Consumer medicine information

Isoptin

Verapamil hydrochloride

BRAND INFORMATION

Brand name

Isoptin SR

Active ingredient

Verapamil hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Isoptin.

SUMMARY CMI

ISOPTIN® and ISOPTIN® SR

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 using ISOPTIN?

In most parts of this leaflet, the name ISOPTIN is used to refer to both ISOPTIN tablets and ISOPTIN SR tablets. Where there is information specific to the type of ISOPTIN, separate names are used.

ISOPTIN contains the active ingredient verapamil hydrochloride. ISOPTIN and ISOPTIN SR are used for high blood pressure (hypertension) and angina (chest pain). ISOPTIN is also used to treat irregular heartbeats, also called arrhythmias.

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

2. What should I know before I use ISOPTIN?

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

3. What if I am taking other medicines?

Some medicines may interfere with ISOPTIN 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 use ISOPTIN?

ISOPTIN is usually taken two or three times a day. The usual dose of ISOPTIN SR is once daily or they may be taken twice daily.

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

5. What should I know while using ISOPTIN?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using ISOPTIN.
  • Tell your doctor if you become pregnant while taking ISOPTIN.
  • If you are being treated for angina, tell your doctor if the medicine is not helping.
  • Visit your doctor regularly so that they can check on your progress.
Things you should not do
  • Do not stop using this medicine or lower the dosage without checking with your doctor.
  • Do not take ISOPTIN with grapefruit or its juice.
Driving or using machines
  • Be careful driving or operating machinery until you know how ISOPTIN affects you.
  • ISOPTIN may cause dizziness, light-headedness or tiredness in some people. If this occurs, do not drive, operate machinery or do anything else that could be dangerous.
Drinking alcohol
  • Avoid alcohol while using ISOPTIN.
  • If you drink alcohol while taking ISOPTIN, dizziness or light-headedness may be worse.
Looking after your medicine
  • Store below 25°C in a cool and dry place.
  • Keep medicines where children cannot reach them.

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

6. Are there any side effects?

Tell your doctor if you notice any of the following and they worry you: constipation, dizziness, light-headedness, feeling sick, upset stomach, headache, tiredness and flushing. These are more common side effects of your medicine.
Tell your doctor immediately if you notice any of the following: chest pain, fainting, irregular heart beat, shortness of breath which may occur with swelling of feet and legs due to fluid built up, fever, upper stomach pain, feeling generally unwell, severe blisters, skin rash, itching or flaking 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

ISOPTIN® and ISOPTIN® SR

Active ingredient: verapamil hydrochloride


Consumer Medicine Information (CMI)

This leaflet provides important information about using ISOPTIN. 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 ISOPTIN.

There are two types of ISOPTIN:

  • ISOPTIN tablets (available as 40 mg and 80 mg tablets)
  • ISOPTIN SR (available as 180 mg and 240 mg tablets)

The letters SR in the name ISOPTIN SR stand for "sustained release". This means the medicine is released into the blood over an extended period of time, usually allowing the medicine to be taken once a day.

In most parts of this leaflet, the name ISOPTIN is used to refer to both ISOPTIN tablets and ISOPTIN SR tablets. Where there is information specific to the type of ISOPTIN, separate names are used.

Where to find information in this leaflet:

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

1. Why am I using ISOPTIN?

ISOPTIN contains the active ingredient verapamil hydrochloride. ISOPTIN and ISOPTIN SR belong to a group of medicines called calcium channel blockers or calcium antagonists. They work by opening up blood vessels, which lets more blood and oxygen reach the heart and at the same time lowers high blood pressure. ISOPTIN tablets also help to control fast or irregular heartbeats.

ISOPTIN does not change the amount of calcium in your blood or bones. Calcium in your diet or in calcium supplements will not interfere with the way ISOPTIN works.

ISOPTIN and ISOPTIN SR are used to treat high blood pressure (hypertension) and angina (chest pain). ISOPTIN is also used to treat irregular heartbeats, also called arrhythmias.

ISOPTIN SR is not recommended for use in children under the age of 18, as there have been no studies of its effects in this age group.

There is no evidence that ISOPTIN is addictive.

2. What should I know before I use ISOPTIN?

Warnings

Do not use ISOPTIN if:

  • you are allergic to verapamil hydrochloride, or any of the ingredients listed at the end of this leaflet. Some of the 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.
    Always check the ingredients to make sure you can use this medicine.
  • You have certain heart conditions (such as heart failure, a very slow heart rate, heart conduction problems, some irregular heartbeats or disease of the heart muscle).
  • You have low blood pressure, also called hypotension.
  • You are taking medicines containing ivabradine, Direct Oral Anticoagulants (DOACs) such as dabigatran (in certain situations).
  • The packaging is torn or shows signs of tampering.

Check with your doctor if you have or have had any of the following medical conditions:

  • any other heart problems
  • blood vessel (circulatory) disease or a stroke
  • liver or kidney problems
  • neuromuscular conditions such as Duchenne muscular dystrophy, myasthenia gravis, Lambert-Eaton syndrome.

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

Tell your doctor if you are pregnant or plan to become pregnant.

ISOPTIN may affect your baby if you take it in pregnancy. Your doctor will discuss the possible risks and benefits of taking ISOPTIN during pregnancy.

Tell your doctor if you are breastfeeding or plan to breastfeed.

ISOPTIN passes into breast milk. Your doctor will discuss the possible risks and benefits of taking ISOPTIN when breastfeeding.

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 ISOPTIN and affect how it works.

Medicines to treat heart problems or high blood pressure:

  • Beta-blockers e.g. atenolol, propranolol, metoprolol
  • Ivabradine
  • Digoxin
  • Medicines used to control irregular heartbeat e.g. quinidine, flecainide, amiodarone, disopyramide
  • Medicines used to control high blood pressure, especially prazosin or terazosin

Medicines used to lower cholesterol:

  • Statins such as atorvastatin or simvastatin

Medicines used to treat or prevent blood clots (sometimes referred to as "blood thinners"):

  • Direct Oral Anticoagulants (DOACs) such as dabigatran
  • Aspirin

Medicines used to treat or prevent gout:

  • Colchicine, sulfinpyrazone

Medicines used to treat psychological problems

  • Medicines to treat depression, or psychosis such as St John's Wort, imipramine, buspirone, midazolam or lithium

Medicines to treat epilepsy or seizures:

  • Phenytoin, carbamazepine, phenobarbital

Medicines to treat or prevent organ transplant rejection:

  • Cyclosporin, everolimus, sirolimus, tacrolimus

Medicines used to treat infections or tuberculosis:

  • Such as erythromycin, clarithromycin, telithromycin or rifampicin

Medicines used in the treatment of Human Immunodeficiency Virus (HIV):

  • Such as ritonavir

Medicines used in surgical procedures:

  • General anaesthetics used for inducing sleep
  • Muscle relaxants

Other medicines that may react with ISOPTIN:

  • Theophylline, a medicine used to treat asthma
  • Doxorubicin, a medicine used to treat certain cancers
  • Cimetidine, a medicine commonly used to treat stomach ulcers and reflux
  • Metformin and glibenclamide, medicines used to treat diabetes
  • Aspirin
  • Almotriptan

Avoid alcohol while using ISOPTIN. You may experience greater blood pressure lowering effects than usual.

Avoid grapefruit juice, as this may increase the blood levels of verapamil.

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

4. How do I use ISOPTIN?

How much to take

  • Your doctor will tell you how many tablets you will need to take each day and when to take them. This depends on your condition and whether you are taking any other medicines.
  • ISOPTIN tablets are usually taken two or three times a day.
  • The usual dose of ISOPTIN SR is once daily or they may be taken twice daily.
  • Treatment with ISOPTIN is usually long term. Keep taking ISOPTIN for as long as your doctor recommends.

When to take ISOPTIN

  • Take ISOPTIN SR with food.
  • ISOPTIN 40 mg and 80 mg tablets can be taken with or without food.

How to take ISOPTIN

  • Swallow ISOPTIN with a glass of water.
  • ISOPTIN 40 mg and 80 mg tablets are to be swallowed whole. They are not meant to be broken.
  • ISOPTIN SR tablets can be broken in half if your doctor has prescribed half a tablet.
  • Do not crush or chew ISOPTIN SR tablets.

If you forget to use ISOPTIN

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

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 miss more than one dose, or are not sure what to do, check with your doctor or pharmacist.

If you use too much ISOPTIN

If you think that you have used too much ISOPTIN, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26); New Zealand telephone 0800 POISON or 0800 764 766 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 ISOPTIN, you may have difficulty breathing, a slow heartbeat, chest pain, feel very faint or collapse; however, if you are taking ISOPTIN SR (sustained release) tablets the medicine is released into the blood over an extended period of time, so you may not notice these symptoms immediately.

5. What should I know while using ISOPTIN?

Things you should do

  • If you become pregnant while taking ISOPTIN, tell your doctor.
  • Tell all doctors, dentists and pharmacists who are treating you that you are taking ISOPTIN.
  • If you are going to have surgery including dental surgery, tell your doctor or dentist that you are taking ISOPTIN.
  • Visit your doctor regularly so that they can check on your progress.
  • Your doctor may ask you to have blood tests to check your liver from time to time.

Call your doctor straight away if you:

  • are being treated for angina, tell your doctor if you continue to have angina attacks or if they become more frequent while you are using ISOPTIN.

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

Things you should not do

  • Do not stop taking ISOPTIN, or lower the dosage without checking with your doctor.
  • Do not take ISOPTIN with grapefruit or its juice.
  • Do not give ISOPTIN to anyone else, even if they have the same condition as you.
  • Do not take ISOPTIN to treat any other complaints unless your doctor tells you to.

Be careful getting up from a sitting position

  • Dizziness, light-headedness or fainting may occur, especially when you get up quickly. Getting up slowly may help.

Driving or using machines

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

ISOPTIN may cause dizziness, light-headedness or tiredness in some people. If this occurs, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

If you drink alcohol while taking ISOPTIN, dizziness or light-headedness may be worse.

Looking after your medicine

  • Keep ISOPTIN tablets below 25°C.
  • Keep your tablets in the pack until it is time to take them.

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.

As with most medicines, if you are over 65 years of age you may have an increased chance of getting side effects. Report any side effects to your doctor promptly.

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
  • Constipation
  • Feeling sick, upset stomach
  • dizziness, light-headedness
  • headache
  • flushing
  • tiredness
Speak to your doctor if you have any of these more common side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • chest pain, fainting, collapse
  • slow, fast, or irregular heart beat
  • shortness of breath (sometimes with tiredness, weakness and reduced ability to exercise), which may occur together with swelling of the feet and legs due to fluid build up
  • severe blisters, skin rash, itching or flaking skin
  • fever, upper stomach pain, feeling generally unwell
  • swollen eyes and mouth
  • muscle weakness
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 atwww.tga.gov.au/reporting-problems or New Zealand at nzphvc.otago.ac.nz/reporting. 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 ISOPTIN 40mg and 80mg contain

Active ingredient
(main ingredient)
verapamil hydrochloride
Other ingredients
(inactive ingredients)
calcium hydrogen phosphate dihydrate
microcrystalline cellulose
croscarmellose sodium
magnesium stearate
colloidal anhydrous silica
hypromellose
purified talc
sodium lauryl sulfate
macrogol 6000
titanium dioxide

What ISOPTIN 180 SR contains

Active ingredient
(main ingredient)
verapamil hydrochloride
Other ingredients
(inactive ingredients)
sodium alginate
microcrystalline cellulose
povidone
magnesium stearate
hypromellose
macrogol 400
macrogol 6000
purified talc
titanium dioxide
iron oxide red
glycol/butylene glycol montanate
Potential allergenssulfites

What ISOPTIN 240 SR contains

Active ingredient
(main ingredient)
verapamil hydrochloride
Other ingredients
(inactive ingredients)
sodium alginate
powdered cellulose
povidone
magnesium stearate
hypromellose
purified talc
macrogol 400
macrogol 6000
titanium dioxide
quinoline yellow
indigo carmine
glycol/butylene glycol montanate
purified water
Potential allergenssulfites

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

What ISOPTIN looks like

ISOPTIN 80mg is white, biconvex film coated tablet, embossed "Isoptin 80" on the front and "Knoll" above the score on the back (AUST R 65503).

ISOPTIN SR 180mg is old rose, oval film coated tablet. ‘KNOLL’ on one face and ‘SR’; score; ‘180’ on the other face (AUST R 54032).

ISOPTIN SR 240mg is light green, oblong film-coated tablet (curved tooling). Score and 2 logos on one face and score on the other face. (AUST R 12801)

Who distributes ISOPTIN

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 December 2022.

ISOPTIN® is a Viatris company trade mark

ISOPTIN_cmi\Dec22/00

Published by MIMS February 2023

BRAND INFORMATION

Brand name

Isoptin SR

Active ingredient

Verapamil hydrochloride

Schedule

S4

 

1 Name of Medicine

Verapamil hydrochloride.

2 Qualitative and Quantitative Composition

Each Isoptin SR (modified release) film coated tablet contains 180 mg or 240 mg of verapamil hydrochloride as the active ingredient.
Each Isoptin (immediate release) film coated tablet contains 40 mg or 80 mg of verapamil hydrochloride as the active ingredient.

Excipients with known effect in Isoptin SR 180 mg and 240 mg tablets.

Trace quantities of sulfites.

Excipients with known effect in Isoptin 40 mg and 80 mg tablets.

None.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Isoptin 40 mg tablets are white, biconvex, film coated tablets, embossed "40" on one side and the Knoll triangle on the other side.
Isoptin 80 mg tablets are white, biconvex, film coated tablets, embossed "Isoptin 80" on the front and "Knoll" above the score on the back.
Isoptin SR 180 mg tablets are old rose, oval film coated tablets with 'KNOLL' on one face and 'SR'; score; '180' on the other face.
Isoptin SR 240 mg tablets are light green, oblong film coated tablets (curved tooling) with score and 2 logos on one face and score on the other face.
Isoptin SR tablets are designed for sustained release of the drug in the gastrointestinal tract; sustained release characteristics are not altered when the tablet is divided in half.

4 Clinical Particulars

4.1 Therapeutic Indications

Modified release tablets.

Isoptin SR is indicated for the management of hypertension and angina pectoris.

Immediate release tablets.

Isoptin is indicated for:
hypertension;
angina of effort;
angina at rest;
vasospastic angina (including Prinzmetal's variant angina);
tachyarrhythmias including paroxysmal supraventricular tachycardia;
atrial fibrillation with rapid ventricular response;
atrial flutter with rapid ventricular response.

4.2 Dose and Method of Administration

Isoptin SR (modified release).

Hypertension.

The dose of Isoptin SR should be individualised by titration and the drug should be administered with food. The usual daily dose of sustained release verapamil, Isoptin SR, in clinical trials has been 240 mg given by mouth once daily in the morning. Some patients may respond to initial therapy of one 180 mg tablet once daily. However, initial doses of 120 mg (½ 240 mg tablet) a day may be warranted in patients who may have an increased response to verapamil (e.g. elderly, small people, etc). Upward titration should be based on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of Isoptin SR are evident within the first week of therapy.
If adequate response is not obtained, the dose may be titrated upward in the following manner:
a) 240 mg each morning plus 120 mg (½ 240 mg tablet) each evening, or 180 mg each morning plus 180 mg each evening.
b) 240 mg every twelve hours.

Angina pectoris.

The usual dose is one 240 mg tablet once daily. In patients with an increased response to verapamil, (e.g. the elderly, people with low bodyweight), an initial dose of one 180 mg tablet may be more appropriate. Depending on individual response the dosage can be increased to a total of 480 mg daily, given in two divided doses. Such dose titration can be carried out using the 180 mg or 240 mg strengths of Isoptin SR.
Isoptin SR is for use only in adults as its safety and efficacy in children has not yet been established.

Isoptin (immediate release).

Isoptin tablets are to be swallowed whole. The tablets are not designed to be broken.
The individual dose, and frequency of dosing, should be determined in accordance with the indication and individual patient response.
The usual starting dose is one 80 mg tablet two or three times a day. The maintenance dose may be adjusted to 160 mg two or three times a day. Usual maintenance dose 160 mg twice daily.

Paediatric.

Dose range 40 to 360 mg per day in two or three divided daily doses according to age and response.

Geriatric/renal failure.

The recommended daily dosage is usually well tolerated.

Hepatic failure.

Caution should be exercised when initiating therapy since the pharmacological action of Isoptin may be increased or prolonged by hepatic insufficiency.
When switching from Isoptin (immediate release) to Isoptin SR (modified release) (see above) the total daily dose in milligrams may remain the same.

4.3 Contraindications

Verapamil is contraindicated in:
Severe left ventricular dysfunction (see Section 4.4 Special Warnings and Precautions for Use).
Hypotension (less than 90 mmHg systolic pressure) or cardiogenic shock.
Sick sinus syndrome (except in patients with a functioning artificial pacemaker).
Second or third degree A-V block (except in patients with a functioning artificial pacemaker).
Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see Section 4.4 Special Warnings and Precautions for Use). These patients are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if verapamil is administered.
Heart failure with reduced ejection fraction of less than 35%, and/or pulmonary wedge pressure above 20 mmHg.
Patients concomitantly administered ivabradine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Simultaneous initiation of treatment with dabigatran etexilate and oral verapamil (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Treatment initiation with oral verapamil in patients following major orthopaedic surgery who are already treated with dabigatran etexilate (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients with known hypersensitivity to verapamil hydrochloride or any of the inactive ingredients.

4.4 Special Warnings and Precautions for Use

Heart failure.

Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary oedema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g. ejection fraction less than 30%, pulmonary wedge pressure above 20 mmHg, or severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment. (Note interactions with digoxin under Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)

Acute myocardial infarction.

Use with caution in patients with acute myocardial infarction complicated by bradycardia, marked hypotension, or left ventricular dysfunction.

Hypotension.

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension.

Elevated liver enzymes.

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge. Half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

Accessory bypass tract (Wolff-Parkinson-White or Lown-Ganong-Levine).

Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory A-V pathway have developed increased antegrade conduction across the accessory pathway bypassing the A-V node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see Section 4.3 Contraindications).
Treatment is usually DC cardioversion. Cardioversion has been used safely and effectively after oral verapamil.

Atrioventricular block.

Verapamil affects the A-V and S-A nodes and prolongs A-V conduction time. Use with caution as development of second or third degree A-V block (contraindication) or unifascicular, bifascicular or trifascicular bundle branch block requires discontinuation in subsequent doses of verapamil and institution of appropriate therapy, if needed.
Verapamil affects the A-V and S-A nodes and may produce second or third degree A-V block, bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (S-A nodal disease), which is more common in older patients.
Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to A-V nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately.
In studies using Isoptin SR, prolongation of PR interval values of 0.21 to 0.22 sec occurred in 59 of 3,670 patients (= 1.6%) and to 0.23 to 0.28 sec in 4 patients whose PR intervals had been normal before treatment (0.1 to 0.2 sec). Second or third degree A-V block was not observed. Higher degrees of A-V block, however, were infrequently (0.8%) observed.

Patients with hypertrophic cardiomyopathy (IHSS).

In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary oedema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary oedema and/or severe hypotension; abnormally high (over 20 mmHg) capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary oedema). Sinus bradycardia occurred in 11% of the patients, second degree A-V block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.

Use in patients with impaired neuromuscular transmission.

Verapamil should be used with caution in the presence of diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy). It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.

Interchangeability of Isoptin SR with other sustained release verapamil products.

Other sustained release capsule formulations of verapamil should not be considered interchangeable with equivalent doses of Isoptin SR.

Use in hepatic impairment.

Since verapamil is highly metabolised by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate release verapamil to about 14 to 16 hours, hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see Section 4.9 Overdose) should be carried out.

Use in renal impairment.

About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Although impaired renal function has been shown to have no effect on verapamil pharmacokinetics in patients with endstage renal failure, verapamil should be used cautiously and with close monitoring in patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage (see Section 4.9 Overdose). Verapamil is not removed by haemodialysis.

Use in the elderly.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.

Paediatric use.

Isoptin SR (modified release).

Isoptin SR is for use only in adults as its safety and efficacy in children has not yet been established.

Isoptin (immediate release).

See Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro metabolic studies indicate that verapamil is metabolised by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil, therefore, patients should be monitored for drug interactions. Coadministration of verapamil and a drug primarily metabolised by CYP3A4 or being a P‐gp substrate may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug.

Beta-blockers.

Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. The combination of sustained release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excessive bradycardia and A-V block, including complete heart block, when the combination has been used for the treatment of hypertension. For hypertensive patients, the risks of combined therapy may outweigh the potential benefits. The combination should be used only with caution and close monitoring.
Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eye drops and oral verapamil.
Atenolol, metoprolol and propranolol plasma levels may be increased by concomitant administration of verapamil.

Ivabradine.

Concomitant administration of verapamil and ivabradine is contraindicated. Ivabradine use in combination with verapamil is associated with increased plasma concentrations of ivabradine and additional heart rate lowering effects (see Section 4.3 Contraindications).

Digitalis.

Clinical use of verapamil in digitalised patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. Chronic verapamil treatment can increase serum digoxin levels by 50 to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance digitalis doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid over or underdigitalisation. Whenever overdigitalisation is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. Upon discontinuation of Isoptin (verapamil HCl), the patient should be reassessed to avoid underdigitalisation. In clinical trials related to the control of ventricular response in digitalised patients who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.

Antihypertensive agents.

Verapamil administered concomitantly with oral antihypertensive agents (e.g. vasodilators, angiotensin converting enzyme inhibitors, diuretics, beta-blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin.

Antiarrhythmic agents.

When combined with antiarrhythmic drugs (e.g. disopyramide, flecainide, mexiletine, amiodarone) additive (depressant) effects on myocardial contractility and A-V conduction may occur.
In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided.
The electrophysiological effects of quinidine and verapamil on A-V conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on A-V conduction. There has been a report of increased quinidine levels during verapamil therapy.

Nitrates.

Verapamil has been given concomitantly with short and long acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.

Cimetidine.

The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers, clearance of verapamil was either reduced or unchanged.

Lithium.

Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil/lithium therapy with either no change or an increase in serum lithium levels. However, the addition of verapamil has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs must be monitored carefully.

Prazosin, terazosin.

Additive hypotensive effect.

HIV antiviral agents.

Due to the metabolic inhibitory potential of some of the HIV antiviral agents, such as ritonavir, plasma concentrations of verapamil may increase. Caution should be used or the dose of verapamil may be decreased.

Carbamazepine.

Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects, such as diplopia, headache, ataxia, or dizziness.

Erythromycin, clarithromycin and telithromycin.

Erythromycin, clarithromycin and telithromycin therapy may increase serum levels of verapamil.

Rifampicin.

Blood pressure lowering effect may be reduced.

Phenobarbital (phenobarbitone).

Phenobarbital (phenobarbitone) therapy may increase verapamil clearance.

Ciclosporin.

Verapamil therapy may increase serum levels of ciclosporin.

Everolimus, sirolimus and tacrolimus.

Verapamil therapy may increase serum levels of everolimus, sirolimus and tacrolimus.

Buspirone.

Verapamil therapy may increase plasma levels of buspirone.

Midazolam.

Verapamil therapy may increase plasma levels of midazolam.

Theophylline.

Verapamil therapy may inhibit the clearance and increase the plasma levels of theophylline.

Phenytoin.

Phenytoin may decrease verapamil plasma concentrations.

Alcohol.

Verapamil therapy may inhibit metabolism of alcohol, increasing its CNS depressant effects.

Inhalation anaesthetics.

Animal experiments have shown that inhalation anaesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anaesthetics and calcium antagonists, such as verapamil, should be titrated carefully to avoid excessive cardiovascular depression.

Neuromuscular blocking agents.

Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarising). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

Grapefruit juice.

Grapefruit juice has been shown to increase the plasma levels of verapamil and, therefore grapefruit and its juice should not be taken with verapamil.

HMG-CoA reductase inhibitors.

Treatment with HMG-CoA reductase inhibitors (e.g. simvastatin or atorvastatin) in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. If verapamil treatment is to be added to patients already taking an HMG-CoA reductase inhibitor (e.g. simvastatin or atorvastatin), consider a reduction in the statin dose and retitrate against serum cholesterol concentrations.
Verapamil may increase the serum levels of HMG-CoA reductase inhibitors primarily metabolised by CYP3A enzymes (e.g. atorvastatin and simvastatin). An interaction in healthy subjects demonstrated a 43% increase in verapamil AUC in combination with atorvastatin. Consider using caution when these HMG-CoA reductase inhibitors and verapamil are concomitantly administered.
Fluvastatin, pravastatin and rosuvastatin are not metabolised by CYP3A4 and are less likely to interact with verapamil.

Metformin.

Co-administration of verapamil with metformin may reduce the efficacy of metformin.

Sulfinpyrazone.

Blood pressure lowering effect may be reduced.

Aspirin.

Increased tendency to bleed.

Dabigatran.

Use of dabigatran with verapamil may increase the bioavailability of dabigatran.
Verapamil immediate release: increased dabigatran (Cmax up to 180% and AUC up to 150%).
Verapamil sustained release: increased dabigatran (Cmax up to 90% and AUC up to 70%).
When coadministered with oral verapamil, the dose of dabigatran may need to be reduced (refer to dabigatran product information for dabigatran dosing instructions) as the risk of bleeding may increase.
No meaningful interaction was observed when verapamil was given 2 hours after dabigatran etexilate (increase of Cmax by about 10% and AUC by about 20%).
Close clinical surveillance is recommended when verapamil is combined with dabigatran etexilate and particularly in the occurrence of bleeding, notably in patients having mild to moderate renal impairment.
Simultaneous initiation of treatment with dabigatran etexilate and oral verapamil is contraindicated (see Section 4.3 Contraindications).
Treatment initiation with oral verapamil in patients following major orthopaedic surgery who are already treated with dabigatran etexilate is contraindicated (see Section 4.3 Contraindications).

Other direct oral anticoagulants (DOACs).

Use of DOACs with verapamil may increase the absorption of DOACs since they are P-glycoprotein (P‐gp) substrates. If applicable, coadministration with verapamil may also reduce elimination of DOACs which are metabolised by CYP3A4, and this may increase the systemic bioavailability of DOACs.
When co-administered with oral verapamil, the dose of DOAC may need to be reduced (refer to DOAC Product Information for DOAC dosing instructions) as the risk of bleeding may increase especially in patients with further risk factors.

Doxorubicin.

Caution should be used when oral verapamil is administered in combination with doxorubicin due to the potential for increased doxorubicin levels.

Colchicine.

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (P-gp). Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine. Combined use is not recommended.

Imipramine.

Verapamil therapy may increase serum levels of imipramine.

Glibenclamide.

Verapamil therapy may increase serum levels of glibenclamide.

Almotriptan.

Verapamil therapy may increase serum levels of almotriptan.

St. John's wort.

May decrease plasma levels of verapamil.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.
(Category C)
Verapamil carries the potential to produce foetal hypoxia associated with maternal hypotension.
Reproduction studies have been performed in rabbits and rats at oral doses up to 180 mg/m2/day and 360 mg/m2/day (compared to a maximum recommended human oral daily dose of 317 mg/m2) and have revealed no evidence of teratogenicity. In the rat, however, a dose similar to the clinical dose (360 mg/m2) was embryocidal and retarded foetal growth and development. These effects occurred in the presence of maternal toxicity (reflected by reduced food consumption and weight gain of dams). This oral dose has also been shown to cause hypotension in rats. There are, however, no adequate and well controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labour and delivery.

Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. It is not known whether the use of verapamil during labour or delivery has immediate or delayed adverse effects on the foetus or whether it prolongs the duration of labour or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labour.
Verapamil is excreted in human milk. Limited human data from oral administration have shown that the estimated infant dose is low (0.01-1% of the mother's oral dose). Due to the potential for serious adverse reaction in nursing infants, Isoptin should only be used during lactation if it is essential for the welfare of the mother.

4.7 Effects on Ability to Drive and Use Machines

Due to its antihypertensive effect, depending on the individual response, verapamil may affect the ability to react to the point of impairing the ability to drive a vehicle, operate machinery or work under hazardous conditions. This applies all the more at the start of treatment, when the dose is raised, when switching from another drug and in conjunction with alcohol. Verapamil may increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

4.8 Adverse Effects (Undesirable Effects)

Verapamil is usually well tolerated.
Serious adverse reactions are uncommon when Isoptin therapy is initiated with upward dose titration within the recommended single and total daily dose. See Section 4.4 Special Warnings and Precautions for Use for discussion of heart failure, hypotension, elevated liver enzymes, A-V block, and rapid ventricular response.

Isoptin SR (modified release).

In 11 clinical trials with Isoptin SR, including a phase IV multicentre trial, on a total of 4,538 patients, the following side effects occurred at rates of 1% or more which appeared to be drug related: constipation 4.1%, dizziness 2.6%, flushing 1.2%, headaches 1.2%, nausea 1.2%, tiredness 1.0%.
The following side effects occurred at rates of 0.25 to 0.99%:

Cardiovascular.

Bradycardia, palpitations, oedema, orthostasis, abrupt BP fall.

Digestive system.

Gastric complaints/discomfort.

Skin.

Itching, urticaria, exanthema.
The following reactions, the majority at rates of 1% or less, occurred under Isoptin administration in general (all formulations) and most of them under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Cardiovascular.

Angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope.

Digestive system.

Diarrhoea, dry mouth, gastrointestinal distress, abdominal discomfort/pain, gingival hyperplasia.

Haemic and lymphatic.

Ecchymosis or bruising.

Nervous system.

Cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, paraesthesia, psychotic symptoms, shakiness, somnolence.

Skin.

Arthralgia and rash, exanthema, hair loss, hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme.

Special senses.

Blurred vision.

Ear and labyrinth disorders.

Vertigo, tinnitus.

Urogenital.

Gynaecomastia, impotence, increased urination, spotty menstruation.

Treatment of acute cardiovascular adverse reactions.

The frequency of cardiovascular adverse reactions which require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete A-V block occur following oral administration of verapamil, the appropriate emergency measures should be applied immediately, e.g. intravenously administered isoprenolol, noradrenaline (norepinephrine), atropine (all in the usual doses), or calcium gluconate monohydrate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine, metaraminol bitartrate or methoxamine) should be used to maintain blood pressure, and isoprenolol and noradrenaline (norepinephrine) should be avoided. If further support is necessary, inotropic agents (dopamine or dobutamine) may be administered. Actual treatment and dosage should depend on the severity and the clinical situation and the judgement and experience of the treating physician.

Isoptin (immediate release).

The following reactions to orally administered verapamil occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug related in clinical trials in 4,954 patients.
Constipation 7.3%, dizziness 3.3%, nausea 2.7%, hypotension 2.5%, headache 2.2%, oedema 1.9%, CHF/pulmonary oedema 1.8%, fatigue 1.7%, dyspnoea 1.4%, bradycardia (HR < 50/min) 1.4%, A-V block (total, 10, 20, 30) 1.2%, A-V block (20 and 30) 0.8%, rash 1.2%, flushing 0.6%, elevated liver enzymes (see Section 4.4 Special Warnings and Precautions for Use).
In clinical trials related to the control of ventricular response in digitalised patients who had atrial fibrillation or flutter, ventricular rate below 50 at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.

Adverse effects from post-marketing surveillance.

There has been a single post-marketing report of paralysis (tetraparesis) associated with the combined use of verapamil and colchicine. This may have been caused by colchicine crossing the blood brain barrier due to CYP3A and P-gp inhibition by verapamil. Combined use of verapamil and colchicine is not recommended.
Other adverse effects reported from post-marketing surveillance include myalgia, vomiting, tachycardia, ileus, galactorrhea, increased blood prolactin, extrapyramidal syndrome, hyperkalaemia, dyspnoea, seizures, asystole, bronchospasm, angioedema, muscular weakness and renal failure.

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

Symptoms.

Hypotension, bradycardia, second and third degree AV block, cardiac arrest, myocardial insufficiency, hyperglycaemia, stupor, metabolic acidosis and acute respiratory distress syndrome.

Isoptin SR.

Symptoms and signs of overdose may be delayed due to the controlled release properties of these products, so patients should be kept under observation for at least 24 hours.
Fatalities have occurred as a result of overdose.

Treatment.

Treatment of overdosage should be supportive. Beta-adrenergic stimulation and/or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel, and have been used effectively in treatment of deliberate overdosage with verapamil. Verapamil cannot be removed by haemodialysis. Clinically significant hypotensive reactions or fixed high degree A-V block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation.
In poisoning with large quantities of the sustained release preparation one should bear in mind that the active drug substance may be released into and absorbed by the intestine over a period exceeding 48 hours after ingestion. Dependent upon the time of intake, agglomerates of puffed tablet residues are to be anticipated along the whole length of the GI tract, acting as depots.
Thus, in suspected Isoptin SR poisoning intensive measures for complete elimination of the drug are indicated: induced vomiting, endoscope monitored aspiration of GI contents, purgation, high enemas.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Verapamil is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) which exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle, as well as in conductile and contractile myocardial cells.

Mechanism of action.

Hypertension.

Verapamil exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). During isometric or dynamic exercise verapamil does not alter systolic cardiac function in patients with normal ventricular function.

Angina pectoris.

Verapamil dilates the main coronary arteries and coronary arterioles, both in normal and ischaemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of verapamil in vasospastic (Prinzmetal's or variant) as well as unstable angina at rest. Whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate pressure product, a widely accepted measure of oxygen utilisation. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina.
Verapamil regularly reduces the total systemic resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles.
Verapamil does not alter total serum calcium levels. However, one report suggested that calcium levels above the normal range may alter the therapeutic effect of verapamil.

Other pharmacological actions of verapamil include the following.

Electrical activity through the A-V node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, verapamil prolongs the effective refractory period within the A-V node and slows A-V conduction in a rate related manner. Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, verapamil may interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without pre-existing conduction defects (see Section 4.4 Special Warnings and Precautions for Use).
Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarisation and conduction in depressed atrial fibres. Verapamil may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory A-V pathway following administration of verapamil (see Section 4.4 Special Warnings and Precautions for Use).
Verapamil has a local anaesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in humans.

Clinical trials.

See Section 4.8 Adverse Effects (Undesirable Effects).

5.2 Pharmacokinetic Properties

Absorption.

With the immediate release formulation, more than 90% of the orally administered dose of verapamil is absorbed.
In multiple dose studies under fasting conditions the bioavailability measured by AUC of modified release verapamil was similar to immediate release verapamil; rates of absorption were, of course, different.

Distribution.

Because of rapid biotransformation of verapamil during its first-pass through the portal circulation, bioavailability ranges from 20% to 35%. Peak plasma concentrations are reached between 1 and 2 hours after oral administration. Chronic oral administration of 120 mg of verapamil every 6 hours resulted in plasma levels of verapamil ranging from 125 to 400 nanogram/mL with higher values reported occasionally. A nonlinear correlation between the verapamil dose administered and verapamil plasma levels does exist.
In early dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the PR interval. However, during chronic administration this relationship may disappear.
After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid. Estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil.
In a randomised, single dose, crossover study using healthy volunteers, administration of 240 mg modified release verapamil with food produced peak plasma verapamil concentrations of 63 nanogram/mL, time to peak plasma verapamil concentration of about 12 hours, and AUC (0-∞) of 1,300 nanogram.hour/mL. When modified release verapamil was administered to fasting subjects, peak plasma verapamil concentration was 92 nanogram/mL, time to peak plasma verapamil concentration was about 7 hours, and AUC (0-∞) was 1,270 nanogram.hour/mL. Similar results were demonstrated for plasma norverapamil. Good correlation of dose and response is not available but controlled studies of modified release verapamil have shown effectiveness of doses similar to the effective doses of immediate release verapamil in hypertensive patients. Plasma verapamil levels are not directly related to antihypertensive efficacy at the dosages usually administered (240 to 480 mg/day).

Metabolism.

In healthy subjects, orally administered verapamil undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the faeces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins.

Excretion.

The mean elimination half-life in single dose studies ranged from 2.8 to 7.4 hours. In these same studies, after repetitive dosing the half-life increased to a range from 4.5 to 12.0 hours (after less than 10 consecutive doses given 6 hours apart). Half-life of verapamil may increase during titration.

Effect of advanced age.

Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly.

Hepatic impairment.

In patients with hepatic insufficiency, metabolism of immediate release verapamil is delayed and elimination half-life prolonged up to 14 to 16 hours (see Section 4.4 Special Warnings and Precautions for Use); the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one-third of the oral daily dose required for patients with normal liver function.

Renal impairment.

Impaired renal function has no effect on verapamil hydrochloride pharmacokinetics in patients with endstage renal failure and subjects with healthy kidneys.

Haemodynamics and myocardial metabolism.

Verapamil reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with hypertrophic cardiomyopathy (IHSS) and those with coronary heart disease has also been observed with verapamil therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil is countered by reduction of afterload and cardiac index is usually not reduced. In patients with severe left ventricular dysfunction however (e.g. pulmonary wedge pressure above 20 mmHg or ejection fraction lower than 30%), or in patients on beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Pulmonary function.

Verapamil does not induce bronchoconstriction and hence does not impair ventilatory function.

5.3 Preclinical Safety Data

Genotoxicity.

Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.

Carcinogenicity.

An 18 month toxicity study in rats, at a low multiple (6-fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35 and 120 mg/kg/day or approximately 1x, 3.5x and 12x, respectively, the maximum recommended human daily dose (480 mg/day or 9.6 mg/kg/day).

Animal pharmacology and/or animal toxicology.

In chronic animal toxicology studies verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not the rat.
Development of cataracts due to verapamil has not been reported in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Isoptin SR (modified release).

Isoptin SR 180 mg: Glycol/butylene glycol montanate, hypromellose, iron oxide red, macrogol 400, macrogol 6000, magnesium stearate, microcrystalline cellulose, povidone, purified talc, sodium alginate and titanium dioxide.
Isoptin SR 240 mg: Glycol/butylene glycol montanate, hypromellose, indigo carmine, macrogol 400, macrogol 6000, magnesium stearate, povidone, powdered cellulose, purified talc, purified water, quinoline yellow, sodium alginate and titanium dioxide.

Isoptin (immediate release).

The excipients are: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal anhydrous silica, hypromellose, purified talc, sodium lauryl sulfate, macrogol 6000 and titanium dioxide.

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 25°C.

6.5 Nature and Contents of Container

Isoptin SR.

Sustained release tablets, 180 mg - 7*, 15*, 30 tablets in PVC/PVDC/Al blister packs.
Sustained release tablets, 240 mg - 7*, 15*, 30 tablets in PVC/PVDC/Al blister packs.
*Not currently marketed.

Isoptin (immediate release).

Tablets, 40 mg - 10*, 100* tablets in PVC/Al blister packs.
Tablets, 80 mg - 10*, 100 tablets in PVC/Al blister packs or PVC/PVDC blister packs.
*Not currently marketed.

Australian register of therapeutic goods (ARTG).

AUST R 54032 - Isoptin 180 SR 180 mg verapamil hydrochloride tablet blister pack.
AUST R 12801 - Isoptin SR 240 mg verapamil hydrochloride tablet blister pack.
AUST R 65502 - Isoptin verapamil hydrochloride 40 mg tablet blister pack.
AUST R 65503 - Isoptin verapamil hydrochloride 80 mg 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

Verapamil hydrochloride is present as a racemic mixture and different activities reside in the two enantiomers. Verapamil HCl is an almost white, crystalline powder, practically free of odour, with a bitter taste. It is soluble in water, sparingly soluble in alcohol, and practically insoluble in ether. Verapamil HCl is not chemically related to other cardioactive drugs.

Chemical structure.


CAS number.

152-11-4.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes