaxine and desvenlafaxine have similar pharmacological profiles, and significant clinical exposure to desvenlafaxine occurs with administration of venlafaxine. Therefore, the clinical effects of desvenlafaxine are expected to be similar to those seen with venlafaxine.
Venlafaxine and desvenlafaxine have been shown to be potent inhibitors of neuronal serotonin and norepinephrine reuptake, and weak inhibitors of dopamine reuptake. Neither venlafaxine nor desvenlafaxine have significant affinity for muscarinic, histaminergic, or α1-adrenergic receptors in vitro. Desvenlafaxine also lacked significant affinity for various ion channels, including calcium, chloride, potassium and sodium ion channels. Neither venlafaxine nor desvenlafaxine possess monoamine oxidase (MAO) inhibitory activity.
In the Phase I studies, the dose-limiting side effects of desvenlafaxine at doses ≥600 mg/day were nausea, vomiting, and orthostatic hypotension. Electrocardiogram studies, including a thorough placebo and moxifloxacin-controlled QTc study, failed to show statistically significant effects of desvenlafaxine on QTc interval.
3.3.2 Pharmacokinetics
Absorption
The pharmacokinetics of desvenlafaxine were linear over the dose range of 75 to 600 mg. Desvenlafaxine was well absorbed with an absolute oral bioavailability of 80%. The time to reach the maximum plasma concentration (tmax) was approximately 6-8 hours after oral administration.
In the food-effect studies, oral administration of desvenlafaxine demonstrated a small but statistically significant increase (~15%) in the maximum plasma concentration (Cmax) parameters under high-fat meal conditions. However, the drug exposure (AUC) values were similar between the fasted and fed conditions.
Distribution
Plasma protein binding of desvenlafaxine in humans was low (29.8%) and not dependent on concentration. Following intravenous administration, the volume of distribution at steady-state was 3.4 L/kg indicating distribution into nonvascular compartments.
Metabolism
Desvenlafaxine was primarily metabolized in the liver by glucuronidation, and to a lesser extent by oxidative metabolism. CYP3A4 was the major CYP450 isozyme responsible for the oxidative metabolism of desvenlafaxine to N,O-didesmethylvenlafaxine.
Excretion
Elimination of desvenlafaxine was primarily by renal excretion. Urinary recovery of conjugated and unconjugated desvenlafaxine along with the oxidative metabolite (N,O-didesmethylvenlafaxine) accounted for 69% of the oral dose of desvenlafaxine. Of the amount of dose excreted in the urine, 19% was excreted as conjugated desvenlafaxine, 45% was excreted as unconjugated desvenlafaxine, and 3.5% was excreted as conjugated and unconjugated N,O-didesmethylvenlafaxine.
Drug Interactions
In vitro and in vivo studies suggest that there is a low potential for clinically relevant pharmacokinetic interactions between Pristiq and other prescribed medications.
Special Populations
Renal Impairment
The AUC values increased by approximately 108% and 116% in patients with severe renal impairment and end-stage renal disease, respectively, compared with healthy subjects. Dosage adjustments are recommended in patients with significant impairment of renal function.
Hepatic Impairment
In patients with Child-Pugh B and Child-Pugh C hepatic impairment, AUC values were 31% and 35% higher, respectively, compared with healthy subjects. The systemic clearance of desvenlafaxine was similar between subjects with Child-Pugh A hepatic impairment and healthy subjects, but it was 20% and 36% lower in patients with Child-Pugh B and Child-Pugh C hepatic impairment, respectively, compared with healthy subjects. Based on the relatively small changes in drug exposure with hepatic impairment, no specific dosage adjustment for Pristiq in hepatically impaired patients should be required.
3.3.3 Clinical Efficacy
Eight short-term Phase III studies were submitted to support the efficacy of Pristiq in doses of 50, 100, 200 or 400 mg/day in the treatment of MDD. Four of the Phase III studies were fixed-dose studies and four were flexible-dose studies. All of the studies were multicentre, randomized, double-blind (DB), placebo-controlled, parallel-group studies in adults with MDD, with a treatment period of 8 weeks. In addition a 'relapse prevention' study was submitted, where responders to 12-week open-label treatment with Pristiq 200 to 400 mg/day were randomly assigned to Pristiq (200 or 400 mg) or placebo (DB) for up to 6 months.
The primary efficacy variable in the studies was change in the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score, baseline to endpoint, with the Last-Observation-Carried-Forward (LOCF) technique for missing values. Two additional pre-specified efficacy analyses were also performed for the primary variable: the Mixed Model Repeated Measure (MMRM, overall and at week 8) and the statistical software ETRANK. The MMRM analyzes all data, taking into account the correlation between observations. ETRANK uses a randomization technique to analyze incomplete repeated measures of data when the pattern of withdrawal is treatment-related.
In all of the short-term Phase III studies, the key secondary variable was the overall improvement measured by the Clinical Global Impressions Scale - Improvement (CGI-I). Other secondary variables included change in the Montgomery Asberg Depression Rating Scale (MADRS score), the percentage of responders based on CGI-I, the percentage of responders based on HAM-D17, and percentage of remitters defined as having a HAM-D17 total score of 7 or less. There were 120-160 patients per treatment arm in each of the short-term Phase III studies.
All of the Phase III fixed-dose studies demonstrated superior efficacy of Pristiq over placebo in the primary efficacy variable. In contrast, the flexible-dose studies failed to show statistical superiority for the Pristiq group over placebo for the primary outcome measure. Two of the four flexible-dose studies also used an active control arm. In one of these two studies the active control group failed to show superiority over placebo, while in the second of these studies, the active control group showed a positive outcome while the Pristiq group did not. Two of the studies were considered negative studies; one study was considered a failed study; and one study equivocal (failed on primary outcome with the intent-to-treat population, but was positive using the per-protocol population). The flexible-dose studies had higher early drop-out rates in the Pristiq group, resulting in worse outcomes using the LOCF analyses. Secondary protocol specified analyses using other statistical methods (ETRANK, MMRM, or observe case analyses) resulted in statistically superiority of Pristiq over placebo in most (3 out of 4) of the flexible-dose studies.
The positive results from the "relapse prevention" study were considered supportive of the acute efficacy of Pristiq for the treatment of a major depressive episode. As with the other studies, higher doses of Pristiq showed no evidence of greater efficacy than the lowest dose in the study.
Of the nine Phase III studies (eight short-term and one long-term study), five studies were considered to positively support the efficacy of Pristiq, two (flexible dose) were equivocal, and two (flexible dose) were negative. Overall, there is sufficient data to support the efficacy of Pristiq in the treatment of MDD.
3.3.4 Clinical Safety
In the Phase II and Phase III MDD studies, the total number of patients exposed to Pristiq was 3292. In the short-term (8 week) placebo-controlled studies, the safety population consisted of 1834 patients who received Pristiq, 1116 patients who received placebo, and 244 patients who received venlafaxine. Of the 1834 patients that were treated with Pristiq, 18% received doses of 50 mg/day, 25% received a maximum of 100 mg/day, 30% received 200 mg/day, and 27% received a maximum of 400 mg/day. Therefore, 82% of the patients received doses of 100 mg/day or more.
In all of the Phase III MDD clinical studies, 1070 patients had 6 months of exposure and 274 patients had 1 year of exposure to Pristiq. For the patients that were treated for at least 6 months, the mean dose was approximately 290 mg/day. For the patients that were treated up to 6 months, 50% were exposed to 400 mg/day, 44% were exposed to 200 mg/day, and 6% were exposed to 100 mg/day. For the patients that were treated up to 1 year, 47% were exposed to 400 mg/day, 42% were exposed to 200 mg/day, and 1% were exposed to 100 mg/day.
In the short-term placebo-controlled studies, the most common treatment-emergent adverse events (TEAEs, occurrence of at least 5% and twice that of placebo) were fatigue, somnolence, dizziness, dry mouth, constipation, nausea, vomiting, decreased appetite, mydriasis, blurred vision, tremor, hyperhydrosis, headache, insomnia, anorgasmia, and erectile dysfunction. Most common TEAEs were dose-related. Generally, there was a dose-response for the level of severity or the incidence of events within a given level of severity. In the short-term studies, among the patients that were treated with Pristiq, the most common adverse events (AEs) that let to discontinuation were nausea, vomiting, dizziness, headache, and insomnia. The incidence of withdrawal for these AEs was generally dose-related. Adverse events during longer-term treatment had a similar profile.
The AEs observed with Pristiq were consistent with the pharmacology of SNRIs, and the safety profile of Pristiq was similar to that of venlafaxine. As with venlafaxine, the main safety concern associated with Pristiq treatment is the risk of hypertension. The Product Monograph provides warnings that Pristiq may be associated with behavioural and emotional changes, including self-harm.
Results from the controlled studies and the dedicated QT study demonstrated that there were no signals suggesting that Pristiq leads to prolongation of the QT interval. Treatment with Pristiq was associated with dose-related increases in heart rate although few potentially significant increases were observed. There was also a dose-related risk of hyperlipidemia in the studies. Lipid elevations are also known to occur with venlafaxine treatment.
Significant serum alanine transaminase elevations were somewhat more frequent with Pristiq treatment compared to placebo; however, there was no dose-response relationship; and the frequency of potentially clinically important changes in aspartate aminotransferase, alanine transaminase, and total bilirubin were not greater with long-term Pristiq treatment than with short-term treatment. There were no adverse events associated with the elevation in the liver function tests. Mild increases in alanine transaminase have been observed with other antidepressant medications.
Approximately 2% of the patients treated with Pristiq in all of the placebo-controlled studies had treatment-emergent proteinuria, a significantly higher rate compared to patients that received placebo. Generally the proteinuria was of trace amounts and was not associated with any other signs or symptoms of renal problems. No dose relationship was observed in the short-term, fixed-dose studies. Overall, the data do suggest that treatment with Pristiq may be associated with increased urinary protein excretion. The mechanism of the enhanced protein excretion is not clear but may be related to noradrenergic stimulation.
Overall, the safety profile of Pristiq is very similar to that of venlafaxine which is currently marketed in Canada for a variety of psychiatric indications including MDD.
The Pristiq Product Monograph contains warnings similar to the venlafaxine Product Monograph. Safety issues arising with the use of Pristiq can be managed through labelling.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Efficacy of Pristiq for the symptomatic relief of MDD is supported by the submitted clinical trial program. Desvenlafaxine, the medicinal ingredient of Pristiq, is the active metabolite of venlafaxine. Using the metabolite of venlafaxine avoids one metabolic step mediated by CYP2D6, and thus compared to venlafaxine, Pristiq has a reduced risk of drug-drug interactions due to interaction with this CYP isozyme.
The clinical safety profile is as expected for the active metabolite of venlafaxine; meaning it is very similar. It should be noted that the Phase III clinical development program for Pristiq began using doses of 100 mg to 400 mg/day. At these doses, AEs with Pristiq tended to be more frequent and more severe than those observed with venlafaxine (although similar in nature). As there was an increase in the incidence of side-effects but no evidence of increased efficacy at doses higher than 100 mg/day, studies were conducted at lower doses (50 mg/day). In the lower dose studies, there was no evidence that the Pristiq doses greater than 50 mg/day had any greater efficacy. While there is no evidence of improved efficacy at the 100 mg/day dose, it is reasonable to allow the market authorization of the 100 mg dose, to allow physicians and patients the flexibility to try a higher dose if the 50 mg/day dose does not prove sufficiently efficacious. This has been a standard regulatory approach with previous SSRIs, which have also not shown any increase in efficacy at doses above the minimal recommended dose. Higher dosage strengths have been allowed when safety and tolerability data support this.
Overall, the benefit/risk profile for Pristiq for the proposed indication is favourable. Restrictions to manage risks associated with the identified safety concerns have been incorporated into the Pristiq Product Monograph.
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 Pristiq is favourable for the symptomatic relief of major depressive disorder. 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: PristiqTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2007-06-19 |
| Submission filed | 2007-10-16 |
| Screening | |
| Screening Deficiency Notice issued: | 2007-12-19 |
| Response filed: | 2008-01-15 |
| Screening Acceptance Letter issued: | 2008-02-29 |
| Review | |
| Biopharmaceutics Evaluation complete | 2008-12-17 |
| Quality Evaluation complete | 2009-01-23 |
| Clinical Evaluation complete | 2009-01-27 |
| Labelling Review complete | 2009-01-23 |
| Notice of Compliance issued by Director General | 2009-02-04 |
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| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| PRISTIQ | 02321106 | PFIZER CANADA ULC | DESVENLAFAXINE (DESVENLAFAXINE SUCCINATE) 100 MG |
| PRISTIQ | 02321092 | PFIZER CANADA ULC | DESVENLAFAXINE (DESVENLAFAXINE SUCCINATE) 50 MG |