Biovail Pharmaceuticals Canada
7150 Mississauga Road Mississauga, Ontario L5N 8M5
June 27, 2008
Table of Contents Page
PART I: HEALTH PROFESSIONAL INFORMATION Summary Product Information 2 Indications and Clinical Use 2 Contraindications 3 Warnings and Precautions 3 Adverse Reactions 8 Drug Abuse, Addiction and Dependence ................................................................ .......... 12 Drug Interactions 13 Dosage and Administration 14 Overdosage 16 Action and Clinical Pharmacology 17 Storage and Stability 19 Dosage Forms, Composition and Packaging 19 PART II: SCIENTIFIC INFORMATION Pharmaceutical Information 20 Clinical Trials 21 Detailed Pharmacology 23 Toxicology 24 References 25 PART III: CONSUMER INFORMATION ................................................................ 26
RALIVIA(tm)
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| oral | Tablets: 100 mg, 200 mg and 300 mg | Tablet components: colloidal silicon dioxide, ethylcellulose, dibutyl sebacate, polyvinyl alcohol, polyvinyl pyrrolidone, and sodium stearyl fumarate, black ink (containing: shellac glaze, isopropyl alcohol, iron oxide black, n-Butyl alcohol, propylene glycol and ammonium hydroxide.) |
For Complete Information see Dosage Forms, Composition and Packaging Sections
Adults
Ralivia
(tramadol hydrochloride) extended-release tablets are indicated for the management of moderate to moderately severe pain in adults who require continuous treatment for several days or more.
Geriatrics: (>65 years of age)
Healthy elderly subjects aged 65 to 75 years administered tramadol have plasma concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. Ralivia should be administered with greater caution in patients older than 75 years, due to the greater potential for adverse events in this population. (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION).
Pediatrics (<18 years of age):
The safety and efficacy of Ralivia in patients under 18 years of age have not been established. The use of
Ralivia
in the pediatric population is not recommended.
Patients who have previously demonstrated hypersensitivity to tramadol, opioids or any other component of this product. For a complete listing of nonmedicinal ingredients, see Dosage Forms, Composition and Packaging.
In any situation where opioids are contraindicated, including acute intoxication with any of the following: alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs. Ralivia may worsen central nervous system and respiratory depression in these patients.
With concomitant MAO inhibitors (or within 14 days of such therapy).
In severe
renal or hepatic impairment (creatinine clearance of less than 30 mL/min and/or Child-Pugh Class C)
General
Seizure Risk
Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking: Selective serotonin re-uptake inhibitors (SSRI antidepressants or anorectics), or Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc. ), or opioids. Administration of tramadol may enhance the seizure risk in patients taking: MAO inhibitors (see CONTRAINDICATIONS), Neuroleptics, Other drugs that reduce the seizure threshold. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure.
Anaphylactoid Reactions
Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive Ralivia. (see CONTRAINDICATIONS).
Drug Abuse, Addiction and Dependence
Tramadol has a potential to cause psychic and physical dependence of the morphine-type (u-opioid). The drug has been associated with craving, drug-seeking behaviour and tolerance development. Cases of abuse and dependence on tramadol have been reported. Ralivia tablets should not be used in opioid-dependent patients. Tramadol can re-initiate physical dependence in patients who have been previously dependent or chronically using other opioids. In patients with a tendency to abuse drugs or a history of drug dependence, and in patients who are chronically abusing opioids, treatment with Ralivia is not recommended. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. A Risk Management program to support the safe and effective use of Ralivia has been established. The following are considered to be the essential components of the Risk Management program: Commitment to not emphasize or highlight the scheduling status of Ralivia (i.e., not listed under a schedule to the CDSA) in its advertising or promotional activities; Inclusion of a PAAB-approved fair balance statement in all Ralivia advertising and promotional materials; Provision of progress reports to TPD, MHPD and HECSB from a drug abuse surveillance program for
;
Assurance that health-care education activities on pain management with Ralivia include balanced, evidence-based and current information. Commitment to take reasonable actions to inform health-care professionals that there is Health Canada-approved patient information on benefits and risks, and to ensure that this information can be readily accessed through electronic and/or hard copy sources; Reassessment of the risk management program 2 years post product launch.
is intended for oral use only.
could be abused by breaking, crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of tramadol, and pose a significant risk to the abuser that could result in seizures, overdose, and death. These risks are increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the tablet excipients can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury.
should not be used in opioid-dependent patients since it cannot suppress morphine withdrawal symptoms, even though it is an opioid agonist.
Abuse and addiction are separate and distinct from physical dependence and tolerance. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Tolerance as well as both physical and psychological dependence may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
Withdrawal Symptoms
Withdrawal symptoms may occur following abrupt discontinuation of therapy. 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 tramadol discontinuation include: panic attacks, severe anxiety and paresthesias. Patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of tramadol therapy followed by a gradual, tapered dose reduction of the medication combined with symptomatic support.
Risk of Overdosage
Serious potential consequences of overdosage with Ralivia are seizures, central nervous system depression, respiratory depression, and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE). Do not prescribe Ralivia for patients who are suicidal or addiction prone.
should not be taken in doses higher than those recommended by the physician. The judicious prescribing of tramadol is essential to the safe use of this drug. With patients who are depressed or suicidal, consideration should be given to the use of non-narcotic analgesics. Patients should be cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS-additive effects of these agents. Because of its added depressant effects, tramadol should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Patients should be advised of the additive depressant effects of these combinations.
should be used with caution in patients with increased intracranial pressure or head injury, since the respiratory depressant effects of opioid receptor agonism include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and such effects may be markedly exaggerated in these patients. Also, pupillary changes (miosis) from tramadol may obscure the existence, extent or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol (see
).
Respiratory Depression
Administer Ralivia cautiously in patients at risk for respiratory depression. In these patients alternative non- opioid analgesics should be considered. When large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures (see WARNINGS AND PRECAUTIONS, Seizure Risk and OVERDOSAGE).
Interaction With Central Nervous System (CNS) Depressants
should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics.
increases the risk of CNS and respiratory depression in these patients.
may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
As drugs may be abused in conjunction with alcohol, the effect of alcohol on the rate of drug release from Ralivia tablets was evaluated in dissolution studies using the product dissolution medium compared to 60% 0.1N HCl : 40% ethanol. Dissolution profiles for all tablet strengths in the alcohol medium were found to be within proposed dissolution specifications. The 60% 0.1N HCl : 40% ethanol medium resulted in a slight decrease in the rate of release of tramadol from Ralivia tablets. The clinical significance of the slight decrease in dissolution rate is unknown.
Use with Alcohol
should not be used concomitantly with alcohol consumption.
The use of Ralivia in patients with severe hepatic impairment is contraindicated. (see CONTRAINDICATIONS)
Use in Ambulatory Patients
may impair the mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Patients using
should be cautioned accordingly
Use With Serotonin Re-uptake Inhibitors
Use Ralivia with great caution in patients taking SSRIs. Concomitant use of Ralivia with SSRIs increases the risk of adverse events, including seizure and serotonin syndrome. (See WARNINGS AND PRECAUTIONS, Seizure Risk and DRUG INTERACTIONS). Acute Abdominal Conditions: The administration of Ralivia may complicate the clinical assessment of patients with acute abdominal conditions. (e.g., cholecystitis, appendicitis, acute pancreatitis, etc. ).
Use in Drug and Alcohol Addiction
is an opioid with no approved use in the management of addictive disorders.
Carcinogenesis and Mutagenesis
See animal data in Toxicology section.
Special Populations
Renal Impairment
Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. Ralivia has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). Raliva is contraindicated in patients with severe renal impairment (see CONTRAINDICATIONS, ACTION and CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
: Metabolism of tramadol and it's M1 metabolite is reduced in patients with advanced cirrhosis of the liver. The pharmacokinetics of
has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
is contraindicated in patients with severe hepatic impairment
see
and
).
There are no adequate and well-controlled studies in pregnant women. Safe use in pregnancy has not been established. Ralivia should not be used during pregnancy, prior to or during labor, unless in the opinion of the physician, the expected benefit to the patient outweighs the possible risk to the fetus. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn (see Drug Abuse And Dependence). Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labour. Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported during post-marketing reports with tramadol HCl immediate-release products. The effect of Ralivia, if any, on the later growth, development, and functional maturation of the child is unknown.
Tramadol and its metabolites are found in small amounts in human breast milk.
Ralivia
is not recommended for obstetrical preoperative medication, for post-delivery analgesia or at any time in nursing
mothers because its safety in infants and newborns has not been studied.
The safety and efficacy of Ralivia has not been studied in the pediatric population. Therefore, use of Ralivia is not recommended in patients under 18 years of age.
In general, caution should be used when selecting the dose for an elderly patient. The elimination half-life of tramadol may be prolonged in patients over 75 years, thereby increasing the potential for adverse events. Usually, dose administration should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy (see DOSAGE AND ADMINISTRATION) Nine-hundred-one elderly (>= 65 years of age) subjects were exposed to Ralivia in clinical trials. Of those subjects, 156 were >= 75 years of age. Based on all dosage groups combined, the incidence of adverse events was similar for patients >= 65 years, compared with patients < 65 years, except for constipation which was higher, and headache which was lower, in patients >= 65 years of age.
ADVERSE REACTIONS
Ralivia
was administered to a total of 3108 patients in four double-blind studies in patients with chronic pain of osteoarthritis or low back pain, and one 1-year open-label study in patients with chronic non-malignant
pain. A total of 901 patients were >= 65 years.
Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials
The most common adverse events with Ralivia were dizziness, nausea, constipation, headache.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Table 1 >=
shows incidence of all adverse events
1% in the four randomized, placebo- controlled studies, whether considered by the clinical investigator to be related to the study drug or not. The adverse events observed in the open label study were similar to those seen in the 4 randomized, placebo-controlled, clinical trials.
Table 1: Adverse Events: Placebo-Controlled Studies
Treatment - Emergent Adverse Experiences Occurring in >= 1% of Patients taking Ralivia (with an incidence greater than placebo)
| Ralivia | |||||||
| Flexible * | 100 mg QD | 200 mg QD (N=529) | 300 mg QD | Total | Placebo | ||
| MedDRA | (N=133) | (N=403) | n (%) | (N=528) | (N=1795) | (N=664) | |
| Preferred Term | n (%) | n (%) | n (%) | n (%) | n (%) | ||
| Eye disorders | Vision blurred | 0 (0.0) | 4 (1.0) | 2 (0.4) | 5 (0.9) | 14 (0.8) | 3 (0.5) |
| Gastrointestinal | |||||||
| disorders | Nausea | 33 (24.8) | 61 (15.1) | 102 (19.3) | 128 (24.2) | 377 (21.0) | 51 (7.7) |
| Constipation | 32 (24.1) | 49 (12.2) | 76 (14.4) | 104 (19.7) | 321 (17.9) | 25 (3.8) | |
| Diarrhea NOS | 12 (9.0) | 15 (3.7) | 38 (7.2) | 43 (8.1) | 118 (6.6) | 29 (4.4) | |
| Vomiting NOS | 10 (7.5) | 20 (5.0) | 36 (6.8) | 44 (8.3) | 129 (7.2) | 13 (2.0) | |
| Dry mouth | 4 (3.0) | 20 (5.0) | 29 (5.5) | 39 (7.4) | 110 (6.1) | 8 (1.2) | |
| Abdominal pain upper | 3 (2.3) | 5 (1.2) | 12 (2.3) | 16 (3.0) | 41 (2.3) | 5 (0.8) | |
| Abdominal pain NOS | 3 (2.3) | 5 (1.2) | 6 (1.1) | 6 (1.1) | 24 (1.3) | 3 (0.5) | |
| Dyspepsia | 2 (1.5) | 7 (1.7) | 10 (1.9) | 14 (2.7) | 38 (2.1) | 8 (1.2) | |
| Sore throat NOS | 3 (2.3) | 6 (1.5) | 5 (0.9) | 5 (0.9) | 22 (1.2) | 9 (1.4) | |
| General Disorders and | |||||||
| Administration Site | |||||||
| Conditions | Asthenia | 10 (7.5) | 14 (3.5) | 29 (5.5) | 32 (6.1) | 98 (5.5) | 10 (1.5) |
| Feeling hot | 4 (3.0) | 7 (1.7) | 7 (1.3) | 7 (1.3) | 28 (1.6) | 3(0.5) | |
| Rigors | 3 (2.3) | 3 (0.7) | 3 (0.6) | 11 (2.1) | 27 (1.5) | 2 (0.3) | |
| Influenza like illness | 3 (2.3) | 1 (0.2) | 7 (1.3) | 8 (1.5) | 23 (1.3) | 4 (0.6) | |
| Chest pain NEC | 3 (2.3) | 3 (0.7) | 4 (0.8) | 4 (0.8) | 17 (0.9) | 4 (0.6) | |
| Lethargy | 3 (2.3) | 4 (1.0) | 4 (0.8) | 1 (0.2) | 14 (0.8) | 3 (0.5) | |
| Pain NOS | 2 (1.5) | 10 (2.5) | 16 (3.0) | 16 (3.0) | 49 (2.7) | 14 (2.1) | |
| Fall | 2 (1.5) | 5 (1.2) | 5 (0.9) | 5 (0.9) | 19 (1.1) | 3 (0.5) | |
| Malaise | 2 (1.5) | 0 (0.0) | 1 (0.2) | 5 (0.9) | 10 (0.6) | 0 (0.0) | |
| Drug withdrawal | |||||||
| syndrome | 2 (1.5) | 1 (0.2) | 2 (0.4) | 0 (0.0) | 7 (0.4) | 0 (0.0) | |
| Weakness | 1 (0.8) | 3 (0.7) | 11 (2.1) | 15 (2.8) | 39 (2.2) | 5 (0.8) | |
| Infections and | |||||||
| infestations | Influenza | 9 (6.8) | 4 (1.0) | 4 (0.8) | 3 (0.6) | 23 (1.3) | 3 (0.5) |
| Upper respiratory tract | |||||||
| infection NOS | 5 (3.8) | 15 (3.7) | 12 (2.3) | 13 (2.5) | 49 (2.7) | 20 (3.0) | |
| Sinusitis NOS | 3 (2.3) | 7 (1.7) | 13 (2.5) | 12 (2.3) | 40 (2.2) | 12 (1.8) | |
| Investigations | Weight decreased | 3 (2.3) | 0 (0.0) | 4 (0.8) | 10 (1.9) | 23 (1.3) | 1 (0.2) |
| Blood creatine | |||||||
| phosphokinase | |||||||
| increased | 0 (0.0) | 7 (1.7) | 8 (1.5) | 10 (1.9) | 28 (1.6) | 6 (0.9) | |
| Metabolism and nutrition | |||||||
| disorders | Anorexia | 3 (2.3) | 3 (0.7) | 7 (1.3) | 23 (4.4) | 48 (2.7) | 1 (0.2) |
| Appetite decreased | |||||||
| NOS | 2 (1.5) | 5 (1.2) | 9 (1.7) | 8 (1.5) | 31 (1.7) | 3 (0.5) | |
| Gout | 2 (1.5) | 1 (0.2) | 0 (0.0) | 1 (0.2) | 5 (0.3) | 2 (0.3) | |
| Musculosketal, | |||||||
| connective tissue and | |||||||
| bone disorders | Back pain | 3 (2.3) | 11 (2.7) | 9 (1.7) | 8 (1.5) | 36 (2.0) | 10 (1.5) |
| Muscle spasms | 3 (2.3) | 4 (1.0) | 2 (0.4) | 3 (0.6) | 12 (0.7) | 4 (0.6) | |
| Nervous system | |||||||
| disorders | Dizziness (exc vertigo) | 46 (34.6) | 64 (15.9) | 95 (18.0) | 108 (20.5) | 370 (22.6) | 54 (8.1) |
| Headache NOS | 18 (13.5) | 49 (12.2) | 78 (14.7) | 65 (12.3) | 242 (13.5) | 77 (11.6) | |
| Ralivia | |||||||
| Flexible * | 100 mg QD | 200 mg QD (N=529) | 300 mg QD | Total | Placebo | ||
| MedDRA | (N=133) | (N=403) | n (%) | (N=528) | (N=1795) | (N=664) | |
| Preferred Term | n (%) | n (%) | n (%) | n (%) | n (%) | ||
| Somnolence | 10 (7.5) | 33 (8.2) | 46 (8.7) | 32 (6.1) | 162 (9.0) | 11 (1.7) | |
| Insomnia NEC | 8 (6.0) | 26 (6.5) | 42 (7.9) | 54 (10.2) | 152 (8.5) | 22 (3.3) | |
| Paresthesia NEC | 3 (2.3) | 1 (0.2) | 3 (0.6) | 3 (0.6) | 15 (0.8) | 7 (1.1) | |
| Irritability | 3 (2.3) | 2 (0.5) | 3 (0.6) | 3 (0.6) | 12 (0.7) | 3 (0.5) | |
| Tremor NEC | 1 (0.8) | 3 (0.7) | 4 (0.8) | 14 (2.7) | 24 (1.3) | 1 (0.2) | |
| Dizziness aggravated | 0 (0.0) | 2 (0.5) | 7 (1.3) | 3 (0.6) | 16 (0.9) | 2 (0.3) | |
| Psychiatric disorders | Restlessness | 2 (1.5) | 3 (0.7) | 2 (0.4) | 10 (1.9) | 18 (1.0) | 2 (0.3) |
| Nervousness | 0 (0.0) | 7 (1.7) | 13 (2.5) | 20 (3.8) | 48 (2.7) | 5 (0.8) | |
| Anxiety NEC | 0 (0.0) | 2 (0.5) | 9 (1.7) | 15 (2.8) | 28 (1.6) | 4 (0.6) | |
| Depression NEC | 0 (0.0) | 2 (0.5) | 4 (0.8) | 8 (1.5) | 17 (0.9) | 2 (0.3) | |
| Renal and urinary | |||||||
| disorders | Hematuria | 3 (2.3) | 1 (0.2) | 2 (0.4) | 6 (1.1) | 13 (0.7) | 1 (0.2) |
| Difficulty in micturition | 2 (1.5) | 2 (0.5) | 0 (0.0) | 5 (0.9) | 11 (0.6) | 2 (0.3) | |
| Respiratory, thoracic | |||||||
| and mediastinal | |||||||
| disorders | Sneezing | 0 (0.0) | 10 (2.5) | 10 (1.9) | 12 (2.3) | 36 (2.0) | 2 (0.3) |
| Rhinorrhea | 1 (0.8) | 8 (2.0) | 11 (2.1) | 7 (1.3) | 28 (1.6) | 5 (0.8) | |
| Skin and subcutaneous | |||||||
| tissue disorders | Pruritus NOS | 9 (6.8) | 25 (6.2) | 36 (6.8) | 31 (5.9) | 125 (7.0) | 6 (0.9) |
| Sweating increased | 5 (3.8) | 6 (1.5) | 9 (1.7) | 18 (3.4) | 51 (2.8) | 1 (0.2) | |
| Dermatitis NOS | 5 (3.8) | 5 (1.2) | 9 (1.7) | 13 (2.5) | 35 (1.9) | 10 (1.5) | |
| Urticaria NOS | 2 (1.5) | 1 (0.2) | 2 (0.4) | 1 (0.2) | 8 (0.4) | 3 (0.5) | |
| Contusion | 1 (0.8) | 5 (1.2) | 6 (1.1.) | 4 (0.8) | 17 (0.9) | 1 (0.2) | |
| Vascular disorders | Flushing | 13 (9.8) | 31 (7.7) | 47 (8.9) | 42 (8.0) | 165 (9.2) | 26 (3.9) |
| Postural hypotension | 3 (2.3) | 7 (1.7) | 21 (4.0) | 18 (3.4) | 60 (3.3) | 15 (2.3) | |
| Vasodilatation | 2 (1.5) | 1 (0.2) | 4 (0.8) | 2 (0.4) | 14 (0.8) | 3 (0.5) | |
| Hot flushes NOS | 0 (0.0) | 4 (1.0) | 11 (2.1) | 13 (2.5) | 32 (1.8) | 5 (0.8) | |
* Patients in the flexible dose study received Ralivia 200 to 400mg per day
The following listings include adverse events for the four placebo-controlled studies and the open-label study (N = 3108):
Adverse events with incidence rates >= 1.0% and not noted in the placebo-controlled studies.
General disorders:
, pyrexia,
Infections and infestations: bronchitis, viral gastroenteritis, nasopharyngitis Musculoskeletal, connective tissue and bone disorders: neck pain, arthralgia Nervous system disorders: hypoaesthesia
Respiratory, thoracic and mediastinal disorders:
dyspnoea, nasal congestion, sinus congestion
Adverse events with incidence rates <1.0%: Cardiac disorders: palpitations, myocardial infarction. Ear and labyrinth disorders: tinnitus.
Gastrointestinal disorders:
flatulence, constipation aggravated, toothache, pancreatitis.
General disorders:
feeling jittery, edema lower limb, shivering, joint swelling, malaise, drug withdrawal syndrome, peripheral swelling.
Hepato-biliary disorders:
cholelithiasis, cholecystitis.
Infections and infestations:
appendicitis, cellulitis, ear infection, gastroenteritis, pneumonia urinary tract infection, viral infection.
Injury and poisoning:
joint sprain, muscle injury.
Investigations:
heart rate increased, liver function tests abnormal, blood pressure increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood glucose increased.
Musculoskeletal, connective tissue and bone disorders:
joint stiffness, myalgia, muscle cramps, muscle spasms, muscle twitching, osteoarthritis aggravated.
Nervous system disorders:
migraine, syncope, disturbance in attention, dizziness aggravated, vertigo, sedation.
Psychiatric disorders:
irritability, libido decreased, euphoric mood, sleep disorder, agitation, disorientation, abnormal dreams.
Renal and urinary disorders:
difficulty in micturition, urinary frequency, urinary retention, dysuria, haematuria.
Respiratory, thoracic and mediastinal disorders:
yawning.
Skin and subcutaneous tissue disorders:
contusion, clamminess, night sweats, urticaria, piloerection.
Vascular disorders:
hypertension aggravated, hypertension, peripheral ischaemia.
Abnormal Hematologic and Clinical Chemistry Findings
In clinical trials where clinical abnormalities were recorded (n = 230), the following clinical laboratory abnormalities were reported: alanine aminotransferase increased (0.8%), aspartate aminotransferase increased (0.7%), liver function tests NOS abnormal (0.4%), blood lactate dehydrogenase increased (0.3%), white blood cell count increased (0.3%), blood alkaline phosphatase NOS increased (0.3%), hematocrit decreased (0.3%), rectal hemorrhage (0.3%), and hypokalemia (0.3%). The following abnormalities occurred in 0.2% of patients: red blood cell count decreased, hemoglobin decreased, blood calcium increased, blood creatinine increased, anemia NOS, blood potassium decreased, and neutrophil count increased. The following abnormalities occurred in 0.1% of patients: thrombocythemia, blood potassium increased, blood bilirubin increased, blood in stool, hemoglobin increased, hypercalcemia, hematocrit increased, eosinophil count increased, blood sodium increased, and hyponatremia. The following abnormalities were single occurrences in patients: blood sodium decreased, hyperkalemia, blood calcium decreased, hypophosphatemia, hemoptysis, hematemesis, red blood cell count increased, band neutrophil count increased, monocyte count increased, and lymphocyte count increased
Other Adverse Experiences Previously Reported in Clinical Trials or Post-Marketing Reports with Tramadol Hydrochloride
Adverse events which have been reported with the use of tramadol products include: allergic reactions (including anaphylaxis, angioneurotic edema and urticaria, Stevens-Johnson syndrome), bradycardia, convulsions, drug dependence, hyperactivity, hypoactivity, and respiratory depression. Other adverse events which have been reported with the use of tramadol products and for which a causal association has not been determined include: difficulty concentrating, hepatitis liver failure, pulmonary edema, and suicidal tendency. Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRI's and MAOIs.
Tramadol may induce psychic and physical dependence of the morphine-type (u-opioid) (see WARNINGS AND PRECAUTIONS, Drug Abuse, Addiction and Dependence). Dependence and abuse, including drug-seeking behaviour and taking illicit actions to obtain the drug are not limited to those patients with a prior history of opioid dependence. The risk in patients with substance abuse has been observed to be higher. Tramadol is associated with craving and tolerance development. A Risk Management program to support the safe and effective use of Ralivia has been established. The following are considered to be the essential components of the Risk Management program: Commitment to not emphasize or highlight the scheduling status of Ralivia (i.e., not listed under a schedule to the CDSA) in its advertising or promotional activities; Inclusion of a PAAB-approved fair balance statement in all Ralivia advertising and promotional materials; Provision of progress reports to TPD, MHPD and HECSB from a drug abuse surveillance program for
;
Assurance that health-care education activities on pain management with Ralivia include balanced, evidence-based and current information. Commitment to take reasonable actions to inform health-care professionals that there is Health Canada approved patient information on benefits and risks, and to ensure that this information can be readily accessed through electronic and/or hard copy sources; Reassessment of the risk management program 2 years post product launch.
Withdrawal symptoms may occur if tramadol 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 Ralivia 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.
Overview
In vitro studies indicated that tramadol is unlikely to inhibit the CYP3A4-mediated metabolism of other drugs when tramadol is administered concomitantly at therapeutic doses. Tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single dose data. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.
Drug-Drug Interactions
MAO Inhibitors
Tramadol is contraindicated in patients receiving MAO inhibitors or who have used them within the previous 14 days (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS).
Drugs that Lower Seizure Threshold
Tramadol can increase the potential for selective serotonin re-uptake inhibitors (SSRIs), tricyclic anti- depressants (TCAs), anti-psychotics and other seizure threshold lowering drugs to cause convulsions (see WARNINGS AND PRECAUTIONS).
CNS Depressants
Concurrent administration of tramadol with other centrally acting drugs, including alcohol, centrally acting analgesics, opioids and psychotropic drugs may potentiate CNS depressant effects.
Carbamazepine
Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because of the seizure risk associated with tramadol, concomitant administration of Ralivia and carbamazepine is not recommended (see WARNINGS and PRECAUTIONS).
Quinidine
Tramadol is metabolized to M1 by CYP2D6. A study was conducted to examine the effect of quinidine, a selective inhibitor of CYP2D6, on the pharmacokinetics of tramadol by administering 200 mg of quinidine two hours before the administration of Ralivia 100 mg. The results demonstrated that the exposure of tramadol increased 50-60% and the exposure of M1 decreased 60-65%. In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism.
Inhibitors of CYP2D6
Inhibitors of CYP2D6 (e.g., quinidine, fluoxetine, paroxetine, amitriptyline) may inhibit the metabolism of tramadol, resulting in increased serum concentrations of tramadol and decreased concentrations of its O- demethylated metabolite (M1). Co-administration of quinidine did not diminish the analgesic effect of tramadol in human experimental pain models.
Inhibitors or Inducers of CYP3A4
Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John's Wort may affect the metabolism of tramadol, leading to altered tramadol exposure.
Cimetidine
Concomitant administration of tramadol immediate-release tablets with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the Ralivia dosage regimen with cimetidine is recommended.
Digoxin
Digoxin toxicity has occurred rarely during co-administration of digoxin and tramadol.
Protease inhibitors, e.g., ritonavir
Co-administered ritonavir may increase the serum concentration of tramadol, resulting in tramadol toxicity.
Warfarin and other coumarin anticoagulants
Alteration of the effect of warfarin, including elevation of prothrombin times, has been reported rarely during co-administration of warfarin and tramadol. While such changes have been generally of limited clinical significance for the individual products, periodic evaluation of prothrombin time should be performed when Ralivia tablets and warfarin-like compounds are administered concurrently.
Drug-Food Interactions
After a single dose administration of 200 mg Ralivia tablet with a high fat meal, the Cmax and AUC0-[?] of tramadol decreased 28% and 14%, respectively, compared to fasting conditions. Mean Tmax was increased by 3 hr (from 14 hr under fasting conditions to 17 h under fed conditions). While Ralivia may be taken without regard to food, it is recommended that it be taken in a consistent manner.
Dosing Considerations
(tramadol hydrochloride extended- release tablets) is not recommended for minor pain, or acute short-term pain that may be treated adequately through lesser means where benefit does not outweigh the
possible opioid-related side effects. Due to possible differences in pharmacokinetic properties, Ralivia tablets are not interchangeable with other tramadol extended-release formulations. The maximum recommended daily dose of Ralivia should not be exceeded.
can be administered without regard to food.
Administration
is designed for once-daily dosing, i.e., dosing at 24-hourly intervals. Treatment with
should be initiated at the lowest available dose (100 mg). Clinical studies of
have not demonstrated a clinical benefit at a total daily dose exceeding 300 mg. The maximum dose is 300 mg daily.
The correct dosage for any individual patient is that which controls the pain for a full 24 hours, with no or tolerable side effects. As with all analgesic drugs, the dose of tramadol should be adjusted according to the severity of the pain and the clinical response of the individual patient. It is recommended that doses be slowly titrated (dosage adjustments generally separated by five days), to higher doses to minimize side effects.
The usual initial dose of Ralivia for patients who have not previously received opioid analgesics is 100 mg q24h.
Patients currently receiving oral immediate-release tramadol preparations may be transferred to Ralivia tablets at the same or lowest nearest total daily tramadol dosage.
Adults (18 years of age and older):
should be initiated at a dose of 100 mg once daily and may be titrated up by 100 mg increments every five days, as necessary and depending on tolerability, to relief of pain.
should not be
administered at doses exceeding 300 mg per day.
Geriatric Patients (>65 years old):
In general, dose selection for patients over 65 years of age, who may have decreased hepatic or renal function, or other concomitant diseases, should be initiated cautiously, usually starting at the low end of the dosing range. Ralivia should be administered with greater caution at the lowest effective dose in patients over 75 years, due to the potential for greater frequency of adverse events in this population.
Pediatrics (< 18 years old): The safety and efficacy of Ralivia has not been studied in the pediatric population. Therefore, Ralivia is not indicated for use in children under 18 years of age.
The elimination half-life of tramadol and its active metabolite may be prolonged in these patient populations. A starting dose of 100 mg daily is recommended. Upward dosage titration should be done with careful monitoring. Tramadol is contraindicated in patients with severe renal impairment and/or severe hepatic impairment. (creatinine clearance less than 30 mL/min and/or Child-Pugh Class C, see
)
If immediate release tramadol is used for breakthrough pain, the total daily dose of tramadol should not exceed 300 mg. Selection of breakthrough medication should be based on individual patient conditions. For patients whose dose has been titrated to the recommended maintenance dose, without attainment of adequate analgesia, the total daily dose may be increased, unless precluded by side effects.
If a patient forgets to take one or more doses, they should take their next dose at the normal time and in the normal amount.
Withdrawal symptoms may occur if Ralivia is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be reduced by tapering
.
Deaths due to overdose have been reported with abuse and misuse of tramadol, by ingesting, inhaling, or injecting the crushed tablets. Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.
Symptoms of Overdose:
Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death. Deaths due to overdose have been reported with abuse and misuse of tramadol, by ingesting, inhaling, or injecting the crushed tablets. Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.
Treatment of Overdose:
In the treatment of tramadol overdosage, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. Seizures may be controlled with diazepam In animals, convulsions following the administration of toxic doses of Ralivia could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period. Emptying of the gastric contents is useful to remove any unabsorbed drug.
Tramadol is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, animal tests suggest that at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to u-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to u-opioid receptors. In animal models, M1 is up to 6-times more potent than tramadol in producing analgesia and 200-times more potent in u-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound. Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in the Ralivia clinical studies. Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. Tramadol produces less respiratory depression than other opioids and has no significant cardiac effects. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.
The administration of naloxone only partially antagonizes tramadol's antinociceptive and analgesic effects in animals and man, indicating a contribution from non-opioid analgesic mechanisms. In animals and man the effect of tramadol is attenuated by the a2-adrenoceptor antagonist, yohimbine, and in animals, the serotonin antagonist rianserin reduces the antinociceptive effect of tramadol. This indicates the potential for a contribution to the analgesic effect of tramadol through modulation of monaminergic inhibitory pain pathways in the dorsal horn of the spinal cord, in addition to an opioidergic effect.
The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. Ralivia is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of Ralivia are approximately dose-proportional over a 100-400 mg dose range in healthy subjects. However, the observed tramadol AUC values for the 400-mg dose were 26% higher than predicted based on the AUC values for the 200-mg dose. The clinical significance of this finding has not been studied and is not known.
Absorption
Consistent with the extended-release nature of the formulation, there is a lag time in drug absorption following Ralivia administration. The mean peak plasma concentrations of tramadol and M1 after administration of Ralivia tablets to healthy volunteers are attained at about 12 h and 15 h, respectively, after dosing. Following administration of the Ralivia, steady-state plasma concentrations of both tramadol and M1 are achieved within four days with once daily dosing.
Food Effects
After a single dose administration of 200 mg Ralivia tablet with a high fat meal, the Cmax and AUC0-[?] of tramadol decreased 28% and 14%, respectively, compared to fasting conditions. Mean Tmax was increased by 3 hr (from 14 hr under fasting conditions to 17 h under fed conditions). While Ralivia may be taken without regard to food, it is recommended that it be taken in a consistent manner.
Distribution
The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100-mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 ug/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
Metabolism
Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N- (mediated by CYP3A4 and CYP2B6) and O- (mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyl tramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see Drug Interactions).
Elimination
Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 after administration of Ralivia are approximately 7.9 and 8.8 h, respectively.
Pediatrics
The pharmacokinetics of Ralivia in individuals under 18 years old has not been evaluated. Therefore, its use is not recommended in patients under 18 years of age.
Geriatric:(>65 years of age):
Healthy elderly subjects aged 65 to 75 years administered tramadol have plasma concentrations and elimination half lives comparable to those observed in healthy subjects less than 65 years of age. Ralivia should be administered with greater caution in patients older than 75 years due to the greater potential for adverse events in this population (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION).
Gender
Based on pooled multiple-dose pharmacokinetics studies for Ralivia in 166 healthy subjects (111 males and 55 females), the dose-normalized AUC values for tramadol were somewhat higher in females than in males. There was a considerable degree of overlap in dose normalized AUC values for males and females, thus, dosage adjustment based on gender is not recommended.
Race
Due to the small sample size for Asian, Hispanic, and other populations, conclusions cannot be drawn about the pharmacokinetics of tramadol in these populations.
Hepatic Insufficiency
Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of Ralivia 100 mg. The exposure of (+)- and (-)-tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients with normal hepatic function. However, exposure of (+)- and (-)-M1 decreased ~50% with increased severity of the hepatic impairment (from normal to mild and moderate). The pharmacokinetics of tramadol after the administration of Ralivia has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). After the administration of tramadol immediate-release tablets to patients with advanced cirrhosis of the liver, tramadol area under the plasma concentration time curve was larger and the tramadol and M1 half-lives were longer than subjects with normal hepatic function. Ralivia is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, Hepatic and DOSAGE AND ADMINISTRATION).
Renal Insufficiency
Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The pharmacokinetics of tramadol were studied in patients with mild or moderate renal impairment after receiving multiple doses of Ralivia 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal impairment in comparison to patients with normal renal function. However, exposure of M1 increased 20-40% with increased severity of the renal impairment (from normal to mild and moderate). Ralivia has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). Ralivia is contraindicated in patients with severe renal impairment (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, Renal, and DOSAGE AND ADMINISTRATION). The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose.
Store at room temperature (15 -30 oC).
extended-release tablets are supplied as:
100-mg, round, white tablets, imprinted with "100" over "ER" in black ink 200-mg, round, white tablets, imprinted with "200" over "ER" in black ink 300-mg, round, white tablets, imprinted with "300" over "ER" in black ink Each Ralivia tablet contains the labelled amount of tramadol hydrochloride and the inactive ingredients: colloidal silicon dioxide, ethylcellulose, dibutyl sebacate, polyvinyl alcohol, polyvinyl pyrrolidone, and sodium stearyl fumarate and black ink (containing: shellac glaze, isopropyl alcohol, iron oxide black, n- Butyl alcohol, propylene glycol and ammonium hydroxide).
100 mg, 200 mg and 300 mg tablets are available in bottles of 30 tablets, 90 tablets, and 500 tablets.