1. Name Of The Medicinal Product
Zamadol® Capsules 50 mg
2. Qualitative And Quantitative Composition
Tramadol hydrochloride 50 mg
3. Pharmaceutical Form
Hard gelatin capsules.
4. Clinical Particulars
4.1 Therapeutic Indications
For the treatment and prevention of moderate to severe pain.
4.2 Posology And Method Of Administration
The capsules are for oral administration. As with all analgesic drugs the dosing of Zamadol Capsules 50 mg should be adjusted depending on the severity of the pain and the individual clinical response of the patient.
Adults:
For acute pain - an initial dose of 100 mg 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.
For pain associated with chronic conditions -use in an initial dose of 50 mg 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 oral daily dose of 400 mg should not be exceeded except in special clinical circumstances.
Elderly patients:
Dosing as for adults but it should be noted that in a study in elderly volunteers (aged over 75 years) the elimination half-life for orally administered tramadol was increased by 17%.
Patients with renal insufficiency:
The usual initial adult doses should be employed, but the elimination of tramadol may be prolonged in patients with renal impairment and therefore the dosage interval should be adjusted.
For creatinine clearance <30 ml/min the dosing should be increased to 12 hourly intervals.
For creatinine clearance <10 ml/min (severe renal impairment) tramadol is not recommended.
Tramadol is removed very slowly by haemodialysis or haemofiltration and therefore post-dialysis dosing to maintain analgesia is usually unnecessary.
Patients with hepatic insufficiency:
The usual adult doses should be used, but it should be noted that elimination of tramadol may be prolonged in severe hepatic impairment and dosing should be at 12 hourly intervals.
Children:
Over 12 years: Dosage as for adults
Under 12 years: Not recommended for children under 12 years
4.3 Contraindications
Zamadol Capsules 50 mg should not be given to patients who have previously shown hypersensitivity to the active substance or to any of the excipients.
The product should not be administered to patients suffering from acute intoxication with hypnotics, centrally acting analgesics, opioids, psychotropic drugs or alcohol.
In common with other opioid analgesics, tramadol should not be administered to patients who are receiving monoamine oxidase inhibitors or within 2 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.
Zamadol Capsules 50 mg are not a suitable substitute in opioid dependent patients. The product does not suppress morphine withdrawal symptoms although it is an opioid agonist.
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).
Precautions:
In patients with severe renal or hepatic impairment, head injury, increased intracranial pressure, or patients in shock or at risk of convulsions, Zamadol Capsules 50 mg should be used with caution.
At present Zamadol Capsules 50 mg should not be used during light planes of anaesthesia as enhanced intra-operative recall was reported in a study of the use of tramadol during anaesthesia with enflurane and nitrous oxide.
At therapeutic doses of tramadol respiratory depression has been reported infrequently. Therefore care should be taken when administering Zamadol Capsules 50 mg to patients with existing respiratory depression or to patients taking concomitant CNS depressant drugs.
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.
Zamadol Capsules 50 mg may potentiate the CNS depressant effects of other centrally acting drugs (including alcohol) when administered concomitantly with such drugs.
Tramadol may increase the potential for 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.
Administration of Zamadol Capsules 50 mg together with carbamazepine results in markedly decreased serum concentrations of tramadol which may reduce analgesic effectiveness and shorten the duration of action.
Theoretically, tramadol could interact with noradrenaline, 5-HT or lithium, due to their mechanisms of action, and 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:
Zamadol Capsules 50 mg should not be used in pregnancy, as there is inadequate evidence available to assess the safety of tramadol in pregnant women.
Studies of tramadol in rats and rabbits have revealed no teratogenic effects. However, embryotoxicity was shown in the form of delayed ossification. Fertility, reproductive performance and development of offspring were unaffected.
Lactation:
Zamadol Capsules 50 mg should not be administered during breast feeding as tramadol and its metabolites have been detected in breast milk. An infant could ingest 0.1% of the dose administered to the mother.
4.7 Effects On Ability To Drive And Use Machines
Zamadol Capsules 50 mg may cause drowsiness and this effect may be potentiated by alcohol and other CNS depressants. 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, dry mouth and constipation.
• 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 4.2 and 4.4).
• 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 tramadol overdose include vomiting, miosis, sedation, coma, seizures, cardiovascular collapse and respiratory depression. Such symptoms are typical of opioid analgesics.
Treatment of overdose requires the maintenance of the airway and cardiovascular functions. Respiratory depression may be reversed using naloxone and fits controlled with diazepam.
The treatment of acute overdose of tramadol using haemodialysis or haemofiltration alone is not sufficient or suitable due to the slow elimination of tramadol from the serum by these routes.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Analgesic, 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 as capsules or tablets, 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
6. Pharmaceutical Particulars
6.1 List Of Excipients
Capsule Contents: Dibasic calcium phosphate anhydrous, magnesium stearate, colloidal anhydrous silica.
Capsule Shell: Gelatin and Titanium Dioxide (E171).
Printing ink: Shellac, Iron oxide black (E172) and Propylene glycol.
6.2 Incompatibilities
No pharmaceutical incompatibilities reported.
6.3 Shelf Life
Four years, as packaged for sale.
6.4 Special Precautions For Storage
No special requirements.
6.5 Nature And Contents Of Container
White opaque PVC/PVDC and aluminium foil blister strips. Each strip contains 10 capsules. The blister strips are packed in cartons containing 100 capsules.
6.6 Special Precautions For Disposal And Other Handling
None.
7. Marketing Authorisation Holder
Meda Pharmaceuticals Ltd
249 West George Street
Glasgow
G2 4RB
Trading as:
Meda Pharmaceuticals Ltd
Skyway House
Parsonage Road
Takeley
Bishop's Stortford
CM22 6PU
UK
8. Marketing Authorisation Number(S)
PL 15142/0119
9. Date Of First Authorisation/Renewal Of The Authorisation
6th August 2009
10. Date Of Revision Of The Text
®ZAMADOL is a registered trademark of Meda
©Meda
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