Summary Basis of Decision for Nucynta ™ CR
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:
NucyntaTM CR
Tapentadol hydrochloride, 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg, Tablets (controlled release), Oral
Janssen Inc.
Submission control no: 133167
Date issued: 2011-04-15
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):
- 02360373 - 50 mg
- 02360381 - 100 mg
- 02360403 - 150 mg
- 02360411 - 200 mg
- 02360438 - 250 mg
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
All trademark rights used under licence
2 Notice of decision
On December 2, 2010, Health Canada issued a Notice of Compliance to Janssen Inc. for the drug product, Nucynta™ CR (tapentadol hydrochloride controlled-release tablets).
Nucynta™ CR contains the medicinal ingredient tapentadol (as tapentadol hydrochloride) which is an opioid analgesic and an inhibitor of the norepinephrine transporter to a lesser degree.
Nucynta™ CR is indicated for the management of moderate to moderately severe pain in adults who require continuous treatment for several days or more. Although its exact mechanism is unknown, analgesic efficacy is thought to be due to mu-opioid agonist activity and the inhibition of norepinephrine reuptake.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Nucynta™ CR have been demonstrated in two studies in patients with moderate to severe chronic pain. The studies were randomized, double-blind, placebo- and active-controlled; one in patients with low back pain and one in patients with pain related to osteoarthritis. In both studies, Nucynta™ CR provided statistically significantly greater pain reduction from baseline at the last week of a 12-week maintenance period compared with placebo.
Nucynta™ CR (50 mg, 100 mg, 150 mg, 200 mg, and 250 mg tapentadol hydrochloride) is presented as a controlled-release tablet. Patients currently not taking opioid analgesics should begin Nucynta™ CR therapy with 50 mg twice a day (approximately every 12 hours) and then be individually titrated to an optimal dose, balancing pain relief and tolerability, within the therapeutic range of 100 mg to 250 mg twice daily. For patients currently taking opioid analgesics, the recommended initial Nucynta™ CR daily dose is half of the dose calculated from the published relative equianalgesic information, taken approximately every 12 hours. Nucynta CR™ showed comparable pain relief with oxycodone controlled-release tablets at a dose ratio of 5:1 in clinical studies. The maximum daily Nucynta™ CR dose should not exceed 500 mg in total. Detailed dosing guidelines are available in the Nucynta™ CR Product Monograph. The tablets are to be swallowed whole and not to be broken, chewed, dissolved, or crushed. Taking broken, chewed, dissolved, or crushed Nucynta™ CR tablets will lead to rapid release and absorption of a potentially fatal dose of tapentadol.
Nucynta™ CR is contraindicated for the following patients:
- Patients who are hypersensitive to tapentadol, to opioids, or to any ingredient in the formulation or component of the container;
- Patients with known or suspected mechanical gastrointestinal obstruction [for example (e.g.), bowel obstruction, strictures] or any diseases/conditions that affect bowel transit (e.g., ileus of any type);
- Patients taking monoamine oxidase inhibitors (or within 14 days of such therapy);
- Patients with severe renal or hepatic impairment (creatinine clearance of less than 30 mL/min and/or Child-Pugh Class C);
- Patients with mild, intermittent or short-duration pain that can be managed with other pain medications;
- Patients with peri-operative pain;
- Patients with acute asthma or other obstructive airway, and status asthmaticus;
- Patients with acute respiratory depression, elevated carbon dioxide levels in the blood, and cor pulmonale;
- Patients with acute alcoholism, delirium tremens, and convulsive disorders;
- Patients with severe central nervous system depression, increased cerebrospinal or intracranial pressure, and head injury; and
- Women who are breastfeeding, pregnant, or during labour and delivery.
Nucynta™ CR 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 Nucynta™ CR 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 Nucynta™ CR is favourable for the management of moderate to moderately severe pain in adults who require continuous treatment for several days or more.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Tapentadol (as tapentadol hydrochloride) is the medicinal ingredient of Nucynta™ CR. Tapentadol is an opioid analgesic and the analgesic efficacy is thought to be due to muopioid agonist activity and the inhibition of norepinephrine reuptake.
Manufacturing Process and Process Controls
The drug substance is synthetically derived. Each step of the manufacturing process is considered to be controlled within acceptable limits.
Characterization
The structure of tapentadol hydrochloride has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits are adequately qualified.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of tapentadol hydrochloride are acceptable.
Validation reports were provided and are satisfactory. The levels of product- and process-related impurities are adequately monitored throughout the manufacturing process. Batch analysis results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed retest period for the drug substance is supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Nucynta™ CR tablets contain tapentadol hydrochloride as the medicinal ingredient. The tapentadol hydrochloride controlled-release tablets are available in dosage strengths of 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg tapentadol base in bottles of 60 tablets as follows:
- 50 mg tablet: a white capsule-shaped tablet debossed with "O-M" on one side and "50" on the other side;
- 100 mg tablet: a light blue capsule-shaped tablet debossed with "O-M" on one side and "100" on the other side;
- 150 mg tablet: a blue-green capsule-shaped tablet debossed with "O-M" on one side and "150" on the other side;
- 200 mg tablet: a blue capsule-shaped tablet debossed with "O-M" on one side and "200" on the other side; and
- 250 mg tablet: a dark blue capsule-shaped tablet debossed with "O-M" on one side and "250" on the other side.
The following non-medicinal ingredients are common to all tablet strengths: silicified microcrystalline cellulose, hypromellose, magnesium stearate, polyvinyl alcohol, talc, polyethylene glycol, and titanium dioxide. The 100 mg, 150 mg, 200 mg, and 250 mg tablets also contain FD&C Blue Number 2 Aluminum Lake. The 150 mg tablets also contain yellow iron oxide.
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 tapentadol hydrochloride 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 acceptable and the process is adequately controlled within justified limits.
Control of Drug Product
Nucynta™ CR is tested to verify that its identity, appearance, content uniformity, assay, dissolution, and levels of degradation products and drug-related impurities are within acceptance criteria. The test specifications are acceptable to control the drug product, and the impurity limits were set according to International Conference on Harmonisation recommendations.
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 Nucynta™ CR.
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 real-time, long-term, and accelerated stability data submitted, the proposed 36-month shelf-life at 15-30oC is considered acceptable for Nucynta™ CR when packaged in the proposed container closure system.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Nucynta™ CR are considered suitable for the activities and products manufactured.
All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
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 Nucynta™ CR 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
Tapentadol binds to the mu-opioid receptor and norepinephrine transporter. It is an agonist at the mu-opioid receptor and an inhibitor of the norepinephrine transporter to a lesser degree.
In pharmacodynamic studies, tapentadol demonstrated a weak inhibitory effect on the serotonin transporter. This activity may become more pronounced under conditions of special sensitivity or synergy with other drugs with similar activities.
In pharmacodynamic studies at identical mg/kg doses, the pain relief effects of tapentadol were generally stronger than tramadol and weaker than morphine.
Similar to other mu-opioids agonists, tapentadol was shown to be an antitussive and a weak emetic. It also inhibited gut motility. At doses relative to clinical use, Tapentadol enhanced the inhibitory effects of other inhibitors of the central nervous system, such as strong opiods and barbiturates.
The effects of tapentadol on the QT interval were studied in several laboratory species. QT prolongation was observed at 80 and 120 mg/kg dose groups in dogs, and the effect was observed to diminish or dissipate over time. Additional QT interval studies were performed clinically, and it was found that there was no effect of therapeutic doses of tapentadol on the QT interval.
Tapentadol may have proconvulsive effects under some conditions, such as high dose, special sensitivity, and drug interactions. This risk was managed during the clinical studies with stringent exclusion criteria to exclude patients with a history of seizures and any clinical condition that may increase that risk of seizures. Cases of seizures have been reported during post-market surveillance.
3.2.2 Pharmacokinetics
Absorption
Following oral administration, tapentadol appeared to be completely absorbed in all animal models studied (dog, mice, and rats); however, bioavailability was low in dogs and rats due to highly efficient hepatic clearance.
Distribution
In rats, tapentadol was widely distributed. Tapentadol crossed the blood-brain barrier, and crossed the placenta-blood barrier to a lesser amount. The concentration of tapentadol inside the blood-brain barrier directly reflected its blood concentration. Its main metabolite, tapentadol-O-glucuronide, had lower permeability through the bloodbrain barrier but it did accumulate, suggesting a slower transfer mechanism.
Plasma protein binding was low at 15-20% in all species tested including humans. Tapentadol had a higher binding to sepia melanin at 25-50%.
Metabolism
Tapentadol was extensively metabolized to tapentadol-O-glucuronide via the uridine 5'-diphospho-glucuronosyltransferase (UDP-UGT) systems. The UGT isoenzymes conjugate the parent drug and also many of the non-glucuronidation intermediate metabolites. Oxidation was a minor metabolic pathway. Studies on inhibition and induction of hepatic microsomal drug metabolising enzymes showed that tapentadol has no effect on the cytochrome P450 (CYP) isoenzymes.
Excretion
The conjugated tapentadol was predominantly eliminated via the urine and to a much lesser extent in the faeces.
3.2.3 Toxicology
Single-Dose Toxicity
With intravenous (IV) administration, the lethal dose for 50% of the population (LD50) was 45 mg/kg in rats and 47 mg/kg in mice. With oral administration, the LD50 was >1000 mg/kg in rats and 300-350 mg/kg in mice. Causes of death were respiratory depression and convulsions.
Repeat-Dose Toxicity
The repeat-dose toxicity results showed that the chronic toxic effects of tapentadol were consistent with the exaggerated pharmacological effects on the central nervous system. Hepatic hypertrophy, both macroscopic and microscopic, was present in all animal species that received chronic tapentadol dosing. The enlargement of the liver was probably an adaptive response to the consistent high metabolic load of tapentadol. There was also an increased activity of the hepatic metabolic enzymes studied.
In a 52-week dog study with oral dosing, exaggerated pharmacological effects of tapentadol were observed at 30 mg/kg. Convulsions were observed at tapentadol dose ranges slightly higher than human therapeutic doses in rats. Tapentadol is suspected of a proconvulsion effect at 6 mg/kg IV in rats.
QT prolongation was observed at 80 and 120 mg/kg dose groups in dogs. This effect was observed to diminish or dissipate over time.
Genotoxicity
In vitro and in vivo genotoxicity studies demonstrated that tapentadol is not genotoxic.
Carcinogenicity
Life-time toxicity studies (104 weeks) in rats and mice showed that long-term exposure to tapentadol resulted in toxic symptoms consistent with chronic opioid exposure. The increased long-term metabolic load resulted in both macroscopic and microscopic hypertrophy, as well as increased liver enzyme activities; however, no signal of neoplasticity was found.
Reproductive and Developmental Toxicity
Tapentadol had general adverse effects on maternal health and function, as well as effects on foetal growth at clinically relevant dosing levels. There was no evidence in rats and mice to suggest teratogenicity.
Dependence
In a study with monkeys administered IV tapentadol, a dose-dependent antinociceptic effect was observed with an effective dose for 50% of the population (ED50) of 0.54 mg/kg. The reinforcing effect was observed at 0.03 and 0.10, but less so at 0.01 (the lowest dose tested) and 0.30 mg/kg/infusion self administration. The data from two intraperitoneal (IP) withdrawal studies in mice showed a withdrawal effect precipitated by naloxone. The order of withdrawal potency was reported to be morphine, tramadol, and tapentadol. In studies in rats with IP dosing, the opioid potency of tapentadol was lower than morphine but higher than tramadol.
In other studies in rats administered IP tapentadol, the data suggested that tapentadol had a delayed tolerance development compared with morphine and tramadol. Tolerant animals showed complete cross-tolerance to morphine.
3.2.4 Summary and Conclusion
The non-clinical findings were consistent with the understanding that tapentadol is an agonist at the mu-receptor and an inhibitor at the norepinephrine transporter to a lesser degree. Its non-clinical pharmacokinetics are relatively well understood. Key non-clinical safety issues included proconvulsion effects under certain clinical and pharmacological conditions, potential attenuating effects on serotonin syndrome, and sympathomimetic effects at high doses.
Overall, the non-clinical pharmacology and toxicology data submitted support the use of Nucynta™ CR for the approved indication, and provide an adequate identification of the risks of the drug. Adequate statements are in place in the Product Monograph to address the identified safety concerns.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Nucynta™ CR (tapentadol hydrochloride controlled-release tablets) is a centrally-acting synthetic analgesic with a dual mechanism of action acting as a mu-opioid agonist and a norepinephrine-reuptake inhibitor. Tapentadol is structurally similar to tramadol and has similar pharmacological properties with more potent mu-opioid receptor activity. Tapentadol is 18-times less potent than morphine in binding to the human mu-opioid receptor. The pharmacodynamic effects of Nucynta™ CR are consistent with the combined effects of a mu-opioid agonist and sympathomimetic. The main therapeutic actions of tapentadol and its potential risks identified to date are derived from these pharmacological activities.
Pharmacodynamic data show that tapentadol reduced gut motility and tapentadol had dose-dependent reinforcing tendencies, similar to those of hydromorphone. A thorough QT/QTc study indicates that tapentadol did not have adverse effects on the QT interval within the clinically recommended dose ranges, as confirmed by our QT expert review.
3.3.2 Pharmacokinetics
Absorption
Maximum serum concentrations (Cmax) of tapentadol were observed 3-6 hours after administration of Nucynta™ CR. Dose proportional increases in drug exposure [area under the curve (AUC) values] were observed following administration of Nucynta™ CR as single doses over a range of 50-250 mg.
A single-dose, crossover comparative bioavailability study evaluated the effect of food on the Nucynta™ CR 250 mg tablet in healthy subjects. Data provided indicate a lack of significant effect of food on the bioavailability of the 250 mg tablet and supports the proposed labelling and dosing recommendations with regard to food.
Distribution
The volume of distribution results (540 ±98 L) show that tapentadol was widely distributed throughout the body. The plasma protein binding for tapentadol was low at approximately 20%.
Metabolism
Tapentadol was extensively metabolized in the liver. The major metabolic pathway was glucuronidation with tapentadol-O-glucuronide as the main conjugate. Tapentadol demonstrated no inhibitory activity on the CYP isoenzymes relevant in clinical pharmaceutically metabolism. Tapentadol showed no significant induction of CYP isoenzymes.
Excretion
Tapentadol and its metabolites were predominantly excreted via the kidneys.
In four healthy men administered a single oral dose of 100 mg radiolabelled tapentadol, the Cmax was at 1.25-1.5 hours; the ratio of conjugated tapentadol/unconjugated tapentadol was 24:1; the exposure to the conjugates was approximately 64% of the total; 95% of the total dose was excreted within 24 hours, 99% via urine. Of the related compounds excreted in the urine, 3% was the parent drug, 69% was in the conjugated form, and 27% were other forms of metabolites. Approximately 1% of the total drug was excreted in the faeces. On average, 99.9% of the drug was recovered in 5 days.
Drug Interactions
The pharmacokinetics of tapentadol was not affected by omeprazole and metoclopramide. Commonly used coxib analgesics including naproxen, acetylsalicylic acid, and acetaminophen had no significant pharmacokinetic interactions with tapentadol. Probenecid may interact with the pharmacokinetics of tapentadol; its metabolic interaction may be more prominent than its secretion interaction.
Special Populations
Mild to moderate renal impairment had a minor impact on the elimination of tapentadol and tapentadol-O-glucuronide. Severe renal impairment reduced the metabolism of tapentadol resulting in a longer half-life for tapentadol and a delayed time to reach the maximum concentration (Tmax) for tapentadol-O-glucuronide. Severe renal impairment also reduced the clearance of tapentadol-O-glucuronide. Tapentadol is contraindicated in patients with severe renal impairment.
Moderate hepatic impairment more than doubled the exposure of tapentadol, therefore Nucynta™ CR is not recommended for these patients. Tapentadol is contraindicated for patients with severe hepatic impairment.
No significant differences were reported in the pharmacokinetics of tapentadol between the elderly and younger adults. Because geriatric patients are generally more sensitive to the pharmacological effects of opioids, general caution is advised.
3.3.3 Clinical Efficacy
Key support for the efficacy of Nucynta™ CR was demonstrated in two pivotal studies: Study PAI-3011; and Study PAI-3008.
Study PAI-3011 was a three-arm parallel-group efficacy study of Nucynta™ CR with randomized placebo- and positive-controls in patients with moderate to severe chronic low back pain. The positive control was oxycodone CR (controlled release) 10-50 mg twice daily. After a 3- to 7-day washout period, patients were instructed to titrate up or down at 3-day intervals for 3 weeks, starting with Nucynta™ CR 50 mg or oxycodone CR 10 mg twice daily. During this titration phase, the target dose range was Nucynta™ CR 100-250 mg or oxycodone CR 20-50 mg twice daily. Following the titration, the patients entered a 12-week maintenance phase with flexible dosing of Nucynta™ CR 100-250 mg or oxycodone CR 20-50 mg twice daily. A total of 981 of patients were randomized and 965 took at least one dose; 319 received placebo, 318 received Nucynta™ CR, and 328 received oxycodone CR. The study patients included 406 men and 559 women with an average age of 49.9 (range 18-89). The majority of patients (88.9%) reported severe pain upon entry. Both opioid naïve and experienced patients were included.
The primary efficacy endpoint was the change from baseline of the average pain intensity over the last week of the maintenance phase of the daily pain intensity on an 11-point numerical rating scale (NRS). The results for the primary efficacy endpoint (change from baseline to Week 12 of maintenance phase) were -2.1 for the placebo group, -2.9 for the Nucynta™ CR group, and -2.9 for the oxycodone CR group. The placebo-adjusted mean effect size was -0.8 for the Nucynta™ CR group and -0.9 for the oxycodone CR group. The proportion of patients that had a 30% reduction in pain score from baseline to the end of Week 12 of the maintenance period (a secondary endpoint) was 27.1% for the placebo group, 39.7% for the Nucynta™ CR group, and 30.4% for the oxycodone CR group.
Study PAI-3008 was a three-arm parallel-group efficacy study with randomized placeboand positive-controls in patients with moderate to severe chronic pain resulting from osteoarthritis of the knee. The positive control was oxycodone CR 10-50 mg twice daily. After a 3- to 7-day washout period, the patients were instructed to titrate up or down at 3- day intervals for 3 weeks, starting with Nucynta™ CR 50 mg or oxycodone CR 10 mg twice daily. During this titration phase, the target dose range was 100-250 mg twice daily for Nucynta™ CR or 20-50 mg twice daily for oxycodone CR. Following the titration, the patients entered the 12-week maintenance phase with flexible dosing in the range of Nucynta™ CR 100-250 mg or oxycodone CR 20-50 mg twice daily. A total of 1030 patients were randomized; 339 on placebo, 346 on Nucynta™ CR, and 345 on oxycodone CR. The study patients included 405 men and 618 women with an average age of 58.3 (range 40-91). The majority of patients (83.4%) reported severe pain upon entry. Both opioid naïve and experienced patients were included.
The primary efficacy endpoint was the change from baseline of the average pain intensity over the last week of the maintenance phase of the daily pain intensity on an 11-point NRS. The results for the primary efficacy endpoint were -2.3 for the placebo group, -2.9 for the Nucynta™ CR group, and -2.6 for the oxycodone CR group. The placebo-adjusted mean effect size was -0.7 for the Nucynta™ CR group and -0.3 for the oxycodone CR group. The proportion of patients that had a 30% reduction in pain score from baseline to the end of Week 12 of the maintenance period (a secondary endpoint) was 35.9% for the placebo group, 43.0% for the Nucynta™ CR group, and 24.9% for the oxycodone CR group.
3.3.4 Clinical Safety
The safety profile for Nucynta™ CR was consistent throughout the development phases. The pattern of the adverse events, described below, reflects the pharmacological effects of tapentadol at the mu-opioid receptor and norepinephrine transporter.
Based on data from the placebo- and/or active-controlled studies that administered multiple doses of Nucynta™ CR, 62% of the patients treated with Nucynta™ CR experienced adverse reactions. These were predominantly reported as being mild or moderate in severity. The most common adverse reactions (reported by ≥10% in any Nucynta™ CR group) were: nausea; dizziness; constipation; headache; and somnolence. No differences in tolerability were observed between the opioid naïve and opioid experienced patients. The most common reasons for discontinuation for the patients treated with Nucynta™ CR and the patients treated with placebo were nausea [4.3% versus (vs.) 1.3%], dizziness (3.1% vs. 0.7%), vomiting (2.8% vs. 0.5%), somnolence (2.0% vs. 0.2%), constipation (1.4% vs. 0.2%), headache (1.2% vs. 0.3%) and fatigue (1.2% vs. 0.3%), respectively.
Patients with any history of seizure or suspected vulnerability to seizure were excluded from the clinical studies. No case of serotonin syndrome was identifiable during the development program. Cases of seizures and serotonin syndrome have nonetheless been identified in the post-market safety database. Hypertension with clinical importance was observed in 1.5-1.7% of the clinical study patients. Nucynta™ CR had no clinically relevant effect on the QT interval at the maximum recommended dose.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Nucynta™ CR, 100-250 mg twice a day, provided pain reduction in adult patients with moderate to moderately severe chronic pain. The efficacy of Nucynta™ CR was supported in patients with low back pain and in patients with pain related to osteoarthritis.
Nucynta™ CR appears to have the safety profile of a moderately strong opioid in combination with a weak sympathomimetic. Nucynta™ CR is recommended to be scheduled as a narcotic.
The identified safety issues are seizures and hypertension in vulnerable patients, serotonin syndrome, drug abuse and drug dependence, and respiratory depression. These risks are clearly outlined in the Product Monograph and are manageable through the use of instructions in the Product Monograph. Overall, the benefit to risk profile is favourable and supports the use of Nucynta™ CR for the approved indication.
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 Nucynta™ CR is favourable in the management of moderate to moderately severe pain in adults who require continuous treatment for several days or more. The New Drug Submission (NDS) complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: NucyntaTM CR
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2009-04-16 |
| Submission filed: | 2009-12-14 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2010-02-05 |
| Review 1 | |
| Biopharmaceutics Evaluation complete: | 2010-11-23 |
| Quality Evaluation complete: | 2010-12-02 |
| Clinical Evaluation complete: | 2010-12-02 |
| Labelling Review complete: | 2010-12-01 |
| Notice of Compliance issued by Director General: | 2010-12-02 |