Tramadol Hydrochloride Capsules 50mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Tramadol Hydrochloride Capsules 50mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains Tramadol hydrochloride 50mg.
For the 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
Posology
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 400mg active substance should not be exceeded, except in special circumstances.
Unless otherwise prescribed Tramadol Capsules should be administered as follows:
Adults and adolescents aged 12 years and over:
Acute pain: An initial dose of 100mg 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 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).
Geriatric 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 tramadol is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements.
Children:
Tramadol Capsules are not suitable for children below the age of 12 years.
Method of administration For oral administration.
The capsules are to be taken whole, not divided or chewed, with sufficient liquid, independent of meals.
Duration of administration
Tramadol Capsules should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Tramadol Capsules 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
Tramadol should not be administered to patients who have previously demonstrated hypersensitivity to it, or to any of the ingredients, or in cases of acute intoxication with alcohol, hypnotics, analgesics, opioids or other psychotroic medicinal drugs.
In common with other opioid analgesics it should not be administered to patients who are receiving monoamine oxidase (MAO) inhibitors or within two weeks of their withdrawal (see section 4.5).
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. Tramadol has a low dependence potential and rarely, cases of dependence and abuse have been reported.
On long-term use tolerance, psychic and physical dependence may develop.
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 in patients receiving tramadol at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit (400mg). 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).
Tramadol has a low dependence potential and rarely cases of dependence and abuse have been reported. On long-term use tolerance, psychic and physical dependence may develop. In patients with a tendency to drug abuse or dependence, treatment should be for short periods and under strict medical supervision
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 opioid-dependent patients, patients with head injury, a reduced level of consciousness of uncertain origin, increased intracranial pressure, severe impairment of hepatic and renal function, disorders of the respiratory centre or function and in patients prone to convulsive disorders or in shock.
In patients sensitive to opiates the product should only be used with caution.
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. At therapeutic doses, respiratory depression has infrequently been reported.
4.5 Interaction with other medicinal products and other forms of interaction
Tramadol should not be combined with monoamine oxidase (MAO) inhibitors (see section 4.3).
Patients treated with MAO 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 (see section 4.8).
The results of pharmacokinetic 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.
The combination with mixed agonist/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not advisable, because the analgesic effect of a pure agonist may be theoretically reduced in such circumstances.
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 or ocular clonus.
Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type 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.
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 (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. 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 breastfeeding.
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 drowsiness and dizziness and this effect may be potentiated by alcohol and other central nervous system (CNS) depressants or psychotropic substances. Ambulant patients should be warned not to drive or operate machinery if affected.
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: ^ 1/1000, <1/100 Rare: > \/\0 000, <1/1000 Very rare: <1/10 000
Not known: cannot be estimated from the available data Blood and lymphatic system disorders
There have also been cases of blood dyscrasias observed with tramadol treatment, but direct causality has not been confirmed.
Immune system disorders
Rare: hypersensitivity/allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.
Psychiatric disorders:
Rare: sleep disturbance, delirium, anxiety, confusion, nightmares and hallucinations, have been reported. 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). Dependence may occur.
Dependence: Prolonged administration of tramadol may lead to dependence.
Withdrawal reactions: Symptoms of withdrawal reactions, 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).
Nervous system disorders:
Very common: dizziness
Common: headache and drowsiness (somnolence)
Rare: changes in appetite, paraesthesia, tremor, respiratory depression, involuntary muscle contractions, abnormal coordination. 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) (see sections 4.4 and 4.5), syncope.
If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5), respiratory depression may occur.
Not known: speech disorders
Eye disorders:
Rare: blurred vision, mydriasis, blurred vision Cardiac disorders:
Uncommon: cardiovascular regulation (palpitations, tachycardia). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.
Rare: bradycardia, hypertension (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 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.
Gastrointestinal disorders:
Very common: nausea
Common: vomiting, constipation and dry mouth.
Uncommon: retching; gastrointestinal discomfort (a feeling of pressure in the stomach, bloating), diarrhoea
Skin and subcutaneous tissue disorders:
Common: sweating
Uncommon: dermal reactions (e.g. pruritus, rash, urticaria)
Musculoskeletal and connective tissue 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)
Metabolism and nutrition disorders:
Not known: hypoglycaemia
General disorders and administration site conditions:
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, sedation and consciousness disorders up to coma, seizures 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 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 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 intoxication with exceptionally large quantities.
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: N02AX02
Tramadol, a cyclohexanol derivative, 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 contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release.
Tramadol also 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).
Elimination half-life t1/2,B 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 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
Lactose monohydrate Microcrystalline cellulose (E460(i)) Croscarmellose sodium (E466) Magnesium stearate (E572)
Capsule shell excipients :
Body : Erythrosine (E127)
Titanium dioxide, (E171) Yellow iron oxide (E172) Gelatin
Cap : Indigo carmine (E132)
Titanium dioxide (E171)
Black iron oxide (E172)
Yellow iron oxide (E172)
Gelatin
Printing ink (Opacode S-1-17823 black): Shellac Glaze
Black iron oxide (E172) Propylene glycol (E1520) Ammonium hydroxide (E527)
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 55pm thick paper-lined aluminium cover foil and 250pm 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
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
25/02/2015