Summary of Product Characteristics Updated 09-Sep-2014 | Accord Healthcare Limited
TabletIsosorbide mononitrate 20mg tablets:White to off white, round, flat, bevelled edge uncoated tablets, debossed with 'AS' on one side and break line on the other side. The tablets can be divided in to equal halves.
AdultsThe usual dose of Isosorbide mononitrate is 1 tablet of Isosorbide mononitrate 20 mg, taken asymmetrically (to allow a nitrate low period) 2 to 3 times daily. If result is not adequate, the dose may be increased to 1 tablet of Isosorbide mononitrate 40 mg, 2 to 3 times daily.The dosage may be increased to 120mg per day.Dosage regime should be designed according to the clinical response of the patient. The lowest effective dose should be used.In patients taking isosorbide mononitrate twice daily, the second dose should be taken 8 hours after the 1st dosage. If the dose is one three times daily, take one every 6 hours. This provides a nitrate-free period of 6 8 hours.The maximum dose is 3 tablets isosorbide mononitrate 40 mg per day.In order to prevent possible initial undesirable effect, it may be adequate to initiate treatment with possible lowest dose and slowly increase to the required dose. To prevent tolerance, it is recommended that the dosage be kept as low as possible and that a sufficiently long nitrate-free interval is ensured to restore sensitivity (first dose in the morning and last dose late in the afternoon, e.g. at 8 am and 15 pm).The duration of application is decided by the treating physician.Treatment with isosorbide mononitrate, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually (see section 4.4).
ElderlyThere is no evidence to suggest that an adjustment of the dosage is necessary in elderly.Pediatric populationThere is as yet no data on the safety and efficacy of isosorbide mononitrate in children.For oral administration.Method of administrationThe tablet should be swallowed whole, taken after meals. It should be unchewed with little fluid.
PregnancyData on the use of isosorbide mononitrate during pregnancy are insufficient to be able to assess the possible harmful effect. Limited data from animal studies indicate no adverse effects on the pregnancy or the unborn child. As precautionary measure, it is preferable to avoid the use of isosorbide mononitrate during pregnancy.
BreastfeedingThere is data that nitrates are excreted in breast milk and may cause methemoglobinemia in infants. There are no data on passage of isosorbide mononitrate in human milk, but some excretion seems likely. The effects of this exposure on a nursing infant are unknown. As precautionary measure, breast-feeding should be discontinued during treatment with isosorbide mononitrate.
FertilityAnimal data do not suggest an effect of the treatment of isosorbide mononitrate on male and female fertility. Human data are lacking.Therefore isosorbide monohydrate should only be used in pregnancy and during lactation if, in the opinion of the physician, the possible benefits of treatment outweigh the hazards.
|The frequencies of adverse events are ranked according to the following: Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000), Not known (cannot be estimated from the available data)|
|System Organ Class||Frequency||Adverse event|
|Nervous System Disorders||Very common||Headache|
|Common||Dizziness, (including dizziness postural), Somnolence|
|General disorders and administration site conditions||Common||Asthenia|
|Vascular Disorders||Common||Orthostatic Hypotension, Hypotension|
|Uncommon||Circulatory collapse with worsening of symptoms of angina pectoris (sometimes accompanied by bradyarrhythmia and syncope); Transient hypoxemia with myocardial hypoxia in patients with coronary artery disease.|
|Uncommon||Angina pectoris aggravated|
|Not known||Paroxysmal bradycardia|
|Gastrointestinal disorders||Uncommon||Nausea, vomiting, diarrhoea|
|Very rare||Dyspepsia (heartburn)*|
|Skin and subcutaneous tissue disorders||Uncommon||Allergic skin reactions (e.g. rash, pruritus), flushing|
|Not known||Exfoliative dermatitis, flushing, allergic skin reactions**|
Reporting of suspected adverse reactionsReporting 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 Website: www.mhra.gov.uk/yellowcard.
Animal experience:In rats and mice, significant lethality at oral doses of 1965mg/kg and 2581mg/kg, respectively, was observed.
Human experience:Signs and symptoms: - Headache- Hypotension (fall in blood pressure ≤ 90 mmHg- Paleness- Nausea- Vomiting- Sweating- Weak pulse- Tachycardia- Light-headedness of standing- Weakness- Dizziness- Anxiety- hot and red skin- blurred vision - syncope- Diarrhoea. - An increase in intracranial pressure with confusion and neurological deficit occurs uncommonly. In very high doses the intracranial pressure may be increased. This may lead to cerebral symtoms. Methaemoglobinaemia (cyanosis, hypoxaemia, agitation, respiratory depression, convulsions, cardiac arrhythmias, circulatory insufficiency, increased intracranial pressure) occurs rarely. Methaemoglobinaemia has been reported in patients receiving other organic nitrates. During isosorbide mononitrate biotransformation nitrite ions are released, which may induce methaemoglobinaemia and cyanosis with subsequent tachypnoea, anxiety, loss of consciousness and cardiac arrest. It cannot be excluded that an overdose of isosorbide mononitrate may cause this adverse reaction.
TreatmentThe following treatments are intended only as guidelines and are at the discretion of the treating physician.
General procedure:• Stop using isosorbide mononitrate.• Consider absorption-reducing therapy (administration of activated charcoal) and in case of suspected severe intoxication consider flushing of the stomach (where practicable within one hour after ingestion). • General procedure in case of incident of nitrate-related low blood pressure: - Put the patient in horizontal position with the legs up and lower the head.- Give oxygen. Expand plasma volume (I.V. fluids)- Specific treatment for shock (admit patient to intensive care unit). Special procedure: Raising the blood pressure if the blood pressure is very low. Treatment of methaemoglobinaemia- Reduction therapy of choice with vitamin C, methylene-blue or toluidine-blue- Administer oxygen (if necessary)- Initiate artificial ventilation- Hemodialysis (if necessary) Resuscitation measures
In case of persistent hypotension• Administration of norepinephrine HCl or dopamine.
Treatment for methemoglobinemia• Administration of antidote:- methylene blue: up to 50 ml of a 1% solution i.v.; - vitamin C: 1 g p.o. or as sodium salt i.v; - toluidine blue: initially 2 - 4 mg/kg body weight strictly i.v.; if necessary repeated several times with a time lag of one hour with 2 mg/kg body weight.• If necessary, apply artificial respiration. • In severe refractory methemoglobinemia (metHEB> 70%) consider hemodialysis, exchange transfusion. In case of signals of a respiratory and circulatory arrest, start reanimation immediately.
Mechanism of action:Like all organic nitrates, isosorbide mononitrate acts as a donor of nitric oxide (NO). NO causes a relaxation of vascular smooth muscle via the stimulation of guanylyl cyclase and the subsequent increase of intracellular cyclic guanosine monophosphate (cGMP) concentration. A cGMP-dependent protein kinase is thus stimulated, with resultant alteration of the phosphorylation of various proteins in the smooth muscle cell. This eventually leads to the dephosphorylation of the light chain of myosin and the lowering of smooth muscle tone. Continuous treatment with nitro-preparations is associated with the development of tolerance. For this reason, the tablets should be taken once a day in order to obtain an interval with low nitrate concentration.
Acute toxicity:Studies on acute toxicity in mice and rats with different routes of administration indicate a low acute toxicity (LD50 oral approximately 2,000 - 2,500 mg/kg b.w.).
Chronic toxicity:Long term toxicity has been tested in rats for 78 weeks and in dogs for 52 weeks. First toxic reactions occurred in dosages of 90 mg/kg (dog) and 405 mg/kg (rat), respectively. Thus taking into account the recommended dosage of 20 to 30 mg/d in humans, the therapeutic index can be stated as high.
Reproduction studies:These studies included a fertility and breeding study over two generations in rats; teratology studies in rats and rabbits; and a rat peri-postnatal study. The dosage levels used were generally high and produced maternal toxic effects at the highest dose. No teratogenic effects of isosorbide mononitrate were observed.
Mutagenicity:Isosorbide mononitrate was tested in different studies both in vitro and in vivo (Ames test,Human peripheral lymphocytes, Bone marrow of rats and hamsters, V 79 test, SCE test) on possible mutagenic effects. As all tests were negative the mutagenic risk in humans is considered low.
Carcinogenicity:Neither the long term toxicity studies in rats and dogs nor a special carcinogenicity study, performed in rats over 125 weeks (males) and 138 weeks (females), indicated neoplastic properties of isosorbide mononitrate. Therefore, it can be concluded that the carcinogenic risk in humans is low.
Sage House, 319 Pinner Road, North Harrow, Middlesex, HA1 4HF, UK
+44 (0)208 8631 427
+44 (0)208 861 4867
+44 (0)1271 385257
0800 373 573