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CYCLIMORPH 15 INJECTION

Active substance(s): CYCLIZINE / MORPHINE TARTRATE / CYCLIZINE / MORPHINE TARTRATE

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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.
Excipients: Each 1 ml contains 1 mg sodium metabisulphite (E223).
For a full list of 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

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.
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 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-6glucuronide. 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.
antiemetic properties of cyclizine may increase the toxicity of alcohol.

The

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

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:
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.
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.

4.5

Interaction with Other Medicaments and other forms of Interaction

The central nervous system depressant effects of this medicine may be enhanced by other centrallyacting 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.
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 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

As this medicine contains morphine and cyclizine, the type and frequency of adverse effects
associated with such compounds may be expected.
Following are the adverse reactions attributable to morphine and cyclizine with frequency of
Unknown:
System Organ Class
Blood and lymphatic system disorder
Cardiac disorders
Eye disorders
Gastrointestinal disorders
General disorders and administration site
conditions
Hepatobiliary disorders

Immune system disorders

Adverse reactions
Agranulocytosis,
morphine-induced
thrombocytopenia
tachycardia
Miosis, blurred vision
Constipation, nausea, vomiting, dryness of the
mouth, nose and throat
Injection site reactions including vein tracking,
erythema, pain and thrombophlebitis
biliary tract spasm, cholestatic jaundice has
occurred in association with cyclizine,
cholestatic hepatitis, , hepatic dysfunction
hypersensitivity reactions, including
anaphylaxis, angioedema, allergic skin

System Organ Class

Nervous system disorders

Psychiatric disorders

Adverse reactions
reactions, hypersensitivity hepatitis,
Anaphylactic shock
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,
dysphoria

Renal and urinary disorders

renal spasm, difficulty with micturition, urinary
retention

Reproductive system and breast disorders

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

Respiratory, thoracic and mediastinal disorders

Skin and subcutaneous tissue disorders

skin reactions (e.g. urticaria)
drug rash, fixed drug eruption (rash)

Vascular disorders

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
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

4.9

Overdose

Signs
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.
Drowsiness, floppiness, miosis and apnoea are signs of opioid overdosage in children as are
convulsions.
Rhabdomyolysis progressing to renal failure 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.
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.
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
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

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-6glucuronide.
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 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 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
Capital House,
85 King William Street,
London, EC4N 7BL,
United Kingdom

8.

MARKETING AUTHORISATION NUMBER
PL 20072/0008

9.

DATE OF FIRST AUTHORISATION / RENEWAL OF AUTHORISATION
3rd November 2003

10

DATE OF REVISION OF THE TEXT
18/01/2017

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Source: Medicines and Healthcare Products Regulatory Agency

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