ZOMORPH 100 MG CAPSULES - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

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

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Morphine sulfate BP

Morphine sulfate BP

Morphine sulfate BP

Morphine sulfate BP

Morphine sulfate BP

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

ZOMORPH capsules should be used at 12-hourly intervals. The dosage is dependent upon the severity of the pain, the patient's age and previous history of analgesic requirements.

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with morphine in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

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.

Increasing severity of pain will require an increased dosage of the capsules 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. 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. 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 receiving Zomorph capsules in place of 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%. In such patients, individual dose adjustments are required.

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 semisolid 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

Zomorph capsules are contraindicated in patients with:

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Severe chronic obstructive pulmonary disease

Severe bronchial asthma

Severe respiratory depression with hypoxia and/or hypercapnia

Paralytic ileus

‚Acute abdomen‘

Delayed gastric emptying

Acute hepatic disease

Head injury with raised intracranial pressure

Concurrent treatment with MAO (MAO = monoamine oxidase) inhibitors or within two weeks of discontinuation of their use

Children

Not recommended for pre-operative use or for the first 24 hours post-operatively.

4.4 Special warnings and precautions for use

Zomorph capsules should be administered with caution in patients with:

Impaired respiratory function

Respiratory depression (see below)

Severe cor pulmonale

Sleep apnoea

CNS depressants co-administration (see below and section 4.5)

Tolerance, physical dependence and withdrawal (see below)

Psychological dependence [addiction], abuse profile and history of substance and/or alcohol abuse (see below)

Acute alcoholism

Delirium tremens

Head injury, intracranial lesions or increased intracranial pressure, reduced level of consciousness of uncertain origin

Hypotension with hypovolemia

Hypothyroidism

Adrenocortical insufficiency

Convulsive disorders

Biliary tract disorders

Pancreatitis

Prostatic hypertrophy

Inflammatory bowel disorders

Severely impaired renal function

Severely impaired hepatic function

Constipation

As with all narcotics a reduction in dosage may be advisable in the elderly.

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

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

Respiratory depression

The major risk of opioid excess is respiratory depression.

Opioids may cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use may increase the risk of CSA in a dose-dependent manner in some patients. Opioids may also cause worsening of pre-existing sleep apnoea (see section 4.8). In patients who present with CSA, consider decreasing the total opioid dosage.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs Concomitant use of Zomorph capsules 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 capsules concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).

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).

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.

Patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive Zomorph capsules for 24 hours prior to the intervention. If further treatment with Zomorph capsules is then indicated, the dosage should be adjusted to the new post-operative requirement.

Zomorph capsules should be used with caution post-operatively, and following abdominal surgery as morphine impairs intestinal motility and should not be used until the physician is assured of normal bowel function.

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

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.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with morphine.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose or a change in opioid.

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

Some changes that can be seen with long-term use of opioid analgesics include an increase in serum prolactin, and decreases in plasma cortisol and testosterone in association with inappropriately low or normal ACTH, LH or FSH levels. Some premenopausal women may have low oestrogen levels.

Clinical symptoms include decreased libido, impotence or amenorrhea which may be manifested from these hormonal changes.

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 (see section 4.5).

Oral P2Y12 inhibitor antiplatelet therapy

Within the first day of concomitant P2Y12 inhibitor and morphine treatment, reduced efficacy of P2Y12 inhibitor treatment has been observed (see section 4.5).

The prolonged release 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.).

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

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

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 capsules 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.

This medicine contains less than 1 mmol sodium (23mg) per capsule, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

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).

Drugs which depress the CNS include, but are not limited to: other opioids, anxyolitics, sedatives, and hypnotics (including benzodiazepines), antiepileptics (including gabapentinoids, e.g., pregabalin), general anaesthetics (including barbiturates), antipsychotics (including phenothiazines), antidepressants, muscle relaxants, antihypertensives, centrally acting anti-emetics and alcohol. Morphine sulfate should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy (see section 4.3).

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

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

Plasma concentrations of morphine sulfate may be reduced by rifampicin (see section 4.4).

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.

Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine sulfate, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine sulfate, and may possibly decrease plasma concentrations of morphine sulfate.

4.6 Fertility, pregnancy and lactation

Pregnancy

Since this product rapidly crosses the placental barrier, its use is not recommended during pregnancy and labour. Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

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 may be secreted in breast milk and may cause respiratory depression in the infant.

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 you have this medicine in your body over a specified limit unless

you have a defence (called the ‚statutory defence‘).

This defence applies when:

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.

Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected).”

Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/…-driving-law.

4.8 Undesirable effects

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

The following frequencies are the basis for assessing undesirable effects:

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)

Not known (cannot be estimated from available data).

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. Death may occur from respiratory failure.

Circulatory failure and deepening coma may occur in more severe cases.

Overdose can result in death. 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.

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Treatment of morphine overdose

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

Oral activated charcoal (50g for adults) may be considered if a substantial amount has been ingested within one hour, provided the airway can be protected.

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

In the case of massive overdose, administer naloxone 0.4mg – 2mg intravenously. Repeat at 2–3 minute intervals as necessary, or by an infusion of 2 mg in 500 ml of normal saline or 5% dextrose (0.004 mg/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 reestablished. 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.

Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on morphine. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

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 250 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

Not applicable.

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 THE FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

16 July 2010 (10mg, 30mg)

17 July 2010 (60mg, 100mg & 200mg)