Pharma-Q Morphine 10 and 15 mg Solution for injection

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 a loading dose for continuous or patient-controlled infusion:

Adults: Doses of up to 15 mg have been given.
Maintenance dose for continuous intravenous administration and continuous subcutaneous infusion: Doses have generally ranged from 0,8 mg to 80 mg per hour.
Intrathecal doses range from 0,2 mg to 1 mg and should only involve the administration of a single dose.

Method of administration

Doses should generally be reduced in the elderly or 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.

• Patients with a hypersensitivity to morphine sulphate or to any of the excipients of Pharma-Q Morphine Injection listed in section 6.1.
• 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 in 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).
• Phaeochromocytoma.
• Paralytic ileus.
• Acute diarrhoea caused by poisoning or invasive pathogens.
• Patients taking monoamine oxidase inhibitors or within 10 days of stopping such treatment.

The euphoric activity of morphine sulphate may lead to abuse. Dependence and tolerance to Pharma-Q Morphine Injection may occur. Pharma-Q Morphine Injection 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 Pharma-Q Morphine Injection should either be avoided in patients with biliary disorders, or they should be given with an antispasmodic. Pharma-Q Morphine Injection 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 Pharma-Q Morphine Injection after cholecystectomy, biliary pain has been induced.

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

Concomitant use of Pharma-Q Morphine Injection 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 inadequate. When using Pharma-Q Morphine Injection 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 Pharma-Q Morphine Injection, 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.

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 Pharma-Q Morphine Injection 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. 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.

Pregnancy

The safety and efficacy of Pharma-Q Morphine Injection has not been established. Regular use during pregnancy may cause physical dependence in the foetus, leading to withdrawal symptoms in the neonate. Use during labour may cause respiratory depression in the neonate.

Breastfeeding

The safety of Pharma-Q Morphine Injection has not been established in breastfeeding women.

Fertility

Animal studies have shown that morphine may reduce fertility.

Patients should be advised not to drive or use machines until they know how they are affected by the administration of Pharma-Q Morphine Injection, as drowsiness and dizziness may occur with the use of Pharma-Q Morphine Injection and may affect the ability to perform skilled tasks. Patients who experience such effects should be advised not drive or operate machinery.

Adverse effects are listed below according to system organ class and their frequency of occurrence: frequent, less frequent and frequency unknown.

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).
• Frequency unknown Anaphylactoid reactions.

Metabolism and nutritional disorders

• Less frequent Loss of appetite.

Psychiatric disorders

• Frequent Physical and psychological dependence.
• 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, dizziness, increased intracranial pressure, myoclonus; opioid-induced hyperalgesia (or hyperaesthesia), vertigo.
• Less frequent Headache, paradoxical CNS stimulation (unusual excitement or restlessness, especially in children).
• Frequency unknown Allodynia, coma, convulsions.

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, circulatory failure, tachycardia.
• 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

• Frequent Bronchospasm, pulmonary oedema, which can lead to death.
• Less frequent Atelectasis, bronchospastic allergic reaction, laryngeal oedema, allergic laryngospasm, respiratory depression.
• Frequency unknown Respiratory failure, which also can lead to death.

Gastrointestinal disorders

• Frequent Nausea, vomiting, constipation.
• Less frequent Dry mouth, paralytic ileus, gastrointestinal irritation (stomach cramps or pain), toxic megacolon, increased risk of abdominal pain, including pancreatitis.
• Frequency unknown Anorexia, intestinal functional disorder, narcotic bowel syndrome.

Hepato-biliary disorders

• Less frequent Biliary spasm, hepatic enzyme increase.
• Frequency unknown Hepatotoxicity, spasm of the sphincter of Oddi.

Skin and subcutaneous tissue disorders

• Frequent Pruritus, 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.

General disorders and administration site conditions

• Frequent Unusual tiredness or weakness, medicine tolerance, fatigue, facial flushing, hypothermia.
• 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).

c. Description of selected adverse reactions

Histamine release

• Due to the histamine-releasing effect, urticarial, pruritus and contact dermatitis as well as hypotension and flushing may occur.
• Anaphylactic reactions following intravenous injection may occur as well as muscle rigidity.
• Toxic doses vary considerably with the individual and regular users may tolerate large doses.

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, u201cdrug cravingu201d is often involved.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Signs and symptoms of overdose which indicate a need for medical attention: Cold and clammy skin, confusion, convulsions, severe dizziness, severe drowsiness, low blood pressure, severe nervousness or restlessness, pinpoint pupils of eyes, slow heartbeat, slow or troubled breathing, unconsciousness and 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 mg to 2 mg is given intravenously, repeated at an interval of 2 to 3 minutes if necessary, administering up to 10 mg. For children, the initial dose is 0,01 mg/kg. Naloxone may also be given by subcutaneous or intramuscular injection. Additional doses may be required to prevent relapses. 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.