Tramadol Hydrochloride 50mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Tramadol Hydrochloride 50mg Capsules
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 50 mg tramadol hydrochloride (equivalent to 43.9 mg of tramadol base)
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Capsule
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Tramadol capsules are indicated for the management (treatment and prevention) of moderate to severe pain.
4.2 Posology and method of administration
Posology
As with all analgesic drugs, 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. A total daily oral dose of 400 mg should not be exceeded except in special clinical circumstances.
Unless otherwise prescribed, tramadol should be administered as follows:
Adults and children aged 12 years and over Acute Pain
An initial dose of 100 mg is usually necessary. This can be followed by doses of 50 mg or 100 mg at 4 - 6 hourly intervals, and duration of therapy should be matched to clinical need.
Pain Associated with Chronic Conditions
Use 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 (see section 4.4).
Paediatric population
Tramadol is not suitable for children below the age of 12 years.
Older people
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 tramadol is delayed. In these patients the initial dosage should be used and prolongation of the dosage intervals should be carefully considered according to the patient's requirements.
Method of administration For oral administration
The capsules are to be taken whole, not divided or chewed, with sufficient liquid, with or without food.
Duration of administration
Tramadol should under no circumstances be administered for longer than absolutely necessary. If long-term 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.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed section 6.1.
• Acute intoxication with alcohol, hypnotics, analgesics, opioids or other psychotropic drugs.
• Patients who are receiving monoamine oxidase (MAO) inhibitors or have taken them in the last 14 days (see section 4.5).
• Patients with epilepsy not adequately controlled by treatment.
• For use in narcotic withdrawal treatment.
4.4 Special warnings and precautions for use
Tramadol may only be used with particular caution in opioid-dependant patients, patients with head injury, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, increased intracranial pressure or in shock.
In patients sensitive to opiates the product 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 medicinal products that lower the seizure threshold (see section 4.5). Patients with epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling circumstances.
Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered (see section 4.5), or if the recommended dosage is significantly exceeded (see section 4.9) as the possibility of respiratory depression cannot be excluded in these situations.
Tramadol has a low dependence potential. Upon long-term use tolerance, psychic and physical dependence may develop. In patients with a tendency to drug abuse or dependence, treatment should only 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.
4.5 Interactions with other medicinal products and other forms of interaction
Tramadol should not be combined with MAO inhibitors (see section 4.3).
In patients treated with MAO inhibitors in the 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.
Concomitant administration of Tramadol with other centrally acting medicinal products including alcohol may potentiate the CNS effects (see section 4.8).
The results of pharmacokinetics studies have so far shown that on the 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 reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics 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 reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), 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 ocular clonus.
Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type 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) and probably the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied (see section 4.8).
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.
4.6 Fertility, pregnancy and lactation
Pregnancy
Animal studies with tramadol revealed at very high doses effects on organ development, ossification and neonatal mortality. Teratogenic effects were not observed. 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.
Breast-feeding
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 does not suggest an effect of tramadol on fertility. Animal studies did not show an effect of tramadol on fertility.
4.7 Effects on ability to drive and use machines
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.
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
The most commonly reported adverse reactions are nausea and dizziness, both occurring in more than 10% of patients.
The frequencies are defined as follows:
Very common: > 1/10 Common: > 1/100, <1/10 Uncommon: > 1/1,000, < 1/100 Rare: > 1/10,000, < 1/1,000 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.
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.
Respiratory, thoracic and mediastinal disorders:
Rare: respiratory depression, dyspnoea.
If the recommended doses are considerably exceeded and other centrally acting depressant substances are administered concomitantly (see section 4.5), 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: paraesthesia, tremor, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, syncope, speech disorders.
Convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with medicinal products which can lower the seizure threshold (see sections 4.4 and 4.5).
Psychiatric disorders:
Rare: hallucinations, confusion, sleep disturbance, 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 elation, occasionally dysphoria), changes in activity (usually suppression, occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders). Drug dependence may occur.
Symptoms of 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, personalisation, derealisation, paranoia).
Eye disorders:
Rare: miosis, mydriasis, blurred vision.
Gastrointestinal disorders:
Very common: nausea.
Common: vomiting, constipation, dry mouth.
Uncommon: retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea.
Skin and subcutaneous disorders:
Common: hyperhidrosis.
Uncommon: dermal reactions (e.g. pruritus, rash, urticaria).
Musculoskeletal disorders:
Rare: motorial weakness.
Hepatobiliary disorders:
In a few isolated cases an increase in liver enzyme values has been reported in a temporal connection with the therapeutic use of tramadol.
Renal and urinary disorders:
Rare: micturition disorders (difficulty in passing urine, dysuria and urinary retention). Immune system disorders:
Rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.
Metabolism and nutrition disorders:
Rare: changes in appetite.
Not known: hypoglycaemia.
General disorders:
Common: fatigue
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
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. Keep open the respiratory tract (aspiration), maintain respiration and circulation depending on 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 orally, gastrointestinal decontamination with activated charcoal or by gastric lavage is only recommended within 2 hours after tramadol intake. Gastrointestinal decontamination at a later time point may be useful in case of intoxification with exceptionally large quantities or prolonged release formulation.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other opioids; ATC code: N02A X02.
Tramadol is a centrally acting opioid analgesic. It is a non-selective pure agonist at p, 5 and k opioid receptors with a higher affinity for the p receptor. Other mechanisms which may contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release.
Tramadol has an antitussive effect. In contrast to morphine, analgesic doses of tramadol over a wide range have no respiratory 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.
5.2 Pharmacokinetic properties
More than 90% of tramadol is absorbed after oral administration. The mean absolute bioavailability is approximately 70 %, irrespective of the concomitant intake of food. The difference between absorbed and non-metabolised available tramadol is probably due to the low first-pass effect. The first-pass effect after oral administration is a maximum of 30 %.
Tramadol has a high tissue affinity (V d,B = 203 + 40 l). It has a plasma protein binding of about 20 %.
Following a single oral dose administration of tramadol 100 mg as capsules or tablets to young healthy volunteers, plasma concentrations were detectable within approximately 15 to 45 minutes within a mean Cmax of 280 to 208 mcg/L and Tmax of 1.6 to 2h.
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 half-life of the terminal elimination phase (t'/2,P) was approximately 6 hours, 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 humans tramadol is mainly metabolised by means of N- and O-demethylation and conjugation 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 the factor 2 - 4. Its half-life t1/2,B (6 healthy volunteers) is 7.9 h (range 5.4 - 9.6 h) and is approximately that of tramadol.
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. In cases of impaired hepatic and renal function the half-life may be slightly prolonged. 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 an extreme case 19.5 h and 43.2 h respectively.
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.
5.3 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 haematological, 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 fertility was not affected. After higher doses (from 50 mg/kg/day upwards) females exhibited a reduced pregnancy rate. In rabbits there were toxic effects in dams from 125 mg/kg upwards and skeletal anomalies in the 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 hydrochloride have been carried out in rats and mice. The study in rats showed no evidence of any substance-related increase in the incidence of tumours. In the study in mice there was an increased incidence of liver cell adenomas in male animals (a dose-dependent, non-significant increase from 15 mg/kg upwards) and an increase in pulmonary tumours in females of all dosage groups (significant, but not dose-dependent).
6.1 List of excipients
Calcium hydrogen phosphate dihydrate Magnesium stearate Colloidal anhydrous silica
Capsule shell Gelatin
Quinoline yellow (E104)
Red iron oxide (E172)
Titanium dioxide (E171)
Yellow iron oxide (E172)
Patent Blue V
Printing ink Opacode Black S-1-17823
Shellac
Iron Oxide Black N-butyl alcohol Isopropyl alcohol
Propylene Glycol
Ammonium hydroxide 28% (for pH adjustment)
6.2 Incompatibilities
None.
6.3 Shelf life
24 months
6.4 Special precautions for storage
Store in a dry place below 30°C (86°F).
6.5 Nature and contents of container
White opaque PVC 250p/A1 foil (20p) blister pack containing 10 capsules. Pack sizes 30 and 100 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Winthrop Pharmaceuticals UK Limited
One Onslow Street
Guildford
Surrey
GU1 4YS
United Kingdom
Trading as
Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS
Or
Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
MARKETING AUTHORISATION NUMBER(S)
PL 17780/0139
9
10
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
22/04/2004
DATE OF REVISION OF THE TEXT
26/04/2016