Zamadol Capsules 50mg
SUMMARY OF PRODUCT CHARACTERISTICS
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. The dose of Zamadol Capsules 50 mg 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.
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:
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.
Renal insufficiency/dialysis and hepatic impairment:
In patients with renal and/or hepatic insufficiency the elimination of Zamadol 50 mg capsules is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient’s requirements.
For creatinine clearance <30 ml/min the dosing should be increased to 12 hourly intervals.
For creatinine clearance <10 ml/min (severe renal impairment) Zamadol 50 mg capsules is not recommended.
Tramadol is removed very slowly by haemodialysis or haemofiltration and therefore post-dialysis dosing to maintain analgesia is usually unnecessary.
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 product.
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 can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), anti-psychotics and other seizure threshold lowering drugs (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions (see section 4.4).
Concomitant therapeutic use of tramadol and serotonergic drugs, such as selective serotonin re-uptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO-inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine may cause serotonin toxicity. Serotonergic 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 serotoninergic drugs usually brings about a rapid improvement. Treatment depends on the type 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.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
The medicine is likely to affect your ability to drive
Do not drive until you know how the medicine affects you
It is an offence to drive while under the influence of this medicine
However, you would not be committing an offence (called ‘statutory defence’)
if:
- The medicine has been prescribed to treat a medical or dental problem and
- You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
- It was not affecting your ability to drive safely
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.
Metabolism and nutrition disorders: Frequency not known (cannot be estimated from the available data): hypoglycaemia.
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.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
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
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
General
Following oral dosing, tramadol is rapidly and almost completely absorbed. After oral administration as capsules or tablets, tramadol appears in the plasma within 1545 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 of 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 0-demethylation products. Eleven metabolites have so far been identified in man.
Only one metabolite, 0-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.
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 (t'A) may be prolonged in patients with hepatic or renal dysfunction. However, the increase in t'A is relatively small if either excretory organ is functioning normally. In liver cirrhosis patients, the mean t'A of tramadol was 13.3 ± 4.9 hours. In patients with renal failure (creatinine clearance <
5 mL/min) the t'A of tramadol was 11.0 ± 3.2 hours and that of Ml 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.
Preclinical safety data
5.3
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), propylene glycol and ammonium hydroxide.
6.2 Incompatibilities
No pharmaceutical incompatibilities reported.
6.3 Shelf life
Two 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
None.
7. MARKETING AUTHORISATION HOLDER
Meda Pharmaceuticals Ltd Skyway House Parsonage Road
Takeley
Bishop’s Stortford CM22 6PU
8 MARKETING AUTHORISATION NUMBER(S)
PL 15142/0119
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
12 August 1996
10 DATE OF REVISION OF THE TEXT
25/07/2014