TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN
Generic: TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN
Basic Information
Manufacturer
Micro Labs Limited
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
ab84058e-e52c-4b81-badc-4b0c26aab259
Indications & Usage
1 INDICATIONS AND USAGE Tramadol hydrochloride and acetaminophen tablets are indicated for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
Limitations of Use Tramadol hydrochloride and acetaminophen tablets are indicated for short-term use of five days or less.
Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warning and Precautions ( 5.1 )] , reserve opioid analgesics, including tramadol hydrochloride and acetaminophen, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
Tramadol hydrochloride and acetaminophen tablet is a combination of tramadol hydrochloride, an opioid agonist, and acetaminophen, and is indicated for the management of acute pain, severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
( 1 ) Limitations of Use Tramadol hydrochloride and acetaminophen tablets are indicated for short-term use of five days or less.
Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including tramadol hydrochloride and acetaminophen tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
( 1 , 5.1 )
Limitations of Use Tramadol hydrochloride and acetaminophen tablets are indicated for short-term use of five days or less.
Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warning and Precautions ( 5.1 )] , reserve opioid analgesics, including tramadol hydrochloride and acetaminophen, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
Tramadol hydrochloride and acetaminophen tablet is a combination of tramadol hydrochloride, an opioid agonist, and acetaminophen, and is indicated for the management of acute pain, severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
( 1 ) Limitations of Use Tramadol hydrochloride and acetaminophen tablets are indicated for short-term use of five days or less.
Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including tramadol hydrochloride and acetaminophen tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
( 1 , 5.1 )
Adverse Reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children [see Warnings and Precautions ( 5.6 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Hepatotoxicity [see Warnings and Precautions ( 5.9 )] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.3 )] Serotonin Syndrome [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Suicide [see Warnings and Precautions ( 5.12 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.14 )] Severe Hypotension [see Warnings and Precautions ( 5.15 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.18 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.19 )] Withdrawal [see Warnings and Precautions ( 5.21 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.8 )] .
The most common incidence of treatment-emergent adverse events (≥3%) in patients from clinical trials were constipation, diarrhea, nausea, somnolence, anorexia, dizziness, and sweating increased.
( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc.
at 1-855-839-8195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most common incidence of treatment-emergent adverse events (≥3%) in subjects from clinical trials was constipation, diarrhea, nausea, somnolence, anorexia, dizziness, and sweating increased.
Table 1 shows the incidence rate of treatment-emergent adverse events reported in ≥2% of subjects over five days of tramadol hydrochloride and acetaminophen use in clinical trials (subjects took an average of at least 6 tablets per day).
Table 1: Incidence of Treatment-Emergent Adverse Events ( ≥ 2%) Body System Preferred Term Tramadol Hydrochloride and Acetaminophen (N=142) (%) Gastrointestinal System Disorders Constipation 6 Diarrhea 3 Nausea 3 Dry Mouth 2 Psychiatric Disorders Somnolence 6 Anorexia 3 Insomnia 2 Central & Peripheral Nervous System Dizziness 3 Skin and Appendages Sweating Increased 4 Pruritus 2 Reproductive Disorders, Male* Prostatic Disorder 2 * Number of males = 62 Incidence at least 1%, causal relationship at least possible or greater: The following lists adverse reactions that occurred with an incidence of at least 1% in single-dose or repeated-dose clinical trials of tramadol hydrochloride and acetaminophen.
Body as a Whole - Asthenia, fatigue, hot flushes Central and Peripheral Nervous System - Dizziness, headache, tremor Gastrointestinal System - Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting Psychiatric Disorders - Anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence Skin and Appendages - Pruritus, rash, increased sweating Selected adverse events occurring at less than 1%: The following lists clinically relevant adverse reactions that occurred with an incidence of less than 1% in tramadol hydrochloride and acetaminophen clinical trials.
Body as a Whole - Chest pain, rigors, syncope, withdrawal syndrome Cardiovascular Disorders - Hypertension, aggravated hypertension, hypotension Central and Peripheral Nervous System - Ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesias, stupor, vertigo Gastrointestinal System - Dysphagia, melena, tongue edema Hearing and Vestibular Disorders - Tinnitus Heart Rate and Rhythm Disorders - Arrhythmia, palpitation, tachycardia Liver and Biliary System - Hepatic function abnormal Metabolic and Nutritional Disorders - Weight decrease Psychiatric Disorders - Amnesia, depersonalization, depression, drug abuse, emotional lability, hallucination, impotence, paroniria, abnormal thinking Red Blood Cell Disorders - Anemia Respiratory System - Dyspnea Urinary System - Albuminuria, micturition disorder, oliguria, urinary retention Vision Disorders - Abnormal vision 6.2 Postmarketing Experiences The following adverse reactions have been identified during post-approval use of tramadol-containing products.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis : Anaphylaxis has been reported with ingredients contained in tramadol hydrochloride and acetaminophen tablets.
Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] .
Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.8 )].
QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use.
Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in the overdose setting.
Eye disorders - miosis, mydriasis Metabolism and nutrition disorders - Hyponatremia: Cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy [see Warnings and Precautions ( 5.23 )].
Hypoglycemia: Cases of hypoglycemia have been reported in patients taking tramadol.
Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients [see Warnings and Precautions ( 5.24 )] .
Nervous system disorders - movement disorder, speech disorder Psychiatric disorders - delirium Other clinically significant adverse experiences previously reported with tramadol hydrochloride: Other events which have been reported with the use of tramadol products and for which a causal association has not been determined include: vasodilation, orthostatic hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson syndrome/TENS), cognitive dysfunction, difficulty concentrating, depression, suicidal tendency, hepatitis, liver failure, and gastrointestinal bleeding.
Reported laboratory abnormalities included elevated creatinine and liver function tests.
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 SSRIs and MAOIs.
Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.18 )] .
Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021.
Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244).
Those included also had no dispensing of the qualifying opioids in the previous 6 months.
Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence (9.2)] , respectively, as measured with a validated self-reported instrument.
A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249).
Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months.
New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months.
Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry.
Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database.
The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up.
Approximately 17% of first opioid overdoses observed over the entire study period (5 to 11 years, depending on the study site) were fatal.
Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death.
Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.
The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.
The most common incidence of treatment-emergent adverse events (≥3%) in patients from clinical trials were constipation, diarrhea, nausea, somnolence, anorexia, dizziness, and sweating increased.
( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc.
at 1-855-839-8195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most common incidence of treatment-emergent adverse events (≥3%) in subjects from clinical trials was constipation, diarrhea, nausea, somnolence, anorexia, dizziness, and sweating increased.
Table 1 shows the incidence rate of treatment-emergent adverse events reported in ≥2% of subjects over five days of tramadol hydrochloride and acetaminophen use in clinical trials (subjects took an average of at least 6 tablets per day).
Table 1: Incidence of Treatment-Emergent Adverse Events ( ≥ 2%) Body System Preferred Term Tramadol Hydrochloride and Acetaminophen (N=142) (%) Gastrointestinal System Disorders Constipation 6 Diarrhea 3 Nausea 3 Dry Mouth 2 Psychiatric Disorders Somnolence 6 Anorexia 3 Insomnia 2 Central & Peripheral Nervous System Dizziness 3 Skin and Appendages Sweating Increased 4 Pruritus 2 Reproductive Disorders, Male* Prostatic Disorder 2 * Number of males = 62 Incidence at least 1%, causal relationship at least possible or greater: The following lists adverse reactions that occurred with an incidence of at least 1% in single-dose or repeated-dose clinical trials of tramadol hydrochloride and acetaminophen.
Body as a Whole - Asthenia, fatigue, hot flushes Central and Peripheral Nervous System - Dizziness, headache, tremor Gastrointestinal System - Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting Psychiatric Disorders - Anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence Skin and Appendages - Pruritus, rash, increased sweating Selected adverse events occurring at less than 1%: The following lists clinically relevant adverse reactions that occurred with an incidence of less than 1% in tramadol hydrochloride and acetaminophen clinical trials.
Body as a Whole - Chest pain, rigors, syncope, withdrawal syndrome Cardiovascular Disorders - Hypertension, aggravated hypertension, hypotension Central and Peripheral Nervous System - Ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesias, stupor, vertigo Gastrointestinal System - Dysphagia, melena, tongue edema Hearing and Vestibular Disorders - Tinnitus Heart Rate and Rhythm Disorders - Arrhythmia, palpitation, tachycardia Liver and Biliary System - Hepatic function abnormal Metabolic and Nutritional Disorders - Weight decrease Psychiatric Disorders - Amnesia, depersonalization, depression, drug abuse, emotional lability, hallucination, impotence, paroniria, abnormal thinking Red Blood Cell Disorders - Anemia Respiratory System - Dyspnea Urinary System - Albuminuria, micturition disorder, oliguria, urinary retention Vision Disorders - Abnormal vision 6.2 Postmarketing Experiences The following adverse reactions have been identified during post-approval use of tramadol-containing products.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis : Anaphylaxis has been reported with ingredients contained in tramadol hydrochloride and acetaminophen tablets.
Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] .
Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.8 )].
QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use.
Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in the overdose setting.
Eye disorders - miosis, mydriasis Metabolism and nutrition disorders - Hyponatremia: Cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy [see Warnings and Precautions ( 5.23 )].
Hypoglycemia: Cases of hypoglycemia have been reported in patients taking tramadol.
Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients [see Warnings and Precautions ( 5.24 )] .
Nervous system disorders - movement disorder, speech disorder Psychiatric disorders - delirium Other clinically significant adverse experiences previously reported with tramadol hydrochloride: Other events which have been reported with the use of tramadol products and for which a causal association has not been determined include: vasodilation, orthostatic hypotension, myocardial ischemia, pulmonary edema, allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson syndrome/TENS), cognitive dysfunction, difficulty concentrating, depression, suicidal tendency, hepatitis, liver failure, and gastrointestinal bleeding.
Reported laboratory abnormalities included elevated creatinine and liver function tests.
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 SSRIs and MAOIs.
Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.18 )] .
Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021.
Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244).
Those included also had no dispensing of the qualifying opioids in the previous 6 months.
Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence (9.2)] , respectively, as measured with a validated self-reported instrument.
A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249).
Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months.
New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months.
Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry.
Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database.
The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up.
Approximately 17% of first opioid overdoses observed over the entire study period (5 to 11 years, depending on the study site) were fatal.
Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death.
Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.
The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.