PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION Pr ZYTRAM XL® Tramadol Hydrochloride Controlled Release Tablets Tablets, 75, 100, 150, 200, 300 and 400 mg, Oral Purdue Pharma Standard Opioid Analgesic Purdue Pharma Date of Initial Approval: 575 Granite Court Sept 28, 2006 Pickering, Ontario L1W 3W8 Date of Revision: August 4, 2020 Submission Control No: 237703 ZYTRAM XL® is a registered trademark of Purdue Pharma ZYTRAM XL® (tramadol HCl controlled release tablets) Page 1 of 48 RECENT MAJOR LABEL CHANGES 7 WARNINGS AND PRECAUTIONS, Neurologic, Serotonin toxicity / Serotonin syndrome, July 2020 7 WARNINGS AND PRECAUTIONS, Respiratory, Sleep Apnea, July 2020 TABLE OF CONTENTS RECENT MAJOR LABEL CHANGES ......................................................................................... 2 TABLE OF CONTENTS ............................................................................................................... 2 PART I: HEALTH PROFESSIONAL INFORMATION .................................................................. 4 1 INDICATIONS ................................................................................................................... 4 1.1 Pediatrics ................................................................................................................. 4 1.2 Geriatrics ................................................................................................................. 4 2 CONTRAINDICATIONS ................................................................................................... 4 3 SERIOUS WARNINGS AND PRECAUTIONS BOX ........................................................ 5 4 DOSAGE AND ADMINISTRATION .................................................................................. 6 4.1 Dosing Considerations ............................................................................................ 6 4.2 Recommended Dose and Dosage Adjustment ....................................................... 7 4.3 Administration .......................................................................................................... 9 4.4 Missed Dose ............................................................................................................ 9 5 OVERDOSAGE ................................................................................................................ 9 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ....................... 10 7 WARNINGS AND PRECAUTIONS ................................................................................ 10 7.1 Special Populations ............................................................................................... 20 7.1.1 Pregnant Women ............................................................................................... 20 7.1.2 Breast-feeding ................................................................................................... 20 7.1.3 Pediatrics (<18 years of age) ............................................................................. 21 7.1.4 Geriatrics (>65 years of age) ............................................................................. 21 7.1.5 Patients with Hepatic Impairment ...................................................................... 21 7.1.6 Patients with Renal Impairment ......................................................................... 21 8 ADVERSE REACTIONS ................................................................................................. 21 8.1 Adverse Reaction Overview .................................................................................. 21 8.2 Clinical Trial Adverse Reactions ............................................................................ 22 8.3 Less Common Clinical Trial Adverse Reactions ................................................... 24 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................ 25 8.5 Clinical Trial Adverse Reactions (Pediatrics) ........................................................ 25 8.6 Post-Market Adverse Reactions ............................................................................ 25 9 DRUG INTERACTIONS .................................................................................................. 26 9.1 Serious Drug Interactions Box ............................................................................... 26 9.2 Overview ............................................................................................................... 27 9.3 Drug-Drug Interactions .......................................................................................... 27 9.4 Drug-Food Interactions .......................................................................................... 29 ZYTRAM XL® (tramadol HCl controlled release tablets) Page 2 of 48 9.5 Drug-Herb Interactions .......................................................................................... 29 9.6 Drug-Laboratory Test Interactions ......................................................................... 29 9.7 Drug-Lifestyle Interactions ..................................................................................... 30 10 ACTION AND CLINICAL PHARMACOLOGY ................................................................ 30 10.1 Mechanism of Action ......................................................................................... 30 10.2 Pharmacodynamics ........................................................................................... 31 10.3 Pharmacokinetics .............................................................................................. 32 11 STORAGE, STABILITY AND DISPOSAL ...................................................................... 34 12 SPECIAL HANDLING INSTRUCTIONS ......................................................................... 34 13 PHARMACEUTICAL INFORMATION ............................................................................ 35 14 CLINICAL TRIALS ......................................................................................................... 36 14.1 Trial Design and Study Demographics .............................................................. 36 15 NON-CLINICAL TOXICOLOGY ..................................................................................... 38 PATIENT MEDICATION INFORMATION .................................................................................. 40 ZYTRAM XL® (tramadol HCl controlled release tablets) Page 3 of 48 PART I: HEALTH PROFESSIONAL INFORMATION 1 INDICATIONS 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. 1.1 Pediatrics 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. 1.2 Geriatrics 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, and DOSAGE AND ADMINISTRATION). 2 CONTRAINDICATIONS ZYTRAM XL is contraindicated in: • Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING. • 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 peri-operative 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. ZYTRAM XL® (tramadol HCl controlled release tablets) Page 4 of 48 • Patients with severe CNS depression, increased cerebrospinal or intracraial pressure, brain tumour and/or 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 (see SERIOUS WARNINGS AND PRECAUTIONS BOX and WARNINGS AND PRECAUTIONS). • Pediatric patients less than 18 years of age who have undergone tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. • Pediatric patients less than 12 years of age. 3 SERIOUS WARNINGS AND PRECAUTIONS BOX Serious Warnings and Precautions