Oramorph Oral Solution 10mg/5ml
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Oramorph Oral Solution 10 mg/5 ml
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 5 ml of Oramorph Oral Solution contains 10 mg of Morphine Sulfate.
Excipient(s) with known effect: Each 5 ml also contains 1500 mg sucrose, 0.525 ml Ethanol (96%), 9 mg methyl parahydroxybenzoate (E218) and 1 mg propyl parahydroxybenzoate (E216).
For full list of excipients, see Section 6.1.
3 PHARMACEUTICAL FORM
Oral solution.
A clear, colourless oral solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For the relief of severe pain in adults, adolescents (aged 13-18 years) and children (aged 1-12 years).
4.2 Posology and method of administration
Posology
Adults: Recommended dose 10-20 mg (5-10 ml) every 4 hours.
Maximum daily dose: 120 mg per day
Paediatric population:
Children 13-18 years: Recommended dose 5-20 mg (2.5 - 10 ml) every 4 hours Maximum daily dose: 120 mg per day
Children 6-12 years: Recommended dose 5-10 mg (2.5-5 ml) every 4 hours Maximum daily dose: 60 mg per day
Children 1-5 years: Recommended dose 5 mg (2.5 ml) every 4 hours Maximum daily dose: 30 mg per day
Children under 1 year: Not recommended
Dosage can be increased under medical supervision according to the severity of the pain and the patient's previous history of analgesic requirements.
Special populations :
Reductions in dosage may be appropriate in the elderly and in patients with chronic hepatic disease (for acute hepatic disease see section 4.3), renal impairment, severe hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy, shock or where sedation is undesirable.
Method of Administration For oral use.
When patients are transferred from other morphine preparations to Oramorph Oral preparations dosage titration may be appropriate.
Morphine sulfate is readily absorbed from the gastro-intestinal tract following oral administration. However, when oral Oramorph preparations are used in place of parenteral morphine, a 50 % to 100 % increase in dosage is usually required in order to achieve the same level of analgesia.
4.3 Contraindications
Oramorph is contraindicated in:
• patients known to be hypersensitive to morphine sulfate or to any other component of the product
• 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
• patients with known morphine sensitivity
• 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 warnings and precautions for use
Care should be exercised if morphine sulfate is given
• in the first 24 hours post-operatively,
• in hypothyroidism (see section 4.2),
• and where there is reduced respiratory function, such as kyphoscoliosis, emphysema, cor pulmonale and severe obesity.
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
Oramorph 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 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 sulfate 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, Oramorph 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.
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).
Drug dependence and abuse
Tolerance and dependence may occur. Withdrawal symptoms may occur on abrupt discontinuation or on the administration of a narcotic antagonist e.g. naloxone.
Morphine sulfate is an opioid agonist and controlled drug. Such drugs are sought by drug abusers and people with addiction disorders. Morphine sulfate can be abused in a manner similar to other opioid agonists, legal or illicit.
This should be considered when prescribing or dispensing morphine in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Morphine should be used with particular care in patients with a history of alcohol and drug abuse.
Morphine sulfate may be abused by inhaling or injecting the product. These practices pose a significant risk to the abuser that could result in overdose and death.
Hypersensitivity
Hypersensitivity and anaphylactic reactions have both occurred with the use of Oramorph. Care should be taken to elicit any history of allergic reactions to opiates. Oramorph is contraindicated in patients known to be hypersensitive to morphine sulfate (see section 4.3).
Risk in special populations
Morphine is metabolised by the liver and should be used with caution in patients with hepatic disease as oral bioavailability may be increased. It is wise to reduce dosage in chronic hepatic and renal disease, severe hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy or shock (see section 4.2).
The active metabolite Morphine-6-glucuronide may accumulate in patients with renal failure, leading to CNS and respiratory depression.
Excipient related warnings
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
Oramorph Oral Solution contains the excipients methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) which may cause allergic reactions (possibly delayed).
Oramorph Oral Solution contains 10 vol % ethanol (alcohol). Each dose contains up to 0.81 g of alcohol which is equivalent to 20 ml beer or 8.3 ml wine. Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.
4.5 Interaction with other medicinal products and other forms of interaction
Monoamine oxidase inhibitors
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 Oramorph is contraindicated (see section 4.3).
Gabapentin
Interactions have been reported in those taking morphine and gabapentin. Reported interactions suggest an increase in opioid adverse events when coprescribed, the mechanism of which is not known. Caution should be taken where these medicines are co-prescribed.
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.
Rifampicin
Rifampicin can reduce the serum concentration of morphine and decrease its analgesic effect, the mechanism of which is not known.
Cimetidine
Cimetidine inhibits the metabolism of morphine.
CNS depressants
It should be noted that morphine potentiates the effects of CNS depressants such as tranquillisers, anaesthetics (see section 4.4), hypnotics, sedatives, antipsychotics, tricyclic antidepressants and alcohol.
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).
4.6 Fertility, pregnancy and lactation
Pregnancy
Although morphine sulfate has been in general use for many years, there is inadequate evidence of safety in human pregnancy.
Morphine is known to cross the placenta. Therefore, Oramorph should not be used in pregnancy, especially the first trimester unless the expected benefit is thought to outweigh any possible risk to the foetus.
Infants born from mothers who have been taking morphine on a chronic basis may exhibit withdrawal symptoms. This should be borne in mind when considering the use of Oramorph in patients during pregnancy.
The risk of gastric stasis and inhalation pneumonia is increased in the mother during labour. Since morphine rapidly crosses the placental barrier it should not be used during the second stage of labour or in premature delivery because of the risk of secondary respiratory depression in the newborn infant.
The quantity of ethanol contained in Oramorph Oral Solution should be considered in pregnant women (See section 4.4).
Breast-feeding
Although morphine sulfate has been in general use for many years, there is inadequate evidence of safety during lactation.
Morphine is not recommended for nursing mothers. Morphine is excreted in breast milk, and may thus cause respiratory depression in the newborn infant.
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.
4.7 Effects on ability to drive and use machines
Morphine sulfate is likely to impair ability to drive and to use machinery. This effect is even more enhanced, when used in combination with alcohol or CNS depressants. Patients should be warned not to drive or operate dangerous machinery after taking Oramorph.
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
In normal doses, the commonest side effects of morphine sulfate are nausea, vomiting, constipation, drowsiness and confusion. If constipation occurs, this may be treated with appropriate laxatives. The effects of morphine have led to its abuse and misuse. Dependence and addiction may develop with regular, inappropriate use.
Data from clinical trials are not available. Therefore it is not possible to provide information on the frequencies of undesirable effects. A full list of currently known adverse reactions is presented below:
|
SOC Category |
Side effect |
|
Immune system disorders |
Hypersensitivity Anaphylactic reaction (see section 4.4) |
|
Psychiatric disorders |
Confusional state Restlessness Altered mood Hallucination Dependence (see section 4.4) |
|
Nervous system disorders |
Somnolence Headache Increased intracranial pressure (see section 4.4) |
|
Eye Disorders |
Miosis |
|
Ear and labyrinth disorders |
Vertigo |
|
Respiratory, thoracic and |
Respiratory depression (see section 4.4 and |
|
mediastinal disorders |
section 4.6) |
|
Cardiac disorders |
Bradycardia Tachycardia Palpitations |
|
Vascular disorders |
Hypotension Flushing |
|
Gastrointestinal disorders |
Nausea |
|
Vomiting Constipation (see section 4.4) Dry mouth | |
|
General disorders and |
Hypothermia |
|
administration site |
Drug tolerance (see section 4.4) |
|
conditions |
Drug withdrawal syndrome (see section 4.4 and section 4.6) |
|
Hepatobiliary Disorders |
Biliary colic |
|
Skin and subcutaneous |
Urticaria |
|
tissue disorders |
Pruritus Hyperhidrosis |
|
Musculoskeletal and connective tissue disorders |
Muscle rigidity |
|
Renal and urinary disorders |
Dysuria Ureteral spasm Oliguria |
|
Reproductive system and |
Decreased libido |
|
breast disorders |
Erectile dysfunction |
Reporting of suspected adverse reactions
Reporting suspected adverse reaction 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
Signs of morphine toxicity and overdosage are likely to consist of pin-point pupils, respiratory depression and hypotension. Circulatory failure and deepening coma may occur in more severe cases. Convulsions may occur in infants and children. Death may occur from respiratory failure.
Treatment
Adults: Administer 0.4-2 mg of naloxone intravenously. Repeat at 2-3 minute intervals as necessary to a maximum of 10 mg, or by 2 mg in 500 ml of normal saline or 5 % dextrose (4 micrograms/ml). Children: 5-10 micrograms per kilogram body weight intravenously. If this does not result in the desired degree of clinical improvement, a subsequent dose of 100 mcg/kg body weight may be administered.
Care should always be taken to ensure that the airway is maintained. Assist respiration if necessary. Maintain fluid and electrolyte levels. Oxygen, i.v. fluids, vasopressors and other supportive measures should be employed as indicated. Peak plasma concentrations of morphine are expected to occur within 15 minutes of oral ingestion. Therefore gastric lavage and activated charcoal are unlikely to be beneficial.
Caution: the duration of the effect of naloxone (2-3 hours) may be shorter than the duration of the effect of the morphine overdose. It is recommended that a patient who has regained consciousness after naloxone treatment should be observed for at least 6 hours after the last dose of naloxone.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Natural opium alkaloids. ATC code: NO2AA01
Morphine binds to specific receptors which are located at various levels of the central nervous system and also in various peripheral organs. The pain sensation and the affective reaction to pain is relieved by interaction with the receptors in the central nervous system.
5.2 Pharmacokinetic properties
Absorption
Morphine is modestly absorbed from the gastrointestinal tract following oral administration. Following oral administration of radiolabelled morphine to humans, peak plasma levels were reached after approximately 15 minutes. Morphine undergoes significant first pass metabolism in the liver resulting in a systemic bioavailability of approximately 25%.
Distribution
Approximately one third of morphine in the plasma is protein bound after a therapeutic dose.
Biotransformation
Metabolism of morphine principally involves conjugation to morphine 3- and 6-glucuronides. Small amounts are also metabolised by N-demethylation and N-dealkylation. Morphine-6-glucuronide has pharmacological effects indistinguishable from those of morphine. The half-life of morphine is approximately 2 hours. The t1/2 of morphine-6-glucuronide is somewhat longer.
Elimination
A small amount of a dose of morphine is excreted through the bowel into the faeces. The remainder is excreted in the urine, mainly in the form of conjugates. Approximately 90 % of a single dose of morphine is excreted in the first 24 hours. Enterohepatic circulation of morphine and its metabolites can occur, and may result in small quantities of morphine to be present in the urine or faeces for several days after the last dose.
5.3. Pre-clinical safety data
No further relevant preclinical data are available.
6.1 List of excipients
Ethanol (96%), com syrup, sucrose, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216) and purified water.
6.2. Incompatibilities
None stated.
6.3 Shelf life
3 years.
Discard Oramorph Oral Solution 3 months after first opening.
6.4 Special precautions for storage
Do not store above 25 °C. Store in the original container to protect from light.
6.5 Nature and contents of container
Amber glass bottles with a tamper-evident, child resistant polypropylene closure with expanded PE liner are available in packs of 100 ml, 250 ml, 300 ml or 500 ml.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
None stated.
ADMINISTRATIVE DATA
7. MARKETING AUTHORISATION HOLDER
Boehringer Ingelheim Limited
Ellesfield Avenue
Bracknell
Berkshire
RG12 8YS
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
PL 0015/0122
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 8 th March 1988 /
Date of last renewal: 8th March 1993