Consumer medicine information

Zanidip

Lercanidipine hydrochloride

BRAND INFORMATION

Brand name

Zanidip

Active ingredient

Lercanidipine hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zanidip.

SUMMARY CMI

ZANIDIP®

Consumer Medicine Information (CMI) summary

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

1. Why am I taking ZANIDIP?

ZANIDIP contains the active ingredient lercanidipine hydrochloride. ZANIDIP is used to lower high blood pressure, which doctors call hypertension.

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

2. What should I know before I take ZANIDIP?

Do not take if you have ever had an allergic reaction to ZANIDIP 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 ZANIDIP? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ZANIDIP 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 ZANIDIP?

  • ZANIDIP should be taken at about the same time each day, at least 15 minutes before a meal.

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

5. What should I know while taking ZANIDIP?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking ZANIDIP.
  • Tell your doctor if you become pregnant while you are taking ZANIDIP.
  • If you have an operation, tell the anaesthetist that you are taking this medicine.
Things you should not do
  • Do not take ZANIDIP with grapefruit or grapefruit juice as these may increase the effects of this medicine.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how ZANIDIP affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep it in a cool dry place away from sunlight where the temperature stays below 30°C.

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

6. Are there any side effects?

Speak to your doctor if you have any of these less serious side effects and they worry you: flushing, swelling of the ankles, feet or lower legs, palpitations, headache, dizziness or fainting, gastrointestinal disturbances such as heartburn, nausea, epigastric pain or diarrhoea, fatigue or sleepiness. 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: angina (chest pain or tightness), increased heartbeat, signs of allergy such as rash, itching or hives on the skin

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

ZANIDIP®

Active ingredient: lercanidipine hydrochloride


Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I taking ZANIDIP?

ZANIDIP contains the active ingredient lercanidipine hydrochloride. ZANIDIP belongs to a group of medicines called calcium channel blockers (of the dihydropyridine group).

ZANIDIP is used to lower high blood pressure, which doctors call hypertension. It works by relaxing some of the blood vessels in the body and reducing resistance to the flow of blood through the blood vessels.

Everyone has blood pressure. This pressure helps get your blood all around your body. Your blood pressure may be different at different times of the day, depending on how busy or worried you are. You have hypertension (high blood pressure) when your blood pressure stays higher than is needed, even when you are calm and relaxed.

There are usually no symptoms of hypertension. The only way of knowing that you have hypertension is to have your blood pressure checked on a regular basis. If high blood pressure is not treated it can lead to serious health problems. You may feel fine and have no symptoms, but eventually hypertension can cause stroke, heart disease and kidney failure. ZANIDIP helps lower your blood pressure.

2. What should I know before I take ZANIDIP?

Warnings

Do not take ZANIDIP if:

  • you are allergic to lercanidipine, any drugs closely related to lercanidipine (such as amlodipine, felodipine or nifedipine) or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can take this medicine.
  • you have an obstruction to flow of blood from the heart
  • you have untreated heart failure
  • you have unstable angina (chest pain or tightness at rest or that progressively increases) or you have had a heart attack one month ago or less
  • you have severe liver or kidney disease
  • you are also taking another medicine called ciclosporin
  • you eat grapefruit or drink grapefruit juice
  • you are pregnant or intend to become pregnant
  • you are breastfeeding or plan to breastfeed
  • packaging is torn or shows signs of tampering.
  • the tablets show visible sign of deterioration (for example, are broken or discoloured).

If you are not sure whether you should start taking ZANIDIP, talk to your doctor.

Do not give ZANIDIP to a child under the age of 18 years. ZANIDIP is not recommended for use in children.

Tell your doctor if you:

  • are allergic to any other medicine, any foods, dyes or preservatives, or have a lactose intolerance.
  • are taking other drugs for high blood pressure, such as beta-blockers, diuretics, ACE-inhibitors or angiotensin II receptor antagonists.
  • have or have ever had any other health problems/medical conditions, including:
    - liver or kidney disease or are on dialysis
    - certain other heart conditions such as: uncontrolled heart failure, an obstruction to flow of blood from the heart, unstable angina (chest pain or tightness at rest or that progressively increases) or you have had a heart attack one month ago or less and/or if you require a pacemaker

If you have not told your doctor about any of the above or if you are not sure, tell them before you take ZANIDIP.

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.

Like most calcium channel blockers, ZANIDIP is not recommended for use during pregnancy.

Tell your doctor immediately if you become pregnant while you are taking ZANIDIP.

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

Like most calcium channel blockers ZANIDIP is not recommended while you are breast-feeding.

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 the way ZANIDIP works or may be affected by ZANIDIP. These include:

  • astemizole
  • ciclosporin
  • cimetidine (more than 800 mg daily)
  • clarithromycin, erythromycin, troleandomycin
  • fluoxetine
  • itraconazole, ketoconazole
  • medicines known as corticosteroids which are used to treat inflammation, allergies and autoimmune conditions
  • metoprolol, propranolol
  • rifampicin
  • ritonavir
  • some medicines used to treat an enlarged prostate and improve urinary symptoms
  • some medicines used to treat depression
  • some medicines used to treat epilepsy such as carbamazepine, phenobarbital (phenobarbitone), phenytoin
  • terfenadine

You may need different amounts of your medicine, or you may need to take different medicines. Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

Also ask your doctor or pharmacist what to do if you are taking or are about to take the following medicines: amiodarone, digoxin, midazolam, quinidine, simvastatin or sotalol.

If you have not told your doctor about any of the medicines listed above, tell them before you start taking ZANIDIP.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ZANIDIP.

4. How do I take ZANIDIP?

How much to take

  • Follow the instructions provided and take ZANIDIP until your doctor tells you to stop.
  • The usual dose is one 10 mg tablet taken once daily but may be increased to 20 mg once daily.
  • If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

When to take ZANIDIP

  • ZANIDIP will have the best effect if it is taken at the same time each day at least 15 minutes before meals. This will also help you remember when to take the tablets.
  • Swallow ZANIDIP whole with a glass of water.

If you forget to take ZANIDIP

ZANIDIP should be taken regularly at the same time each day.

If you miss your dose at the usual time but remember within 12 hours from when the dose was due, take it straight away, then continue as normal the next day. Otherwise skip that day's dose but be sure to take the next day's dose when it is due.

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

Do not take a double dose to make up for the dose you missed.

If you have trouble remembering to take your tablets, ask your pharmacist for some hints.

If you have missed several doses, consult your doctor.

If you take too much ZANIDIP

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

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26) for advice, 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.

If you take too much ZANIDIP it may cause your blood pressure to become too low, you may become dizzy, you may get a headache and you may feel your heart beats become irregular and faster. It may also lead to unconsciousness.

5. What should I know while taking ZANIDIP?

Things you should do

  • Use ZANIDIP exactly as your doctor has prescribed. If you do not follow your doctor's instructions correctly, your blood pressure may not be controlled.
  • Be sure to keep all of your doctor's appointments so that your progress can be checked.
  • If you are about to start taking any new medicine, tell your doctor and pharmacist that you are taking ZANIDIP.
  • If you have an operation, tell the anaesthetist that you are taking this medicine.

Tell your doctor straight away if you:

  • become pregnant while you are taking ZANIDIP

Remind any doctor, dentist or pharmacist you visit that you are taking ZANIDIP.

Things you should not do

  • Do not give ZANIDIP to anyone else, even if they have the same condition as you.
  • Do not use ZANIDIP to treat any other complaints unless your doctor tells you to.
  • Do not take ZANIDIP with grapefruit or grapefruit juice as these may increase the effects of this medicine.

Driving or using machines

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

ZANIDIP generally does not cause any problems with your ability to drive a car or operate machinery. However, as with other medicines used to treat high blood pressure, a few people may feel dizzy, light-headed or faint, especially when first taking ZANIDIP or when starting to take a different amount of medicine.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

Drinking alcohol

Tell your doctor if you drink alcohol.

Your doctor may also ask you to limit or stop your alcohol intake while taking medicines to control your blood pressure, such as ZANIDIP, as alcohol may increase these effects.

Looking after your medicine

  • Keep your tablets in the blister pack until it is time to take them.
  • If you take the tablets out of the blister pack they may not keep well.
  • Keep it in a cool dry place away from sunlight where the temperature stays below 30°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.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

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

Do not take this medicine after the expiry date.

6. Are there any side effects?

ZANIDIP helps most people with high blood pressure, but it may have unwanted side effects in a few people.

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
These effects when they occur are usually mild.
  • flushing
  • swelling of the ankles, feet or lower legs
  • palpitations
  • headache
  • dizziness or fainting
  • gastrointestinal disturbances such as heartburn, nausea, epigastric pain or diarrhoea
  • fatigue or sleepiness
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
These side effects are usually rare but may be serious and need urgent medical attention.
  • angina (chest pain or tightness)
  • increased heartbeat
  • signs of allergy such as 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.

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.

What ZANIDIP contains

Active ingredient
(main ingredient)
lercanidipine hydrochloride 10 mg or 20 mg per tablet
Other ingredients
(inactive ingredients)
lactose monohydrate
microcrystalline cellulose
sodium starch glycollate type A
povidone
magnesium stearate
hypromellose
purified talc
titanium dioxide
macrogol 6000
iron oxide yellow (10 mg tablet) or
iron oxide red (20 mg tablet)
Potential allergenslactose

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

What ZANIDIP looks like

ZANIDIP 10 mg film-coated tablets are yellow and round with a score line across the middle (AUST R 77506).

ZANIDIP 20 mg film-coated tablets are round and pink (AUST R 93733).

ZANIDIP comes in packs of 28 tablets.

Who distributes ZANIDIP

Viatris Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in February 2022.

ZANIDIP® is licensed to the Viatris company group

Zanidip_cmi\Feb22/00

Published by MIMS April 2022

BRAND INFORMATION

Brand name

Zanidip

Active ingredient

Lercanidipine hydrochloride

Schedule

S4

 

1 Name of Medicine

Lercanidipine hydrochloride.

2 Qualitative and Quantitative Composition

Lercanidipine hydrochloride is a microcrystalline, odourless, citrine powder.
Each Zanidip 10 mg tablet contains 9.4 mg of lercanidipine (present as lercanidipine hydrochloride 10 mg) as the active ingredient.
Each Zanidip 20 mg tablet contains 18.8 mg of lercanidipine (present as lercanidipine hydrochloride 20 mg) as the active ingredient.

Excipients with known effect.

Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zanidip 10 mg tablet is available as a yellow, round, scored, film-coated tablet.
Zanidip 20 mg tablet is available as a pink, circular, biconvex, film-coated tablet.

4 Clinical Particulars

4.1 Therapeutic Indications

Zanidip is indicated for the treatment of hypertension.

4.2 Dose and Method of Administration

The recommended dose is 10 mg once daily, at least 15 minutes before a meal. The dose may be increased to 20 mg once daily depending on the individual response. Dose titration should be gradual, as it may take about 2 weeks for the maximal antihypertensive effect to be apparent. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently. Since it is unlikely that increasing the dose beyond 20 mg will further improve the efficacy, and may be associated with side effects, doses above 20 mg are not recommended. Some individuals not adequately controlled on a single antihypertensive agent may benefit from the addition of lercanidipine at the same doses used in monotherapy to the existing regimen with a beta-blocker, a diuretic or an ACE inhibitor.

Use in elderly, children, hepatic and renal impairment.

See Section 4.4 Special Warnings and Precautions for Use.

4.3 Contraindications

Hypersensitivity to any dihydropyridine or any ingredient of Zanidip.
Left ventricular outflow tract obstruction.
Untreated congestive cardiac failure.
Unstable angina pectoris or recent (within 1 month) myocardial infarction.
Severe hepatic impairment.
Severe renal impairment (GFR < 30 mL/min), including patients undergoing dialysis.
Zanidip coadministration with:
strong inhibitors of CYP3A4 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), ciclosporin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), grapefruit or grapefruit juice (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Ischaemic heart disease.

It has been suggested that some short acting dihydropyridines may be associated with increased cardiovascular risk in patients with ischaemic heart disease. Although lercanidipine is long acting, caution should be required in such patients.
Some dihydropyridines may rarely lead to precordial pain or angina pectoris. Very rarely patients with pre-existing angina pectoris may experience increased frequency, duration or severity of these attacks. Isolated cases of myocardial infarction may be observed.

Left ventricular dysfunction.

Care is required in patients with left ventricular dysfunction.

Congestive heart failure.

Safety of lercanidipine in patients with congestive heart failure has not been established. Lercanidipine should be used with caution in patients receiving treatment for heart failure. Lercanidipine is contraindicated in patients with untreated congestive cardiac failure (see Section 4.3 Contraindications).

Peritoneal dialysis.

Lercanidipine has been associated with the development of cloudy peritoneal effluent in patients on peritoneal dialysis. The turbidity is due to an increased triglyceride concentration in the peritoneal effluent. Whilst the mechanism is unknown, the turbidity tends to resolve soon after withdrawal of lercanidipine. This is an important association to recognise as cloudy peritoneal effluent can be mistaken for infective peritonitis with consequential unnecessary hospitalisation and empiric antibiotic administration.

Sick sinus syndrome.

Lercanidipine should be administered with caution in patients with sick sinus syndrome (without a pacemaker).

Inducers of CYP3A4.

Inducers of CYP3A4 like anticonvulsants (e.g. phenytoin, carbamazepine) and rifampicin may reduce lercanidipine plasma levels and, therefore, the efficacy of lercanidipine may be less than expected (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Lactose.

This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use in hepatic impairment.

The pharmacokinetics of lercanidipine in patients with mild hepatic impairment are similar to those observed in the general population. However, there are no studies in patients with moderate hepatic impairment and dosage recommendations have not been established. Lercanidipine should therefore be used with caution in this patient group and careful monitoring undertaken during treatment, since the bioavailability and hypotensive effect may be increased. The use of lercanidipine in patients with moderate hepatic impairment should only be undertaken if the benefits are considered to outweigh the risks. Lercanidipine is contraindicated in patients with severe hepatic disease.
A study in patients with mild hepatic impairment (Child-Pugh class A) showed that the pharmacokinetic behaviour of the drug is similar to that observed in the general population. No studies have been undertaken in patients with moderate or severe hepatic impairment.

Use in renal impairment.

In patients with severe renal dysfunction or dialysis-dependent patients, plasma levels were increased by about 70%. As a consequence, lercanidipine is contraindicated in patients with severe renal impairment (GFR < 30 mL/min), including patients undergoing dialysis (see Section 4.3 Contraindications).
Although the pharmacokinetics of lercanidipine in patients with mild to moderate renal impairment are similar to those observed in the general population, special care should be exercised when commencing treatment in such patients. The usual recommended dose of 10 mg daily may be tolerated; however, an increase to 20 mg daily should be approached with caution.

Use in the elderly.

In elderly patients, the pharmacokinetics of lercanidipine are similar to those observed in the general population.
Although the pharmacokinetic data and clinical experience suggest that no adjustment of the daily dose is required, special care should be exercised when initiating treatment in the elderly.

Paediatric use.

Due to lack of clinical experience and because the safety and efficacy of lercanidipine have not been demonstrated in children, lercanidipine is not recommended for use in patients under the age of 18.

Effects on laboratory tests.

There were reports of isolated and reversible increases in serum levels of hepatic transaminases; no other clinically significant pattern of laboratory test abnormalities related to lercanidipine has been observed. Lercanidipine does not appear to influence adversely blood sugar or serum lipid levels.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Inhibitors of cytochrome CYP3A4.

Since the main metabolic pathway of lercanidipine involves the enzyme CYP3A4, drugs that inhibit this enzyme have the potential to alter the plasma concentration of the compound and may interact with the metabolism and elimination of lercanidipine.
An interaction study with a strong CYP3A4 inhibitor, ketoconazole, has shown a considerable increase in plasma levels of lercanidipine (a 15-fold increase of the AUC and an 8-fold increase of the Cmax for the eutomer S-lercanidipine).
Therefore, inhibitors of CYP3A4 (such as ketoconazole, itraconazole, erythromycin, ritonavir, troleandomycin, clarithromycin and fluoxetine) may increase the plasma concentration of lercanidipine, and such combinations should be avoided (see Section 4.3 Contraindications).

Ciclosporin.

Co-administration of lercanidipine with ciclosporin resulted in a 3-fold increase in the plasma levels of lercanidipine and a 21% increase in the bioavailability of ciclosporin. However, when ciclosporin was administered 3 hours after lercanidipine, no increase in plasma levels was observed for lercanidipine, while the bioavailability of ciclosporin increased by 27%. Therefore, ciclosporin and lercanidipine should not be administered together (see Section 4.3 Contraindications).

Grapefruit or grapefruit juice.

The metabolism of dihydropyridines can be inhibited by grapefruit juice, leading to increased plasma concentration and hypotensive effect. Lercanidipine must not be taken with grapefruit or grapefruit juice (see Section 4.3 Contraindications).

Inducers of cytochrome CYP3A4.

Since the main metabolic pathway of lercanidipine involves the enzyme CYP3A4, drugs that induce this enzyme have the potential to alter the plasma concentration of the compound.
Co-administration with CYP3A4 inducers, such as anticonvulsants (e.g. phenytoin, phenobarbital (phenobarbitone), carbamazepine) and rifampicin should be approached with caution since the antihypertensive effect of lercanidipine may be reduced and, therefore, blood pressure should be monitored more frequently than usual (see Section 4.4 Special Warnings and Precautions for Use).

Alcohol.

Alcohol should be avoided while taking lercanidipine since it may potentiate the effect of vasodilating antihypertensive drugs.

CYP3A4 and CYP2D6 substrates.

The potential for in vivo inhibition of CYP3A4 by lercanidipine is negligible, as confirmed by an interaction study with midazolam in healthy volunteers. After repeated coadministration with lercanidipine, midazolam (a probe for CYP3A4 activity) was found to be essentially bioequivalent to the drug administered alone. However, unless specific data are available, caution should also be exercised when lercanidipine is coprescribed with other substrates of CYP3A4 which have a narrow therapeutic index, such as ciclosporin, terfenadine, astemizole, and class III antiarrhythmic drugs (e.g. amiodarone, sotalol and quinidine).
Coadministration of lercanidipine with ciclosporin resulted in a 3-fold increase in the plasma levels of lercanidipine and a 21% increase in the bioavailability of ciclosporin. However, when ciclosporin was administered 3 hours after lercanidipine, no increase in plasma levels was observed for lercanidipine, while the bioavailability of ciclosporin increased by 27%. Therefore, ciclosporin and lercanidipine should not be administered together.
Moreover, interaction studies in humans have shown that lercanidipine did not modify the plasma levels of metoprolol, (a typical substrate of CYP2D6). Therefore, at therapeutic doses it is unlikely that lercanidipine will inhibit the biotransformation of drugs metabolized by CYP2D6.
These findings confirm that the inhibition of cytochrome P450 isoenzymes observed in vitro with lercanidipine is devoid of any clinical significance. In vitro experiments with human liver microsomes demonstrated that lercanidipine inhibits CYP3A4 and CYP2D6 (IC50 of 2.6 micromolar and 0.8 micromolar, respectively). The IC50 concentrations for CYP3A4 and CYP2D6 are 160 and 40-fold higher, respectively, than those reached at peak in the plasma after a 20 mg dose.

Midazolam.

When concomitantly administered at a dose of 20 mg with midazolam orally to volunteers aged 63 +/- 6 years, lercanidipine absorption was increased (by approximately 40%) and the rate of absorption was decreased (tmax was delayed from 1.75 to 3 hours). Midazolam systemic availability was not affected, while Cmax showed a slight increase of about 18%.

Beta-blockers.

When lercanidipine was administered with metoprolol, a beta-blocker eliminated mainly by the liver, the bioavailability of metoprolol was not changed, while that of lercanidipine was reduced by 50%. Therefore, when coadministered with metoprolol, it may be necessary to increase the dose of lercanidipine. It is anticipated that a similar effect may occur with propranolol.

Cardiac glycosides.

Coadministration of lercanidipine (20 mg) in patients chronically treated with beta-methyldigoxin (a prodrug of digoxin) showed no evidence of a pharmacokinetic interaction. Healthy volunteers treated with digoxin following dosing with 20 mg lercanidipine given fasted showed a mean increase of 33% in digoxin Cmax, while AUC and renal clearance were not significantly modified. Patients on concomitant digoxin treatment should be closely monitored clinically for signs of digoxin toxicity.

Cimetidine.

Concomitant administration of cimetidine 400 mg BD does not cause significant changes in the plasma levels of lercanidipine: AUC and Cmax were increased by a mean of 11%. However, at higher doses caution is required since the bioavailability and the hypotensive effect of lercanidipine may be increased.

Simvastatin.

Coadministration of a 20 mg dose of lercanidipine with 40 mg simvastatin resulted in no increase in the bioavailability of lercanidipine, however a 56% increase was observed for simvastatin and a 28% increase for its active metabolite, β-hydroxyacid. It is unlikely that these changes are clinically relevant. However, it is recommended that when required, lercanidipine be administered in the morning and simvastatin in the evening.

Warfarin.

The co-administration of 20 mg lercanidipine to healthy volunteers given fasted did not alter the pharmacokinetics of warfarin.

Diuretics and ACE inhibitors.

Lercanidipine has been safely administered with diuretics and ACE inhibitors.

Other medications affecting blood pressure.

As for all antihypertensive medications, an increased hypotensive effect may be observed when lercanidipine is administered with other medications affecting blood pressure, such as alpha blockers for the treatment of urinary symptoms, tricyclic antidepressants, neuroleptics. On the contrary, a reduction of the hypotensive effect may be observed with a concomitant use with corticosteroids.

Food.

For the effect of food on bioavailability, see Section 5.2 Pharmacokinetic Properties.
For the effect of alcohol and grapefruit juice, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No clinical data are available with lercanidipine. Reversible biochemical changes in the head of spermatozoa which can impair fecundation have been reported in some patients treated by calcium channel blockers. In cases where repeated in vitro fertilisation is unsuccessful and where another explanation cannot be found, the possibility of calcium channel blockers as the cause should be considered.
Administration of lercanidipine at oral doses up to 12 mg/kg/day (associated with plasma lercanidipine concentration (AUC) about 20-40 times higher than the expected human AUC) had no effect in male or female fertility in rat.
(Category C)
There is no clinical experience with lercanidipine in pregnancy, but other dihydropyridine compounds have been found to cause irreversible malformations in animals. Therefore, lercanidipine should not be administered during pregnancy or to women with childbearing potential unless effective contraception is used.
In animal studies, pregnant rats given lercanidipine orally at doses ≥ 2.5 mg/kg/day, beginning prior to mating, or 12 mg/kg/day, beginning from early gestation, showed signs of dystocia and had an increased incidence of stillbirths and a lower neonatal survival index. The no-effect dose for effects on parturition and neonatal survival was 0.5 mg/kg/day (associated with lercanidipine concentration (AUC) about 50% of the expected human AUC) when dosing started before pregnancy or 2.5 mg/kg/day (about 3 times the human AUC) when dosing started during early gestation. Administration with lercanidipine at doses of 2.5 mg/kg/day during gestation also caused a higher incidence of foetal visceral abnormalities (mono/ bilateral renal pelvic and/or ureteric dilatation) and skeletal abnormalities (mainly delayed ossification) at all dose levels. A no-effect dose was not established. The effects of lercanidipine during pregnancy have not been investigated adequately in a nonrodent species.
There is no clinical experience with lercanidipine in lactation. Distribution into milk may be expected, due to the high lipophilicity of lercanidipine. Therefore, lercanidipine should not be administered to lactating women.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. However, caution should be exercised because dizziness, asthenia, fatigue and rarely somnolence may occur.

4.8 Adverse Effects (Undesirable Effects)

Treatment with lercanidipine is generally well tolerated. In nine placebo controlled clinical trials with a treatment duration lasting at least 4 weeks, 582 patients were initially treated with lercanidipine, and 292 patients received placebo. Most of the events reported in the studies were related to the vasodilatory effects of lercanidipine, and were classified mild-moderate in severity.
Table 1 lists, according to organ system, adverse events that were reported in placebo controlled trials in hypertensive patients with lercanidipine tablets at an incidence greater than or equal to 1% in at least one of the active treatment groups.
More extensively, over 15,500 patients were treated with lercanidipine in clinical trials (including PMS studies) with doses from 2.5 mg daily up to 40 mg daily, and with treatment duration ranging from single dose up to more than 1 year. Adverse experiences which were not clearly drug related and which occurred in < 1% but ≥ 0.1% of patients are summarized according to organ system.

Cardiovascular.

Palpitations/tachycardia.

Central and peripheral nervous system.

Dizziness, vertigo.

Gastrointestinal.

Nausea, dyspepsia, abdominal pain, diarrhoea.

Psychiatric.

Somnolence.

General.

Flushing, asthenia (including fatigue and muscle weakness).
The following events have been rarely reported.

Cardiovascular.

Hypotension, orthostatic hypotension, periorbital oedema, anginal pain, myocardial infarction, cardiac failure.

Respiratory.

Dyspnoea.

Central and peripheral nervous system.

Migraine, paraesthesia, cramps legs.

Special senses.

Taste alteration.

Gastrointestinal.

Vomiting, GI disorder NOS.

Liver and biliary system.

GGT increased.

Genitourinary.

Polyuria, urinary frequency, impotence.

Musculoskeletal.

Myalgia.

Skin and appendages.

Rash, pruritus, allergic dermatitis, hives, sweating increased.

Psychiatric.

Anxiety, insomnia.

Metabolic.

Hypercholesterolaemia.

General.

Chest pain, malaise.
Serious adverse events have been reported in clinical trials in less than 0.002% of the patients. The remaining adverse events have been reported as mild to moderate in intensity.

Other adverse effects.

Gastrointestinal.

Cloudy peritoneal effluent (in patients on peritoneal dialysis).
Adverse reactions reported in clinical trials and in the worldwide post-marketing experience (observational studies and spontaneous cases) for which a reasonable causal relationship exists are:
hypersensitivity, headache, dizziness, somnolence, syncope, tachycardia, palpitations, angina pectoris, flushing, hypotension, dyspepsia, nausea, abdominal pain upper, vomiting, diarrhoea, gingival hypertrophy, peritoneal cloudy effluent, serum transaminase increased, rash, pruritus, urticaria, angioedema, myalgia, polyuria, pollakiuria, oedema peripheral, asthenia, fatigue, chest pain.

Reporting suspected adverse effects.

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

In the post-marketing experience of lercanidipine, some cases of overdose have been reported ranging from 30-40 mg up to 800 mg, including reports of suicide attempt.

Symptoms.

As with other dihydropyridines, overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and reflex tachycardia. However, at very high doses, the peripheral selectivity may be lost, causing bradycardia and a negative inotropic effect. In case of severe hypotension, bradycardia and unconsciousness, cardiovascular and respiratory monitoring will be required, and supportive treatment may be necessary. The most common adverse drug reactions associated to cases of overdose have been hypotension, dizziness, headache and palpitations.

Treatment.

Clinically significant hypotension requires active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output. In view of the prolonged pharmacological effect of lercanidipine, it is essential that the cardiovascular status of the patient is monitored for 24 hours at least. Since the product has a high protein binding, dialysis is not likely to be effective. Patients in whom a moderate to severe intoxication is anticipated should be observed in a high-care setting.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Lercanidipine is a calcium antagonist of the dihydropyridine group and selectively inhibits the transmembrane influx of calcium into cardiac and vascular smooth muscle, with a greater effect on vascular smooth muscle than on cardiac smooth muscle. The antihypertensive action is due to a direct relaxant effect on vascular smooth muscle which lowers total peripheral resistance and hence blood pressure. Lercanidipine has a prolonged antihypertensive activity because of its high membrane partition coefficient. It is devoid of negative inotropic effects and its vascular selectivity is due to its voltage dependent calcium antagonist activity. Since the vasodilatation induced by lercanidipine hydrochloride is gradual in onset, acute hypotension with reflex tachycardia has rarely been observed in hypertensive patients.
As for other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is mainly due to the (S)-enantiomer.
No significant effects on ECG have been seen.

Clinical trials.

Placebo controlled studies.

Lercanidipine has been compared to placebo in four (4) to 16 week studies, involving 671 patients with mild-moderate essential hypertension. All studies used a 3 week placebo run-in period. Endpoints were diastolic and systolic blood pressure 24 hours postdose. Both 10 mg and 20 mg once daily significantly lowered diastolic and systolic blood pressure compared to placebo, and the reduction in blood pressure was maintained throughout the 24 hour dosing period.
Diastolic blood pressure changes observed after 4 week treatment with 10-20 mg daily lercanidipine ranged between 8 and 13 mmHg, as compared to 3-6 mmHg induced by placebo.
Studies with 24 hour ambulatory blood pressure monitoring have documented that the antihypertensive effect of lercanidipine is maintained throughout the 24 hour dosing period, with limited variations between peak (5-7 hours postdosing) and trough blood pressure changes.

Active controlled studies.

Four clinical trials involving 538 patients with mild-moderate essential hypertension have compared lercanidipine with nifedipine SR, atenolol, hydrochlorothiazide and captopril. Trials included a 2 week washout period followed by a 3 week placebo run-in, and 12-16 weeks of active treatment. Diastolic and systolic blood pressure was measured 24 hours postdose. Lercanidipine was as effective as the comparator drugs, and at least as well tolerated. 24 hour blood pressure monitoring was used in a comparative, crossover trial of lercanidipine versus amlodipine (n = 16). The effect of lercanidipine paralleled that of amlodipine throughout the 24 hour period.

Patients with isolated systolic hypertension.

The effect of lercanidipine 10-20 mg daily on isolated systolic hypertension was studied in a double blind, randomised, placebo controlled study in 83 elderly patients (sitting SBP > 160 mmHg and sitting DBP < 95 mmHg). The study consisted of 1 week washout, 3 weeks placebo run-in, and 8 weeks of active treatment. Systolic and diastolic blood pressure was measured 24 hours postdose. Lercanidipine 10 to 20 mg was efficacious in lowering systolic blood pressure from the initial values of 172.6 ± 5.6 mmHg to 140.2 ± 8.7 mmHg (mean ± SD, per protocol population in all patients completing the whole 8 weeks of double blind treatment), as compared to the changes in the placebo group (from 172.4 ± 6.3 to 162.8 ± 9.7 mmHg). Therefore, at study endpoint, patients treated with lercanidipine experienced a significantly greater decrease (-22.6 mmHg, p < 0.001) in sitting systolic blood pressure in comparison to placebo. The diastolic blood pressure was within normal range.

Long-term studies.

In long-term studies, 399 patients were followed for 12 months, with dose titration allowed every 4 weeks, to 30 mg daily. Development of tolerance was not seen. The antihypertensive effect was maintained, and the heart rate was not significantly affected. A further fall in blood pressure was seen after the first and second month, with blood pressure stabilising in the third month. The majority of patients remained on 10 mg once daily.

5.2 Pharmacokinetic Properties

Absorption and bioavailability.

Lercanidipine is completely absorbed after oral administration. Peak plasma levels of 3.30 nanogram/mL ± 2.09 s.d and 7.66 nanogram/mL ± 5.90 s.d occur 1.5-3 hours after dosing with 10 mg and 20 mg, respectively. The absolute bioavailability of lercanidipine is about 10%, because of high first pass metabolism. The bioavailability increases 4-fold when lercanidipine is ingested up to 2 hours after a high fat meal, and about 2-fold when taken immediately after a carbohydrate rich meal. Consequently, lercanidipine should be taken at least 15 minutes before a meal.
With oral administration, lercanidipine exhibits nonlinear kinetics. After 10, 20 or 40 mg, peak plasma concentrations observed were in the ratio 1:3:8 and areas under plasma concentration time curves in the ratio 1:4:18, showing a progressive saturation of first pass metabolism. Accordingly, bioavailability increases as dosage increases.
The two enantiomers of lercanidipine have a similar time to peak plasma concentration. The peak plasma concentration and AUC are, on average, 1.2-fold higher for the (S)-enantiomer. No in vivo interconversion of enantiomers is observed.

Distribution.

Distribution of lercanidipine from plasma to tissues and organs is rapid and extensive. Serum protein binding exceeds 98%. The free fraction of lercanidipine may be increased in patients with renal or hepatic impairment as plasma protein levels are decreased in these disease states.

Metabolism.

As for other dihydropyridine derivatives, lercanidipine is extensively metabolised by CYP3A4. It is predominantly converted to inactive metabolites; no parent drug is found in the urine or faeces. About 50% of the dose is excreted in the urine.

Excretion.

The mean terminal elimination half-life of S and R-lercanidipine enantiomers is 5.8 ± 2.5 and 7.7 ± 3.8 hours, respectively. No accumulation was seen upon repeated administration. The therapeutic activity of lercanidipine lasts for 24 hours, due to its high binding to lipid membranes.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence for genotoxic activity was observed with lercanidipine in in vitro assays of gene mutation (reverse mutation in S. typhimurium, forward mutation in Chinese hamster V79 fibroblasts), gene conversion (in Saccharomyces cerevisiae D4) or chromosomal damage (CHO cytogenetic assay). Negative findings were also obtained with lercanidipine in an in vivo assay of chromosomal damage (mouse micronucleus test).

Carcinogenicity.

Carcinogenicity studies of lercanidipine (administered via the diet) have been performed in rats and mice (18 months), using doses up to 60 mg/kg/day for mice and 5 mg/kg/day for rats. Plasma concentrations (AUC) of lercanidipine at the highest doses used in these studies were about 2-4 times the highest AUC expected in humans during treatment with lercanidipine. Lercanidipine showed no evidence of carcinogenic activity in these studies.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, microcrystalline cellulose, sodium starch glycollate type A, povidone, magnesium stearate, hypromellose, purified talc, titanium dioxide, macrogol 6000, iron oxide yellow (10 mg) or iron oxide red (20 mg).

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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 30°C. Protect from moisture and light.

6.5 Nature and Contents of Container

Container type: PVC/aluminium blisters.
Pack sizes: 7, 14, 28 or 30 tablets.
Some pack sizes may not be marketed.

Australian Register of Therapeutic Goods (ARTG).

AUST R 77506 - Zanidip lercanidipine hydrochloride 10 mg film-coated tablet blister pack.
AUST R 93733 - Zanidip lercanidipine hydrochloride 20 mg film-coated tablet blister pack.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.


3,5-pyridinedicarboxylic acid, 1,4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-2-[(3,3-diphenylpropyl)methylamino]-1,1-dimethylethyl methyl ester hydrochloride.
MW: 648.2 (free base: 611.7).

CAS number.

132866-11-6.
Lercanidipine is a dihydropyridine derivative. It is a racemate due to the presence of a chiral carbon atom at position 4 of the 1,4-dihydropyridine ring.
Lercanidipine is readily soluble in chloroform and methanol, practically insoluble in water. Octanol: water partition coefficient (LogP): 6.4.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes