4.1. Therapeutic indications

Treatment of moderate to severe pain.

4.2. Posology and method of administration

Posology

The dose of Zamadol Melt 50 mg Tablets 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

For oral use:

Acute pain:

An initial dose is 50 - 100 mg depending on the intensity of pain. This can be followed by doses of 50 or 100 mg not more frequently than 4 hourly, and duration of therapy should be matched to clinical need. A total daily dose of 400 mg should not be exceeded except in special clinical circumstances.

Pain associated with chronic conditions:

Use an initial dose of 50 mg and then titrate dose according to pain severity. The initial dose may be followed if necessary by 50 - 100 mg every 4 to 6 hours. The recommended doses are intended as a guideline. Patients should always receive the lowest dose that provides effective pain control. A total daily dose of 400 mg should not be exceeded except in special clinical circumstances. The need for continued treatment should be assessed at regular intervals as withdrawal symptoms and dependence have been reported (see section 4.4 Special warnings and special precautions for use).

Paediatric population:

Zamadol Melt 50 mg Tablets 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 not usually 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 tramadol is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements.

In patients with severe renal and/or hepatic impairment, the use of Zamadol Melt 50 mg Tablets is not recommended.

As tramadol is only removed very slowly by haemodialysis or haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary.

Method of administration

The tablet disperses rapidly in the mouth and is then swallowed. Alternatively, the tablet can be dispersed in half a glass of water, stirred and drunk immediately independently of meals.

Treatment goals and discontinuation

Before initiating treatment with Zamadol Melt 50 mg Tablets, 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

Hypersensitivity to the active substance tramadol hydrochloride or to any of the excipients listed in section 6.1.

The product must not be administered to patients suffering from acute intoxication or overdose with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs.

In common with other opioid analgesics it must not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal. It must not be administered concomitantly with nalbuphine, buprenorphine or pentazocine (see 4.5, interactions with other medicinal products and other forms of interaction).

Contraindicated in patients suffering from uncontrolled epilepsy.

Tramadol must not be administered during breast-feeding if long term treatment is necessary.

Zamadol Melt 50 mg Tablets are not suitable for children under 12 years of age.

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 Melt 50 mg Tablets 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 Melt 50 mg Tablets 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 Melt 50 mg Tablets. Repeated use of Zamadol Melt 50 mg Tablets 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 Melt 50 mg Tablets 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 Melt 50 mg Tablets 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.

Zamadol Melt 50 mg Tablets are not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, it cannot suppress morphine 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.

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%

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.

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. These factors may worsen symptoms of opioid toxicity.

Alcohol intake and concomitant use of carbamazepine are not recommended during treatment.

Precautions:

Zamadol Melt 50 mg Tablets should be used with caution in patients with head injury, increased intracranial pressure, impairment of hepatic and renal function, decreased level of consciousness and in patients prone to convulsive disorders or in shock.

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

At the recommended doses Zamadol Melt 50 mg Tablets are unlikely to produce clinically relevant respiratory depression. However, care should be taken when treating patients with existing respiratory depression, or excessive bronchial secretion and in those patients taking concomitant CNS depressant drugs.

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.

This medicinal product contains 20 mg aspartame in each orodispersible tablet. Aspartame is a source of phenylalanine, which may be harmful to patients with phenylketonuria.

The mint rootbeer flavouring contains maltodextrin (glucose). Patients with rare glucose-galactose malabsorption should not take this medicine.

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

Concomitant use of the following is contraindicated:

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 (risk of serotonergic syndrome – see below). The possibility of similar interactions occurring between monoamine oxidase inhibitors (including the selective MAO-A and -B inhibitors and linezolid) and tramadol cannot be ruled out.

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 and that a withdrawal syndrome may occur.

Sedative medicines such as benzodiazepines or related drugs:

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).

Concomitant therapeutic use of tramadol and serotonergic agents 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).

Concomitant administration of Zamadol Melt 50 mg Tablets with other centrally acting drugs (including other opioid derivatives, benzodiazepines, barbiturates, other anxiolytics, hypnotics, sedative anti-depressants, sedative anti-histamines, neuroleptics, centrally acting anti-hypertensive drugs, baclofen and alcohol) may potentiate CNS depressant effects including respiratory depression. The concomitant use of Zamadol Melt 50 mg Tablets with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death.

Simultaneous administration of carbamazepine markedly decreases serum concentrations of tramadol to an extent that a decrease in analgesic effectiveness and a shorter duration of action may occur.

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 medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions (see sections 4.4 Special warnings and special precautions for use and 5.2 Pharmacokinetic properties).

There have been isolated reports of interaction with coumarin anticoagulants resulting in an increased international normalised ratio (INR) and so care should be taken when commencing treatment with tramadol in patients on anticoagulants.

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.

4.6. Fertility, pregnancy and lactation

Pregnancy:

In humans, there are no sufficient data to assess malformative effect of tramadol when given during the first trimester of pregnancy. Animal studies have not shown any teratogenic effects, but at high doses, foetotoxicity due to maternotoxicity appeared (See 5.3 Preclinical data).

Tramadol crosses the placenta, therefore as with other opioid analgesics, chronic use of tramadol during the third trimester may induce a withdrawal syndrome in new-born. At the end of pregnancy, high dosages, even for short term treatment, may induce respiratory depression in new-born. There is inadequate evidence available on the safety of tramadol in human pregnancy, therefore Zamadol Melt 50 mg Tablets should not be used in pregnant woman.

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.

4.7. Effects on ability to drive and use machines

Zamadol Melt 50 mg Tablets may cause drowsiness and this effect may be potentiated by alcohol and other CNS depressants. Ambulant patients should be warned not to drive or operate machinery if affected.

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 table below presents possible adverse drug reactions in system organ class order and sorted by frequency.

Frequency:

Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000), not known (cannot be estimated from the available data).

Tabulated list of adverse reactions

Organ System

Frequency

Adverse drug reaction

Immune system disorders

Rare

- allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.

Metabolism and nutritional disorders

Rare

- changes in appetite.

Not known

- hypoglycaemia, hyponatremia

Psychiatric disorders

Rare

The following may vary in nature and intensity depending on the individual (see below):

- changes in mood (e.g. elation, dysphoria)

- changes in activity (e.g. suppression, increase)

- change in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders)

- hallucinations

- confusion

- sleep disturbances

- nightmares

- dependency (see below)

Nervous system disorders

Very Common

- dizziness

Common

- headache

- drowsiness

Rare

- epileptiform convulsions (see below)

- paraesthesia

- tremor.

Very rare (including isolated cases)

- vertigo

Not known

- serotonin syndrome

Eye disorders

Rare

- blurred vision

Cardiac disorders

Uncommon

- cardiovascular regulation (e.g. palpitation, tachycardia, postural hypotension, cardiovascular collapse). These effects may occur especially on intravenous administration and in patients who are physically stressed.

Rare

- bradycardia, increase in blood pressure

Vascular disorders

Very rare (including isolated cases)

- flushing

Respiratory, thoracic and mediastinal disorders

Very rare (including isolated cases)

- worsening of asthma, respiratory depression (see below)

Not known

- hiccups

Gastrointestinal disorders

Very Common

- vomiting, nausea

Common

- constipation, dry mouth

Uncommon

- retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating)

Hepatobiliary disorders

Very rare (including isolated cases)

- increase in liver enzyme values (a few isolated cases have been reported)

Skin and subcutaneous tissue disorders

Common

- sweating

Uncommon

- dermal reactions (e.g. pruritus, rash, urticaria)

Musculoskeletal, connective tissue and bone disorders

Rare

- motorial weakness

Renal and urinary system disorders

Rare

- micturition disorders (difficulty in passing urine and urinary retention)

General disorders

Common

- fatigue

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.

Drug dependence

Repeated use of Zamadol Melt 50 mg Tablets 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).

Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms.

Epileptiform convulsions are rare and occur 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”.

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.

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 overdose are typical of other opioid analgesics, and include miosis, vomiting, hypotension, cardiovascular collapse, sedation and coma, epileptic seizures and respiratory depression. Respiratory failure may also occur. Serotonin syndrome has also been reported.

Supportive measures such as maintaining the patency of the airway and maintaining cardiovascular function should be instituted; naloxone should be used to reverse respiratory depression; fits can be controlled with diazepam. Naloxone administration may increase the risk of seizures. The use of benzodiazepines (intravenously) should be considered for patients with seizures.

Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with Zamadol Melt 50 mg Tablets with haemodialysis or haemofiltration alone is not suitable for detoxification.