Consumer medicine information

Cizinate

Cinnarizine; Dimenhydrinate

BRAND INFORMATION

Brand name

Cizinate

Active ingredient

Cinnarizine; Dimenhydrinate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cizinate.

SUMMARY CMI

CIZINATE®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I taking CIZINATE?

CIZINATE contains the two active ingredients, cinnarizine and dimenhydrinate. CIZINATE is used for the short term treatment of the symptoms of vertigo.

For more information, see Section 1. Why am I taking CIZINATE? in the full CMI.

2. What should I know before I take CIZINATE?

Do not use if you have ever had an allergic reaction to CIZINATE or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take CIZINATE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CIZINATE and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take CIZINATE?

  • The standard dose for this medicine is one tablet three times a day, although your doctor may have prescribed a different dose.
  • CIZINATE tablets should be swallowed without chewing and with a glass of liquid, following a meal, at the same time each day.
  • Usually you will take CIZINATE for up to 4 weeks. Your doctor will however decide how long you will need to take this medicine.

More instructions can be found in Section 4. How do I take CIZINATE? in the full CMI.

5. What should I know while taking CIZINATE?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using CIZINATE.
  • If you are about to be started on a new medicine, tell your doctor, dentist or pharmacist that you are taking CIZINATE.
  • Tell your doctor if you have kidney or liver problems, suffer from an eye disease, have convulsions, fits or seizures, have increased pressure in the brain, suffer from alcohol abuse or have prostate problems which cause difficulty in urinating, or are under 18 years of age. Tell your doctor if you have other medical conditions.
  • If you plan to have surgery requiring a general anaesthetic, tell your doctor or dentist that you are taking CIZINATE.
  • If you become pregnant while taking CIZINATE, tell your doctor immediately.
Things you should not do
  • Do not give CIZINATE to anyone else, even if they have the same condition as you.
  • Do not take CIZINATE to treat any other complaints unless your doctor tells you to.
  • Do not stop taking CIZINATE, or lower the dosage without checking with your doctor.
Driving or using machinesAs CIZINATE may cause dizziness in some people, be careful before you drive or use any machines or tools until you know how CIZINATE affects you.
Drinking alcoholAvoid alcoholic drinks while taking CIZINATE.
Looking after your medicine
  • Keep your tablets in a cool, dry place out of the reach of children where the temperature stays below 25°C.
  • Do not store CIZINATE in the bathroom, near a sink, on a windowsill or in the car on hot days.

For more information, see Section 5. What should I know while taking CIZINATE? in the full CMI.

6. Are there any side effects?

Common side effects: drowsiness, dry mouth, headache and stomach pain. Less common side effects: sweating, reddening of the skin, indigestion, feeling sick, diarrhoea, nervousness, cramps, forgetfulness, ringing in the ear, tingling of the hands or feet, shaking, light sensitivity, impaired vision, allergic reactions, difficulty in urinating, weakness, bruising, infections. Weight gain and constipation have been reported.

Serious side effects include skin reactions, difficulty breathing, shortness of breath, severe eye pain, convulsions or fitting, trembling and shaking of the hands and fingers, uncontrollable body or face movements, body twisting movements, muscle stiffness with difficulty walking, arms and legs stiffness, or severe excitement or restlessness and desire to keep moving; swelling of the face, lips, tongue or other body parts; rash, itching or hives on the skin or other skin reactions; tightness of the chest; yellowing of the skin or whites of the eyes.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

CIZINATE®

Active ingredient(s): cinnarizine and dimenhydrinate

Consumer Medicine Information (CMI)

This leaflet provides important information about using CIZINATE. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using CIZINATE.

Where to find information in this leaflet:

1. Why am I taking CIZINATE?
2. What should I know before I take CIZINATE?
3. What if I am taking other medicines?
4. How do I take CIZINATE?
5. What should I know while taking CIZINATE?
6. Are there any side effects?
7. Product details

1. Why am I taking CIZINATE?

CIZINATE contains the two active ingredients cinnarizine and dimenhydrinate. The two substances belong to different groups of medicines. Cinnarizine is part of a group called calcium antagonists and also has anti-dopamine and anti-histamine effects. Dimenhydrinate belongs to a group called antihistamines. Both substances work by reducing symptoms of vertigo (a feeling of dizziness or ‘spinning’) and nausea (feeling sick). When these two substances are used together they are more effective than when each one is used on its own.

CIZINATE is used for short-term symptomatic treatment of vertigo, in adults who have not responded to alternative treatments. Vertigo can have a number of different causes.

2. What should I know before I take CIZINATE?

Warnings

Do not use CIZINATE if:

  • you are allergic to cinnarizine and/or dimenhydrinate or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
  • you are allergic to any other similar medicines such as diphenhydramine or other antihistamines such as chlorpheniramine.
Symptoms of an allergic reaction may include: shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body rash, itching or hives on the skin.
  • have severe kidney problems (renal impairment)
  • have severe liver problems (hepatic impairment)
  • suffer from angle-closure glaucoma (a specific type of eye disease)
  • have convulsions, fits or seizures (epilepsy)
  • have increased pressure in the brain
  • suffer from alcohol abuse
  • have prostate problems which cause difficulty in urinating
  • are under 18 years of age
Safety and effectiveness in children younger than 18 years have not been established.

Check with your doctor if you have:

  • low or high blood pressure
  • severe heart disease
  • raised pressure in the eye
  • obstruction in the bowels
  • an enlarged prostate
  • an overactive thyroid
  • kidney or liver problems
  • movement disorders such as disease of the brain affecting movement (Parkinson's disease) or tremor
  • depression
  • have allergies to any other medicines, foods, preservatives or dyes
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with CIZINATE and affect how it works.

CIZINATE may increase the effects of the following medicines:

  • tricyclic antidepressants (used to treat depression and anxiety)
  • atropine (a medicine that relaxes muscles and is often used to examine your eye)
  • ephedrine (can be used to treat cough or blocked nose)
  • procarbazine (a medicine used to treat some kinds of cancer)
  • medicines taken to lower blood pressure

Amino glycosides (a type of antibiotic) can damage the inner ear. If you take CIZINATE you may not notice that this damage is happening.

You should not take CIZINATE with drugs that are used to correct problems with your heart beat (anti-arrhythmics).

CIZINATE can make you tired or sleepy when taken with the medicines listed below:

  • barbiturates (medicines that are often taken to calm you down)
  • narcotic analgesics (strong painkillers such as morphine and codeine)
  • any antihistamine medications
  • tranquillisers (a type of medicine used to treat depression and anxiety)
  • monoamine oxidase inhibitors (used to treat depression and anxiety)

You may need different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

CIZINATE may also change the way your skin reacts to allergy tests.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while taking CIZINATE.

4. How do I take CIZINATE?

How much to take

The standard dose for this medicine is one tablet three times a day. Your doctor may have prescribed a different dose.

CIZINATE tablets should be swallowed without chewing and with a glass of liquid.

Follow the instructions provided and use CIZINATE until your doctor tells you to stop.

Do not take more than the dose your doctor has prescribed for you.

When to take CIZINATE

CIZINATE should be used regularly at the same time each day. Taking your tablets at the same time each day will have the best effect. It will also help you remember when to take the tablets.

Take CIZINATE immediately after a meal, at about the same time each day. If you take CIZINATE on an empty stomach, it may cause stomach upsets.

Usually you will take CIZINATE for up to 4 weeks. Your doctor will tell you if you need to take CIZINATE for a different amount of time.

Continue taking your medicine for as long as your doctor tells you.

If you forget to take CIZINATE

If you forget to take a tablet of CIZINATE just miss out that tablet. Take the next tablet of CIZINATE the next time when you would usually take it.

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you take too much CIZINATE

If you think that you have taken too much CIZINATE, you may need urgent medical attention.

If you take too much CIZINATE you may become very tired, dizzy and shaky. Your pupils might dilate and you may not be able to urinate. Your mouth may feel dry, your face flush, you may have a faster heart rate, fever, sweat and have a headache.

If you have taken a massive amount of CIZINATE you could have fits, hallucinations, high blood pressure, feel shaky, get excited, and find it difficult to breathe. Coma could occur.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking CIZINATE?

Things you should do

Remind any doctor, dentist or pharmacist health you visit that you are using CIZINATE.

Tell any other doctors, dentists, and pharmacists who are treating you that you are taking CIZINATE.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking CIZINATE.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking CIZINATE.

If you become pregnant while taking CIZINATE, tell your doctor immediately.

Things you should not do

Do not give CIZINATE to anyone else, even if they have the same condition as you.

Do not take CIZINATE to treat any other complaints unless your doctor tells you to.

Do not stop taking CIZINATE, or lower the dosage without checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how CIZINATE affects you.

CIZINATE may cause dizziness in some people. If you have these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may alter how this medicine affects you. You should avoid alcoholic drinks while taking CIZINATE.

Looking after your medicine

  • Keep your tablets in the pack until it is time to take them.
If you take the tablets out of the pack they will not keep well.
  • Keep your tablets in a cool, dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Common side effects:
  • drowsiness
  • dry mouth
  • headache
  • stomach pain

Uncommon side effects:
(affect up to 1 in 100 people):

  • sweating
  • reddening of the skin
  • indigestion
  • nausea (feeling sick)
  • diarrhea
  • nervousness
  • cramps
  • forgetfulness
  • tinnitus (ringing in the ear)
  • paraesthesia (tingling of the hands or feet)

Rare side effects:
(affect up to 1 in 1,000 people):

  • tremor (shaking)
  • impaired vision
  • allergic reactions (e.g. skin reactions)
  • light sensitivity
  • difficulty in urinating

Very rare side effects:
(affect fewer than 1 in 10,000 people):

  • weakness
  • bruising
  • infections more likely

The following side effects have also been reported:

  • weight gain
  • constipation
Speak to your doctor if you have any of these less serious side effects and they worry you.

If CIZINATE causes stomach pain this may be reduced if CIZINATE is taken with food.

Common side effects are usually mild and disappear within a few days even if you keep taking CIZINATE.

If you suffer from infections with fever and serious deterioration of your general health, see your doctor and tell him about your medicine.

Serious side effects

Serious side effectsWhat to do
  • tightness of the chest
  • jaundice (yellowing of the skin or whites of the eyes)
  • increased pressure inside the eye or severe eye pain
  • unusual excitement
  • severe skin reactions
  • skin reactions
  • difficulty breathing
Extrapyramidal symptoms:
  • convulsions or fitting
  • uncontrollable movements of the body or face
  • trembling and shaking of the hands and fingers
  • twisting movement of the body
  • muscle stiffness with difficulty walking
  • stiffness of the arms and legs
  • severe feeling of restlessness and desire to keep moving
Allergic reactions:
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects. Stop taking CIZINATE immediately.

Extrapyramidal symptoms affect the nervous system. and may be serious. You may need immediate medical attention.

They have been reported more frequently in older people, women and people taking high doses for long periods of time. In rare cases these effects are irreversible.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription and is not addictive.

What CIZINATE contains

Active ingredient
(main ingredient)		20 mg cinnarizine
40 mg dimenhydrinate
Other ingredients
(inactive ingredients)		microcrystalline cellulose
croscarmellose sodium
maize starch
hypromellose
colloidal anhydrous silica
purified talc
magnesium stearate

Do not take this medicine if you are allergic to any of these ingredients.

What CIZINATE looks like

CIZINATE tablets are white to almost white, round, biconvex uncoated tablets.

They are available in packs of 20, 30, 50 and 100 tablets. (AUST R 288566).

Who distributes CIZINATE

Southern XP Pty Ltd
Unit 5/118 Church Street
Hawthorn, VIC, 3122
Australia

Sponsor:

Southern XP IP Pty Ltd
Unit 5/118 Church Street
Hawthorn, 3122, Victoria
Australia

This leaflet was prepared in June 2022.

Published by MIMS August 2022

BRAND INFORMATION

Brand name

Cizinate

Active ingredient

Cinnarizine; Dimenhydrinate

Schedule

S4

 

Notes

Distributed by Southern XP Pty Ltd

1 Name of Medicine

Cinnarizine, dimenhydrinate.

2 Qualitative and Quantitative Composition

Cizinate tablets contain the active ingredients cinnarizine and dimenhydrinate.
Each Cizinate 20 mg/40 mg tablet contains 20 mg of cinnarizine and 40 mg of dimenhydrinate.
Cinnarizine is a white to almost white powder. It is practically insoluble in water, freely soluble in methylene chloride, soluble in acetone and slightly soluble in ethanol and methanol.
Dimenhydrinate, the chlorotheophylline salt of diphenhydramine, is a white to almost white, crystalline powder or colourless crystals. It is slightly soluble in water and freely soluble in ethanol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cizinate 20 mg/40 mg tablets are a white to almost white, round, biconvex uncoated tablet 8 mm in diameter.

4 Clinical Particulars

4.1 Therapeutic Indications

Short-term, symptomatic treatment of vertigo of various causes, in adults who have not responded to alternative treatments.

4.2 Dose and Method of Administration

Adults.

The recommended dose for adults is one tablet three times daily. The lowest dose for the shortest duration to achieve symptom control should be used. The recommended dose should not be exceeded.
Cizinate tablets should be swallowed without chewing with some liquid after meals to minimise any gastric irritation.
In general, the duration of treatment should not exceed four weeks. Patients should undergo a reassessment of the risk/benefit if treatment beyond 4 weeks is contemplated.

Elderly.

No dose adjustment is necessary.

Renal impairment.

Cizinate is contraindicated in patients with a creatinine clearance of ≤ 25 mL/min (severe renal impairment) (see Section 4.3 Contraindications).
Cizinate should be used with caution in patients with mild to moderate renal impairment (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Cizinate is contraindicated in patients with severe hepatic impairment (see Section 4.3 Contraindications).
Cizinate should be used with caution in patients with mild to moderate hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Hypersensitivity to cinnarizine, dimenhydrinate, diphenhydramine, other antihistamines of a similar structure, or to any of the excipients.
Patients with a creatinine clearance of ≤ 25 mL/min (severe renal impairment) (see Section 4.4 Special Warnings and Precautions for Use).
Patients with severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).
Patients with angle-closure glaucoma, convulsions, suspicion of raised intracranial pressure, alcohol abuse or urine retention due to urethroprostatic disorders.

4.4 Special Warnings and Precautions for Use

Extrapyramidal effects.

Extrapyramidal effects including tremor, dyskinesia, parkinsonism, tardive dyskinesia and akathisia have been reported rarely with cinnarizine. These effects are more likely to occur in older patients (> 60 years), women, those on high doses (> 150 mg daily) and those with prolonged exposure to cinnarizine. Symptoms have arisen after exposures between weeks and years and can commence after exposure has ceased. It is unclear if these effects are due to the medicine itself, or as a result of an unmaking of a pre-existing primary degenerative process.
While symptoms are usually reversible on cessation of cinnarizine some cases have been irreversible. It should be taken at the lowest effective dose for the shortest duration required to reduce the likelihood of extrapyramidal effects.
Patients should be advised to cease treatment with Cizinate immediately and seek medical advice if any abnormal movements such as, shaking, twitching or twisting movements, muscle stiffness, restless legs, stiff posture, slowed shuffling walk or a need to be in constant motion arise.
Cizinate should not be given to patients with pre-existing extrapyramidal movement disorders such as Parkinson's disease.

Use with caution in the following circumstances.

Cinnarizine/dimenhydrinate does not reduce blood pressure significantly; however, it should be used with caution in hypotensive patients.
Cinnarizine/dimenhydrinate tablets should be used with caution in patients with conditions that might be aggravated by anticholinergic therapy, e.g. raised intra-ocular pressure, pyloroduodenal obstruction, prostatic hypertrophy, hypertension, hyperthyroidism or severe coronary heart disease.

Use in hepatic impairment.

Cizinate is contraindicated in patients with severe hepatic impairment (see Section 4.3 Contraindications).
No studies in patients with hepatic impairment are available.
Both cinnarizine and dimenhydrinate are extensively metabolised by hepatic cytochrome P450 enzymes. The plasma concentrations of the unchanged drugs and their half-lives will increase in patients with severe hepatic impairment. This has been shown for diphenhydramine in patients with cirrhosis.

Use in renal impairment.

Cizinate is contraindicated in patients with a creatinine clearance of ≤ 25 mL/min (severe renal impairment) (see Section 4.3 Contraindications).
Diphenhydramine is completely excreted renally, and patients with severe renal impairment were excluded from the clinical development programme.

Use in the elderly.

Safety and efficacy trials conducted with FDC included patients up to 83 years of age, however no relevant sub-analyses were performed in patients aged over 65 years.
Increased age may be a potential risk factor associated with cinnarizine induced extrapyramidal adverse events.

Paediatric use.

The safety and efficacy of Cizinate in children and adolescents under the age of 18 years has not been established. No data is available. Cizinate should not be given to children or adolescents aged less 18 years.

Effect on laboratory tests.

Interactions with laboratory tests have not been established.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Information relevant to potential interactions between cinnarizine and diphenhydramine and other medicinal products is limited.
In vitro studies in human microsomal fractions and other animal studies demonstrate that cinnarizine metabolism is mediated by CYP2D6, CYP2B6, CYP2C9 and CYP1A2, with CYP2D6 the predominant pathway.
As CYP2D6 is prominently involved in the metabolism of both diphenhydrinate and cinnarizine, and diphenhydramine is known to inhibit CYP2D6 mediated metabolism.
Accordingly, care should be taken when administering the combination product with CYP2D6 substrates such as tricyclic antidepressants, selective serotonin reuptake inhibitors, neuroleptics, beta blockers and antiarrhythmics.
The anticholinergic and sedative effects of cinnarizine/dimenhydrinate may be potentiated by monoamine oxidase inhibitors. Procarbazine may enhance the effect of cinnarizine/dimenhydrinate tablets.
In common with other antihistamines, cinnarizine/dimenhydrinate tablets may potentiate the sedative effects of CNS depressants including alcohol, barbiturates, narcotic analgesics and tranquillisers. Patients should be advised to avoid alcoholic drinks. Cinnarizine/dimenhydrinate tablets may also enhance the effects of anti-hypertensives, ephedrine and anticholinergics such as atropine and tricyclic antidepressants.
Cinnarizine/dimenhydrinate tablets may mask ototoxic symptoms associated with amino glycosidic antibiotics and mask the response of the skin to allergic skin tests.
The concomitant administration of medicines that prolong the QT interval of the ECG (such as Class Ia and Class III anti-arrhythmics) should be avoided.
Cinnarizine may oppose the effect of betahistine. Cizinate should not be administered with betahistine.
Dimenhydrinate contains a caffeine derivative (8-chlorotheophylline). Caffeine is metabolised by the cytochrome P450 1A2 enzyme, and therefore it is possible that 8-chlorotheophylline may inhibit or potentiate the response of common medications such as diltiazem, verapamil, olanzapine, oral contraceptives and omeprazole.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of cinnarizine and dimenhydrinate on fertility are not known.
(Category B2)
Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of foetal damage.
At high doses associated with maternal toxicity in rats, cinnarizine decreased litter size, increased the number of resorbed foetuses and decreased the birth weight of pups. The teratogenic risk of the single actives dimenhydrinate/diphenhydramine and cinnarizine is low. No teratogenic effects were observed in animal studies.
When administered to pregnant guinea pigs, cinnarizine was recovered from the foetus. The proportion of administered dose recovered from the foetus, compared to the dam, was generally less than 25%.
There are no data from the use of cinnarizine/dimenhydrinate tablets in pregnant women.
Based on human experience dimenhydrinate is suspected to have an oxytocic effect and may shorten labour.
Cinnarizine/dimenhydrinate tablets are not recommended during pregnancy.
 Cinnarizine and dimenhydrinate are excreted in human breast milk. Cinnarizine/dimenhydrinate tablets should not be used during breastfeeding.

4.7 Effects on Ability to Drive and Use Machines

Cinnarizine/dimenhydrinate tablets may have minor influence on the ability to drive and use machines.
Cinnarizine/dimenhydrinate tablets may cause drowsiness, especially at the start of treatment. Patients affected in this way should not drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

The most frequently reported adverse drug reactions (ADR) in patients taking FDC in clinical trials are somnolence (including drowsiness, tiredness, fatigue, daze), dry mouth and headache. These reactions are usually mild and disappear within a few days even if treatment is continued. The overall frequency of ADRs associated with Cizinate in all clinical trials and following spontaneous reports are included in Table 1.
In addition the following adverse reactions are associated with cinnarizine and dimenhydrinate (frequency cannot be estimated from the available data).

Dimenhydrinate.

Paradoxical excitability (especially in children), worsening of an existing angle-closure glaucoma, reversible agranulocytosis.

Cinnarizine.

Constipation, weight gain, tightness of the chest, cholestatic jaundice, extrapyramidal symptoms, lupus-like skin reactions, lichen planus.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

Symptoms.

Symptoms of overdose with Cizinate include drowsiness, dizziness and ataxia with anticholinergic effects such as dry mouth, flushing of the face, dilated pupils, tachycardia, pyrexia, headache and urinary retention. Convulsions, hallucinations, excitement, respiratory depression, hypertension, tremor and coma may occur, particularly in cases of ingestion of larger doses.

Management.

In case of overdose treatment should be supportive and symptomatic.
General supportive measures should be used to treat respiratory insufficiency or circulatory failure. Body temperature should be closely monitored, since pyrexia may occur as a consequence of antihistamine intoxication, especially in children.
Cramp-like symptoms may be controlled by careful application of a short-acting barbiturate. In cases of marked central-anticholinergic effects, physostigmine (after physostigmine test) should be administered slowly intravenously (or, if necessary, intramuscularly): 0.03 mg/kg body weight (adults max. 2 mg, children max. 0.5 mg).
Dimenhydrinate is dialyzable, however treatment of overdose by this measure is considered as unsatisfactory. Sufficient elimination can be achieved by means of haemoperfusion using activated charcoal.
No data are available concerning the dialysability of cinnarizine.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

In vitro studies have demonstrated that both diphenhydramine and cinnarizine have inhibitory activity at multiple molecular targets. Diphenhydramine is a potent inhibitor of histamine H1 receptors and muscarinic acetylcholine receptors, whilst cinnarizine is a potent inhibitor of histamine H1 and H4 receptors and dopamine D2 receptors and a less potent inhibitor of pressure sensitive potassium channels and serotonin 2 receptors. All the aforementioned proteins are known to have functions in the central and/or peripheral vestibular system.
The rationale for combining both compounds into a fixed dose combination tablet is to provide a product with a dual mechanism of action, with cinnarizine primarily acting peripherally on the labyrinth, and dimenhydrinate acting predominately centrally on the vestibular nuclei and related vegetative centres in the brainstem. This product may then be useful in treating vertigo of various origins.

Clinical trials.

The safety and efficacy of the fixed dose combination tablet (FDC) containing cinnarizine 20 mg and dimenhydrinate 40 mg is supported by five publications summarising the outcome of 9 well designed, randomised, controlled clinical trials (RCT). All RCT used a three times daily dosing regimen for FDC.
Four of the 9 RCT compared the efficacy of the FDC to equi-doses of the individual component medicines, while 3 studies compared the FDC to doses of the component monotherapies which were 2.5 times greater (cinnarizine 50 mg and dimenhydrinate 100 mg respectively) than the amount included in the FDC. Two of the RCT also included a placebo arm. The remaining study compared the FDC to betahistine 12 mg three times daily.
The FDC used in all trials contain the same quantities of cinnarizine and dimenhydrinate as the Australian formulation. The studies were performed in a total of 1235 adult patients with an average age in the early 50's. More females than males were included in the studies, with most individual RCT recruiting more than 60% females. All but one of the RCT recruited patients with vertigo of central, peripheral or combined central and peripheral origin. The remaining study recruited patients with vertigo due to unilateral vestibular failure or neuropathy.
The pivotal studies supporting the efficacy of FDC were reported as publications by Hahn 2001 and Pytel 2007.
Hahn 2006 was a multicentre, double blind, randomised, three arm, parallel-group, trial comparing the tolerability and efficacy of a FDC medicine containing 20 mg of cinnarizine and 40 mg of dimenhydrinate, to monotherapy with either 20 mg cinnarizine or 40 mg dimenhydrinate, in adult patients with vertigo of central, peripheral or mixed origin.
The objective of the study was to compare the efficacy and safety of FDC compared to the monocomponents in patients presenting to clinical practice with any symptom of vertigo, regardless of origin, and to test whether the efficacy of the FDC exceeds that of single components without increasing the incidence of adverse events.
The primary efficacy variable was the change in mean vertigo score (MVS) at week 4. The MVS was calculated by adding the individual scores recorded for each of the 12 vertigo symptoms by patients using a 5 point VAS (0 = not present, 4 = very strong), divided by 12. Secondary efficacy endpoints were the change in severity of vegetative symptoms associated with vertigo using the same VAS and the Unterberger and Romberg lateral and angular deviation tests, and nystagmus frequency in the caloric test. All assessments were performed at baseline, after one week of treatment and at 4 weeks.
The incidence, severity and relationship to study medicine of all observed or reported adverse events were recorded. The overall tolerability of treatments was assessed by both the participant and investigator at week 1 and 4 using a 4 point scale (poor to very good).
The change in MVS following the 4 week treatment period is shown in Table 2. Patients assigned FDC treatment demonstrated the greatest improvement in vertigo score during the 4 week study. At week 4 the MVS had decreased by > 80% in the FDC group compared to around 60% in the cinnarizine or dimenhydrinate groups. The differences in efficacy were significantly (P < 0.001) at both week 1 and 4.
Furthermore, 11 of the 59 participants treated with FDC were completely symptom free (defined as a MVS = 0) after 4 weeks of treatment, compared to none of the 60 participants treated with cinnarizine (difference p < 0.001) and one of 58 treated with dimenhydrinate (difference p < 0.01).
Cinnarizine was significantly less effective in reducing vegetative symptoms compared to FDC or dimenhydrinate at week 4. Significantly greater improvements in lateral sway were observed at 1 week but not week 4 in the FDC group compared to the other treatments.
Pytel 2007 was a multicentre, double blind, randomised, four arm, parallel-group, trial comparing the tolerability and efficacy of a FDC medicine containing 20 mg of cinnarizine and 40 mg of dimenhydrinate to monotherapy with 50 mg cinnarizine or 100 mg dimenhydrinate, or placebo, in adult patients with vertigo of central, peripheral or mixed origin.
The objective of the study was to compare the efficacy and safety of FDC to the monocomponents in patients presenting to clinical practice with any symptom of vertigo, regardless of origin.
Similar to Hahn 2006, the primary efficacy variable was the change in mean vertigo score (MVS) at week 4. The MVS was calculated by adding the individual scores recorded for each of the 12 vertigo symptoms by patients using a 5 point VAS (0 = not present, 4 = very strong), divided by 12. Secondary efficacy endpoints were the change in severity of vegetative symptoms associated with vertigo using the same VAS and the Unterberger and Romberg lateral and angular deviation tests, and spontaneous and positional nystagmus and caloric tests with electronystagmography was also performed.
Participants and investigators rated overall efficacy of treatment using a 5 point scale ranging from much improved to deteriorated. All assessments were performed at baseline, after one week of treatment and at 4 weeks.
The incidence, severity and relationship to study medicine of all observed or reported adverse events were recorded. The overall tolerability of treatments was assessed by both the participant and investigator at week 1 and 4 using a 4 point scale (poor to very good).
The decrease in MVS at week 4 was significantly greater in the FDC treatment group (1.37 ± 0.66) compared to 50 mg cinnarizine (0.87 ± 0.53; p < 0.001) or 100 mg dimenhydrinate alone (0.83 ± 0.66; p < 0.001), even though the dose used for the single components were larger than those used in the FDC.
Compared to placebo, the change in MVS at 4 weeks was 1.37 ± 0.66 in the FDC group, and 0.76 ± 0.48 in placebo (p < 0.001). See Table 3.
The proportion of participants with no vertigo symptoms (MVS = 0) at week 4 was 21.3% in the FDC group, 6.6% in the cinnarizine group (p = 0.034), 3.4% in the placebo arm (p = 0.005) and 8.5% in the dimenhydrinate group (NS).
The most frequently reported vegetative symptoms of vertigo at baseline were nausea and headache. Nausea improved to a significantly greater degree with FDC compared to other treatments. For the routine balance tests included in the secondary analysis, only the difference in change in lateral sway between FDC and placebo reached statistical significance. In general, the various nystagmus tests indicated no specific treatment effect, or difference between groups.
The primary efficacy endpoint, and the majority of secondary efficacy variables, used to evaluate comparative benefit of the FDC in remaining supportive RCT were similar in all but one of the individual RCT. The primary efficacy endpoint generally used was mean reduction in vertigo score, which was based on a combination of type and intensity of vertigo symptoms experienced by the participants. One study evaluated the intensity of vertigo symptoms, however the classification system used to assess this parameter was less comprehensive compared to the other 8 studies. The supportive efficacy studies in all cases showed at least a trend towards greater efficacy with the FDC given three times daily compared to either active when administered as 20 or 50 mg cinnarizine or 40 or 100 mg dimenhydrinate.
All but one of the 9 RCT also evaluated the comparative safety of the FDC. In general, the studies found no statistically or clinically significant difference in the safety profile of the FDC compared to the equi-dose monotherapy components, based on comparative adverse event analysis. Participant assessment of overall tolerability generally indicated high levels of satisfaction, with little difference (slightly favoring FDC) between the FDC and equi-dose monocomponent cinnarizine and dimenhydrinate formulations, and better than the individual high dose formulations.

5.2 Pharmacokinetic Properties

Absorption and distribution.

Dimenhydrinate rapidly releases its diphenhydramine moiety after oral administration. Diphenhydramine and cinnarizine are rapidly absorbed from the gastro-intestinal tract. Maximum plasma concentrations (Cmax) of cinnarizine and diphenhydramine are reached in humans within 2-4 hours.
The plasma elimination half-lives of diphenhydramine, and possibly also cinnarizine, are known to be age-dependent, but typically range from 4-5 hours for both substances, when given either alone or as the combination product.
Animal and human studies show active uptake and accumulation of diphenhydramine in the brain. This effect was not seen in animal studies using cinnarizine.

Metabolism.

Cinnarizine and diphenhydramine are extensively metabolised in the liver. The metabolism of cinnarizine involves ring hydroxylation reactions, mainly catalysed by CYP2D6 and to a lesser extent by CYP2B6, and N-dealkylation reactions catalysed by CYP2CP and CYP1A2. The major pathway of diphenhydramine metabolism is the sequential N-demethylation of the tertiary amine, which is mainly catalysed by CYP2D6.

Excretion.

Cinnarizine is mainly eliminated via the faeces (40-60%) and to a lower extent also in urine, mainly in the form of metabolites conjugated with glucuronic acid. The major route of elimination of diphenhydramine is in the urine, mainly in the form of metabolites, with the deaminated compound, diphenylmethoxy acetic acid, being the predominant metabolite (40-60%).

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of cinnarizine/dimenhydrinate combination tablets has not been fully evaluated.

Carcinogenicity.

The carcinogenic potential of cinnarizine/dimenhydrinate combination tablets has not been fully evaluated.

6 Pharmaceutical Particulars

6.1 List of Excipients

Cizinate tablets also contain the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, maize starch, hypromellose, colloidal anhydrous silica, purified talc and magnesium stearate.

6.2 Incompatibilities

Incompatibilities have not been assessed.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Cizinate 20 mg/40 mg tablets are available in OPA-Al-PVC/Al blisters packs of 20, 30, 50 and 100 tablets.
Not all pack sizes may be marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Cinnarizine.

Chemical Name: (E)-1-(Diphenylmethyl)-4-(3-phenylprop-2-enyl)piperazine.
Structure:
Molecular Formula: C26H28N2.
Molecular Weight: 368.5.

Dimenhydrinate.

Chemical Name: Diphenhydramine [2-(diphenylmethoxy)-N,N-dimethylethanamine] 8-chlorotheophylline (8-chloro-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione).
Structure:
Molecular Formula: C24H28ClN5O3.
Molecular Weight: 470.0.

CAS number.

Cinnarizine: 298-57-7.
Dimenhydrinate: 523-87-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes