- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11. Dosimetry
- 12 Instructions for preparation of radiopharmaceuticals
PosologyThe 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.
Adults and children over 12 yearsAcute pain: Adults and children over age 12 years: 50-100mg 3-4 times daily. Patients with low weight should use 0.7mg/kg bodyweight. Duration of therapy depends upon clinical need.Chronic pain: An initial dose of 50mg or 100mg is followed by doses of 50mg or 100mg, every 4 to 6 hours, according to pain severity. The need for continued treatment should be assessed at regular intervals (as withdrawal symptoms and dependence have been reported). A total daily dose of 400mg should not be exceeded.Tramadol should under no circumstances be administered for longer than absolutely necessary. If long-term pain 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.
Older peopleA 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.
Patients with renal impairment/renal dialysisThe elimination of tramadol may be prolonged in these patients. The usual initial dosage should be used. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements.For patients with creatinine clearance <30ml/min, the dosage interval should be increased to 12 hours. Tramadol is not recommended in patients with severe renal impairment (creatinine clearance <10ml/min). Tramadol is removed very slowly by haemodialysis or haemofiltration so post-dialysis administration to maintain analgesia is not usually necessary.
Patients with hepatic impairmentThe elimination of tramadol may be prolonged. The usual dosage should be divided in 2, or the dosage interval should be extended to 12 hours. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements. In severe hepatic impairment, the product is contraindicated.
Paediatric populationChildren under 12 years: Not recommended.
Method of administrationThe capsules are taken orally, independent of meals, swallowed whole with water
PregnancyAnimal 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 new-born infants 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-feedingDuring 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.
Cardiovascular disorders:Uncommon ( 1/1000, <1/100): cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.Rare ( 1/10000, <1/1000): bradycardia, increase in blood pressure
Nervous system disorders:Very common ( 1/10): dizziness Common ( 1/100, <1/10): headache, somnolenceRare ( 1/10000, <1/1000): changes in appetite, paraesthesia, tremor, respiratory depression, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, syncope.If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5), respiratory depression may occur.Epileptiform 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).Not known: speech disorders
Psychiatric disorders:Rare ( 1/10000, <1/1000): 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).Dependence may occur.
Eye disorders:Rare ( 1/10000, <1/1000): blurred vision
Respiratory disorders:Rare ( 1/10000, <1/1000):dyspnoeaWorsening of asthma has been reported, though a causal relationship has not been established.
Gastrointestinal disorders:Very common ( 1/10): nauseaCommon ( 1/100, <1/10): vomiting, constipation, dry mouthUncommon ( 1/1000, <1/100): retching; gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea
Skin and subcutaneous disorders:Common ( 1/100, <1/10): sweatingUncommon ( 1/1000, <1/100):dermal reactions (e.g. pruritus, rash, urticaria)
Musculoskeletal disorders:Rare ( 1/10000, <1/1000): 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 ( 1/10000, <1/1000): micturition disorders (difficulty in passing urine, dysuria and urinary retention)
Metabolism and nutrition disorder:Not known: Hypoglycaemia
General disorders:Common ( 1/100, <1/10): fatigueRare ( 1/10000, <1/1000): allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis; 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.
Reporting of suspected adverse reactionsReporting 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; website: www.mhra.gov.uk/yellowcard
Pharmacotherapeutic group: other opiods
ATC code: N02A X02Tramadol is a centrally acting synthetic analgesic compound. It is a non-selective pure agonist at mu, delta and kappa opioid receptors with a higher affinity for the mu receptor. Other mechanisms which may contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline (norepinephrine) and enhancement of serotonin release. Tramadol opioid activity derives from low affinity binding of the parent compound to mu-opioid receptors and higher affinity binding of the active metabolite, O-desmethyl tramadol. Compared to morphine, tramadol does not show respiratory depression when given within the analgesic dosage interval. The effect of tramadol is considered 1/10 to 1/6 the effect of morphine. The gastrointestinal motility is not affected. There is minimal effect on the cardiovascular system. The contribution to human analgesia of tramadol relative to the active metabolite is unknown. Tramadol has an antitussive effect. Animal studies have revealed a reduced dependence potential compared with morphine and a very slight tolerance potential.
AbsorptionMore 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 %.
DistributionTramadol has a high tissue affinity (V d,ß = 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).
EliminationElimination half-life t1/2,ß 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,ß (6 healthy volunteers) is 7.9 h (range 5.4 - 9.6 h) and is approximately that of tramadol.
BiotransformationThe 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.
Linerarity/non-linerityTramadol 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.
Actavis UK Ltd
Whiddon Valley, Barnstaple, Devon, EX32 8NS, UK
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