Epstell 50 mg Capsule

EPSTELL is indicated for the management of moderate to moderately severe pain.

The dosage should be adjusted to the intensity of pain and the sensitivity of the individual patient.
In principle, the lowest pain-relieving dose should be selected. In general, a total oral daily dose of 400 mg of Tramadol (equivalent to 8 EPSTELL capsules) should not be exceeded. The recommended dosages are guidelines. EPSTELL capsules should be taken as follows:

• Adults and children over 12 years
  Moderate pain: Initial dose of 50 mg of Tramadol (1 EPSTELL capsule), followed by 50 mg or 100 mg 4 u2013 6 hourly.
  Severe pain: Initial dose of 100 mg followed by 50 mg or 100 mg 4 u2013 6 hourly.
• Special populations
  Elderly population: A downward adjustment of the dose and/or prolongation of the interval between doses are recommended in the elderly over 75 years.
  Renal impairment: In patients with renal insufficiency, the elimination of tramadol hydrochloride, as in EPSTELL is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements. In cases of severe renal insufficiency EPSTELL capsules are not recommended.
  Hepatic impairment: In patients with hepatic insufficiency the elimination of tramadol hydrochloride, as in EPSTELL is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements. In cases of severe hepatic insufficiency EPSTELL capsules are not recommended.
  Paediatric population: On account of the high dosage strength, EPSTELL capsules are not intended for children below the age of 12 years.
  Duration of treatment: Under no circumstances should EPSTELL capsules be given for longer than absolutely necessary. If the nature and severity of the disease require long-term pain treatment, careful checks should be carried out initially and at regular intervals to assess efficacy and adverse events and to what extent further treatment with EPSTELL capsules is necessary.
  Method of administration: Capsules are to be taken whole, not divided or chewed, with sufficient liquid, with or without food.

• Hypersensitivity to the tramadol hydrochloride or opioids or any of the excipients listed in section 6.1.
• All children younger than 12 years of age (See section 4.4)
• Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.
• In acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic medicines.
• It should not be administered to patients who are receiving monoamine oxidase (MAO) inhibitors or within two weeks of their withdrawal.
• EPSTELL capsules should not be given to patients with epilepsy.
• EPSTELL capsules must not be used for narcotic withdrawal treatment.
• EPSTELL capsules should not be given to patients with respiratory depression, or in the presence of cyanosis and excessive bronchial secretions.
• EPSTELL capsules should not be given to patients with increased intracranial pressure or central nervous depression due to head injury or cerebral disease.
• EPSTELL capsules should not be used in pregnant and breastfeeding women (see section 4.6).

Tramadol 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 the product should only be used with caution. Concomitant use of EPSTELL and sedating medicines such as benzodiazepines or related substances, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedating medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe EPSTELL concomitantly with sedating medicines, the lowest effective dose of EPSTELL should be used, and the duration of the concomitant treatment should be as short as possible. The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper daily dose limit (400 mg). In addition, tramadol may increase the seizure risk in patients taking other medicines that lowers the seizure threshold (see section 4.5). Patients with epilepsy or those susceptible to seizures should be only treated with tramadol if there are compelling circumstances.

Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant medicines 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.

Sleep-related breathing disorders: Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Serotonin Syndrome: Serotonin syndrome, a potentially life-threatening condition, has been reported in patients receiving tramadol in combination with other serotonergic medicines or tramadol alone (see sections 4.5, 4.8 and 4.9). If concomitant treatment with other serotonergic medicines is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose escalations. Symptoms of serotonin syndrome may include mental status change, autonomic instability, neuromuscular abnormalities and/or gastrointestinal symptoms. Serotonin syndrome is likely when one of the following is observed:

• Spontaneous clonus
• Inducible or ocular clonus with agitation or diaphoresis
• Tremor and hyperreflexia
• Hypertonia and body temperature > 38 u00b0C and inducible or ocular clonus

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms. Withdrawal of the serotonergic medicines usually brings about a rapid improvement.

Drug dependence, tolerance and Potential for abuse: For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression). Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions. Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient. Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give EPSTELL to anyone else. Patients should be closely monitored for signs of misuse, abuse, or addiction. The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal Syndrome: Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with EPSTELL. Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid medicine withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take EPSTELL during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome. EPSTELL is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.

Hyperalgesia: Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid as in EPSTELL dose.

CYP2D6 metabolism: Tramadol is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect may not be obtained. However, if the patient is an ultra-rapid metaboliser there is a risk of developing side effects of opioid toxicity even at commonly prescribed doses. General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life threatening and very rarely fatal.

Hyponatraemia: Hyponatraemia has been reported with the use of tramadol as in EPSTELL, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatraemia. This hyponatraemia appeared to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resolved with discontinuation of tramadol as in EPSTELL and appropriate treatment (e.g. fluid restriction). During EPSTELL treatment, monitoring for signs and symptoms of hyponatraemia is recommended for patients with predisposing risk factor.

Adrenal insufficiency: Opioid analgesics as in EPSTELL may occasionally cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of acute or chronic adrenal insufficiency may include e.g. severe abdominal pain, nausea and vomiting, low blood pressure, extreme fatigue, decreased appetite, and weight loss.

Paediatric population: EPSTELL is not suitable for children under the age of 12 years.

Post-operative use in children: There have been reports in the published literature that tramadol as in EPSTELL given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events. Extreme caution should be exercised when EPSTELL is administered to children for post-operative pain relief and should be accompanied by close monitoring for symptoms of opioid toxicity including respiratory depression.

Children with compromised respiratory function: EPSTELL is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of opioid toxicity.

Monoamine oxidase inhibitors (MAOIs): EPSTELL 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 EPSTELL.

Central nervous system (CNS) depression-producing medicines, including alcohol: Concomitant administration of EPSTELL with other centrally depressant medicines including alcohol may potentiate the CNS effects (see section 4.8).

Sedating medicines: The concomitant use of opioids with sedating medicines such as benzodiazepines or related substances increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose of EPSTELL and the duration of the concomitant use should be limited (see section 4.4).

Cimetidine: 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.

Carbamazepine: Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action.

Serotonergic medicines: Tramadol as in EPSTELL can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRis), serotonin-norepinephrine reuptake inhibitors (SNRis), tricyclic antidepressants, antipsychotics and other seizure threshold-lowering medicines (such as bupropion, mirtazapine, tehrahydrocannabinol) to cause convulsions. Concomitant therapeutic use of tramadol as in EPSTELL and serotonergic medicines, such as selective serotonin reuptake inhibitors (SSRis), serotonin-norepinephrine reuptake inhibitors (SNRis), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine may cause serotonin syndrome, a potentially life-threatening condition (see sections 4.4 and 4.8).

Coumarin derivatives: Caution should be exercised during concomitant treatment with EPSTELL and coumarin derivatives (e.g. warfarin) due to reports of increased INR with major bleeding and ecchymoses in some patients.

CYP3A4 inhibitors: Other active substances known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol as in EPSTELL (N-demethylation) probably also the metabolism of the active 0-demethylated metabolite. The clinical importance of such an interaction has not been studied (see section 4.8).

Ondansetron: 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.

Pregnancy: Safety during pregnancy and lactation has not been established. Therefore, EPSTELL capsules should not be used in pregnant women. EPSTELL crosses the placenta. Animal studies with EPSTELL revealed effects on organ development, ossification and neonatal mortality. The administration of EPSTELL capsules during pregnancy may lead to habituation in the unborn child. The child may experience withdrawal symptoms after birth (see section 4.3).

Breastfeeding: EPSTELL passes into breastmilk. Mothers on EPSTELL should not breastfeed their infants.

Fertility: Post marketing surveillance does not suggest an effect of tramadol on fertility. Animal studies did not show an effect of tramadol on fertility.

EPSTELL may cause effects such as somnolence and dizziness and therefore may impair the reactions of drivers and machine operators. This applies particularly in conjunction and other psychotropic substances, particularly alcohol.

Summary of the safety profile: The frequent side effects during treatment with Tramadol as in EPSTELL are nausea and dizziness.

a) Tabulated list of adverse reactions: The table below shows all adverse drug reactions (ADRs) observed during clinical trials and postmarket spontaneous reports with tramadol hydrochloride.

System Organ Class Frequency Frequent Less Frequent Not known Immune system disorders allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis Metabolism and nutrition disorders Changes in appetite Hypoglycaemia Psychiatric disorders confusion, hallucinations sleep disturbance, delirium, anxiety and drug dependence nightmares. Changes in mood (euphoria, dysphoria), decreased activity, restlessness and changes in cognitive and sensorial capacity (such as decision behaviour, perception disorders). Nervous system disorders Dizziness, headache, somnolence Sedation, drowsiness, seizures (see section 4.4), amnesia, paraesthesia. speech disorders, tremor, involuntary muscle contraction, abnormal coordination, syncope. Serotonin syndrome Eye disorders Blurred vision, mydriasis, miosis Cardiac disorders Bradycardia, tachycardia, dysrhythmias, palpitation Vascular disorders Flushing, syncope, postural hypotension, cardiovascular collapse, increase in blood pressure. Respiratory, thoracic and mediastinal disorders respiratory depression, dyspnoea, bronchospasm Hiccups Gastrointestinal disorders Nausea, vomiting, dry mouth, dyspepsia, constipation retching, gastrointestinal discomfort (a feeling of pressure in the stomach, bloating), diarrhoea. Hepatobiliary disorders Increase in liver enzymes (Alanine transaminase-ALT; Aspartate transaminase-AST) Skin and subcutaneous tissue disorders hyperhidrosis dermal reactions (e.g. pruritus, rash, urticaria) Stevens Johnson Syndrome, Toxic Epidermal Necrolysis. Musculoskeletal and connective tissue disorders Muscular weakness Renal and urinary disorders micturition disorders (dysuria and urinary retention) General disorders and administration site conditions Fatigue drug withdrawal syndrome # Cases of hyponatraemia and/or SIADH have been reported in patients taking tramadol, usually in patients with predisposing risk factors, such as the elderly or those using concomitant medications that may cause hyponatraemia. # Symptoms of drug withdrawal syndrome, 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, depersonalisation, derealisation, paranoia).

Signs and symptoms: 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. Serotonin syndrome has also been reported.

Treatment of overdose: 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 orally, gastrointestinal decontamination with activated charcoal 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 formulation. Tramadol is minimally eliminated from the serum by haemodialysis or haemo-filtration. Therefore, treatment of acute intoxication with EPSTELL this medic with haemodialysis or haemofiltration alone is not suitable for detoxification.