SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Morphine Sulfate Injection 10 mg per ml

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of sterile solution for injection contains 10 mg Morphine Sulfate

For excipients see 6.1

3.    PHARMACEUTICAL FORM

Solution for injection

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Analgesic for severe and very severe pain.

4.2    Posology and method of administration

Morphine injection may be administered subcutaneously, intramuscularly or intravenously. Dosage should be adjusted according to the severity of the pain and the response of the patient.

Appropriate starting doses are as follows:

Administration	Adults and adolescents over 12 years
Intravenously	2.5 - 10 mg
Subcutaneously, intramuscularly	5 - 20 mg

Individuals might require considerably higher doses for sufficient relief of pain. In general, the minimum effective dose should be administered.

For intravenous administration it is important to inject morphine slowly over a period of 4 to 5 minutes with the patient in the recumbent position.

For continuous intravenous infusion of morphine, appropriate starting doses are 1-2 mg per hour in adults and adolescents over 12 years. Daily doses will not usually exceed 100 mg per day in adults and adolescents over 12 years, however, in cancer patients chronic administration of higher doses up to 4 g per day may occasionally be required.

Children under 12 years

This formulation is not recommended for use in children under 12 years.

In the Elderly

The dose of morphine should be reduced in elderly patients and titrated to provide optimal pain relief with minimal side effects. Morphine clearance decreases and half -life increase in older patients.

In patients with disturbed Renal Function

Caution should be exercised in the use of Morphine in patients with renal dysfunction i.e. renal failure, because such patients can show signs of overdose following conservative dosage regimens.

In patients with impaired Liver Function

Caution should be exercised in the use of Morphine in patients with impaired liver function e.g. cirrhosis as this condition is likely to affect elimination. The dose therefore should be carefully titrated to provide optimal pain relief.

4.3 Contraindications

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

Respiratory depression or insufficiency Obstructive airways disease Cerebral trauma Increased intracranial pressure Coma

Convulsive disorders Acute alcoholism Renal failure Ureteral stenosis Pancreatitis Liver failure

Gall-bladder dysfunction Ileus

Inflammatory bowel disease Hypotension with hypovolaemia Prostatic hypertrophy

Myxoedema

Phaeochromocytoma

Concurrent administration of MAO inhibitors or within two weeks of discontinuation of their use.

4.4 Special warnings and precautions for use

Drug dependence and tolerance

Morphine can produce drug dependence and therefore has the potential for being abused. Upon repeated administration of morphine, psychological and physical dependence may occur and tolerance may develop. However, when doses of morphine are carefully titrated against pain, clinically significant respiratory depression, addiction, rapid tolerance and euphoria rarely develop. With regular administration of morphine at doses optimised for the individual patient drug dependence does not develop, and psychological dependence does not occur. A certain degree of physical dependence is possible, however. If patients no longer require morphine for relief of pain, doses should be gradually reduced in order to prevent withdrawal symptoms. Clinically significant tolerance to morphine is unusual in cancer patients with severe pain.

Hypotension, hypothyroidism, asthma (avoid during attack), and decreased respiratory reserve; pregnancy and breast-feeding; may precipitate coma in hepatic impairment (reduce dose but many such patients tolerate morphine well); reduce dose in renal impairment, elderly and debilitated (reduce dose); dependence (severe withdrawal symptoms if withdrawn abruptly).

4.5 Interaction with other medicinal products and other forms of interaction

•    CNS depressants: In patients concurrently receiving other central nervous system depressants (including sedatives, hypnotics, general anaesthetics, phenothiazines, other tranquillisers and alcohol) morphine should be used with caution and in reduced dosage because of the risk of respiratory depression, hypotension and profound sedation or coma.

•    Muscle relaxants: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants.

•    Mixed agonist/ antagonist opioid analgesics: Mixed agonist/antagonist opioid analgesics (e.g. pentazocine, nalbuphine, and buprenorphine) can reduce the analgesic effect of morphine by competitive blocking of the receptor. Therefore these drugs should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic.

•    Monoamine oxidase inhibitors (MAOIs): MAOIs intensify the effect of morphine and other opioid drugs. Severe and even fatal events (e.g. anxiety, confusion and significant depression of respiration, sometimes leading to coma) have been observed with co-administration of both drugs. Morphine should not be given to patients taking MAOIs or within 14 days of stopping such treatment.

•    Cimetidine: Higher plasma concentrations of morphine due to decreased metabolism

of morphine have been observed with co-administration of cimetidine. Confusion and severe respiratory depression were reported after a haemodialysis patient had received both morphine and cimetidine.

•    Diuretics: Morphine reduces the efficacy of diuretics by inducing the release of antidiuretic hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with prostatism.

•    Alcohol: enhanced sedative and hypotensive effect.

•    Anti-Arrhythmtics: delayed absorption of mexiletine.

•    Antidepressants: CNS excitation or depression (hypertension or hypotension) if pethidine and possibly other opioid analgesic are given to patients receiving MAOIs (including moclobemide).

•    Anxiolytics and Hypnotics: enhanced sedative effect.

•    Cisapride: possible antagonism of gastro-intestinal effect.

•    Domperidone and metoclopramide: antagonism of gastro-intestinal effects.

•    Dopaminergics: hyperpyrexia and CNS toxicity reported with selegiline.

4.6    Fertility, pregnancy and lactation

Pregnancy

Animal reproduction studies have shown that morphine can cause foetal damage when administered throughout pregnancy. An association with increased frequency of inguinal hernias in Infants has been postulated in man. Pregnant patients should only be given morphine when the benefits clearly outweigh potential risks to the foetus.

Breast-feeding

Morphine is excreted in human milk and breast-feeding is not recommended while a patient is receiving morphine. Withdrawal syndrome was observed in breast-fed infants after maternal administration of morphine sulfate had been stopped.

Use in labour/ delivery

Morphine may prolong labour by temporarily reducing the strength, duration and frequency of uterine contractions. Conversely, it may tend to shorten labour by increasing the rate of cervical dilatation. Infants born to mothers receiving opioid analgesics during labour should be observed closely for signs of respiratory depression. In such infants a specific opioid antagonist, naloxone hydrochloride, should be available for reversal of narcotic-induced respiratory depression. After chronic morphine use by the mother, new-borns may develop withdrawal symptoms.

4.7    Effects on ability to drive and use machines

Morphine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. Morphine in combination with other narcotic analgesics, phenothiazines, sedative-hypnotics, and alcohol have additive depressant effects.

Patients should not drive or operate machinery

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-driving-law

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

Common (> 10%):

Nausea, vomiting, respiratory depression, constipation, sedation, drowsiness, disorientation, itching, sweating, hallucinations, dysphoria, euphoria; with long-term treatment: tolerance and dependence.

Occasional (1 -9%):

Skin: Urticaria, skin rash, pain at injection site, contact dermatitis CNS and nervous system: Headache, vertigo, agitation, convulsions, impairment of taste, mood changes, changes of cognitive and sensory abilities, insomnia, intracranial hypertension, tremor.

Musculoskeletal system: Muscle spasms.

Eye: Miosis, visual disturbances (blurred vision, nystagmus, diplopia)

Gastrointestinal system: Dryness of mouth, pylorospasm, singultus, diarrhoea, abdominal cramps, biliary colic.

Cardiovascular system: Flushing, chills, orthostatic hypotension, bradycardia, hypertension,

tachycardia, heart failure, pulmonary oedema.

Respiratory system: Laryngeal spasm, bronchospasm, cough attenuation.

Urogenital system: Urinary retention or hesitancy, oliguria, loss of libido, impotence. Endocrine: Inappropriate antidiuretic hormone (ADH) secretion characterised by hyponatraemia secondary to decreased free water excretion.

General: Oedema, hypothermia, hyperthermia, withdrawal syndrome.

Pulmonary oedema after overdose is a common cause of fatalities among opioid addicts.

Morphine and some other opioids have a dose-related histamine effect, which may be responsible in part for reactions such as urticaria and pruritis as well as hypotension and flushing. Contact dermatitis has been reported and pain and irritation may occur on injection. Anaphylactic reactions following intravenous injection have been reported rarely.

Rare (< 1 %):

Anaphylactic reaction after i.v. injection.

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.

4.9 Overdose

Symptoms

Overdosage with morphine is characterised by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), pinpoint pupils, extreme somnolence progressing to stupor and coma, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. In severe overdosage, apnoea, circulatory collapse, cardiac arrest and death may occur.

Treatment

Immediate attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, intravenous fluid, vasopressors and other supportive measures should be employed as indicated.

The narcotic antagonist, naloxone, is a specific antidote for morphine. The recommended adult dose of naloxone is 0.4 to 2.0 mg IV every 2 to 3 minutes as necessary, simultaneously with assisted respiration. For children, the initial recommended dose is 0.01 mg/kg naloxone. A response should be seen after 23 doses. Note that the duration of action of naloxone is usually shorter than that of morphine and thus patients should be carefully monitored for signs of CNS depression returning.

If the response to naloxone is suboptimal or not sustained, additional naloxone may be administered as needed to maintain alertness and respiratory function. There is no additional information available about the cumulative dose of naloxone that may be safely administered.

To sustain opioid antagonism, an intravenous infusion of naloxone has been suggested. Naloxone (4 pg per ml) in sodium chloride injection (0.9 %) or glucose injection (5 %) may be infused at a rate titrated in accordance with the patient’s response both to the infusion and previous bolus injections.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdosage. It should be administered cautiously to persons who are known or suspected to be physically dependant to morphine. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. The severity of the withdrawal syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. If it is necessary to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.

Morphine toxicity may be the result of overdosage but because of the large inter-individual variation in sensitivity to opioids it is difficult to assess the exact dose of any opioid that is toxic or lethal. The toxic effects of morphine tend to be overshadowed by the presence of pain or tolerance. Patients receiving chronic morphine therapy have been known to take in excess of 3000 mg/day with no apparent toxic effect.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Morphine is pharmacologically the most important alkaloid of opium. It is used primarily as an analgesic for severe pain.

The analgesic effect of morphine is primarily due to an interaction with the OP₃(p)-receptor, one of three major classes of opioid receptors that can be distinguished in the central nervous system. The metabolite morphine-6-glucuronide also acts as an agonist on opioid-receptors and contributes significantly to the pharmacological effects of chronic morphine treatment. Doses of 0.1 mg/kg body-weight of morphine and higher are effective in various animal analgesic tests.

Morphine causes respiratory depression by diminishing the response of the respiratory centres to CO₂. This effect is mediated by the action on OP₃-receptors and can be antagonised by naloxone.

Morphine stimulates the chemo-receptor trigger zone by action on dopamine-receptors and may cause nausea and vomiting.

Other effects: Morphine can induce euphoria and miosis. Hypotension may occur due to increased histamine release, especially in hypovolaemic patients.

5.2 Pharmacokinetic properties

Approximately 35 % of morphine is bound to plasma proteins. Morphine is rapidly metabolized. Approximately 50 % is converted to the major metabolite, the pharmacologically inactive morphine-3-glucuronide and 10-15 % is converted to the active morphine-6-glucuronide. Further metabolites include a diglucuronide, normorphine and its glucuronides. Approximately 60% of morphine is excreted in the urine in 24 hours, of which less than 10% of the dose is excreted as unchanged drug.

Preclinical safety data

There are no preclinical safety data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Sodium chloride, hydrochloric acid, water for injections, nitrogen.

6.2. Incompatibilities

Morphine sulfate is physically incompatible with aciclovir sodium, aminophylline, amobarbital sodium, cefepime hydrochloride, chlorothiazide sodium, floxacillin sodium, furosemide, gallium nitrate, heparin sodium, meperidine hydrochloride, meperidine sodium, methicillin sodium, minocycline hydrochloride, pentobarbital sodium, phenobarbital sodium, phenytoin sodium, sargramostim, sodium bicarbonate, thiopental sodium.

6.3 Shelf life

Three years

6.4    Special precautions for storage

Do not store above 25°C. Keep the ampoule in the outer carton.

6.5    Nature and contents of container

1 ml colourless glass DIN ampoules, glass type I Ph Eur, packed in cardboard cartons and containing 10 x 1 ml ampoules.

6.6 Special precautions for disposal and other handling

For Single Dose Use Only. Discard any unused solution immediately and safely after initial use.

MARKETING AUTHORISATION HOLDER

hameln pharmaceuticals ltd Nexus

Gloucester Business Park Gloucester GL3 4AG United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 01502/0063

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

10^th February 2005

10 DATE OF REVISION OF THE TEXT

22/09/2015