Tramal 50mg Capsules

Management of moderate to moderately severe pain.

• Known hypersensitivity to tramadol hydrochloride or opioids or any of the ingredients of TRAMAL.
• in acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic medicines.
• It should not be administered to patients who are receiving monoamine oxidase (MAO) inhibitors or within two weeks of their withdrawal.
• TRAMAL capsules should not be given to patients with epilepsy.
• TRAMAL capsules must not be used for narcotic withdrawal treatment.
• TRAMAL capsules should not be given to patients with respiratory depression, or in the presence of cyanosis and excessive bronchial secretions.
• TRAMAL capsules should not be given to patients with increased intracranial pressure or central nervous depression due to head injury or cerebral disease.
• TRAMAL capsules should not be used in pregnant and breastfeeding women (see PREGNANCY AND LACTATION).

TRAMAL capsules may only be taken with special care in opioid dependence. TRAMAL capsules are not suitable for children under the age of 12 years. TRAMAL capsules should be used with care in patients with increased reactivity to opioids.

Respiratory depression may develop if the recommended dosages are exceeded or other centrally depressant medicines are given concomitantly.

TRAMAL capsules should not be used in the treatment of minor pain.

TRAMAL capsules should be used with caution in patients with impairment of hepatic and renal function and in patients prone to convulsive disorders or in shock. (See DOSAGE AND DIRECTIONS FOR USE).

Seizures have been reported in patients receiving TRAMAL capsules at dosages within the recommended dosage range. The risk of seizures may be enhanced in patients exceeding the recommended dose, or in patients taking tricyclic anti-depressants or other tricyclic compounds e.g. promethazine, selective serotonin re-uptake inhibitors, MAO-inhibitors and neuroleptics.

Drug Abuse and Dependence: Tolerance, psychic and physical dependence of the morphine-type (u03bc opioid) may develop. TRAMAL capsules have been associated with craving drug-seeking behaviour and tolerance development. Symptoms of drug withdrawal syndrome, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastro-intestinal symptoms. Other symptoms that have been seen with TRAMAL capsules discontinuation include: panic attacks; severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, depersonalisation, derealisation and paranoia).

TRAMAL capsules should not be used in opioid-dependent patients. TRAMAL capsules can reinstate physical dependence in patients that have been previously dependent or chronically using other opioids. In patients with a tendency to drug abuse, a history of drug dependence or who are chronically using opioids, treatment with TRAMAL capsules are not recommended.

CYP2D6 Ultra-rapid metabolism of tramadol: Patients who are CYP2D6 ultra-rapid metabolisers may convert tramadol to its active metabolite (M1) more rapidly and completely than other patients. This rapid conversion may lead to higher than expected serum M1 levels which could lead to an increased risk of respiratory depression. Alternative medication, dose reduction and/or increased monitoring for signs of tramadol overdose, such as respiratory depression is recommended in patients known to be CYP2D6 ultra-rapid metabolisers.

Hyponatraemia: Hyponatraemia has been reported with the use of TRAMAL, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatraemia. This hyponatraemia appeared to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resolved with discontinuation of TRAMAL and appropriate treatment (e.g. fluid restriction). During TRAMAL treatment, monitoring for signs and symptoms of hyponatraemia is recommended for patients with predisposing risk factors.

Effects on ability to drive or operate machinery: TRAMAL capsules may affect reactions to the extent that driving ability and the ability to operate machinery may be impaired. This applies particularly in conjunction with other psychotropic medicines including alcohol.

TRAMAL capsules should not be combined with MAO inhibitors within 14 days of withdrawal of MAO inhibitors (see CONTRAINDICATIONS). In patients treated with MAO inhibitors in the 14 days prior to the use of the opioid pethidine, life-threatening interactions of the central nervous system, respiratory and cardiovascular function have been observed. The same interactions with MAO inhibitors cannot be ruled out during treatment with TRAMAL capsules.

Concomitant administration of TRAMAL capsules with other centrally depressant medicines including alcohol may potentiate the CNS effects (see CONTRAINDICATIONS).

Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action. TRAMAL capsules can induce convulsions and increase the potential for selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, anti-psychotics and other seizure threshold-lowering medicinal products (such as bupropion, mirtazapine, tetra-hydrocannabinol) to cause convulsions.

Concomitant therapeutic use of TRAMAL capsules and serotonergic medicines such as selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see CONTRAINDICATIONS), tricyclic antidepressants and mirtazapine may cause serotonin toxicity. The Serotonin syndrome is likely when one of the following is observed:

• Spontaneous clonus;
• Inducible or ocular clonus with agitation or diaphoresis;
• Tremor and hyperreflexia;
• Hypertonia and body temperature > 38 oC and inducible or ocular clonus.

Withdrawal of the serotonergic medicines usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.

Caution should be exercised during concomitant treatment with TRAMAL capsules and warfarin u2013 like medicines due to reports of increased International Normalised Ratio (INR) with major bleeding and ecchymoses in some patients. The inhibition of one or both types of isoenzymes CYP3A4 and CYP2D6 involved in the biotransformation of tramadol may affect the plasma concentration of tramadol or its active metabolite. Other active substances known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied (see Pharmacokinetic properties).

The antiemetic 5-HT3 antagonist ondansetron increases the requirement of TRAMAL capsules in patients with postoperative pain. TRAMAL capsules may decrease the antiemetic efficacy of ondansetron.

Pregnancy: Safety during pregnancy and lactation has not been established. Therefore, TRAMAL capsules should not be used in pregnant women. TRAMAL crosses the placenta.

Animal studies with TRAMAL revealed effects on organ development, ossification and neonatal mortality. The administration of TRAMAL capsules during pregnancy may lead to habituation in the unborn child. The child may experience withdrawal symptoms after birth (see CONTRAINDICATIONS).

Breastfeeding: TRAMAL passes into breastmilk. Mothers on TRAMAL capsules should not breastfeed their infants.

TRAMAL capsules have side effects. These are classified as follows:

• very common (u2265 1/10)
• common (u2265 1/100, <1/10)
• uncommon (u2265 1/1000, <1/100)
• rare (u2265 1/10 000, <1/1000)
• very rare (<1/10 000, including isolated reports)

The most common side effects during treatment with TRAMAL capsules are nausea and dizziness, which occur more frequently than 1 in 10 patients.

Immune system disorders: Rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioedema) and anaphylaxis.

Metabolism and nutrition disorders: Rare: changes in appetite.

Psychiatric disorders: Rare: Hallucinations, confusional states, sleep disturbances, delirium, anxiety and nightmares. Changes in mood (euphoria, dysphoria), decreased activity, restlessness and changes in cognitive and sensorial capacity (such as decision behaviour, perception disorders).

Nervous system disorders: Very common: dizziness. Common: headaches, somnolence. Rare: speech disorders, paraesthesia, tremor, convulsions, involuntary muscle contractions, abnormal coordination, syncope.

Eye disorders: Rare: miosis, mydriasis, blurred vision.

Cardiac disorders: Uncommon: dysrhythmias, palpitation, tachycardia. Rare: bradycardia.

Vascular disorders: Uncommon: postural hypotension, cardiovascular collapse. Rare: increase in blood pressure.

Respiratory, thoracic and mediastinal disorders: Rare: respiratory depression, dyspnoea, bronchospasm.

Gastrointestinal disorders: Very common: nausea. Common: vomiting, constipation, dry mouth. Uncommon: retching, gastrointestinal discomfort.

Hepatobiliary disorders: Very rare: increase in transaminases (ALT and AST) is expected.

Skin and subcutaneous tissue disorders: Common: hyperhidrosis. Uncommon: dermal reactions (e.g. pruritus, rash, urticaria).

Musculoskeletal, connective tissue and bone disorders: Rare: muscular weakness.

Renal and urinary disorders: Rare: micturition disorders (dysuria and urinary retention).

General disorders and administration site conditions: Common: fatigue.

Post-marketing experience: The following post-marketing experiences have been reported: Nervous system complaints, Speech disorders, Eye disorders, Mydriasis, Skin and subcutaneous tissue disorders, Stevens Johnson Syndrome, Toxic Epidermal Necrolysis. Cases of hyponatraemia and/or SIADH have been reported in patients taking tramadol, usually in patients with predisposing risk factors, such as the elderly or those using concomitant medications that may cause hyponatraemia.

Symptoms: Following an overdose with TRAMAL capsules, symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These include in particular constriction of the pupil of the eye, vomiting, cardiovascular collapse, consciousness disorders, coma, convulsions, respiratory depression and respiratory arrest.

Treatment: The general emergency measures apply. Keep open the respiratory tract, maintain respiration and circulation depending on the symptoms. Suitable measures should be taken to avoid aspiration dangers. Respiratory depression can be antagonised with a pure opiate antagonist (naloxone). Convulsions should be treated with intravenous diazepam. In cases of intoxication with oral formulations, gastrointestinal decontamination with activated charcoal is only recommended within 2 hours after TRAMAL capsules intake. Gastrointestinal decontamination at a later time point may be useful in case of intoxication with exceptionally large quantities. Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Treatment of acute intoxication with TRAMAL capsules with haemodialysis or haemofiltration alone is therefore not suitable for detoxification.