Consumer medicine information

APO-Nicorandil Tablets

Nicorandil

BRAND INFORMATION

Brand name

APO-Nicorandil

Active ingredient

Nicorandil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Nicorandil Tablets.

SUMMARY CMI

APO-NICORANDIL

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 APO-NICORANDIL?

APO-NICORANDIL contains the active ingredient nicorandil. APO-NICORANDIL is used to to treat chronic stable angina pectoris (chest pain). It works by widening blood vessels and increases blood supply to heart muscle.

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

2. What should I know before I use APO-NICORANDIL?

Do not use if you have ever had an allergic reaction to nicorandil 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 APO-NICORANDIL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APO-NICORANDIL 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 APO-NICORANDIL?

  • Take APO-NICORANDIL exactly as your doctor has prescribed
  • Your doctor will prescribe the correct dose for you depending on your condition and whether you are taking any other medicines

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

5. What should I know while using APO-NICORANDIL?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using APO-NICORANDIL.
  • Tell your doctor if you are taking APO-NICORANDIL if you are about to have any blood tests or you are having surgery, or any anaesthetic or you are going into hospital
Things you should not do
  • Do not stop using this medicine or lower the dosage without talking to your doctor
  • Do not give this medicine to anyone ese, even if they have the same condition as you
Driving or using machines
  • Be careful driving or operating machinery until you know how APO-NICORANDIL affects you
Drinking alcohol
  • It is recommended to avoid alcohol while taking APO-NICORANDIL. The affects of alcohol could be made worse by taking APO-NICORANDIL
Looking after your medicine
  • Keep APO-NICORANDIL in a cool, dry place where the temperature stays below 25°C
  • Keep this medicine where children cannot reach it

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

6. Are there any side effects?

The most common side effect of APO-NICORANDIL is headache. Tell your doctor immediately if you notice any of the following, these may be serious side effects and you may need urgent medical attention: high blood pressure, fast or irregular heart beats, swelling of the face, hands, ankles or feet, difficulty in breathing or shortness of breath, tingling or numbness of the hands or feet, rash, ringing or other persistent noise in the ears, persistent mouth and tongue ulcers or genital, anal or skin ulcers, dark bowel motions and/or bloody diarrhoea, inflammation of the bowel wall (fever, vomiting and stomach pain or discomfort), high potassium levels in the blood, nerve paralysis.

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

APO-NICORANDIL

Active ingredient(s): nicorandil

Consumer Medicine Information (CMI)

This leaflet provides important information about using APO-NICORANDIL. 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 APO-NICORANDIL.

Where to find information in this leaflet:

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

1. Why am I using APO-NICORANDIL?

APO-NICORANDIL contains the active ingredient nicorandil. Nicorandil belongs to a group of medicines called "potassium channel openers". This means it increases the exit of potassium from certain muscle cells, particularly those found in arteries. This widens the arteries and reduces the workload required by the heart to pump the blood.

In addition, nicorandil has a "nitrate" property, which relaxes smooth muscle in the blood vessels, particularly in the veins.

APO-NICORANDIL is used to treat chronic stable angina pectoris (chest pain). It works by widening blood vessels and increases blood supply to heart muscle.

2. What should I know before I use APO-NICORANDIL?

Warnings

Do not use APO-NICORANDIL if:

  • You are allergic to nicorandil, nicotinic acid, nicotinamide, or any of the ingredients listed at the end of this leaflet.
  • You have a low blood pressure (which could make you feel faint, weak or dizzy, especially when you stand up suddenly)
  • You suffer from any other type of serious heart diseases
  • You have been prescribed a phosphodiesterase 5 inhibitor by your doctor (medicines used to treat impaired sexual function, e.g. sildenafil (Viagra®), tadalafil (Cialis®), vardenafil (Levitra®))
  • You have been prescribed any soluble guanylate cyclase stimulators e.g. rioriguat (Adempas®)

Check with your doctor if you:

  • Have any other medical conditions, especially the following:
    - liver disease
    - renal disease
    - diverticular disease (a condition affecting the muscles of the bowel)
    - low blood pressure (which can make you feel faint, weak or dizzy, especially when you stand up suddenly)
    - other types of serious heart diseases
    - depression
    - glaucoma
    - hyperkalaemia (high potassium levels in the blood)
    - mouth, stomach or skin ulcers
  • Take any medicines for any other condition or are planning to take any other medicines.
  • You are planning to have surgery or an anaesthetic.
  • You are currently receiving or are planning to receive dental treatment.

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

Pregnancy and breastfeeding

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

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

It is not known whether nicorandil passes into breast milk, hence it is recommended that you do not breastfeed while taking nicorandil. Your doctor will discuss the risks and benefits of taking it if 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.

Some medicines may be affected by nicorandil or may affect how well it works. These include:

  • phosphodiesterase 5 inhibitors (e.g. Viagra®, Cialis®, Levitra®) medicines often used to treat impaired sexual function
  • soluble guanylate cyclase stimulators (e.g. Adempas®)
  • other vasodilators - medicines used to widen blood vessels
  • tricyclic antidepressants (e.g. Endep®, Tofranil®, Sinequan®, Allegron®, Surmontil®, Prothiaden®, Anafranil®, etc) - medicines used to treat depression
  • other nitrates - medicines used to treat angina
  • medicines used to treat high blood pressure
  • corticosteroids (e.g. prednisone or cortisone)
  • aspirin or other Non Steroidal Anti-inflammatories (NSAIDS) e.g. ibuprofen, diclofenac

Nicorandil may also increase the effects of alcohol.

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

4. How do I use APO-NICORANDIL?

How much to take / use

  • Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.
  • The standard adult dose of nicorandil is 10 mg to 20 mg twice a day. A lower starting dose (e.g. 5 mg twice a day) may be needed in some patients.

When to take / use APO-NICORANDIL

  • APO-NICORANDIL should be taken in the morning and in the evening, either with or without food.
  • Take nicorandil at about the same time each day.

How to take APO-NICORANDIL

  • Swallow the tablet with a full glass of water.

If you forget to use APO-NICORANDIL

If you miss your dose at the usual time, if it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

If there is still a long time to go before your next dose, take it as soon as you remember, and then go back to taking it as you would normally.

If you use too much APO-NICORANDIL

If you think that you have used too much APO-NICORANDIL, you may need urgent medical attention.

You should immediately:

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

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

5. What should I know while using APO-NICORANDIL?

Things you should do

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Things you should not do

  • take more than the recommended dose unless your doctor tells you to.
  • give this medicine to anyone else, even if they have the same condition as you.
  • take your medicine to treat any other complaints unless your doctor tells you to.
  • stop taking your medicine, or lower the dosage, without checking with your doctor.
    Your doctor may want you to gradually reduce the amount you are using before stopping completely.
  • stop taking your tablets because you are feeling better, unless advised by your doctor or pharmacist.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how APO-NICORANDIL affects you.

APO-NICORANDIL may cause dizziness or lightheadedness in some people.

Drinking alcohol

Tell your doctor if you drink alcohol.

The effects of alcohol could be made worse while taking nicorandil. It is not recommended that you drink alcohol while taking nicorandil.

Looking after your medicine

  • Store below 25°C
  • Keep the tablets in their pack until it is time to take them. If you take your tablets out of the pack, they may not keep as well.

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

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

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
Nervous system
  • headache
  • dizziness and light-headedness, especially when getting up from a sitting or lying down position
  • tiredness, drowsiness
  • trouble sleeping
  • nervousness
  • depression
Cardiovascular
  • flushing, sweating
Gastrointestinal
  • nausea, vomiting, indigestion
  • diarrhoea
  • constipation
  • stomach ache
Respiratory
  • cough
Body as a whole
  • loss of appetite, weight loss
  • leg, neck, back, chest or muscular pain, pain in the arm or general pain
  • fever
Other side effects
  • itching
  • double vision
  • nose bleed
  • skin abscess
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
Allergy related:
  • cough, shortness of breath, wheezing, difficulty breathing or tightness in chest
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms
Cardiovascular
  • high blood pressure
Special senses
  • ringing or other persistent noise in the ears
Skin/ tissue
  • persistent mouth and tongue ulcers or genital, anal or skin ulcers
Gastrointestinal
  • dark bowel motions and/or bloody diarrhoea
  • inflammation of the bowel wall (fever, vomiting and stomach pain or discomfort)
Metabolic
  • high potassium levels in the blood
Nervous system
  • nerve paralysis
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

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

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

7. Product details

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

What APO-NICORANDIL contains

Active ingredient
(main ingredient)		10 mg or 20 mg of nicorandil
Other ingredients
(inactive ingredients)
  • cetyl alcohol
  • croscarmellose sodium
  • povidone
  • sodium stearylfumarate
  • mannitol
Potential allergensn/a

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

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

What APO-NICORANDIL looks like

APO-NICORANDIL is available in two strengths:

  • 10 mg tablet: white to off-white round tablets scored on one side and engraved with "10" on the other side. AUST R 277346
  • 20 mg tablet: white to off-white round tablets scored on one side and engraved with "20" on the other side. AUST R 277343

Nicorandil 10 mg and 20 mg tablets are available in blister packs of 60 tablets in a carton.

Who distributes APO-NICORANDIL

Arrotex Pharmaceuticals Pty Ltd
15 – 17 Chapel St
Cremorne VIC 3121
Ph: 1800 195 055

This leaflet was prepared in November 2024.

Published by MIMS January 2025

BRAND INFORMATION

Brand name

APO-Nicorandil

Active ingredient

Nicorandil

Schedule

S4

 

1 Name of Medicine

Nicorandil.

2 Qualitative and Quantitative Composition

Each tablet contains 10 mg or 20 mg of nicorandil, as the active ingredient.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Nicorandil 10 mg.

White to off-white round tablets scored on one side and engraved with "10" on the other side.

Nicorandil 20 mg.

White to off-white round tablets scored on one side and engraved with "20" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Nicorandil is indicated for the treatment of chronic stable angina pectoris.

4.2 Dose and Method of Administration

APO-Nicorandil tablet is intended for oral administration.

Dosage.

Adults.

The recommended therapeutic dose for nicorandil is 10 to 20 mg twice daily. The usual starting dose is 10 mg twice daily (preferably in the morning and in the evening). A lower starting dose of 5 mg twice daily may be used in patients who are prone to headache or other adverse reactions. Dosage should be titrated to the minimum effective dose.

Elderly.

There are no dosage adjustments required for the elderly patients. However, as with all other medications, the lowest effective dose should be used.

Children.

Not recommended for use in children as safety and efficacy have not been established.

4.3 Contraindications

Known or idiosyncratic hypersensitivity to nicorandil, nicotinamide, nicotinic acid or any of the excipients in this product.
Cardiogenic shock.
Hypotension.
In patients with severe hypotension or with a risk of developing severe hypotension including acute myocardial infarction with acute left ventricular failure and low filling pressures and hypovolaemia.
In patients receiving any soluble guanylate cyclase stimulators (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Due to the risk of severe hypotension, the concomitant use of nicorandil and phosphodiesterase 5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Nicorandil should be used with caution in patients who may have blood volume depletion or in those who present low systolic blood pressure (e.g. below 100 mmHg). The use of nicorandil in patients with cardiogenic shock, or acute myocardial infarction with acute left ventricular failure and low filling pressures should be avoided.
If mouth ulceration stomatitis or persistent or severe buccal ulcerations appear, this drug should be discontinued and appropriate measures taken.
Nicorandil may lower the blood pressure of hypertensive patients and therefore should be used with care when prescribed with antihypertensive drugs.
Gastrointestinal, skin, mucosal, corneal and conjunctival ulcerations have been reported with nicorandil (see Section 4.8 Adverse Effects (Undesirable Effects)). Ulceration may occur at different locations in the same patient.
Gastrointestinal haemorrhage secondary to gastrointestinal ulceration has also been reported with nicorandil. The onset of ulceration may vary from shortly after initiation of nicorandil treatment to several years after starting nicorandil. Weight loss has been reported in association with gastrointestinal ulcerations. Gastrointestinal ulcerations, if advanced, may develop into perforation, fistulating disease, or abscess formation or may lead to gastrointestinal haemorrhage or weight loss. Occurrence of persisting ulcers should lead to drug discontinuation because the ulcers may be refractory to treatment while taking nicorandil (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients with diverticular disease may be at particular risk of fistula formation or bowel perforation during nicorandil treatment.
Gastrointestinal perforations in the context of concomitant use of nicorandil and corticosteroids have been reported. Caution is advised when concomitant use is considered.
Gastrointestinal ulcerations and haemorrhage in the context of concomitant use of acetylsalicylic acid or nonsteroidal anti-inflammatory drugs (NSAIDs) with nicorandil have also been reported. Caution is advised when concomitant use is considered.
Nicorandil should be used with care in combination with other medical products that may increase potassium levels because hyperkalaemia has been reported with nicorandil (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in hepatic impairment.

The pharmacokinetics of nicorandil in cirrhotic patients (n = 8) was compared with age matched controls (n = 8) after a single 10 mg oral tablet and IV dose of 0.1 mg/kg. In cirrhotic patients, the AUC after oral dosing was less and t1/2 was longer (1.6 h versus 1.1 h) than those for the control groups. As the changes after oral dosing were minor, it is unlikely that dosage adjustment would be necessary in patients with stabilised liver impairment based solely on pharmacokinetic consideration. However, as nicorandil is primarily metabolised in the liver, the need to reduce the nicorandil dose in patients with severe liver disease cannot be excluded to prevent the potential accumulation following repeated dosing.

Use in renal impairment.

The pharmacokinetics of nicorandil was investigated in 3 groups of subjects with varying degrees of renal function (GFR > 80 mL/min, n = 6; 20-80 mL/min, n = 8 and < 20 mL/min, n = 7) receiving 20 mg of nicorandil twice daily for 5 days. Renal impairment did not significantly modify the rate and extent of nicorandil absorption. No correlation exists between nicorandil clearance and creatinine clearance. Thus the decrease of glomerular filtration rate does not significantly alter the disposition profile of nicorandil; thus no dosage adjustment is necessary in patients with renal impairment.

Use in the elderly.

The pharmacokinetics of nicorandil in 12 elderly patients was compared with 12 young adults receiving 10 mg twice daily for 8 days. There were no clinically relevant differences in the nicorandil pharmacokinetic parameters. Results from this study suggest that dosage adjustment for elderly patients may not be necessary. However, as with all medicines, use of the lowest effective dose is recommended.

Paediatric use.

Nicorandil is not recommended for use in children as its safety and efficacy in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Smoking.

The effect of smoking on the pharmacokinetics of nicorandil has not been studied.

Cimetidine.

The effects of cimetidine (400 mg twice daily for 7 days) on the pharmacokinetics of nicorandil (20 mg twice daily given for 7 days alone and then another 7 days with cimetidine) were assessed in 12 healthy volunteers. The coadministration of cimetidine with nicorandil did not significantly modify the rate of absorption of nicorandil or other pharmacokinetic parameters (such as Cmax, tmax and urinary excretion parameters). Thus, cimetidine does not significantly inhibit the liver enzymes involved in the metabolism of nicorandil. A dose adjustment of nicorandil in patients treated concomitantly with cimetidine, a drug known to be an inhibitor of liver drug metabolising enzymes, may not be necessary.

Rifampicin.

The influence of rifampicin (600 mg/day) on nicorandil (20 mg twice daily) pharmacokinetics was assessed in 16 male volunteers. Rifampicin did not modify significantly the pharmacokinetics of nicorandil, except for a slight decrease of t1/2β. Therefore, rifampicin does not modify significantly the extent of nicorandil metabolism or its disposition pattern. As a consequence, a dose adjustment of nicorandil in patients treated concomitantly with rifampicin, a drug known to be a potent inducer of liver drug metabolising enzymes, may not be necessary.

Combination with nitrate.

Although clinical experience to date suggests that long acting nitrate administered concomitantly with nicorandil does not appear to alter nicorandil's clinical acceptability, however, as nicorandil contains a nitrate moiety, caution should be taken for the likelihood of additive hypotensive effects.

Other medicines.

Co-administration of nicorandil does not affect the anticoagulation effect of warfarin. No pharmacological and/or pharmacokinetic interaction has been observed in animal and clinical studies when nicorandil is administered concomitantly with β-blockers, a calcium antagonist, digoxin, a combination of digoxin/furosemide (frusemide), acenocoumarol, rifampicin, and cimetidine. However, the possibility that nicorandil may potentiate the effect of tricyclic antidepressants, antihypertensive drugs or other vasodilators, particularly alcohol, cannot be excluded.

Phosphodiesterase 5 inhibitors.

As hypotensive effects of nitrates or nitric oxide donors are potentiated by phosphodiesterase 5 inhibitors (e.g. sildenafil, tadalafil, vardenafil), the concomitant use of nicorandil and phosphodiesterase 5 inhibitors is contraindicated (see Section 4.3 Contraindications). Combination use can lead to a serious fall in blood pressure.

Soluble guanylate cyclase stimulators.

Nicorandil is contraindicated in the concomitant use of soluble guanylate cyclase stimulators such as riociguat, since it can lead to a serious fall in blood pressure (see Section 4.3 Contraindications).

Corticosteroids.

Gastrointestinal perforations in the context of concomitant use of nicorandil and corticosteroids or acetylsalicylic acid have been reported. Caution is advised when concomitant use is considered.

Interactions with food.

Although food has been shown to delay the absorption of nicorandil (16%), it does not affect the extent of absorption. Thus, nicorandil tablets can be taken with meals.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Nicorandil did not affect the fertility of male and female rats at oral doses up to 100 mg/kg/day.
(Category B3)
Nicorandil has not been studied in pregnant women. Although animal studies have shown that nicorandil is not teratogenic, it has been shown to increase preimplantation loss at oral doses of 40 mg/kg/day in rats and to increase fetal mortality at doses of 100 mg/kg/day. The significance of these findings in human use is unknown. Nicorandil should not be used during pregnancy unless it is considered essential by the physician.
 It is not known whether nicorandil is excreted in milk. Animal studies have shown that nicorandil increases perinatal mortality at 50 mg/kg/day. The significance of this finding to human use is unclear. Thus, nicorandil is not recommended for use during breast feeding.

4.7 Effects on Ability to Drive and Use Machines

Nicorandil, as with other vasodilators, may cause dizziness and patients should be advised not to drive or operate any machinery, should dizziness occur. This is especially the case in combination with alcohol.

4.8 Adverse Effects (Undesirable Effects)

The following CIOMS frequency rating is used: very common ≥ 1/10 (10%); common ≥ 1/100 (1%) and < 1/10 (10%); uncommon ≥ 1/1000 (0.1%) and < 1/100 (1%); rare ≥ 1/10,000 (0.01%) and < 1/1000 (0.1%); very rare < 1/10,000 (< 0.01%).

Infections and infestations.

Common: abscess (skin abscess). Uncommon: abscess (anal, genital or other gastrointestinal locations).

Body as a whole.

Common: lethargy, back pain, chest pain, infection, feeling of weakness. Uncommon: malaise, face oedema, fever, leg pain, neck pain, pain, pain in the arm.

Cardiovascular system.

Common: increase in heart rate particularly following the administration of nicorandil in high doses, angina pectoris, hypertension, palpitations, vasodilation/flush. Uncommon: decrease in blood pressure particularly following the administration of nicorandil in high doses, postural hypotension, hypotension, tachycardia, arrhythmia, myocardial infarction, syncope, peripheral vascular disorder.

Gastrointestinal disorders.

Common: diverticulitis, gastrointestinal haemorrhage, gastrointestinal ulcerations (stomatitis, aphthosis, mouth ulcer, tongue ulcer, small intestinal ulcer, large intestinal ulcer, anal ulcer) (see Section 4.4 Special Warnings and Precautions for Use), dyspepsia, nausea, vomiting. Uncommon: gastrointestinal perforation, fistula (anal, genital, gastrointestinal and skin fistula), anorexia, diarrhoea, constipation, abdominal pain, gastrointestinal disorder.

Musculoskeletal and connective tissue disorders.

Common: myalgia.

Nervous system.

Very common: headache, usually transient in nature, especially when treatment is initiated. Common: dizziness, vertigo. Uncommon: insomnia, sleep disorder, nervousness, paraesthesia, somnolence, depression. Unknown: IIIrd nerve paralysis, VIth nerve paralysis.
Headache is the most commonly reported adverse event (up to 36.4%). It is dose related, and usually occurs during the first week of treatment and tends to diminish with time. Occasionally, headache may be severe and prolonged. In clinical trials, 5.3% of patients discontinued nicorandil treatment due to headache. Careful dose titration, using low starting dose (5 mg twice daily) for even two days, has significantly reduced the incidence of headache and number of patients discontinuing treatment due to headache.

Respiratory system.

Common: bronchitis, dyspnoea, respiratory disorder. Uncommon: epistaxis, increased cough.

Metabolic disorders.

Uncommon: peripheral oedema, oedema. Rare: hepatic function abnormalities. Very rare: liver disorders such as hepatitis, cholestasis, or jaundice. Unknown: hyperkalaemia (see Section 4.4 Special Warnings and Precautions for Use).

Skin and subcutaneous tissue disorders.

Common: skin and mucosal ulcerations (mainly peri-anal ulcerations, genital ulcerations and para-stomal ulcerations) (see Section 4.4 Special Warnings and Precautions for Use). Uncommon: pruritus, different types of rash, sweating. Very rare: angioedema.

Eye disorders.

Uncommon: conjunctivitis, conjunctival ulcer and corneal ulcer. Unknown: diplopia, ophthalmoplegia.

Special senses.

Uncommon: vestibular disorder. Rare: tinnitus.

Blood and lymphatic system disorders.

Unknown: thrombocytopenia has been rarely reported in association with nicorandil treatment.

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 and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

No data are available concerning overdosage of nicorandil in humans. However, in case of overdosage, peripheral vasodilation with a fall in blood pressure and reflex tachycardia can be expected. In such an event, monitoring of cardiac function and general supportive measures should be used. If not successful, circulating plasma volume should be increased by substitution of fluid. In life threatening situations, administration of vasopressors should be considered.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Nicorandil, a potassium channel opener with nitrate moiety, is an antianginal agent with a dual mechanism of action:
(i) It opens ATP dependent potassium (KATP) channels in vascular smooth muscle and hence causes a hyperpolarisation of the smooth muscle cells. This leads to arterial dilatation and afterload reduction.
(ii) Due to its nitrate moiety, nicorandil also relaxes vascular smooth muscle, particularly in the venous vascular system, via an increase in intracellular cyclic GMP. This results in an increase pooling in capacitance vessels with a decrease in preload.
Nicorandil has been shown to exert a direct effect on the coronary arteries, both on normal and stenotic segments, without leading to a steal phenomenon. Furthermore, the reduction of end diastolic pressure and wall tension decreases the extravascular component of vascular resistance.
Ultimately, this results in an improved oxygen balance in the myocardium and improved blood flow in the poststenotic areas of the myocardium and, thus, reducing infarct size. Nicorandil has no direct effect on myocardial contractility, cardiac conduction and rhythm. Furthermore, nicorandil has demonstrated a powerful spasmolytic activity in both in vitro and in vivo studies and reverses coronary spasm induced by methacholine or noradrenaline.
The activation of ATP dependent K channels by nicorandil or other potassium channel openers causes relaxation of all types of smooth muscle. In an asthma model, the three known K channel openers (cromakalim, pinacidil and nicorandil) were compared. Nicorandil was weakest of the three in terms of bronchodilator activity. Results from clinical trials with nicorandil have not shown any deterioration of airways function during treatment.
Nicorandil has no effect on renal function and electrolytes. Following 1 year therapy of nicorandil, plasma levels of sodium, potassium, creatinine and blood urea nitrogen remained unchanged.
Nicorandil has specificity for the KATP channels in the blood vessels and not for the KATP channels present in the pancreas. At the doses used for its vasodilatory action, nicorandil does not produce hyperpolarisation on the β-cells in the pancreas and therefore does not affect insulin secretion and hence blood glucose. There was no change in plasma glucose levels in patients receiving nicorandil therapy for 1 year. Animal studies show that the vascular effects of potassium channel openers can be inhibited by glibenclamide, however to inhibit the vascular effect of potassium channel openers the sulphonylureas have to be administered at doses 100 to 1000 times higher than the therapeutic dose. There was no change in plasma lipids in patients receiving nicorandil therapy.
The pharmacological data and clinical findings give no indication of a direct interaction between nicorandil and the sympathetic adrenergic system or neurohumoural mechanism. Indirect activation of the adrenergic system and the renin angiotensin system may occur as a result of excessive vasodilation or reduction in blood pressure, but only at doses higher than the therapeutic recommended dosage.

Clinical trials.

Clinical studies employing exercise tolerance test as major end point show that nicorandil at doses 10 to 20 mg twice daily is as efficacious as other antianginal agents (including diltiazem, nifedipine, isosorbide mononitrate, isosorbide dinitrate, propranolol, metoprolol and atenolol) in treating patients with chronic stable angina. Most of the controlled, comparative studies were of limited duration (= 3 months) and included patients with anginal attacks usually less than five per week. Data on the influence of nicorandil on myocardial infarction and mortality was limited. There is a trend to increased antianginal efficacy when nicorandil is added to β-blocker or calcium channel blocker, but this was not statistically significant. Efficacy testings at 2 hour and 12 hour suggest a prolonged antianginal effect of nicorandil which is longer than nicorandil's half-life. Some studies did investigate three times daily dosing with nicorandil, but this did not appear to present any advantages over twice daily dosing, although no strictly comparative studies of different dosing frequencies were performed. Long-term uncontrolled studies show that nicorandil maintains its efficacy with no evidence of tolerance developing up to 2 years after commencement of therapy.
The efficacy of nicorandil in preventing coronary artery spasm in patients with vasospastic angina was compared to nifedipine in provocation test using methylergometrine. Nicorandil was shown to be at least as effective as nifedipine. The benefit of nicorandil in unstable angina has not yet been fully established.

Laboratory safety monitoring.

Abnormal laboratory test results were very infrequent with nicorandil. However, in the short and medium term studies, the testings were performed at the beginning of the study (as a baseline) and at its termination (up to 3 months later). Thus transient laboratory abnormalities could have been missed.

Haemodynamic safety monitoring.

In hypertensive patients (n = 12), single doses of nicorandil (10, 20 and 30 mg) compared to placebo produced an acute and significant reduction in both systolic and diastolic, supine and upright blood pressure which peaked at 4 to 6 hours. After 24 hours, only the 30 mg dose continued to have a significant effect. Heart rate did not alter significantly. In patients with ischaemic heart disease undergoing routine cardiac catheterisation, a single dose of 40 mg nicorandil caused significant decreases in aortic systolic and diastolic pressure which occurred 30 minutes after dosing and reached maximum at 45 minutes. When nicorandil was administered in doses of 60 mg and, to a lesser extent 40 mg, dizziness and hypotension became relatively common side effects. In normotensive volunteers, a single 10 mg and 20 mg nicorandil dose did not affect blood pressure.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration, nicorandil is absorbed rapidly and maximum plasma concentrations are reached after about 30-60 minutes. The absolute bioavailability of nicorandil is about 75% indicating that nicorandil is well absorbed from the gastrointestinal tract without undergoing significant hepatic first-pass effect. The plasma concentrations (and the area under the curve) show linear proportionality to the dose (5 mg to 40 mg). The drug disposition parameters (distribution volume, mean residence time, total body clearance and apparent elimination half-life) remain unchanged within the therapeutic dose range. Following repeated dosing of 10 or 20 mg nicorandil twice daily, higher nicorandil concentrations were observed at day 10 compared to day 1. Accumulation ratios (AUCday10/AUCday1) of 1.7 for 10 mg and 2.0 for 20 mg were observed. Steady-state plasma concentrations of nicorandil usually are reached within approximately 96-120 h after twice daily dosing.

Distribution.

The decrease in plasma concentration reveals two distinct phases:
a rapid elimination phase with a half-life of about 1 hour responsible for approximately 96% of the decline in the plasma concentration;
a slow elimination phase occurring between the 8th and the 24th hour following oral dosing.
Nicorandil is not extensively bound to human plasma proteins (free fraction estimated to be about 75%).

Metabolism.

Metabolism occurs mainly by denitration of the molecule. The denitrated product is then further metabolised via the nicotinamide pathway.

Excretion.

Nicorandil and its metabolites are mainly excreted in the urine. Only 1% of the administered dose was excreted in the faeces, whereas more than 60% of the administered dose was eliminated in the urine 24 hours after dosing. Only approximately 1% of nicorandil is excreted unchanged in the urine, and the remaining being mainly the denitrated metabolite (9%) and its derivatives (e.g. nicotinuric acid 6%, nicotinamide 1%, N-methylnicotinamide < 1% and nicotinic acid < 1%).

5.3 Preclinical Safety Data

Genotoxicity.

Mutagenicity and carcinogenicity studies did not reveal any adverse effect of nicorandil under the experimental conditions. Nicorandil has shown no genotoxic potential in a series of assays for gene mutations and chromosomal damage.

Carcinogenicity.

Nicorandil has shown no carcinogenic potential in two year old studies in mice (100 mg/kg/day) and rats (20 and 40 mg/kg/day for male and female rats, respectively).

6 Pharmaceutical Particulars

6.1 List of Excipients

Cetyl alcohol, mannitol, croscarmellose sodium, povidone, sodium stearylfumarate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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. Store in a dry place. Protect from light.
Store in original container.

6.5 Nature and Contents of Container

Nicorandil 10 mg.

Blister pack (Aluminium/Aluminium silver foil or Clear PVC/PVDC/Aluminium silver foil) of 60 tablets (AUST R 277346).

Nicorandil 20 mg.

Blister pack (Aluminium/Aluminium silver foil or Clear PVC/PVDC/Aluminium silver foil) of 60 tablets (AUST R 277343).
Not all strengths and/or pack sizes may be available.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Nicorandil is N-(2-hydroxyethyl)-nicotinamide nitrate (ester). It is a white crystalline powder or white needles with a faint, characteristic odour. It is freely soluble in acetone, methanol, ethanol and acetonitrile; soluble in ethylacetate and chloroform; sparingly soluble in water; slightly soluble in ether.

Chemical structure.


Chemical Name: 2-amino-2-(2-(4-octyl-phenyl)ethyl) propan-1,3-diol hydrochloride.
Molecular Formula: C8H9N3O4.
Molecular Weight: 211.2.

CAS number.

65141-46-0.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes