MORPHINE SULPHATE 30MG/ML SOLUTION FOR INJECTION

MORPHINE SULPHATE SOLUTION FOR INJECTION INFORMATION FOR PATIENTS

a pre-medication before operations. BEFORE ADMINISTRATION OF THIS MEDICINE Morphine Sulphate Injection should not be administered if: You have ever had a reaction or been told that you are allergic to morphine sulphate or any of the other ingredients in the injection. Check by reading the list of ingredients above. You have severe breathing problems. You are suffering from acute alcohol poisoning. You have head injuries or raised intracranial pressure (increased pressure in the skull). The patient is in a coma. You have severe stomach cramps caused by a condition known as biliary colic. You are at risk from blocked intestine. You are suffering from severe diarrhoea caused by an antibiotic or a poison. You have been told you have phaeochromocytoma (a problem with your adrenal gland).

Please read this leaflet carefully before this medicine is administered. It gives an outline of the more important things you should know. If you want to know more about this medicine, or you are not sure about anything, ask your doctor or pharmacist. You should keep this leaflet throughout your course of treatment. THE NAME OF YOUR MEDICINE IS MORPHINE SULPHATE SOLUTION FOR INJECTION Morphine Sulphate Solution for Injection contains the active ingredient Morphine Sulphate. The injection is available in three strengths, 10mg/ml (10mg of active ingredient in 1ml of solution), 15mg/ml (15mg of active ingredient in 1ml of solution) and 30mg/ml (30mg of active ingredient in 1ml of solution). Other ingredients in your injection are water for injections, sodium metabisulphite (E223), hydrochloric acid and sodium hydroxide. Morphine Sulphate Solution for Injection is a colourless or almost colourless solution, practically free from particles. Morphine Sulphate 10mg/ml Solution for Injection is available in cartons containing 5 1ml glass ampoules and 10 1ml glass ampoules. Morphine Sulphate 15mg/ml Solution for Injection is available in cartons containing 5 1ml glass ampoules and 10 1ml glass ampoules. Morphine Sulphate 30mg/ml Solution for Injection is available in cartons containing 5 1ml glass ampoules and 10 1ml glass ampoules. It is also available in cartons containing 5 x 2ml ampoules. Marketing Authorisation Holder: Wockhardt UK Ltd, Ash Road North, Wrexham Industrial Estate, Wrexham LL13 9UF, UK. Manufacturer: CP Pharmaceuticals Ltd, Ash Road North, Wrexham, LL13 9UF, UK. HOW DOES YOUR MEDICINE WORK? Morphine sulphate belongs to a group of medicines called opioid analgesics which relieve pain. WHAT IS MORPHINE SULPHATE FOR? Morphine Sulphate Solution for Injection is used for the relief of severe pain and difficulty in breathing due to pulmonary oedema (waterlogging of the lungs due to heart failure). It is also used as

Before this medicine is administered, you should let your doctor know if : You are pregnant or breast-feeding or planning to become pregnant or start breast-feeding. You suffer from asthma. If your asthma is controlled you can receive the medicine but it should be used with care. You should not be given this medicine if you are having an acute asthma attack. You suffer from bronchitis, emphysema, cor-pulmonale (a type of heart failure), severe obesity or a severely deformed spine. You have a tendency to abuse drugs or have ever suffered from drug abuse. You suffer from bowel disease such as Crohns disease or ulcerative colitis. You have low blood pressure, are in a state of severe shock or very run down. You have an under-active thyroid or adrenal gland. You have liver or biliary disease or kidney problems. You suffer from an enlarged prostate or have difficulty passing water. You suffer from convulsions (fits).



If the injection makes you feel drowsy, do not drive or operate machinery. Taking another medicine when morphine sulphate is administered can affect how it or the other medicine works. Make sure that your doctor knows what other medicines you are taking. Do not take any other medicines when morphine sulphate is being administered unless you have told your doctor or pharmacist and asked their advice. This includes medicines you may have bought yourself. Examples of medicines that can affect morphine sulphate are: Monoamine oxidase inhibitors (MAOIs), such as moclobemide or phenelzine, used in the treatment of depression. Tricyclic antidepressants, such as dothiepin, used in the treatment of depression.

SUMMARY OF PRODUCT CHARACTERISTICS 1 2 3 NAME OF THE MEDICINAL PRODUCT Morphine Sulphate Solution for Injection QUALITATIVE AND QUANTITATIVE COMPOSITION Morphine Sulphate 10mg/ml Morphine Sulphate 15mg/ml Morphine Sulphate 30mg/ml For full list of excipients, see 6.1. PHARMACEUTICAL FORM Solution for injection

4 CLINICAL PARTICULARS 4.1 Therapeutic indications The symptomatic relief of severe pain; relief of dyspnoea of left ventricular failure and pulmonary oedema; pre-operative use. 4.2 Posology and method of administration Morphine Sulphate may be given by the subcutaneous, intramuscular or intravenous route. The subcutaneous route is not suitable for oedematous patients. The dosage should be based on the severity of the pain and the response and tolerance of the individual patient. The epidural or intrathecal routes must not be used as the product contains a preservative. Adults: Subcutaneous or intramuscular injection: 10mg every four hours if necessary (the dose may vary from 5-20mg depending on the individual patient). Slow intravenous injection (2mg/minute): Quarter to half of corresponding intramuscular dose not more than four hourly. Elderly and debilitated patients: The dose should be reduced because of the depressant effect on respiration. Caution is required. Children: Use in children is not recommended. Hepatic impairment: A reduction in dosage should be considered in hepatic impairment. Renal impairment: The dosage should be reduced in moderate to severe renal impairment. For concomitant illnesses/conditions where dose reduction may be appropriate see 4.4 Special Warnings and Precautions for use. 4.3 Contraindications Acute respiratory depression, known morphine sensitivity, biliary colic (see also biliary tract disorders 4.4 Special Warnings and Precautions), acute alcoholism. Conditions in which intracranial pressure is raised, comatose patients, head injuries, as there is an increased risk of respiratory depression that may lead to elevation of CSF pressure. The sedation and pupillary changes produced may interfere with accurate monitoring of the patient. Morphine is also contraindicated where there is a risk of paralytic ileus, or in acute diarrhoeal conditions associated with antibiotic-induced pseudomembranous colitis or diarrhoea caused by poisoning (until the toxic material has been eliminated). Phaeochromocytoma (due to the risk of pressor response to histamine release). 4.4 Special warnings and precautions for use Morphine should be given in reduced doses or with caution to patients with asthma or decreased respiratory reserve (including cor pulmonale, kyphoscoliosis, emphysema, severe obesity). Avoid use during an acute asthma attack (see 4.3 Contraindications). Opioid analgesics in general should be given with caution or in reduced doses to patients with hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy, urethral stricture, hypotension, shock, inflammatory or obstructive bowel disorders, or convulsive disorders. Opioids such as morphine should either be avoided in patients with biliary disorders or they should be given with an antispasmodic. Morphine can cause an increase in intrabiliary pressure as a result of effects on the sphincter of Oddi. Therefore in patients with biliary

tract disorders morphine may exacerbate pain (use in biliary colic is a contraindication, see 4.3). In patients given morphine after cholecystectomy, biliary pain has been induced. Caution is advised when giving morphine to patients with impaired liver function due to its hepatic metabolism (see 4.2 Posology). Severe and prolonged respiratory depression has occurred in patients with renal impairment who have been given morphine (see 4.2 Posology). Dependence can develop rapidly with regular abuse of opioids but is less of a problem with therapeutic use. Abrupt withdrawal from persons physically dependent on them precipitates a withdrawal syndrome, the severity of which depends on the individual, the drug used, the size and frequency of the dose and the duration of drug use. Great caution should be exercised in patients with a known tendency or history of drug abuse. Dosage should be reduced in elderly and debilitated patients (see 4.2 Posology). Palliative care - in the control of pain in terminal illness, these conditions should not necessarily be a deterrent to use. 4.5 Interaction with other medicinal products and other forms of interaction Alcohol: enhanced sedative and hypotensive effects. Anti-arrhythmics: There may be delayed absorption of mexiletine. Antibacterials: The opioid analgesic papaveretum has been shown to reduce plasma ciprofloxacin concentration. The manufacturer of ciprofloxacin advises that premedication with opioid analgesics be avoided. Antidepressants, anxiolytics, hypnotics: Severe CNS excitation or depression (hypertension or hypotension) has been reported with the concurrent use of pethidine and monoamine oxidase inhibitors (MAOIs) including selegiline, moclobemide and linezolid. As it is possible that a similar interaction may occur with other opioid analgesics, morphine should be used with caution and consideration given to a reduction in dosage in patients receiving MAOIs. The sedative effects of morphine (opioid analgesics) are enhanced when used with depressants of the central nervous system such as hypnotics, anxiolytics, tricyclic antidepressants and sedating antihistamines. Antipsychotics: possible enhanced sedative and hypotensive effect. Antidiarrhoeal and antiperistaltic agents (such as loperamide and kaolin): concurrent use may increase the risk of severe constipation. Antimuscarinics: agents such as atropine antagonise morphine-induced respiratory depression and can partially reverse biliary spasm but are additive to the gastrointestinal and urinary tract effects. Consequently, severe constipation and urinary retention may occur during intensive antimuscarinic-analgesic therapy. Metoclopramide and domperidone: There may be antagonism of the gastrointestinal effects of metoclopramide and domperidone. 4.6 Pregnancy and lactation Morphine sulphate should only be used when benefit is known to outweigh risk. As with all drugs it is not advisable to administer morphine during pregnancy. Morphine crosses the placental barrier. Administration during labour may cause respiratory depression in the new born infant and gastric stasis during labour, increasing the risk of inhalation pneumonia. Therefore, it is not advisable to administer morphine during labour. Babies born to opioid-dependent mothers may suffer withdrawal symptoms including CNS hyperirritability, gastrointestinal dysfunction, respiratory distress and vague autonomic symptoms including yawning, sneezing, mottling and fever. While morphine can suppress lactation, the quantity from therapeutic doses that may reach the neonate via breast milk is probably insufficient to cause major problems of dependence or adverse effects. 4.7 Effects on ability to drive and use machines Morphine causes drowsiness so patients should avoid driving or operating machinery. Undesirable effects 4.8 The most serious hazard of therapy is respiratory depression (see also 4.9 Overdose). Morphine Injection contains sodium metabisulphite, which may rarely cause severe hypersensitivity reactions and bronchospasm. The commonest side-effects of morphine are nausea, vomiting, constipation, drowsiness and dizziness. Tolerance generally develops with long term use, but not to constipation. Other side effects include the following: Anaphylaxis: Anaphylactic reactions following intravenous injection have been reported rarely.



Some medicines used to treat anxiety and insomnia such as diazepam, nitrazepam and temazepam. Some antihistamines, used to treat allergies, hayfever and asthma. Psychotropic drugs taken for other mental problems like schizophrenia, such as chlorpromazine and haloperidol. Certain antibiotics ciprofloxacin and linezolid, used to treat infections. Selegiline, a drug used in the treatment of Parkinsons Disease. Metoclopramide and domperidone, medicines used to prevent nausea and vomiting. Medicines used for diarrhoea (e.g. loperamide, kaolin). Antimuscarinics, such as atropine, which are used as pre-medication before operations and during heart attacks. Mexiletine, used to control heart rhythm.

Other side-effects include itching, wheals or skin rashes, difficulty in passing water, passing less water than usual, stomach pains, dry mouth, sweating, flushing of the face, giddiness, slow or rapid pulse, palpitations, low blood pressure (you may feel faint, especially on standing), mental clouding or confusion, headache, mood swings, imagining things (hallucinations), small pupils (in the eye), blurred vision, double vision or other changes in vision. Long term use may lead to reduced sexual drive or impotence. Occasionally the skin where the medicine has been injected may become irritated or hardened. Very rarely, intravenous injection (injection into a vein) may cause a severe allergic reaction. If you have to be given this injection for a long time, you may need higher doses and it is possible that you could become dependent on it and have withdrawal symptoms if it is stopped suddenly. If you are given morphine during pregnancy, there is a risk that the new-born baby may become dependent on it and suffer from withdrawal symptoms following delivery. If you are given morphine during labour, there is a risk that you could be sick and have breathing difficulties, or the baby could have difficulty starting breathing. If you experience any other side effects or feel that the medicine is affecting you badly, tell your doctor or pharmacist. SAFE KEEPING FOR THIS MEDICINE This medicine should not be given to you if the expiry date on the label has passed or if the injection shows signs of going off such as discoloration. Do not store this injection above 25oC. Keep this injection in the package or container in which it was supplied in order to protect from light. Morphine Sulphate Injection must be kept in a secure place where children cannot get at it. September 2007
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If you have any doubts about whether you should be given this medicine then talk to your doctor. ADVICE WHEN MORPHINE SULPHATE SOLUTION FOR INJECTION IS ADMINISTERED If morphine sulphate injection is used for too long, you may become dependent on it and find that it no longer works as well. You may develop withdrawal symptoms when you stop having the injections. You should avoid alcohol while having morphine sulphate injections. Morphine sulphate can cause drowsiness so you should not drive or operate machinery after it is given.



ADMINISTRATION OF THIS MEDICINE The usual adult dose for relief of pain by subcutaneous injection (an injection underneath the skin) or intramuscular injection (an injection into a muscle) is 10mg every four hours, if necessary. However, this can vary between 5mg and 20mg depending on your size and response to the drug. For severe pain your doctor may give you a slow intravenous injection (an injection given slowly into a vein). The usual dose is quarter to half of the intramuscular dose. In general, doses will be reduced if you are elderly or debilitated or have kidney or liver problems. You may also be given a reduced dose if you suffer from any of the conditions listed above in the Section headed Before this medicine is administered, you should let your doctor know if: Your doctor will decide the dose that is best for you. If you do not understand what you are being given, or think you are being given too much morphine, talk to your doctor or nurse. ARE THERE ANY SIDE-EFFECTS? Like many medicines Morphine Sulphate Solution for Injection may cause side-effects in some patients, particularly when it is first given. The most serious problem is with breathing which may become shallower. Morphine Injection contains sodium metabisulphite, which may rarely cause severe hypersensitivity reactions and bronchospasm. The most common side-effects that some other patients have had with Morphine Sulphate Solution for Injection include feeling sick, being sick, constipation, drowsiness and dizziness.

DATE OF LAST REVISION

Cardiovascular: facial flushing bradycardia, palpitations, tachycardia, orthostatic hypotension. Central Nervous System: mental clouding, confusion (with large doses), hallucinations, headache, vertigo, mood changes including dysphoria and euphoria. Gastrointestinal: dry mouth, biliary spasm. Disorders of the eye: blurred or double vision or other changes in vision, miosis. Sexual dysfunction: long term use may lead to a reversible decrease in libido or potency. Skin: pruritus, urticaria, rash, sweating. Contact dermatitis has been reported and pain and irritation may occur on injection. Urinary: difficulty with micturition, ureteric spasm, urinary retention, antidiuretic effect. Tolerance develops to the effects of opioids on the bladder. The euphoric activity of morphine has led to its abuse and physical and psychological dependence may occur (see also 4.4 Special Warnings and Precautions). 4.9 Overdose Toxic doses vary considerably with the individual, and regular users may tolerate large doses. The triad of respiratory depression, coma and constricted pupils is considered indicative of opioid overdosage with dilatation of the pupils occurring as hypoxia develops. Death may occur from respiratory failure Other opioid overdose symptoms include hypothermia, confusion, severe dizziness, severe drowsiness, hypotension, bradycardia, circulatory failure pulmonary oedema, severe nervousness or restlessness, hallucinations, convulsions (especially in infants and children). Rhabdomyolysis, progressing to renal failure, has been reported in overdosage. Treatment: The medical management of overdose involves prompt administration of the specific opioid antagonist naloxone if coma or bradypnoea are present using one of the recommended dosage regimens. Both respiratory and cardiovascular support should be given where necessary. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Morphine is obtained from opium, which acts mainly on the CNS and smooth muscle. Morphine is a potent analgesic with competitive agonist actions at the -receptor, which is thought to mediate many of its other actions of -receptor, respiratory depression, euphoria, inhibition of gut motility and physical dependence. It is possible that analgesia, euphoria and dependence may be due to the effects of morphine on a -1 receptor subtype, while respiratory depression and inhibition of gut motility may be due to actions on a -2 receptor subtype. Morphine is also a competitive agonist at the-receptor that mediates spinal analgesia, miosis and sedation. Morphine has no significant actions at the other two major opioid receptors, the- and the-receptors. Morphine directly suppresses cough by an effect on the cough centre in the medulla. Morphine also produces nausea and vomiting by directly stimulating the chemoreceptor trigger zone in the area postrema of the medulla. Morphine provokes the release of histamine. 5.2 Pharmacokinetic properties Absorption: Variably absorbed after oral administration; rapidly absorbed after subcutaneous or intramuscular administration. Blood concentration: After an oral dose of 10mg as the sulphate, peak serum concentrations of free morphine of about 10ng/ml are attained in 15 to 60 minutes. After an intramuscular dose of 10mg, peak serum concentrations of 70 to 80ng/ml are attained in 10 to 20 minutes. After an intravenous dose of 10mg, serum concentrations of about 60ng/ ml are obtained in 15 minutes falling to 30ng/ml after 30 minutes and to 10ng/ml after three hours. Subcutaneous doses give similar concentrations to intramuscular doses at 15 minutes but remain slightly higher during the following three hours; serum concentrations measured soon after administration correlate closely with the ages of the subjects studied and are increased in the elderly. Half-life: Serum half-life in the period ten minutes to six hours following intravenous administration-two to three hours; serum half-life in the period six hours onwards-10 to 44 hours. Distribution: Widely distributed throughout the body, mainly in the kidneys, liver, lungs and spleen; lower concentrations appear in the brain and muscles. Morphine crosses the placenta and traces are secreted in sweat and milk. Protein binding-about 35% bound to albumin and to immunoglobulins at

concentrations within the therapeutic range. Metabolic reactions: Mainly glucuronic acid conjugation to form morphine-3 and 6-glucuronides. N-demethylation, O-methylation and N-oxide glucuronide formation occurs in the intestinal mucosa and liver; N-demethylation occurs to a greater extent after oral than parental administration; the O-methylation pathway to form codeine has been challenged and codeine and norcodeine metabolites in urine may be formed from codeine impurities in the morphine sample studied. Excretion: After an oral dose, about 60% is excreted in the urine in 24 hours, with about 3% excreted as free morphine in 48 hours. After a parental dose, about 90% is excreted in 24 hours, with about 10% as free morphine, 65 to 70% as conjugated morphine, 1% as normorphine and 3% as normorphine glucuronide. After administration of large doses to addicts about 0.1% of a dose is excreted as norcodeine. Urinary excretion of morphine appears to be pH dependent to some extent; as the urine becomes more acidic more free morphine is excreted and as the urine becomes more alkaline more of the glucuronide conjugate is excreted. Up to 10% of a dose may be excreted in the bile. 5.3 Preclinical safety data There are no pre-clinical data of relevance to the prescriber, which are additional to those included in other sections. 6 6.1 PHARMACEUTICAL PARTICULARS List of excipients Water for injections Sodium metabisulphite Sodium hydroxide Hydrochloric acid

6.2 Incompatibilities Morphine salts are sensitive to changes in pH and morphine is liable to be precipitated out of solution in an alkaline environment. Compounds incompatible with morphine salts include aminophylline and sodium salts of barbiturates and phenytoin. Other incompatibilities (sometimes attributed to particular formulations) have included aciclovir sodium, doxorubicin, fluorouracil, frusemide, heparin sodium, pethidine hydrochloride, promethazine hydrochloride and tetracyclines. Specialised references should be consulted for specific compatibility information. 6.3 Shelf life 36 months

6.4 Special precautions for storage Do not store above 25C. Keep container in the outer carton. 6.5 6.6 7 8 9 10 Nature and contents of container 5 x 1ml Type I glass ampoules 10 x 1ml Type I glass ampoules Special precautions for disposal None MARKETING AUTHORISATION HOLDER Wockhardt UK Ltd, Ash Road North, Wrexham, LL13 9UF, UK MARKETING AUTHORISATION NUMBER(S) Morphine Sulphate 10mg/ml Injection PL 29831/0146 Morphine Sulphate 15mg/ml Injection PL 29831/0145 Morphine Sulphate 30mg/ml Injection PL 29831/0147 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Morphine Sulphate 10mg/ml Injection 08/05/2007 Morphine Sulphate 15mg/ml Injection 21/04/2007 Morphine Sulphate 30mg/ml Injection 16/04/2007 DATE OF REVISION OF THE TEXT September 2007

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