Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Aventis Pharma Limited, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PT, UK Trading as: Sanofi, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PT, UK
Gastrointestinal ulcerations, skin and mucosal ulceration have been reported with nicorandil (see section 4.8).
Nicorandil induced ulceration may occur at different locations in the same patient. They are refractory to treatment and most only respond to withdrawal of nicorandil treatment. If ulceration(s) develops, nicorandil should be discontinued (see section 4.8). Healthcare professionals should be aware of the importance of a timely diagnosis of nicorandil-induced ulcerations and of a rapid withdrawal of nicorandil treatment in case of occurrence of such ulcerations. Based on available information, the time between starting nicorandil use and the onset of ulceration ranges from shortly after initiating nicorandil treatment to several years after starting nicorandil.
Gastrointestinal haemorrhage secondary to gastrointestinal ulceration has been reported with nicorandil. Patients taking acetylsalicylic acid or NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) concomitantly are at increased risk for severe complications such as gastrointestinal haemorrhage. Therefore caution is advised when concomitant use of acetylsalicylic acid or NSAIDs and nicorandil is considered (see section 4.5).
If advanced, ulcers may develop into perforation, fistula, or abscess formation. Patients with diverticular disease may be at particular risk of fistula formation or bowel perforation during nicorandil treatment.
Gastrointestinal perforations in context of concomitant use of nicorandil and corticosteroids have been reported. Therefore, caution is advised when concomitant use is considered.
Very rare conjunctivitis, conjunctival ulcer and corneal ulcer have been reported with nicorandil. Patients should be advised of the signs and symptoms and monitored closely for corneal ulcerations. If ulceration(s) develops, nicorandil should be discontinued (see section 4.8).
Caution is advised if nicorandil is used in combination with other medicinal products with blood pressure lowering effect (see sections 4.5 and 4.8).
Due to lack of data, caution is advised to use nicorandil in patients with heart failure class NHYA III or IV.
Severe hyperkalaemia has been reported very rarely with nicorandil. Nicorandil should be used with care in combination with other medical products that may increase potassium levels, especially in patients with moderate to severe renal impairment (see sections 4.5 and 4.8).
The tablets are sensitive to moisture; hence the patients should be advised to keep the tablets in their blister until intake. Besides the nicorandil tablets, each blister contains active substance-free silica gel desiccant capsule in a separate blister segment which is marked accordingly. The patients should be advised not to take this desiccant capsule. Although any accidental intake of this desiccant capsule is usually harmless, it may alter the scheduled intake of the active tablets.
Ikorel is not recommended in paediatric patients since its safety and efficacy have not been established in this patient group.
Ikorel should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency. Nicorandil acts in part through its organic nitrate moiety. The metabolism of organic nitrates can result in the formation of nitrites which may trigger methemoglobinaemia in patients with glucse-6-phosphate dehydrogenase deficiency.
Concurrent use of nicorandil and phosphodiesterase 5 inhibitors, e.g. sildenafil, tadalfil, vardenafil, is contraindicated, since it can lead to a serious drop in blood pressure (synergic effect).
Concomitant use of soluble guanylate cyclase stimulators (such as riociguat) is contraindicated, since it can lead to a serious drop in blood pressure.
Therapeutic doses of nicorandil may lower the blood pressure of hypotensive patients.
If nicorandil is used concomitantly with antihypertensive agents or other medicinal products with blood pressure lowering effect (e.g. vasodilators, tricyclic antidepressants, alcohol), the blood pressure lowering effect may be increased.
Dapoxetine should be prescribed with caution in patients taking nicorandil due to possible reduced orthostatic tolerance.
Gastrointestinal perforations in the context of concomitant use of nicorandil and corticosteroids have been reported. Caution is advised when concomitant use is considered.
In patients concomitantly receiving NSAIDs including acetylsalicylic acid for both cardiovascular prevention and anti-inflammatory doses, there is an increased risk for severe complications such as gastrointestinal ulceration, perforation and haemorrhage (see section 4.4).
Caution is advised when nicorandil is used in combination with other medical products that may increase potassium levels (see sections 4.4 and 4.8).
The metabolism of nicorandil is not significantly affected by cimetidine (a CYP inhibitor), or rifampicin (a CYP3A4 inducer). Nicorandil does not affect the pharmacodynamics of acenocoumarol.
There are no or limited amount of data from the use of nicorandil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of Ikorel during pregnancy.
Animal studies have shown that nicorandil is excreted in small amounts into the breast milk. It is not known whether nicorandil is excreted in human milk, therefore Ikorel is not recommended during breastfeeding.
There are insufficient data on fertility to estimate the risk for humans (see section 5.3).
Ikorel has an influence on the ability to drive and use machines. Indeed, as with other vasodilators, blood pressure lowering effects as well as dizziness and feeling weakness induced by nicorandil can reduce the ability to drive or to use machines. This effect can be increased in conjunction with alcohol or other medicinal products with blood pressure lowering effect (e.g. vasodilators, tricyclic antidepressants) (see section 4.5). Therefore, patients should be advised not to drive or use machines if these symptoms occur.
The most common adverse reaction reported in clinical trials is headache occurring in more than 30% of patients, particularly in the first days of treatment and responsible for most of study withdrawal.
Progressive dose titration may reduce the frequency of these headaches (see section 4.2).
In addition, serious adverse reactions including ulcerations and their complications (see section 4.4) were reported during the post marketing surveillance of nicorandil.
The frequencies of adverse reactions reported with nicorandil are summarised in the following table by system organ class (in MedDRA) and by frequency. Frequencies are defined as: Very common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000, <1/100); Rare (≥1/10,000, <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Common: Abscess (skin abscess)* (see section 4.4)
Uncommon: Abscess (genital, anal or other gastrointestinal locations)* (see section 4.4)
Very rare: Hyperkalaemia (see sections 4.4 and 4.5)
Very common: Headache
Common: Dizziness
Very rare: Corneal ulcer, conjunctival ulcer, conjunctivitis (see section 4.4)
Not known: Diplopia, ophthalmoplegia (often associated with headache)
Common: Heart rate increased
Common: Cutaneous vasodilation with flushing
Uncommon: Decrease in blood pressure (see section 4.4)
Common: Diverticulitis*, gastrointestinal haemorrhage*, gastrointestinal ulcerations (stomatitis, aphthosis, mouth ulcer, tongue ulcer, small intestinal ulcer, large intestinal ulcer, anal ulcer)* (see section 4.4), vomiting, nausea
Uncommon: Gastrointestinal perforation*, fistula (anal, genital, gastrointestinal and skin fistula)* (see section 4.4)
Very rare: Liver disorders such as hepatitis, cholestasis, or jaundice
Common: Skin and mucosal ulcerations (mainly peri-anal ulcerations, genital ulcerations and parastomal ulcerations)* (see section 4.4)
Rare: Rash, pruritus
Very rare: Angioedema
Rare: Myalgia
Common: Feeling of weakness
* The frequencies were calculated on the basis of the results of the Post Authorisation Safety Study (PASS), which is a retrospective cohort study which was conducted using the UK Clinical Practice Research Datalink (CPRD) database. Therefore, the frequencies represent those of the UK population.
Complications of gastrointestinal ulceration such as perforation, fistula, or abscess formation sometimes leading to gastrointestinal haemorrhage and weight loss have been reported (see section 4.4).
In addition, the following adverse reactions have been reported with different frequencies in the IONA (Impact of Nicorandil in Angina) study, where nicorandil has been used on top of standard therapy in patients with stable angina and at high risk of cardiovascular events (see section 5.1).
Common: Rectal bleeding
Uncommon: Mouth ulcer
Very rare: Abdominal pain
Uncommon: Angioedema
Uncommon: Myalgia
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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