TRAMADOL HYDROCHLORIDE (Page 6 of 13)
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)] .
5.19 Hyponatremia
Hyponatremia (serum sodium < 135 mmol/L) has been reported with the use of tramadol, and many cases are severe (sodium level < 120 mmol/L). Most cases of hyponatremia occurred in females over the age of 65 and within the first week of therapy. In some reports, hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Monitor for signs and symptoms of hyponatremia (e.g., confusion, disorientation), during treatment with tramadol hydrochloride extended-release tablets, especially during initiation of therapy. If signs and symptoms of hyponatremia are present, initiate appropriate treatment (e.g., fluid restriction) and discontinue tramadol hydrochloride extended-release tablets [ see Dosage and Administration: Safe Reduction or Discontinuation of tramadol hydrochloride extended-release tablets ( 2.5)].
5.20 Hypoglycemia
Cases of tramadol- associated hypoglycemia have been reported, some resulting in hospitalization. In most cases, patients had predisposing risk factors (e.g. diabetes). If hypoglycemia is suspected, monitor blood glucose levels and consider drug discontinuation as appropriate [ see Dosage and Administration: Safe Reduction or Discontinuation of tramadol hydrochloride extended-release tablets ( 2.5)].
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.
| 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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