Amdipharm Limited

Cyclimorph 15 Injection.

Cyclimorph 15 Injection contains morphine tartrate 15mg and cyclizine tartrate 50mg in each 1ml ampoule.

Solution for Injection.

A clear very slightly coloured solution.

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

Adults and children over 12 years:

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 Cyclimorph 15) should be given in any 24-hour period.

Children 612 years: 510 mg morphine tartrate as a maximum single dose.

Children 15 years: 2.55 mg morphine tartrate as a maximum single dose.

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.

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

Cyclimorph Injection, like other opioid-containing preparations, is contraindicated in patients with respiratory depression or obstructive airways disease. Patients with excessive bronchial secretions should not be given Cyclimorph Injection as morphine diminishes the cough response.

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

Cyclimorph Injection is contraindicated 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 Cyclimorph Injection 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 Cyclimorph Injection should not be administered to patients with severe hepatic impairment as it may precipitate coma.

Cyclimorph Injection is contraindicated in the presence of acute alcohol intoxication. The antiemetic properties of cyclizine may increase the toxicity of alcohol.

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

Cyclimorph Injection, 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.

Cyclimorph Injection is contraindicated in biliary and renal tract spasm and in patients immediately after operative interventions in the biliary tract.

In common with other opioid containing preparations, Cyclimorph Injection 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.

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

Cyclimorph Injection should be used with caution in the presence of the following: hypothyroidism, adrenocortical insufficiency, hypopituitarism, myxoedema, prostatic hypertrophy, shock and diabetes mellitus.

Extreme caution should be exercised when administering Cyclimorph Injection 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. Cyclimorph Injection should therefore be used with caution in patients with severe heart failure.

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 Cyclimorph Injection may be enhanced by combination with other centrally acting agents (see Interaction with Other Medicinal Products and Other Forms of Interaction). Patients should therefore be cautioned against activities requiring vigilance including driving vehicles and operating machinery.

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.

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

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 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.

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.

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.

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.

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 Cyclimorph Injection 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.

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 Cyclimorph Injection may be enhanced by combination with other centrally acting agents (see Interaction with Other Medicinal Products and Other Forms of Interaction). Patients should therefore be cautioned against activities requiring vigilance including driving vehicles and operating machinery.

As Cyclimorph Injection 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 intra-cranial 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, dryness of the mouth, nose and throat, blurred vision, tachycardia, hypotension, urinary retention, constipation, restlessness, nervousness, insomnia, apnoea and auditory and visual hallucinations, particularly when dosage recommendations have been exceeded.

Other Central Nervous System effects which have been reported rarely include dystonia, dyskinesia, extrapyramidal motor disturbances, tremor, twitching, muscle spasms, convulsions, disorientation, dizziness, decreased consciousness and transient speech disorders. Rare reports of cholestatic hepatitis and hypersensitivity reactions, including anaphylaxsis, angioedema, allergic skin reactions and bronchospasm have been reported in association with cyclizine. There have also been a few reports have been documented of fixed drug eruption (rash), generalised chorea, hypersensitivity hepatitis, hepatic dysfunction, agranulocytosis and paraesthesia.

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 tacking, erythema, pain and thrombophlebitis have been reported rarely.

Signs:

The signs of overdosage with Cyclimorph Injection 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.

Mode of Action:

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

In a healthy adult volunteer the administration of a single oral dose of 50 mg cyclizine resulted in a peak plasma concentration of approximately 70 ng/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 2.95h (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.

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.

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.

Carcinogenicity:

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

Tartaric acid Ph Eur

Sodium metabisulphite (E223) BP

Water for injections Ph Eur

None

3 years.

Do not store above 25°C. Keep ampoules in outer carton.

Ampoules comply with the requirements of the European Pharmacopoeia for Type I neutral glass. Cyclimorph Injection is supplied in boxes of 5 x 1ml ampoules.

No special instructions are required.

Amdipharm Limited

Temple Chambers

3 Burlington Road

Dublin 4

Ireland.

PA 1142/3/2

1 April 1978 / 1 April 2003.

June 2005