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Militian Inessa Mesropovna tarafından tıbbi olarak gözden geçirilmiştir, Eczane Son güncelleme: 26.03.2022
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Uniket Geciktirici Tabletler, koroner arter hastalığına bağlı anjina pektorisin önlenmesi için endikedir. Oral izosorbit mononitratın etki başlangıcı, bu ürünün akut anjinal atak iptalinde yararlı olması için yeterince hızlı değildir.
Uniket Geciktirici Tabletlerin önerilen başlangıç dozu günde bir kez 30 mg (tek bir 30 mg tablet veya 60 mg tabletin 1 / 2'si olarak verilir) veya 60 mg'dır (tek bir tablet olarak verilir). Birkaç gün sonra, dozaj günde bir kez 120 mg'a (tek bir 120 mg tablet veya iki 60 mg tablet olarak verilir) arttırılabilir. Nadiren 240 mg gerekebilir. Uniket Geciktirici Tabletlerin günlük dozu ortaya çıktıktan sonra sabah alınmalıdır. Uniket Geciktirici Genişletilmiş Serbest Bırakma Tabletleri çiğnenmemeli veya ezilmemeli ve yarım bardak sıvı ile birlikte yutulmalıdır. 30 mg tableti kırmayın.
Uniket Retard Tablets are contraindicated in patients who have shown hypersensitivity or idiosyncratic reactions to other nitrates or nitrites.
WARNINGS
Amplification of the vasodilatory effects of Uniket Retard by sildenafil can result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion.
The benefits of ISMN in patients with acute myocardial infarction or congestive heart failure have not been established; because the effects of isosorbide mononitrate are difficult to terminate rapidly, this drug is not recommended in these settings.
If isosorbide mononitrate is used in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia.
PRECAUTIONS
General
Severe hypotension, particularly with upright posture, may occur with even small doses of isosorbide mononitrate. This drug should, therefore, be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by isosorbide mononitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.
Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence. The importance of these observations to the routine, clinical use of oral isosorbide mononitrate is not known.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No evidence of carcinogenicity was observed in rats exposed to isosorbide mononitrate in their diets at doses of up to 900 mg/kg/day for the first 6 months and 500 mg/kg/day for the remaining duration of a study in which males were dosed for up to 121 weeks and females were dosed for up to 137 weeks. No evidence of carcinogenicity was observed in mice exposed to isosorbide mononitrate in their diets for up to 104 weeks at doses of up to 900 mg/kg/day.
Isosorbide mononitrate did not produce gene mutations (Ames test, mouse lymphoma test) or chromosome aberrations (human lymphocyte and mouse micronucleus tests) at biologically relevant concentrations.
No effects on fertility were observed in a study in which male and female rats were administered doses of up to 750 mg/kg/day beginning, in males, 9 weeks prior to mating, and in females, 2 weeks prior to mating.
Pregnancy
Teratogenic Effects
Pregnancy Category B
In studies designed to detect effects of isosorbide mononitrate on embryo-fetal development, doses of up to 240 or 248 mg/kg/day, administered to pregnant rats and rabbits, were unassociated with evidence of such effects. These animal doses are about 100 times the maximum recommended human dose (120 mg in a 50 kg woman) when comparison is based on body weight; when comparison is based on body surface area, the rat dose is about 17 times the human dose and the rabbit dose is about 38 times the human dose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Uniket Retard Tablets should be used during pregnancy only if clearly needed.
Nonteratogenic Effects
Neonatal survival and development and incidence of stillbirths were adversely affected when pregnant rats were administered oral doses of 750 (but not 300) mg isosorbide mononitrate/kg/day during late gestation and lactation. This dose (about 312 times the human dose when comparison is based on body weight and 54 times the human dose when comparison is based on body surface area) was associated with decreases in maternal weight gain and motor activity and evidence of impaired lactation.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ISMN is administered to a nursing mother.
Pediatric Use
The safety and effectiveness of ISMN in pediatric patients have not been established.
Geriatric Use
Clinical studies of Uniket Retard Tablets did not include sufficient information on patients age 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience for Uniket Retard has not identified differences in response between elderly and younger patients. Clinical experience for organic nitrates reported in the literature identified a potential for severe hypotension and increased sensitivity to nitrates in the elderly. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Elderly patients may have reduced baroreceptor function and may develop severe orthostatic hypotension when vasodilators are used. Uniket Retard should therefore be used with caution in elderly patients who may be volume depleted, on multiple medications or who, for whatever reason, are already hypotensive. Hypotension induced by isosorbide mononitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.
Elderly patients may be more susceptible to hypotension and may be at a greater risk of falling at therapeutic doses of nitroglycerin.
Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy, particularly in the elderly.
The table below shows the frequencies of the adverse events that occurred in >5% of the subjects in three placebo-controlled North American studies in which patients in the active treatment arm received 30 mg, 60 mg, 120 mg, or 240 mg of isosorbide mononitrate as Uniket Retard Tablets once daily. In parentheses, the same table shows the frequencies with which these adverse events were associated with the discontinuation of treatment. Overall, 8% of the patients who received 30 mg, 60 mg, 120 mg, or 240 mg of isosorbide mononitrate in the three placebo-controlled North American studies discontinued treatment because of adverse events. Most of these discontinued because of headache. Dizziness was rarely associated with withdrawal from these studies. Since headache appears to be a dose-related adverse effect and tends to disappear with continued treatment, it is recommended that Uniket Retard treatment be initiated at low doses for several days before being increased to desired levels.
FREQUENCY AND ADVERSE EVENTS (DISCONTINUED)*
Three Controlled North American Studies | |||||
Dose | Placebo | 30 mg | 60 mg | 120 mg† | 240 mg† |
Patients | 96 | 60 | 102 | 65 | 65 |
Headache | 15% (0%) | 38% (5%) | 51% (8%) | 42% (5%) | 57% (8%) |
Dizziness | 4% (0%) | 8% (0%) | 11% (1%) | 9% (2%) | 9% (2%) |
*Some individuals discontinued for multiple reasons. †Patients were started on 60 mg and titrated to their final dose. |
In addition, the three North American trials were pooled with 11 controlled trials conducted in Europe. Among the 14 controlled trials, a total of 711 patients were randomized to Uniket Retard Tablets. When the pooled data were reviewed, headache and dizziness were the only adverse events that were reported by >5% of patients. Other adverse events, each reported by ≤5% of exposed patients, and in many cases of uncertain relation to drug treatment, were:
Autonomic Nervous System Disorders: Dry mouth, hot flushes.
Body as a Whole: Asthenia, back pain, chest pain, edema, fatigue, fever, flu-like symptoms, malaise, rigors.
Cardiovascular Disorders, General: Cardiac failure, hypertension, hypotension.
Central and Peripheral Nervous System Disorders: Dizziness, headache, hypoesthesia, migraine, neuritis, paresis, paresthesia, ptosis, tremor, vertigo.
Gastrointestinal System Disorders: Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gastric ulcer, gastritis, glossitis, hemorrhagic gastric ulcer, hemorrhoids, loose stools, melena, nausea, vomiting.
Hearing and Vestibular Disorders: Earache, tinnitus, tympanic membrane perforation.
Heart Rate and Rhythm Disorders: Arrhythmia, arrhythmia atrial, atrial fibrillation, bradycardia, bundle branch block, extrasystole, palpitation, tachycardia, ventricular tachycardia.
Liver and Biliary System Disorders: SGOT increase, SGPT increase.
Metabolic and Nutritional Disorders: Hyperuricemia, hypokalemia.
Musculoskeletal System Disorders: Arthralgia, frozen shoulder, muscle weakness, musculoskeletal pain, myalgia, myositis, tendon disorder, torticollis.
Myo-, Endo-, Pericardial and Valve Disorders: Angina pectoris aggravated, heart murmur, heart sound abnormal, myocardial infarction, Q wave abnormality.
Platelet, Bleeding and Clotting Disorders: Purpura, thrombocytopenia.
Psychiatric Disorders: Anxiety, concentration impaired, confusion, decreased libido, depression, impotence, insomnia, nervousness, paroniria, somnolence.
Red Blood Cell Disorder: Hypochromic anemia.
Reproductive Disorders, Female: Atrophic vaginitis, breast pain.
Resistance Mechanism Disorders: Bacterial infection, moniliasis, viral infection.
Respiratory System Disorders: Bronchitis, bronchospasm, coughing, dyspnea, increased sputum, nasal congestion, pharyngitis, pneumonia, pulmonary infiltration, rales, rhinitis, sinusitis.
Skin and Appendages Disorders: Acne, hair texture abnormal, increased sweating, pruritus, rash, skin nodule.
Urinary System Disorders: Polyuria, renal calculus, urinary tract infection.
Vascular (Extracardiac) Disorders: Flushing, intermittent claudication, leg ulcer, varicose vein.
Vision Disorders: Conjunctivitis, photophobia, vision abnormal.
In addition, the following spontaneous adverse event has been reported during the marketing of isosorbide mononitrate: syncope.
Hemodinamik Etkiler
İzosorbit mononitrat doz aşımının kötü etkileri genellikle izosorbit mononitratın vazodilatasyon, venöz havuzlama, azalmış kardiyak çıktı ve hipotansiyon indükleme kapasitesinin sonucudur. Bu hemodinamik değişikliklerin protean belirtileri olabilir, artan kafa içi basınç dahil, kalıcı zonklama baş ağrısının herhangi biri veya tamamı ile, karışıklık, ve orta ateş; baş dönmesi, çarpıntı; görme bozuklukları; mide bulantısı ve kusma (muhtemelen kolik ve hatta kanlı ishal ile) senkop (özellikle dik duruşta) hava açlığı ve dispne, daha sonra ventilasyon çabasının azalması izledi; diyaforez, cilt kızarık veya soğuk ve rutubetli; kalp bloğu ve bradikardi; felç; koma; nöbetler ve ölüm.
İzosorbit mononitrat ve metabolitlerinin serum seviyelerinin laboratuvar belirlemeleri yaygın olarak mevcut değildir ve bu tür tespitler her halükarda izosorbit mononitrat doz aşımının yönetiminde yerleşik bir role sahip değildir.
İnsanlarda hangi doz izosorbit mononitratın yaşamı tehdit edici olabileceğini gösteren veri yoktur. Sıçanlarda ve farelerde, sırasıyla 2000 mg / kg ve 3000 mg / kg dozlarında önemli bir ölümcüllük vardır.
İzosorbit mononitratın ortadan kaldırılmasını hızlandırabilecek fizyolojik manevraları (örn. İdrarın pH'ını değiştirmek için manevralar) öneren veri mevcut değildir. Özellikle diyalizin, izosorbit mononitratın vücuttan çıkarılmasında etkisiz olduğu bilinmektedir.
İzosorbit mononitratın vazodilatör etkilerine spesifik bir antagonist bilinmemektedir ve müdahale yoktur İzosorbit mononitratın vazodilatör etkilerine spesifik bir antagonist bilinmemektedir ve izosorbit mononitrat doz aşımı tedavisi olarak kontrollü çalışmaya hiçbir müdahale yapılmamıştır. İzosorbit mononitrat doz aşımı ile ilişkili hipotansiyon venodilatasyon ve arteriyel hipovoleminin bir sonucu olduğundan, bu durumda ihtiyatlı tedavi merkezi sıvı hacminde bir artışa yönlendirilmelidir. Hastanın bacaklarının pasif yükselmesi yeterli olabilir, ancak normal salin veya benzeri sıvının intravenöz infüzyonu da gerekebilir.
Bu ortamda epinefrin veya diğer arteriyel vazokonstriktörlerin kullanılması, yarardan çok zarar verebilir.
Böbrek hastalığı veya konjestif kalp yetmezliği olan hastalarda, merkezi hacim genişlemesine neden olan tedavi tehlikesiz değildir. Bu hastalarda izosorbit mononitrat doz aşımının tedavisi ince ve zor olabilir ve invaziv izleme gerekebilir.
Methemoglobinemi
Diğer organik nitratları alan hastalarda methemoglobinemi bildirilmiştir ve muhtemelen izosorbit mononitratın bir yan etkisi olarak da ortaya çıkabilir. Kesinlikle izosorbit mononitrat metabolizması sırasında serbest bırakılan nitrat iyonları hemoglobini methemoglobine oksitleyebilir. Bununla birlikte, tamamen sitokrom b redüktaz aktivitesi olmayan hastalarda ve hatta izosorbit mononitratın nitrat kısmının hemoglobinin oksidasyonuna kantitatif olarak uygulandığı varsayılarak bile, bu hastaların herhangi biri klinik olarak anlamlı (≥% 10) methemoglobinemi. Normal redüktaz fonksiyonu olan hastalarda, önemli miktarda methemoglobin üretimi daha da büyük dozlarda izosorbit mononitrat gerektirmelidir. 36 hastanın 3.1 ila 4.4 mg / saatte 2-4 hafta sürekli nitrogliserin tedavisi aldığı bir çalışmada (eşdeğer, toplam uygulanan nitrat iyonları dozunda, saatte 7.8-11.1 mg izosorbit mononitrat) ölçülen ortalama methemoglobin seviyesi% 0.2 idi; bu plasebo alan paralel hastalarda gözlemlenenle karşılaştırılabilir düzeydeydi.
Bu gözlemlere rağmen, orta derecede aşırı dozda organik nitratlarla ilişkili olarak önemli methemoglobineminin vaka raporları vardır. Etkilenen hastaların hiçbirinin alışılmadık derecede duyarlı olduğu düşünülmemiştir.
Methemoglobin seviyeleri çoğu klinik laboratuvarda mevcuttur. Yeterli kardiyak çıktıya ve yeterli arteriyel pO'ya rağmen oksijen iletiminde bozulma belirtileri gösteren hastalarda tanıdan şüphelenilmelidir2 Klasik olarak, methemoglobinemik kan, havaya maruz kaldığında renk değişikliği olmadan çikolata kahverengisi olarak tanımlanır. Methemoglobinemi teşhis edildiğinde, tercih edilen tedavi intravenöz olarak 1-2 mg / kg metilen mavisidir.
However, we will provide data for each active ingredient