4.1. Therapeutic indications

Sendolor is indicated for the treatment of severe acute pain, cancer pain and breakthrough cancer pain.

4.2. Posology and method of administration

Adults

Intravenous:

2.5 to 15 mg administered over 4-5 minutes.*

Subcutaneous, intramuscular:

5 - 20 mg, usually 10 mg per time, if necessary, up to every 4 hours

Epidural:

initially 5 mg, if necessary after one hour 1-2 mg, repeated if necessary, usually to a total of 10 mg per day.

Epidural infusion:

initially 3.5 to 7.5 mg per day (=24 hours), if necessary increased by 1-2 mg per day.

Intrathecal:

0.2 - 1 mg one time, preferably not repeat; with an implanted micro-infusion system, the daily dose can gradually increase to 25 mg (after 40 weeks of continuous treatment).

Continuous subcutaneous infusion in case of palliative care:

If the patient becomes unable to swallow, generally morphine is administered as a continuous subcutaneous infusion. The equivalent parenteral dose of morphine is about half of the oral dose. If breakthrough pain occurs give a subcutaneous (preferable) or intramuscular injection equivalent to one-tenth to one-sixth of the total 24-hour subcutaneous infusion dose.

Children and adolescents

Intravenous:

Only where particularly rapid onset of action is required: 0.05 - 0.1 mg / kg body weight, very slowly administered (dilution with isotonic sodium chloride solution is recommended).

Subcutaneous, intramuscular:

0.05 - 0.2 mg / kg of body weight, if necessary, up to every 4 hours. Single dose should not exceed 10 mg.

Elderly

Generally morphine doses need to be reduced in elderly patients.

Subcutaneous, intramuscular, intravenous: 2.5 - 10 mg at a time. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range with incremental titration to the desired effect.

*, Careful consideration should be given when administering high doses, like 10 mg to 15 mg, to naive patients.

In case of bad circulation slow intravenous administration should be used, since subcutaneously or intramuscularly the active substance is not sufficiently absorbed.

For premedication up to 10 mg may be given by subcutaneous or intramuscular injection 60 to 90 minutes before surgery.

For continuous intravenous administration maintenance doses generally range from 0.8 to 80 mg/hour, although some patients require and been given much higher doses.

The recommended initial dose for continuous epidural infusion in opioid-naïve patients ranges from 3.5 to 7.5 mg daily; those who have some degree of opioid tolerance may be given 4.5 to 10 mg daily. However, dosage requirements may increase significantly during treatment and up to 20 to 30 mg daily may be required in some patients.

Intrathecal use

The dose of morphine may be reduced when it is combined intrathecally with bupivacaine.

Patient-controlled analgesia (PCA)**

PCA is used to mean intermittent or continuous parenteral infusion of morphine with patient-controlled administration of rescue doses on an "as needed" basis programmed into a portable pump. Postoperatively, the PCA technique may involve intermittent patient-directed rescue boluses and/or a baseline infusion plus patient directed rescue dosing. PCA is given intravenously or subcutaneously.

A PCA device for chronic cancer pain is indicated when:

1. Oral administration is not advisable.

2. When the total dose of oral morphine is large.

3. When PCA is necessary to obtain better compliance.

4. When PCA provides immediate relief from incident pain.

For patients with breakthrough cancer pain despite optimised round the clock opioid use, an intravenous bolus of 20% of the total daily equivalent oral morphine dose of the background opioid therapy is recommended.

Technically, the patient self-administers a rescue dose by pushing a button that activates a program operating a computerised drug injector connected to the infusion pump. The rescue dose is 25-50% of the continuous hourly dose, with a minimum PCA bolus of 1 mg morphine. A lockout interval (the time during which no drug is delivered even if an attempt is made to activate the machine) is programmed in and may be set for intervals of 5 min to hourly or 2 hours intervals for incident or breakthrough. Patients and responsible family members or the principal caregiver should be trained in pump operation, battery changing, and interpretation of pump alarms. A 24 hours telephone contact and a constant home care support system are essential for outpatient PCA.

**Local clinical guidelines could differ from the above.

Impaired renal function

Morphine is one of the opioids whose dosing is greatly affected by renal failure. As a result of decreased renal clearance, accumulation of the metabolites can lead to serious adverse effects. Morphine doses must be carefully titrated in patients with decreased renal function or renal failure.

Hepatic impairment

In patients with severe hepatic impairment, a doubling of the dose interval should be considered. Caution is advised when giving morphine to patients with hepatic impairment.

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.

4.3. Contraindications

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

- Respiratory depression; obstructive airways disease; excessive bronchial secretions; during a bronchial asthma attack or in heart failure secondary to chronic lung disease.

- Head injury; raised intra-cranial pressure.

- Coma.

- Convulsion disorders.

- Ulcerative colitis.

- Presence of a risk of paralytic ileus.

- Biliary and renal tract spasm.

- Acute alcoholism.

- Phaeochromocytoma.

- Moderate to severe renal impairment (glomerular filtration rate <20 ml/min).

- Severe or acute liver failure.

- Patients receiving monoamine oxidase inhibitors or within two weeks of discontinuing such treatment.

4.4. Special warnings and precautions for use

As with other narcotics, a dose reduction may be appropriate in elderly patients, in patients with Hypothyroidism, renal and chronic hepatic disease.

Addictive agent. Take extreme caution when prescribing this drug. The dose may need to be reduced in bronchial asthma or in case of excessive presence of bronchial secretions, cyanosis, head injuries, hypotension associated with hypovolaemia, hypothyroidism, impaired hepatic and renal function (see also section 4.2), inflammatory bowel diseases and ileus, pancreatitis, bile duct spasm or after biliary duct surgery and after surgical anastomosis, urinary tract spasm, coma, convulsive disease, delirium tremens and in the treatment of elderly patients.

Morphine hydrochloride injection should be used with caution in debilitated patients; hypopituitarism; prostatic hypertrophy; shock; diabetes mellitus; diseases of the biliary tract; myasthenia gravis; cardiac arrhythmias; excessive obesity; hypotension and severe cardiac failure. It should also be used with caution post-operatively following total joint arthroplasty (colonic pseudo-obstruction).

Morphine should not be used in idiopathic or psychopathological pain conditions.

For the treatment with MAO inhibitors, see section 4.5 Interaction with other medicinal products and other forms of interaction.

Concomitant use of other opioid analgesics such as codeine, administered orally or by some other route of administration, increases the CNS depressant effect of morphine (see section 4.5 – Interaction with other medicinal products and other forms of interaction).

Hyperalgesia that does not respond to a further dose increase of morphine may occur in particular in high doses. A morphine dose reduction or change in opioid may be required.

Morphine has an abuse potential similar to other strong agonist opioids, and should be used with particular caution in patients with a history of alcohol or drug abuse.

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.

Sendolor contains sodium

Sendolor 1 mg/ml, solution for infusion contains 354.5 mg sodium per 100 ml, equivalent to 17.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Sendolor 10 mg/ml, solution for infusion contains 295.4 mg sodium per 100 ml, equivalent to 14.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Sendolor 20 mg/ml, solution for infusion contains 236.3 mg sodium per 100 ml, equivalent to 11.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Paediatric population

Respiratory depression is a risk in all children.

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.

Adrenal insufficiency

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.

Decreased sex hormones and increased prolactin

Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or cessation of amenorrhea.

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.

Rifampicin

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 (see section 4.5).

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).

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

Concomitant use of 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 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).

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over- the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance.

The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give 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.

Dependence and withdrawal (abstinence) syndrome

Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance. The risk increases with the time the drug is used, and with higher doses. Symptoms can be minimised with adjustments of dose or dosage form, and gradual withdrawal of morphine. For individual symptoms, see section 4.8.

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.

However, when doses of morphine are carefully titrated against pain, clinically significant respiratory depression, dependence, rapid tolerance and euphoria rarely develop. Clinically significant tolerance to morphine is unusual in cancer patients with severe pain.

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

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

The combined use of morphine and sedative drugs like anaesthetics, antihistamine drugs, anxiolytic drugs, hypnotics, tricyclic antidepressants and phenothoazine, could increase the risk of sedation and ventilator depression.

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, low blood pressure, 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).

In a crossover study in 10 healthy subject rifampicin 600 mg daily for 13 days increased the clearance of a single oral 10-mg dose of morphine by 49%, and its analgesic effects were abolished. The mechanism of this interaction is not clear and the clinical relevance of this interaction for parenteral presentations of morphine is not known.

Cimetidine increases opioid analgesia with negligible respiratory depression.

Nimodipine, a calcium channel blocker, enhances analgesia in cancer patients requiring regular dose increments of morphine to control pain.

MAO inhibitors may potentiate the effect of morphine (respiratory depression and hypotension).

Serotonergic syndrome has been reported with concomitant use of pethidine and MAO inhibitors, and can therefore not be excluded in the combination of morphine and MAO inhibitors.

Small amounts of alcohol can dramatically potentiate the weak respiratory depressant effect of morphine. The combination should therefore be avoided.

Combined morphine agonists/antagonists (buprenorphine, nalbuphine, pentazocine) reduce the analgesic effect by competitive blocking of receptors, thereby increasing the risk of withdrawal symptoms.

Gabapentin may enhance the analgesic effect of morphine.

Other CNS depressants:

The CNS depressant effects of morphine are increased by the co-administration of CNS depressants including alcohol, anaesthetics, muscle relaxants, hypnotics, sedatives, tricyclics, neuroleptics and phenothiazines as well as other opioid analgesics.

The analgesic effects of opioids tend to be enhanced by the concomitant administration of dexamphetamine, hydroxyzine and some phenothiazines (although the latter may also cause respiratory depression).

Diuretics:

Morphine may reduce the efficacy of diuretics by inducing the release of the antidiuretic hormone.

Anticholinergics:

The combination of morphine with anticholinergics may enhance the constipatory effect and urinary retention.

Antihistamines:

Cimetidine and ranitidine appear to interfere with the metabolism of morphine.

Disulfiram:

The metabolism and excretion of morphine may be inhibited by disulfiram.

Prokinetics:

Increased morphine levels may result from the co-administration of cisapride.

Metoclopramide and domperidone may antagonise morphine's gastrointestinal effects and metoclopramide enhances it sedative effect.

Antibiotics:

Ciprofloxacin concentration may be reduced.

Anti-arrhythmics:

Mexiletine absorption may be delayed by co-administered opiate. Co-administration of morphine with esmolol results in a slight increase in the esmolol levels, but the clinical implications of this increase are not considered very significant.

Enzyme modulating agents:

Animal data suggest that propranolol may increase the toxicity of opioids. Ritonavir can induce the formation of metabolising enzymes made in the liver and can cause increased metabolism of morphine which can reduce the clinical efficacy of the analgesic.

Oral P2Y12 inhibitor antiplatelet therapy

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 co-administered 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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Morphine has the potential to promote the occurrence of chromosomal damage germ cells (see section 5.3). Therefore, men and women of procreative or childbearing potential should take effective contraceptive measures.

Pregnancy

There are insufficient human data to evaluate the potential teratogenic risk. Morphine crosses the placenta. Animal reproduction studies have shown that morphine can cause foetal damage when administered throughout pregnancy (see section 5.3). For this reason, pregnant women should only be given Sendolor when the benefits clearly outweigh potential risks to the foetus.

Regular use during 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 a pregnant woman, 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 may be secreted in breast milk and may cause respiratory depression in the infant.

Fertility

There are no clinical data on the effects of morphine on male or female fertility.

Animal studies have shown that morphine may reduce fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Morphine has major influence on the ability to drive and use machines. It may modify the patient's reactions to a varying extent depending on the dosage and individual susceptibility. Ambulatory patients should be warned not to use machines.

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:

o The 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

In usual doses the commonest adverse effects of opioid analgesics are nausea, vomiting, constipation, drowsiness, and confusion. Tolerance to these (except constipation) generally develops with long-term use. Sedation normally declines after a few days of administration. Nausea and vomiting often decline during ling-term use. Spasm of the biliary and urinary tract may occur in predisposed individuals. The respiratory depressant effect is dose-dependent and rarely a clinical problem. Habituation and tolerance do not usually cause any problems in the treatment of sever cancer pain. Constipation may be treated with appropriate laxatives. Most side-effects are dose-dependent.

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)

- Unknown (cannot be estimated from the available data).

Very common

Common

Uncommon

Rare

Unknown

Immune system disorders

Allergic reaction

Anaphylactic reaction

Anaphylactoid reaction

Psychiatric disorders

Confusion

Insomnia

Agitation

Euphoria

Hallucinations

Changes in mood

Dysphoria

Drug dependence

Nervous system disorders

Drowsiness

Dizziness

Head ache

Somnolence

Sedation

Hyperhidrosis

Convulsions

Hypertonia

Allodynia

Hyperalgesia (see section 4.4)

Eye disorders

Miosis

Cardiac disorders

Palpitations

Bradycardia

Tachycardia

Vascular disorders

Facial flushing

Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Pulmonary oedema

Respiratory depression

Gastrointestinal disorder

Anorexia

Vomiting

Constipation

Nausea

Dry mouth

Skin and subcutaneous tissue disorders

Contact dermatitis

Urticaria

Pruritis

Renal and urinary disorders

Urinary retention

Liver and gallbladder disorders

Alterations in liver enzymes

Reproductive system and breast disorders

Decreased libido

Decreased potency

General disorders and administration site conditions

Pain

Irritation administration site

Drug withdrawal (abstinence) syndrome

Drug tolerance

Muscle rigidity

Drug dependence and withdrawal (abstinence) syndrome

Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance. An abstinence syndrome may be precipitated when opioid administration is suddenly discontinued or opioid antagonists administered, or can sometimes be experienced between doses. For management, see section 4.4.

Physiological withdrawal symptoms include: Body aches, tremors, restless legs syndrome, diarrhoea, abdominal colic, nausea, flu-like symptoms, tachycardia and mydriasis. Psychological symptoms include dysphoric mood, anxiety and irritability. In drug dependence, “drug craving” is often involved. Other symptoms may also develop including hyperkinesia, weakness, insomnia, anorexia, increased blood pressure, increased respiratory rate or heart rate.

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:

United Kingdom

Yellow Card Scheme

Webiste: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. 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.

Symptoms of overdose: Signs of overdose include pin-point pupils, respiratory depression, pneumonia aspiration and hypotension. Circulatory disorders and coma may occur in severe cases. Death may occur from respiratory failure.

Treatment of overdose: Respiratory depression at morphine intoxication can be reversed with naloxone.

Respiratory treatment on the indication (with PEEP in pulmonary oedema). Naloxone cannot replace respiratory therapy in serious intoxication. Intravenous fluids (electrolyte, glucose), blood gas control, acidosis correction. Symptomatic therapy.

Toxicity: Toxic dose for adults (no onset of tolerance) is usually in the range of 30 mg parenterally. Scopolamine, hypnotics and alcohol potentiate toxic effects.