Tramadol Hydrochloride and Acetaminophen (Page 5 of 12)

5.14 Severe Hypotension

Tramadol hydrochloride and acetaminophen may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of tramadol hydrochloride and acetaminophen. In patients with circulatory shock, tramadol hydrochloride and acetaminophen may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of tramadol hydrochloride and acetaminophen in patients with circulatory shock.

5.15 Risk of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), tramadol hydrochloride and acetaminophen may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with tramadol hydrochloride and acetaminophen.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of tramadol hydrochloride and acetaminophen in patients with impaired consciousness or coma.

5.16 Serious Skin Reactions

Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

5.17 Risk of Use in Patients with Gastrointestinal Conditions

Tramadol hydrochloride and acetaminophen is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications (4)].

The tramadol in tramadol hydrochloride and acetaminophen may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.18 Anaphylaxis and Other Hypersensitivity Reactions

Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to tramadol and other opioids may be at increased risk and therefore should not receive tramadol hydrochloride and acetaminophen. If anaphylaxis or other hypersensitivity occurs, stop administration of tramadol hydrochloride and acetaminophen immediately, discontinue tramadol hydrochloride and acetaminophen permanently, and do not rechallenge with any formulation of tramadol. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction [see Contraindications (4), Information for Patients (17)].

There have been postmarketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue tramadol hydrochloride and acetaminophen immediately and seek medical care if they experience these symptoms. Do not prescribe tramadol hydrochloride and acetaminophen for patients with acetaminophen allergy.

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 (2.4), 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:

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

Diarrhea

Nausea

Dry Mouth

6

3

3

2

Psychiatric Disorders

Somnolence

Anorexia

Insomnia

6

3

2

Central & Peripheral Nervous System

Dizziness

3

Skin and Appendages

Sweating Increased

Pruritus

4

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

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