50mg/ml i.v. Injection
100mg/2ml i.v. Injection
Tramadol is a centrally acting analgesic with binding to specific opioid receptors. It is a nonselective, 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 (t1/2ka) of 0.38 ± 0.18 hours, leading to an analgesic effect lasting for up to 9 hours. The parenteral form of Tramadol has 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 metabolized 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 (t1/2β) is likely to be prolonged in the (t1/2β) values is relatively low if at least one of these organs is functioning normally. In patients with liver cirrhosis, the mean of t1/2β of Tramadol was 13.3 ± 4.9h, t1/2β/m1 18.5 ± 9.4 h; in patients with renal insufficiency (creatinine clearance ≤5ml/min) the values were 11.0 ± 3.2h (Tramadol) and 16.9 ± 3.0h (M1) respectively.
There are six 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 100mg i.v. dose. Following a single oral dose and after adjusting for body weight, females had 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.
Management of moderate to moderately severe pain.
Tramadol is contraindicated 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. Tramadol must not be used for narcotic withdrawal treatment.
Tramadol should not be given to patients with increased intracranial pressure or central nervous system depression due to head injury or cerebral disease.
PRECAUTIONS AND WARNINGS:
Rapid intravenous use:
Rapid intravenous administration may be associated with higher incidence of adverse events and should therefore be avoided.
Liver and kidney impairment:
Tramadol 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.
Seizures have been reported in patients receiving Tramadol at dosages within the recommended dosage range. The risk of seizures is enhanced in patients exceeding the recommended dose, or in patients taking tricyclic antidepressants 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 recognized risk for seizures e.g. drug and alcohol withdrawal and intracranial infections, head trauma, metabolic disorders and naloxone treatment with Tramadol overdose. Patients known to suffer from cerebral convulsions should be carefully monitored during treatment with Tramadol.
Drug abuse and dependence:
Although Tramadol 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 behavior and tolerance development. Cases of abuse and dependence on Tramadol have been reported. Tramadol should not be used in opioid-dependent patients. Tramadol can re-initiate 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 Tramadol is not recommended.
Tramadol should not be given to patients with respiratory depression especially in the presence of cyanosis and excessive bronchial secretions.
Pregnancy and Lactation:
Tramadol is toxic to animal fetuses at doses only 3 to 15 times the maximum adult dose. In people, Tramadol passes into the blood circulation of the developing fetus. Pregnant women should not take this drug unless it is absolutely necessary. This drug should not be taken by nursing mothers.
In people age 75 and older, blood concentrations are somewhat higher than in younger adults. Older adults can also be expected to be more sensitive to the side effects of this drug. Older adults should not take more than 300mg a day.
Effects on ability to drive and operate machinery:
Tramadol 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 ADMINSTRATION:
The dosage should be adjusted to the intensity of pain and the individual's response to the analgesic action of Tramadol. It should not be used to treat minor pain. In general a total daily dose should not exceed 400mg of Tramadol.
For post-operative pain, administer an initial bolus of 100mg. During the 90 minutes following the initial bolus further doses of 50mg may be given every 30 minutes, up to a total dose of 250mg including the initial bolus.
Subsequent doses should be 50mg or 100mg 4 to 6 hourly up to a total daily dose of 600mg. For less severe pain administer 50mg or 100mg 4 to 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 hemodialysis or hemofiltration, postdialysis administration to maintain analgesia is not usually necessary.
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.
Tramadol may be taken without regard to food or meals. If you forget a dose of Tramadol, take it as soon as you remember. If it is almost time for your next dose, skip the one you forgot and continue with your regular schedule. Do not take a double dose.
ADVERSE DRUG REACTIONS:
The following side-effects have reported:
Gastrointestinal system: Nausea, vomiting, dry mouth, heartburn, constipation.
Central nervous system and psychiatric: Fatigue, sedation, drowsiness, dizziness, confusion, hallucinations, seizures.
Others: Sweating (especially when intravenous administration is too rapid), skin rashes, bradycardia, tachycardia, flushing, bronchospasm, angioedema, syncope, anaphylaxis and anaphylactic reactions have been reported.
The reactions may occur after the first dose. Postural hypotension or cardiovascular collapse has been observed, potential for Toxic Epidermal Necrolysis and Stevens-Johnson syndrome. Tramadol should not be use for the treatment of minor pain.
- Tramadol 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 alternation of the Tramadol dosage regimen is recommended for patients receiving chronic Cimetidine therapy.
- Animal studies have shown that the duration of anesthesia is prolonged when Tramadol is combined with barbiturates.
- The analgesic effect and duration of action may be reduced on concomitant or previous use of Carbamazipine. People taking this combination may need twice the usual dose of Tramadol.
- The concomitant administration of Tramadol tablet with centrally acting depressants may produce intensified effects.
- On the other hand combining Tramadol with tranquilizer may produce favorable effects on pain sensation and management.
- Quinidine may slow the breakdown of Tramadol because it affects the liver enzyme that breaks down Tramadol. The full impact of this interaction is not known.
The most serious effects of Tramadol are usually difficulty breathing and seizures. Some people have died from Tramadol overdose; it is estimated that they took between 3000 and 5000 mg (3 to 5 grams)of the drug. The lowest fatal dose was thought to be between 500 and 1000mg in an 40kg (88 pound) woman.
Respiratory depression can be antagonized 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 hemodialysis or hemofiltration. Treatment of acute intoxication with hemodialysis or hemofiltration alone is therefore not suitable for detoxification.
Store in a dry place at temperatures not exceeding 30oC. Protect from light. Keep out of reach of children.