PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION

Transcription

1 PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION Pr Zytram XL Tramadol Hydrochloride Controlled Release Tablets 75, 100, 150, 200, 300 and 400 mg Purdue Pharma Standard Opioid Analgesic Purdue Pharma 575 Granite Court Pickering, ON L1W 3W8 Date of Revision: May 15, 2017 Submission Control No: Zytram XL is a trademark of Purdue Pharma Zytram XL (tramadol HCl CR tablets) Page 1 of 44

2 TABLE OF CONTENTS PART I: HEALTH PROFESSIONAL INFORMATION... 3 SUMMARY PRODUCT INFORMATION... 3 INDICATIONS AND CLINICAL USE... 3 CONTRAINDICATIONS... 4 WARNINGS AND PRECAUTIONS... 5 ADVERSE REACTIONS DRUG INTERACTIONS DOSAGE AND ADMINISTRATION OVERDOSAGE ACTION AND CLINICAL PHARMACOLOGY STORAGE SPECIAL HANDLING INSTRUCTIONS DOSAGE FORMS, COMPOSITION AND PACKAGING PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION CLINICAL TRIALS DETAILED PHARMACOLOGY TOXICOLOGY PATIENT MEDICATION INFORMATION Zytram XL (tramadol HCl CR tablets) Page 2 of 44

3 Pr Zytram XL Tramadol Hydrochloride Controlled Release (CR) Tablets PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Dosage Form / Strength Oral Controlled release tablets / 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg Nonmedicinal Ingredients FD&C Blue No. 2 (75 mg only), hydrogenated vegetable oil, hypromellose, iron oxide (75 mg only), lactose, magnesium stearate, polyethylene glycol, talc, titanium dioxide INDICATIONS AND CLINICAL USE Adults Zytram XL (tramadol hydrochloride controlled release tablets) is 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) In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease or other drug therapy. 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. ZYTRAM XL 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 Zytram XL has not been studied in the pediatric population. Therefore, use of Zytram XL tablets is not recommended in patients under 18 years of age. Zytram XL (tramadol HCl CR tablets) Page 3 of 44

4 CONTRAINDICATIONS Patients who are hypersensitive to tramadol or other opioids, or to any ingredient in the formulation In patients with known or suspected mechanical gastrointestinal obstruction (e.g., bowel obstruction, strictures) or any diseases/conditions that affect bowel transit (e.g., ileus of any type) Patients with suspected surgical abdomen (e.g., acute appendicitis or pancreatitis) Severe renal or hepatic impairment (creatinine clearance of less than 30 ml/min and/or Child-Pugh Class C) Patients with mild pain that can be managed with other pain medications The management of perioperative pain Patients with acute or severe bronchial asthma, chronic 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 CNS depression, increased cerebrospinal or intracranial pressure, and head injury Patients taking monoamine oxidase (MAO) inhibitors (or within 14 days of such therapy) Women who are breastfeeding, pregnant, or during labour and delivery. Zytram XL (tramadol HCl CR tablets) Page 4 of 44

5 WARNINGS AND PRECAUTIONS SERIOUS WARNINGS AND PRECAUTIONS Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the risks of overdose and death with extended-release opioid formulations, Zytram XL should only be used in patients for whom alternative treatment options are ineffective, not tolerated (e.g., non-opioid analgesics), or would be otherwise inadequate to provide sufficient management of pain (see DOSAGE AND ADMINISTRATION). Addiction, Abuse, and Misuse Zytram XL (tramadol hydrochloride controlled release tablets) poses risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Each patient s risk should be assessed prior to prescribing Zytram XL, and all patients should be monitored regularly for the development of these behaviours or conditions (see WARNINGS AND PRECAUTIONS). Zytram XL should be stored securely to avoid theft or misuse. Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Zytram XL tablets. Patients should be monitored for respiratory depression, especially during initiation of Zytram XL or following a dose increase. Zytram XL must be swallowed whole; cutting, breaking, crushing, chewing, or dissolving Zytram XL tablets can cause rapid release and absorption of a potentially fatal dose of tramadol (see WARNINGS AND PRECAUTIONS). Accidental Exposure Accidental ingestion of even one dose of Zytram XL, especially by children, can result in a fatal overdose of tramadol (see DOSAGE AND ADMINISTRATION, Disposal, for instructions on proper disposal). Neonatal Opioid Withdrawal Syndrome Prolonged maternal use of Zytram XL during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening (see WARNINGS AND PRECAUTIONS). Interaction with Alcohol The co-ingestion of alcohol with Zytram XL may result in increased plasma levels and a potentially fatal overdose of tramadol (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS). Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (see WARNINGS AND PRECAUTIONS, Neurologic and DRUG INTERACTIONS). Reserve concomitant prescribing of Zytram XL and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. Zytram XL (tramadol HCl CR tablets) Page 5 of 44

6 General Zytram XL must be swallowed whole and should not be cut, broken, chewed, dissolved or crushed, since this can lead to the rapid release and absorption of a potentially fatal dose of tramadol. Patients should be instructed not to give Zytram XL to anyone other than the patient for whom it was prescribed, as such inappropriate use may have severe medical consequences, including death. Zytram XL should be stored securely to avoid theft or misuse. Zytram XL should only be prescribed by healthcare professionals who are knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for the treatment of pain, and in the detection and management of respiratory depression, including the use of opioid antagonists. Patients should be cautioned not to consume alcohol while taking Zytram XL, as it may increase the chance of experiencing dangerous side effects, including death. Hyperalgesia that will not respond to a further dose increase of oxycodone can occur at particularly high doses. An oxycodone dose reduction or change in opioid may be required. Addiction, Abuse and Misuse Like all opioids, Zytram XL is a potential drug of abuse and misuse, which can lead to overdose and death. Therefore, Zytram XL should be prescribed and handled with caution. Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids, such as Zytram XL, should be used with particular care in patients with a history of alcohol and illicit/ prescription drug abuse. However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain. Zytram XL is intended for oral use only. The tablets should be swallowed whole, and not chewed or crushed. Abuse of oral dosage forms can be expected to result in serious adverse events, including death. A Risk Management Program to support the safe and effective use of Zytram XL has been established. The following are considered to be the essential components of the Risk Management Program: a) Commitment to not emphasize or highlight the scheduling status of Zytram XL (i.e., not listed under a schedule to the CDSA) in its advertising or promotional activities; b) Inclusion of a PAAB-approved fair balance statement in all Zytram XL advertising and promotional materials. Zytram XL (tramadol HCl CR tablets) Page 6 of 44

7 Anaphylactoid Reactions Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these rare reactions do occur it is often following the first dose. Other reported reactions include pruritus, hives, bronchospasm and angioedema. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive tramadol (see CONTRAINDICATIONS). Cardiovascular Tramadol administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquilizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of Zytram XL. The use of Zytram XL in patients with circulatory shock should be avoided as it may cause vasodilation that can further reduce cardiac output and blood pressure. Dependence/Tolerance As with other opioids, tolerance and physical dependence may develop upon repeated administration of Zytram XL and there is a potential for development of psychological dependence. Physical dependence and tolerance reflect the neuroadapatation of the opiate receptors to chronic exposure to an opiate, and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning (see ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION, Adjustment or Reduction of Dosage). In Vitro Dissolution Studies of Interaction with Alcohol Increasing concentrations of alcohol in the dissolution medium, resulted in a slight decrease in the rate of release of tramadol from Zytram XL tablets. The clinical significance of the slight decrease in dissolution rate is unknown. Zytram XL (tramadol HCl CR tablets) Page 7 of 44

8 Use in Drug and Alcohol Addiction Zytram XL is an opioid with no approved use in the management of addictive disorders. Its proper usage in individuals with drug or alcohol dependence, either active or in remission is for the management of pain requiring opioid analgesia. Endocrine Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Gastrointestinal Tramadol and other morphine-like opioids have been shown to decrease bowel motility. Tramadol may obscure the diagnosis or clinical course of patients with acute abdominal conditions (see CONTRAINDICATIONS). Neonatal Opioid Withdrawal Syndrome (NOWS) Prolonged maternal use of opioid during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Use of Zytram XL is contraindicated in pregnant women (see CONTRAINDICATIONS). Neurologic Interactions with CNS Depressants (including benzodiazepines and alcohol): Tramadol hydrochloride controlled release tablets should be used with caution and in reduced dosages during concomitant administration of other opioid analgesics, general anesthetics, phenothiazines and other tranquilizers, sedative-hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, benzodiazepines, centrally-active anti-emetics and other CNS depressants. Respiratory depression, hypotension and profound sedation, coma or death may result. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see DRUG Zytram XL (tramadol HCl CR tablets) Page 8 of 44

9 INTERACTIONS). If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when Zytram XL is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see DRUG INTERACTIONS). Zytram XL should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects, including death (see CONTRAINDICATIONS, ADVERSE REACTIONS, Sedation, and DRUG INTERACTIONS). Severe pain antagonizes the subjective and respiratory depressant actions of opioid analgesics. Should pain suddenly subside, these effects may rapidly become manifest. Serotonin Syndrome: Zytram XL could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g. anti-depressants, migraine medications). Treatment with the serotonergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Zytram XL should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, tramadol, St. John s Wort) due to the risk of serotonergic syndrome (see DRUG INTERACTIONS). Head Injury: The respiratory depressant effects of tramadol, and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated intracranial pressure produced by trauma. Also, tramadol may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, tramadol must be used with extreme caution and only if it is judged essential (see CONTRAINDICATIONS). Zytram XL (tramadol HCl CR tablets) Page 9 of 44

10 Respiratory Respiratory Depression: Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient s clinical status. Tramadol should be used with extreme caution in patients with substantially decreased respiratory reserve, pre-existing respiratory depression, hypoxia or hypercapnia (see CONTRAINDICATIONS). While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Zytram XL, the risk is greatest during the initiation of therapy or following a dose increase. Patients should be closely monitored for respiratory depression when initiating therapy with Zytram XL and following dose increases. Life-threatening respiratory depression is more likely to occur in the elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. To reduce the risk of respiratory depression, proper dosing and titration of Zytram XL are essential. Overestimating the Zytram XL dose when converting patients from another opioid product can result in fatal overdose with the first dose. In these patients, the use of non-opioid analgesics should be considered, if feasible (see WARNINGS AND PRECAUTIONS, Special Populations, Special Risk Groups and DOSAGE AND ADMINISTRATION). Cytochromes P450 (CYP 2D6) Ultra-Rapid Metabolism: Some individuals may be CYP2D6 ultra-rapid metabolizers. These individuals convert tramadol more rapidly than other people into its more potent opioid metabolite O-desmethyltramadol (M1). This rapid conversion could result in higher than expected opioid-like side effects including life-threatening respiratory depression (see Special Populations, Nursing Women; DRUG INTERACTIONS, Overview). The prevalence of this CYP2D6 phenotype varies widely in the population (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Race). Use in Patients with Chronic Pulmonary Disease: Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with Zytram XL, as in these patients, even usual therapeutic doses of Zytram XL may decrease respiratory drive to the point of apnea. In these patients, use of alternative non-opioid analgesics should be considered, if possible. The use of Zytram XL is contraindicated in patients with acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus (see CONTRAINDICATIONS). Zytram XL (tramadol HCl CR tablets) Page 10 of 44

11 Risk of Overdosage Serious potential consequences of overdosage with Zytram XL are 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 Zytram XL for patients who are suicidal or addiction prone. Zytram XL 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. Peri-operative Considerations Zytram XL is contraindicated for perioperative pain relief. Zytram XL is not indicated for preemptive analgesia (administration pre-operatively for the management of post-operative pain). In the case of planned chordotomy or other pain-relieving operations, patients should not be treated with Zytram XL for at least 48 hours before the operation and Zytram XL should not be used in the immediate post-operative period and until the patient is ambulatory and gastrointestinal function is normal. If Zytram XL is to be continued after the patient recovers from the post-operative period, a new dosage should be administered in accordance with the changed need for pain relief. The risk of withdrawal in opioid-tolerant patients should be addressed as clinically indicated (see Withdrawal Symptoms). The administration of analgesics in the peri-operative period should be managed by healthcare providers with adequate training and experience (e.g., by an anesthesiologist). Tramadol may decrease bowel motility. Ileus is a common post-operative complication, especially after intra-abdominal surgery with opioid analgesia. Caution should be taken to monitor for decreased bowel motility in post-operative patients receiving tramadol. Standard supportive therapy should be implemented. Zytram XL should not be used in the early post-operative period (12 to 24 hours post-surgery) unless the patient is ambulatory and gastrointestinal function is normal. Psychomotor Impairment Zytram XL may impair the mental and/or physical abilities needed for potentially hazardous tasks such as driving a car or operating machinery. Patients should be cautioned accordingly. Patients should also be cautioned about the combined effects of tramadol with other CNS Zytram XL (tramadol HCl CR tablets) Page 11 of 44

12 depressants, including other opioids, phenothiazine, sedative/hypnotics and alcohol. 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 serotoninnorepinephrine reuptake inhibitors (SNRIs), Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, mirtazapine), or Opioids. Administration of tramadol may also enhance the seizure risk in patients taking: MAO inhibitors (see CONTRAINDICATIONS), Neuroleptics, or Other drugs that reduce the seizure threshold. Risk of seizures 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). Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons and used with extreme caution. In tramadol overdose, naloxone administration may increase the risk of seizure. Serotonin Syndrome Risk The development of a potentially life-threatening Serotonin Syndrome may occur with use of tramadol products, including Zytram XL, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, with drugs which impair metabolism of serotonin (including MAOIs), and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors) (see CONTRAINDICATIONS and DRUG INTERACTIONS). This may occur within the recommended dose. Serotonin Syndrome is likely when one of the following is observed: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, hypertonia and body temperature >38 C and inducible or ocular clonus. Withdrawal of the serotonergic medicines usually brings about a rapid improvement; treatment depends on the type and severity of the symptoms. As Serotonin Syndrome may result in a potentially life-threatening condition, treatment with Zytram XL should be discontinued if these events occur and supportive symptomatic treatment should be initiated. Zytram XL (tramadol HCl CR tablets) Page 12 of 44

13 Carcinogenesis and Mutagenesis See animal data in TOXICOLOGY section. Patient Counselling Information A patient information sheet should be provided to patients when Zytram XL tablets are dispensed to them. Patients receiving Zytram XL should be given the following instructions by the physician: 1. Patients should be informed that accidental ingestion or use by individuals (including children) other than the patient for whom it was originally prescribed, may lead to severe, even fatal, consequences. 2. Patients should be advised that Zytram XL contains tramadol, an opioid pain medicine. 3. Patients should be advised that Zytram XL should only be taken as directed. The dose of Zytram XL should not be adjusted without consulting a physician. 4. Zytram XL should be swallowed whole (not cut, broken, chewed, dissolved or crushed) due to the risk of fatal tramadol overdose. 5. Patients should be advised to report episodes of pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication. 6. Patients should not combine Zytram XL with alcohol or other central nervous system depressants (sleep aids, tranquilizers) because dangerous additive effects may occur, resulting in serious injury or death. 7. Patients should be advised that serious anaphylactoid reactions have rarely been reported, however patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive tramadol. 8. Patients should be advised that Zytram XL may increase the risk of seizures, particularly when taken above the recommended dose range or in combination with SSRIs, tricyclic antidepressants or other tricyclic compounds or with other opioids. 9. Patients should be informed that Zytram XL may increase the risk of Serotonin Syndrome with concomitant use of serotonergic drugs (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol. 10. Patients should be advised to consult their physician or pharmacist if other medications are being used or will be used with Zytram XL. 11. Patients should be advised that if they have been receiving treatment with Zytram XL and cessation of therapy is indicated, it may be appropriate to taper Zytram XL dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Zytram XL (tramadol HCl CR tablets) Page 13 of 44

14 12. Patients should be advised of the most common adverse reactions that may occur while taking Zytram XL: constipation, dizziness, headache, nausea, somnolence and vomiting. 13. Patients should be advised that Zytram XL may cause drowsiness, dizziness, or lightheadedness and may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Patients started on Zytram XL or patients whose dose has been adjusted should be advised not to drive a car or operate machinery unless they are tolerant to the effects of Zytram XL. 14. Patients should be advised that Zytram XL is a potential drug of abuse. They should protect it from theft or misuse. 15. Patients should be advised that Zytram XL should never be given to anyone other than the individual for whom it was prescribed. 16. Women of childbearing potential who become or are planning to become pregnant should be advised to consult a physician prior to initiating or continuing therapy with Zytram XL. Women who are breastfeeding or pregnant should not use Zytram XL. 17. Patients should be advised that they may pass empty matrix tablet remnants in the stool, or via colostomy, and that this should not be a concern since the analgesic medication, tramadol, has already been released. Sexual Function / Reproduction Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility (see ADVERSE REACTIONS, Post- Marketing Experience). Special Populations Special Risk Groups: Tramadol should be administered with caution to patients with a history of alcohol and drug abuse and in a reduced dosage to debilitated patients, and in patients with severely impaired pulmonary function, Addison s disease, hypothyroidism, myxedema, toxic psychosis, prostatic hypertrophy or urethral stricture. Pregnant Women: Studies in humans have not been conducted. While animal reproduction studies have revealed no evidence of harm to the fetus due to tramadol (TOXICOLOGY, Reproductive and Developmental Toxicity), Zytram XL does cross the placental barrier. Thus, Zytram XL should not be administered to pregnant women unless in the judgement of the physician, potential benefits outweigh the risks. Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal Opioid Withdrawal Syndrome (NOWS), unlike opioid withdrawal syndrome in adults, may be life-threatening (see WARNINGS AND PRECAUTIONS, Neonatal Opioid Withdrawal Syndrome (NOWS), ADVERSE REACTIONS). Neonatal seizures, neonatal withdrawal syndrome, fetal death and stillbirth have been reported with tramadol hydrochloride during post-marketing reports with tramadol hydrochloride immediate-release products. Zytram XL (tramadol HCl CR tablets) Page 14 of 44

15 Use of Zytram XL is contraindicated in pregnant women (see CONTRAINDICATIONS). The effect of tramadol, if any, on the later growth, development and functional maturation of the child is unknown. Labour and Delivery: Since opioids can cross the placental barrier and are excreted in breast milk, Zytram XL should not be used unless, in the judgement of the physician, the potential benefits outweigh the risks. Respiratory depression can occur in the infant if opioids are administered during labour. Naloxone, a drug that counters the effects of opiates, should be readily available. Nursing Women: Zytram XL is contraindicated in nursing women (see CONTRAINDICATIONS). Following a single 100 mg i.v. dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1. Some women are CYP2D6 ultra-rapid metabolizers of tramadol, which may lead to dangerously higher-than-expected serum levels of M1 that could pass to their breast-fed infants. Therefore, maternal use of tramadol can lead to serious adverse reactions, including death in nursing infants (see WARNINGS AND PRECAUTIONS, Respiratory). Since its safety in infants and newborns has not been studied, tramadol should not be administered for obstetrical preoperative medication, post-delivery analgesia or at any time during breastfeeding. Pediatrics (<18 years of age): The safety and efficacy of Zytram XL has not been studied in the pediatric population. Therefore, use of Zytram XL tablets is not recommended in patients under 18 years of age. Geriatrics (>65 years of age): In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and titrate slowly, reflecting the greater frequency of decreased hepatic, renal or cardiac function, of concomitant disease and multiple drug therapy. The elimination half-life of tramadol may be prolonged in patients over 75 years, thereby increasing the potential for adverse events (see DOSAGE AND ADMINISTRATION). Hepatic/Biliary/Pancreatic Impairment: Zytram XL is contraindicated in patients with severe hepatic impairment. The elimination half-life of tramadol and its active metabolite may be prolonged in patients with hepatic impairment. Renal Impairment: Zytram XL is contraindicated in patients with severe renal impairment. The elimination half-life of tramadol and its active metabolite may be prolonged in patients with renal impairment. Zytram XL (tramadol HCl CR tablets) Page 15 of 44

16 Monitoring and Laboratory Tests Not applicable. ADVERSE REACTIONS Adverse Drug Reaction Overview Adverse effects of Zytram XL (tramadol hydrochloride controlled release tablets) are similar to those of other opioid analgesics and represent an extension of pharmacological effects of the drug class. The major hazards of opioids include respiratory and central nervous system depression and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest. The pre-marketing development program for Zytram XL (tramadol hydrochloride controlled release tablets) included exposure to a total of 1,213 participants in seven randomized, doubleblind controlled clinical trials (n = 1,028) and one six-month open-label trial (n = 185). A summary of adverse events occurring at an incidence of 1% or more is given in Table 1, which includes all events, whether considered by the clinical investigator to be related to the study drug or not. The most common adverse effects with Zytram XL are constipation, dizziness, headache, nausea, somnolence and vomiting. These are common effects associated with other drugs with opioid-agonist activity. Slower titration a 7 day as compared to a 2 day schedule, may be an effective strategy to reduce adverse effects. 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. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Zytram XL (tramadol HCl CR tablets) Page 16 of 44

17 Table 1: Adverse Events Reports in Zytram XL Clinical Trials ( 1%) Number of Patients % of Patients n = 1,213 Body as a Whole Headache Asthenia Hyperhidrosis Pain Central Nervous System Dizziness Somnolence Depression Insomnia Tremor Vasodilation Digestive System Constipation Nausea Vomiting Diarrhea Abdominal pain Anorexia Dry mouth Dyspepsia Flatulence Respiratory System Cough increased Pharyngitis Skin and Appendages Pruritus Sedation: Sedation is a common side effect of opioid analgesics, especially in opioid naïve individuals. Sedation may also occur partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Most patients develop tolerance to the sedative effects of opioids within three to five days and, if the sedation is not severe, will not require any treatment except reassurance. If excessive sedation persists beyond a few days, the dose of the opioid should be reduced and alternate causes investigated. Some of these are: concurrent CNS Zytram XL (tramadol HCl CR tablets) Page 17 of 44

18 depressant medication, hepatic or renal dysfunction, brain metastases, hypercalcemia and respiratory failure. If it is necessary to reduce the dose, it can be carefully increased again after three or four days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension, particularly in elderly or debilitated patients, and may be alleviated if the patient lies down. Nausea and Vomiting: Nausea is a common side effect on initiation of therapy with opioid analgesics and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea declines following continued treatment with opioid analgesics. When instituting therapy with an opioid for chronic pain, the routine prescription of an antiemetic should be considered. In the cancer patient, investigation of nausea should include such causes as constipation, bowel obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of celiac plexus and concurrent use of drugs with emetogenic properties. Persistent nausea which does not respond to dosage reduction may be caused by opioid-induced gastric stasis and may be accompanied by other symptoms including anorexia, early satiety, vomiting and abdominal fullness. These symptoms respond to chronic treatment with gastrointestinal prokinetic agents. Constipation: Practically all patients become constipated while taking opioids on a persistent basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid therapy. Stimulant laxatives, stool softeners, and other appropriate measures should be used as required. As fecal impaction may present as overflow diarrhea, the presence of constipation should be excluded in patients on opioid therapy prior to initiating treatment for diarrhea. The following adverse effects occur less frequently with opioid analgesics and include those reported in Zytram XL clinical trials, whether related or not to tramadol. Less Common Clinical Trial Adverse Drug Reactions (< 1%) Body as a Whole: Cardiovascular: Digestive: Endocrine: Hemolytic & Lymphatic: abnormal gait, accidental injury, back pain, chest pain, chills and fever, flu syndrome, infection, malaise, photosensitivity, syncope. angina pectoris, arrhythmia, atrial flutter, hypertension, migraine, palpitation, peripheral vascular disorder, phlebitis, tachycardia. abnormal stools, bloating, diverticulitis, eructation, gastric motility reduced, gastritis, gastroenteritis, gastrointestinal hemorrhage, hiccup, irritable bowel syndrome, laryngitis, melena, pancreatitis, rectal disorder, rectal hemorrhage, thirst, tongue disorder, weight decrease. abnormal ejaculation, impotence, libido decreased. hemolytic anemia, liver function test abnormal. Zytram XL (tramadol HCl CR tablets) Page 18 of 44

19 Metabolic & Nutritional: Musculoskeletal: Nervous: Respiratory: Skin: Special Senses: Urogenital: alkaline phosphatase increased, hypercholesteremia, hyperglycemia, hyperlipemia, peripheral edema, hepatic enzymes increased. arthritis, arthrosis, bursitis, cramps, fatigue, gout, joint disorder, knee effusion, muscle pain, muscle weakness, myalgia, myopathy, pathological fracture, tendon disorder. abnormal coordination, abnormal dreams, abnormal thinking, amnesia, anxiety, apathy, ataxia, carpal tunnel syndrome, confusional state, depersonalization, affect lability, euphoric mood, hallucinations, hyperesthesia, hypertonia, anosmia or hyposmia, malaise, myoclonus, nervousness, paresthesia, vertigo. asthma, bronchospasm, dyspnea, epistaxis, hemoptysis, hyperventilation, pneumonia, respiratory disorder, rhinitis, sinusitis. acne, dermatitis, dry skin, eczema, flushing, gooseflesh, herpes simplex, herpes zoster, purpura, rash, sebaceous cyst. amblyopia, blepharitis, cellulitis, conjunctivitis, dry eyes, eustachian tube dysfunction, eye pain, halitosis, lacrimation disorder, otitis media, sore mouth, taste perversion, tinnitus, tooth disorder, visual impairment. albuminuria, calcium crystalluria, cystitis, dysuria, enlarged prostate, gynecomastia, hematuria, nocturia, polyuria, renal pain, urinary retention, urinary tract infection, urine abnormality, vaginal hemorrhage. Abnormal Hematologic and Clinical Chemistry Findings In clinical trials where clinical abnormalities were recorded (n= 245), the following laboratory abnormalities were reported: ALT (3%), AST (2%), alkaline phosphatase (4%), creatinine (2%), BUN (4%), potassium (2%), sodium (1%), bilirubin (0.4%), basophils (0.4%), eosinophils (0.4%), lymphocytes (3%), monocytes (3%), neutrophils (1%), LDH (4%), RBC (3%), platelets (2%), WBC (2%), glucose (0.4%), triglycerides (1%) and TSH (0.4%). 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, angioedema and urticaria), bradycardia, cognitive disorders, seizures, decreased activity, drug dependence, drug withdrawal (including agitation, anxiety, gastrointestinal symptoms, hyperkinesia, insomnia, nervousness, tremor), hypotension, micturition disorder, psychomotor hyperactivity, respiratory depression and sensory disturbance. Cases of hypoglycemia have been reported in patients taking tramadol, mostly in patients with pre-disposing risk factors, including diabetes, elderly and renal insufficiency. Caution should be Zytram XL (tramadol HCl CR tablets) Page 19 of 44

20 exercised when prescribing tramadol to diabetic patients. More frequent monitoring of blood glucose levels may be appropriate. 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, Stevens-Johnson Syndrome 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. Neonatal opioid withdrawal syndrome has resulted from prolonged use of tramadol. Post-Marketing Experience Androgen deficiency: Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation. DRUG INTERACTIONS 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. Interaction with Benzodiazepines and Other CNS Depressants: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants (e.g. other opioids, sedatives/hypnotics, antidepressants, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, phenothiazines, neuroleptics, antihistamines, antiemetics, and alcohol) and beta-blockers, increases the risk of respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation (see WARNINGS AND PRECAUTIONS, Neurologic, Interactions with CNS Depressants (including benzodiazepines and alcohol) and Psychomotor Impairment). Zytram XL should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects. Zytram XL (tramadol HCl CR tablets) Page 20 of 44

21 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), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic anti-depressants (TCAs), antipsychotics and other seizure threshold lowering drugs (i.e., bupropion, mirtazapine, tetrahydrocannabinol) to cause seizures (see WARNINGS AND PRECAUTIONS). Drugs That Increase Serotonin Syndrome Risk The development of a potentially life-threatening Serotonin Syndrome may occur with use of tramadol products, including Zytram XL, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium or St. John s Wort, with drugs which impair metabolism of serotonin (including MAOIs), and with drugs which may impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). If concomitant treatment of Zytram XL with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. 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 or exacerbate adverse drug reactions of tramadol. Carbamazepine Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Since carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of Zytram XL (tramadol HCl controlled release tablets) and carbamazepine is not recommended. Quinidine Tramadol is metabolized to M1 by the CYP2D6 isoenzyme. Quinidine is a selective inhibitor of that isoenzyme, so that concomitant administration of quinidine and tramadol results in increased concentrations of tramadol and reduced concentrations of M1. The clinical consequences of these findings are unknown. 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. Zytram XL (tramadol HCl CR tablets) Page 21 of 44

22 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 and cimetidine is associated with a small prolongation of the half-life of tramadol, but no alteration of the Zytram XL dosage regimen 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 (international normalized ratio/inr), 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, care should be taken when commencing treatment with tramadol in patients on anticoagulants. Periodic evaluation of prothrombin time should be performed when Zytram XL tablets and warfarin-like compounds are administered concurrently. Drug-Food Interactions In the presence of food, the availability and controlled-release properties of Zytram XL tablets were maintained with no evidence of dose dumping. Drug-Herb Interactions Interactions with herbal products have not been established. Drug-Laboratory Interactions Interactions with laboratory tests have not been established. Drug-Lifestyle Interactions The concomitant use of alcohol should be avoided (see WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions Box). DOSAGE AND ADMINISTRATION Zytram XL (tramadol hydrochloride controlled release tablets) should only be used in patients for whom alternative treatment options are ineffective or not tolerated (e.g., nonopioid analgesics), or would be otherwise inadequate to provide sufficient management of pain (e.g., immediate-release opioids). Zytram XL (tramadol HCl CR tablets) Page 22 of 44