4.1. Therapeutic indications

Treatment of moderate to severe pain.

4.2. Posology and method of administration

Posology

The dose should be adjusted to the intensity of the pain and the sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected.

Dosage for adults and adolescents from 12 years of age:

The usual initial dose is 50-100 mg twice daily, in the morning and in the evening. This dose may be titrated up to 150-200 mg twice daily according to pain severity.

If long-term pain treatment with tramadol hydrochloride 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.

A total oral daily dose of 400 mg should not be exceeded except in special clinical circumstances.

Paediatric population:

Zamadol SR prolonged-release hard capsules should not be used in children under 12 years of age since safety and efficacy have not been established.

Elderly patients:

A dose adjustment is usually not necessary in patients up to 75 years of age without clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years of age elimination may be prolonged. Therefore, if necessary the dosage interval is to be extended according to the patient's requirements.

Patients with renal or hepatic impairment:

In patients with renal and/or hepatic insufficiency the elimination of Zamadol SR prolonged-release hard capsules is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements. Zamadol SR prolonged-release hard capsules are not recommended for patients with severe hepatic and/or renal impairment.

Method of administration

The capsules are intended for twice daily oral administration and can be taken independently of meal times, swallowed whole with water.

Patients who have swallowing problems:

Zamadol SR prolonged-release hard capsules can be opened, carefully, so that the pellets are deposited on a spoon. The spoon and pellets should be taken into the mouth, followed by a drink of water to rinse the mouth of all pellets. The pellets must not be chewed or crushed.

Treatment goals and discontinuation

Before initiating treatment with Zamadol SR prolonged-release hard capsules, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. When a patient no longer requires therapy with tramadol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4).

4.3. Contraindications

Tramadol must not be used in patients:

• With hypersensitivity to the active substance tramadol hydrochloride or to any of the excipients listed in section 6.1.

• With acute intoxication with hypnotics, centrally acting analgesics, opioids, psychotropic drugs or alcohol.

• If monoamine oxidase inhibitors (specific drugs acting against depression) are taken concomitantly or have been taken within the last 14 days before treatment with Zamadol SR prolonged-release hard capsules.

• Who are suffering from uncontrolled epilepsy.

Tramadol must not be used for narcotic withdrawal treatment.

4.4. Special warnings and precautions for use

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs:

Concomitant use of Zamadol SR prolonged-release hard capsules and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Zamadol SR prolonged-release hard capsules concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of 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).

Tolerance and opioid use disorder (abuse and dependence)

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids such as Zamadol SR prolonged-release hard capsules. Repeated use of Zamadol SR prolonged-release hard capsules can lead to opioid use disorder (OUD). A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of Zamadol SR prolonged-release hard capsules may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before initiating treatment with Zamadol SR prolonged-release hard capsules and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician.

Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

In rare cases at therapeutic doses, tramadol has the potential to cause withdrawal symptoms.

When a patient no longer requires therapy with tramadol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

Zamadol SR prolonged-release hard capsules are not a suitable substitute in opioid dependent patients. The product does not suppress morphine withdrawal symptoms although it is an opioid agonist.

Serotonin syndrome

Serotonin syndrome, a potentially 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 agents 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 changes, autonomic instability, neuromuscular abnormalities and/or gastrointestinal symptoms.

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 drugs usually brings about a rapid improvement.

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. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. 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. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised below:

Population

African/Ethiopian

African American

Asian

Caucasian

Greek

Hungarian

Northern European

Prevalence %

29%

3.4% to 6.5%

1.2% to 2%

3.6% to 6.5%

6.0%

1.9%

1% to 2%

Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit. Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons. The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold (see section 4.5).

Zamadol SR prolonged-release hard capsules should be used with prudence in patients who have shown previous hypersensitivity to opiates, and in patients with severe renal or hepatic impairment, head injury, decreased level of consciousness, increased intracranial pressure, or patients in shock or at risk of convulsions.

At recommended therapeutic doses Zamadol SR prolonged-release hard capsules are unlikely to produce clinically relevant respiratory depression. Care should however be taken when administering Zamadol SR prolonged-release hard capsules to patients with existing respiratory depression or excessive bronchial secretion and in those patients taking concomitant CNS depressant drugs.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (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.

Adrenal insufficiency

Opioid analgesics 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.

Opioid-induced ventilatory impairment (OIVI) and persistent postoperative opioid use (PPOU)

Do not use for acute post-operative pain owing to the increased risk of persistent post-operative opioid use (PPOU) and opioid-induced ventilatory impairment (OIVI).

Paediatric population

Post-operative use in children:

There have been reports in the published literature that tramadol 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 tramadol 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:

Tramadol 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.

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 dose.

Information related to excipients

This medicinal product contains sucrose and therefore should not be used by patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.

4.5. Interaction with other medicinal products and other forms of interaction

Patients treated with monoamine oxidase inhibitors within 14 days prior to the administration of the opioid pethidine have experienced life-threatening interactions affecting the central nervous system as well as the respiratory and circulatory centres. The possibility of similar interactions occurring between monoamine oxidase inhibitors and tramadol cannot be ruled out.

Tramadol may potentiate the CNS depressant effects of other centrally acting drugs (including alcohol) when administered concomitantly with such drugs. The concomitant use of Tramadol with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death.

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

Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), antipsychotics and other seizure threshold lowering drugs (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions (see section 4.4).

Concomitant therapeutic use of tramadol and serotonergic drugs 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).

Administration of Zamadol SR prolonged-release hard capsules together with carbamazepine results in markedly decreased serum concentrations of tramadol which may reduce analgesic effectiveness and shorten the duration of action.

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

The combination of mixed agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not recommended because it is theoretically possible that the analgesic effect of a pure agonist is attenuated under these circumstances.

The analgesic effect of tramadol is in part mediated by inhibition of the re-uptake of norepinephrine and enhancement of the release of serotonin (5-HT). In studies the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirements of tramadol in patients with postoperative pain.

There is no interaction with food.

4.6. Fertility, pregnancy and lactation

Pregnancy:

Zamadol SR prolonged-release hard capsules should not be used during pregnancy as there is inadequate evidence available to assess the safety of tramadol in pregnant women. Tramadol - administered before or during birth - does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant.

Breast-feeding:

Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In the immediate post-partum period, for maternal oral daily dosage up to 400 mg, this corresponds to a mean amount of tramadol ingested by breast-fed infants of 3% of the maternal weight-adjusted dosage. For this reason tramadol should not be used during lactation or alternatively, breast-feeding should be discontinued during treatment with tramadol. Discontinuation of breast-feeding is generally not necessary following a single dose of tramadol.

Fertility:

Animal studies did not show an effect of tramadol on fertility, reproductive performance and development of offspring.

4.7. Effects on ability to drive and use machines

Zamadol SR prolonged-release hard capsules may cause drowsiness and this effect may be potentiated by alcohol, anti-histamines and other CNS depressants. If patients are affected they should be warned not to drive or operate machinery.

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:

- The medicine has been prescribed to treat a medical or dental problem and

- You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

- It was not affecting your ability to drive safely

4.8. Undesirable effects

The most commonly reported adverse drug reactions are nausea and dizziness, both occurring in more than 10% of patients.

Immune system disorders:

Rare (≥ 1/10,000 to < 1/1,000): Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.

Metabolism and nutrition disorders:

Rare (≥ 1/10,000 to < 1/1,000): Changes in appetite.

Frequency not known (cannot be estimated from the available data): Hypoglycaemia, hyponatremia.

Psychiatric disorders:

Rare (≥ 1/10,000 to < 1/1,000): psychiatric side effects may occur following administration of tramadol which 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), hallucinations, confusion, sleep disturbances and nightmares.

Prolonged administration of Zamadol SR prolonged-release hard capsules may lead to dependence (see section 4.4). Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms.

Nervous system disorders:

Very common (≥ 1/10) dizziness.

Common (≥ 1/100 to < 1/10): headache, drowsiness.

Rare (≥ 1/10,000 to < 1/1,000): epileptiform convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with drugs which can lower the seizure threshold or themselves induce cerebral convulsions (e.g. antidepressants or anti-psychotics, see section 4.5 “Interaction with other medicinal products and other forms of interaction”.

Paraesthesia and tremor.

Very rare (< 1/10,000): vertigo.

Not known (frequency cannot be estimated from the available data): Serotonin syndrome

Eye disorders:

Rare (≥ 1/10,000 to < 1/1,000): blurred vision.

Cardiac disorders:

Uncommon (≥ 1/1,000 to < 1/100): effects on cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse effects may occur especially on intravenous administration and in patients who are physically stressed.

Rare (≥ 1/10,000 to < 1/1,000): bradycardia, increase in blood pressure.

Vascular disorders:

Very rare (< 1/10,000): flushing.

Respiratory, thoracic and mediastinal disorders:

Not known (frequency cannot be estimated from the available data): hiccups

Gastrointestinal disorders:

Very common (≥ 1/10): vomiting, nausea.

Common (≥ 1/100 to < 1/10): constipation, dry mouth.

Uncommon (≥ 1/1,000 to < 1/100): retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating).

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.

Skin and subcutaneous tissue disorders:

Common (≥ 1/100 to < 1/10): sweating.

Uncommon (≥ 1/1,000 to < 1/100): dermal reactions (e.g. pruritus, rash, urticaria).

Musculoskeletal, connective tissue and bone disorders:

Rare (≥ 1/10,000 to < 1/1,000): motorial weakness.

Renal and urinary system disorders:

Rare (≥ 1/10,000 to < 1/1,000): micturition disorders (difficulty in passing urine and urinary retention).

General disorders and administration site conditions:

Common (≥ 1/100 to < 1/10): fatigue.

Worsening of asthma has also been reported, though a causal relationship has not been established.

Respiratory depression has been reported. If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5 “Interaction with other medicinal products and other forms of interaction”) respiratory depression may occur.

Drug dependence

Repeated use of Zamadol SR prolonged-release hard capsules can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms of tramadol overdose include vomiting, miosis, sedation, seizures, respiratory depression and hypotension, with circulatory failure and coma. Respiratory failure may also occur. Such symptoms are typical of opioid analgesics. Serotonin syndrome has also been reported.

Treatment of overdose requires the maintenance of the airway and cardiovascular functions. Respiratory depression may be reversed using naloxone and fits controlled with diazepam. Naloxone administration may increase the risk of seizures.

The treatment of acute overdose of tramadol using haemodialysis or haemofiltration alone is not sufficient or suitable due to the slow elimination of tramadol from the serum by these routes.