Dorner

Dorner

beraprost

Manufacturer:

Astellas
Full Prescribing Info
Contents
Beraprost sodium.
Description
Beraprost sodium is a white powder. It is very soluble in methanol, freely soluble in water and ethanol (99.5). It is hygroscopic. Aqueous solution of beraprost sodium (1 in 200) has no specific rotation.
Beraprost sodium is monosodium(1RS,2RS,3aSR,8bSR)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(1E,3SR,4SR)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl]-1H-cyclopenta[b]benzofuran-5-butanoate. It has a molecular formula of C24H29NaO5 and a molecular weight of 420.47.
Partition Coefficient (Water-n-octanol System): 460 (pH 3), 15 (pH 7), 0.41 (pH 9).
Action
Pharmacotherapeutic Group: Prostacyclin (PGI2) derivative.
Pharmacology: Mechanism of Action: Similar to prostacyclin, beraprost sodium shows actions eg, antiplatelet and vasodilating action by binding to PGI2 receptors of platelets and vascular smooth muscle cells, which induces the activation of adenylate cyclase, increasing intracellular concentration of cAMP, inhibiting Ca+2 influx and thromboxane A2 synthesis or other modes.
Antiplatelet Effects: Oral administration of beraprost sodium to patients with peripheral circulatory disorders and healthy adult subjects inhibits platelet aggregating and adhering ability.
Beraprost sodium has dissociating action on human platelet aggregates formed by platelet-stimulating agents (in vitro).
Blood Flow-Increasing Effects: Beraprost sodium has been found to increase the skin blood flow when orally administered to healthy adults. It has been found to increase the tissue partial oxygen pressure (PO2) at rest, to shorten the PO2 recovery time after avascularization, and to increase the skin blood flow (laser Doppler flowmetry) measured in subcutaneous of instep when orally administered to patients with peripheral circulatory disorders.
Beraprost sodium has inhibited K+ or PGF-induced contraction of various isolated arteries of dogs eg, femoral, mesenteric and other arteries, has inhibited serotonin- or phenylephrine-induced contraction of isolated pulmonary arteries of dogs (in vitro), and has increased the blood flow in various organs in dogs.
Inhibiting Effects on the Growth of Vascular Smooth Muscle Cell: Beraprost sodium inhibited the growth of human vascular smooth muscle cell stimulated by platelet-derived growth factor (in vitro).
Effects on Animal Models of Disease: Chronic Arterial Occlusion Model: Beraprost sodium inhibited the progression of ischemic lesions or thrombus formation in the following animal models disease: Lauric acid-induced circulatory disorder of the hind paw in rats, ergotamine- and epinephrine-induced circulatory disorder of the tail in rats, and electric stimulus-induced arterial thrombus formation in rabbits.
Thrombosis Model: Beraprost sodium inhibited thrombus formation in thrombosis models eg, arterial and venous thrombosis models in rats.
Skin Ulcer Model: Beraprost sodium facilitated the healing of acetic acid-induced skin ulcers in rats.
Pulmonary Hypertension Model: Orally administered beraprost sodium inhibited the increase in right ventricular systolic pressure and the medial muscular hypertrophy in pulmonary artery on the model of monocrotaline-induced pulmonary hypertension in rats.
IV administered beraprost sodium inhibited the increased pulmonary arterial pressure and pulmonary vascular resistance on the model of thromboxane agonist-induced pulmonary hypertension induced in dogs. IV administered beraprost sodium inhibited the increased right ventricular systolic pressure on the model of thromboembolism-induced pulmonary hypertension in rats.
Pharmacokinetics: Plasma Concentration: Tmax, Cmax and t½ after single oral administration of beraprost sodium 100 mcg+ to 8 healthy adults are shown as follows: Pharmacokinetic Parameter: Tmax: 1.42 hrs; Cmax: 0.44 ng/mL; t½: 1.11 hrs.
Maximum plasma concentrations were 0.3-0.5 ng/mL after a 3-times-a-day, consecutive 10-day oral administration of beraprost sodium 50 mcg+. Therefore, no accumulability due to repeated administration was noted.
Metabolism and Excretion: Urinary excretion of the unchanged form by 24 hrs after single oral administration of beraprost sodium 50 mcg+ to 12 healthy adults was 2.8 mcg while that of the β-oxidation product was 5.4 mcg. Both the unchanged form and the β-oxidation product were excreted as glucuronide conjugates as well. The percentages of the free form in the unchanged form and the β-oxidation product in the urinary excretion were 14% and 70%, respectively.
In addition, although beraprost sodium was slightly (approximately 3% of the amount added) metabolized by CYP2C8 (in vitro), it was not metabolized by any other CYP isoforms (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4 and 4A11) (in vitro). Beraprost did not inhibit any of the CYP isoforms (1A2, 2A6, 2C8, 2C9, 2C19, 2D6 and 3A4) (in vitro) and did not reduce any of the CYP isoform activities (1A2, 2C9, 2C19 and 3A4) (in vitro).
+It is different from approved dosage and administration of beraprost sodium (see Dosage & Administration).
Clinical Studies: Improvement of Ulcer, Pain and Feeling of Coldness Associated with Chronic Arterial Occlusion: Efficacy of beraprost sodium was proven in double-blind clinical trials in chronic arterial occlusion. In 205 patients of the clinical trials, including a double-blind clinical trial, the improvement rate for symptoms of ischemia eg, ulcer, pain and feeling of coldness, was 63.9% (131 patients) in the "moderately improved" or better cases and 82.9% (170 patients) in the "slightly improved" or better cases.
Primary Pulmonary Hypertension: In 21 patients of multicentre open clinical trials in pulmonary hypertension, the improvement rate for total symptoms including hemodynamic indications eg, pulmonary vascular resistance, subjective and objective symptoms, was 38.1% (8 patients) in the "moderately improved" or better cases and 61.9% (13 patients) in the "slightly improved" or better cases.
Indications/Uses
Improvement of ulcer, pain and feeling of coldness associated with chronic arterial occlusion. Primary pulmonary hypertension.
Dosage/Direction for Use
Adults: Improvement of Ulcer, Pain and Feeling of Coldness Associated with Chronic Arterial Occlusion: Usual Dosage: 120 mcg daily, administered orally in 3 divided doses after meals.
Primary Pulmonary Hypertension: Usual Dosage: 60 mcg daily, administered orally in 3 divided doses after meals and gradually increased under careful monitoring. When the dosage is increased, its maximum is 180 mcg daily, in 3-4 divided doses.
Contraindications
Patients with hemorrhage (eg, hemophilia, capillary fragility, upper gastrointestinal hemorrhage, urinary tract hemorrhage, hemoptysis and bleeding of ocular fundus) as Dorner may aggravate hemorrhage.
Pregnant women or women who may possibly be pregnant (see Use in pregnancy under Precautions).
Special Precautions
Dorner should be administered with care in the following patients: Patients on medication with anticoagulants, antiplatelet or thrombolytic agents (see Interactions); in menstruation and those with bleeding tendency or diathesis thereof as Dorner may enhance bleeding tendency.
Use only in patients who were diagnosed with primary pulmonary hypertension.
Dorner may not be effective in some patients with severe symptoms and others because its administration route is oral. If haemodynamic parameters and/or symptoms are not improved sufficiently, an appropriate treatment should be considered including changing to injectable preparation or another treatment.
Use in pregnancy & lactation: Safety of Dorner in pregnant women has not been established. Therefore, it should not be used in pregnant women or in women who may possibly be pregnant.
Administration of Dorner to nursing mothers should be avoided. If use is unavoidable, the nursing mother should discontinue breastfeeding. Beraprost sodium has been reported to be migrated to milk in animal experiments (rats).
Use in children: Safety in children has not been established (no clinical experience).
Use in the elderly: Since physiological functions are often lowered in the elderly, caution should be taken for dose.
Use In Pregnancy & Lactation
Safety of Dorner in pregnant women has not been established. Therefore, it should not be used in pregnant women or in women who may possibly be pregnant.
Administration of Dorner to nursing mothers should be avoided. If use is unavoidable, the nursing mother should discontinue breastfeeding. Beraprost sodium has been reported to be migrated to milk in animal experiments (rats).
Adverse Reactions
Improvement of Ulcer, Pain and Feeling of Coldness Associated with Chronic Arterial Occlusion: Adverse reactions to Dorner, including abnormalities in laboratory data, were reported in 370 of 7515 patients treated (4.9%). The major adverse reactions were headache in 91 patients (1.2%), facial hot flushes in 60 patients (0.8%), hot flushes in 39 patients (0.5%), diarrhea in 29 patients (0.4%), nausea in 20 patients (0.3%), etc. (As of time at notification Japanese re-examination result.)
Primary Pulmonary Hypertension: Adverse reactions to Dorner, including abnormalities in laboratory data, were reported in clinical studies on the pulmonary hypertension in 24 patients (65 events) of 40 patients treated (60%). The major adverse reactions were headache in 9 patients (22.5%), increased LDH in 5 patients (12.5%), increased bilirubin in 4 patients (10%), hot flushes 3 patients (7.5%), diarrhea 3 patients (7.5%), nausea 3 patients (7.5%) and increased triglyceride in 3 patients (7.5%), etc. (As of time at Japanese approval.)
Adverse reactions to Dorner, including abnormalities in laboratory data, were reported in the use-results surveillance, in 57 patients of 244 patients treated (23.4%). The major adverse reactions were headache in 15 patients (6.1%), increased AST (GOT) in 9 patients (3.7%), increased ALT (GPT) in 8 patients (1.6%), etc. Of these adverse reactions to Dorner, including abnormalities in laboratory data, were reported in 14 patients (21.2%) out of 66 children (<15 years). The major adverse reactions were epitaxis in 3 patients (4.5%), increased AST (GOT) in 3 patients (4.5%), headache in 2 patients (3%) and hot flush in 2 patients (3%), etc. (As of time at Japanese re-examination application).
Clinically Significant Adverse Reactions:
Bleeding tendency [cerebral hemorrhage (<0.1%), hemorrhage of digestive tract (<0.1%) and pulmonary hemorrhage (<0.1%), bleeding of ocular fundus (<0.1%)]. The patient should be carefully monitored. Medication should be discontinued and appropriate treatments should be conducted, if such abnormalities are observed.
Shock (<0.1%), syncope (<0.1%) and loss of consciousness (<0.1%)  may occur. The condition of the patient should be carefully monitored. Medication should be discontinued and appropriate treatments should be conducted, if symptoms eg, decreased blood pressure, tachycardia, facial pallor or nausea are observed.
Interstitial pneumonia** may occur. The patient should carefully be monitored. Medication should be discontinued and appropriate treatments should be conducted, if such symptoms are observed.
Hepatic function disorders(<0.1%)** accompanied by jaundice and markedly increased AST (GOT) and ALT (GPT) may occur. The patient should carefully be monitored. Medication should be discontinued and appropriate treatments should be conducted, if such symptoms are observed.
Angina pectoris** and myocardial infarction** (incidences unknown) may occur.
The patient should be carefully monitored. Medication should be discontinued and appropriate treatments should be conducted if such abnormalities are observed.
Others: The following adverse reactions may occur. Appropriate treatments including discontinuation of medication should be conducted if such abnormalities are observed.
Bleeding Tendency**: <0.1%: Bleeding tendency, subcutaneous hemorrhage, epistaxis.
Blood**: ≥0.1% to <5%: Anemia. <0.1%: Eosinophillia, increased white blood cell, decreased platelet, decreased white blood cell.
Hypersensitivity**: ≥0.1% to <5%: Rash. <0.1%: Eczema, itching, urticaria. Incidence Unknown*: Erythema.
Psychoneurologic: ≥0.1% to <5%: Headache, dizziness, lightheaded feeling. <0.1%: Dizziness on standing up, sleepiness, twilight state, numbness, tremor. Incidence Unknown*: Sleep loss, feeling of floating.
Gastrointestinal: ≥0.1% to <5%: Nausea, diarrhea, upper abdominal pain, anorexia, stomach discomfort. <0.1%: Gastric ulcer, vomiting, gastric disorder, thirst, heartburn, abdominal pain.
Hepatic: ≥0.1% to <5%: Increased AST (GOT), increased ALT (GPT), increased γ-GTP, increased LDH. <0.1%: Increased bilirubin, increased Al-P. Incidence Unknown*: Jaundice.
Renal: ≥0.1% to <5%: Incresed BUN; <0.1%: Hematuria; Incidence Unknown*: Pollakiuria.
Cardiovascular: 5 to ≥0.1%: Facial flushes, hot flushes, feeling of hot flushes, palpitations, flushing. <0.1%: Decreased blood pressure, tachycardia.
Others: ≥0.1% to <5%: Malaise, increased triglycerides. <0.1%: Edema, pain, chest discomfort, chest pain, arthralgia, respiratory distress, tinnitus, pyrexia, hot feeling, sweaty, cold sweat, pain in jaw. Incidence Unknown*: Back pain, neck pain, alopecia, cough, myalgia, feeling of weakness.
The incidences of adverse reactions are based on the results of clinical studies completed by the time of approval and post-marketing studies.
*The incidence of adverse reactions on the basis of spontaneous reports is unknown.
**Medication should be discontinued if such abnormalities are observed.
Drug Interactions
Dorner should be administered with care when co-administered with the following drugs: Mechanism and Risk Factors: The effect of the drugs used in combination may be intensified.
Anticoagulants (eg, warfarin), antiplatelet agents (eg, aspirin, ticlopidine) and fibrinolytic agents (eg, urokinase) may enhance bleeding tendency. The condition of the patient should be carefully monitored. Appropriate treatment should be conducted, including reducing the dose or discontinuing one of either drugs, if such abnormalities are observed.
Prostaglandin I2 Preparations (eg, Epoprostenol), Endothelin-Receptor Antagonist (eg, Bosentan): May enhance decreasing effect in blood pressure. The blood pressure of the patients should be carefully be monitored.
Storage
Store at room temperature 25°C.
ATC Classification
B01AC19 - beraprost ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.
Presentation/Packing
Tab 20 mcg (6.2-mm diameter, 2.8-mm thick, weighs 83 mg) x 30's.
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