Tramadol Hydrochloride and Acetaminophen (Page 6 of 13)
5.19 Increased Risk of Hepatotoxicity with Concomitant Use of Other Acetaminophen-containing Products
Due to the potential for acetaminophen hepatotoxicity at doses higher than the recommended dose, tramadol hydrochloride and acetaminophen should not be used concomitantly with other acetaminophen containing products.
5.20 Withdrawal
Do not abruptly discontinue tramadol hydrochloride and acetaminophen in a patient physically dependent on opioids. When discontinuing tramadol hydrochloride and acetaminophen in a physically dependent patient, gradually taper the dosage. Rapid tapering of tramadol and acetaminophen in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain
[see
Dosage and Administration (2.5),
Drug Abuse and Dependence (9.3)]
.
Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including tramadol hydrochloride and acetaminophen. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms
[see
Drug Interactions (7)]
.
5.21 Driving and Operating Machinery
Tramadol hydrochloride and acetaminophen may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of tramadol hydrochloride and acetaminophen and know how they will react to the medication [see Patient Counseling Information (17)] .
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 (5.3)]
- Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children [see Warnings and Precautions (5.4)]
- Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5)]
- Hepatotoxicity [see Warnings and Precautions (5.7)]
- Interactions with Benzodiazepines or Other CNS Depressants [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 (5.12)]
- Severe Hypotension [see Warnings and Precautions (5.14)]
- Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.17)]
- Hypersensitivity Reactions [see Warnings and Precautions (5.18)]
- Withdrawal [see Warnings and Precautions (5.20)]
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 (≥3.0%) 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 ≥2.0% 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 (≥2.0%)
Body System Preferred Term | Tramadol Hydrochloride and Acetaminophen (N=142) (%) |
Gastrointestinal System Disorders Constipation Diarrhea Nausea Dry Mouth Psychiatric Disorders Somnolence Anorexia Insomnia Central & Peripheral Nervous System Dizziness Skin and Appendages Sweating Increased Pruritus Reproductive Disorders, Male* Prostatic Disorder | 6 3 3 2 6 3 2 3 4 2 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 Experience
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 chronic use of opioids
[see
Clinical Pharmacology (12.2)]
.
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 – Cases of hypoglycemia have been reported very rarely in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients.
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.
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