Summary Basis of Decision for Tramacet
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:
Tramacet
37.5 mg tramadol hydrochloride/325 mg acetaminophen, film-costed tablet, Oral
Janssen Ortho Inc.
Submission control no: 095167
Date issued: 2008-09-17
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):
- 02264846
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On July 20, 2005, Health Canada issued a Notice of Compliance to Janssen-Ortho Inc. for the drug product Tramacet. Tramacet contains two active medicinal ingredients: tramadol hydrochloride, a centrally-acting synthetic opioid analgesic; and acetaminophen, a non-opiate non-salicylate analgesic.
Tramacet is indicated for short-term (five days or less) management of acute pain.
The market authorization for Tramacet was based on submitted data from quality control studies, data from preclinical and clinical studies, as well as post-marketing data. The data from three single-dose and two multiple-dose clinical studies for treatment of acute pain generally showed that tramadol hydrochloride/acetaminophen was more effective than placebo in helping subjects manage acute pain.
Tramacet (37.5 mg tramadol hydrochloride and 325 mg acetaminophen) is not recommended for minor pain that may be treated adequately through lesser means where benefit does not outweigh the possible opioid-related side effects. For the short-term (five days or less) management of acute pain, the recommended dose is 1 or 2 tablets orally every 4 to 6 hours as needed for pain relief up to a maximum of 8 tablets per day. Detailed conditions for the use of Tramacet are described in the Product Monograph.
Tramacet is contraindicated in any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs. Tramacet should not be administered to patients who have previously demonstrated hypersensitivity to tramadol, acetaminophen, opioids or any other component of this product.
A Risk Management strategy to support the safe and effective use of Tramacet has been established. The following are considered to be the essential components of the Risk Management strategy:
- Commitment to not emphasize or highlight the scheduling status of Tramacet in its advertising or promotional activities.
- Inclusion of an approved fair balance statement in all Tramacet advertising and promotional materials.
- Provision of progress reports to Health Canada from the ongoing drug abuse surveillance program, including data from four key informant Canadian sites in the program.
- Reassessment of the success of the risk management strategy 2 years post product launch.
Based on the Health Canada review of quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Tramacet is acceptable for short-term (five days or less) management of acute pain.
3 Scientific and Regulatory Basis for Decision
In 1992, Ortho-McNeil Pharmaceuticals submitted a New Drug Submission (NDS) for tramadol hydrochloride, Control Number 10692. The company withdrew their drug submission after it was recommended and accepted that tramadol be added to the Narcotic Control Act.
In 1999, an NDS was filed for the combination tablet, 37.5 mg tramadol hydrochloride and 325 mg acetaminophen (Control Number 063726). With the data submitted, the tramadol/acetaminophen combination had equivalent efficacy, but an inferior safety profile compared to ibuprofen. The company withdrew their submission and re-filed the NDS (Control Number 085030) in 2003, with eight additional studies. The data did not adequately address the key issue of whether the analgesic effects of the combination tablet was statistically superior to the individual effects of each component administered alone, under the proposed conditions of use. Consequently, a Notice of Non-Compliance (NON) was issued.
The NDS was re-filed in June 2004 with a modification to the Tramacet indication. Tramacet received market authorization in July 2005 under restricted conditions of use, and with the Tramacet Product Monograph appropriately reflecting the potential for abuse and dependence liability. The Risk Management strategy to support the safe and effective use of Tramacet was included in the Tramacet Product Monograph.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (medicinal ingredient)
Manufacturing Process and Process Controls
Tramacet contains two medicinal ingredients: tramadol hydrochloride and acetaminophen. Both drug substances are manufactured by a multi-step synthesis. The manufacturing processes are considered to be adequately controlled within justified limits and all materials are considered suitable and/or meet standards appropriate for their intended use.
Characterization
Impurities arising from manufacturing and/or storage were reported and characterized. The proposed limits were considered satisfactorily qualified (e.g., within recommended ICH limits, toxicological studies). Control of impurities in the drug substance is therefore considered to be acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were considered satisfactory for all analytical procedures used for release and stability testing of tramadol hydrochloride and acetaminophen.
The specifications are considered acceptable for the drug substance. Batch analysis results were reviewed and were within the proposed acceptance criteria. The proposed packaging components are also considered acceptable.
Stability
Based upon the real-time and accelerated stability study data submitted, the proposed
re-test period, storage and shipping conditions for the two drug substances are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Tramacet is a light yellow, film-coated, caplet-shaped tablet debossed with "J-C" on one side and "T/P" on the other side. The tablet contains two medicinal ingredients, 37.5 mg of tramadol hydrochloride and 325 mg of acetaminophen.
The non-medicinal ingredients are powdered cellulose, pre-gelatinized starch, sodium starch glycolate, maize starch, purified water, and magnesium stearate. The film coating consists of Opadry® light yellow, purified water and carnauba wax.
The excipients stated above are commonly used in tablet dosage forms and are acceptable by the Canadian Food and Drug Regulations.
The tablets are contained in high-density polyethylene (HDPE) bottles or in polyvinyl chloride (PVC) blisters with aluminum push-lid foil. A polypropylene (PP) blister with aluminum push-lid foil or a PP lidding-film may also be used.
Pharmaceutical Development
All changes made to the manufacturing process and to the formulation throughout the development are considered acceptable upon review.
Manufacturing Process and Process Controls
The manufacturing process consists of the following steps: pre-blending, granulation and drying, final blending, compression and coating. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Tramacet is tested to verify its physical description, identity, assay, purity, uniformity and dissolution.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits for degradation products were considered satisfactorily qualified (e.g., within recommended ICH limits, toxicological studies).
Copies of the analytical methods and, where appropriate, validation reports were considered satisfactory for all analytical procedures used for release and stability testing of Tramacet.
Stability
Based upon the long term and accelerated stability study data submitted, the proposed shelf life of 24 months is considered acceptable when Tramacet tablets are packaged in the approved containers and stored at 15-30 °C.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment are considered to be suitable for the activities and products manufactured at the site.
3.1.4 Adventitious Agents Safety Evaluation
Confirmation has been provided that the drug product does not contain, and is not derived from specified risk material. Magnesium stearate is sourced from plant/vegetable material and the Opadry® product contains no material of animal origin, hence carry no risk of TSE transmission.
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Tramacet has demonstrated that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
The submission included non-clinical information to support the authorization of Tramacet. The non-clinical information relates to tramadol and the combination of tramadol and acetaminophen.
3.2.1 Pharmacodynamics
Tramacet is composed of two medicinal ingredients: tramadol and acetaminophen.
Tramadol appears to exert its analgesic effects predominantly through agonistic activity at µ receptors. In some rodent models, the analgesic effects appeared to be related to an additional non-µ receptor mediated component. In rats, a component of the analgesia appeared to be related to noradrenergic and serotonergic effects, although this could not be demonstrated for mouse pain models. As tramadol inhibits noradrenaline and
5_HT uptake, in vitro, this mechanism has been speculated to play a role in the analgesic effects of the drug.
Acetaminophen appears to produce analgesia by elevation of the pain threshold. The potential mechanism may involve inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate and Substance P.
The effectiveness of fixed-ratio combinations of tramadol and acetaminophen were evaluated in a standard mouse antinociceptive test and results showed a synergistic antinociceptive effect.
3.2.2 Pharmacokinetics
Pharmacokinetic studies of tramadol were conducted in mice, rats, hamsters, guinea pigs, monkeys, and dogs. Toxicokinetic studies for tramadol/acetaminophen were conducted in rats. Drug interactions for tramadol/acetaminophen were conducted in liver microsomes from rats, dogs, and humans.
Absorption of tramadol was rapid in all species studied. Both tramadol and its primary active metabolite M1 (mono-O-desmethyltramadol) exerted analgesic effects, although the parent compound was less potent. In mice that received tramadol intravenously, both the parent compound and its active metabolite were present in sufficient quantities to account for antinociceptive effects. The major route of excretion was renal in all species studied. Faecal excretion was approximately 13% in rats and dogs.
Hepatic drug metabolizing enzyme activities were assayed in mice and dogs. In mice, 7-ethoxycoumarin O-deethylase activity was significantly increased during tramadol treatment when data for both sexes were combined, but not when the two sexes were evaluated separately. Tramadol treatment had no effect on hepatic microsomal protein content, cytochrome P450 content, ethoxyresorufin O-deethylase, or acetaminophen glucuronyl transferase. In dogs, chronic tramadol treatment was associated with a dose-dependent reduction in acetaminophen glucuronyl transferase activity. Ethoxyresorufin O-deethylase activity was increased at all dose levels in animals of both sexes, an effect which showed a weak dose-dependence. Cytochrome P450 activity was increased in female dogs of the mid and high dose group.
3.2.3 Toxicology
Non-clinical toxicology studies for tramadol hydrochloride were submitted and evaluated in prior new drug submissions for tramadol hydrochloride as a single medicinal ingredient and in a combination drug, 37.5 mg tramadol hydrochloride and 325 mg acetaminophen. Although both submissions were withdrawn by the sponsor in Canada prior to authorization, the toxicology reviews were considered to be relevant to this submission.
Non-clinical toxicology studies included single dose, repeated dose, reproductive and developmental toxicity, genotoxicity, and carcinogenicity studies. The significant results are documented in the Product Monograph. The toxicology studies did not suggest significant clinical concerns resulting from combined exposure to tramadol hydrochloride and acetaminophen. This is supported by clinical experience with products containing tramadol in other markets.
The combination drug (37.5 mg tramadol hydrochloride and 325 mg acetaminophen) has been marketed in the United States and Europe for several years, and adverse event profiles submitted have supported the toxicology review conclusions. Periodic Safety Update Reports (PSURs) for Tramacet were available since August 2001. The data provided in the PSURs are consistent with the component products of tramadol hydrochloride and acetaminophen and do not modify the risk/benefit relationship of either product. Furthermore, there were no events reported that were suggestive of a new safety signal resultant from the combined exposure to tramadol hydrochloride and acetaminophen.
3.2.4 Summary and Conclusion
Tramacet is a combination of tramadol hydrochloride and acetaminophen. Tramadol is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests it appears that at least two complimentary mechanisms may be applicable: binding of parent and M1 metabolite to µ-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin. Acetaminophen is a non-opiate, non-salicylate analgesic. The combination of drugs has been shown to have a synergistic analgesic effect in the pharmacodynamic studies.
On the basis of the preclinical pharmacology studies sedation, constipation, mydriasis, ataxia, respiratory depression, and elevated body temperature would be anticipated side effects of tramadol. Clinically significant drug interactions with monamine oxidase inhibitors should be expected.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Clinical pharmacodynamic studies were not required for this drug submission. The pharmacodynamic properties of acetaminophen and tramadol (an opioid) are both well known.
3.3.2 Pharmacokinetics
The data available from two separate studies suggest that bioavailability of tramadol in females is approximately 20% higher than in males. The half-life of tramadol appeared to be 1-2 hours longer in female patients and absorption following oral administration appeared to be delayed relative to male patients.
The administration of tramadol following food slightly increased the bioavailability of the drug. However, these results were not clinically significant and therefore the administration of tramadol to fed or fasted patients is appropriate. It is worth noting that nausea occurred in 17% of the fasted patients and this adverse event was not reported by the fed patients.
Steady-state tramadol levels were achieved by the second day of multiple-dose treatment. The half-life and clearance values for tramadol during multiple-dose treatment differed significantly from those observed during single-dose treatment perhaps reflecting saturation of first-pass metabolism.
Tramadol exhibited poor protein binding to plasma proteins.
Tramadol was metabolized primarily by oxidative dealkylization reactions in the liver. The principle metabolite, M1, was formed by dealkylization of the methyl ester group. This compound was excreted in the urine, mainly as glucuronide conjugate. A second conjugated metabolite, M5, was also identified.
During the 24 hours post-administration of tramadol, the quantity of drug excreted in the urine accounted for 68-81% of the dose following oral administration and 60-80% of the dose following intravenous administration, suggesting that tramadol is completely absorbed from the gastrointestinal tract. In lactating women, approximately 0.13% of the dose was estimated to be excreted in the milk as the parent compound and its metabolites.
A 50% reduction of tramadol dosage should be recommended for patients with hepatic or renal impairment (creatinine clearance <80 mL/min). Dose selection for an elderly patient should be cautious. Tramacet is not recommended for patients under 18 years of age.
Drug Interactions
Use with Carbamezapine - Administration of tramadol during steady state carbamezapine conditions was associated with a reduction in the elimination half-life of tramadol, resulting in a decrease of tramadol exposure. These effects were attributed to both decreased bioavailability and increased metabolism during carbamezapine treatment. Carbamezapine is known to be an inducer of drug metabolizing enzymes. If tramadol is to be administered to patients undergoing treatment with carbamezapine, the dosage of tramadol may need to be doubled.
Use with Cimetidine - Administration of tramadol with cimetidine did not result in significant changes in tramadol pharmacokinetics. Therefore, the need for tramadol dosage adjustment is not necessary.
Drug Dependence and Abuse
Studies compared the abuse potential of tramadol with morphine and oxycodone, respectively. Results were based on a Subject Specific Drug Effect Questionnaire.
In the morphine study, single 75 and 150 mg tramadol doses were generally no different from placebo by subjects with a history of opioid dependence, However, the 300 mg tramadol dose group showed a consistent trend for higher scores relative to placebo.
Similar to the 40 mg dose of oxycodone, the 350 and 700 mg doses of tramadol were identified as being different from placebo and similar to an opiate agonist. While dose-dependence was evident over the 175 to 450 mg range, higher doses (600-750 mg) were not associated with increased scores on abuse liability ratings. These data are consistent with an abuse liability comparable to that of oxycodone.
3.3.3 Clinical Efficacy
Three single-dose studies (TRAMAP-ANAG 010, TRAMAP-ANAG 012, TRAMAP-ANAG 013) were submitted in a prior NDS Control No. 063726 to support the efficacy of single doses of Tramacet in oral surgical procedures. A subsequent re-filing in NDS Control No. 095167 provided two supportive studies, CAPSS-105 and CAPSS-115, with data on the efficacy of multiple dosing of Tramacet for the short-term management (up to five days) of acute pain.
Single Dose Studies
In the double-blind, placebo- and active-controlled, parallel-group, single-dose, factorial design studies, two tablets of Tramacet administered to patients with pain following oral surgical procedures provided greater relief than placebo or either of the individual components given at the same dose. The onset of pain relief after Tramacet was faster than tramadol alone. Onset of analgesia occurred in less than one hour. The duration of pain relief after Tramacet was longer than acetaminophen alone. Analgesia was generally comparable to that of the comparator, ibuprofen. In another single dose study of subjects experiencing pain following an oral surgical procedure, there was a statistically significant dose response for pain relief over placebo, 37.5 mg tramadol HCL/325 mg acetaminophen, and 75 mg tramadol HCL/650 mg acetaminophen.
Studies for Treatment of Acute Pain
CAPSS-105 evaluated the safety and efficacy of Tramacet in the treatment of a painful flare of osteoarthritis of the knee or hip. All 308 randomized subjects were included in the Intent-to-Treat population and in the Evaluation-for-Safety population. Of these subjects, 197 were randomized to tramadol HCl/acetaminophen (102 subjects, 37.5 mg tramadol HCl/325 mg acetaminophen; 95 subjects, 75 mg tramadol HCl/65 mg acetaminophen for their initial dose) and 111 were randomized to placebo. The treatment groups were similar with regard to demographic characteristics such as gender and age. The majority of subjects designated the knee (77.9%) as the target joint for the study. After the initial dose, subjects received 1 to 2 tablets of 37.5 mg tramadol HCl/325 mg acetaminophen or matching placebo every 4 to 6 hours as needed. Overall, tramadol HCl/acetaminophen was more effective than placebo in helping subjects manage a painful flare of osteoarthritis. During Days 1 to 5, tramadol HCl/acetaminophen was significantly more effective than placebo in decreasing the average daily Pain Intensity Score and in increasing the average daily Pain Relief Score.
CAPSS-115 compared tramadol HCl /acetaminophen and acetaminophen/codeine in subjects with post-surgical (orthopedic or abdominal) pain. Of the 306 randomized subjects, 98 were randomized to tramadol HCl/acetaminophen, 99 to placebo, and 109 to acetaminophen with codeine phosphate (30 mg). There were no clinically meaningful differences among the three treatment groups for any of the demographic or baseline characteristics. Tramadol HCl /acetaminophen was statistically superior to placebo for all three primary efficacy variables: TOTPAR (total pain relief), SPID (sum of pain intensity difference), and SPRID (sum of total pain relief and sum of pain intensity differences).
In summary, the results from single-dose studies TRAMAP-ANAG 010, TRAMAP-ANAG 012, TRAMAP-ANAG 013, together with multiple-dose studies CAPSS-105 and CAPSS-115 demonstrate that tramadol/acetaminophen is effective for the short-term treatment of pain. It is concluded that for a short-term indication for pain relief up to 5 days, the synergistic effect seen after single doses would be sufficient, if the safety data supported the use of the combination.
3.3.4 Clinical Safety
The accumulated safety data support the claim of safety for the indication that qualifies the type of pain as short-term acute pain, and limits the duration of treatment to 5 days or less. The two studies Study CAPSS-105 and Study CAPSS-115 (described in Section 3.3.3), as well as the post-marketing data support the safe use of the drug product for the revised indication.
In Study CAPSS-105, 45% of the subjects treated with tramadol/acetaminophen and 23% of the subjects treated with placebo reported treatment-emergent adverse events. Nausea, dizziness, and vomiting were the most common adverse events in the tramadol/acetaminophen group, occurring in 17%, 12%, and 9% of the subjects, respectively. In the placebo group, 4% of subjects experienced nausea, 5% of subjects experienced dizziness, and 2% of subjects experienced vomiting. Only 1 subject (placebo) had a treatment-emergent serious adverse event (syncope). More subjects treated with tramadol/acetaminophen than subjects treated with placebo withdrew from the study due to adverse events. The most frequent adverse events leading to withdrawal in the combined tramadol/acetaminophen group were nausea (9%), vomiting (6%), dizziness (5%), and pruritus (2%). In summary, the results of this multicentre, outpatient, randomized, doubleblind, and placebo-controlled study demonstrated that tramadol/acetaminophen is safe in the short-term treatment of the painful flare of osteoarthritis.
In Study CAPSS-115, tramadol/acetaminophen was well tolerated in subjects undergoing abdominal or orthopedic procedures. Adverse events were reported for 40% of subjects in the tramadol/acetaminophen group, 39% of subjects in the placebo group, and 51% of subjects in the acetaminophen/codeine group. Nausea, dizziness, and vomiting were the most common adverse events in the tramadol/acetaminophen group, occurring in 21%, 10%, and 9% of subjects, respectively. The incidence of these adverse events was similar in the acetaminophen/codeine group (24%, 8%, and 15%, respectively). In the placebo group, 16% of subjects experienced nausea, 3% of subjects experienced dizziness, and 9% of subjects experienced vomiting. Serious adverse experiences were reported by 2 subjects in the placebo group (1 subject with pain and 1 subject with nausea and vomiting) and 1 subject in the acetaminophen/codeine group (constipation). Eight subjects (8%) in the tramadol/acetaminophen group, 3 subjects (3%) in the placebo group, and 11 subjects (10%) in the acetaminophen/codeine group discontinued treatment due to an adverse event. The most common treatment limiting adverse events in the tramadol/acetaminophen group were vomiting (4%) and nausea (3%). In summary, the results of Study CAPSS-115 demonstrate that tramadol/ acetaminophen is well-tolerated for the short-term treatment of postsurgical pain.
The sponsor provided all Periodic Safety Update Reports from the U.S., where the combination drug has been marketed since 2001 under the trade name of ULTRACET. The accumulated safety data support their claim of safety in short-term use of up to 5 days.
Adverse Events
The most frequently reported events were in the central nervous and gastrointestinal systems.
The unfavourable adverse event profile as compared to over-the-counter (OTC) analgesics was only seen in the single-dose dental extraction studies. In post-surgical settings, the adverse event profile was comparable to those of other OTC single drug or combination product analgesics. The adverse events are appropriately discussed in the Product Monograph.
Warnings and precautions regarding seizure risk, anaphylactoid reactions, cross-sensitivity with codeine and other opioids, and drug abuse and dependence were updated in the Product Monograph. The sponsor accepted all Product Monograph revisions regarding the central nervous system (CNS).
Tramacet should be used with caution in patients with increased intracranial pressure or head injury and in patients taking CNS depressants, serotonin reuptake inhibitors, neuroleptics (or antipsychotics) and tricyclic antidepressants. It should be used with great caution in patients taking monoamine oxidase inhibitors.
Patients with a history of anaphylactoid reactions to codeine and other opioids should not receive Tramacet. Serious and, rarely, fatal anaphylactoid reactions have been reported in patients receiving tramadol. Seizures have been reported in patients receiving tramadol within the recommended dose range.
Withdrawal symptoms may occur if Tramacet is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Other symptoms that have been seen less frequently with Tramacet discontinuation include: panic attacks, severe anxiety, and paresthesias. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The revised, limited indication and proposed dosage and administration for Tramacet make the risk/benefit profile acceptable. Tramacet has been marketed with similar labeling for several years in the U.S., with no obvious safety signals.
Tramacet (tramadol hydrochloride/acetaminophen) is not recommended for minor pain that can be treated adequately through lesser means where benefit does not outweigh the possible opioid-related side effects.
Tramadol has a potential to cause psychic and physical dependence of the morphine-type (µ-opioid). The drug has been associated with craving, drug-seeking behaviour and tolerance development. Cases of abuse and dependence on tramadol have been reported. Tramacet tablets should not be used in opioid-dependent patients. Tramadol can re-initiate physical dependence in patients that have been previously dependent or chronically using other opioids. Treatment with Tramacet is not recommended in patients with a tendency to abuse drugs or a history of drug dependence, and in patients who are chronically using opioids.
A risk management strategy to support the safe and effective use of Tramacet under Schedule F has been established. The following elements are considered to be the essential components of the risk management strategy:
- Commitment to not emphasize or highlight the scheduling status of Tramacet as required by the Product Monograph.
- Inclusion of an approved fair balance statement in all Tramacet promotional material and activities, as required by the Product Monograph.
- Provision of progress reports to Health Canada from the ongoing drug abuse surveillance program, including data from four key informant Canadian sites in the program, as required by the Product Monograph.
- Reassessment of the success of the risk management strategy 2 years post product launch, as required by the Product Monograph.
In addition, Periodic Safety Update Reports with respect to Tramacet are to be filed with Health Canada every 6 months for the first 3 years of marketing and on an annual basis thereafter.
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 Tramacet is favourable for the short-term (five days or less) management of acute pain. 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: Tramacet
| Submission Milestone | Date |
|---|---|
| 063726 Submission filed | 1999-11-03 |
| Screening 1 | |
| Screening Acceptance Letter issued | 1999-12-09 |
| Review 1 | |
| Submission cancelled by sponsor | 2001-01-11 |
| 085030 Submission filed | 2003-06-20 |
| Screening 1 | |
| Screening Deficiency Notice issued | 2003-08-25 |
| Response filed | 2003-09-29 |
| Screening Acceptance Letter issued | 2003-10-02 |
| Review 1 | |
| Quality Evaluation complete | 2004-07-07 |
| Clinical Evaluation complete | 2004-06-30 |
| NON issued by Director General (effectiveness issues) | 2004-08-18 |
| Response filed | 2004-09-24 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2004-10-01 |
| Review 2 | |
| Submission cancelled by sponsor | 2004-11-01 |
| 095167 Submission filed | 2004-11-09 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2004-11-15 |
| Review 1 | |
| Clinical Evaluation complete | 2004-11-15 |
| Labelling Evaluation complete | 2005-02-14 |
| NOC issued by Director General | 2005-07-20 |