Composition:
Each 1ml Solution contains 50mg Tramadol hydrochloride.
Pharmacodynamic properties:
Effects of enteral and parenteral administration of tramadol have been investigated in clinical trials involving more than 2000 paediatric patients ranging from neonate to 17 years of age. The indications for pain treatment studied in those trials included pain after surgery (mainly abdominal), after surgical tooth extractions, due to fractures, burns and traumas as well as other painful conditions that likely require analgesic treatment for at least 7 days.
At single doses of up to 2 mg/kg or multiple doses of up to 8 mg/kg per day (to a maximum of 400 mg per day) efficacy of tramadol was found to be superior to placebo, and superior or equal to paracetamol, nalbuphine, pethidine or low dose morphine. The results confirmed the efficacy of tramadol. The safety profile of tramadol was similar in adult and paediatric patients older than 1 year.
Pharmacokinetics:
- After oral administration, tramadol undergo first - pass effect of maximum 30 %, and more than 90% is absorbed .The mean absolute bioavailability is approximately 70 %, regardless of food intake. The difference between absorbed and non-metabolised available tramadol is probably due to the low first-pass effect.
- Tramadol has a high tissue affinity and a plasma protein binding of about 20%.
- In humans tramadol is mainly metabolised by N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyltramadol is pharmacologically active.
- 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.
- Paediatric population: The pharmacokinetics of tramadol and O-desmethyltramadol after single-dose and multiple- dose oral administration to subjects aged 1 year to 16 years were found to be generally similar to those in adults when adjusting for dose by body weight, but with a higher between-subject variability in children aged 8 years and below.
Indications:
Tramadol Domina is indicated for the treatment and prevention of moderate to severe pain.
Contraindication:
- Hypersensitivity to the active substance or to any of the excipients.
- Patients suffering from acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs.
- Patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal.
- Patients with epilepsy not adequately controlled by treatment.
- Narcotic withdrawal treatment.
Dosage & Method of administration:
- The solution can be administered either intramuscularly, intravenously or subcutaneously
- Intravenous doses should be administered slowly over 2–3 minutes or diluted in solution.
- Tramadol may also be diluted in solution for infusion.
- Tramadol should not 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 regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether, and to what extent, further treatment is necessary.
- 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 tramadol hydrochloride should not be exceeded, except in special clinical circumstances.
Adults and children 12 years and over:
- The usual dose is 50 mg or 100 mg 4 to 6 hourly by either intramuscular or intravenous routes. The dose should be adjusted according to the severity of the pain and the response.
- For post-operative pain, an initial bolus of 100mg is administered. During the 60 minutes following the initial bolus, further doses of 50mg may be given every 10-20 minutes, up to a total dose of 250mg including the initial bolus.
- Subsequent doses should be 50mg or 100mg 4- 6 hourly up to a total daily dose of 400mg.
Elderly:
- 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 under 12 years:
Not recommended.
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.
Management: The general emergency measures are to keep the respiratory tract open (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 haemo-filtration. Therefore treatment of acute tramadol intoxication with haemodialysis or haemofiltration alone is not suitable for detoxification.
Side effects:
Rapid intravenous administration may be associated with a higher incidence of adverse effects and therefore should be avoided. The most commonly reported adverse drug reactions are nausea and dizziness, both occurring in more than 10 % of patients
|
System Organ Class |
Frequency |
Adverse reactions |
|
Cardiovascular disorders |
Uncommon |
Cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). |
|
Rare |
bradycardia |
|
|
Eye disorders |
Rare |
Blurred vision, miosis, and mydriasis. |
|
Gastrointestinal disorders |
Very common |
Nausea and Vomiting |
|
Uncommon |
retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhea |
|
|
Common |
Vomiting, constipation, dry mouth. |
|
|
Respiratory system disorders: |
Rare |
Respiratory depression, dyspnea. |
|
Nervous system disorders |
Very common |
Dizziness |
|
Common |
Headache, somnolence. |
|
|
Skin disorder |
Common |
Sweating. |
|
Uncommon |
Dermal reactions (e.g. pruritus, rash, urticaria). |
|
|
Muscular-skeletal system disorders |
Rare |
Muscle weakness |
|
Hepatobiliary system disorders |
Rare |
In a few isolated cases, increases in liver enzyme values have been reported with the therapeutic use of tramadol. |
|
Renal and urinary system disorders |
Rare |
Micturition disorders (difficulty in passing urine, dysuria and urinary retention) |
|
General disorders |
Common |
fatigue |
|
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 |
Investigations:
Rare: increase in blood pressure
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, paraesthesia, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, personalisation, derealisation, paranoia).
Note: Patients should inform their doctor or pharmacist if they notice any side effect not mentioned in this leaflet
Precautions:
- Tramadol should be used with caution in opioid-dependent patients, patients with head injury, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, increased intracranial pressure, severe impairment of hepatic and renal function and in patients prone to convulsive disorders or in shock.
- In patients sensitive to opiates the product should only be used with caution.
- Convulsions have been reported 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.
- At therapeutic doses, tramadol has the potential to cause withdrawal symptoms at a frequency of 1 in 8,000. Rarely, cases of dependence and abuse have been reported.
- Tolerance, psychic and physical dependence may develop, especially after long-term use. When a patient no longer requires therapy with tramadol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.
- In patients with a tendency to drug abuse or dependence, treatment should be for short periods and under strict medical supervision.
- The product does not suppress morphine withdrawal symptoms although it is an opioid agonist.
- Tramadol may cause drowsiness and this effect may be potentiated by alcohol and other CNS depressants. Ambulant patients should be warned not to drive or operate machinery if affected.
- Concomitant use of Tramadol and sedating medicinal substances such as benzodiazepines or related substances, may result in respiratory depression, sedation, coma and death. Concomitant prescribing with these sedating medicinal products should be only undertaken where no other option is available and the lowest effective dose of Tramadol should be used, with as possible short duration. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation. It is recommended to inform patients and their caregivers to be aware of these symptoms.
- In one study using a nitrous oxide/opioid (tramadol) anaesthetic technique (with only intermittent administration of enflurane as required) tramadol was reported to enhance intra- operative recall. Hence its use during potentially very light planes of general anaesthesia should be avoided.
- Two studies of tramadol administration during anaesthesia comprising continuous administration of isoflurane have shown clinically significant lightening of anaesthetic depth or intra-operative recall. Therefore providing the current practice of administering continuous, potent (volatile or intravenous) anaesthetic agent is followed; tramadol may be used intra- operatively in the same way as other analgesic agents are routinely used.
CYP2D6 metabolism:
Tramadol is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect may not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is a risk of developing side effects of opioid toxicity even at commonly prescribed doses.
General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life threatening and very rarely fatal.
Post-operative use in children:
There have been reports that tramadol given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life threatening adverse events. Extreme caution should be exercised when tramadol is administered to children for post-operative pain relief and should be accompanied by close monitoring for symptoms of opioid toxicity including respiratory depression.
Children with compromised respiratory function:
Tramadol is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of opioid toxicity.
Drug Interactions:
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.
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.
Theoretically there is a possibility that tramadol could interact with lithium. There have been no reports of this potential interaction.
Concomitant therapeutic use of tramadol and serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors, 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.
- Withdrawal of the serotonergic drugs usually brings about a rapid improvement.
Treatment depends on the type and severity of the symptoms.
There have been isolated reports of interaction with coumarin anticoagulants resulting in an increased INR with major bleeding and ecchymoses in some patients and so care should be taken when commencing treatment with tramadol in patients on anticoagulants.
Pharmacokinetic studies were conducted to investigate the effects of cimetidine, quinidine and carbamazepine on the pharmacokinetics of tramadol.
Carbamazepine – The 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.
Cimetidine - With the concomitant or previous administration of cimetidine clinically relevant interactions are unlikely to occur. Therefore no alteration of the tramadol dosage regimen is recommended for patients receiving chronic cimetidine therapy.
Quinidine - A study in 12 healthy volunteers has shown that quinidine causes an approximate 25% increase in the tramadol Cmax and AUC; Tmax is unaffected. However, the increases in Cmax and AUC fall within the normal therapeutic range for tramadol, and no dosage adjustment is required.
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.
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.
Effects on ability to drive and use machines:
Tramadol may cause somnolence and dizziness and these effects may be potentiated by alcohol and other CNS depressants. Ambulant 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.
Incompatibilities:
Precipitation will occur if Tramadol is mixed in the same syringe with injections of diazepam, diclofenac sodium, indometacin, midazolam and piroxicam.
Tramadol must not be mixed with other medicinal products except those mentioned in section of excipients.
Use during Pregnancy or lactation:
Animal studies with tramadol at very high doses have revealed 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: Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In the immediate post-partum period, for maternal oral daily dosage up to 400 mg, this corresponds to a mean amount of tramadol ingested by breast-fed infants of 3% of the maternal weight- adjusted dosage. For this reason tramadol should not be administered during breast-feeding or alternatively, breast-feeding should be discontinued during treatment with tramadol. After a single administration of tramadol however, it is not usually necessary to interrupt breast feeding.
Special precautions for disposal and other handling:
The prepared infusion solution should be made up immediately before use.
Tramadol is physically and chemically compatible for up to:
- 24 hours with 4.2% sodium bicarbonate and Ringer's solution.
Or up to 5 days with the following infusion solutions:
- 0.9% sodium chloride
- 0.18% sodium chloride and 4% glucose
- Sodium lactate compound
- 5% glucose