Consumer medicine information

Isoptin Injection

Verapamil hydrochloride

BRAND INFORMATION

Brand name

Isoptin Injection

Active ingredient

Verapamil hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Isoptin Injection.

SUMMARY CMI

ISOPTIN® injection

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 injection?

ISOPTIN injection contains the active ingredient verapamil hydrochloride. ISOPTIN injection is used to treat unusual fast heart beat, treat high blood pressure, also called hypertension, treat poor blood flow to the heart and prevent certain heart problems occurring during surgery.

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

2. What should I know before I use ISOPTIN injection?

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

3. What if I am taking other medicines?

Some medicines may interfere with ISOPTIN injection 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 injection?

  • ISOPTIN injection must only be given by a doctor.

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

5. What should I know while using ISOPTIN injection?

Drinking alcohol
  • Avoid alcohol while on ISOPTIN injection.
  • You may experience greater blood pressure lowering effects than usual.
Looking after your medicine
  • ISOPTIN injection will be stored in the pharmacy or on the ward at a temperature below 25 degrees Celsius.

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

6. Are there any side effects?

Tell your doctor if you notice any of the following: constipation, bloating, nervousness, dizziness, light-headedness, feeling sick, vomiting, headache, tiredness, shakiness, pins and needles, muscular weakness or muscle and joint pains, flushing, buzzing, hissing, whistling, ringing or other persistent noise in the ears, unexpected secretion of breast milk, breast enlargement in men, impotence, increased skin sensitivity to sunlight or enlarged gums.

Tell your doctor immediately if you notice any of the following: chest pain, difficulty in breathing, wheezing or coughing, rash, itching or hives on the skin, swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing, swelling of the hands, ankles or feet, severe blisters and bleeding in the lips, eyes, mouth, nose and genitals (Stevens Johnson Syndrome), throbbing and burning pain in the hands and feet with redness of the skin, bleeding under the skin or tissues, fast or irregular heartbeats, shortness of breath, and swelling of the feet or legs due to fluid build up.

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® injection

Active ingredient(s): verapamil hydrochloride


Consumer Medicine Information (CMI)

This leaflet provides important information about using ISOPTIN injection. 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 injection.

Where to find information in this leaflet:

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

1. Why am I using ISOPTIN injection?

ISOPTIN injection contains the active ingredient verapamil hydrochloride. ISOPTIN injection belongs to a group of medicines called calcium channel blockers or calcium antagonists. They work by widening blood vessels which lets more blood and oxygen reach the heart and at the same time lowers high blood pressure. ISOPTIN injection also helps control fast heart rate.

ISOPTIN injection 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 injection works.

ISOPTIN injection is used to:

  • treat unusual fast heart beat
  • treat high blood pressure, also called hypertension
  • treat poor blood flow to the heart
  • prevent certain heart problems occurring during surgery

Your doctor may have prescribed ISOPTIN injection for another reason. Ask your doctor if you have any questions about why ISOPTIN injection has been prescribed for you.

ISOPTIN injection is not addictive.

2. What should I know before I use ISOPTIN injection?

Warnings

You should not be given ISOPTIN injection 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, 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 any of the following medications, or medications containing these ingredients:
    - ivabradine
    - Direct Oral Anticoagulants (DOACs) such as dabigatran (in certain situations)
    - beta-blockers
  • The packaging is torn or shows signs of tampering.

Check with your doctor if you:

  • have or have had any medical conditions, especially the following:
    - recent heart attack
    - any other heart condition
    - liver disease
    - kidney disease
    - tumour in the head
    - high or low blood pressure
    - muscle 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 intend to become pregnant.

ISOPTIN injection is not recommended for use during pregnancy, particularly the first 6 months. If there is a need to consider ISOPTIN injection during the last 3 months of your pregnancy, your doctor will discuss with you the benefits and risks of using it.

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

ISOPTIN injection is not recommended while you are 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.

Several medicines can cause unwanted reactions if used with ISOPTIN injection.

  • Medicines to treat heart problems or high blood pressure:
    - Beta-blockers e.g. atenolol, propranolol, metoprolol, etc
    - Ivabradine
    - Digoxin
    - Any other medicines used to control an irregular heart beat e.g. quinidine, flecainide, disopyramide
    - Diuretics (also called fluid tablets).
    - Any other 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 or sulfinpyrazone
  • Medicines used to treat psychological problems:
    - Any medicines to treat depression, or psychosis. Such as 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 surgical procedures:
    - General anaesthetics used for inducing sleep
    - Muscle relaxants e.g. dantrolene
  • Medicines used in the treatment of Human Immunodeficiency Virus (HIV):
    - Such as ritonavir
  • Other medicines that may react with ISOPTIN injection:
    - 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
    - almotriptan, a medicine to treat migraine headaches.
    - St John's Wort, a herbal medicine used to treat depression

Avoid alcohol while using ISOPTIN injection. 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 injection.

4. How do I use ISOPTIN injection?

How much is given

  • Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight.

How it is given

  • ISOPTIN injection is given as a slow injection or "drip" injection into a vein (intravenously). The doctor will continuously check your heart rate and blood pressure while you are being given ISOPTIN injection.
  • ISOPTIN Injection must only be given by a doctor.

Overdose

As ISOPTIN injection is most likely given to you in hospital by a doctor, it is very unlikely that you will receive too much.

Your doctor has information on how to recognise and treat an overdose.

Ask your doctor if you have any concerns.

5. What should I know while using ISOPTIN injection?

Your doctor and nursing staff are trained to look after you while you are being given ISOPTIN injection.

Drinking alcohol

Tell your doctor if you drink alcohol.

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

Storage

ISOPTIN injection will be stored in the pharmacy or on the ward at a temperature below 25 degrees Celsius.

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.

Tell your doctor as soon as possible if you do not feel well while you are being given ISOPTIN injection.

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

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Less serious side effects

Less serious side effectsWhat to do
  • constipation
  • bloating
  • nervousness, dizziness, light-headedness
  • feeling sick, vomiting
  • headache
  • tiredness
  • shakiness
  • pins and needles
  • muscular weakness or muscle and joint pains
  • flushing
  • buzzing, hissing, whistling, ringing or other persistent noise in the ears
  • unexpected secretion of breast milk
  • breast enlargement in men
  • impotence (inability to get or maintain an erection)
  • increased skin sensitivity to sunlight
  • enlarged gums
  • excessive sweating
  • drowsiness
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
  • chest pain
  • difficulty in breathing, wheezing or coughing
  • rash, itching or hives on the skin
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • swelling of the hands, ankles or feet
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals (Stevens Johnson Syndrome)
  • throbbing and burning pain in the hands and feet with redness of the skin
  • bleeding under the skin or tissues
  • fast or irregular heartbeats
  • shortness of breath, and swelling of the feet or legs due to fluid build up
Tell your doctor immediately 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 above may occur in some patients. Ask your doctor or pharmacist for more information about side effects, as they have a more complete list of side effects. Inform your doctor promptly about these or any other symptoms. If the condition persists or worsens, seek medical attention.

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.

Further information

This is not all the information available on ISOPTIN injection. If you have any more questions or are not sure about anything, ask your doctor or pharmacist.

7. Product details

This medicine is only available with a doctor's prescription.

What ISOPTIN injection contains

Active ingredient
(main ingredient)
verapamil hydrochloride
Other ingredients
(inactive ingredients)
  • sodium chloride
  • hydrochloric acid
  • water for injections

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

What ISOPTIN injection looks like

ISOPTIN injection a clear colourless solution in a clear glass ampoule. (AUST R 12796).

Who distributes ISOPTIN injection

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 September 2023.

ISOPTIN® is a Viatris company trade mark

ISOPTIN injection_cmi\Sep23/00

Published by MIMS October 2023

BRAND INFORMATION

Brand name

Isoptin Injection

Active ingredient

Verapamil hydrochloride

Schedule

S4

 

1 Name of Medicine

Verapamil hydrochloride.

2 Qualitative and Quantitative Composition

Each 2 mL ampoule contains 5 mg of verapamil hydrochloride (equivalent to 4.6 mg of verapamil).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Verapamil hydrochloride injection is a sterile, nonpyrogenic, clear colourless solution. The solution contains no bacteriostat or antimicrobial agent and is intended for single dose intravenous administration.

4 Clinical Particulars

4.1 Therapeutic Indications

Tachycardias, such as paroxysmal supraventricular tachycardia, atrial fibrillation with rapid ventricular response, (except in WPW syndrome, see Section 4.4 Special Warnings and Precautions for Use), atrial flutter with rapid conduction, extrasystoles.
For the prophylaxis and/or therapy of ectopic arrhythmias (predominantly ventricular extrasystoles).
In halothane anaesthesia and in the application of adrenaline (epinephrine) in halothane anaesthesia, respectively.
Acute hypertension.
Acute coronary insufficiency.

4.2 Dose and Method of Administration

Adults.

5 mg slowly intravenously, in tachycardias and hypertensive crises repeated, if necessary, after 5 to 10 minutes. Drip infusion to maintain the therapeutic effect: 5-10 mg/hour in physiological saline, glucose, laevulose or similar solutions, on average up to a total dose of 100 mg/day.

Elderly.

The dose should be administered over at least three minutes to minimise the risk of adverse effects (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Children.

Newborn.

0.75-1 mg (= 0.3-0.4 mL).

Infants.

0.75-2 mg (= 0.3-0.8 mL).

Aged 1-5 years.

2-3 mg (= 0.8-1.2 mL).

Aged 6-14 years.

2.5-5 mg (= 1-2 mL).
Isoptin should be given intravenously, depending on age and action. The injection should be made slowly under electrocardiographic control and only until onset of the effect. Intravenous infusion in hypertensive crises: initially 0.05-0.1 mg/kg/hour; if the effect proves to be insufficient, the dose is increased at 30-60 minute intervals until twice the dose or more is reached. Average total dose up to 1.5 mg/kg/day.

Method of administration.

For intravenous use only.
The medicine should be inspected visually for particulate matter and discolouration prior to administration. Any unused solution should be discarded immediately. Verapamil will precipitate in any solution with a pH above 6.0 (see Section 6.2 Incompatibilities).
Do not dilute with Sodium Lactate Injection in polyvinyl chloride bags. For stability reasons, this product is not recommended for dilution with Sodium Lactate Injection USP in polyvinyl chloride bags.
Administering intravenous verapamil with albumin, amphotericin B, hydralazine HCl, and trimethoprim with sulfamethoxazole should be avoided.

4.3 Contraindications

Cardiogenic shock (except for arrhythmia induced shock), complicated acute myocardial infarction (bradycardia, hypotension, left ventricular failure), second and third degree AV block, sick sinus syndrome (bradycardia-tachycardia syndrome), manifest heart failure.
In the presence of first degree AV block, sinus bradycardia and hypotension, the use of Isoptin should be given critical consideration. In acute coronary insufficiency, intravenous administration is only admissible with careful indication and continuous monitoring of the patient. Where heart failure is present, full compensation with cardiac glycosides must be achieved before the administration of Isoptin.
Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). These patients are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if verapamil is administered.
Patients with ventricular tachycardia. Administration of intravenous verapamil to patients with wide complex ventricular tachycardia (QRS > 0.12 sec) can result in marked haemodynamic deterioration and ventricular fibrillation. Proper diagnosis and differentiation from wide complex supraventricular tachycardia is imperative in the emergency room setting.
Severe hypotension.
Isoptin injection should not be administered intravenously to patients on beta-blockers (except in an intensive care setting).
In patients with diminished hepatic function (parenchymal loss/reduced blood supply) the effect of Isoptin is intensified and prolonged depending on the severity of the disease, due to impaired drug metabolism. In these cases, dosage should be adjusted with special care.
Concomitant administration of verapamil and ivabradine is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Known hypersensitivity to verapamil hydrochloride or any of the excipients.

4.4 Special Warnings and Precautions for Use

Verapamil should be given as a slow intravenous injection over at least 2 minutes under continuous ECG and blood pressure monitoring (see Section 4.2 Dose and Method of Administration).
Intravenous injection should only be given by the physician.
In atrial fibrillation and simultaneous WPW syndrome there is a risk of inducing ventricular fibrillation.
Some patients treated with verapamil responded with life-threatening adverse responses including rapid ventricular rate (in atrial flutter/fibrillation in the presence of an accessary bypass tract), marked hypotension or extreme bradycardia/asystole.

Hypotension.

Severe hypotension has occasionally occurred following intravenous administration of the drug. On rare occasions this has been followed by a loss of consciousness. If severe hypotension develops, verapamil should be promptly discontinued, and vasoconstrictor substances used.
In patients using antihypertensive drugs, the additional hypotensive effect should be taken into consideration.

Acute myocardial infarction.

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

Ventricular fibrillation.

Intravenous administration may precipitate ventricular fibrillation. Patients with atrial flutter/fibrillation and an accessory AV pathway may develop increased antegrade conduction across the aberrant pathway bypassing the AV node, producing a very rapid ventricular response after receiving intravenous verapamil. Its use in these patients is contraindicated (see Section 4.3 Contraindications).

Bradycardia/asystole.

Isoptin slows conduction across the AV node and rarely may produce second or third degree AV block, bradycardia and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease). Asystole in patients other than those with sick sinus syndrome is usually of short duration (a few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately (see Section 4.8 Adverse Effects (Undesirable Effects), Treatment of acute cardiovascular side effects).

Heart failure.

Because of the drug's negative inotropic effect, verapamil should not be used in patients with poorly compensated congestive heart failure, unless the failure is complicated by or caused by an arrhythmia. If verapamil is used in such patients, they must be digitalized prior to treatment. Continuous monitoring is mandatory when intravenous verapamil is used in digitalized patients. It has been reported that digoxin plasma levels may increase with chronic oral administration.

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).
Intravenous verapamil can precipitate respiratory muscle failure in patients with progressive muscular dystrophy and should, therefore, be used with caution.

Increased intracranial pressure.

Intravenous verapamil has been seen to increase intracranial pressure in patients with supratentorial tumors at the time of anaesthesia induction. Caution should be taken and appropriate monitoring performed.

Sick sinus syndrome.

Precaution should be taken when treating any supraventricular arrhythmia on an emergency basis as it may be caused by an undiagnosed sick sinus syndrome (see Section 4.3 Contraindications).

Heart block.

Development of second or third degree AV block or unifascicular, bifascicular or trifascicular bundle branch block requires reduction in subsequent doses or discontinuation of verapamil and institution of appropriate therapy, if needed (see Section 4.8 Adverse Effects (Undesirable Effects), Treatment of acute cardiovascular side effects).

Use in hepatic impairment.

Verapamil should be used with caution in patients with hepatic impairment.

Use in renal impairment.

Although impaired renal function has been shown to have no effect on verapamil pharmacokinetics in patients with end stage renal failure, verapamil should be used cautiously and with close monitoring in patients with impaired renal function. Verapamil cannot be removed by haemodialysis.
These patients should be monitored carefully for abnormal prolongation of the PR interval or other signs of excessive pharmacological effects.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

There have been rare cases of severe haemodynamic events, some fatal, after intravenous administration of verapamil to neonates and infants. Intravenous verapamil should not be administered to this group of patients unless it is absolutely necessary and there is no alternative.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of 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.

Almotriptan.

Verapamil therapy may increase serum levels of almotriptan.

Antihypertensives, diuretics, vasodilators.

Potentiation of the hypotensive effect.

Aspirin.

Increased tendency to bleed.

Beta-blockers.

During the simultaneous administration of Isoptin and drugs with cardiodepressive action and/or inhibitory effect on AV conduction watch should be kept for additive effects. Above all Isoptin should not be administered intravenously without compelling reason if the patient is on β-adrenergic blockers.
The concomitant administration of intravenous beta-blockers and intravenous verapamil has resulted in serious adverse reactions, especially in patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction. Intravenous beta-blockers should not be given to patients under treatment with verapamil (see Section 4.3 Contraindications).
The additional hypotensive effect of Isoptin should be borne in mind particularly in patients on antihypertensive drugs.
Verapamil may increase the plasma concentrations of propranolol, atenolol and metoprolol which may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).

Buspirone.

Verapamil therapy may increase plasma levels of buspirone.

Carbamazepine.

Potentiation of carbamazepine effect, enhanced neurotoxicity.

Cardiac glycosides.

Verapamil has been shown to increase the serum concentration of digoxin and digitoxin and caution should be exercised with regard to digitalis toxicity. The digitalis level should be determined and the glycoside dose reduced, if required.

Digitoxin.

Reduction in total body clearance and extrarenal clearance of digitoxin.

Digoxin.

Elevation of digoxin plasma levels because of diminished renal excretion. However, since both drugs slow AV conduction, patients should be monitored for AV block or excessive bradycardia.

Ciclosporin.

Elevation of ciclosporin plasma levels.

Cimetidine.

Cimetidine reduces verapamil clearance following intravenous verapamil administration.

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.

Dantrolene.

Animal studies suggest that concomitant use of IV verapamil and IV dantrolene may result in cardiovascular collapse.

Disopyramide.

Possible additive effects and impairment of left ventricular function. Pending further accumulation of data, disopyramide should be discontinued 48 hours prior to initiating verapamil therapy and should not be reinstituted until 24 hours after verapamil has been discontinued.

Doxorubicin.

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

Ethanol (alcohol).

Delayed ethanol breakdown and elevation of ethanol plasma levels, resulting in enhancement of the alcoholic effect through verapamil.

Erythromycin, clarithromycin and telithromycin.

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

Flecainide.

Verapamil may slightly decrease the plasma clearance of flecainide whereas flecainide has no effect on the verapamil plasma clearance.
May result in an additive negative inotropic effect and prolongation of atrioventricular conduction. and repolarisation.

Glibenclamide.

Verapamil therapy may increase serum levels of glibenclamide.

Grapefruit juice.

Increase in verapamil serum level has been reported. Therefore, grapefruit and its juice should not be taken with verapamil.

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.

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.

Imipramine.

Verapamil therapy may increase serum levels of imipramine.

Immunosuppressants.

Verapamil therapy may increase serum levels of everolimus, sirolimus and tacrolimus. Concentration determinations and dose adjustments of everolimus and sirolimus may be necessary.

Inhalation anaesthetics.

Mutual potentiation of cardiovascular effects (higher grade AV block, higher grade lowering of heart rate, induction of heart failure, enhanced blood pressure lowering).
When used concomitantly, inhalation anaesthetics and calcium antagonists, such as verapamil injection, should each be titrated carefully to avoid excessive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure).

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).

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. The addition of verapamil, however, has also resulted in the lowering of the serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs should be monitored carefully.

Metformin.

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

Midazolam.

Elevation of midazolam.

Muscle relaxants.

Possible potentiation by verapamil.

Neuromuscular blocking agents.

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.

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.

Phenytoin, phenobarbital (phenobarbitone).

Lowering of the plasma level and attenuation of the effects of verapamil.

Prazosin, terazosin.

Additive hypotensive effect.

Protein bound drugs.

As verapamil is highly protein bound, it should be administered with caution to patients receiving other highly protein bound drugs.

Quinidine.

Elevation of quinidine plasma level.
Enhanced blood pressure lowering is possible. Caution should be exercised when administering intravenous verapamil to patients receiving oral quinidine due to the risk of hypotension. Pulmonary oedema may occur in patients with hypertrophic obstructive cardiomyopathy.

Rifampicin.

Blood pressure lowering effect may be reduced.

St John's wort.

May decrease plasma levels of verapamil.

Sulfinpyrazone.

Blood pressure lowering effect may be reduced.

Theophylline.

Elevation of theophylline plasma levels.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category C)
Verapamil carries the potential to produce fetal hypoxia associated with maternal hypotension.
Verapamil should not be administered intravenously during the first six months of pregnancy. There are no data on use in the first and second trimester. Verapamil should not be used in the final trimester unless the benefits clearly outweigh the risks.
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 fetal 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. Isoptin crosses the placental barrier and can be detected in umbilical vein blood at delivery.
Verapamil is excreted in human breast milk. There are currently no reports of verapamil injection or infusion use during breastfeeding. Due to the potential for serious adverse reactions in nursing infants, intravenous verapamil is not recommended during lactation.

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.

4.8 Adverse Effects (Undesirable Effects)

As with all drugs which inhibit AV conduction, Isoptin can produce first or second degree AV block; in extreme cases there may be complete block with or without subsequent asystole. Occasionally, heart failure may develop or existing heart failure may be exacerbated.
The risk of inducing ventricular fibrillation is minute, as Isoptin has no effect on the conduction velocity and refractory period in either atria or ventricles. By diminishing the peripheral resistance, the intravenous administration of Isoptin may lead to a slight and transient decrease of blood pressure even in normotensive patients. If the heart is no longer able to increase cardiac output for maintaining normal blood pressure, a critical blood pressure fall may occur. There are rare reports of symptoms such as palpitations and rapid heart beat (tachycardia) in patients receiving verapamil.
Elevation of the pacing and sensing threshold cannot be ruled out in pacemaker wearers on verapamil.
Bradycardia has been observed commonly.
Frequently, nausea (rarely, vomiting), bloating or constipation, in isolated cases to the point of ileus, abdominal discomfort and pain.
Occasionally, there may be headache, nervousness, dizziness or lightheadedness, fatigue, sensory disturbances, such as tingling, numbness (paraesthesia, neuropathy), shakiness (tremor), and vertigo.
Flushing has been observed commonly.
Occasionally, allergic reactions, such as erythema, pruritus, urticaria, maculopapular exanthema and erythromelalgia, may occur. Rarely bronchospasm may occur.
Rarely - tinnitus. Peripheral oedema may occur as a result of local arteriole dilation.
Rarely, reversible elevation of liver enzymes has been observed, probably as a manifestation of allergic hepatitis.
Relevant lowering of glucose tolerance is rare.
There are rare reports of impotence.
Gynaecomastia has been observed very rarely in elderly patients on long-term treatment. In the cases reported to date, the condition was reversible upon discontinuation of the drug. Elevated prolactin levels has been described, with isolated cases of milk (galactorrhoea).
Very rarely, there have been cases of purpura in the skin or mucous. There are isolated reports of photodermatitis.
Very rarely, muscular weakness or muscle and joint pain may occur.
There are isolated reports of angioneurotic oedema and Stevens-Johnson syndrome.
There may be isolated cases of gingival hyperplasia which is reversible when the drug is discontinued.

Adverse effects from postmarketing 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 postmarketing surveillance include erythema multiforme extrapyramidal syndrome, hyperkalaemia, dyspnoea, seizures, somnolence, hyperhidrosis and renal failure.

Investigations.

A reversible impairment of liver function characterised by an increase of transaminase and/or alkaline phosphatase may occur on very rare occasions during verapamil treatment and is most probably a hypersensitivity reaction.

Cardiac disorders/vascular disorders.

Decreased myocardial contractility has been reported. On rare occasions, 2nd and 3rd block may occur and in extreme cases, this may lead to asystole. The asystole is usually of short duration and cardiac action returns spontaneously after a few seconds, usually in the form of sinus rhythm. If necessary, the procedures for the treatment of overdosage should be followed as described below. Flushing has been reported commonly.

Treatment of acute cardiovascular side effects.

Cardiac arrest.

External cardiac massage, artificial respiration, ECG for differentiating between asystole and ventricular fibrillation; then appropriate intensive measures, such as defibrillation or pacemaker therapy, as required.

Second or third degree AV block.

Atropine, isoprenaline, if necessary, pacemaker therapy.

Development of myocardial insufficiency.

Dopamine, dobutamine, cardiac glycosides or calcium.

Blood pressure fall.

Proper positioning, dopamine, dobutamine, noradrenaline (norepinephrine).

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 up to high degree AV block and sinus arrest, hyperglycaemia, stupor, metabolic acidosis, acute respiratory distress syndrome, shock, loss of consciousness, first and second degree AV block (frequently as Wenckebach's phenomenon with or without escape rhythms), total AV block with total AV dissociation, escape rhythm and asystole. Fatalities have occurred as a result of overdose.

Treatment.

Treatment of overdosage should be supportive and individualised. Beta-adrenergic stimulation and/or parenteral administration of calcium injection (calcium chloride dihydrate) have been effectively used in treatment of deliberate overdosage with oral verapamil hydrochloride. Verapamil hydrochloride cannot be removed by haemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including beta adrenergic stimulation (e.g. isoproterenol hydrochloride), other vasopressor agents or cardiopulmonary resuscitation.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia) or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

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

Clinical data.

Verapamil has a pronounced antiarrhythmic action, particularly in supraventricular cardiac arrhythmias. It prolongs impulse conduction in the AV node and thereby, depending on the type of arrhythmia, restores the sinus rhythm and/or normalises the ventricular rate.
The calcium antagonist verapamil reduces myocardial oxygen consumption directly by intervening in the energy consuming metabolic processes of the myocardial cell and indirectly by diminishing the peripheral resistance (afterload).
The decrease of the vascular smooth muscle tone, moreover, prevents coronary spasms and lowers raised blood pressure.

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

The injection contains sodium chloride (17 mg) and water for injections. It may contain hydrochloric acid for pH adjustment; pH is 4.5 to 6.0.

6.2 Incompatibilities

Isoptin injection is incompatible with alkaline solutions.

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

Container type.

Clear Type I glass ampoules.

Pack size.

5 x 2 mL ampoules.

Australian register of therapeutic goods (ARTG).

AUST R 12796 - Isoptin verapamil hydrochloride 5 mg/2 mL injection ampoule.

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 a white or practically white crystalline powder. It is practically odourless and has a bitter taste. It is soluble in water, freely soluble in chloroform, sparingly soluble in alcohol and practically insoluble in ether.

Chemical structure.


Chemical name: Benzeneacetonitrile, α-[3-[[2-(3,4-dimethoxyphenyl) ethyl]methylamino]propyl]]- 3,4-dimethoxy-α-(1-methylethyl), monohydrochloride.
Molecular weight: 491.07.
Molecular formula: C27H38N2O4.HCl.

CAS number.

152-11-4.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes