4.1 Therapeutic indications
MORPHINE[QA1] HCl STEROP is indicated in adults and children for the treatment of intense pain that cannot be relieved by lower-level analgesics

Posology
The dose-efficacy-safety relationship varies considerably from one patient to another. It is therefore important to assess efficacy and safety frequently, and to adjust the dosage gradually as a function of the patient's needs. There does not appear to be a maximum dose, for as long as the adverse effects can be controlled.
As a guide, the table below summarises the order of dose equivalences as a function of the route of administration.
Route of administration
Equivalent of one dose
Oral route
1 mg
Subcutaneous route
equivalent to 1/2 to 1/3 mg
Intravenous route
equivalent to 1/2 to 1/3 mg
Epidural route
equivalent to 1/10 to 1/20 mg
Intrathecal route
equivalent to 1/50 to 1/200 mg
The simultaneous administration of morphine via two different routes of administration should be avoided because it exposes the patient to a risk of overdose due to the differing pharmacokinetics attached to different routes of administration.
• Treatment of acute pain (notably postoperative pain):
Intravenous and subcutaneous routes
In adults:
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Morphine is usually administered via intravenous route in a fractionated manner ("by titration") at a dose of 1 to 3 mg (mainly depending on the age of the patient) and approximately every 10 minutes, until satisfactory analgesia is achieved (or the onset of adverse effects) and while the patient is being continuously monitored. If relay treatment proves necessary, use can be made of either subcutaneous injections of 5 to 10 mg every 4 to 6 hours, or of intravenous patient-controlled analgesia with boluses of 0.5 to 1 mg followed by periods when injections are impossible (lockout periods) of about 10 minutes. Morphine by intravenous infusion (1 to 5 mg/hour) is usually reserved for patients under controlled ventilation in an intensive care unit.
Paediatric population:
Because of its painful nature, the subcutaneous route is not recommended in children.
Morphine is usually administered via slow intravenous route. An initial dose of 0.025 to 0.1 mg/kg (mainly depending on the age of the patient) is followed, if necessary, by a bolus of about 0.025 mg/kg every 5 to 10 minutes until satisfactory analgesia is achieved (or the onset of adverse effects) and while the patient is being continuously monitored. If relay treatment proves necessary, use can be made of a continuous intravenous infusion of 0.01 to 0.02 mg/kg/hour under supervision in a surgical recovery ward or intensive care unit.
Patient-controlled analgesia via the intravenous route can be implemented from the age of 6 years: the boluses are of 0.015 to 0.02 mg/kg, followed by periods when injections are impossible (lockout periods) of 10 to 15 minutes. This can be combined with a continuous dose of 0.005 to 0.02 mg/kg/hour.
Epidural route
In adults: 2 to 6 mg every 12 to 24 hours.
Paediatric population: 0.03 to 0.05 mg/kg, to be repeated if necessary as a function of clinical surveillance after 12 to 24 hours.
Intrathecal route
In adults: 0.1 to 0.2 mg every 12 to 24 hours.
• Treatment of chronic pain (notably in the context of cancer):
Initial doses depend on the route of administration. When related to body weight, the doses in children and adults are equivalent.
Subcutaneous route
In patients who have not received prior treatment with oral morphine, the initial daily dose should be 0.5 mg/kg/day (classically 30 mg/day in adults), preferably via a continuous infusion or via injections repeated every 4 to 6 hours. .
In patients who have previously received oral morphine therapy, the initial daily dose should be half that of the oral dose administered. If the oral dose was insufficient, it is possible to switch immediately to a higher dosage.
Intravenous route
In patients who have not received prior treatment with oral morphine, the initial daily dose should be 0.3 mg/kg/day (classically 20 mg/day in adults), preferably via a continuous infusion.
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In patients who have received prior treatment with oral morphine, the initial daily dosage should be one third of the oral dose administered. If the oral dose was insufficient, it is possible to switch immediately to a higher dosage.
In patients presenting with pain of variable intensity over the day, it is possible to use a patient-controlled analgesia system; a continuous infusion (at the usual dosage) should be associated with self-administered boluses equivalent to approximately one hour of infusion. Each bolus should be followed by periods when injections are impossible (lockout periods) of a minimum of 10 minutes.
Epidural, intrathecal and intraventricular routes
In the case of chronic pain, these routes should be used when other methods of administration cause unacceptable adverse effects.
Comparison of initial dosages in function of the chosen route:
Route of administration envisaged
Parenteral equivalence
Epidural route
1/10th
Intrathecal route
1/100th
The intraventricular route is reserved for use by certain specialists at an initial dosage of approximately 0.1 to 0.2 mg/24 hours.
After the initiation of treatment, the dosage should be adjusted.
There should be no delay in adjusting a dose that proves ineffective. The patient should therefore be seen frequently, mainly at the start of treatment, for as long as the pain is not under control. If the pain is not controlled, the morphine daily dosage should be increased by about 30 to 50%. During this dose titration period, there does not appear to be an upper limit, for as long as any adverse effects can be controlled.
Method of administration
Solution for injection for subcutaneous, intramuscular, intravenous and intrathecal use.
The intramuscular route is not recommended as it is painful and does not have any pharmacokinetic advantages over the subcutaneous route.
The epidural, intrathecal and intraventricular routes require filtration of the solution through a 0.22 μm filter prior to injection in order to prevent any particulate contamination after the ampoule has been opened.

4.3 Contraindications[AP3] • Hypersensitivity to morphine or to any of the excipients listed in section 6.1. • Respiratory depression. • Obstructive airways disease. • Paralytic ileus (see section 4.4). • Acute hepatic disease. • Acute alcoholism. • Head injuries (see section 4.4). • Coma (see section 4.4). • Increased intracranial pressure (see section 4.4). • Convulsive disorders. • Concurrent administration with monoamine oxidase inhibitors or within two weeks of discontinuation of their use (see section 4.5). • Patients with phaeochromocytoma. Morphine and some other opioids can induce the release of endogenous histamine and thereby stimulate catecholamine release. • Acute asthma exacerbations (see section 4.4 for information relating to use in controlled asthma).

4.4 Special[AP4] warnings and precautions for use
Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs
Concomitant use of MORPHINE HCl STEROP and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of morphine with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe MORPHINE HCl STEROP 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
[QA5]Morphine is an opioid agonist and controlled drug.
For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. Dependence can appear after one or two weeks of treatment but in certain cases it can be observed after 2-3 days only. 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
Drug withdrawal syndrome
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[QA6]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 receive 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.
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 amenorrhoea
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.
Hypotensive effect
The administration of morphine may result in severe hypotension in individuals whose ability to maintain homeostatic blood pressure has already been compromised by depleted blood volume or the concurrent administration of drugs such as phenothiazine or certain anaesthetics (see section 4.5).
Asthma
It has been suggested that opioids can be used with caution in controlled asthma. However, opioids are contraindicated in acute asthma exacerbations (see section 4.3).
Head injury and increased intracranial pressure
This medicine is contraindicated in patients with increased intracranial pressure, head injuries and coma (see section 4.3). The capacity of morphine to elevate cerebrospinal fluid pressure may be greatly increased in the presence of already elevated intracranial pressure produced by
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trauma. Also, morphine may produce confusion, miosis, vomiting and other adverse reactions which may obscure the clinical course of patients with head injury.
Abdominal conditions
Morphine must not be given if paralytic ileus is likely to occur (see section 4.3), or if the patient has bowel or obstructive biliary disease. Should paralytic ileus be suspected or occur during use, this medicine should be discontinued immediately.
Caution should be exercised where there is an obstructive bowel disorder, biliary colic, operations on the biliary tract, acute pancreatitis or prostatic hyperplasia.
If constipation occurs this may be treated with the appropriate laxatives.
Care should be exercised in patients with inflammatory bowel disease.
Morphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions and complications following abdominal surgery.
Other precautions
• [QA7]Morphine should be administered with care in patients suffering from hypothyroidism, in case of myasthenia gravis, in patients with corticosurrenal, liver and kidneys insufficiency, where there is reduced respiratory function, such as kyphoscoliosis, emphysema, cor pulmonale and severe obesity.
• The [AP8]active metabolite Morphine-6-glucuronide may accumulate in patients with renal failure, leading to CNS and respiratory depression.
• The respiratory function of patients with respiratory insufficiency should be monitored. Drowsiness constitutes a warning sign of decompensation.
• In the event of hypovolemia, morphine may trigger a collapse. Hypovolemia should be corrected before injecting morphine.
Paediatric population
Morphine should not be administered preoperatively to children below the age of 1 year and should be given with extreme caution to neonates and premature infants. The initial dose must be reduced and the patient monitored in an Intensive Care Unit for the treatment of acute pain, with the preparation of an antidote.
Elderly
The dosage should be reduced in elderly or frail patients, particularly in the event of kidney and liver insufficiency, given their particular sensitivity to analgesic effects and central or digestive undesirable effects.
Injection
Do not use the solution if you notice the presence of particles in the ampoule or if it is not clear.
There is a risk of irritation or necrosis at the injection site when the administration is too rapid or when the injection has a too big volume. In order to reduce the risk of thrombophlebitis, it is recommended to change the injection site every 24 hours.
Excipients
This medicine contains less than 1 mmol sodium (23mg) per ml, that is to say essentially

Monoamine oxidase inhibitors[AP9]
Monoamine oxidase inhibitors are known to interact with narcotic analgesics producing CNS excitation or depression with hyper- or hypotensive crisis, therefore their concomitant use with MORPHINE HCl STEROP is contraindicated (see section 4.3).
Alcohol
The sedative effect of morphine is enhanced by alcohol. Alertness may be impaired.
Other morphine derivatives and barbiturates
The risk of respiratory depression is increased.
CNS depressants
Depressant effects of morphine are enhanced by central nervous system depressants: anaesthetics, antipsychotics (e.g phenothiazines), anxiolytics, antidepressants and H1 antihistamines, neuroleptics, central antihypertensive agents, thalidomide, baclofen. The dose and duration of concomitant use should be limited (see section 4.4).
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).
Morphine agonists-antagonists (buprenorphine, nalbufine, pentazocine)
Reduction of the analgesic or antitussive effect through the competitive blockade of receptors, with a risk of appearance of withdrawal syndrome.
Rifampicin
Rifampicin can reduce the serum concentration of morphine and decrease its analgesic effect. Clinical surveillance and adaptation if necessary of the morphine dosage during treatment with rifampicin and after its discontinuation are essential.
Gabapentin
Interactions have been reported when morphine and gabapentin are taken concomitantly. Reported interactions suggest an increase in opioid adverse events, the mechanism of which is not known. Caution should be taken where these medicines are prescribed concomitantly.
In a study involving healthy volunteers (N=12), when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule, mean gabapentin AUC increased 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.
Ritonavir
Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine, ritonavir may increase the activity of glucuronyl transferases. Consequently, co-administration of ritonavir and morphine may result in decreased serum concentrations of morphine with possible loss of analgesic effectiveness.
Cimetidine
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Cimetidine inhibits the metabolism of morphine.
Esmolol
Morphine may increase plasma concentrations of esmolol.
Domperidone/metoclopramide
Opioid analgesics including morphine may antagonise the actions of domperidone and metoclopramide on gastro-intestinal activity.
Mexiletine
The absorption of mexiletine may be delayed by concurrent use of morphine.
Phenothiazine antiemetics
Phenothiazine antiemetics may be given with morphine. However, hypotensive effects have to be considered (see section 4.4).

Pregnancy
A moderate quantity of data concerning pregnant women has not indicated that morphine exerts any malformative toxicity on the foetus/neonate. Animal studies have demonstrated reproductive toxicity (see section 5.3). As a safety measure, it is preferable not to use morphine during pregnancy.
Do not use morphine during the second phase of labour or in the case of a preterm infant. Morphine crosses the placental barrier and may cause respiratory depression in the neonate.
Habituation and withdrawal syndrome may appear in the neonate if the mother is a drug addict, with irritability, vomiting, convulsions and increased lethality. In this case, neonatal surveillance should be envisaged.
Breast-feeding
Insufficient information is available on the excretion of morphine into breast milk. A risk to the breastfed infant cannot be excluded. The discontinuation of either treatment or breastfeeding should be considered, while taking account of the benefits of breastfeeding to the infant and of the morphine therapy to the mother.
Fertility
Long term use of opioid analgesics can cause hypogonadism and adrenal insufficiency in both men and women. This is thought to be dose related and can lead to amenorrhoea, reduced libido, infertility and erectile dysfunction.
Animal studies have shown that morphine may reduce fertility (see section 5.3. preclinical safety data)

MORPHINE HCl STEROP has a major influence on the ability to drive and use machines.
Because of impaired alertness and the depressant effect of morphine on the central nervous system, patients receiving this medicinal product will abstain from driving vehicles and using tools and/or machines for 48 hours after the last injection.

The hereafter mentioned side effects are classified by organ system and by frequency. Frequencies are defined as follows: very common (≥ 1/10), uncommon: (≥ 1/1.000, < 1/100), rare (≥ 1/10.000, < 1/1.000), not known: cannot be estimated from the available data

a. Summary of the safety profile
The side-effects most commonly seen with morphine and other opioids are respiratory depression, nausea, vomiting, constipation, drowsiness and confusion. With long term use these symptoms generally lessen, although constipation frequently persists.
b. Tabulated list of adverse reactions
Organ system
Side effects
Frequency
Immune system disorders
Hypersensitivity, anaphylactoid reactions, anaphylactic reactions
Not known
Psychiatric disorders
Physical and psychological dependence (see section 4.4)
Very common
Confusional state, restlessness, altered mood, hallucination.
Not known
Nervous system disorders
Sedation, nightmare, excitation, drowsiness
Uncommon
Headache, increased intracranial pressure (see section 4.4), allodynia, hyperalgesia (see section 4.4).
Not known
Eye disorders
Blurred or double vision or other changes in vision, miosis.
Not known
Ear and labyrinth disorders
Vertigo
Not known
Cardiac disorders
Bradycardia, palpitations, tachycardia, orthostatic hypotension.
Not known
Vascular disorders
Facial flushing
Not known
Respiratory, thoracic[QA10] and mediastinal disorders
Respiratory depression (see section 4.4)
Rare
Gastrointestinal disorders
Constipation, nausea, vomiting
Very common
Dry mouth,
Not known
Hepatobiliary disorders
Biliary colic, biliary spasm
Not known
Skin and subcutaneous tissue disorders
Prurit, urticaria, contact dermatite, hyperhidrosis.
Uncommon
Musculoskeletal and connective tissue disorders
Muscle rigidity
Not known
Renal and urinary disorders
Dysuria, Difficulty urinating
Rare
Ureteral spasm.
Not known
Reproductive system and breast disorders
Decreased libido, erectile dysfunction
Not known
General disorders and administration site conditions
Pain or irritation at the injection site, drug withdrawal syndrome (see section 4.4 and section 4.6).
Uncommon
Drug tolerance (see section 4.4), hypothermia.
Not known
To report any side effect(s):
• Saudi Arabia
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The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc
• Other GCC States
Please contact the relevant competent authority

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
Drowsiness, which can be a sign of respiratory insufficiency, marked miosis, hypotension, hypothermia, coma.
Emergency treatment
Emergency treatment should preferably be given in a specialised hospital and will include:
- Discontinuation of current morphine therapy,
- Cardio-respiratory resuscitation,
- Specific therapy with morphine antagonists: administer naloxone 0.4 mg by IV way, to be repeated every 2 to 5 minutes if necessary (0.4 to 4 mg in fractionated doses). In children, the initial dose is 0.01 mg/kg. If no effect is observed after 2 to 3 doses, the diagnosis can reasonably be questioned.
Precaution: in patients dependent on morphinomimetics, an injection of a too large quantity of naloxone may trigger a withdrawal syndrome. In these patients, naloxone must be injected cautiously at gradually increasing doses.

Pharmacotherapeutic group: morphinic analgesic
ATC code: N02AA01
Action on the central nervous system
Morphine is a potent, centrally-acting analgesic and narcotic in the opiate family. Its analgesic activity is dose-dependent. It may act on psychomotor behaviour and, depending on the doses and terrain, cause sedation or excitation. Even at therapeutic doses, morphine exerts a depressant action on the respiratory and cough centres. The respiratory depressive effects of morphine gradually diminish in the event of long-term administration. The action of morphine on the vomiting centre and on gastric emptying endows it with variable emetic properties. Finally, morphine causes myosis of central origin.
Action on smooth muscle
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Morphine diminishes the tone and the peristaltism of longitudinal fibres, and increases the tone of circular fibres, thus causing the spasm of sphincters (pyloric, ileocaecal valve [Bauhin's valve], anal sphincter, sphincter of Oddi, bladder sphincter).

Absorption[QA11]
Blood resorption via the epidural route is more rapid than via the intrathecal route, hence a longer analgesic action via the intrathecal route. Via the epidural and intrathecal routes, supraspinal diffusion is delayed. The bioavailability of forms administered via the subcutaneous route is double that of forms administered by oral use. The bioavailability of forms administered via the intravenous route is at least triple that of forms administered by oral use.
Distribution
After resorption, the plasma protein binding to morphine reaches 30%. Morphine crosses the blood-brain barrier and the placenta.
Biotransformation
Morphine is largely metabolised into glucuronide conjugate derivatives which pass through an enterohepatic cycle. 6-glucuronide and normorphine are two active metabolites of the parent substance. The plasma half-life of morphine is 2 to 6 hours.
Elimination
Glucuronide conjugates are mainly excreted via the urine, following both glomerular filtration and tubular excretion. There is little excretion via the faeces (<10%).

5.3 Preclinical safety data
In vitro and in vivo preclinical experiments have demonstrated that morphine may be genotoxic.
In vitro studies showed that morphine did not cause any chromosomal abnormalities in mouse splenocytes. However, it was found that morphine provokes DNA fragmentation in a human lymphoma cell line. In vivo, during the micronucleus test in mice, it was seen that morphine caused an increase in the frequency of micronuclei in bone marrow cells and in immature red blood cells. Morphine can also cause chromosomal abnormalities in certain lymphocytes and spermatids. Long-term studies of the carcinogenic potential of morphine have not been performed. The importance of these data in humans is not known.
During animal experiments, morphine displayed teratogenic and embryotoxic characteristics and caused a drop in postnatal survival and behavioural and cerebral anomalies among progeny. Data obtained in humans have not demonstrated that any malformations or toxic effects on the foetus are linked to the therapeutic use of morphine.
In male rats, reduced fertility and chromosomal damage in gametes have been reported.

Sodium chloride.
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Hydrochloric acid (pH adjustment).
Water for injections.

This medicine product is incompatible with bases, iodine and iron, lead, manganese, silver, copper and zinc salts, tannic acid and potassium permanganate.

3 years.

Keep the ampoules in the outer carton in order to protect from light. Store below 25°C.

1ml type I uncoloured glass ampoules. Packaging in boxes of 10 ampoules and 100 ampoules.

This medicine contains no antimicrobial preservatives and therefore cannot avoid the growth of microorganisms. The drug solution is intended for single and individual use.
Do not keep the unused remainder of the medicinal product for later administration.
Any unused medicinal product, waste material or remaining medicinal solution should be disposed of in accordance with local requirements.
In case of infusion, the medicinal solution and infusion set should be kept in an aseptic environment throughout the duration of the infusion according to the rules of clinical good practice recommendations. It is good clinical practice to use any medicinal solution prepared within 24 hours. At the end of the infusion, any medicinal solution and all infusion equipment containing this solution must be eliminated in compliance with current regulations.