4.1. Therapeutic indications

Sevredol tablets are indicated for the relief of severe pain.

4.2. Posology and method of administration

Posology

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with morphine in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

Route of administration

Oral.

Treatment goals and discontinuation

Before initiating treatment with Sevredol 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 Sevredol tablets, 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).

Duration of treatment

Sevredol tablets should not be used longer than necessary.

Discontinuation of therapy

An abstinence syndrome may be precipitated if opioid administration is suddenly discontinued. Therefore, the dose should be gradually reduced prior to discontinuation.

Adults and children over 12 years.

The dosage of Sevredol tablets is dependent on the severity of pain and the patient's previous history of analgesic requirements. One tablet to be taken every four hours or as directed by a physician. Increasing severity of pain or tolerance to morphine will require increased dosage of Sevredol tablets using 10 mg, 20 mg or 50 mg alone or in combination to achieve the desired relief.

Patients receiving Sevredol tablets in place of parenteral morphine should be given a sufficiently increased dosage to compensate for any reduction in analgesic effects associated with oral administration. Usually such increased requirement is of the order of 100%. In such patients, individual dose adjustments are required.

Elderly

A reduction in adult dosage may be advisable.

Paediatric population

3-5 years

5mg 4-hourly

6-12 years

5-10mg 4-hourly

4.3. Contraindications

Morphine products are contraindicated in patients with:

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

• Severe chronic obstructive pulmonary disease

• Severe bronchial asthma

• Severe respiratory depression with hypoxia and/or hypercapnia

• Paralytic ileus

• Acute abdomen

• Head injury

• Delayed gastric emptying

• Known morphine sensitivity

• Acute hepatic disease

• Concurrent administration of mono-amine oxidase inhibitors or within two weeks of discontinuation of their use.

Not recommended during pregnancy.

Not recommended for children below 3 years of age.

4.4. Special warnings and precautions for use

Sevredol tablets should be administered in caution in patients with:

• Impaired respiratory function

• Respiratory depression (see below)

• Severe cor pulmonale

• Sleep apnoea

• CNS depressant co-administration (see below and section 4.5)

• Opioid Use Disorder

• Acute alcoholism

• Delirium tremens

• Head injury, intracranial lesions or increased intracranial pressure, reduced level of consciousness of uncertain origin.

• Hypotension with hypovolaemia

• Hypothyroidism,

• Adrenocortical insufficiency

• Convulsive disorders

• Biliary tract disorders

• Pancreatitis

• Prostatic hypertrophy

• Inflammatory bowel disorders

• Severely impaired renal function

• Severely impaired hepatic function

• Constipation

As with all narcotics a reduction in dosage may be advisable in the elderly.

Sevredol tablets should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, Sevredol tablets should be discontinued immediately.

Respiratory Depression

The major risk of opioid excess is respiratory depression.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use may increase the risk of CSA in a dose-dependent fashion. Opioids may also cause worsening of pre-existing sleep apnoea (see section 4.8). In patients who present with CSA, consider decreasing the total opioid dosage.

Severe cutaneous adverse reactions (SCARs)

Acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, has been reported in association with morphine treatment. Most of these reactions occurred within the first 10 days of treatment. Patients should be informed about the signs and symptoms of AGEP and advised to seek medical care if they experience such symptoms.

If signs and symptoms suggestive of these skin reactions appear, morphine should be withdrawn and an alternative treatment considered.

Morphine may lower the seizure threshold in patients with a history of epilepsy.

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

Concomitant use of Sevredol 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 Sevredol tablets concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).

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).

Acute chest syndrome (ACS) in patients with sickle cell disease (SCD) Due to a possible association between ACS and morphine use in SCD patients treated with morphine during a vaso-occlusive crisis, close monitoring for ACS symptoms is warranted.

Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive Sevredol tablets for 4 hours prior to the intervention. If further treatment with Sevredol tablets is indicated then the dosage should be adjusted to new post-operative requirements. Sevredol tablets should be used with caution pre-operatively and within the first 24 hours post-operatively. Sevredol tablets should also be used with caution following abdominal surgery as morphine impairs intestinal motility and should not be used until the physician is assured of normal bowel function.

Opioid Use Disorder (abuse and dependence)

Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as Sevredol tablets.

Repeated use of Sevredol 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 Sevredol 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 (eg. major depression, anxiety and personality disorders).

Before initiating treatment with Sevredol 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 behavior (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.

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 online, 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 and do not give this medicine 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.

Hepatobiliary disorders

Morphine may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Patients with diseases of the biliary tract should be monitored for worsening of symptoms while administering morphine.

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 morphine.

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 drug 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 this drug during pregnancy there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

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.

Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include e.g. nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.

Some changes that can be seen with long-term use of opioid analgesics include an increase in serum prolactin, and decreases in plasma cortisol, oestrogen and testosterone in association with inappropriately low or normal ACTH, LH or FSH levels. Clinical symptoms include decreased libido, impotence or amenorrhea which may be manifested from these hormonal changes.

Plasma concentrations of morphine may be reduced by rifampicin. The analgesic effect of morphine should be monitored and doses of morphine adjusted during and after treatment with rifampicin.

Oral P2Y12 inhibitor antiplatelet therapy

Within the first day of concomitant P2Y12 inhibitor and morphine treatment, reduced efficacy of P2Y12 inhibitor treatment has been observed (see section 4.5)

Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, which may be fatal.

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

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 dosage and duration of concomitant use should be limited (see section 4.4).

Morphine should be used with caution in patients who are concurrently receiving other central nervous system depressants, which include, but are not limited to: other opioids, anxiolytics, sedatives and hypnotics (including benzodiazepines), antiepileptics (including gabapentinoids, e.g., pregabalin), general anaesthetics (including barbiturates), antipsychotics (including phenothiazines), other tranquilisers, antidepressants, gabapentin, muscle relaxants, antihypertensives, centrally acting antiemetics and alcohol. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual doses of morphine.

In a study involving healthy volunteers (N=12), when a 60-mg controlledrelease morphine capsule was administered 2 hours prior to a 600-mg gabapentin capsule, mean gabapentin AUC increase by 44% compared to gabapentin administered without morphine. Therefore, patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately.

Mixed agonist/antagonist opioid analgesics (e.g. buprenorphine, nalbuphine, pentazocine) should not be administered to a patient who has received a course of therapy with a pure opioid agonist analgesic.

Medicinal products that block the action of acetylcholine, for example antihistamines, anti-parkinsons and anti-emetics, may interact with morphine to potentiate the anticholinergic adverse effects.

Cimetidine inhibits the metabolism of morphine.

Monoamine oxidase inhibitors are known to interact with narcotic analgesics producing CNS excitation or depression with hyper- or hypotensive crisis. Morphine should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy.

Plasma concentrations of morphine may be reduced by rifampicin (see section 4.4).

A delayed and decreased exposure to oral P2Y12 inhibitor antiplatelet therapy has been observed in patients with acute coronary syndrome treated with morphine. This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is unknown, but data indicate the potential for reduced P2Y12 inhibitor efficacy in patients coadministered morphine and a P2Y12 inhibitor (see section 4.4). In patients with acute coronary syndrome, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered.

Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine, and may possibly decrease plasma concentrations of morphine.

4.6. Fertility, pregnancy and lactation

Pregnancy

Sevredol tablets are not recommended during pregnancy and labour. Regular use in pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate. If opioid use is required for a prolonged period in pregnant women, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Breastfeeding

Administration to nursing women is not recommended as morphine is secreted in breast milk and may cause respiratory depression in the infant.

Fertility

Animal studies have shown that morphine may reduce fertility (see 5.3 Preclinical safety data).

4.7. Effects on ability to drive and use machines

Treatment with Sevredol tablets may cause sedation and it is not recommended that patients drive or use machines if they experience drowsiness.

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 you have this medicine in your body over a specified limit unless you have a defence (called the 'statutory defence').

• This defence applies when:

• 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.

• Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected).”

Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-drivinglaw

4.8. Undesirable effects

In normal doses, the commonest side effects of morphine are nausea, vomiting, constipation and drowsiness. With chronic therapy, nausea and vomiting are unusual with Sevredol tablets but should they occur the tablets can be readily combined with an anti-emetic if required. Constipation may be treated with appropriate laxatives.

The following frequencies are the basis for assessing undesirable effects:

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).

Very Common

Common

Uncommon

Not known

Immune system disorders

Hypersensitivity

Anaphylactic reaction

Anaphylactoid reaction

Psychiatric disorders

Confusion

Insomnia

Agitation

Euphoria

Hallucinations

Mood altered

Drug dependence (see section 4.4)

Dysphoria

Thinking disturbances

Nervous system disorders

Dizziness

Headache

Hyperhidrosis

Involuntary muscle contractions

Somnolence

Convulsions

Hypertonia

Myoclonus

Paraesthesia

Syncope

Allodynia

Hyperalgesia (see section 4.4)

Eye disorders

Visual impairment

Miosis

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Palpitations

Bradycardia

Tachycardia

Vascular disorders

Facial flushing

Hypotension

Hypertension

Respiratory thoracic and mediastinal disorders

Bronchospasm

Pulmonary oedema

Respiratory depression

Cough decreased

Central sleep apnoea syndrome

Gastrointestinal disorders

Constipation

Nausea

Abdominal pain

Anorexia

Dry mouth

Vomiting

Dyspepsia

Ileus

Taste perversion

Pancreatitis

Hepatobiliary disorders

Increased hepatic enzymes

Biliary pain

Exacerbation of pancreatitis

Sphincter of Oddi dysfunction

Skin and subcutaneous tissue disorders

Rash

Urticaria

Acute generalised exanthematous pustulosis (AGEP)

Renal and urinary disorders

Urinary retention

Ureteric spasm

Reproductive system and breast disorders

Amenorrhoea

Decreased libido

Erectile dysfunction

General disorders and administration site conditions

Asthenia

Fatigue

Malaise

Pruritus

Peripheral oedema

Drug withdrawal syndrome

Drug tolerance

Drug withdrawal (abstinence) syndrome neonatal

Drug dependence and withdrawal (abstinence) syndrome

Repeated use of Sevredol 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).

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

Signs of morphine toxicity and overdose are pin-point pupils, skeletal muscle flaccidity, bradycardia, hypotension, respiratory depression, pneumonia aspiration, somnolence and central nervous system depression which can progress to stupor or coma. Death may occur from respiratory failure.

Circulatory failure and deepening coma may occur in more severe cases. Overdose can result in death. Rhabdomyolysis progressing to renal failure has been reported in opioid overdose.

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Toxic leukoencephalopathy has been observed with morphine overdose.

Treatment of morphine overdose:

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

Oral activated charcoal (50g for adults, 1g/kg for children) may be considered if a substantial amount has been ingested within one hour, provided the airway can be protected.

The pure opioid antagonists are specific antidotes against the effects of opioid overdose. Other supportive measures should be employed as needed.

In the case of massive overdose, administer naloxone 0.8 mg intravenously. Repeat at 2-3 minute intervals as necessary, or by an infusion of 2 mg in 500 ml of normal saline or 5% dextrose (0.004 mg/ml).

The infusion should be run at a rate related to the previous bolus doses administered and should be in accordance with the patient's response. However, because the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established.

For less severe overdose, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on morphine. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.