1. NAME OF THE MEDICINAL PRODUCT

Cyclimorph-10 Injection 1 ml Ampoules

Cyclizine Tartrate 50mg/ml and Morphine Tartrate 10mg/ml Injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Morphine Tartrate Cyclizine

For excipients see section 6.1.

3.    PHARMACEUTICAL FORM

Injection.

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.

Route Of Administration:

By subcutaneous, intramuscular or intravenous injection.

4.2.    Posology and method of administration

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: i.e. 3 ml of Cyclizine Tartrate 50mg/ml and Morphine Tartrate 10mg/ml Injection or Cyclizine Tartrate 50mg/ml and Morphine Tartrate 15mg/ml Injection) should be given in any 24 hour period.

Use in the 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.

Children

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

4.3. Contraindications

This medicine is contraindicated in individuals with known hypersensitivity to morphine, cyclizine or any of the other constituents.

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 contra-indicated in patients with head injury or raised intra-cranial pressure.

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 contra-indicated in individuals receiving monoamine oxidase inhibitors or within 14 days of stopping such treatment

This medicine, as with other opioid containing preparations, is contra-indicated in patients with ulcerative colitis, since such preparations may precipitate toxic dilation or spasm of the colon.

This medicine is contra-indicated in biliary and renal tract spasm.

4.4.    Special warnings and precautions for use

In common with the other opioid containing preparations, this medicine has the potential to produce tolerance and physical and psychological dependence in susceptible individuals. Abrupt cessation of therapy after prolonged use may result in withdrawal symptoms.

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:

Hypothyroidism Adrenocortical insufficiency Hypopituitarism Prostatic hypertrophy Shock

Diabetes mellitus

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 increases in heart rate, mean arterial pressure and pulmonary wedge pressure. This medicine should therefore be used with caution in patients with severe heart failure.

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.

4.5.    Interactions 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.

Monoamine oxidase Inhibitors (MAOIs) may prolong and enhance the respiratory depressant effects of morphine. Opioids and MAOI’s used together may cause fatal hypotension and coma (see Contraindications).

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 dexamphetamine, 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.

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. Pregnancy and lactation

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.

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

Lactation

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 drug 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

As this medicine contains morphine and cyclizine, the type and frequency of adverse effects associated with such compounds may be expected.

Adverse reactions attributable to morphine include respiratory depression, raised intracranial pressure, orthostatic hypotension, drowsiness, confusion, dysphoria, restlessness, miosis, constipation, nausea, vomiting, skin reactions (e.g. urticaria) biliary tract and renal spasm, vertigo and difficulty with micturition.

Adverse reactions attributable to cyclizine include urticaria, drug rash, drowsiness/sedation, headache, dryness of the mouth, nose and throat, blurred vision, tachycardia, urinary retention, constipation, restlessness, nervousness, insomnia, auditory and visual hallucination have been reported, particularly when dosage recommendations have been exceeded.

Other Central Nervous System effects which have been reported rarely include dystonia, dyskenesia, extrapyramidal motor disturbances, tremor, twitching, muscle spasms, convulsions, disorientation, dizziness, decreased consciousness, transient speech disorders, hypertension and paraesthesia.

Cholestatic jaundice has occurred in association with cyclizine. Rare reports of cholestatic hepatitis and hypersensitivity reactions, including anaphylaxis, angioedema, allergic skin reactions and bronchospasm have been reported in association with cyclizine. There have also been a few reports of fixed drug eruption (rash), apnoea, generalised chorea, hypersensitivity hepatitis, hepatic dysfunction and agranulocytosis.

Anaphylaxis has been reported following intravenous administration of cyclizine coadministered in the same syringe as propanidid.

Anaphylactic shock is a rare adverse reaction to morphine.

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

A case of morphine-induced thrombocytopenia has been reported.

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.

Injection site reactions including vein tracking, erythema, pain and thrombophlebitis have been reported rarely.

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

Reporting of side effects

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 theYellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Signs

The signs of overdosage with this medicine_are those pathognomic of opioid poisoning i.e. respiratory depression, pin point pupils, hypotension, circulatory failure and deepening coma Mydriasis may replace miosis as asphyxia intervenes.

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

Treatment

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.

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

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

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

Morphine is a competitive agonist at the p-opioid receptor and is a potent analgesic. It is thought that activity at the pi-receptor subtype may mediate the analgesic and euphoric actions of morphine whilst activity at the p2-receptor subtype may mediate respiratory depression and inhibition of gut motility. An action at the K-opioid receptor may mediate spinal analgesia

5.2. Pharmacokinetic Properties

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

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

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.

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.

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.

5.3. Pre-clinical Safety Data

A.    Mutagenicity

Cyclizine was not mutagenic in an Ames test (at a dose level of 100 p,g/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 Drosophilia 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 iv. 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.

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 Contraindications

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. Instructions for Use/Handling

No special instructions..

7 MARKETING AUTHORISATION HOLDER

Amdipharm UK Limited

Regency House

Miles Gray Road

Basildon

Essex

SS14 3AF

United Kingdom.

8. MARKETING AUTHORISATION NUMBER

PL 20072/0007

9. DATE OF FIRST AUTHORISATION / RENEWAL OF AUTHORISATION

3^rd November 2003

10. DATE OF REVISION OF THE TEXT

December 2004

10 DATE OF REVISION OF THE TEXT

09/06/2015