ORAMORPH CONCENTRATED ORAL SOLUTION 20 MG / ML - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Oramorph Concentrated Oral Solution 20 mg/ml.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of Oramorph Concentrated Oral Solution contains 20 mg morphine sulfate

Excipient(s) with known effect: Amaranth (E123) 0.03 mg per 1 ml.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral solution.

A clear, red coloured liquid.

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 (0.5 – 1.0 ml) every 4 hours.

Maximum daily dose: 120 mg per day.

Paediatric population:

Children 13–18 years:       Recommended dose 5–20 mg (0.25 – 1.0 ml) every 4

hours

Maximum daily dose: 120 mg per day

Children 6–12 years:        Recommended dose 5–10 mg (0.25–0.5 ml) every 4

hours

Maximum daily dose: 60 mg per day

Children 1–5 years:         Recommended dose 5 mg (0.25 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.

Discontinuation of therapy

An abstinence syndrome may be precipitated if opioid administration is suddenly discontinued. Therefore the dose should be gradually reduced prior to discontinuation.

Method of Administration

For oral use

A calibrated oral dosing pipette is supplied with this dosage form for accurate and convenient dose adjustment. The required dose may be added to a soft drink immediately prior to administration.

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).

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 drug 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.

Abuse

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).

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.

Hyperalgesia

Hyperalgesia that does not respond to a further dose increase of morphine may occur in particular in high doses. A morphine dose reduction or change in opioid may be required.

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.

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.

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

Concomitant use of Oramorph Concentrated Oral Solution and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death.

Because of these risks, co-prescription of Oramorph Concentrated Oral Solution and sedative medicines should be reserved for patients for whom alternative treatment options are not possible.

Oramorph Concentrated Oral Solution particularly when prescribed concomitantly with sedative medicines, should be used at the lowest effective dose for the shortest period of time.

Patients should be monitored 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).

Use with rifampicin

Plasma concentrations of morphine may be reduced by rifampicin. The analgesic effect of morphine should be monitored and doses of morphine adjusted during and after treatment with rifampicin.

Excipient related warnings

Oramorph Concentrated Oral Solution contains the excipient Amaranth (E123), which may cause allergic reactions.

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 co-prescribed, 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 plasma concentration of morphine and decrease its analgesic effect, the mechanism of which is not known.

Cimetidine

Cimetidine inhibits the metabolism of morphine.

Sedative medicines such as benzodiazepines or related drugs

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs 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).

Other 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.

Newborns whose mothers received opioid analgesics during pregnancy should be monitored for signs of neonatal withdrawal (abstinence) syndrome. Treatment may include an opioid and supportive care.

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.

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.

Animal studies have shown that morphine may reduce fertility (see 5.3. preclinical safety data).

4.7 Effects on ability to drive and use machines

Morphine sulfate is likely to impair ability to drive or 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

Data from clinical trials are not available. Therefore all frequencies of the undesirable effects are unknown.

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.

A full list of currently known adverse reactions is presented below:

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

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, “drug craving” is often involved.

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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

Symptoms

Signs of morphine toxicity and overdosage are likely to consist of pin-point pupils, respiratory depression and hypotension. Circulatory failure, pneumonia aspiration 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 Preclinical safety data

In male rats, reduced fertility and chromosomal damage in gametes have been reported.

6.

6.1. List of excipients

Disodium Edetate

Sodium Benzoate (E211) Citric Acid anhydrous Amaranth (E213) Purified Water

6.2. Incompatibilities

None stated.

6.3 Shelf life

The shelf-life expiry date for this product shall not exceed three years from the date of its manufacture for unopened product. The product will be stored according to the provisions specified by the Home Office.

Discard any remaining Oramorph Concentrated Oral Solution 4 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 of 30 ml and 120 ml with a tamper evident, child resistant closure with an outer overcap in high density polyethylene. A calibrated oral dosing pipette will be enclosed in the carton with each bottle.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

None stated.

7.

MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim Limited

Ellesfield Avenue

Bracknell

Berkshire

RG12 8YS

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

PL 0015/0125

9. DATE OF FIRST AUTHORISATION/ RENEWAL OF THEAUTHORISATION

Date of first authorisation: 9th March 1988

Date of last renewal: 30th June 2005