1 ampoule of 2 ml solution for injection contains 100 mg tramadol hydrochloride.
Excipients/Inactive Ingredients: Sodium acetate 3 H2O, water for injections, nitrogen and argon (as inert gas).
ATC Code: N02AX02.
Pharmacology: Pharmacodynamics: Tramadol is a centrally acting opiate analgesic. It is a non-selective pure agonist on μ-, δ- and κ-opioid receptors with greater affinity to μ-receptors. Other mechanisms contributing to its analgesic action are the inhibition of the neuronal re-uptake of noradrenalin and the intensification of the serotonin release.
Tramadol has an antitussive effect. Contrary to morphine, tramadol in analgesic doses is not respiratory depressant over a wide range. The gastrointestinal motility is also not affected. Effects on cardiocirculatory system are rather low. The active potency of tramadol is specified as 1/10 to 1/6 of that of morphine.
Pharmacokinetics: After oral administration, tramadol is resorbed over 90%. The absolute bioavailability averages to approx. 70%, independent of simultaneous intake of food. The difference between resorbed tramadol and available tramadol in unmetabolised form can probably be explained by a low-degree first-pass metabolism. The first-pass metabolism after oral administration amounts to a maximum of 30%.
After oral application (100 mg) in liquid form, the maximum plasma concentration Cmax after a calculated 1.2 hours is 309 ± 90 ng/ml; after the same dose in solid form, Cmax is 280 ± 49 ng/ml after 2 hours. Tramadol has a high tissue affinity (Vd,β = 203 ± 40 l). The bond to serum proteins is approx. 20%.
Tramadol passes the blood-brain barrier and the placenta. Together with its O-desmethyl derivative, it can be found in mother's milk in very low quantities (0.1% resp. 0.02% of the applied dose).
The elimination half-life t½,β is independent of the method of administration and amounts to about 6 h. In patients over 75 years of age it can be prolonged by a factor of approx. 1.4.
In man, tramadol is mainly metabolised by N- and O-demethylation and by conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyl tramadol is pharmacologically active. The other metabolites differ considerably with regard to quantitative distribution. 11 metabolites have been found in urine so far. According to findings from animal experiments, O-desmethyl tramadol surpasses the effectiveness of the parent substance by a factor of 2-4. Its half-life t½,β (6 healthy probands) is 7.9 h (range 5.4-9.6 h) and lies in the same order of magnitude as tramadol.
The inhibition of the isoenzymes involved in the biotransformation of tramadol, CYP3A4 and/or CYP2D6, may affect the plasma concentration of tramadol or its active metabolite. Until now, no clinically relevant interactions have been reported.
Tramadol and its metabolites are almost completely renally excreted. The cumulative urine excretion is 90% of the total radioactivity of the administered dose. In the case of impairments of the hepatic and renal function, a slight increase of the half-lives is probable. In patients with hepatocirrhosis, elimination half-lives of 13.3 ± 4.9 h (tramadol) resp. 18.5 ± 9.4 h (O-desmethyl tramadol) were determined, with extreme values of 22.3 h resp. 36 h. In patients with renal insufficiency (creatinine clearance <5 ml/min), the values were 11 ± 3.2 h resp. 16.9 ± 3 h, with extreme values of 19.5 h resp. 43.2 h.
In the therapeutic dose range, tramadol demonstrates a linear pharmacokinetic profile. The relation between serum concentrations and analgesic effect is dose-dependent, but there are large variations in individual cases. A serum concentration of 100-300 ng/ml is effective in usual cases.
Toxicology: Preclinical safety data: Some in-vitro test systems indicated mutagenic effects. In-vivo experiments brought no indication of mutagenic effects. According to the available insights and findings, tramadol is not to be considered a mutagenic substance.
Studies on the tumour-causing potential of tramadol hydrochloride were carried out with mice and rats. The rat study yielded no evidence of increased tumour incidences caused by substance. In the mice study, an increased incidence for liver cell adenoma in male animals (from 15 mg/kg dose-dependent, no significant increase) and an increase of lung tumours in female animals of all dose-groups (significant, but no dose-dependent increase) was observed.
In studies on reproduction toxicity, tramadol doses from 50 mg/kg and day caused maternal-toxic effects in rats and an increase of the neonatal mortality. The offspring suffered retardations as ossification disorders and delayed vagina and eye opening. Teratogenic effects were not observed. The fertility of male rats was not impaired. After higher doses (from 50 mg/kg per day), females showed a lower rate of pregnancies. In rabbits, maternal-toxic effects and skeletal anomalies occurred in offspring after doses from 125 mg/kg.
Moderately severe to severe pain.
The dosage should be adjusted to the severity of the pains and the individual sensitivity of the patient.
If not prescribed otherwise, the following doses are recommended for Tramadol-hameln: For moderately severe pains, adults and adolescents aged 12 and up take a single dose of 1 ml Tramadol-hameln (equivalent to 50 mg tramadol hydrochloride). If the pain is not relieved after 30 to 60 minutes, another 1 ml is administered.
If for severe pains a higher need is expected, take a single dose of 2 ml Tramadol-hameln (equivalent to 100 mg tramadol hydrochloride).
For treating severe post-operative pains, higher doses may be required in the initial hours, administered by On-Demand regimen. The 24-hours requirement is usually not higher than during normal administration.
The effect lasts for 4-8 hours, depending on the pains. Generally, daily doses of 8 ml Tramadol-hameln (equivalent to 400 mg tramadol hydrochloride) need not be exceeded. In case of tumour pains and severe post-operative pains, significantly higher doses may be required, however.
Dosage for children:
Children aged between 1 and 11 receive a single dose of 1 to 2 mg tramadol hydrochloride per kilogram bodyweight.
Therefore, dilute Tramadol-hameln with water for injections to facilitate more exact dosage. The following overview shows the concentrations achieved by this (1 ml solution for injection Tramadol-hameln contains 50 mg tramadol hydrochloride): (See Table.)
Click on icon to see table/diagram/image
Example: A child weighing 27 kg shall receive a dose of 1.5 mg tramadol hydrochloride per kilogram bodyweight. You require 40.5 mg tramadol hydrochloride. Thus, dilute 1 ml Tramadol-hameln with 4 ml water for injections. This yields a concentration of 10 mg tramadol hydrochloride per ml. Administer 4 ml (40 mg tramadol hydrochloride) of the diluted solution.
For the treatment of acute pains, Tramadol-hameln is applied as single dose or in few individual doses, so that dose adjustment is not necessary. In the case of chronic pains, dose adjustment is normally not required in elderly patients (up to 75 years), if no clinical manifestation of liver or kidney failure is present. In elderly patients (older than 75 years), elimination time may be prolonged. As a result, the dosage intervals may require individual prolongation.
Hepatic and renal insufficiency / dialysis:
For the treatment of acute pains, Tramadol-hameln is applied as single dose or in few individual doses, so that dose adjustment is not necessary. Patients with severe hepatic and/or renal insufficiency should not be administered Tramadol-hameln. In less severe cases, a prolongation of the dosage interval should be considered. Since only a minor fraction of tramadol hydrochloride is excreted via dialysis and hemofiltration, subsequent administration of Tramadol-hameln for maintaining pain-relief is usually not required.
The recommended doses are reference values. As a basic principle, the lowest active analgesic dose should be used. In the therapy of chronic pains, dosage according to a fixed schedule is preferable.
Method and duration of application:
Tramadol-hameln is injected intravenously, intramuscularly or subcutaneously. Intravenous administration of Tramadol-hameln is done slowly, with 1 ml (equivalent to 50 mg tramadol hydrochloride) per minute.
Intravenous infusion of Tramadol-hameln is also possible after dilution with compatible infusion solutions, particularly 0.9% sodium chloride solution or 5% glucose solution. Tramadol-hameln must not be used longer than therapeutically absolutely necessary. If longer pain-relieving treatment is required, regular checks with short intervals should be carried out (if required, by treatment pauses) to determine whether and in what dose treatment with Tramadol-hameln can be continued.
Symptoms: As a basic principle, tramadol intoxications have similar symptoms as other centrally acting analgesics (opioids). Particular effects to expect are miosis, vomiting, circulatory collapse, depression of consciousness up to comatose conditions, seizures and respiratory depression up to respiratory arrest.
Therapy: The general emergency measures apply for keeping airways open (aspiration!) maintaining respiration and circulation, depending on the symptomatology. Naloxon should be given as antidote in case of respiratory depression. In animal experiments, naloxon had no effect in seizures. In these cases, i.v. diazepam should be used.
Tramadol is only dialysable to a minor extent. Therefore, hemodialysis or hemofiltration alone are not suitable for the treatment of an acute tramadol intoxication.
Tramadol-hameln must not be used in the case of: known hypersensitivity to tramadol or to any of the excipients; acute intoxications with alcohol, soporifics, analgesics, opioids and psychotropic drugs; patients who receive MAO (monoamino oxidase) inhibitors or have received them within the last 14 days (see Interactions); epilepsy that cannot be sufficiently controlled by treatment.
Tramadol-hameln must not be used for drug substitution therapy.
Tramadol-hameln may only be used after strict benefit-risk assessment and appropriate safety measures in the case of: opioids addiction; depression of consciousness of unclear origin, shock; impairments of the respiratory centre and the respiratory function; conditions with increased intracranial pressure after head injury or cerebral diseases; impaired hepatic or renal function.
Caution should be taken in treating patients who react sensitively to opiates.
Seizures have been reported after taking tramadol in the recommended dose. An increased risk is possible with administering doses exceeding the recommended daily dose (400 mg). If simultaneously administering medicines that lower the seizure threshold, tramadol may increase the risk of seizures (see Interactions).
Patients who suffer from epilepsy or who tend to have seizures should be treated with tramadol only in urgent exceptions.
Tramadol has a low dependence potential. After prolonged use, tolerance, mental and physical addiction may develop. Therefore, patients who tend to abuse or become addicted to drugs must only be treated with Tramadol-hameln for a short term and under strict medical monitoring. Tramadol-hameln is not suitable as substitution drug for treating opiate dependency. Although tramadol is an opiate antagonist, it is not able to suppress morphine withdrawal symptoms. Tramadol-hameln must not be administered to children under 1 year.
Effects on ability to drive and use machines: Even if used as directed, Tramadol-hameln can alter reactions by somnolence and blurred vision to such an extent that ability to actively participate in public traffic, operate machines or work without safe support is impaired. This effect is increased at treatment start and after changing preparations, and by interaction with other centrally acting drugs and particularly with alcohol.
If during pregnancy analgesic treatment with opioids is indicated, the administration must be limited to individual doses. Chronic use of Tramadol-hameln must be avoided for the whole duration of the pregnancy, since tramadol passes through the placental barrier and habituation in the child may cause withdrawal symptoms in the newborn after birth.
If administered prior to or during birth, tramadol does not affect the contractility of the uterus. In newborns, the respiratory frequency may be changed, although these are usually not clinically important.
Tramadol is excreted into mother's milk in very low quantities (approx. 0.1% of an i.v. dose). Therefore tramadol should not be used during nursing. In case of a single dose administration of tramadol, nursing usually needs not to be interrupted.
The most frequent side effects that occur during treatment with Tramadol-hameln, are nausea and dizziness, which occur more frequently than in 1 of 10 patients.
Cardiovascular system: Occasional (≤1%, >0.01%): Effect on the circulation regulation (palpitations, increased heart rate, faintness attacks and circulation failure). These side-effects occur particularly if standing upright and upon physical stress.
Rare (≤0.1%, >0.01%): bradycardia (lowering of heart rate), increased blood pressure.
Central nervous system: Very frequent (≥10%): dizziness.
Frequent (≤10%, >1%): headache, somnolence.
Rare (≤0.1%, >0.01%): changed appetite, paresthesia, tremor, reduced rate of breathing, epileptiform seizures.
If the recommended drug doses are exceeded or other cerebrally depressant drugs are taken simultaneously, the rate of breathing may be reduced. Epileptiform seizures mostly occurred after taking high doses of tramadol, or after simultaneous administration of drugs that may cause seizures themselves or reduce the seizure threshold.
Psychology: Rare (≤0.1%, >0.01%): hallucinations, confusion, sleeping disorders and nightmares.
Psychic disorders may occur after treatment with Tramadol-hameln. Their intensity and character is individual, depending on personality and duration of treatment. This includes mood disorders (usually elevated mood, sometimes also irritated mood), altered activity (usually reduced activity, sometimes increased) and changes in the cognitive and sensory performance (altered sensory perception and recognition, which may cause errors in decision behaviour). Addiction may develop.
Sensory organs: Rare (≤0.1%, >0.01%): blurred vision.
Respiratory organs: There have been reports about breathing troubles and worsening of asthma, but a causal connection with the active ingredient tramadol could not be established.
Gastrointestinal tract: Very frequent (≥10%): nausea.
Frequent (≤10%, >1%): vomiting, constipation, dryness of mouth.
Occasional (≤1%, >0.1%): feeling of sickness, diarrhoea, gastric disorders (e.g. abdominal pressure, fullness).
Skin and skin appendages: Frequent (≤10%, >1%): sweating.
Occasional (≤1%, >0.1%): skin phenomena (e.g. itching, eruption, flush).
Locomotor apparatus: Rare (≤0.1%, >0.01%): reduced muscle strength.
Liver, bile: Very rare (≤0.01%): increased transaminase levels.
Kidney: Rare (≤0.1%, >0.01%): miction disorders and reduced diuresis.
General complaints: Rare (≤0.1%, >0.01%): allergic reactions (e.g. breathlessness, "wheezing" breath, swollen skin) and shock reactions (sudden circulatory failure) have occurred very rarely. If Tramadol-hameln is used over a prolonged period of time, an addiction may develop, although the risk is low. After stopping treatment with the medication, withdrawal symptoms may occur.
In patients who were previously treated with MAO (monoamino oxidase) inhibitors within the 14 days prior to administering the opioid pethidine, life-threatening side effects involving the central nervous system and the respiratory and circulatory function have been observed. The same drug interactions with MAO inhibiting agents cannot be excluded for Tramadol-hameln.
If simultaneously administering Tramadol-hameln with substances that also affect the central nervous system, including alcohol, a mutual intensification of the central effects is possible.
In the case of simultaneous or previous application of cimetidine (an enzyme inhibitor), available pharmacokinetic results indicate no clinically relevant drug interactions. If simultaneously or previously administering carbamazepine (an enzyme inductor), a reduction of the analgesic effect and a shortening of the duration of action are possible.
The combination of mixed agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not recommended, since it is theoretically possible that the analgesic effect of a pure agonist is reduced under these circumstances.
Tramadol may cause seizures and increase the seizure-causing potential of selective serotonin re-uptake inhibitors, tricyclic anti-depressants, neuroleptics and other drugs that lower the seizure threshold.
There are isolated reports of a serotonin syndrome in temporal connection with the therapeutic administration of tramadol in combination with other serotoninergic substances, as e.g. selective serotonin re-uptake inhibitors (SSRI). Symptoms of a serotonin syndrome include e.g. confusion, unrest, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea. Withdrawal of the serotoninergic drugs usually results in quick improvement. Medicamentous countermeasures depend on the type and severity of the symptoms.
If simultaneously using tramadol and coumarin derivatives (e.g. warfarin), patients should be carefully monitored, since reduced Quick test results and ecchymoses have been observed in some patients.
Other CYP3A4 inhibiting substances as ketoconazole and erythromycin may inhibit both the metabolism of tramadol (N-demethylation) and possibly the active O-demethylated metabolite. The clinical relevance of this interaction is unknown.
Incompatibilities: Tramadol solutions for injection have proven to be incompatible (not mixable) with solutions for injection of: Diazepam, Diclofenac, Flunitrazepam, Glycerolnitrate, Indomethacin, Midazolam, Phenylbutazone.
Instructions for use and handling: Prepare dilutions of Tramadol-hameln with 0.9% sodium chloride solution or 5% glucose solution only immediately before use.
Do not store above 30°C. Do not freeze.
Keep the ampoules in the outer carton in order to protect from light.
Shelf-Life: 3 years from manufacturing date.
The shelf-life of the preparation is 24 hours at room temperature.
N02AX02 - tramadol ; Belongs to the class of other opioids. Used to relieve pain.
Inj (amp) 50 mg/mL x 2 mL x 10's.