This information is intended for use by health professionals

1. Name of the medicinal product

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

2. Qualitative and quantitative composition

• Morphine sulfate BP 10mg

• Morphine sulfate BP 30mg

• Morphine sulfate BP 60mg

• Morphine sulfate BP 100mg

• Morphine sulfate BP 200mg

Excipients with known effect:

Each 10mg capsule contains:

Sucrose (10.62 mg/capsule)

Each 30mg capsule contains:

Sucrose (31.85 mg/capsule)

Each 60mg capsule contains:

Sucrose (63.69 mg/capsule) and a small amount (<1 mg/capsule) of sunset yellow (E110)

Each 100mg capsule contains:

Sucrose (106.16 mg/capsule)

Each 200mg capsule contains:

Sucrose (212.32 mg/capsule)

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Prolonged release capsule, hard.

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

Posology

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.

The dosage varies according to the severity of pain and the previous analgesic treatments received by the patient. The correct dosage for any individual patient is that which is sufficient to control pain with no, or tolerable, side effects for a full 12 hours.

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.

Higher doses should be made, where possible in 30-50% increments as required.

It is recommended that the 200 mg strength is reserved for patients who have already been titrated to a stable analgesic dose using lower strengths of morphine or other opioid preparations.

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. Usually such increased requirement is of the order of 100%. The dosage should be adjusted to meet the individual requirements of each patient.

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

Route of administration: oral.

The capsules should not be chewed and should normally be swallowed whole. The administration of broken, chewed or crushed capsules or granules may lead to a rapid release and absorption of a potentially fatal dose of morphine (see section 4.9.).

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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, respiratory depression, obstructive airways disease, acute abdominal syndrome of unknown origin, delayed gastric emptying, severely impaired liver function, cranial trauma and raised intracranial pressure, convulsive state, acute alcoholic intoxication and delirium tremens, children, risk of paralytic ileus, concurrent treatment with MAO (MAO = monoamine oxidase) inhibitors or within two weeks of their use.

4.4 Special warnings and precautions for use

The major risk of opioid excess is respiratory depression.

As with all narcotics a reduction in dosage may be advisable in the elderly, in hypothyroidism and in patients with significantly impaired renal or hepatic function.

Use with caution in patients with impaired respiratory function, severe bronchial asthma, convulsive disorders, hypotension, severe cor pulmonale, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, hypoadrenalism and in patients in a state of shock.

Should paralytic ileus be suspected or occur during use, ZOMORPH should be discontinued immediately.

Morphine may lower the seizure threshold in patients with a history of epilepsy

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.

Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, which may be fatal.

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.

It is not possible to ensure bio-equivalence between different brands of prolonged release morphine products. Therefore, it should be emphasised that patients, once titrated to an effective dose, should not be changed from ZOMORPH to other slow, sustained or prolonged release morphine or other potent narcotic analgesic preparations without retitration and clinical assessment.

[all strengths] Patients with rare hereditary problems of fructose intolerance, glucose- galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

[60 mg strength only] This medicinal product contains sunset yellow (E110) which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Morphine sulfate should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy (see section 4.3).

The depressant effects of opioid analgesics are enhanced by depressants of the central nervous system such as but not limited to: other opioids, alcohol, general anaesthetics, antipsychotics, anxyolitics, hypnotics and sedatives, muscle relaxants, antihypertensives, gabapentin, 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).

Medicinal products that block the action of acetylcholine, for example antihistamines, anti-parkinsons and anti-emetics, may interact with morphine sulfate to potentiate anticholinergic adverse events.

Cimetidine inhibits the metabolism of morphine sulfate.

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 decreased by ritonavir.

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

4.6 Fertility, pregnancy and lactation

Pregnancy

Since this product rapidly crosses the placental barrier, its use is not recommended during pregnancy and labour because of the risk of secondary respiratory depression in the newborn infant and neonatal withdrawal syndrome.

Newborns whose mothers received opioid analgesics during pregnancy should be monitored for signs of neonatal withdrawal (abstinence) syndrome 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.

Breast feeding

Administration to nursing mothers is not recommended as morphine is excreted in breast milk.

Fertility

Animal studies have shown that morphine may reduce fertility (see section 5.3.).

4.7 Effects on ability to drive and use machines

Morphine may modify the patient's reactions to a varying extent depending on the dosage and susceptibility. If affected, patients should not drive or operate machinery.

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. With chronic therapy, nausea and vomiting are unusual with Zomorph capsules but should they occur the capsules can be readily combined with an anti-emetic if required. Constipation may be treated with appropriate laxatives.

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

Anaphylactic reaction

Hypersensitivity

Anaphylactoid reaction

Psychiatric disorders

Confusion

Insomnia

Mood change

Agitation

Euphoria

Hallucinations

Libido decreased

Dysphoria

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

Drug dependence

Thinking abnormal

Nervous system disorders

Somnolence

Headache

Dizziness

Muscle contractions involuntary

Convulsions

Hypertonia

Myoclonus

Paraesthesia

Syncope

Taste perversion

Sedation

Intracranial pressure increased which may aggravate existing cerebral disorders

Allodynia, hyperalgesia (see section 4.4)

Hyperhidrosis

Eyes disorders

Visual impairment

Miosis

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Palpitations

Bradycardia

Tachycardia

Vascular disorders

Flushing

Hypotension

Orthostatic hypotension

Hypertension

Respiratory, thoracic and mediastinal disorders

Respiratory depression

Bronchospasm

Pulmonary oedema

Cough decreased

Gastrointestinal disorders

Nausea

Constipation

Vomiting

Dry mouth

Abdominal pain

Dyspepsia

Ileus

Metabolism and nutrition disorders

Anorexia

Hepatobiliary disorders

Biliary pain

Pancreatitis aggravated

Bile duct pressure increased

Skin and subcutaneous tissue disorders

Pruritus

Rash

Urticaria

Renal and urinary disorders

Urinary retention

Dysuria

Uretral spasm

Reproductive system and breast disorders

Amenorrhoea

Erectile dysfunction

General disorders and administration site conditions

Asthenia

Fatigue

Malaise

Peripheral oedema

Hypothermia

Drug withdrawal (abstinence) syndrome

Drug tolerance

Drug withdrawal (abstinence) syndrome neonatal

Investigations

Increased hepatic enzymes

Respiratory depression occurs even at therapeutic 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, 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 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, “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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Signs of morphine toxicity and overdose are extreme miosis (pin-point pupils), skeletal muscle flaccidity, bradycardia, hypotension, hypothermia, respiratory depression, pneumonia aspiration, somnolence and central nervous system depression which can progress to stupor or coma. Circulatory failure and deepening coma may occur in more severe cases. Death may occur from respiratory failure.

Rhabdomyolysis progressing to renal failure has been reported in opioid overdose.

Crushing and taking the contents of a prolonged release dosage form may lead to the release of morphine in an immediate fashion; this might result in a fatal overdose.

Treatment of morphine overdose:

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

The pure opioid antagonists are specific antidotes against the effects of opioid overdose. Other supportive measures should be employed as needed.

Treatment is by intravenous injection of naloxone 0.4mg – 2mg, 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).

The infusion should be run at a rate related to the previous bolus doses administered and should be in accordance with the patient's response. However, because the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. ZOMORPH capsules will continue to release and add to the morphine load for up to 12 hours after administration and the management of morphine overdose should be modified accordingly.

For less severe overdose, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose.

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

Pharmacotherapeutic group: natural opium alkaloid

ATC code: N02A A01

Morphine acts as an agonist at opiate receptors in the CNS particularly Mu and to a lesser extent Kappa receptors. Mu receptors are thought to mediate supraspinal analgesia, respiratory depression and euphoria, and Kappa receptors, spinal analgesia, miosis and sedation.

Central Nervous System

The principal actions of therapeutic value of morphine are analgesia and sedation (i.e., sleepiness and anxiolysis). Morphine produces respiratory depression by direct action on brain stem respiratory centres.

Morphine depresses the cough reflex by direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of narcotic overdose but are not pathognomonic (e.g., pontine lesions of haemorrhagic or ischaemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of morphine overdose.

Gastrointestinal Tract and Other Smooth Muscle

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm resulting in constipation. Morphine generally increases smooth muscle tone, especially the sphincters of the gastrointestinal and biliary tracts. Morphine may produce spasm of the sphincter of Oddi, thus raising intrabiliary pressure.

Cardiovascular System

Morphine may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Endocrine System

Opioids may affect the hypothalamic pituitary adrenal and hypothalamic pituitary gonadal system resulting in adrenal insufficiency or hypogonadism respectively (see section 4.4).

Other Pharmacological Effects

In vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown.

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.

Indeed, Morphine is subject to a significant first-pass effect which results in a lower bioavailability when compared to an equivalent intravenous dose.

The major metabolic transformation of morphine is glucuronidation to morphine 3- glucuronide and morphine-6-glucuronide which then undergo renal excretion. These metabolites are excreted in bile and may be subject to hydrolysis and subsequent reabsorption

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

Sugar spheres containing (sucrose and 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

February 2019