1. Name Of The Medicinal Product
Tramadol Hydrochloride Capsules 50mg
2. Qualitative And Quantitative Composition
Each capsule contains Tramadol hydrochloride 50mg.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Capsule, hard.
Olive/Yellow capsule shell, imprinted'TRM' on the cap and '50' on the body containing white powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Management (treatment and prevention) of moderate to severe pain.
4.2 Posology And Method Of Administration
For oral administration.
As with all analgesic drugs, the dose of tramadol should be adjusted according to the severity of the pain and the clinical response of the individual patient.
Adults:
Acute pain
An initial dose of 100mg is usually necessary. This can be followed by doses of 50 mg or 100 mg not more frequently than 4 hourly, and duration of therapy should be matched to clinical need.
Pain associated with chronic conditions
Use an initial dose of 50mg and then titrate dose according to pain severity. The need for continued treatment should be assessed at regular intervals as withdrawal symptoms and dependence have been reported, although rarely (See section 4.4).
A total daily oral dose of 400mg should not be exceeded except in special clinical circumstances.
Elderly patients:
The usual dosages may be used although it should be noted that in volunteers aged over 75 years the elimination half-life of tramadol was increased by 17% following oral administration.
Patients with Renal impairment/renal dialysis:
The elimination of tramadol may be prolonged. The usual initial adult dosage should be used. For patients with creatinine clearance < 30ml/min., the dosage interval should be increased to 12 hours. Tramadol is not recommended for patients with severe renal impairment (creatinine clearance < 10ml/min.).
Tramadol is removed very slowly by haemodialysis or haemofiltration and therefore post-dialysis dosing to maintain analgesia is usually unnecessary.
Patients with Hepatic impairment
The elimination of tramadol may be prolonged. The usual initial adult dosage should be used but in severe hepatic impairment the dosage interval should be increased to 12 hours.
Children:
Over 12 years:
Dosage as for adults.
Under 12 years
Not recommended.
4.3 Contraindications
Tramadol should not be administered to patients who have previously demonstrated hypersensitivity to it or in cases of acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs.
In common with other opioid analgesics it should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal.
Tramadol should not be given to patients suffering from uncontrolled epilepsy.
Tramadol must not be used for narcotic withdrawal treatment.
4.4 Special Warnings And Precautions For Use
Warnings
At therapeutic doses, tramadol has the potential to cause withdrawal symptoms. Rarely, cases of dependence and abuse have been reported.
At therapeutic doses, withdrawal symptoms have been reported at a reporting frequency of 1 in 8,000. Reports of dependence and abuse have been less frequent. Because of this potential, the clinical need for continued analgesic treatment should be reviewed regularly.
In patients with a tendency to drug abuse or dependence, treatment should be for short periods and under strict medical supervision.
Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.
Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit. Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons. The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold (see section 4.5).
Excipients:
Tramadol capsule contains lactose and therefore should not be used by patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Precautions
Tramadol should be used with caution in patients with head injury, increased intracranial pressure, severe impairment of hepatic and renal function and in patients prone to convulsive disorders or in shock.
Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered, as the possibility of respiratory depression cannot be excluded in these situations. At therapeutic doses, respiratory depression has infrequently been reported.
In one study, use of tramadol during general anaesthesia with enflurane and nitrous oxide was reported to enhance intraoperative recall. Until further information is available use of tramadol during light planes of general anaesthesia should be avoided.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Patients treated with monoamine oxidase inhibitors within 14 days prior to administration of the opioid pethidine have experienced life-threatening interactions affecting the central nervous system as well as the respiratory and circulatory centres. The possibility of similar interactions occurring between monoamine oxidase inhibitors and tramadol cannot be ruled out.
Concomitant administration of tramadol with other centrally acting drugs including alcohol may potentiate CNS depressant effect.
Tramadol may increase the potential for both selective serotonin re-uptake inhibitors (SSRIs),tricyclic antidepressants (TCAs) ,anti-psychotics and other seizure threshold lowering drugs to cause convulsions (See section 4.4).
In isolated cases there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tramadol in combination with other serotoninergic medicines such as selective serotonin re-uptake inhibitors (SSRIs). Signs of serotonin syndrome may be for example confusion, agitation, fever, sweating, ataxia, hyper-reflexia, myoclonus and diarrhoea. Withdrawal of the serotoninergic medicines usually brings about a rapid improvement. Drug treatment depends on the nature and severity of the symptoms.
Simultaneous administration of carbamazepine markedly decreases serum concentrations of tramadol to an extent that a decrease in analgesic effectiveness and a shorter duration of action may occur.
There is a theoretical possibility that tramadol could interact with noradrenaline, 5HT or lithium due to their respective mechanisms of action, thus potentiate their anti-depressant effect. However there have been no reports of such interactions.
Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased INR and ecchymoses in some patients.
4.6 Pregnancy And Lactation
Pregnancy
Animal studies (rat and rabbit, exposure to tramadol up to 7 times that expected in man) have not revealed teratogenic effects and minimal embryotoxicity (delayed ossification). Fertility, reproductive performance and development of offspring were unaffected. There is inadequate evidence available on the safety of tramadol in human pregnancy, therefore tramadol should not be used in pregnant women.
Lactation
Tramadol and its metabolites are found in small amounts in human breast milk. An infant could ingest about 0.1% of the dose given to the mother. Tramadol should not be administered during breast feeding.
4.7 Effects On Ability To Drive And Use Machines
Tramadol may cause drowsiness and this effect may be potentiated by alcohol and other CNS depressants. Ambulant patients should be warned not to drive or operate machinery if affected.
4.8 Undesirable Effects
Gastrointestinal system : Frequently (>10%):-nausea:occasionally (1-10%): vomiting, constipation and dry mouth.
Central nervous system and psychiatric : Frequently (>10%): dizziness; occasionally (1-10%): headache and drowsiness. In very rare cases (<0.1%) somnolence, fatigue, blurred vision, confusion, hallucinations, respiratory depression, dysphoria, nightmares and parasthesia have been reported. Very rarely epileptiform convulsions have been reported occurring mainly after administration of high doses of tramadol or after treatment with drugs which can lower the seizure threshold or themselves induce cerebral convulsions (e.g. anti-depressants or anti-psychotics).
Dependence/Withdrawal reactions : Prolonged administration of tramadol may lead to dependence. In very rare cases (<0.1%)typical opiate withdrawal reactions including agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms have been reported. (See sections 4.4 and 4.2).
Allergic/anaphylactoid reactions: In very rare cases (<0.1%) allergic reactions (dyspnoea, wheezing, bronchospasm and worsening of asthma) and anaphylaxis have been reported. Pruritus, urticaria and skin rashes have also been reported.
Cardiovascular System: Rarely (<1%): palpitations, tachycardia, orthostatic hypotension, flushing; very rarely (<0.1%): bradycardia, hypertension, syncope.
Other adverse events: Occasionally (1-10%): sweating; very rarely (<0.1%): micturition disorders. There have also been cases of blood dyscrasias observed with tramadol treatment, but direct causality has not been confirmed. In a few isolated cases increases in liver enzyme values have been reported concurrently with the therapeutic use of tramadol.
4.9 Overdose
Symptoms of overdosage are typical of other opioid analgesics, and include miosis, vomiting, cardiovascular collapse, sedation and coma, seizures and respiratory depression.
Treatment of overdose requires the maintenance of the airway and cardiovascular functions. Naloxone should be used to reverse respiratory depression and fits can be controlled with diazepam.
Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with tramadol with haemodialysis or haemofiltration alone is not suitable for detoxification.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Other opioids,
ATC code: N02AX02
Tramadol, a cyclohexanol derivative, is a centrally acting analgesic which possesses opioid agonist properties. Tramadol appears to modify the transmission of pain impulses by inhibition of monoamine reuptake. The duration of analgesia with orally administered tramadol has been shown to be 3-6 hours with maximum pain relief at 1-4 hours post-dosing. Tramadol also has an antitussive action but has no effect on gastrointestinal motility. At the recommended dosages, the effects of tramadol given orally on the respiratory and cardiovascular systems appear to be clinically insignificant.
5.2 Pharmacokinetic Properties
a) General
Following oral dosing, tramadol is rapidly and almost completely absorbed. After oral administration tramadol appears in the plasma within 15-45 minutes, reaching peak plasma concentrations at a mean of 2 hours. The mean oral bioavailability of tramadol is approximately 68% after single doses and increases to 90 to 100% on multiple administration.
The half-life absorption for oral tramadol (solid dose formulation) is 0.38 ± 0.18 hours with a peak plasma concentration of 280 ± 49 ng/ml 2 hours after oral dosing with 100 mg tramadol (solid dose formulation). Tramadol has a high tissue affinity with an apparent volume of distribution of 306 litres after oral dosing in healthy volunteers.
Tramadol undergoes hepatic metabolism with approximately 85% of an oral dose being metabolised in young healthy volunteers. Tramadol is biotransformed primarily by N- and O-demethylation and by glucuronidation of the O-demethylation products. Eleven metabolites have so far been identified in man.
Only one metabolite, O-demethyl tramadol (M1), is pharmacologically active showing analgesic activity. The mean elimination half-life of tramadol following oral administration is 5-6 hours. Approximately 90% of an oral dose is excreted by the kidneys.
The inhibition of one or both cytochrome P450 isoenzymes, CYP3A4 and CYP2D6 involved in the metabolism of tramadol, may affect the plasma concentration of tramadol or its active metabolite. The clinical consequences of any such interactions are not known.
b) Characteristics in patients
Effect of age:
Tramadol pharmacokinetics show little age-dependence in volunteers up to the age of 75 years. In volunteers aged over 75 years, the terminal elimination half-life was 7.0 ± 1.6 h compared to 6.0 ± 1.5 h in young volunteers after oral administration.
Effect of hepatic or renal impairment:
As both tramadol and its pharmacologically active metabolite, O-demethyl tramadol, are eliminated both metabolically and renally, the terminal half-life of elimination (t½) may be prolonged in patients with hepatic or renal dysfunction. However, the increase in t½ is relatively small if either excretory organ is functioning normally. In liver cirrhosis patients, the mean t½ of tramadol was 13.3 ± 4.9 hours. In patients with renal failure (creatinine clearance < 5 mL/min) the t½ of tramadol was 11.0 ± 3.2 hours and that of M1 was 16.9 ± 3.0 hours. Extreme values observed to date are 22.3 hours (tramadol) and 36.0 hours (M1) in liver cirrhosis patients and 19.5 hours (tramadol) and 43.2 hours (M1) in renal failure patients.
5.3 Preclinical Safety Data
The standard range of pharmacodynamic, pharmacokinetic and toxicological tests have been carried out for Tramadol and the effects observed from these investigations that are relevant to the prescriber are mentioned in other sections
Single and repeat-dose animal studies demonstrate that 10 times the expected human dose is needed before hepatotoxicity is observed. Carcinogenicity and mutagenicity tests in animals were negative.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose monohydrate
Microcrystalline cellulose (E460(i))
Croscarmellose sodium (E466)
Magnesium stearate (E572)
Capsule shell excipients :
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6.2 Incompatibilities
None known.
6.3 Shelf Life
Tramadol hydrochloride capsules have a shelf life of two years.
6.4 Special Precautions For Storage
Do not store above 25°C. Store in the original package.
6.5 Nature And Contents Of Container
Blister strips formed from 55µm thick paper-lined aluminium cover foil and 250µm thick opaque PVC/PVdC foil
Blister packs of 10, 30, 60 and 100 capsules.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
Not applicable.
7. Marketing Authorisation Holder
ACCORD HEALTHCARE LIMITED
SAGE HOUSE
319 PINNER ROAD
NORTH HARROW
MIDDLESEX
HA1 4HF
UNITED KINGDOM
8. Marketing Authorisation Number(S)
PL 20075/0290
9. Date Of First Authorisation/Renewal Of The Authorisation
10th November 2000
10. Date Of Revision Of The Text
03/02/2011
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