Summary of Product Characteristics - MAROL 100 MG EXTENDED RELEASE TABLETS
SUMMARY OF PRODUCT CHARACTERISTICS
1 DRUG NAME
Marol 100 mg Retardtabletten
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Marol tablets are prolonged-release tablets containing 100 mg tramadol hydrochloride.
For the full list of excipients see section 6.1.
3 PHARMACEUTICAL FORM
Extended release pill.
Marol 100 mg tablets are off-white, round, biconvex tablets with a diameter of 9.1 mm.
4 CLINICAL DATA
4.1 Areas of application
Treatment of moderate to severe pain.
4.2 Dosage and method of administration
Prior to initiating opioid treatment, patients should be discussed to determine a strategy for stopping tramadol treatment to minimize the risk of dependence and withdrawal symptoms (see section 4.4).
route of administration
The dose must be adjusted to the pain intensity and sensitivity of each patient.
Unless otherwise specified, Marol tablets should be taken as follows:
Adults and young people over 12 years:
The usual starting dose is 50 to 100 mg tramadol hydrochloride twice a day, morning and evening.
If pain relief is insufficient, the dose can be increased to:
Tramadol hydrochloride 150 mg or 200 mg twice daily.
For impractical doses at this dosage, other dosages of this drug are available.
Marol tablets must be swallowed whole without breaking or chewing, regardless of meals, with sufficient liquid.
The daily dose of 400 mg tramadol should not be exceeded except in special clinical circumstances.
Under no circumstances should Marol tablets be used longer than absolutely necessary.
If prolonged pain treatment with Marol is required due to the type and severity of the disease, it should be carefully and regularly monitored (if necessary with treatment interruptions) to determine whether and to what extent further treatment is necessary. necessary.
Marol tablets are not suitable for children under 12 years of age.
In general, no dose adjustment is required in patients up to 75 years of age without clinical manifestations of hepatic or renal impairment unrelated to clinical manifestations. Elimination may be prolonged in elderly patients (over 75 years of age). Therefore, if necessary, the administration interval should be extended according to the needs of the patient.
Kidney failure/dialysis and liver failure
The elimination of tramadol is delayed in patients with renal and/or hepatic impairment. In these patients, prolongation of the dosing interval should be carefully considered according to the patient's needs.
Marol tablets are contraindicated:
- in case of hypersensitivity to tramadol hydrochloride or any of the excipients listed in section 6.1.
- in acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs
- in patients who are receiving or have taken MAO inhibitors in the last 14 days (see section 4.5),
- in patients with epilepsy not adequately controlled by treatment
- for use in the treatment of drug withdrawal
4.4 Special warnings and precautions for use
Drug addiction, tolerance and potential for abuse
In all patients, prolonged use of this product, even at therapeutic doses, can lead to drug dependence (addiction). The risks are increased in people with a current or past history of substance use disorders (including alcohol abuse) or mental health disorders (e.g. major depressive disorder).
Additional support and monitoring may be needed when prescribing to patients at risk of opioid abuse.
A complete patient medical history should be taken to document concomitant medications, including over-the-counter and online drugs, and past and current medical and psychiatric conditions.
Patients may find the treatment less effective with chronic use and express a desire to increase the dose to achieve the same level of pain control they originally experienced.
Patients can also supplement their treatment with additional analgesics. These can be signs that the patient is developing tolerance.
The risks of developing tolerance must be explained to the patient.
Excessive or improper use can lead to overdose and/or death. It is important that patients only use the medication prescribed for them in the prescribed dosage and do not pass it on to third parties.
Patients should be closely monitored for signs of abuse, abuse, or addiction.
The clinical need for analgesic treatment should be regularly reviewed.
drug withdrawal syndrome
Before starting treatment with an opioid, patients should be discussed to establish a withdrawal strategy to stop treatment with tramadol.
Withdrawal syndrome may occur after abrupt interruption of treatment or dose reduction. When a patient no longer requires therapy, it is recommended that the dose be decreased gradually to minimize withdrawal symptoms. Gradually tapering off a high dose can take weeks or months.
Opioid withdrawal syndrome is characterized by some or all of the following symptoms: restlessness, watery eyes, runny nose, yawning, sweating, chills, myalgia, mydriasis, and palpitations. Other symptoms such as irritability, restlessness, anxiety, hyperkinesia, tremors, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhea, increased blood pressure, increased breathing or heart rate may also occur.
If women take this drug during pregnancy, there is a risk that their newborns will experience neonatal withdrawal syndrome.
Hyperalgesia can be diagnosed when the patient receiving long-term opioid therapy has increased pain.
This may be qualitatively and anatomically different from pain associated with disease progression or breakthrough pain resulting from the development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction in opioid dose.
Marol tablets should be used with particular caution in opioid-dependent patients with head trauma, shock, reduced consciousness of unknown cause, disorders of the respiratory center or respiratory function, increased intracranial pressure.
The product should be used with caution in opioid-sensitive patients. Caution is advised when treating patients with respiratory depression or when co-administering CNS depressants (see section 4.5) or when the recommended dose is significantly exceeded (see section 4.9) as the possibility of respiratory depression cannot be excluded. in these cases. situations
Opioid analgesics can occasionally cause reversible adrenal insufficiency, necessitating monitoring and glucocorticoid replacement therapy. Symptoms of acute or chronic adrenal insufficiency can include severe abdominal pain, nausea and vomiting, low blood pressure, extreme tiredness, decreased appetite, and weight loss.
Serotonin syndrome, a life-threatening condition, has been reported in patients receiving tramadol in combination with other serotonergic agents or tramadol alone (see sections 4.5, 4.8 and 4.9).
If concomitant treatment with other serotonergic active substances is clinically justified, careful monitoring of the patient is recommended, especially at the beginning of treatment and with dose increases.
Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.
If serotonin syndrome is suspected, dose reduction or treatment discontinuation should be considered depending on the severity of symptoms. Discontinuation of serotonergic drugs usually leads to rapid improvement.
Sleep-Related Breathing Disorders
Opioids can cause sleep-related breathing disorders such as central sleep apnea (CSA) and sleep-related hypoxemia.
The use of opioids increases the risk of CSA in a dose-dependent manner. Consider reducing the total dose of opioids in patients with CSA.
Convulsions have been reported in patients receiving tramadol at recommended doses. The risk may increase when doses exceed the maximum recommended daily dose (400 mg).
In addition, tramadol may increase the risk of seizures in patients taking other medicines that lower the seizure threshold. (see section 4.5). Patients with epilepsy or those prone to seizures should not be treated with tramadol unless there are compelling circumstances.
Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.
Risk of concomitant use of tranquilizers such as benzodiazepines or related drugs:
Concomitant use of tramadol and tranquilizers such as benzodiazepines or related drugs can result in sedation, respiratory depression, coma, and death. Because of these risks, co-prescribing with these sedatives should be reserved for patients for whom alternative treatment options are not available. If it is decided to prescribe tramadol concomitantly with sedatives, the lowest effective dose should be used and the duration of treatment should be as short as possible.
Patients should be carefully monitored for signs and symptoms of respiratory depression and sedation. In this regard, it is strongly recommended that you make patients and their carers aware of these symptoms (see section 4.5).
Tramadol is metabolized by the liver enzyme CYP2D6. If a patient has a deficiency or complete absence of this enzyme, an adequate analgesic effect cannot be obtained. It is estimated that up to 7% of the Caucasian population may suffer from this deficiency. However, if the patient is an ultra-rapid metaboliser, even at commonly prescribed doses, there is a risk of developing opioid toxic side effects.
Common symptoms of opioid toxicity include confusion, drowsiness, shallow breathing, small pupils, nausea, vomiting, constipation, and loss of appetite. In severe cases, these can be symptoms of circulatory and respiratory depression, which can be life-threatening and very rarely fatal. Estimates of the prevalence of ultra-extensive metabolizers in different populations are summarized below:
3,4% bis 6,5%
1,2% bis 2%
3,6% bis 6,5%
1% bis 2%
Postoperative use in children
There are reports in the published literature that postoperative administration of tramadol to children who have had tonsillectomy and/or adenoidectomy for obstructive sleep apnea has resulted in rare but potentially fatal side effects. Extreme caution should be exercised when tramadol is administered to children for postoperative pain relief and close monitoring for symptoms of opioid toxicity, including respiratory depression, should be performed.
Children with impaired respiratory function
Tramadol is not recommended for use in children who may have impaired respiratory function, including neuromuscular disease, severe heart or respiratory problems, lung or upper respiratory tract infection, multiple trauma, or major surgery. These factors can worsen the symptoms of opioid toxicity.
Drug interactions and other interactions
Marol tablets must not be combined with MAO inhibitors (see section 4.3).
Potentially fatal interactions involving the central nervous system, respiratory and cardiovascular functions have been observed in patients treated with MAOIs in the 14 days prior to use of the opioid pethidine. The same interactions with Marol tablets and with MAO inhibitors during treatment with Marol cannot be excluded.
Concomitant use of Marol tablets and other CNS depressants, including alcohol, may potentiate the CNS effects (see section 4.8).
Previous results of pharmacokinetic studies have shown that clinically relevant interactions with simultaneous or previous administration of cimetidine (enzyme inhibitor) are unlikely. The simultaneous or previous administration of carbamazepine (enzyme inducer) can reduce the analgesic effect and shorten the duration of action.
Sedatives such as benzodiazepines or related drugs:
Concomitant use of opioids with tranquilizers such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death due to the additive CNS depressant effects. The dose and duration of concomitant use should be limited (see section 4.4).
The combination of mixed agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not recommended since theoretically the analgesic effect of a pure agonist could be reduced in these circumstances.
Tramadol can induce seizures and increase the potential of selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics, and other drugs that lower the seizure threshold (such as bupropion, mirtazapine, tetrahydrocannabinol) to induce seizures to cause . .
Simultaneous therapeutic use of tramadol and serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors
(SNRIs), MAOIs (see section 4.3), tricyclic antidepressants and mirtazapine can cause serotonin syndrome, a potentially fatal condition (see sections 4.4 and 4.8).
Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased INR with significant bleeding and ecchymosis in some patients.
Other drugs known to inhibit CYP3A4, such as ketoconazole and erythromycin, may inhibit the metabolism of tramadol (N-demethylation) and probably also the metabolism of the active O-demethylated metabolite. The clinical significance of such an interaction has not been studied. (See section 4.8).
A limited number of studies have used the antiemetic 5-HT3 antagonist ondansetron pre- or postoperatively
4.6 Fertility, pregnancy and lactation
Animal studies with tramadol have shown effects at very high doses on organ development, ossification and neonatal mortality. No teratogenic effects have been observed. Tramadol crosses the placenta. Tramadol given before or during labor does not affect uterine contractility. Regular use during pregnancy can lead to drug addiction in the fetus, leading to withdrawal symptoms in the newborn.
If prolonged use of opioids is required in a pregnant woman, inform the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment is available.
Administration during labor and delivery may affect the newborn's breathing and an antidote should be available for the infant.
Use in breastfeeding women is not recommended as tramadol may pass into breast milk and cause respiratory depression in the infant. It is not usually necessary to stop breast-feeding after a single dose of tramadol.
4.7 Effects on ability to drive and use machines
Even when taken as directed, Marol tablets can cause drowsiness and dizziness and thus impair the ability of drivers and machine operators to react. This is especially true in connection with other psychotropic substances and alcohol.
This drug can impair the patient's cognitive functions and ability to drive. This class of drugs is on the list of drugs contained in Regulations under Section 5a of the Road Traffic Act 1988. When prescribing this drug, patients should say:
It is likely that the medicine will affect your ability to drive
Do not drive until you know how the medicine affects you.
It is a criminal offense to drive while under the influence of this drug.
However, you would not commit a crime (referred to as a "legal defense") if:
o The drug was prescribed to treat a medical or dental problem and
o you have taken it in accordance with the prescribing doctor's instructions and the information that came with the medicine
o Your ability to drive safely has not been affected
4.8 Adverse Reactions
The most commonly reported side effects are nausea and dizziness, both of which occur 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
Inferior: >1/10000, <1/1000
Very rare (< 1/10,000)
Not known (cannot be estimated from the available data).
Uncommon: Effects on cardiovascular regulation (palpitations, tachycardia, orthostatic hypotension or cardiovascular collapse). These side effects can occur in particular with intravenous administration and in physically stressed patients.
Rare: bradycardia, increased blood pressure.
Diseases of the nervous system:
Very common: dizziness
Common: headache, drowsiness
Rare: Speech disorders, paraesthesia, tremor, epileptiform seizures, involuntary muscle contractions, incoordination and syncope.
Frequency not known: serotonin syndrome
Epileptiform seizures have occurred mainly after administration of high doses of tramadol or after concomitant treatment with drugs that lower the seizure threshold or may themselves induce seizures (see sections 4.4 and 4.5).
Rare: hallucinations, confusion, delirium, anxiety, sleep disorders and nightmares. After taking Marol tablets, psychological side effects can occur, which vary in intensity and type (depending on personality and duration of treatment). These include changes in mood (usually euphoria, occasionally dysphoria), activity changes (usually suppression, occasionally exacerbation), and changes in cognitive and sensory abilities (eg, decision-making behavior, perceptual disturbances).
Frequency not known: drug dependence (see section 4.4)
Rare: blurred vision, miosis, mydriasis
Respiratory, thoracic and mediastinal disorders:
Rare: respiratory depression, dyspnoea
When the recommended doses are significantly exceeded and other CNS depressants are administered concomitantly (see section 4.5), respiratory depression may occur.
Unknown frequency: hiccups
Worsening of asthma has also been reported, although a causal relationship has not been established.
Very common: nausea
Common: vomiting, constipation, dry mouth.
Uncommon: vomiting, gastrointestinal irritation (sensation of pressure in the stomach, bloated abdomen), diarrhoea.
Skin and subcutaneous diseases:
Less common: skin reactions (e.g. itching, rash, hives)
Diseases of the musculoskeletal system and connective tissue:
Rare: motor weakness
Liver and gallbladder diseases:
In some individual cases, increases in liver enzyme values have been reported in temporal relation to the therapeutic use of tramadol.
Diseases of the kidneys and urinary tract:
Rare: voiding disorders (difficulty urinating, dysuria and urinary retention).
Immune system disorders:
Rare: Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioedema) and anaphylaxis
Disorders of metabolism and nutrition:
Rare: changes in appetite
Frequency not known: hypoglycaemia
General disruptions and management conditions of the website:
Uncommon: drug withdrawal syndrome
Symptoms of withdrawal reactions, similar to those experienced during opioid withdrawal, may include the following: restlessness, anxiety, nervousness, insomnia, hyperkinesia, tremors, and gastrointestinal symptoms. Other symptoms that have been observed very rarely after stopping tramadol are: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms (ie confusion, delusions, depersonalisation, derealisation, paranoia).
Notification of Suspected Side Effects
It is important to report suspected adverse drug reactions after approval. Allows continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are asked to report any suspected adverse reactions via the national yellow card reporting system, website:www.mhra.gov.uk/yellowcardo Purchase the MHRA Yellow Card, no Google Play or the Apple AppStore.
In the case of tramadol intoxication, the same symptoms occur in principle as with all other centrally acting analgesics (opioids). These include, in particular, miosis, vomiting, cardiovascular collapse, impaired consciousness through to coma, convulsions and respiratory depression through to respiratory arrest. Serotonin syndrome has also been reported.
Patients should be made aware of the signs and symptoms of overdose and ensure that family and friends are also aware of these signs and seek immediate medical attention if they occur.
The general emergency measures apply. Keep the airways open (aspiration), maintain breathing and circulation depending on the symptoms.
The antidote for respiratory depression is naloxone. In animal studies, naloxone had no effect on seizures. In this case, diazepam should be administered intravenously.
In the case of oral intoxication, gastrointestinal decontamination with activated charcoal or gastric lavage is recommended only within 2 hours of tramadol ingestion. In the case of poisoning with exceptionally large quantities or slow-release formulations, subsequent gastrointestinal decontamination can be helpful.
Tramadol is minimally removed from serum by hemodialysis or hemofiltration. Therefore, treatment of acute poisoning with Marol tablets with hemodialysis or hemofiltration alone is not suitable for detoxification.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: other opioids; ATC Code No. 02AX02
Tramadol is a centrally acting opioid analgesic.
It is a non-selective full agonist at ^, δ and K opioid receptors with increased affinity for ^ receptors. Other mechanisms contributing to the analgesic effect are inhibition of neural reuptake of norepinephrine and increased serotonin release.
Tramadol has antitussive effects. In contrast to morphine, analgesic doses of tramadol have no respiratory depressant effect over a wide range. Gastrointestinal motility is also less affected. The effects on the cardiovascular system are rather small. The potency of tramadol is reported to be 1/10 (one tenth) to 1/6 (one sixth) that of morphine.
The effects of enteral and parenteral administration of tramadol have been studied in clinical trials involving more than 2,000 pediatric patients ranging in age from neonates to 17 years. Indications for pain management examined in these studies included pain after surgery (mainly abdominal pain), after surgical tooth extraction, due to fractures, burns and trauma, and other painful conditions likely to require analgesic treatment for at least 7 days.
At single doses up to 2 mg/kg or multiple doses up to 8 mg/kg per day (up to a maximum of 400 mg per day), the efficacy of tramadol was superior to placebo and greater than or equal to paracetamol, nalbuphine, pethidine or low doses from morphine. The tests carried out confirmed the effectiveness of tramadol. The safety profile of tramadol was similar in adult and pediatric patients over 1 year (see section 4.2).
5.2 Pharmacokinetic properties
More than 90% of tramadol is absorbed after oral administration. The mean absolute bioavailability is approximately 70%, regardless of concomitant food intake.
The difference between absorbed and unmetabolized available tramadol is probably due to the small first-pass effect. The first-pass effect after oral administration is a maximum of 30%.
Tramadol has a high tissue affinity (Vd,p = 203 ± 40 l). Protein binding is about 20%.
After taking Marol 100 mg tablets, the maximum plasma concentration Cmax 141 ± 40 ng/ml is reached after 4.9 hours. After taking Marol 200 mg tablets, a Cmax of 260 ± 62 ng/ml is reached after 4.8 hours.
Tramadol crosses the blood-brain and placenta barriers. Very small amounts of the substance and its O-demethylated derivative are found in breast milk (0.1% and 0.02% of the administered dose, respectively).
The t^p elimination half-life is approximately 6 hours regardless of the route of administration. In patients over 75 years it can be extended by a factor of 1.4.
In humans, tramadol is primarily metabolised by N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only odesmethyltramadol is pharmacologically active. There are significant inter-individual quantitative differences between the other metabolites. Eleven metabolites have been found in urine to date. Animal experiments have shown that odesmethyltramadol is 2 to 4 times more potent than the original substance. Its t^P half-life (6 healthy subjects) is 7.9 h (range 5.4 to 9.6 h), approximately the same as tramadol.
Inhibition of one or both types of isoenzymes, CYP3A4 and CYP2D6, involved in tramadol biotransformation may affect the plasma concentrations of tramadol or its active metabolite.
Tramadol and its metabolites are almost entirely eliminated via the kidneys. The cumulative urinary excretion is 90% of the total radioactivity of the administered dose. The half-life may be slightly prolonged in the case of impaired liver and kidney function. In patients with liver cirrhosis, elimination half-lives of 13.3 ± 4.9 h (tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol) were determined, in extreme cases 22.3 h or 36 h. In patients with renal insufficiency (creatinine clearance < 5 ml/min), the values were 11±3.2 h or 16.9±3 h, in extreme cases 19.5 h or 43.2 h.
Tramadol has a linear pharmacokinetic profile over the therapeutic dose range.
The relationship between serum concentration and analgesic effect is dose-dependent, but varies considerably in individual cases. A serum concentration of 100 to 300 ng/mL is usually effective.
The pharmacokinetics of tramadol and O-desmethyltramadol following single and multiple oral doses in subjects 1 to 16 years of age were generally similar to those in adults when dose-adjusted for body weight, but with greater inter-subject variability. in children aged 8 years and younger.
In children less than 1 year old, the pharmacokinetics of tramadol and odesmethyltramadol have been studied but not fully characterized. Information from studies in this age group indicates that the rate of formation of O-desmethyltramadol via CYP2D6 increases continuously in neonates and it is assumed that the level of CYP2D6 activity is reached in adults around 1 year of age. In addition, immature glucuronidation systems and immature renal function may result in slow elimination and accumulation of O-desmethyltramadol in children less than 1 year old.
5.3 Preclinical safety data
5.3 Preclinical safety data
After repeated oral and parenteral administration of tramadol for 6 to 26 weeks in rats and dogs and oral administration for 12 months in dogs, haematological, clinical-chemical and histological investigations revealed no evidence of substance-related changes. Manifestations of the central nervous system only appeared after high doses well above the therapeutic range: restlessness, salivation, convulsions and reduced weight gain. Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight, respectively, and dogs tolerated rectal doses of 20 mg/kg body weight without any response.
In rats, tramadol doses of 50 mg/kg/day and above caused maternal toxicity and increased neonatal mortality. In puppies, delays occurred in the form of ossification disorders and delays in vaginal and eye opening. Male fertility was not affected. After higher doses (from 50 mg/kg/day) female animals showed a reduced pregnancy rate. In rabbits, toxic effects occurred in the mothers and skeletal anomalies in the offspring at 125 mg/kg and above.
In some in-vitro test systems there were indications of mutagenic effects. In vivo studies have not shown such effects. According to the current state of knowledge, tramadol is classified as non-mutagenic.
Studies on the tumorigenic potential of tramadol hydrochloride were carried out in rats and mice. The rat study showed no evidence of a substance-related increase in tumor incidence. In the mouse study, there was an increased incidence of hepatocellular adenomas in males (a non-significant dose-related increase from 15 mg/kg) and an increase in lung tumors in females across all dose groups (significant but not significant). . . dose dependent).
6.1 List of excipients
Hochdisperses Siliciumdioxid (E551),
6.3 Duration of Use
6.4 Special storage instructions
This medicinal product does not require special storage conditions.
6.5 Nature and contents of the container
Clear Al/PVC blisters in carton boxes in packs of 10, 20, 30, 50, 60, 90, 100, 120 and 180 tablets.
Opaque Al/PVC blisters in carton boxes in packs of 10, 20, 30, 50, 60, 90, 100, 120 and 180 tablets.
6.6 Special precautions for disposal
6.6 Special precautions for disposal
No special requirements.