This information is intended for use by health professionals

1. Name of the medicinal product

ZOMORPH capsules 10mg, 30mg, 60mg, 100mg, 200mg

2. Qualitative and quantitative composition

• Morphine sulphate BP 10mg

• Morphine sulphate BP 30mg

• Morphine sulphate BP 60mg

• Morphine sulphate BP 100mg

• Morphine sulphate BP 200mg

3. Pharmaceutical form

Sustained-release capsules.

4. Clinical particulars
4.1 Therapeutic indications

Severe chronic pain and/or pain resistant to other analgesics, in particular pain associated with cancer.

4.2 Posology and method of administration

Route of administration: orally.

As directed by a medical practitioner.

Recommended dosage

Adults: Recommended dosage is one capsule twice daily, at 12-hourly intervals.

Elderly: As with all narcotics, a reduction in dosage may be advisable in the elderly, as appropriate.

Children: Not recommended.

The capsules should not be chewed and should normally be swallowed whole.

The dosage varies according to the severity of pain and the previous analgesic treatments received by the patient.

If the pain persists, or if the patient develops tolerance to morphine, the dosage may be increased by prescribing the 10mg, 30mg, 60mg, 100mg and 200mg capsules in various combinations or alone to obtain the desired relief.

Patients previously treated with immediate-release oral morphine should receive the same daily dose of sustained-release capsules, but in two divided doses at 12-hourly intervals.

Patients previously treated with parenteral morphine should be given a sufficiently increased dosage to compensate for any reduction of the analgesic effect associated with oral administration. The dosage should be adjusted to meet the individual requirements of each patient.

For patients who cannot swallow the capsules, their contents can be administered directly in semi-solid food (puree, jam, yoghurt) or via gastric or gastrostomy tubes of a diameter of more than 16 F.G. with an open distal end or lateral pores. It is sufficient to rinse the tube with 30ml to 50ml of water.

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.

4.3 Contraindications

Respiratory impairment, acute abdominal syndrome of unknown origin, severely impaired liver function, cranial trauma and raised intracranial pressure, convulsive state, acute alcoholic intoxication and delirium tremens, children, risk of paralytic ileus, known hypersensitivity to any of the ingredients contained in Zomorph, concurrent treatment with MAO (MAO = monoamine oxidase) inhibitors or within two weeks of their use.

4.4 Special warnings and precautions for use

Caution should be exercised:

- in elderly subjects, in patients with impaired hepatic and/or renal functions, in patients with hypothyroidism or hypoadrenalism, in patients in a state of shock or with asthma. The dose of Zomorph should be reduced, or its use should be avoided in cases of hepatic or renal failure.

- in patients suffering from the following conditions: hypotension, convulsive disorders, dependence (severe withdrawal symptoms if withdrawn abruptly) and prostatic hypertrophy.

Urinary retention may occur in patients with urethral disease or prostatic hypertrophy.

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.

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 amenorrhea.

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.

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

Concomitant use of Zomorph and sedative medicines such as benzodiazepines or related drugs 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 Zomorph 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).

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.

Concomitant use of alcohol and Zomorph may increase the undesirable effects of Zomorph; concomitant use should be avoided.

Morphine has an abuse potential similar to other strong agonist opioids, and should be used with particular caution in patients with a history of alcohol or drug abuse.

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.

4.5 Interaction with other medicinal products and other forms of interaction

As serious and sometimes fatal reactions have occurred following administration of pethidine to patients receiving monoamine oxidase inhibitors, pethidine and related drugs are contra-indicated in patients taking monoamine oxidase inhibitors or within 14 days of stopping such treatment; morphine and other opioid analgesics should be given with extreme caution.

The depressant effects of opioid analgesics are enhanced by depressants of the central nervous system such as alcohol, anaesthetics, antipsychotics, anxyolitics, hypnotics and sedatives, tricyclic antidepressants and phenothiazines.

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).

Cyclizine may counteract the haemodynamic benefits of opioids.

Opioid analgesics with some antagonist activity, such as buprenorphine, butorphanol, nalbuphine or pentazocine may precipitate withdrawal symptoms in patients who have recently used pure agonists such as morphine. The actions of opioids may in turn affect the activities of other compounds. For instance, their gastro-intestinal effects may delay absorption as with mexiletine or may be counteractive as with metoclopramide, domperidone and possibly cisapride.

Plasma concentrations of morphine are possibly increased by ritonavir.

Alcohol may enhance the pharmacodynamic effects of Zomorph; concomitant use should be avoided.

4.6 Use during pregnancy and lactation

Fertility

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

Pregnancy

Since this product 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.

Newborns whose mothers received opioid analgesics during pregnancy should be monitored for signs of neonatal withdrawal (abstinence) syndrome. If the mother is addicted, a withdrawal syndrome is observed in the newborn infant characterised by: convulsions, irritability, vomiting, increased mortality. Treatment may include an opioid and supportive care. As with all drugs, it is not advisable to administer morphine during pregnancy.

4.7 Effects on ability to drive and use machines

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

The most common side effects at usual doses are nausea, constipation, confusion and occasionally vomiting.

Frequency of adverse effects is ranked as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), or not known (cannot be estimated from available data).

System organ class

Very common

(≥ 1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1000 to <1/100)

Not known (cannot be estimated from the available data)

Immune system disorders

Anaphylactoid reactions

Psychiatric disorders

Confusion

Mood change

Libido or potency decreased

Dysphoria

Excitation (particularly in elderly subjects in whom delirium and hallucinations may occur)

Drug dependence

Nervous system disorders

Somnolence

Headache

Sedation

Intracranial pressure increased which may aggravate existing cerebral disorders

Allodynia, hyperalgesia (see section 4.4)

Hyperhidrosis

Eyes disorders

Miosis

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Palpitations

Bradycardia

Tachycardia

Vascular disorders

Flushing

Hypotension

Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Respiratory depression (mild and therapeutic doses; severe, serious even fatal in overdosage)

Gastrointestinal disorders

Nausea

Constipation

Vomiting

Dry mouth

Skin and subcutaneous tissue disorders

Pruritus

Rash

Urticaria

Renal and urinary disorders

Urinary retention in cases of prostatic adenoma or urethral stenosis

Dysuria

General disorders and administration site conditions

Hypothermia

Drug withdrawal (abstinence) syndrome

Investigations

Bile duct pressure increased

Mild respiratory depression occurs even at therapeutic doses. In the event of overdosage it may be severe, serious or even fatal.

Drug dependence and withdrawal (abstinence) syndrome

Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance, which may appear after administration of therapeutic doses for periods of 1 to 2 weeks. Some cases of dependence have been observed after only 2 to 3 days. An abstinence syndrome may be precipitated when opioid administration is suddenly discontinued or opioid antagonists administered, or can sometimes be experienced between doses. It may occur a few hours after withdrawal and is maximal between the 36th and 72nd hours. 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms include respiratory depression, pneumonia aspiration, extreme miosis, hypotension, hypothermia, coma. Death may occur from respiratory failure.

Treatment is by intravenous injection of naloxone 0.4mg, repeated every 2 to 3 minutes if necessary, or by an infusion of 2mg in 500ml of normal saline or 5% dextrose (0.004mg/ml).

In subjects dependent on morphine-like drugs, withdrawal symptoms may occur following injection of a high dose of naloxone. It should therefore be injected in gradually increasing doses to such subjects.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Morphine is an opioid analgesic. It acts mainly on the central nervous system and smooth muscle.

Morphine exerts an analgesic action, and affects psychomotor behaviour: depending on the dose administered, it induces sedation (> 1cg) or, in some cases, excitation (< 1cg). At high doses, greater than those required to produce analgesia, it induces somnolence and sleep.

5.2 Pharmacokinetic properties

Absorption

This is a sustained-release form, which makes twice-daily oral administration possible. Morphine is immediately absorbed from the digestive tract following oral administration. The maximum serum concentrations of morphine are obtained in 2 to 4 hours.

Distribution

The percentage of binding to plasma proteins after absorption is low (about 34%). There is no clearly defined correlation between the plasma concentration of morphine and the analgesic effect.

Metabolism

A considerable quantity of morphine is metabolised by the liver to glucuronides, which undergo enterohepatic recirculation.

Excretion

The product is eliminated essentially in the urine, by glomerular filtration, mainly as glucuronides. A small amount (less than 10%) is eliminated in the faeces.

5.3 Preclinical safety data

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

6. Pharmaceutical particulars
6.1 List of excipients

Sucrose, maize starch, polyethylene glycol 4000, ethyl-cellulose, cetyl alcohol, sodium lauryl sulphate, dibutyl sebacate, talc, gelatin, iron oxide ink (E172), titanium dioxide (E171) (for the 10mg, 30mg, 60mg and 100mg strengths), quinoline yellow (E104) (only for the 10mg strength), erythrosine (E127) (only for the 30mg strength), sunset yellow (E 110) (only for the 60mg strength).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Store below 25°C in a dry place protected from heat.

6.5 Nature and contents of container

Blister packs (aluminium/PVC).

Boxes of 14, 30 and 60 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

Ethypharm

194, Bureaux de la Colline – Bâtiment D

92213 Saint-Cloud cedex

France

8. Marketing authorisation number(s)

10mg: PL 06934/0182

30mg: PL 06934/0183

60mg: PL 06934/0184

100mg: PL 06934/0185

200mg: PL 06934/0186

9. Date of first authorisation/renewal of the authorisation

16 July 2010 (10mg, 30mg)

17 July 2010 (60mg, 100mg & 200mg)

10. Date of revision of the text

August 2018