Tramal

Tramal

tramadol

Manufacturer:

Mundipharma

Distributor:

Zuellig
Full Prescribing Info
Contents
Tramadol hydrochloride.
Description
Capsule: Each capsule contains: Tramadol HCl 50 mg.
Retard tablet: Each prolonged-release tablet contains 100 mg tramadol HCl.
Excipient with known effect: each prolonged-release tablet contains 2.5 mg lactose monohydrate (refer to Precautions).
Dispersible tablet: Each dispersible tablet contains 50 mg tramadol HCl.
Injection: Each ampoule with 1mL or 2mL of solutions for injection contains 50 mg or 100 mg tramadol HCl.
Excipient with known effect: 1mL of solution for injection contains 0.7 mg sodium.
Excipients/Inactive Ingredients: Caspule: Capsule powder: Microcrystalline Cellulose, Sodium Starch Glycolate, Magnesium Stearate, Colloidal Anhydrous Silica. Capsule Shell: Gelatin, Yellow iron oxide (E172), Titanium Dioxide (E171), Sodium Lauryl Sulfate.
Retard tablet: Tablet core: microcrystalline cellulose, hypromellose 100,000 mPa's, magnesium stearate, colloidal anhydrous silica. Film coating: hypromellose 6 mPa's, lactose monohydrate 2.5 mg, macrogol 6000, propylene glycol, talc, titanium dioxide (E171).
Dispersible tablet: Microcrystalline cellulose, Maize starch, Saccharin sodium, Anise flavor, Peppermint flavor, Colloidal anhydrous silica, Magnesium stearate.
Injection: Sodium acetate, water for injection.
Action
Pharmacotherapeutic group: Other opioids. ATC code: N02 AX02.
Pharmacology: Pharmacodynamics: Tramadol is a centrally-acting opioid analgesic. It is a non-selective pure agonist at μ, δ and κ opioid receptors with a higher affinity for the μ receptor. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal re-uptake of noradrenaline and enhancement of serotonin release.
Tramadol has an antitussive effect. In contrast to morphine, analgesic dose of tramadol over a wide range have no respiration-depressant effect. Also gastrointestinal motility is less affected. Effects on the cardiovascular system tend to be slight. The potency of tramadol is reported to be 1/10 (one tenth) to 1/6 (one sixth) that of morphine.
Pharmacokinetics: After intramuscular administration in humans, tramadol absorbed rapidly and completely; the mean peak serum concentration (Cmax) is reached after 45 min, and bioavailability is almost 100%. In humans about 90% of tramadol is absorbed after oral administration of Tramal capsules. The absorption half-life is 0.38±0.18 h.
A comparison of the areas under the serum tramadol concentration curves (AUC) after oral and I.V. administration shows a bioavailability of 68 ± 13% for Tramal capsules. Compared with other opioids analgesics the absolute bioavailability of tramadol HCl capsules is extremely high.
Peak serum concentrations are achieved about 2 h after administration of Tramal capsules. After administration of Tramal prolonged-release tablets 100 mg Cmax=141 ± 40 ng/mL is reached after 4.9 h; after administration of Tramal prolonged-release tablets 200 mg, Cmax 260 ± 62 ng/mL is reached after 4.8 hours.
The pharmacokinetics of Tramal tablets and oral drops, solution are not significantly different from that of tramadol HCl capsules with respect to the extent of bioavailability as measured by AUC. There was a 10% difference in Cmax between oral tramadol HCl capsules and Tramal tablets. The time to reach Cmax was 1 hour for tramadol oral drops, solution, 1.5 hrs for Tramal tablets and 2.2 hours for Tramal capsules reflecting the fast absorption of the oral liquid forms.
Absolute bioavailability of tramadol suppositories is 78 ± 10%.
Tramadol has a high tissue affinity (Vd,β=203 ± 40 L). It has a plasma protein-binding ratio of about 20%.
Tramadol passes the blood-brain and placental barriers. Very small amounts of the substance and its O-desmethyl derivative are found in the breast-milk (0.1% and 0.02% respectively of the applied dose).
The inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6 involved in the biotransformation of tramadol may affect the plasma concentration of tramadol or its active metabolite. Up to now, clinically relevant interactions have not been reported.
Tramadol and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose. Elimination half-life t½,β is approximately 6 h, irrespective of the mode of administration. In patients above 75 years of age, it may be prolonged by a factor of approximately 1.4. In patients with cirrhosis of the liver, elimination half-lives of 13.3 ± 4.9 h (tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol), in an extreme case 22.3 h and 36 h, respectively, have been determined. In patients with renal insufficiency (creatinine clearance <5 mL/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in extreme case 19.5 h and 43.2 h, respectively.
In humans tramadol is mainly metabolized by means of N- and O-desmethylation and conjunction of the O-demethylation products with glucuronic acid. Only O-desmethyltramadol is pharmacologically active. There are considerable interindividual quantitative differences between the other metabolites. So far, eleven metabolites have been found in the urine. Animal experiments have shown that O-desmethyltramadol is more potent than the parent substance by a factor of 2-4. Its half-life t½,β (6 healthy volunteers) is 7.9 h (ranges 5.4-9.6 h) i.e., essentially similar to that of tramadol.
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.
The relationship between serum concentrations and the analgesic effect is dose-dependent, but varies considerably in isolated cases. A serum concentration of 100-300 ng/mL is usually effective.
Toxicology: Preclinical safety data: On repeated oral and parenteral administration of tramadol for 6-26 weeks in rats and dogs and oral administration for 12 months in dogs, hematological, clinico-chemical and histological investigations showed no evidence of any substance-related changes. Central nervous manifestations only occurred after high doses considerably above the therapeutic range: restlessness, salivation, convulsions and reduced weight gain. Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight, respectively, and dogs rectal doses of 20 mg/kg body weight without any reactions.
In rats tramadol dosages from 50 mg/kg/day upwards caused toxic effects in dams and raised neonate mortality. In the offspring retardation occurred in the form of ossification disorders and delayed vaginal and eye opening. Male and female fertility was not affected. In rabbits there were toxic effects in dams in doses from 125 mg/kg upwards and skeletal anomalies in offspring.
In some in-vitro test systems, there was evidence of mutagenic effects. In vivo studies showed no such effects. According to knowledge gained so far, tramadol can be classified as non-mutagenic.
Studies on the tumorigenic potential of tramadol HCl have been carried out in rats and mice. The study in rats showed no evidence of any substance-related increase in the incidence of tumors. In the study in mice, there was an increased incidence of liver cell adenomas in male animals (a dose-dependent, non-significant increase of 50 mg/kg upwards) and an increase in pulmonary tumors in females of all dosage groups (significant, but not dose-dependent).
Indications/Uses
Treatment of moderate to severe pain.
Dosage/Direction for Use
The dose should be adjusted to the intensity of the pain and the sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected. The total daily dose of 400 mg tramadol HCl should not be exceeded, except in special clinical circumstances.
Unless otherwise prescribed, Tramadol HCl (Tramal) should be administered as follows: Adults and adolescents above the age of 12 years: 50-100 mg tramadol HCl 4-6 hourly.
Retard tablet: The usual initial dose is 50-100 mg Tramadol HCl (Tramal) retard twice daily, morning and evening. If pain relief is insufficient, the dose may be titrated upwards to 150-200 mg Tramadol HCl (Tramal) retard twice daily.
Pediatric population: On account of their high dosage strengths, capsules are not intended for children below the age of 12 years.
Injection: Pediatric population above the age of 1 year: Single dose: 1-2 mg/kg body weight.
The total daily dose of 8 mg tramadol HCl per kg body weight or 400 mg tramadol HCl, whichever is lower, should not be exceeded.
Elderly patients: A dose adjustment is not usually necessary in patients up to 75 years without clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years, elimination may be prolonged. Therefore, if necessary the dosage interval is to be extended according to the patient's requirements.
Patients with renal insufficiency/dialysis and hepatic impairment: In patients with renal and/or hepatic insufficiency, the elimination of tramadol is delayed. In these patients, prolongation of the dosage interval should be carefully considered according to the patient's requirements.
Retard tablet: In cases of severe renal and/or hepatic insufficiency Tramadol HCl (Tramal) prolonged-release tablets are not recommended.
Method of administration: The capsules are to be taken whole, not divided or chewed, with sufficient liquid, with or without food.
Dispersible tablet: The tablets are to be dispersed in about 50 mL of water (about half a cupful). They can be taken with or without food.
Injection: The solution for injection is to be injected slowly or diluted in infusion solution and infused.
For instructions on dilution of the medicinal product before administration (refer to Special Precautions for Disposal and Other Handling under Cautions for Usage).
Duration of administration: Tramadol should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with tramadol is necessary in view of the nature and severity of the illness, then careful and regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.
Overdosage
Symptoms: In principle, on intoxication with tramadol symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These include in particular miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.
Treatment: The general emergency measures apply. Keeping open the respiratory tract, maintaining respiration and circulation depending on the symptoms. The antidote for respiratory depression is naloxone. In animal experiments, naloxone had no effect on convulsions. In such cases diazepam should be given intravenously.
In case of intoxication with oral formulations, gastrointestinal decontamination with activated charcoal or by gastric lavage is only recommended within 2 hours after tramadol intake. Gastrointestinal decontamination at a later time may be useful in case of intoxication with exceptionally large quantities or prolonged-release formulations.
Tramadol is minimally eliminated from the serum by hemodialysis or hemofiltration. Therefore treatment of acute Tramal with hemodialysis or hemofiltration alone is not suitable for detoxification.
Contraindications
Tramadol HCl (Tramal) is contraindicated: in patients with hypersensitivity to the active substance or any of the excipients (refer to Description); in patients with acute intoxication with alcohol, hypnotics, analgesics, opioids or other psychotropic medicinal products; in patients who are receiving MAO inhibitors or who have taken them within the last 14 days (refer to Interactions); in patients with epilepsy not adequately controlled by treatment; for use in narcotic withdrawal treatment.
Special Precautions
Tramal may only be used with particular caution in opioid-dependent patients, patients with head injury, shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory center or function, increased intracranial pressure.
In patients sensitive to opiates, Tramal should only be used with caution.
Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper daily dose limit (400 mg). In addition, tramadol may increase the seizure risk in patients taking other medication that lowers the seizure threshold (see Interactions). Patients with epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling circumstances.
Tramadol has a low-dependence potential. On long-term use tolerance, psychic and physical dependence may develop. In patients with a tendency to drug abuse or dependence, treatment with tramadol should only be carried out for short periods under strict medical supervision.
Tramadol is not suitable as a substitute in opioid-dependent patients. Although tramadol is an opiate agonist, it cannot suppress morphine withdrawal symptoms.
Retard tablet: Tramal retard contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take Tramal retard.
Effects on the Ability to Drive or Operate Machinery: Even when taken according to instructions, tramadol may cause effects such as somnolence and dizziness and therefore may impair the reactions of drivers and machine operators. This applies particularly in conjunction with other psychotropic substances, particularly alcohol.
Use In Pregnancy & Lactation
Use in Pregnancy: Animal studies revealed that tramadol used at very high doses has effects on organ development, ossification and neonatal mortality. Tramadol crosses the placenta. There is inadequate evidence available on the safety of tramadol in human pregnancy. Therefore, tramadol should not be used in pregnant women.
Tramadol administered before or during birth does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant. Chronic use during pregnancy may lead to neonatal withdrawal symptoms.
Use in Lactation: During lactation about 0.1% of the maternal dose is secreted into the milk. Tramadol is not recommended during breast-feeding. After a single administration of tramadol, it is not usually necessary to interrupt breast-feeding.
Fertility: Post marketing surveillance did not suggest an effect of tramadol on fertility. Animal Studies did not show an effect of tramadol on fertility.
Adverse Reactions
The most commonly reported adverse reactions are nausea and dizziness, both occurring in >10% of patients.
The frequencies are defined as follows: Very common ≥1/10; Common ≥1/100, <1/10; Uncommon ≥1/1000, <1/100; Rare ≥1/10,000, <1/1000; Very rare <1/10,000. Not Known: Cannot be estimated from the available data.
Cardiac disorders: Uncommon: cardiovascular regulation (palpitation, tachycardia). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed. Rare: bradycardia, increased in blood pressure.
Investigations: Rare: increase in blood pressure.
Vascular disorders: Uncommon: cardiovascular regulation (postural hypotension or cardiovascular collapse). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.
Metabolism and nutrition disorders: Rare: changes in appetite.
Respiratory, thoracic and mediastinal disorders: Rare: respiratory depression, dyspnea.
If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (refer to Interactions), respiratory depression may occur. Worsening of asthma has been reported, though a causal relationship has not been established.
Nervous system disorders: Very common: dizziness. Common: headache, somnolence. Rare: speech disorders, paraesthesia, tremor, epileptiform convulsions, muscle contractions involuntary, coordination abnormal, syncope.
Convulsions occurred mainly after administration of high doses of Tramadol or after concomitant treatment with medicinal products which can lower the seizure threshold. (Refer to Precautions and Interactions).
Psychiatric disorders: Rare: hallucination, confusional state, sleep disturbance, delirium, anxiety and nightmares. Psychic adverse reactions may occur following administration of tramadol which vary individually in intensity and nature (depending on personality and duration of treatment). These include changes in mood (usually euphoric mood, occasionally dysphoria), changes in activity (usually suppression, occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behavior, perception disorders). Drug dependence may occur. Symptoms of drug withdrawal syndrome, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms. Other symptoms that have very rarely been seen with tramadol discontinuation include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, depersonalization, derealization, paranoia).
Eye disorders: Rare: miosis, mydriasis, blurred vision.
Gastrointestinal disorders: Very common: nausea. Common: constipation, dry mouth, vomiting. Uncommon: retching, gastrointestinal discomfort (a feeling of pressure in the stomach, bloating), diarrhea.
Skin and subcutaneous tissue disorders: Common: hyperhidrosis. Uncommon: dermal reactions (e.g. pruritus, rash, urticaria).
Musculoskeletal disorders: Rare: motor weakness.
Hepatobiliary disorders: In a few isolated cases hepatic enzyme increases have been reported in a temporal connection with the therapeutic use of tramadol.
Renal and urinary disorders: Rare: micturition disorders (dysuria and urinary retention).
Immune system disorders: Rare: allergic reactions (e.g. dyspnea, bronchospasm, wheezing, angioneurotic edema) and anaphylaxis.
General disorders: Common: fatigue.
Drug Interactions
Tramadol should not be combined with MAO inhibitors (refer to Contraindications).
In patients treated with MAO inhibitors within 14 days prior to the use of the opioid pethidine, life-threatening interactions on the central nervous system, respiratory and cardiovascular function have been observed. The same interactions with MAO inhibitors cannot be ruled out during treatment with Tramadol HCl (Tramal).
Concomitant administration of Tramadol with other centrally depressant medicinal products including alcohol may potentiate the CNS effects (refer to Adverse Effects).
The results of pharmacokinetic studies have so far shown that on concomitant or previous administration of cimetidine (enzyme inhibitor), clinically relevant interactions are unlikely to occur. Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action.
Tramadol 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, tetrahydrocannabinol) to cause convulsions.
Concomitant therapeutic use of tramadol and serotonergic drugs such as selective serotonin re-uptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (refer to Contraindications), tricyclic antidepressants and mirtazapine may cause serotonin toxicity. 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°C and inducible or ocular clonus.
Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the nature and severity of the symptoms.
Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased INR with major bleeding and ecchymoses in some patients.
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 (refer to Adverse Reactions).
In a limited number of studies, the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.
Caution For Usage
Special Precautions for disposal and other handling: No special requirements for disposal.
Any unused product or waste material should be disposed in accordance with local requirements.
Injection: Instructions for handling: Calculation of injection volume: 1. Calculate the total dose of tramadol HCl (mg) required: bodyweight (kg) x dosage (mg/kg).
2. Calculate the volume (mL) of diluted solution to be injected: divide the total dose (mg) by an appropriate concentration of diluted solution (mg/mL; see table).

Click on icon to see table/diagram/image

According to the calculation, dilute the contents of Tramadol HCl (Tramal) 50 mg/mL or 100 mg/2 mL ampoule by adding a suitable diluent, mix and administer the calculated volume of diluted solution. Discard the excess solution for injection.
Storage
Capsule/Retard tablet/Injection: Store at temperatures not exceeding 30°C.
Dispersible tablet: Store at temperatures not exceeding 25°C.
ATC Classification
N02AX02 - tramadol ; Belongs to the class of other opioids. Used to relieve pain.
Presentation/Packing
Cap 50 mg (hard, yellow-yellow, shiny oblong) x 50's. Retard tab 100 mg (white, round, biconvex, film-coated, marked with Grunenthal's logo on one side and T1 on the other side) x 30's. Dispersible tab 50 mg (white to off-white, flat, round, bevelled) x 30's. Soln for inj (amp, clear, colorless) 50 mg/mL x 10's. 100 mg/2 mL x 10's.
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