Morphine Sulphate 10 Mg/1 Ml/15 Mg Solution

Relief of intractable pain not controlled with non-narcotic analgesics.

Posology
Subcutaneous or intramuscular injection:
Adults: 5 to 20 mg every 4 hours
Children: 1 to 5 years: 2,5 to 5 mg
6 to 12 years: 5 to 10 mg.
Slow intravenous injection or as loading dose for continuous or patient-controlled infusions:
Adults: up to 15 mg.
Maintenance dose for continuous intravenous administration and continuous subcutaneous infusion: From 0,8 to 80 mg per hour.
Intrathecal dose ranges from 0,2 to 1,0 mg and must only be given as a single dose.
Method of Administration
Doses should generally be reduced in the elderly, debilitated patients or in patients with renal impairment. Administer with caution or in reduced doses to patients with hypothyroidism, adrenocortical insufficiency, impaired liver function and prostatic hypertrophy or shock.

• Hypersensitivity to morphine sulphate or to any of the excipients of Morphine Sulphate Fresenius listed in section 6.1.
• Patients taking monoamine oxidase inhibitors or within 10 days of stopping such treatment.
• Acute respiratory depression, and obstructive airway disease especially in the presence of cyanosis and excessive bronchial secretion.
• In the presence of acute alcoholism, convulsive disorders, head injuries, comatose patients and conditions in which intracranial pressure is raised.
• During an attack of bronchial asthma or in heart failure secondary to chronic lung disease.
• Biliary colic (see section 4.4).
• Paralytic ileus.
• Phaeochromocytoma.
• Acute diarrhoeal caused by poisoning or invasive pathogens.

The euphoric activity of morphine may lead to abuse. Dependence and tolerance to Morphine Sulphate Fresenius may occur. Morphine Sulphate Fresenius should be used with extreme caution in patients with decreased respiratory reserve. In the case of geriatric or debilitated patients, and in patients with hypotension, hypothyroidism, convulsive disorders, adrenocortical insufficiency, myasthenia gravis, urethral stricture, impaired kidney or liver function, prostatic hypertrophy, shock or inflammatory or obstructive bowel disorders, it should be used with caution and the dosage reduced.
Biliary disorders
Opioids such as Morphine Sulphate Fresenius should either be avoided in patients with biliary disorders, or they should be given with an antispasmodic. Morphine Sulphate Fresenius 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 contraindicated, see section 4.3). In patients given Morphine Sulphate Fresenius after cholecystectomy, biliary pain has been induced.
Risk from concomitant use of sedative medicines such as benzodiazepines or related medicines
Concomitant use of Morphine Sulphate Fresenius and sedative medicines such as benzodiazepines or related medicines 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 Morphine Sulphate Fresenius 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).
Oral P2Y12 inhibitor antiplatelet therapy
Within the first day of concomitant treatment with a P2Y12 inhibitor and morphine, as in Morphine Sulphate Fresenius, reduced efficacy of P2Y12 inhibitor treatment has been observed (see section 4.5).
Palliative care
In the control of pain in terminal illness, these conditions should not necessarily be a deterrent to use.
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 amenorrhoea.
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 medicine 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.
Hyperalgesia that does not respond to a further dose increase of morphine may occur, particularly at high doses. A dose reduction or change in opioid may be required.
Morphine Sulphate Fresenius contains sodium
Morphine Sulphate Fresenius contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially sodium free.

Alcohol: Enhanced sedative and hypertensive effects.
Dysrhythmics: 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: The sedative effects of Morphine Sulphate Fresenius are enhanced when used with central nervous system depressants such as alcohol, anaesthetics, hypnotics, sedatives, tricyclic antidepressants and phenothiazines.
Antipsychotics: Possible enhanced sedative and hypotensive effect.
Antidiarrhoeal and antiperistaltic medicines (such as loperamide and kaolin): Concurrent use may increase the risk of severe constipation.
Antimuscarinics: Medicines 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.
Sedative medicines such as benzodiazepines or related medicines: The concomitant use of opioids with sedative medicines such as benzodiazepines or related medicines 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).
Cimetidine: inhibits the metabolism of morphine.
Rifampicin: Plasma concentrations of morphine may be reduced by rifampicin.
Ritonavir: Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine and may possibly decrease plasma concentrations of morphine.
Oral P2Y12 inhibitors: A delayed and decreased exposure to oral P2Y12 inhibitor antiplatelet therapy has been observed in patients with acute coronary syndrome treated with morphine.

Pregnancy
The safety of Morphine Sulphate Fresenius during pregnancy has not been established. Regular use during pregnancy may cause physical dependence in the fetus, leading to withdrawal symptoms in the neonate. Use during labour may cause respiratory depression in the neonate.
Breastfeeding
The safety of Morphine Sulphate Fresenius has not been established in breastfeeding women.

Drowsiness may affect the ability to perform skilled tasks. Those affected should not drive a vehicle or operate machinery.

Side effects have been ranked according to frequency within each system organ class. The following adverse reactions have been reported with Morphine Sulphate Fresenius:
MedDRA system organ class
Frequency
Adverse reactions
Immune system disorders: Frequent Histamine release (decreased blood pressure, fast heartbeat, increased sweating, redness or flushing of the face, wheezing or troubled breathing). Less frequent Allergic reaction (skin rash, hives, and/or itching, swelling of face). Metabolism and nutritional disorders: Less frequent Loss of appetite. Psychiatric disorders: Less frequent: False sense of wellbeing, general feeling of discomfort or illness, nervousness or restlessness, insomnia, confusion, hallucinations, mental depression. Decreased libido, mood swings, restlessness. Frequency unknown Nightmares or unusual dreams Nervous system disorders: Frequent Drowsiness, hyperhidrosis. Less frequent Headache, paradoxical CNS stimulation (unusual excitement or restlessness, especially in children). Frequency unknown Convulsions, allodynia
MedDRA system organ class
Frequency
Adverse reactions
Eye disorders Less frequent Miosis, nystagmus. Frequency unknown Blurred or double vision or other changes in vision Ear and labyrinth disorders Frequency unknown Tinnitus (ringing or buzzing in the ears). Cardiac disorders Less frequent Bradycardia, tachycardia, pounding heartbeat. Frequency unknown Palpitations. Vascular disorders Less frequent Dizziness, feeling faint or light-headedness, hypotension, orthostatic hypotension. Frequency unknown Increased blood pressure. Respiratory, thoracic, and mediastinal disorders Less frequent Atelectasis, bronchospastic allergic reaction, laryngeal oedema, allergic laryngospasm, respiratory depression. Gastrointestinal disorders Frequent Nausea and vomiting, constipation. Less frequent Dry mouth, gastrointestinal irritation (stomach cramps or pain), paralytic ileus or toxic megacolon. Frequency unknown Intestinal functional disorder, narcotic bowel syndrome.
MedDRA system organ class
Frequency
Adverse reactions
Hepato-biliary disorders Less frequent Biliary spasm, hepatic enzyme increase. Frequency unknown Hepatotoxicity, spasm of the sphincter of Oddi. Skin and subcutaneous tissue disorder Frequent Pruritus Less frequent Urticaria, rash, angioedema, contact dermatitis. Musculoskeletal and connective tissue disorders Less frequent Muscle rigidity (especially in muscles of respiration), trembling or uncontrolled muscle movements. Frequency unknown Rhabdomyolysis. Renal and urinary disorders Frequent Urinary retention. Less frequent Ureteral spasm (difficult or painful urination, frequent urge to urinate), antidiuretic effect. Frequency unknown Renal failure. Reproductive system and breast disorders Frequent Erectile dysfunction.
MedDRA system organ class
Frequency
Adverse reactions
General disorders and administration site conditions Frequent Unusual tiredness or weakness, medicine tolerance Less frequent Redness, swelling, pain or burning at the site of injection, medicine withdrawal (abstinence) syndrome (babies born to opioid-dependent mothers also at risk of present withdrawal syndrome).
Description of selected adverse reactions: 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 dependence, u201cdrug cravingu201d is often involved. Post-marketing data Less frequent: increased risk of abdominal pain, including pancreatitis has been reported. Reporting of suspected adverse reactions

Signs and symptoms of overdose indicating need for medical attention: cold and clammy skin, confusion, convulsions, severe dizziness, severe drowsiness, low blood pressure, nervousness or severe restlessness, pinpoint pupils of eyes, slow heartbeat, slow or troubled breathing, unconsciousness, severe weakness (see section 4.8). Intensive supportive therapy may be required to correct respiratory failure and shock. Death may occur from respiratory failure. The specific antagonist naloxone hydrochloride is used. A dose of 0,4 to 2 mg is given intravenously every 2 to 3 minutes, if necessary up to 10 mg. For children, the initial dose is 0,01 mg/kg. It may also be given by subcutaneous or intramuscular injection. Additional doses may be required to prevent relapse. The circulation should be maintained with infusions of dextrose injection and suitable electrolyte solutions. Assisted respiration may be necessary. The use of opioid antagonists such as naloxone, nalorphine, and levallorphan in persons physically dependent on morphine or related medicines may induce withdrawal symptoms.