INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo TRAMAL® Drops

SCHEDULING STATUS:
Schedule 5

PROPRIETARY NAME
(and dosage form):

TRAMAL® Drops

COMPOSITION
1,0 mL solution is equivalent to 40 drops and contains
Tramadol hydrochloride 100 mg and Potassium sorbate 0,15% w/v

PHARMACOLOGICAL CLASSIFICATION
A 2.9 Other analgesics

PHARMACOLOGICAL ACTION
Pharmacodynamics
Tramadol hydrochloride 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 mu receptor. Other mechanisms, which may contribute to its analgesic effect, are inhibition of neuronal re-uptake of noradrenaline as well as the enhancement of serotonin release. Tramadol hydrochloride does not promote the release of histamine. Tramadol hydrochloride crosses the blood-brain and placental barrier. Small amounts are excreted in breast milk unchanged or as the metabolite M1. The relationship between serum concentrations and the analgesic effect is dose-dependant, but varies considerably.
Pharmacokinetics
After oral administration of Tramal drops tramadol hydrochloride is absorbed with an absorption half-life (t½ ka) of 0,34 + 0,18 hours. . The absolute bioavailability is approximately 70% independent of food intake. After administration of 100 mg of tramadol hydrochloride, as drops, a peak plasma concentration is achieved after about 1,2 hours.
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range. 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 components is quantitatively insignificant and is therefore subject to hepatic metabolism and renal elimination. The terminal half-life (t½ 
beta) is prolonged in impaired hepatic or renal function. In patients with liver cirrhosis the mean t½beta of tramadol was 13,3 +4,9 h, t½ beta /M1 18,5 +9,4 h, in patients with renal insufficiency (creatinine clearance <5 mL/min) the values were 11.0 +3,2 h (tramadol) and 16,9 +3,0 h (M1) respectively.

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, opioid 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 depression due to head injury or cerebral disease. Tramal drops are not intended for use in children below the age of 12 years.

WARNINGS
Tramal may only be taken with special care in opioid dependence, reduced level of consciousness of uncertain origin, disorders of the respiratory function and increased intracranial pressure. The preparation should be used with care in patients with increased reactivity to opioids.
Seizures:
Seizures have been reported in patients receiving Tramal 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 reuptake 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, intracranial infections, head trauma, metabolic disorders and naloxone administration 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 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 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 sensitivity of the individual patient, in principle, the lowest pain-relieving dose should be selected.
The recommended dosages are guidelines.
Tramal should be taken as follows:
Adults and children over the age of 12 years
The single starting dose is 20 drops (0,5 mL) initially. If, however, the desired analgesia is not achieved within 30 to 60 minutes, a further 20 drops may be taken. In general the total daily dose should not exceed 400 mg of tramadol (equivalent to 160 drops or 4,0 mL).
Elderly
A downward adjustment of the dose and/or prolongation of the interval between doses are recommended in the elderly.
Renal insufficiency/Dialysis/Hepatic insufficiency
In patients with severe renal and/or hepatic insufficiency, Tramal is not recommended. In moderate cases, prolongation of the dosage interval and possibly lower dosage, titrated upwards very carefully, should be carefully considered.
Duration of treatment
Under no circumstances should Tramal drops be given for longer than absolutely necessary. If the nature and severity of the disease require long-term pain treatment with Tramal drops careful checks should be carried out initially at regular intervals to assess efficacy and adverse events, and to what extent further treatment is necessary.

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), headache.
Other
Sweating (especially when intravenous administration is too rapid); skin rashes; blurred vision; micturition disorders (difficulty in passing urine and urinary retention); bradycardia; tachycardia; flushing; bronchospasm; angioedema; syncope, anaphylaxis and anaphylactic reactions have been reported. These reactions may occur after the first dose.
Cases of increased liver enzyme values have been reported with the therapeutic use of tramadol.
Postural hypotension or cardiovascular collapse has been observed and the potential for Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome.
Special Precautions:
The possibility of respiratory depression cannot be excluded if the recommended dosages are exceeded or other centrally depressant drugs are given concomitantly. Tramal should not be used in the treatment of minor pain. 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:
Tramal must not be combined with a MAO-inhibitor, or within 14 days of discontinuation of it, as potentiation of serotonergic and noradrenergic 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, including alcohol may produce intensified Central Nervous System (CNS) effects. On the other hand, combining Tramal with a tranquilliser may produce favourable effects on pain sensation and management.
Other drugs 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.

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
Clear, colourless to weakly yellow, slightly viscous liquid free from visible particles with a mint and weak anise odour.

PRESENTATION
10 mL brown glass bottle with dropper and child resistant screw-on cap.

STORAGE INSTRUCTIONS
Store in a cool, dry place, below 25°C.
Keep out of reach of children

REGISTRATION NUMBER
29/2.9/0145

NAME AND ADDRESS OF APPLICANT
JANSSEN - CILAG
JANSSEN PHARMACEUTICA (PTY) LTD
(Reg No.1980/011122/07)
15th Road
Halfway House
1685
Website: www.janssencilag.co.za

DATE OF PUBLICATION
23 July 2002

024304
2002J
Britepak

Updated on this site: April 2004
Source: Pharmaceutical Industry

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