Sum m ary of Product Characteristics (Sm PC)
1. Nam e of the m edicinal product
Tramadol STADA 100 mg solution f or injection 2. Qualitative and quantitative com position
1ml solution contains 50 mg tramadol hydrochloride.
1 ampoule w ith 2 ml solution f or injection contains 100 mg tramadol hydrochloride Excipients
1 ml solution contains 0,70 mg sodium
For a f ull list of excipients, see section 6.1 3. Pharm aceutical form
Solution f or injection Clear, colourless solution. 4. Clinical particulars
4.1 Therapeutic indications Treatment of moderate to severe pain. 4.2 Posology and m ethod of adm inistration
As w ith all analgesic medicinal products, the dose of tramadol should be adjusted according to the severity of the pain and the clinical response of the individual patient. The duration of the analgesic ef f ect depends on the intensity of pain and lasts f or 4 to 8 hours.
Treatment periods should be short and intermittent as dependence can occur w ith tramadol. The benef its of continued use should be review ed in order to ensure that they outw eigh the risks of dependence (see section 4.4 and 4.8).
Adults and children over 12 years of age
The usual single dose is 50-100 mg tramadol hydrochloride (1-2 ml Tramadol STADA) 3-4 times a day, every 4-6 hours by slow intravenous (2-3 minutes) or intramuscular route or f or administration by inf usion w hen diluted.
If pain control is still inadequate 30 - 60 minutes af ter administration of 50 mg tramadol hydrochloride, the administration of another single dose of 50 mg of tramadol hydrochloride is possible.
In case of severe pain, w here adequate analgesia cannot be reached, a single dose of 100 mg Tramadol hydrochloride should be administered. If pain relief is not achieved, the dosage should be titrated upw ards until pain relief is achieved.
A total daily dose of 400 mg should not be exceeded except f or certain clinical circumstances. Children 1 to 12 years
Tramadol STADA is not suitable f or children younger than 1 year.
The initial paediatric analgesic dose of tramadol is 1 to 2 mg/kg body w eight. A total daily dose of 8 mg active substance/kg body w eight, respectively a maximum of 400 mg, should not be exceeded except f or certain clinical circumstances.
Method of adm inistration
Tram adol STADA 100 m g solution for injection is injected intravenously, intram uscularly or subcutaneously. For this purpose Tramadol STADA has to be diluted w ith w ater for injection. See sectionPoint 6.6 f or f urther inf ormation about suitable dilutions.
Elderly patients
Elderly patients <75 years w ith normal renal and hepatic f unction can be given the adult dose. The elimination half -lif e of tramadol may be prolonged in patients over 75 years of age. In these cases dosing intervals should be prolonged individually.
Patients w ith renal or hepatic insuf f iciency
In patients w ith renal and/or hepatic insuf f iciency the elimination of tramadol is delayed. When single doses are given f or relief of acute pain attacks dose adjustment is not necessar y in these patients. How ever, any dose titration upw ards should be caref ully monitored.
Tramadol is not recommended f or patients w ith severe renal impairment and/or severe hepatic impair ment.
Children 1 to 12 years
Tramadol STADA is not suitable f or children younger than 1 year.
The initial paediatric analgesic dose of tramadol is 1 to 2 mg/kg body w eight. A total daily dose of 8 mg active substance/kg body w eight, respectively a maximum of 400 mg, should not be exceeded except f or certain clinical circumstances.
Method of adm inistration
Tram adol STADA 100 m g solution for injection is injected intravenously, intram uscularly or subcutaneously. For this purpose Tramadol STADA has to be diluted w ith w ater for injection. See Point 6.6 f or f urther inf ormation about suitable dilutions.
Rem ark
The recommended doses are intended as a guideline. Patients should alw ays receive the low est dose that provides ef f ective pain control. Chronic pain management should pref erable be given on a f ixed dosing schedule.
Method of adm inistration
Tramadol STADA 100 mg solution f or injection may be administered subcutaneously, intramuscularly, by slow intravenous injection, or diluted in solution (see Section 6.6) f or administration by inf usion . Duration of adm inistration
Tramadol should never be used longer than absolutely necessary f or pain control. If the nature and severity of the underlying disease suggest the need f or prolonged pain management, continued medical need f or tramadol analgesia should be review ed caref ully at short, regular intervals (i.e. by breaks in treatment).
4.3 Contraindications
Hypersensitivity to tramadol hydrochloride or to any of the excipients
Acute intoxication w ith alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic
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medicinal products
Tramadol should not be administered to patients w ho are receiving monoamine oxidase (MAO) inhibitors or w ithin tw o w eeks of their w ithdraw al
in patients w ith epilepsy not adequately controlled by treatment Tramadol must not be used f or narcotic w ithdraw al treatment. 4.4 Special w arnings and special precautions for use Warnings
Tramadol has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop.
In patients w ith a tendency to medicinal product abuse or dependence, treatment should be f or 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 w ithdraw al symptoms.
Precautions
Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit (400 mg Tramadol). Patients w ith a history of epilepsy or those susceptible to seizures should only be treated w ith tramadol if there are compelling reasons. The risk of convulsions may increase in patients taking tramadol and concomitant medication that can low er the seizure threshold. (See section 4.5).
In patients sensitive to opiates the product Tramadol Stada should only be used w ith caution
Tramadol should be used w ith caution in opioid-dependent patients, patients w ith head injury, increased intracranial pressure, a reduced level of consciousness of uncertain origin and in patients prone to convulsive disorders or in shock.
Care should be taken w hen treating patients (see section 4.9) w ith respiratory depression, or if concomitant CNS depressant medicinal products are being administered or if the recommended dosage is signif icantly exceeded (see section 4.5), as the possibility of respiratory depression cannot be excluded in these situations.
This medicine contains sodium, less than 1 mmol (23 mg) per ampoule, i.e. essentially ‘sodium-free’. 4.5 Interaction w ith other medicinal products and other forms of interaction
Tramadol should not be combined w ith MAO inhibitors (see section 4.3). In patients treated w ith MAO inhibitors in the 14 days prior to the use of the opioid pethidine, lif e-threatening interactions on the central nervous system, respiratory and cardiovascular f unction have been observed. The same interactions w ith MAO inhibitors cannot be ruled out during treatment w ith Tramadol Stada.
Concomitant administration of tramadol w ith other centrally depressant medicinal products including alcohol may potentiate the CNS ef f ects (see section 4.8).
Simultaneous administration of carbamazepine (an enzyme inducer) markedly reduces serum concentrations of tramadol, reducing its analgesic ef f ect and shortening its duration of action. The results of pharmacokinetic studies have so f ar show n that on the concomitant or previous administration of cimetidine (enzyme inhibitor) clinically relevant interactions are unlikely to occur. The combination w ith mixed agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) a nd tramadol is not advisable, because the analgesic ef f ect of a pure agonist may be theoretically reduced in such circumstances.
Tramadol can induce convulsions and increase the potential f or selective serotonin re-uptake inhibitors (f luoxetine, f luvoxamine), tricyclic anti-depressants, anti-psychotics and other seizure threshold low ering medicinal products to cause convulsions (see 4.4 and 5.2).
Caution should be exercised during concomitant treatment w ith tramadol and coumarin derivatives (e.g. w arf arin) due to reports of increased INR and ecchymoses in some patients. The mechanism behind this interaction is unknow n.
In isolated cases there have been reports of serotonin syndrome in a temporal connection w ith the therapeutic use of tramadol in combination w ith other serotonergic medicines such as selective serotonin re-uptake inhibitors (SSRIs) or w ith MAO inhibitors. Serotonin syndrome can be manif ested by symptoms such as conf usion, agitation, f ever, sw eating, ataxia, hyperref lexia, myoclonus and diarrhoea. Withdraw al of serotonergic agent produces a rapid improvement. Treatment depends on the nature and severity of the symptoms.
Other active substances know n to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolis m of tramadol (N-demethylat ion) probably also the metabolis m 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, pre-operative and post-operative administration of the antiemetic 5-HT3 antagonist ondansetron increased the tramadol need in patients w ith post -operative pain. Although not tested, other 5-HT3-receptor antagonists w ould be expected to interact similar ly w ith tramadol. 4.6 Pregnancy and lactation
Pregnancy
There are no adequate and w ell controlled studies w ith tramadol in pregnant w omen. Animal studies revealed ef f ects on organ development, ossif ication and neonatal mortality at maternally toxic doses in rats and rabbits. Teratogenic ef f ects w ere not observed. Theref ore tramadol should be used during pregnancy only if the potential benef it justif ies the potential risk to the f etus.
If pain control w ith opioids is indicated during pregnancy, the use of tramadol should be limited to single doses. Chronic use of tramadol should be avoided in pregnancy because tramadol crosses the placental barrier and the new -born baby may suf f er w ithdraw al symptoms as a consequence of habituation.
Tramadol administered bef ore or during birth does not af f ec t uterine contractility. In neonates it may induce changes in the respiratory rate w hich are usually w ithout clinical signif icance.
Lactation
During lactation very small amounts of tramadol and its metabolites (approximately 0.1% of an intravenous dose) are f ound in human breast milk. Theref ore, tramadol should not be administered during breast-f eeding. How ever, af ter a single administration of tramadol it is usually not necessary to interrupt breast-f eeding.
4.7 Effects on ability to drive and use m achines
Even w hen taken according to instructions Tramadol may cause somnolence and dizziness, and theref ore may impair the reactions of drivers and machine operators. This applies particulary in conjunction w ith alcohol or other CNS depressants. If af f ected, the patient should not drive or operate machinery.
The most commonly reported adverse medicinal product reactions are nausea and dizziness, both occurring in more than 10% of patients.
Within each f requency grouping, undesirable ef f ects are presented in order of decreasing seriousness. In this section f requencies of undesirable ef f ects are def ined as f ollow s: Very common ( >1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not know n (cannot be estimated f rom the available data).
Psychiatric disorders:
Rare: hallucinations, conf usion, sleep disturbance, anxiety and nightmares. Psychic side -ef f ects may occur f ollow ing administration of tramadol w hich vary individually in intensity and nature (depending on personality and duration of medication). 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. Nervous system disorders: Very common: dizziness Common: headache, somnolence
Rare: changes in appetite, paraesthesia, tremor, respiratory depression, epileptif or m convulsions, involuntary muscle contractions, abonormal 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 .
Epileptif orm convulsions occurred mainly af ter administration of high doses of tramadol or af ter concomitant treatment w ith medicinal products w hich can low er the seizure threshold or themselves induce cerebral convulsions (see section 4.5).
Eye disorders: Rare: blurred vision Not know n: mydriasis Cardiac disorders:
Uncommon: cardiovascular deregulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse ef f ects may occur especially on intravenous administration and in patients w ho are physically stressed.
Rare: bradycardia, increase in blood pressure Respiratory, thoracic and mediastinal disorders: Rare: dyspnoea
Worsening of asthma has been reported, though a causal relationship has not been established. Gastrointestinal disorders:
Very common: nausea
Common: vomiting, constipation, dry mouth
Uncommon: retching, gastrointestinal irritation (a f eeling of pressure in the stomach, bloating) diarrhoea
Hepatobiliary disorders:
In a f ew isolated cases an increase in liver enzyme values has been reported in a temporal connection w ith the therapeutic use of tramadol.
Skin and subcutaneous tissue disorders: Common: sw eating
Uncommon: dermal reactions (e.g. Pruritus, rash, urticaria) Musculoskeletal and connective tissue disorders:
Rare: motorial w eakness Renal and urinary disorders:
Rare: micturition disorders (dif f iculty in passing urine, dysuria and urinary retention) General disorders and administration conditions:
Common: f atigue
Rare: Allergic reactions (e.g. dyspnoea, bronchospasm, w heezing, angioneurotic oedema) and anaphylaxis.
Symptoms of w ithdraw al reactions, similar to those occurring during opiate w ithdraw al, may occur as f ollow s: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal
symptoms. Other symptoms that have very rarely been seen w ith tramadol discontinuation include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms (i.e. conf usion, delusions, depersonalization, derealization, paranoia)
4.9 Overdose Symptoms
In principle, on intoxication w ith 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 coma, convulsions and respiratory depression up to respiratory arrest. Treatment
Follow the general rules of emergency management f or maintenance of a patent airw ay (aspiration!) and respiratory and circulatory support, in response to symptoms ; naloxone should be used to reverse respiratory depression; convulsions can be controlled w ith diazepam.
Tramadol is minimally eliminated f rom the serum by haemodialysis or haemo-f iltration. Theref ore treatment of acute intoxication w ith tramadol w ith haemodialysis or haemof iltration alone is inadequate f or detoxif ication.
5. Pharm acological properties
5.1 Pharm acodynam ic properties
Pharmacotherapeut ic group: Analgesics, other opioids. ATC-Code: N02AX02
Tramadol is a centrally acting analgesic. It is a non selective pure agonist at , and opioid receptors w ith a higher af f inity f or the receptor. Other mechanisms that may contribute to its analgesic ef f ect are inhibition of neuronal re-uptake of noradrenaline and enhancement of serotonin release.
5.2 Pharm acokinetic properties Absorption
absolute bioavailability is approximately 70%. The dif f erence betw een absorbed and available parent drug w ould be due to low f irst-pass metabolism, w hich does not exceed 30% f ollow ing oral administration.
Distribution
The data suggest ef f ective distribution and intimate binding to the tissues in view of the values of distribution volume w hich are in excess of body volume. Values of protein binding w ere 4%-20%. Biotransf ormation
Hepatic CYP2D6 appears to be primarily responsible f or O-desmethyl- tramadol f ormation, w hereas f ormation of N-desmethyl-tramadol is catalyzed by CYP2D6 and CYP3A4. Conjugation of the O-demethylation products w ith glucuronic acid occurs. Only O-desmethyl tramadol is pharmacologically active. Approximately 5-10% of the Caucasian population is a poor metaboliser and has reduced activity of the CYP2D6 enzyme. Serum concentrations of tramadol are higher in poor metabolisers versus extensive metabolis ers, w hile O-desmethyltramadol concentrations are low er.
The inhibition of one or both types of the isoenzymes CYP3A4 (e.g. ketoconazole, erythromycin) and CYP2D6 (e.g. f luoxetine, paroxetine, quinidine, ritonavir) involved in the biotransf ormation of tramadol may af f ect the plasma concentrations of tramadol or its active metabolite. The same applies f or enzyme inducers (e.g. rif ampicin, phenytoin). Up to now , clinically relevant interactions have not been reported.
Elimination
Tramadol and its metabolites are excreted almost completely via the kidneys. The cumulative urinar y excretion makes up 90% of the total radioactivity of the dose administered. Irrespective of the mode of administration the terminal half -lif e (t1/2ß) is approx. 6 hours. The half -lif e of O-desmethyl tramadol is comparable to that of tramadol.
Half -lif e can be prolonged by the f actor of 1.4 in patients older than 75 years of age. A small prolongation of the half -lives must be expected in patients w ith impaired liver and kidney f unction. In patients w ith severe organ impairment (e.g. liver cirrhosis, creatinine clearance <5ml/min) a 2 to 3-f old prolongation of the eliminat ion half lif e has been observed.
Linearity/non-linearity
Tramadol show s a linear pharmacokinetic prof ile in the therapeutic dose range.
The relation betw een serum concentrations and analgesic action is dose-dependent, how ever, w ith great dif f erences in the isolated case. A serum concentration of 100-300 ng/ml is generally ef f ective. 5.3 Preclinical safety data
The w eight of evidence f rom in vitro- and in vivo-tests indicate that tramadol does not pose a genotoxic risk to humans. In a mouse carcinogenicity study an increased incidence of common murine tumours (pulmonary and hepatic) w as observed. No such f inding occurred in a rat carcinogenicity study. This f inding is not believed to suggest risk in humans. No ef f ects on f ertility and reproductive perf ormance w ere observed f or tramadol in rats.
6. Pharm aceutical particulars
6.1 List of excipients Sodium acetate trihydrate Water f or injection 6.2 Incom patibilities
This medicinal product must not be mixed w ith other medicinal products except those mentioned in section 6.6
Precipitation w ill occur if Tramadol STADA 100 mg/ml solution f or injection is mixed in the same syringe w ith injections of diazepam, diclof enac sodium, indomethacin, midazolam, piroxicam,
Phenylbutazon, Flunitrazepam, Glyceroltrinitrat. 6.3 Shelf life
Unopened ampoules: 5 years
Shelf lif e af ter opening:
Chemical and physical in-use stability has been demonstrated f or 24 hours at 25°C.
From a microbiological point of view , the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibilit y of the user.
6.4 Special precautions for storage Keep the container in the outer carton. 6.5 Nature and contents of container
Colourless ampoules made of clear neutral borosilicate glass type I Pack sizes 5, 10, 20 ampoules of 2 ml
Not all pack sizes may be marketed. 6.6 Special precautions for disposal
Tramadol Stada 100mg solution f or injection is f or single use only and any solution remaining af ter use should be disposed in an appropriated manner.
Bef ore the use of Tramadol Stada 100 mg solution f or injection it should be inspected visually f or particulate matter, damage of container or any signs of deterioration. Solution f or injection w here such def ects are observed, should be discarded
The chart below indicates the f inal concentrations (1 ml of Tramadol STADA 100 mg injection contains 50 mg tramadol hydrochloride):
Dilution of Tramadol STADA produces the f ollow ing 100 mg w ith w ater f or injection concentrations:
2ml + 2 ml 25.0 mg/ml 2ml + 4 ml 16.7 mg/ml 2ml + 6 ml 12.5 mg/ml 2ml + 8 ml 10.0 mg/ml 2ml + 10 ml 8.3 mg/ml 2ml + 12 ml 7.1 mg/ml 2ml + 14 ml 6.3 mg/ml 2ml + 16 ml 5.6 mg/ml 2ml + 18 ml 5.0 mg/ml
Example: To administer a dose of 1.5 mg tramadol hydrochloride per kg body w eight to a child w eighing 45 kg, 67.5 mg tramadol hydrochloride should be used. So 2 ml of Tramadol STADA® 100 mg injection is diluted w ith 4 ml of w ater f or injection to obtain a concentration of 16.7 mg tramadol hydrochloride per millilitre. Then 4 ml of the diluted solution are administered f or a dose of approximately 67 mg of tramadol hydrochloride.
7. Marketing authorisation holder
To be completed nationally.
8. Marketing authorisation num ber
To be completed nationally.
9. Date of first authorization/renewal of the authorization Date of f irst authorisation:
Date of last renew al: To be completed nationally. 10. Date of revision of the text To be completed nationally.
