TRAMADOL HYDROCHLORIDE: Package Insert and Label Information (Page 4 of 8)

5.16 Anaphylaxis and Other Hypersensitivity Reactions

Serious and rarely fatal hypersensitive reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported hypersensitivity reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of hypersensitivity reactions to tramadol and other opioids may be at increased risk and therefore should not receive tramadol hydrochloride extended-release tablets. If anaphylaxis or other hypersensitivity occurs, stop administration of tramadol hydrochloride extended-release tablets immediately, discontinue tramadol hydrochloride extended-release tablets 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 Patient Counseling Information ( 17)] .

5.17 Withdrawal

Do not abruptly discontinue tramadol hydrochloride extended-release tablets in a patient physically dependent on opioids. When discontinuing tramadol hydrochloride extended-release tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of tramadol hydrochloride extended-release tablets 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) ].

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 extended-release tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [ see Drug Interactions ( 7)].

5.18 Risks of Driving and Operating Machinery

Tramadol hydrochloride extended-release tablets 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 extended-release tablets and know how they will react to the medication [see Patient Counseling Information ( 17)] .

6 ADVERSE REACTIONS

The following serious 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 ( 5.3)]
  • 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)]
  • Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.7)]
  • Serotonin Syndrome [see Warnings and Precautions ( 5.8)]
  • Seizures [see Warnings and Precautions ( 5.9)]
  • Suicide [see Warnings and Precautions ( 5.10)]
  • Adrenal Insufficiency [see Warnings and Precautions ( 5.11)]
  • Severe Hypotension [see Warnings and Precautions ( 5.13)]
  • Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.15)]
  • Hypersensitivity Reactions [see Warnings and Precautions( 5.16)]
  • Withdrawal [see Warnings and Precautions ( 5.17)]

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

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