TRAMADOL HYDROCHLORIDE
Generic: TRAMADOL HYDROCHLORIDE
Basic Information
Manufacturer
Bryant Ranch Prepack
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
acd5d8e0-a4cc-4654-ae04-faff347a60ca
Indications & Usage
1 INDICATIONS AND USAGE Tramadol hydrochloride extended-release tablet is indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.
Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosages or duration, and persist over the course of therapy [see Warnings and Precautions ( 5.1 )] , reserve opioid analgesics, including tramadol hydrochloride extended-release 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.
Tramadol hydrochloride extended-release tablet is not indicated as an as-needed (prn) analgesic.
Tramadol hydrochloride extended-release tablets are an opioid agonist indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.
( 1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosages or duration and persist over the course of therapy , reserve opioids analgesics, including tramadol hydrochloride extended-release 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 ) Tramadol hydrochloride extended-release tablets is not indicated as an as-needed (prn) analgesic.
( 1 )
Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosages or duration, and persist over the course of therapy [see Warnings and Precautions ( 5.1 )] , reserve opioid analgesics, including tramadol hydrochloride extended-release 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.
Tramadol hydrochloride extended-release tablet is not indicated as an as-needed (prn) analgesic.
Tramadol hydrochloride extended-release tablets are an opioid agonist indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.
( 1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosages or duration and persist over the course of therapy , reserve opioids analgesics, including tramadol hydrochloride extended-release 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 ) Tramadol hydrochloride extended-release tablets is not indicated as an as-needed (prn) analgesic.
( 1 )
Adverse Reactions
6 ADVERSE REACTIONS The following serious or otherwise important adverse reactions are 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 )] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions ( 5.6 )] Opioid-Induced Hyperalgesia and Allodynia [See Warnings and Precautions ( 5.8 )] Serotonin Syndrome [see Warnings and Precautions ( 5.9 )] Seizures [see Warnings and Precautions ( 5.10 )] Suicide [see Warnings and Precautions ( 5.11 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.13 )] Severe Hypotension [see Warnings and Precautions ( 5.14 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.16 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.17 )] Withdrawal [see Warnings and Precautions ( 5.18 )] Most common adverse reactions (≥10% and ≥2 x placebo rate): Dizziness, constipation, nausea, headache, somnolence, flushing, pruritus, vomiting, insomnia, dry mouth.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc.
at 1-800-399-2561 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.
Tramadol hydrochloride extended-release tablet was administered to a total of 3108 patients during studies conducted in the U.S.
These included four double-blind studies in patients with osteoarthritis and/or chronic low back pain and one open-label study in patients with chronic non-malignant pain.
A total of 901 patients were 65 years or older.
The frequency of adverse reactions generally increased with doses from 100 mg to 400 mg in the two pooled, twelve-week, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain (see Table 1).
The most common adverse reactions from Table 1 occurring in ≥10% and ≥2 x placebo rate of the patients treated with tramadol hydrochloride extended-release tablets are dizziness (not vertigo), nausea, constipation, headache, somnolence, flushing, pruritus, vomiting, insomnia, and dry mouth.
Table 1: Incidence (%) of patients with adverse reaction rates ≥ 5% from two 12-week placebo-controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1811).
MedDRA Preferred Term Tramadol Hydrochloride Extended-Release Tablets Placebo 100 mg (N=403) n (%) 200 mg (N=400) n (%) 300 mg (N=400) n (%) 400 mg (N=202) n (%) (N=406) n (%) Dizziness (not vertigo) 64 (16) 81 (20) 90 (23) 57 (28) 28 (7) Nausea 61 (15) 90 (23) 102 (26) 53 (26) 32 (8) Constipation 49 (12) 68 (17) 85 (21) 60 (30) 17 (4) Headache 49 (12) 62 (16) 46 (12) 32 (16) 43 (11) Somnolence 33 (8) 45 (11) 29 (7) 41 (20) 7 (2) Flushing 31 (8) 40 (10) 35 (9) 32 (16) 18 (4) Pruritus 25 (6) 34 (9) 30 (8) 24 (12) 4 (1) Vomiting 20 (5) 29 (7) 34 (9) 19 (9) 11 ( 3) Insomnia 26 (7) 32 (8) 36 (9) 22 (11) 13 (3) Dry Mouth 20 (5) 29 (7) 39 (10) 18 (9) 6 (2) Diarrhea 15 (4) 27 (7) 37 (9) 10 (5) 17 (4) Asthenia 14 (4) 24 (6) 26 (7) 13 (6) 7 (2) Postural hypotension 7 (2) 17 (4) 8 (2) 11 (5) 9 (2) Sweating increased 6 (2) 8 (2) 15 (4) 13 (6) 1 (0) Anorexia 3 (1) 7 (2) 21 (5) 12 (6) 1 (0) Adverse reactions With Incidence Rates of 1.0% to <5.0% During Clinical Trials The following adverse reactions were reported from all the chronic pain studies (N=3108).
The lists below include adverse reactions not otherwise noted in Table 1.
Eye disorders : vision blurred Gastrointestinal disorders : abdominal pain upper, dyspepsia, abdominal pain, sore throat General disorders : weakness, pain, feeling hot, influenza like illness, fall, rigors, lethargy, pyrexia, chest pain Infections and infestations : nasopharyngitis, upper respiratory tract infection, sinusitis, influenza, gastroenteritis viral, urinary tract infection, bronchitis Investigations : blood creatine phosphokinase increased, weight decreased Metabolism and nutrition disorders : appetite decreased Musculoskeletal, connective tissue and bone disorders : arthralgia, back pain, pain in limb, neck pain Nervous system disorders : tremor, paresthesia, hypoesthesia Psychiatric disorders : nervousness, anxiety, depression, restlessness Respiratory, thoracic and mediastinal disorders : sneezing, cough, rhinorrhea, nasal congestion, dyspnea, sinus congestion Skin and subcutaneous tissue disorders : sweating increased, dermatitis Vascular disorders : hot flushes, vasodilatation Adverse Reactions With Incidence Rates of 0.5% to <1.0% and Serious Adverse Reactions Reported in at Least 2 patients During Clinical Trials Cardiac disorders : palpitations, myocardial infarction Ear and labyrinth disorders : tinnitus, vertigo Gastrointestinal disorders : flatulence, toothache, constipation aggravated, appendicitis, 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 : cellulitis, ear infection, gastroenteritis, pneumonia, viral infection Injury and poisoning : joint sprain, muscle injury Investigations : alanine aminotransferase increased, blood pressure increased, aspartate aminotransferase increased, heart rate increased, blood glucose increased, liver function tests abnormal Musculoskeletal, connective tissue and bone disorders : muscle cramps, muscle spasms, joint stiffness, muscle twitching, myalgia, osteoarthritis aggravated Nervous system disorders : migraine, sedation, syncope, disturbance in attention, dizziness aggravated Psychiatric disorders : euphoric mood, irritability, libido decreased, sleep disorder, agitation, disorientation, abnormal dreams Renal and urinary disorders : difficulty in micturition, urinary frequency, hematuria, dysuria, urinary retention Respiratory, thoracic and mediastinal disorders : yawning Skin and subcutaneous tissue disorders : contusion, piloerection, clamminess, night sweats, urticaria Vascular disorders : hypertension aggravated, hypertension, peripheral ischemia 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of tramadol.
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 extended-release 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 overdose setting.
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 ( 5.20 )].
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 ( 5.21 )].
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 (5.16) ].
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 (5-11 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.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc.
at 1-800-399-2561 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.
Tramadol hydrochloride extended-release tablet was administered to a total of 3108 patients during studies conducted in the U.S.
These included four double-blind studies in patients with osteoarthritis and/or chronic low back pain and one open-label study in patients with chronic non-malignant pain.
A total of 901 patients were 65 years or older.
The frequency of adverse reactions generally increased with doses from 100 mg to 400 mg in the two pooled, twelve-week, randomized, double-blind, placebo-controlled studies in patients with chronic non-malignant pain (see Table 1).
The most common adverse reactions from Table 1 occurring in ≥10% and ≥2 x placebo rate of the patients treated with tramadol hydrochloride extended-release tablets are dizziness (not vertigo), nausea, constipation, headache, somnolence, flushing, pruritus, vomiting, insomnia, and dry mouth.
Table 1: Incidence (%) of patients with adverse reaction rates ≥ 5% from two 12-week placebo-controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1811).
MedDRA Preferred Term Tramadol Hydrochloride Extended-Release Tablets Placebo 100 mg (N=403) n (%) 200 mg (N=400) n (%) 300 mg (N=400) n (%) 400 mg (N=202) n (%) (N=406) n (%) Dizziness (not vertigo) 64 (16) 81 (20) 90 (23) 57 (28) 28 (7) Nausea 61 (15) 90 (23) 102 (26) 53 (26) 32 (8) Constipation 49 (12) 68 (17) 85 (21) 60 (30) 17 (4) Headache 49 (12) 62 (16) 46 (12) 32 (16) 43 (11) Somnolence 33 (8) 45 (11) 29 (7) 41 (20) 7 (2) Flushing 31 (8) 40 (10) 35 (9) 32 (16) 18 (4) Pruritus 25 (6) 34 (9) 30 (8) 24 (12) 4 (1) Vomiting 20 (5) 29 (7) 34 (9) 19 (9) 11 ( 3) Insomnia 26 (7) 32 (8) 36 (9) 22 (11) 13 (3) Dry Mouth 20 (5) 29 (7) 39 (10) 18 (9) 6 (2) Diarrhea 15 (4) 27 (7) 37 (9) 10 (5) 17 (4) Asthenia 14 (4) 24 (6) 26 (7) 13 (6) 7 (2) Postural hypotension 7 (2) 17 (4) 8 (2) 11 (5) 9 (2) Sweating increased 6 (2) 8 (2) 15 (4) 13 (6) 1 (0) Anorexia 3 (1) 7 (2) 21 (5) 12 (6) 1 (0) Adverse reactions With Incidence Rates of 1.0% to <5.0% During Clinical Trials The following adverse reactions were reported from all the chronic pain studies (N=3108).
The lists below include adverse reactions not otherwise noted in Table 1.
Eye disorders : vision blurred Gastrointestinal disorders : abdominal pain upper, dyspepsia, abdominal pain, sore throat General disorders : weakness, pain, feeling hot, influenza like illness, fall, rigors, lethargy, pyrexia, chest pain Infections and infestations : nasopharyngitis, upper respiratory tract infection, sinusitis, influenza, gastroenteritis viral, urinary tract infection, bronchitis Investigations : blood creatine phosphokinase increased, weight decreased Metabolism and nutrition disorders : appetite decreased Musculoskeletal, connective tissue and bone disorders : arthralgia, back pain, pain in limb, neck pain Nervous system disorders : tremor, paresthesia, hypoesthesia Psychiatric disorders : nervousness, anxiety, depression, restlessness Respiratory, thoracic and mediastinal disorders : sneezing, cough, rhinorrhea, nasal congestion, dyspnea, sinus congestion Skin and subcutaneous tissue disorders : sweating increased, dermatitis Vascular disorders : hot flushes, vasodilatation Adverse Reactions With Incidence Rates of 0.5% to <1.0% and Serious Adverse Reactions Reported in at Least 2 patients During Clinical Trials Cardiac disorders : palpitations, myocardial infarction Ear and labyrinth disorders : tinnitus, vertigo Gastrointestinal disorders : flatulence, toothache, constipation aggravated, appendicitis, 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 : cellulitis, ear infection, gastroenteritis, pneumonia, viral infection Injury and poisoning : joint sprain, muscle injury Investigations : alanine aminotransferase increased, blood pressure increased, aspartate aminotransferase increased, heart rate increased, blood glucose increased, liver function tests abnormal Musculoskeletal, connective tissue and bone disorders : muscle cramps, muscle spasms, joint stiffness, muscle twitching, myalgia, osteoarthritis aggravated Nervous system disorders : migraine, sedation, syncope, disturbance in attention, dizziness aggravated Psychiatric disorders : euphoric mood, irritability, libido decreased, sleep disorder, agitation, disorientation, abnormal dreams Renal and urinary disorders : difficulty in micturition, urinary frequency, hematuria, dysuria, urinary retention Respiratory, thoracic and mediastinal disorders : yawning Skin and subcutaneous tissue disorders : contusion, piloerection, clamminess, night sweats, urticaria Vascular disorders : hypertension aggravated, hypertension, peripheral ischemia 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of tramadol.
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 extended-release 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 overdose setting.
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 ( 5.20 )].
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 ( 5.21 )].
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 (5.16) ].
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 (5-11 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.