This information is intended for use by health professionals

1. Name of the medicinal product

Cyclimorph-15 Injection

Cyclizine Tartrate 50mg/ml and Morphine Tartrate 15mg/ml Injection

2. Qualitative and quantitative composition

This medicine contains morphine tartrate 15 mg and cyclizine tartrate 50 mg (equivalent to 39.01 mg cyclizine) in each 1 ml ampoule.

Excipient with known effect:

Each 1 ml contains 1 mg sodium metabisulphite (E223).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Injection.

A clear very slightly coloured solution. pH 4.3 to 5.0.

4. Clinical particulars
4.1 Therapeutic indications

This medicine is indicated for the relief of moderate to severe pain in all suitable medical and surgical conditions (see Contraindications and Precautions & Warnings) in which reduction of the nausea and vomiting associated with the administration of morphine is required.

4.2 Posology and method of administration

Posology

Adults

The usual dose is 10-20 mg morphine tartrate, given subcutaneously, intramuscularly or intravenously.

Additional doses may not be given more frequently than 4 hourly.

Not more than 3 doses (representing 150 mg cyclizine tartrate: i.e. 3 ml of Cyclimorph 15 Injection) should be given in any 24-hour period.

Elderly

Morphine doses should be reduced in elderly patients and titrated to provide optimal pain relief with minimal side effects since:

- Increased duration of pain relief from a standard dose of morphine has been reported in elderly patients.

- A review of pharmacokinetic studies has suggested that morphine clearance decreases and half-life increases in older patients.

- The elderly may be particularly sensitive to the adverse effects of morphine.

Paediatric population

This medicine should not be used in children under 12 years of age.

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

By subcutaneous, intramuscular or intravenous injection.

4.3 Contraindications

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

This medicine, like other opioid-containing preparations, is contraindicated in patients with respiratory depression. Patients with excessive bronchial secretions should not be given this medicine as morphine diminishes the cough response.

This medicine should not be given during an attack of bronchial asthma or in heart failure secondary to chronic lung disease.

This medicine is contraindicated in patients with head injury or raised intra-cranial pressure.

This medicine, as with other opioid-containing preparations, is contraindicated for children less than one year of age. It is also contraindicated for pre-operative use or during the first 24 hours post-operatively.

Renal impairment

Severe and prolonged respiratory depression may occur in patients with renal impairment given morphine; this is attributed to the accumulation of the active metabolite morphine-6-glucuronide. Therefore, this medicine should not be administered to patients with moderate or severe renal impairment (glomerular filtration rate <20 ml/min).

Hepatic impairment

As with other opioid analgesic containing preparations this medicine should not be administered to patients with severe hepatic impairment as it may precipitate coma.

This medicine is contra-indicated in the presence of acute alcohol intoxication. The antiemetic properties of cyclizine may increase the toxicity of alcohol.

This medicine is contraindicated in individuals receiving monoamine oxidase inhibitors or within 14 days of stopping such treatment.

This medicine, as with other opioid containing preparations, is contraindicated in patients with ulcerative colitis, since such preparations may precipitate toxic dilation or spasm of the colon. This medicine is contraindicated in patients with paralytic ileus and delayed gastric emptying.

This medicine is contraindicated in biliary and renal tract spasm and in patients immediately after operative interventions in the biliary tract.

4.4 Special warnings and precautions for use

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.

This medicine should be used with caution in the debilitated since they may be more sensitive to the respiratory depressant effects.

This medicine should be used with caution (including consideration of dose administered) in the presence of the following:

convulsive disorders

delerium tremens

severe cor pulmonale

hypothyroidism

adrenocortical insufficiency

hypopituitarism

prostatic hypertrophy

shock

diabetes mellitus

myasthenia gravis

hypotension and hypovolaemia

pancreatitis

obstructive bowel disorders

inflammatory bowel disorders

Extreme caution should be exercised when administering this medicine to patients with phaeochromocytoma, since aggravated hypertension has been reported in association with diamorphine.

Cyclizine may cause a fall in cardiac output associated with increase in heart rate, mean arterial pressure and pulmonary wedge pressure. This medicine should therefore be used with caution in patients with severe heart failure.

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.

Cyclizine should be avoided in patients with porphyria. Therefore use of this medicine should also be avoided in these patients.

Case reports of paralysis have been received in patients using intravenous cyclizine. Some of the patients mentioned in these case reports had an underlying neuromuscular disorder. Thus, intravenous cyclizine should be used with caution in all patients in general, and in patients with underlying neuromuscular disorders in particular.

Because cyclizine has anticholinergic activity it may precipitate incipient glaucoma. It should be used with caution and appropriate monitoring in patients with glaucoma and also in obstructive disease of the gastrointestinal tract.

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

Concomitant use of Cyclizine Tartrate 50mg/ml and Morphine Tartrate 10mg/ml Injection 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 Cyclizine Tartrate 50mg/ml and Morphine Tartrate 10mg/ml Injection 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).

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 amenorrhea.

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.

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.

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.

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

This medicinal product contains sodium metabisulphite which may rarely cause severe hypersensitivity reactions and bronchospasm.

4.5 Interaction with other medicinal products and other forms of interaction

The central nervous system depressant effects of this medicine may be enhanced by other centrally-acting agents such as phenothiazines, hypnotics, neuroleptics, alcohol and muscle relaxants.

The action of morphine may in turn affect the activities of other compounds, for example its gastrointestinal effects may delay absorption as with mexilitine or may be counteractive as with metoclopramide.

Monoamine oxidase inhibitors (MAOI's) may prolong and enhance the respiratory depressant effects of morphine. Opioids and MAOI's used together may cause fatal hypotension and coma (see Contra-indications).

Cimetidine inhibits the metabolism of morphine.

Because of its anticholinergic activity cyclizine may enhance the side effects of other anticholinergic drugs.

The analgesic effect of opioids tends to be enhanced by co-administration of 1dexamfetamine, hydroxyzine, and some phenothiazines although respiratory depression may also be enhanced by the latter combination.

Morphine may reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Propranolol has been reported to enhance the lethality of toxic doses of opioids in animals, although the significance of this finding is not known for man. Caution should be exercised when these drugs are administered concurrently.

In vitro data suggest that St. John's Wort (Hypericum perforatum) may induce cytochrome P450 3A4. There is a theoretical possibility therefore, that plasma levels of morphine tartrate may be decreased during concomitant administration and increased upon withdrawal of St. John's Wort.

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

Interference with laboratory tests

Morphine can react with Folin-Ciocalteau reagent in the Lowry method of protein estimation.

Morphine can also interfere with the determination of urinary 17-ketosteroids due to chemical structure effects in the Zimmerman procedure.

4.6 Fertility, pregnancy and lactation

Fertility

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

Pregnancy

There is no evidence on the safety of the combination in human pregnancy nor is there evidence from animal work that the constituents are free from hazard. However, limited data from epidemiological studies of cyclizine and morphine in human pregnancies have found no evidence of teratogenicity. In the absence of definitive human data with the combination the use of this medicine in pregnancy is not advised.

New-born's 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.

Administration of morphine during labour may cause respiratory depression in the newborn infant.

Breast-feeding

Cyclizine is excreted in human milk, however, the amount has not been quantified.

Morphine can significantly suppress lactation. Morphine is excreted in human milk, but the amount is generally considered to be less than 1% of any dose.

4.7 Effects on ability to drive and use machines

In common with other opioids, morphine may produce orthostatic hypotension and drowsiness in ambulatory patients. Sedation of short duration has been reported in patients receiving intravenous cyclizine. The CNS depressant effects of this medicine may be enhanced by combination with other centrally acting agents (see Interaction with Other Medicaments and Other Forms of Interactions). Patients should therefore be cautioned against activities requiring vigilance including driving vehicles and operating 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

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: 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 the available data)

The following undesirable effects have been reported with a frequency of Not known:

System Organ Class

Frequency

Adverse reactions

Blood and lymphatic system disorder

Not known

Agranulocytosis, morphine-induced thrombocytopenia

Cardiac disorders

Not known

tachycardia

Eye disorders

Not known

Miosis, blurred vision, oculogyric crisis

Gastrointestinal disorders

Not known

Constipation, nausea, vomiting, dryness of the mouth, nose and throat

General disorders and administration site conditions

Not known

Injection site reactions including vein tracking, erythema, pain and thrombophlebitis, drug withdrawal (abstinence) syndrome: dysphoric mood, anxiety

Hepatobiliary disorders

Not known

biliary tract spasm, cholestatic jaundice has occurred in association with cyclizine, cholestatic hepatitis, hepatic dysfunction

Immune system disorders

Not known

hypersensitivity reactions including anaphylaxis, angioedema, allergic skin reactions, hypersensitivity hepatitis, Anaphylactic shock, anaphylactoid reactions

Nervous system disorders

Not known

raised intra-cranial pressure, drowsiness, confusion, restlessness, vertigo, sedation, headache, nervousness, insomnia, auditory and visual hallucinations, dystonia, dyskinesia, extrapyramidal motor disturbances, tremor, twitching, muscle spasms, convulsions, disorientation, dizziness, decreased consciousness, transient speech disorders, paraesthesia, generalised chorea, allodynia, hyperalgesia (see section 4.4), hyperhidrosis

Psychiatric disorders

Not known

dysphoria, dependence

Renal and urinary disorders

Not known

renal spasm, difficulty with micturition, urinary retention

Reproductive system and breast disorders

Not known

Morphine has a depressant effect on gonadal hormone secretion which can result in a reduction of testosterone leading to regression of secondary sexual characteristics in men on long-term therapy.

Respiratory, thoracic and mediastinal disorders

Not known

respiratory depression, bronchospasm, apnoea

this medicine has demonstrated significant incidence of single cough or paroxysm of coughing immediately after its administration.

Skin and subcutaneous tissue disorders

Not known

skin reactions (e.g. urticaria)

drug rash, fixed drug eruption (rash)

Vascular disorders

Not known

orthostatic hypotension, hypertension

A case of psychomotor hyperactivity following intravenous administration of morphine during the induction of anaesthesia has been reported.

Case reports of paralysis have been received in patients using intravenous cyclizine. Some of the patients mentioned in these case reports had an underlying neuromuscular disorder.

Rapid IV administration of cyclizine can lead to symptoms similar to overdose.

Case reports of Narcotic bowel syndrome and hyperaesthesia/ allodynia due to Morphine have also been reported.

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

The signs of overdosage with this medicine are those pathognomic of opioid poisoning i.e. respiratory depression, bradycardia, pin point pupils, hypotension, circulatory failure and deepening coma. Mydriasis may replace miosis as asphyxia intervenes. Opioid overdose can result in death from respiratory failure.

Drowsiness, floppiness, miosis and apnoea are signs of opioid overdosage in children as are convulsions.

Rhabdomyolysis progressing to renal failure and Pneumonia aspiration has been reported in opioid overdosage.

Signs and symptoms of acute toxicity from cyclizine arise from peripheral anticholinergic effects and effects on the central nervous system.

Peripheral anticholinergic symptoms include, dry mouth, nose and throat, blurred vision, tachycardia and urinary retention.

Central nervous system effects include drowsiness, dizziness, incoordination, ataxia, weakness, hyperexcitability, disorientation, impaired judgement, hallucinations, hyperkinesia, extrapyramidal motor disturbances, convulsions, hyperpyrexia and respiratory depression.

Management

It is imperative to maintain and support respiration and circulation.

The specific opioid antagonist naloxone is the treatment of choice for the reversal of coma and restoration of spontaneous respiration. The literature should be consulted for details of appropriate dosage.

The use of a specific opioid antagonist in patients tolerant to morphine may produce withdrawal symptoms.

Convulsions should be controlled with parenteral anticonvulsant therapy.

Patients should be monitored closely for at least 48 hours in case of relapse.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, Opioids, Natural opium alkaloids, Morphine combinations; ATC Code: N02AA51

Mechanism of action of cyclizine

Cyclizine is a histamine H1 receptor antagonist of the piperazine class. It possesses anticholinergic and antiemetic properties. The exact mechanism by which cyclizine can prevent or suppress both nausea and vomiting from various causes is unknown.

Pharmacodynamic effects of cyclizine

Cyclizine increases lower oesophageal sphincter tone and reduces the sensitivity of the labyrinthine apparatus.

Mechanism of action of Morphine

Morphine is a competitive agonist at the µ-opioid receptor and is a potent analgesic. It is thought that activity at the μ1-receptor subtype may mediate the analgesic and euphoric actions of morphine whilst activity at the μ2-receptor subtype may mediate respiratory depression and inhibition of gut motility.

Pharmacodynamic effects of Morphine

An action at the K-opioid receptor may mediate spinal analgesia.

5.2 Pharmacokinetic properties

Distribution of cyclizine

In a healthy adult volunteer the administration of a single oral dose of 50 mg cyclizine resulted in a peak plasma concentration of approximately 70ng/ml, occurring at about 2 hours after administration. Urine collected over 24 hours contained less than 1% of the total dose administered.

Biotransformation of cyclizine

Cyclizine is metabolised to its N-dimethylated derivative norcyclizine, which has little antihistaminic (H1) activity compared to cyclizine.

Elimination of cyclizine

In a separate study in one healthy adult volunteer the plasma elimination half-life of cyclizine was approximately 20 hours.

Biotransformation of morphine

Morphine is extensively metabolised by hepatic biotransformation. In addition, the kidney has been shown to have the capacity to form morphine glucuronides. The major metabolite is morphine-3-glucuronide (approximately 45% of a dose). Morphine-6-glucuronide is a minor metabolite (approx. 5% of the dose) but is highly active. Although renal excretion is a minor route of elimination for unchanged morphine, it constitutes the major mechanism of elimination of conjugated morphine metabolites including the active morphine-6-glucuronide.

Distribution of morphine

Morphine is bound to plasma proteins only to the extent of 25-35% and therefore functions that change the extent of protein binding will have only a minor impact on its pharmacodynamic effects.

Elimination of morphine

The mean elimination half-life for morphine in blood and plasma is 2.7h (range 1.2-4.9h) and 2.95 (range 0.8-5h) respectively.

5.3 Preclinical safety data

A. Mutagenicity

Cyclizine was not mutagenic in an Ames test (at a dose level of 100 μg/plate), with or without metabolic activation.

No bacterial mutagenicity studies with morphine have been reported. A review of the literature has indicated that morphine was negative in gene mutation assays in Drosophila melanogaster, but was positive in a mammalian spermatocyte test. The results of another study by the same authors has indicated that morphine causes chromosomal aberrations, in germ cells of male mice when given at dose levels of 10, 20, 40 or 60 mg/kg bodyweight for 3 consecutive days.

B. Carcinogenicity

No long term studies have been conducted in animals to determine whether cyclizine or morphine are potentially carcinogenic.

C. Teratogenicity

Some animal studies indicate that cyclizine may be teratogenic at dose levels up to 25 times the clinical dose level. In another study, cyclizine was negative at oral dose levels up to 65 mg/kg in rats and 75 mg/kg in rabbits.

Morphine was not teratogenic in rats when dosed for up to 15 days at 70 mg/kg/day. Morphine given subcutaneously to mice at very high doses (200, 300 or 400 mg/kg/day) on days 8 or 9 of gestation, resulted in a few cases of exencephaly and axial skeletal fusions. The hypoxic effects of such high doses could account for the defects seen.

Lower doses of morphine (40, 4.0 or 0.4 mg/ml) given to mice as a continuous i.v. infusion (at a dose volume of 0.3 ml/kg) between days 7 and 10 of gestation, caused soft tissue and skeletal malformations as shown in previous studies.

D. Fertility

In a study involving prolonged administration of cyclizine to male and female rats, there was no evidence of impaired fertility after continuous treatment for 90-100 days at dose levels of approximately 15 and 25 mg/kg/day.

Effects of morphine exposure on sexual maturation of male rats, their reproductive capacity and the development of their progeny have been examined. Results indicated that exposure during adolescence led to pronounced inhibition of several indices of sexual maturation (e.g. hormone levels, reduced gonad weights), smaller litters and selective gender specific effects on endocrine function in the offspring. In male rats, reduced fertility and chromosomal damage in gametes have been reported.

A disruption in ovulation and amenorrhoea can occur in women given morphine.

6. Pharmaceutical particulars
6.1 List of excipients

Tartaric Acid

Sodium Metabisulphite

Water for Injections

6.2 Incompatibilities

See Interactions with other medicaments and other forms of interaction and Contra-indications.

Physicochemical incompatibility (formation of precipitates) has been demonstrated between solutions of morphine sulphate and 5- fluorouracil.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 30°C.

Protect from light. Do not freeze.

6.5 Nature and contents of container

Ampoules which comply with the requirements of the European Pharmacopoeia for type I neutral glass.

Pack size: l ml ampoules: Box of five.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Amdipharm UK Limited

Capital House,

85 King William Street,

London, EC4N 7BL,

United Kingdom

8. Marketing authorisation number(s)

PL 20072/0008

9. Date of first authorisation/renewal of the authorisation

3rd November 2003

10. Date of revision of the text

24/12/2018