COMPOSITION: Each ampoule contains tramadol hydrochloride 100 mg.
PHARMACOLOGICAL CLASSIFICATION: A.2.9. Other analgesics
PHARMACOLOGICAL ACTION: Tramadol is a centrally acting analgesic with binding to specific opioid receptors. It is a non-selective, pure agonist at mu (µ), delta (d) and kappa (k) opioid receptors with a higher affinity for the µ receptor. Other mechanisms, which may contribute to its analgesic effect, are inhibition of neuronal re-uptake of noradrenaline and serotonin. Tramadol does not promote the release of histamine. Tramadol is well absorbed after oral or rectal administration, with an absorption half-life (t½ka)of 0,38 ±0,18 hours, leading to a analgesic effect lasting for up to 9 hours. The parenteral form of Tramadol has a more rapid onset of action. The mean systemic bioavailability is 68%.
Tramadol hydrochloride crosses the blood-brain and placental barrier. Only very small amounts are excreted in breast milk unchanged or as the metabolite M1 (tramadol hydrochloride approximately 0,1%, M1 approximately 0,02% of the i.v. dose. The elimination half-life is 5 to 7 hours. Tramadol is mainly metabolised in the liver (90%).
Tramadol hydrochloride and its metabolites are almost completely excreted by the renal route (95%). Biliary excretion of these component is quantitatively insignificant and is therefore subject to hepatic metabolism and renal elimination. The terminal half-life (t½ß) is likely to be prolonged in impaired hepatic or renal function. The increase in the (t½ß) values is relatively low if at least one of these organs is functioning normally. In patients with liver cirrhosis, the mean t½ßof tramadol was 13,3 ±4,9h, t½ß/M1 18,5 ±9,4h; in patients with renal insufficiency (creatinine clearance < 5 mL/min) the values were 11,0 ±3,2h (tramadol) and 16,9 ±3,0h (M1) respectively.
There are sex differences in the pharmacokinetic parameters of tramadol. The absolute bioavailability was 73% in males and 79% in females. Plasma clearance was 6,4 mL/min/kg in males and 5,73 mL/min/kg in females following a 100 mg i.v. dose. Following a single oral dose and after adjusting for bodyweight, females had a 12% higher peak concentration and a 35% higher area under the concentration time curve compared to males. The clinical significance of these differences is unknown.
INDICATIONS: Management of moderate to moderately severe pain.
CONTRA-INDICATIONS Tramal is contra-indicated in known hypersensitivity to tramadol hydrochloride, or opioids, in acute intoxication with alcohol, hypnotics, analgesics or psychotropic medicines. It should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal.
Tramal must not be used for narcotic withdrawal treatment. Safety during pregnancy and lactation has not been established.
Tramal should not be given to patients with respiratory depression especially in the presence of cyanosis and excessive bronchial secretions.
Tramal should not be given to patients with increased intracranial pressure or central nervous system depression due to head injury or cerebral disease.
WARNINGS: The administration of Tramal concurrently with CNS-depressant medicines is likely to intensify and prolong the CNS effects. Patients should be warned not to operate machinery or drive a car while using Tramal. Seizures: Seizures have been reported in patients receiving Tramal at dosages within the recommended dosage range. The risk of seizures is 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. The risk of seizures may also be increased in patients with epilepsy, with a history of seizures or in patients with a recognised risk for seizures e.g. drug and alcohol withdrawal and intracranial infections, head trauma, metabolic disorders and naloxone treatment with Tramal overdose. Patients known to suffer from cerebral convulsions should be carefully monitored during treatment with Tramal. Drug Abuse and Dependence: Although Tramal has a low dependence potential, tolerance, psychic and physical dependence of the morphine-type (µ opioid) may develop with long-term use. The drug has been associated with craving, drug-seeking behaviour and tolerance development. Cases of abuse and dependence on Tramal have been reported. Tramal should not be used in opioid-dependent patients. Tramal can reinitiate physical dependence in patients who have been previously dependent on 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 is not recommended. Effects on ability to drive or operate machinery: Tramal 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.
DOSAGE AND DIRECTIONS FOR USE: The dosage should be adjusted to the intensity of pain and the individuals response to the analgesic action of Tramal.
Tramal should not be used to treat minor pain.
Unless otherwise prescribed, Tramal 100 ampoules should be administered as follows:
Single dose for adults and children over 14 years of age:
1 ampoule (100 mg injected slowly or diluted in solution for infusion and infused)
1 ampoule (100 mg)
1 ampoule (100 mg)
In general a total daily dose should not exceed 400 mg of tramadol (equivalent to 4 ampoules).
Intravenous injection must be given slowly over 2 3 minutes.
For post-operative pain, administer an initial bolus of 100 mg. During the 90 minutes following the initial bolus further doses of 50 mg may be given every 30 minutes, up to a total dose of 250 mg including the initial bolus.
Subsequent doses should be 50 mg or 100 mg 4 6 hourly up to a total daily dose of 600 mg.
For less severe pain administer 50 mg or 100 mg 4 6 hourly. Elderly: The usual dosages may be used except in patients 75 years of age and over where a downward adjustment of the dose and/or prolongation of the interval between doses are recommended. Renal impairment/renal dialysis: The elimination of tramadol may be prolonged. It is recommended that the usual initial dosage be used. For patients with a creatinine clearance <30 mL/min, the dosage interval should be increased to 12 hours. As tramadol is removed very slowly by haemodialysis or haemofiltration, postdialysis administration to maintain analgesia is not usually necessary. Hepatic impairment: The elimination of tramadol may be prolonged. The usual initial dosage should be used but in severe hepatic impairment, the dosage interval should be increased to 12 hours.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS: The following side-effects have been reported: Gastrointestinal system: Nausea; vomiting; dry mouth; heartburn; constipation Central Nervous System and Psychiatric: Fatigue; sedation; drowsiness; dizziness; confusion; hallucinations; seizures (See Warnings) Other: Sweating (especially when intravenous administration is too rapid); skin rashes; bradycardia; tachycardia; flushing; bronchospasm; angioedema; syncope, anaphylaxis and anaphylactic reactions have been reported.
These reactions may occur after the first dose. Postural hypotension or cardiovascular collapse has been observed, potential for Toxic Epidermal Necrolysis and Stevens-Johnson syndrome. Tramal should not be used for the treatment of minor pain. Special Precautions: Rapid intravenous administration may be associated with higher incidence of adverse events and should therefore be avoided. Tramal should be used with caution in patients with severe impairment of hepatic and renal function and in patients prone to convulsive disorders or in shock. Interactions With Other Medicines: Tramal must not be combined with an MAO-inhibitor, or within 14 days of discontinuation of it, as potentiation of serotonergic and noradrenrgic effects may result.
Simultaneous administration with cimetidine is associated with clinically insignificant changes in serum concentrations of tramadol. Therefore, no alteration of the Tramal dosage regimen is recommended for patients receiving chronic cimetidine therapy.
Animal studies have shown that the duration of anaesthesia is prolonged when tramadol is combined with barbiturates. The analgesic effect and duration of action may be reduced on concomitant or previous use of carbamazepine.
The concomitant administration of Tramal with centrally acting depressants may produce intensified effects. On the other hand combining Tramal with a tranquilliser may produce favourable effects on pain sensation and management.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: Respiratory depression can be antagonised with a pure opiate antagonist (naloxone). If naloxone is to be administered, use cautiously because it may precipitate seizures. Treatment of restlessness and/or convulsions is symptomatic and supportive (benzodiazepines/barbiturates).
Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Treatment of acute intoxication with Tramal with haemodialysis or haemofiltration alone is therefore not suitable for detoxification.
IDENTIFICATION: Ampoules: Clear, colourless solution in clear, type 1 glass ampoules.
PRESENTATION: Packs of 5 ampoules, each containing 2 mL
STORAGE INSTRUCTIONS: Store in a cool (below 25°C), dry place. Keep out of reach of children.
REGISTRATION NUMBER: S/2.9/290
NAME AND BUSINESS ADDRESS OF APPLICANT:
JANSSEN-CILAG JANSSEN PHARMACEUTICA (PTY) LTD
(Reg. No. 80/11122/07)
DATE OF PUBLICATION OF THIS PACKAGE INSERT: January 1998