4.1. Therapeutic indications

For 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.

Adults and adolescents aged 12 years and over

200 mg tramadol hydrochloride twice daily (corresponding to 400 mg of tramadol hydrochloride/day), morning and evening administration recommended.

The smallest effective analgesic dose should always be used. Daily doses of 400 mg of active substance must not be exceeded, unless exceptional medical reasons require so. A minimum interval of 8 hours must be respected between administrations.

Paediatric population

MAXITRAM SR is not suitable for use in children below 25 kg body weight which in general does not allow for individualized dosage in children below 12 years of age.

Consequently, a more suitable form of administration should be used.

Geriatric patients

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

Renal insufficiency/dialysis and hepatic impairment

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

Note:

The recommended dosages are indicative only. In general, the smallest effective analgesic dose should be used. For the treatment of chronic pain, a pre-established posology must be respected.

For doses not realisable/practicable with this medicinal product other strengths of this medicinal product or other pharmaceutical forms and products are available.

Method of administration

The prolonged-release capsule, hard, must be swallowed whole with sufficient liquid, irrespective of mealtimes.

MAXITRAM SR must never be used for longer than therapeutically absolutely necessary. Should prolonged pain treatment according to the nature and severity of the illness be necessary, a careful evaluation should be carried out at short regular intervals (if necessary by instituting treatment pauses) to check whether or to what extent prolonged treatment is medically necessary.

Treatment goals and discontinuation

Before initiating treatment with MAXITRAM SR 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

MAXITRAM SR must not be used in the following cases:

- hypersensitivity to tramadol or to any of the excipients listed in section 6.1;

- acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs;

- patients who are taking monoamine oxidase inhibitors or have been taking them within the previous two weeks (see section 4.5);

- epilepsy uncontrolled by treatment.

MAXITRAM SR must not be used for the treatment of opioid dependence.

This medicinal product is contraindicated in children below 12 years of age.

4.4. Special warnings and precautions for use

MAXITRAM SR should only be used following a strict benefit-risk evaluation and appropriate precautionary measures in the following cases:

- opioid-dependent patients,

- impaired consciousness of unclear aetiology, shock

- impaired respiratory centre or function,

- increased intracranial pressure, head injury, or brain disease,

- impaired liver or kidney function.

The medicinal product should be used with caution in patients showing sensitivity reactions to opiates.

Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered (see section 4.5), or if the recommended dosage is significantly exceeded (see section 4.9) as the possibility of respiratory depression cannot be excluded in these situations.

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 MAXITRAM SR. Repeated use of MAXITRAM SR 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 MAXITRAM SR 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 MAXITRAM SR 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.

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.

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.

Risk from concomitant use of sedative medicinal products such as benzodiazepines or related active substances

Concomitant use of tramadol and sedative medicinal products such as benzodiazepines or related active substances may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe MAXITRAM SR concomitantly with sedative medicinal products, 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).

Convulsions have been reported in patients taking tramadol at the recommended dosage. Increased risk may be associated with the administration of doses exceeding the recommended daily dose (400 mg). Tramadol can increase the risk of convulsions if combined with other medicinal products that lower the convulsion threshold (see section 4.5). Patients with a history of epilepsy or those susceptible to convulsions should only be treated with tramadol if there are compelling circumstances.

MAXITRAM SR is not suitable for use as a substitute in opioid-dependent patients. Although it is an opiate agonist, tramadol cannot suppress morphine withdrawal symptoms.

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%

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.

The medicinal product contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Benzoic acid content

This medicine contains 14.5 ng of benzoic acid (E210) in each dosage unit containing 200 mg of tramadol.

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

Tramadol should not be combined with MAO inhibitors (see section 4.3).

Life-threatening interactions affecting the central nervous system as well as respiratory and cardiovascular function have been observed in patients who had been treated with MAO inhibitors within 14 days prior to the administration of the opioid pethidine. The same interactions with MAXITRAM SR as with MAO inhibitors cannot be ruled out.

Tramadol 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 medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.

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).

Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.

The concurrent administration of MAXITRAM SR with other centrally acting drugs, including alcohol, may mutually potentiate effects on the CNS (see section 4.8).

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs or with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

Based on available pharmacokinetic results, no clinically relevant interactions are expected with the co-administration or previous administration of tramadol with cimetidine (enzyme inhibitor). Concurrent or previous treatment with carbamazepine (enzyme inducer) may reduce and shorten the analgesic effect.

The combination of a mixture of agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not recommended, since there is a theoretical possibility that the analgesic effect of a pure agonist becomes decreased in such conditions.

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

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.

Other CYP3A4 inhibitors, such as ketoconazole and erythromycin may inhibit both the metabolism of tramadol (N-demethylation) and possibly also the metabolism of the active O-demethylated metabolites. The clinical significance of this interaction is not known.

4.6. Fertility, pregnancy and lactation

Pregnancy

Animal studies with tramadol revealed at very high doses effects on organ development, ossification and neonatal mortality.

Tramadol crosses the placenta.

Insufficient experience is available on the chronic use of tramadol during pregnancy. The repeated administration of tramadol during pregnancy can lead to increased tolerance of tramadol in the fetus and consequently to withdrawal symptoms in the new-born infant after birth. For this reason, MAXITRAM SR should not be used during pregnancy.

Tramadol administered before or during birth does not affect uterine contractility. In new-born infants it may induce respiratory rate changes which normally are not clinically significant.

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

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

4.7. Effects on ability to drive and use machines

MAXITRAM SR may cause drowsiness and blurred vision altering one's capacity to react, so that the ability to drive and use machines or work without a steady foothold is reduced. This applies especially at the start of treatment, when changing over to another treatment, in combination with other centrally active drugs, and particularly if combined with alcohol.

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:

• This medicine is likely to affect your ability to drive.

• Do not drive until you know how the medicine affects you.

• It is an offence to drive while under the influence of this medicine.

• However, you would not be committing an offence (called 'statutory defence') if:

o This medicine has been prescribed to treat a medical or dental problem and

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

o It was not affecting your ability to drive safely.

4.8. Undesirable effects

The most frequent side effects occurring during treatment with MAXITRAM SR are nausea and vertigo, which occur in more than 1 out of 10 patients.

The reactions are classified according to frequency (very common (≥ 1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

System organ class

Very common

(≥ 1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Not known

(cannot be estimated from the available data)

Immune system disorders

allergic reactions (e.g., dyspnea, bronchospasm, wheezing, angioneurotic oedema), anaphylaxis

Metabolism and nutrition disorders

change in appetite

hypoglycaemia

Psychiatric disorders

hallucinations, confusion, sleep disturbances, delirium, anxiety, night-mares

Nervous system disorders

dizziness

headaches, somnolence

paraesthesia, tremor, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, syncope, speech disorders

Serotonin syndrome

Eye disorders

blurred vision, miosis, mydriasis

Cardiac disorders

effects on cardiovascular regulation: palpitations, tachycardia.

bradycardia

Vascular disorders

cardiovascular regulation (postural hypotension or cardiovascular collapse.

Respiratory, thoracic and mediastinal disorders

dyspnoea, respiratory depression

Hiccups

Gastrointestinal disorders

nausea

vomiting, constipation, dry mouth

retching, diarrhoea, gastrointestinal discomfort (a feeling of pressure in the stomach, bloating)

Skin and subcutaneous tissue disorders

hyperhidrosis

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

Musculoskeletal and connective tissue disorders

motorial weakness

Renal and urinary disorders

disorders of micturition (dysuria and urinary retention)

General disorders and administration site conditions

fatigue

Investigations

increased blood pressure

Drug dependence

Repeated use of MAXITRAM SR 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).

For cardiac disorders, adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.

For vascular disorders, adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.

For nervous system disorders, convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with medicinal products which can lower the seizure threshold (see sections 4.4 and 4.5).

Psychic adverse reactions may occur following administration of tramadol which vary individually in intensity and nature (depending on personality and duration of treatment). These include changes in mood (usually elation, occasionally dysphoria), changes in activity (usually suppression, occasionally increase), change in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders).

Drug dependence may occur.

Symptoms of withdrawal syndrome, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesias, 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).

For respiratory disorders, if the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5), respiratory depression may occur. Worsening of asthma has been reported, though a causal relationship has not been established.

In a few isolated cases an increase in liver enzyme values has been reported in a temporal connection with the therapeutic use of tramadol.

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

The symptoms of tramadol poisoning are typical of other centrally active analgestics (opioids). In particular, miosis, vomiting, cardiovascular collapse, impaired conciousness and coma, convulsions and respiratory depression as well as respiratory arrest may occur.

Serotonin syndrome has also been reported.

Management

Depending on symptoms, treatment ordinarily consists of general emergency measures for freeing the airways (beware of aspiration!) and for maintaining breathing and cardiovascular function. Naloxone can be used as an antidote in case of respiratory depression. Naloxone has been shown to have no effect on convulsions in animal experiments. Intravenous diazepam should be used instead.

In case of intoxication orally, gastrointestinal decontamination with activated charcoal or by gastric lavage is only recommended within 2 hours after tramadol intake. Gastrointestinal decontamination at a later time point may be useful in case of intoxication with exceptionally large quantities or prolonged-release formulations.

Tramadol is only slightly dialysable. For this reason, haemodialysis or haemofiltration on their own are not suitable for the treatment of acute poisoning with MAXITRAM SR.