Date of approval.
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Date of revision.
Isosorbide mononitrate extended release tablets instructions
Please read the instructions carefully and use according to the instructions or buy and use under the guidance of a pharmacist
Drug Name
Generic name: Isosorbide Mononitrate Sustained-release Tablets
English name: Isosorbide Mononitrate Sustained- release Tablets
Hanyu Pinyin: Danxiaosuan Yishanlizhi Huanshipian
Ingredients
The main ingredient of this product is: Isosorbide mononitrate
Chemical name: 1,4:3,6-dianhydro-D-sorbitol-5-mononitrate
Chemical structure formula.
Molecular formula: C6H9NO6
Molecular weight: 191.14
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
Long-term treatment of coronary artery disease.
Long-term treatment and prevention of angina pectoris (including after myocardial infarction).
Used in combination with digitalis and/or diuretics for the treatment of chronic congestive heart failure.
Specification
(1) 30mg (2) 40mg.
Dosage
The dose should be individualized and adjusted according to the clinical response, and should be taken in the early morning.
Generally once a day, 30mg or 40mg each time, swallow the whole tablet with appropriate amount of warm water (do not chew). In patients with unstable circulation, the first dose may cause vasovagal deficiency symptoms and may produce nitrous headache. Isosorbide mononitrate may be given at the beginning of treatment at 10mg each morning and evening to significantly reduce these symptoms.
Adverse reactions]
Adverse reactions were assessed and classified based on the following frequencies.
Very common (≥1/10),Common (≥1/100,<1/10); Uncommon (≥1/1000,<1/100); Rare (≥1/10,000,<1/1000); Very rare (<1/10,000); Unknown (estimation cannot be made based on available data).
Nervous system
Very common.
Headache, especially nitrate-induced headache at the beginning of treatment, usually resolves with continued medication.
Common.
Sleepiness, dizziness, drowsiness.
Cardiovascular system
Common.
Decreased blood pressure and/or postural hypotension occurs with first dose and dose escalation and may be accompanied by reflex tachycardia, dizziness, and malaise.
Uncommon.
Exacerbation of angina pectoris. Circulatory deficit, sometimes accompanied by bradycardia and syncope.
Gastrointestinal
Uncommon.
Nausea, vomiting.
Very rare.
Heartburn.
Skin and subcutaneous tissue
Uncommon.
Flushing, allergic skin reactions (e.g., rash).
Very rare: Stevens-Johnson syndrome, angioneurotic edema.
Unknown.
Exfoliative dermatitis.
Hematologic
Methemoglobinemia may occur, particularly in patients with methemoglobin reductase deficiency or cardiac flavoprotein deficiency and structural abnormalities of hemoglobin.
Systemic and administration site conditions
Very common.
Cross-resistance with other nitrate drugs.
Common.
Weakness, drug tolerance. Higher doses should always be avoided to prevent diminished or lost efficacy.
Transient hypoxemia can result from redistribution of blood flow in the poorly ventilated alveolar region during use of this product. This can lead to myocardial hypoxia, especially in patients with coronary artery disease.
Increasing the dose and/or changing the dosing interval may result in reduced efficacy.
Contraindications
This product is contraindicated in patients with the following conditions.
– Hypersensitivity to the known active ingredients of this product, to nitrates or to any of the excipient ingredients.
– Low cardiac filling pressures (e.g., acute myocardial infarction).
– aortic stenosis/mitral stenosis
– hypertrophic obstructive cardiomyopathy.
– constrictive pericarditis, restrictive cardiomyopathy, pericardial tamponade.
– acute circulatory failure (shock, vascular deficiency).
– cardiogenic shock (in addition to the use of appropriate measures to ensure sufficiently high left ventricular end-diastolic pressure)
– Hypotension (systolic blood pressure below 90 mmHg).
– Severe hypovolemia.
– Severe anemia.
– Increased intracranial pressure.
– Closed-angle glaucoma.
– Concomitant use of phosphodiesterase 5 (PDE5) inhibitors such as sildenafil, vardenafil, or tadalafil, as PDE5 inhibitors may potentiate the vasodilatory effects of isosorbide mononitrate and lead to severe hypotension.
– Lioresisquat (a soluble guanylate cyclase stimulator) is being used.
[Caution].
1. Isosorbide mononitrate should be used with caution when there are the following conditions.
(1) recent history of myocardial infarction; (2) impaired left ventricular function (left ventricular failure); (3) aortic stenosis and/or mitral stenosis; (4) disease with increased intracranial pressure; (5) postural circulatory dysregulation; (6) hypertrophic cardiomyopathy; (7) constrictive pericarditis; (8) pericardial tamponade.
2. Please consult your physician before taking this product in the following cases.
Hypothyroidism; malnutrition (severe intake deficiency); suffering from liver or kidney disease; suffering from hypothermia; severe circulatory disorders; slow intestinal motility.
3. This product is not indicated for acute angina pectoris attacks and acute myocardial infarction. Although the release of this product is carried out in two stages, such as 30% of the active ingredients are released rapidly after taking the drug, it is not immediately effective for acute angina attack.
4. Nitrate therapy carries the risk of drug resistance. Therefore, it should be administered once a day, and there will be an interval of reduced blood concentration within between doses, thus reducing the risk of resistance occurring. And there is cross-resistance with other nitro compounds. As with other nitrates, treatment with isosorbide mononitrate should not be stopped abruptly and requires a gradual reduction in dosage.
After a missed dose of the drug, do not take twice the dose to supplement the dose, and take the next dose normally as prescribed by the doctor.
5.Patients with severe cerebral arteriosclerosis should be observed carefully.
6, Patients using isosorbide mononitrate for maintenance therapy should be advised not to use phosphodiesterase inhibitors (such as sildenafil, tadalafil, vardenafil). Treatment with this product should not be interrupted by the use of products containing type 5 phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil), as that would tend to increase the risk of angina attack.
7.
The use of this product may cause transient hypoxemia due to increased blood supply to poorly ventilated alveoli (formation of a pulmonary “bypass”). Especially in patients with coronary artery disease can lead to myocardial hypoxia.
8. This product contains lactose and sucrose. Therefore, if you are intolerant to certain sugars, please consult your doctor before taking this product.
9. Effects on driving and operating machinery.
Dizziness may occur during treatment with this product and may affect the reaction speed to some extent. Therefore, this product should be used with caution when concentration is required, such as driving and operating machinery.
Pregnant women and nursing mothers
Pregnancy
Data from animal studies do not suggest direct or indirect adverse effects on pregnancy, fetal/neonatal development, birth or postnatal development. Experience with this product in pregnant women is limited and it should be used with caution and is recommended to be contraindicated in women in the first trimester of pregnancy.
Lactation
It is not known whether isosorbide mononitrate is secreted through breast milk.
Therefore, breastfeeding should be discontinued prior to the use of this product.
Fertility
It is not known.
Pediatric use
The safety and efficacy of this product in children have not been established.
Geriatric use]
Postural hypotension is more likely to occur in elderly patients, so the drug should be administered from a lower starting dose and used with caution.
Drug Interactions
1. Concomitant use of drugs with vasodilatory and antihypertensive effects, such as (beta-blockers, calcium channel blockers, diuretics, angiotensin converting enzyme inhibitors), psychostimulants, tricyclic antidepressants and alcohol, may enhance the hypotensive effect of this product.
2. Combination with type 5 phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil) may increase the hypotensive effect of this product and may cause fatal cardiovascular complications, therefore, type 5 phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil) should not be used with this product (see [Contraindications]).
3. Combination with dihydroergotamine may increase dihydroergotamine blood levels and its hypertensive effects.
4. Acetylsalicylic acid may reduce the efficacy of isosorbide mononitrate.
5. Sapropterin (tetrahydrobiopterin, BH4) is a nitric oxide synthase cofactor, and special caution should be exercised when combining products containing sapropterin, as this class of drugs can cause vasodilation by affecting nitric oxide (nitric oxide metabolism or action, including classical nitric oxide donors such as glyceryl trinitrate, isosorbide nitrate, isosorbide mononitrate, and others).
6. This product should not be used in combination with liothyronine, a soluble guanylate cyclase agonist, because the combination may cause hypotension (see [Contraindications]).
Overdose]
The following symptoms may occur with overdose.
Orthostatic hypotension, reflex tachycardia and headache, weakness, dizziness, drowsiness, flushing, sweating, pallor, weak pulse
nausea, vomiting and diarrhea.
High doses (>20 mg/kg/body weight) can cause cyanosis, methemoglobinemia, dyspnea and shortness of breath due to the release of nitrite from isosorbide mononitrate metabolism. Chronic overdose may result in elevated methemoglobin levels.
Increased intracranial pressure combined with cerebral symptoms may occur at ultra-high doses.
Treatment measures for overdose.
1. general measures such as supination, elevation of the legs, oxygen, administration of activated charcoal, gastric lavage, and close monitoring and correction of vital signs.
2. For significant hypotension and/or shock, blood volume replacement and treatment for shock are required; in exceptional cases, norepinephrine may be given. Vasopressin should be used only in patients who do not respond adequately to volume expansion therapy.
3. Depending on the severity of methemoglobinemia, treatment with vincristine C, methylene blue, and toluidine blue may be given. For severe methemoglobinemia, oxygenation, artificial ventilation, hemodialysis and blood replacement may be given.
4. Resuscitation therapy: If there are signs of respiratory and circulatory arrest, resuscitation therapy should be taken immediately.
Pharmacology and Toxicology
This product is the main active metabolite of isosorbide nitrate. Like other organic nitrates, isosorbide mononitrate releases nitric oxide, which relaxes vascular smooth muscle by activating guanylate cyclase, increasing cGMP, activating cGMP-dependent protein kinase, and altering the cyclic phosphorylation of various proteins in smooth muscle cells.
Isosorbide mononitrate dilates peripheral arteries and veins by relaxing vascular smooth muscle and causing vasodilation. By dilating the veins, it increases the venous volume and reduces the return blood volume, thus decreasing the end-diastolic pressure and volume of the ventricle (preload); by dilating the arteries and small arteries, it decreases the systemic vascular resistance (afterload) and myocardial work is reduced; the reduction of cardiac pre and post load, thus decreasing myocardial oxygen consumption. Moreover, when the coronary arteries are partially blocked due to atherosclerosis, isosorbide mononitrate can selectively enlarge the coronary arteries, which can promote the redistribution of myocardial blood flow and increase the coronary perfusion, and nitrates can also dilate coronary stenosis sites as well as relieve coronary spasm. Isosorbide mononitrate has anti-myocardial ischemic effects through the above effects.
Acute toxicity studies in rats and mice showed an oral LD50 of approximately 2000-2500 mg/kg, and long-term toxicity studies were conducted in rats and dogs for 72 and 52 weeks, respectively, with the first toxic reaction occurring at doses of 405 mg/kg and 90 mg/kg, respectively. fertility studies were conducted in two generations of mice, and teratogenicity studies were conducted in mice and rabbits at maternally toxic doses. No teratogenic effect of isosorbide mononitrate was found. In vitro and in vivo mutagenicity studies on isosorbide mononitrate showed that all mutagenicity tests were negative. Long-term toxicity studies in mice and rabbits and carcinogenicity studies in mice at 125 weeks (males) and 138 weeks (females) did not reveal any carcinogenic effect, indicating that isosorbide mononitrate has low carcinogenic potential for humans.
Pharmacokinetics]
The literature shows that isosorbide mononitrate is rapidly and completely absorbed orally, with a systemic bioavailability of 90 – 100%. No hepatic first pass effect. The plasma half-life is 4-5 hours. Metabolites are mainly excreted through the kidneys, with only about 2% of the dose excreted in its original form.
The clinical effect of nitrate may be diminished despite relatively stable blood levels. Drug tolerance may be reduced within 24 hours after discontinuation of therapy, and intermittent dosing may prevent the development of drug tolerance.
This product is prescribed as an extended release isosorbide mononitrate. The release of the active ingredient is pH independent and can take up to 10 hours. The absorption period and duration of action are prolonged in extended release prescriptions compared to regular tablets. Food has no effect on absorption.
Storage】Sealed and stored.
Package】
30mg: polyvinyl chloride solid medicinal hard tablets and medicinal aluminum foil, 12 tablets/plate, 1 plate/box, 2 plates/box.
40mg: polyvinyl chloride solid medicinal hard tablets and medicinal aluminum foil, 12 tablets/plate, 1 plate/box, 2 plates/box, 10 plates/box.
【Validity】24 months
【Execution standard
【Approval number】.
30mg：Guohuazhongzhi H20066716
40mg：Guohuazhongzhi H20066717
Drug marketing license holder
Name: Qilu Pharmaceutical Co.
Registered Address: No. 317 Xinluo Street, Jinan High-tech Zone
Manufacturer
Company Name: Qilu Pharmaceutical Co.
Production Address: No. 317 Xinluo Street, Jinan High-tech Zone
Postal Code: 250100
Tel: 400-127-7799
Fax: (0531)83126288/83126545
Web
Address: http://www.qilu-pharma.com