Amdipharm Plc

Update sections 4.4 & 4.8 per MHRA request as noted below in bold (additionally presentation of undesirable effects has changed):

4.4.      Special Warnings and Precautions for Use

As with other anticholinergic agents, Valoid may precipitate incipient glaucoma and it should be used with caution and appropriate monitoring in patients with glaucoma, obstructive disease of the gastrointestinal tract, hepatic disease, epilepsy and in males with possible prostatic hypertrophy.  Valoid injection, may have a hypotensive effect.

Cyclizine should be used with caution in patients with severe heart failure.  In such patients, cyclizine may cause a fall in cardiac output associated with increases in heart rate, mean arterial pressure and pulmonary wedge pressure.

Cyclizine should be avoided in porphyria. 

There have been reports of abuse of cyclizine, either oral or intravenous, for its euphoric or hallucinatory effects. The concomitant misuse of Valoid with large amounts of alcohol is particularly dangerous, since the antiemetic effect of cyclizine may increase the toxicity of alcohol (see also Section 4.5 Interactions).

There have been isolated case reports of transient paralysis occurring in patients using intravenous cyclizine. Two of the patients mentioned in these 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.

4.8.      Undesirable Effects

Blood and lymphatic system disorders

Agranulocytosis

Cardiac disorders

Tachycardia

Eye disorders

Blurred vision, oculogyric crisis

Gastrointestinal system disorders

Dryness of the mouth, nose and throat, constipation

General disorders and administration site conditions

Asthenia

Injection site reactions including vein tracking, erythema, pain, thrombophlebitis and blisters. A sensation of heaviness, chills and pruritus have been reported rarely. Anaphylaxis has been recorded following intravenous administration of cyclizine co-administered with propanidid in the same syringe.

Hepatobiliary disorders

Hepatic dysfunction, hypersensitivity hepatitis, cholestatic jaundice and cholestatic hepatitis have occurred in association with cyclizine.

Immune system disorders

Hypersensitivity reactions, including anaphylaxis have occurred.

Musculoskeletal and connective tissue disorders

Twitching, muscle spasms

Nervous system disorders

Effects on the central nervous system have been reported with cyclizine these include somnolence, headache, dystonia, dyskinesia, extrapyramidal motor disturbances, tremor, convulsions, dizziness, decreased consciousness, transient speech disorders, paraesthesia and generalised chorea.

There have been rare case reports of patients experiencing depressed levels of consciousness/loss of consciousness. The use of cyclizine has been associated with cases of transient paralysis following administration of the intravenous formulation of the medicine. The onset of paralysis is usually within minutes of administration, affects the limbs, and fully resolves within hours of discontinuation of the medicine (see also Section 4.4 Special Warnings).

Psychiatric disorders

Disorientation, restlessness or agitation, nervousness, insomnia and auditory and visual hallucinations have been reported, particularly when dosage recommendations have been exceeded.

Renal and urinary disorders

Urinary retention

Respiratory, thoracic and mediastinal disorders

Bronchospasm, apnoea

Skin and subcutaneous tissue disorders

Urticaria, pruritus, drug rash, angioedema, allergic skin reactions, fixed drug eruption

Vascular disorders

Hypertension, hypotension

The following changes to verbiage or additional verbiage, and [REMOVED] verbiage, as noted in bold or brackets, respectively, have occurred:

 2. Qualitative and Quantitative Composition

Tablets containing 50 mg of cyclizine hydrochloride.

3. Pharmaceutical Form

Tablet

White, biconvex, uncoated tablet, scored; coded T4A.

The tablet can be divided into two halves.

4.2 Posology and Method of Administration

Route of administration: oral

Adults and Children over 12 Years:

50 mg orally, which may be repeated up to three times a day.

Children 6 – 12 Years:

25 mg orally, which may be repeated up to three times a day.

Children less than 6 years of age:

Valoid tablets are not recommended for children less than 6 years of age.

Use in the Elderly:

There have been no specific studies of Valoid in the elderly. Experience has indicated that normal adult dosage is appropriate.

To prevent motion sickness Valoid should be taken about one to two hours before departure.

4.4 Special Warnings and Precautions for Use

[REMOVE

Cyclizine was not mutagenic in a full Ames test, including use of S9-microsomes.

No long-term studies have been conducted in animals to determine whether cyclizine has a potential for carcinogenesis.]

4.6 Pregnancy and Lactation

[REMOVE

Some animal studies are interpreted as indicating that cyclizine may be teratogenic.

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 to 100 days. There is no experience of the effect of Valoid on human fertility.]

5.1 Pharmacodynamic Properties

ATC Code: R60AE03

Pharmacotherapeutic Group: Piperazine derivatives

Mode of Action:

Cyclizine is a histamine H1 receptor antagonist of the piperazine class which is characterised by a low incidence of drowsiness. 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. It may inhibit the part of the midbrain known collectively as the emetic centre.

Pharmacodynamics: Cyclizine produces its antiemetic effect within two hours and last approximately four hours.

5.2 Pharmacokinetic Properties

In healthy adult volunteers 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 two hours after drug administration. The plasma elimination half-life was approximately 20 hours.

The N-demethylated derivative, norcyclizine, has been identified as a metabolite of cyclizine. Norcyclizine has little antihistaminic (H1) activity compared to cyclizine. It is widely distributed throughout the tissues and has a plasma elimination half-life of approximately 20 hours.

After a single dose of 50 mg cyclizine given to a single adult male volunteer, urine collected over the following 24 hours contained less than 1% of the total dose administered.

5.3 Preclinical Safety Data

A. Mutagenicity:

Cyclizine was not mutagenic in a full Ames test, including use of S9-microsomes but can nitrosate in vitro to form mutagenic products.

B. Carcinogenicity:

No long term studies have been conducted in animals to determine whether cyclizine has a potential for carcinogenesis. However, long-term studies with cyclizine administered with nitrate have indicated no carcinogenicity.

C. Teratogenicity:

Some animal studies are interpreted as indicating that Cyclizine may be teratogenic. The relevance of these studies to the human situation is not known.

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. There is no experience of the effect of Valoid on human fertility.

6.3 Shelf Life

Five years.

10. Date of (Partial) Revision of Text

July 2007

As with other anticholinergic agents, Valoid should be used with caution and appropriate monitoring in patients with glaucoma, obstructive disease of the gastrointestinal tract, hepatic disease, epilepsy and in males with possible prostatic hypertrophy. 

Addition of the following text:

There have been reports of abuse of cyclizine, either oral or intravenous, for its euphoric or hallucinatory effects. The concomitant misuse of cyclizine with large amounts of alcohol is particularly dangerous, since the antiemetic effect of cyclizine may increase the toxicity of alcohol (see also Section 4.5 Interactions).

The following text has been removed: 'There have been no specific studies in hepatic and/or renal dysfunction.' and has been replaced by: 'A dose reduction may be necessary in patients with renal impairment.'

Addition of the following text:

Cyclizine should be avoided in porphyria.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Urticaria, drug rash, drowsiness, headache, dryness of the mouth, nose and throat, blurred vision, tachycardia, urinary retention, constipation, restlessness, nervousness, insomnia and auditory and visual hallucinations have been reported, particularly when dosage recommendations have been exceeded. Other Central Nervous System effects which have been recorded rarely include dystonia, dyskinesia, extrapyramidal motor disturbances, tremor, twitching, muscle spasms, convulsions, disorientation, dizziness, decreased consciousness, transient speech disorders, hypertension and paraesthesia.

The following text has been removed: 'Single case reports have been documented of fixed drug eruption, generalised chorea, hypersensitivity hepatitis and agranulocytosis.' and has been replaced by: '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, apnoea, generalised chorea, hypersensitivity hepatitis, hepatic dysfunction and agranulocytosis.'