Zydol SR 50mg Tablets
Last Updated on eMC 21-Mar-2017 View document | Grunenthal Ltd Contact details
When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC. For each version, we show the dates it was published on the eMC and the reasons for change.
Updated on 21-Mar-2017 and displayed until Current
Reasons for adding or updating:
- Change to section 4.2 - Posology and method of administration
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 10 - Date of revision of the text
Date of revision of text on the SPC: 07-Jul-2016
Legal Category:POM
Black Triangle (CHM): NO
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Section 4.2: Posology and method of adminstration
- Reference is made to section 5.1
Section 5.1: Pharmacodynamic properties
- Information on use of tramadol in paediatric population is included
Section 5.2: Pharmacokinetic properties
- Information on pharmacokinetics in paediatric population is included
Section 10: Date of revision of the text
- 7 July 2016
Updated on 03-Jul-2014 and displayed until 21-Mar-2017
Reasons for adding or updating:
- Change to section 4.7 - Effects on ability to drive and use machines
- Change to section 10 - Date of revision of the text
Date of revision of text on the SPC: 28-Feb-2014
Legal Category:POM
Black Triangle (CHM): NO
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Section 4.7:Drug driving warning wording added as per MHRA directions:
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:
o The medicine has been prescribed to treat a medical or dental problem and
o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
o It was not affecting your ability to drive safely
Updated on 27-Feb-2014 and displayed until 03-Jul-2014
Reasons for adding or updating:
- Change to section 2 - Qualitative and quantitative composition
- Change to section 3 - Pharmaceutical form
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.6 - Fertility, pregnancy and lactation
- Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC: 29-Jan-2014
Legal Category:POM
Black Triangle (CHM): NO
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Section 2: editorial changesSection 3: editorial changes
Section 4.1: changes to align with PhVWP recommended changes from 2012 - geriatric patients and renal insufficiency/dialysis and hepatic impairment
Section 4.3: align to current QRD template
Section 4.5: deletion of text on combination with mixed agonists/antagonists
addition of text as recommended by PhVWP from 2012 - combination of tramadol and SSRI, SNRI, TCAs and antipsychotics. Symptoms of serotonin syndrome.
Section 4.6: Added 'Post marketing surveillance does not suggest an effect of tramadol on fertility. Animal studies did not show an effect of tramadol on fertility.'
Section 4.8:
- Frequency of Speech disorders changed to Rare
- Frequency of Mydriasis changed to Rare
- Delirium added as a Rare adverse reaction
- Miosis added as a Rare adverse reaction
Updated on 31-Jan-2014 and displayed until 27-Feb-2014
Reasons for adding or updating:
- Change to section 1 - Name of the medicinal product
- Change to section 2 - Qualitative and quantitative composition
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.6 - Fertility, pregnancy and lactation
- Change to section 4.8 - Undesirable effects
- Change to section 4.8 - Undesirable effects - how to report a side effect
- Change to section 10 - Date of revision of the text
Date of revision of text on the SPC: 01-Sep-2013
Legal Category:POM
Black Triangle (CHM): NO
Free-text change information supplied by the pharmaceutical company:
Section 1 - formatting changes
Section 2 - Editorial changes/ align to current QRD template
Section 4.2 - Editorial changes/ align to current QRD template
Section 4.3 - Editorial changes/ align to current QRD template
Section 4.4 - formatting changes
Section 4.5 - formatting changes
Section 4.6 - align to current QRD template
Section 4.8 - addition of hypoglycaemia as a side effect of unknown frequency
- Details on reporting side effects
Section 10 - Spetemebr 2013
Updated on 08-Feb-2011 and displayed until 31-Jan-2014
Reasons for adding or updating:
- Change to section 2 - Qualitative and quantitative composition
- Change to section 3 - Pharmaceutical form
- Change to section 4.2 - Posology and method of administration
- Change to section 4.4 - Special warnings and precautions for Use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.9 - Overdose
- Change to section 5.1 - Pharmacodynamic Properties
- Change to section 5.2 - Pharmacokinetic Properties
- Change to section 6.1 - List of Excipients
- Change to section 6. 3 - Shelf Life
- Change to section 10 date of revision of the text
Date of revision of text on the SPC: 30-Nov-2009
Legal Category:POM
Black Triangle (CHM): NO
Free-text change information supplied by the pharmaceutical company:
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Active substance: tramadol hydrochloride
Zydol SR 50 mg prolonged-release tablets
1 prolonged-release tablet contains 50 mg tramadol hydrochloride.
Excipient: Each prolonged-release tablet contains 2.5 mg lactose monohydrate (see section 4.4).
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Prolonged-release tablets.
rRound, biconvex, pale yellow coloured film-coated tablets, marked with the manufacturer‘s logo on one side, marked T0 on the other side.
- 50 mg tablet: pale yellow coloured, marked T0 on the other side.
4.2 Posology and method of administration
The dose should be adjusted to the intensity of the pain and the sensitivity of the individual patient.
Unless otherwise prescribed, Zydol SR should be administered as follows:
Adults and adolescents above the age of 12 years:
The usual initial dose is 50-100 mg tramadol hydrochloride twice daily, morning and evening. If pain relief is insufficient, the dose may be titrated upwards to 150 mg or 200 mg tramadol hydrochloride twice daily.
For doses not practicable with this strength, other strengths of this medicinal product are available.
The tablets are to be taken whole, not divided or chewed, with sufficient liquid, independent of meals.
The lowest analgesically effective dose should generally be selected. Daily doses of 400 mg active substance should not be exceeded, except in special clinical circumstances.
Zydol SR should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Zydol SR 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.
Children:
Zydol SR is not suitable for children below the age of 12 years.
Geriatric patients:
A dose adjustment is not usually necessary in elderly 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 iInsufficiency/dDialysis and hHepatic iInsufficiency:
In patients with severe renal and/or hepatic insufficiency Zydol SRthe elimination of tramadol is not recommendeddelayed. In moderate casethese patientss prolongation of the dosage intervals should be carefully considered according to the patients requirements. In cases of severe renal and/or severe hepatic insufficiency Zydol SR prolonged-release tablets are not recommended.
4.4 Special warnings and precautions for use
Zydol SR may only be used with particular caution in opioid-dependent patients, patients with head injury, shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, increased intracranial pressure.
In patients sensitive to opiates Zydol SRthe 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.
Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol hydrochloride exceed the recommended upper daily dose limit (400 mg). In addition, tramadol may increase the seizure risk in patients taking other medicinal products that lowers the seizure threshold (see section 4.5). Patients with epilepsy or those susceptible to seizures should be only be treated with tramadol if there are compelling circumstances.
Tramadol has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop. In patients with a tendency to drug abuse or dependence, treatment with Zydol SR should only be carried out for short periods 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.
This medicinal productZydol SR prolonged-release tablets contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Zydol SR should not be combined with MAO inhibitors (see section 4.3).
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 Zydol SR.
Concomitant administration of Zydol SR with other centrally depressant medicinal products including alcohol may potentiate the CNS effects (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 like tramadol may be theoretically reduced in such circumstances.
Tramadol can induce convulsions and increase the potential for selective serotonin re-uptake inhibitors, tricyclic anti-depressants, anti-psychotics and other seizure threshold- lowering medicinal products to cause convulsions.
In isolated cases there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tramadol in combination with other serotoninergic medicinal products such as selective serotonin re-uptake inhibitors (SSRIs) or with MAO inhibitors. Signs of serotonin syndrome may be for example confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea. Withdrawal of the serotoninergic medicinal products usually brings about a rapid improvement. Treatment depends on the nature and severity of the symptoms.
Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased INR with major bleeding 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.
4.8 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: ≥1/10 000, <1/1000
Very rare: <1/10 000
Not known: cannot be estimated from the available data
Cardiovascular disorders:
Uuncommon (≥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.
Rrare (≥1/10000, <1/1000): bradycardia, increase in blood pressure
Nervous system disorders:
Vvery common (≥1/10): dizziness
cCommon (≥1/100, <1/10): headache, somnolence
rRare (≥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:
rRare (≥1/10000, <1/1000): hallucinations, confusion, sleep disturbance, anxiety and nightmares. Psychic adverse reactions may occur following administration of Zydol SR 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:
rRare (≥1/10000, <1/1000): blurred vision
Not known: mydriasis
Respiratory disorders:
rRare (≥1/10000, <1/1000): dyspnoea.
Worsening of asthma has been reported, though a causal relationship has not been established.
Gastrointestinal disorders:
vVery common (≥1/10): nausea
cCommon (≥1/100, <1/10): vomiting, constipation, dry mouth, vomitting
uUncommon (≥1/1000, <1/100): retching,; gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea
Skin and subcutaneous tissue disorders:
cCommon (≥1/100, <1/10): sweating
uUncommon (≥1/1000, <1/100): dermal reactions (e.g. pruritus, rash, urticaria)
Musculo-skeletal disorders:
rRare (≥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:
rRare (≥1/10000, <1/1000): micturition disorders (difficulty in passing urine, dysuria and urinary retention)
General disorders:
cCommon (≥1/100, <1/10): fatigue
rRare (≥1/10000, <1/1000): allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis; Ssymptoms 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, depersonalization, derealization, paranoia).
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, consciousness disorders up to coma, convulsions 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 stomach is to be emptied by vomiting (conscious patient) or gastric irrigation.
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 with oral formulations, 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 or prolonged-release formulations.
Tramadol is minimally eliminated from the serum by haemodialysis or haemo-filtration. Therefore treatment of acute intoxication with Zydol SR with haemodialysis or haemofiltration alone is not suitable for detoxification.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other opioids; ATC-code: N 02 AX 02
Tramadol is a centrally- acting opioid analgesic. It is a non-selective pure agonist at µ, δ and κm, d and k opioid receptors with a higher affinity for the µm receptor. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal re-uptake of noradrenaline and enhancement of serotonin release.
Tramadol 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 Zydol SR 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,ß = 203 ±+ 40 l). It has a plasma protein binding of about 20 %.
After administration of Zydol SR 100 mg the peak plasma concentration Cmax =141 ±+ 40 ng/ml is reached after 4.9 h. A; after administration of Zydol SR 200 mg Cmax 260 ±+ 62 ng/ml is reached after 4.8 hours.
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,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.
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 andor 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.
Zydol SR 50 mg prolonged-release tablets 1 prolonged-release tablet contains 50 mg tramadol hydrochloride. Excipient: Each prolonged-release tablet contains 2.5 mg lactose monohydrate (see section 4.4). For a full list of excipients, see section 6.1. Prolonged-release tablets r - 50 mg tablet: pale yellow coloured, marked T0 on the other side
3 PHARMACEUTICAL FORM
.
Round, biconvex, pale yellow coloured film-coated tablets, marked with the manufacturer‘s logo on one side, marked T0 on the other side..
Unless otherwise prescribed, Zydol SR should be administered as follows:
Adults and adolescents above the age of 12 years: The usual initial dose is 50-100 mg tramadol hydrochloride twice daily, morning and evening. If pain relief is insufficient, the dose may be titrated upwards to 150 mg or 200 mg tramadol hydrochloride twice daily. The tablets are to be taken whole, not divided or chewed, with sufficient liquid, independent of meals. The lowest analgesically effective dose should generally be selected. Daily doses of 400 mg active substance should not be exceeded, except in special clinical circumstances. Zydol SR should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Zydol SR 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. Children: Zydol SR is not suitable for children below the age of 12 years. Geriatric patients: A dose adjustment is not usually necessary in elderly patients (up to 75 years) without clinically manifest hepatic or renal insufficiency. In elderly patients (over 75 years) elimination may be prolonged. Renal i In patients with Zydol SR may only be used with particular caution in opioid-dependent patients, patients with head injury, shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, increased intracranial pressure. In patients sensitive to opiates Zydol SR 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. Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol hydrochloride exceed the recommended upper daily dose limit (400 mg). In addition, tramadol may increase the seizure risk in patients taking other medicinal products that lowers the seizure threshold (see section 4.5). Patients with epilepsy or those susceptible to seizures should Tramadol has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop. In patients with a tendency to drug abuse or dependence, treatment with Zydol SR should only be carried out for short periods 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. Zydol SR should not be combined with MAO inhibitors (see section 4.3). In patients treated with MAO inhibitors in the 14 Concomitant administration of Zydol SR with other centrally depressant medicinal products including alcohol may potentiate the CNS effects (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. The combination with mixed agonist/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not advisable, because the analgesic effect of a pure agonist like tramadol may be theoretically reduced in such circumstances. Tramadol can induce convulsions and increase the potential for selective serotonin re-uptake inhibitors, tricyclic anti-depressants, anti-psychotics and other seizure threshold- In isolated cases there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tramadol in combination with other serotoninergic medicinal products such as selective serotonin re-uptake inhibitors (SSRIs) or with MAO inhibitors. Signs of serotonin syndrome may be for example confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea. Withdrawal of the serotoninergic medicinal products usually brings about a rapid improvement. Treatment depends on the nature and severity of the symptoms. Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased INR with major bleeding 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. 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: ≥1/10 000, <1/1000
Very rare: <1/10 000 Not known: cannot be estimated from the available data Cardiovascular disorders: U R Nervous system disorders: V 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 section Not known: speech disorders
Psychiatric disorders: Eye disorders: Not known: mydriasis Respiratory disorders: Worsening of asthma has been reported, though a causal relationship has not been established. Gastrointestinal disorders: Skin and subcutaneous tissue disorders: Musculo-skeletal disorders: 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: General disorders: 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. 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 with oral formulations, 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 or prolonged-release formulations.
Tramadol is minimally eliminated from the serum by haemodialysis or haemo Pharmacotherapeutic group: other opioids; ATC-code: N 02 AX Tramadol is a centrally- Tramadol has an antitussive effect. More than 90% of Zydol SR is absorbed after oral administration. The mean absolute bioavailability is approximately 70 %, irrespective of the concomitant intake of food. Tramadol has a high tissue affinity (V After administration of Zydol SR 100 mg the peak plasma concentration Cmax =141 ± 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,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. 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 caseFor doses not practicable with this strength, other strengths of this medicinal product are available.
Therefore, if necessary, the dosage interval is to be extended according to the patient's requirements.Insufficiency/dDialysis and hHepatic iInsufficiency:severe renal and/or hepatic insufficiency Zydol SRthe elimination of tramadol is not recommendeddelayed. In moderate casethese patientss prolongation of the dosage intervals should be carefully considered according to the patients requirements. In cases of severe renal and/or severe hepatic insufficiency Zydol SR prolonged-release tablets are not recommended.
4.4 Special warnings and precautions for use
the product should only be used with caution.
be only be treated with tramadol if there are compelling circumstances.
This medicinal productZydol SR prolonged-release tablets contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicinal product.4.5 Interaction with other medicinal products and other forms of interaction
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 Zydol SR.
Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action.
lowering medicinal products to cause convulsions.
4.8 Undesirable effects
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
very common (≥1/10): dizziness
cCommon (≥1/100, <1/10): headache, somnolence
rRare (≥1/10000, <1/1000): changes in appetite, paraesthesia, tremor, respiratory depression, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, syncope.
s 4.4 and 4.5).rRare (≥1/10000, <1/1000): hallucinations, confusion, sleep disturbance, anxiety and nightmares. Psychic adverse reactions may occur following administration of Zydol SR 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.
rRare (≥1/10000, <1/1000): blurred vision
rRare (≥1/10000, <1/1000): dyspnoea.
vVery common (≥1/10): nausea
cCommon (≥1/100, <1/10): vomiting, constipation, dry mouth, vomitting
uUncommon (≥1/1000, <1/100): retching,; gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea
cCommon (≥1/100, <1/10): sweating
uUncommon (≥1/1000, <1/100): dermal reactions (e.g. pruritus, rash, urticaria)
rRare (≥1/10000, <1/1000): motorial weakness
rRare (≥1/10000, <1/1000): micturition disorders (difficulty in passing urine, dysuria and urinary retention)
cCommon (≥1/100, <1/10): fatigue
rRare (≥1/10000, <1/1000): allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis; Ssymptoms 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, depersonalization, derealization, paranoia).
4.9 Overdose
The stomach is to be emptied by vomiting (conscious patient) or gastric irrigation. -filtration. Therefore treatment of acute intoxication with Zydol SR with haemodialysis or haemofiltration alone is not suitable for detoxification.
5.1 Pharmacodynamic properties
02 acting opioid analgesic. It is a non-selective pure agonist at µ, δ and κm, d and k opioid receptors with a higher affinity for the µm receptor. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal re-uptake of noradrenaline and enhancement of serotonin release.
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
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 %.
d,ß = 203 ±+ 40 l). It has a plasma protein binding of about 20 %.
+ 40 ng/ml is reached after 4.9 h. A; after administration of Zydol SR 200 mg Cmax 260 ±+ 62 ng/ml is reached after 4.8 hours.
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.
s of impaired hepatic andor 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.