Dorner

Oral preparation of prostacyclin (PGI2) derivative 
Dorner^® Tablet 20µg
‹ Beraprost Sodium ›
PowerfuI drug, Designated drug, and Prescription-only drug

DESCRIPTION

Brandname	Dorner® Tablets 20 µg
(Content per tablet)	Beraprost Sodium 20 µg
Diameter	6.2 mm
Thickness	2.8 mm
Weight	83 mg

INDICATIONS

1. Improvement of ulcer, pain and feeling of coldness associated with chronic arterial occlusion.
2. Primary pulmonary hypertension

CONTRAINDICATIONS (DORNER is contraindicated in the following patients)

1. Patients with hemorrhage (e.g., hemophilia, capillary fragility, upper gastrointestinal hemorrhage, urinary tract hemorrhage, hemoptysis, and bleeding of ocular fundus). [This product may aggravate hemorrhage]
2. Pregnant women or women who may possibly be pregnant. [See"Use during Pregnancy, Delivery or Lactation"].

PRECAUTION
Primary pulmonary hypertension

1. Use only in the patients who were diagnosed with primary pulmonary hypertension.
2. This product may not be effective in some patients with severe symptoms and others because its administration route is oral. If hemodynamic parameters and/or symptoms are not improved sufficiently, an appropriate treatment should be considered including changing to injectable preparation or another treatment.

DOSAGE AND ADMINISTRATION

1. Improvement of ulcer, pain and feeling of coldness associated with chronic arterial occlusion. The usual dosage for adults is 120 µg of beraprost sodium daily, administered orally in 3 divided doses after meals.
2. Primary pulmonary hypertension; The usual dosage for adults should be started at 60 µg of beraprost sodium daily, administered orally in 3 divided doses after meals, and gradually increased under careful monitoring. When the dosage is increased,its maximum is 180 µg daily, 3 to 4 divided doses.

PRECAUTION
Primary pulmonary hypertension
Medication should be started from lower dosage. When the dosage is increased, the patient should carefully be monitored, because it has been reported that tolerance to the drug varies among patients with primary pulmonary hypertension.

1.	Careful Administration (DORNER should be administered with care in the following patients.) Patients on medication with anticoagulants, antiplatelet or fibrinolytic agents.[See "Drug interactions.] Patients in menstruation. [This product may enhance bleeding tendency. J Patients with bleeding tendency or diathesis thereof. [This product may enhance bleeding tendency.]
2.	Drug Interactions Precautions for coadministration (DORNER should be administered with care when coadministerd with the following drugs) Drugs Signs, Symptoms, and Treatment Mechanism and Risk Factors Anticoagulants e.g. warfarin Antiplatelet agents e.g. Aspirin, ticlopidine Fibrinolytic agents e.g. urokinase This product may enhance bleeding tendency. The condition of the patient should carefully be monitored. Appropriate treatment should be conducted, including reducing the dose or discontinuing one of either drugs, if such abnormalities are observed. The effect of the drug used in combination may be intensified. Prostaglandin I2 Preparations This product may enhance decreasing effect in blood pressure. The blood pressure of the patients should carefully be monitored. The effect of the drugs used in combination may be intensified.
3.	Adverse Reactions 1. Improvement of ulcer, pain and feeling of coldness associated with chronic arterial occlusion. Adverse reactions to this drug, including abnormalities in laboratory data, were reported in 370 of 7,515 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 the end of Japanese reexamination period) 2. Primary pulmonary hypertension Adverse reactions to this drug, including abnormalities in laboratory data, were reported in clinical studies on the pulmonary hypertension, in 24 patients (65 events) of 40 patients treated (60.0%). The major adverse reactions were headache in 9 patients (22.5%), increased LDH in 5 patients (12.5%), increased bilirubin in 4 patients (10.0%), hot flushes in 3 patients (7.5%), diarrhea in 3 patients (7.5%), nausea in 3 patients (7.5%), increased triglyceride in 3 patients (7.5%), etc. (As of time at Japanese approval) (1) Clinically significant adverse reactions 1) Bleeding tendency [cerebral hemorrhage (‹ 0.1%), hemorrhage of digestive tract (‹ 0.1 %), pulmonary hemorrhage (Incidence unknown) Note l), bleeding of ocular fundus (‹0.1%)]. The patient should carefully be monitored. Medication should be discontinued and appropriate treatments should be conducted, if such abnormalities are observed. 2) Shock  (‹ 0.1%) A shock may occur. The condition of the patients should carefully be monitored. Medication should be discontinued and appropriate treatments should be conducted, if symptoms, such as decreased blood pressure, tachycardia, facial pallor, or nausea are observed 3) Interstitial Pneumonia (Incidence unknown) Note 1) 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. 4) Hepatic function disorders (Incidence unknown) Note l) Hepatic function disorders 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. 5) Angina Pectoris (Incidence unknown) Note l) Angina pectoris may occur. Medication should be discontinued and appropriate treatments should be conducted., if such symptoms are observed. 6) Myocardial Infarction (Incidence unknown) Note l) It has been reported that myocardial infarction might occur. Medication should be discontinued and appropriate treatments should be conducted, if such symptoms are observed. (2) Other adverse reactions The following adverse reactions may occur. Appropriate treatments including discontinuation of medication, should be conducted, if such abnormalities are observed 5% › ≥ 0.1 % ‹ 0.1% Incidence Unknown Note 1) Bleeding tendency Note 2)  Bleeding tendency, subcutaneous hemorrhage  Epistaxis Blood Note 2) Anemia, eosinophilia Thrombocytopenia, leucopenia Hypersensitivity Note 2) Rash Eczema, pruritus Erythema Psycho-neurologic  Headache, dizziness  Light-headed feeling, Dizziness on standing up, sleepiness, twilight state, numbness Gastrointestinal  Nausea, diarrhea, abdominal pain, anorexia  Gastric ulcer, vomiting, gastric disorder, thirst, heartburn Hepatic  Increased AST(GOT), Increased ALT (GPT), increased γ - GTP, increased LDH Increased bilirubin, increased A1-P Jaundice Renal  Increased BUN  Hematuria Pollakiuria Cardiovascular Facial hot flushes, hot flushes, feeling of hot flushes, heart pounding, flushing Decreased blood pressure, tachycardia Others Increased triglyceride Oedema, pain, chest pain, arthalgia, respiratory distress, tinnitus, malaise, fever, feeling of warmth, diaphoresis, cold sweat Back pain, alopecia, coughing Note 1) The Incidence of adverse reactions only based on spontaneous reports is unknown Note 2) Medication should be discontinued if such abnormalities are observed
4.	Use in the Elderly Since physiological functions often lowered in the elderly, caution should be taken for dose.
5.	Use during Pregnancy, Delivery, or Lactation Safety of this product in pregnant women has not been established. Therefore this product should be used in pregnant women or women who may possibly be pregnant only when expected therapeutic benefits outweigh the risk of the treatment. Administration of this product to nursing mothers should be avoided. If use of this product is unavoidable, the nursing mother should discontinue breast-feeding. Beraprost sodium has been reported to be migrated to milk in animal experiments (rats).
6.	Pediatric use Safety in children has not be en established. [no clinical experience]
7.	Precautions concerning use Caution in delivery: In the case of press-through packages, instruct the patients to remove the drug from the package prior to use. [If the PTP sheet unintentionally swallowed, its sharp corners may penetrate the esophageal mucosa, leading to severe complications such as mediastinitis.]
8.	Other precautions In the treatment of chronic arterial occlusion, higher incidence of adverse reactions has been reported with a daily dosage of beraprost sodium 180 μg.

PHARMACOKINETICS
(1) Plasma concentration
T_max, C_max and T_1/2 after single oral administration of beraprost sodium 100 μg ^Note3) to eight healthy adults are shown below;

Pharmacokinetics parameter

Tmax (h)	Cmax (ng/mL)	T1/2 (h)
1.42 hours	0.44 ng/mL	1.11 hours

Maximum plasma concentrations were 0.3-0.5 ng/mL after three time-a-day, 10-day consecutive oral administration of beraprost sodium 50 μg ^{Note 3)}. Therefore, no accumulability due to repeated administration was noted.

(2) Metabolism excretion
Urinary excretion of the unchanged form by 24 hours after single oral administration of beraprost sodium 50 μg ^{Note 3)} to twelve healthy adults was 2.8 μg, while that of the β-oxidation product was 5.4 μg. 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.
^Note3) It is different from approved dosage and administration of beraprost sodium. [See "DOSAGE AND ADMINISTRATION"]


CLINICAL STUDIES

1. 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, e.g. 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.
2. Primary pulmonary hypertension; In 21 patients of multi centre open clinical trials in pulmonary hypertension, the improvement rate for total symptoms including haemodynamic indications, such as 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.

PHARMACOLOGY 
(pharmacological action) 

1. Antiplatelet effects
   1. Oral administration of beraprost sodium to patients with peripheral circulatory disorders and healthy adult subjects inhibits platelet aggregating and adhering ability,
   2. Beraprost sodium has dissociating action on human platelets aggregates formed by platelet-stimulating agents (in vitro).
2. Blood-flow-increasing-effects
   1. Beraprost sodium has been found to increase the skin blood flow when orally administration to healthy adults.
   2. Beraprost sodium 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.
   3. Beraprost sodium has inhibited K⁺ or PGF2α-induced contraction of various isolated arteries of dogs e.g., 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.
3. 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)
4. Effects on animal models of disease
   1. Chronic arterial occlusion model; Beraprost sodium inhibited the progression of ischemic lesions or thrombus formation in the following animal models of disease: lauric acid-induced circulatory disorder of the hind paw in rats, ergotamine- and ephinephrine-induced circulatory disorder of the tail in rats, and electric stimulus-induced arterial thrombus formation in rabbits.
   2. Thrombosis model; Beraprost sodium inhibited thrombus formation in thrombosis models, e.g., arterial thrombosis and venous thrombosis models in rats.
   3. Skin ulcer model; Beraprost sodium facilitated the healing of acetic acid-induced skin ulcer in rats.
   4. Pulmonary hypertension model; Orally administered beraprost sodium inhibited the increasing in right ventricular systolic pressure and the medial muscular hypertrophy in pulmonary artery on the model of monocrotaline induced pulmonary hypertension in rats. Intravenously administered beraprost sodium inhibited the increased pulmonary arterial pressure and pulmonary vascular resistance on the model of thromboxane agonist induced pulmonary hypertension induced by in dogs. Intravenously administered beraprost sodium inhibited the increased right ventricular systolic pressure on the model of thromboembolism induced pulmonary hypertension in rats.

‹ Mechanism of Action ›
Similar to prostacyclin, beraprost sodium shows actions such as antiplatelet and vasodilating action by binding to PGI₂ receptors of platelets and vascular smooth muscle cells, which induces the activation of adenylate cyc1ase, increasing intracellular concentration of cAMP, inhibiting of Ca²⁺ influx and of thromboxane A₂ synthesis or other modes.

PHYSICOCHEMISTRY
Description:
Beraprost sodium is a white, hygroscopic, and odorless powder. It is very soluble in methanol, freely soluble in water and dehydrated ethanol, soluble in isopropanol and dioxane, and practically insoluble in ether. Aqueous solution of beraprost sodium (1 → 200) has no specific rotation.

Melting point: 205-208°C

Partition coefficient: (water-n-octanol system)
460 (pH3), 15 (pH7), 0.41 (PH9)

Packaging
DORNER TABLETS 20 μg:
Box of 3 x 10 Tablets
Store at 25°C

"Harus dengan resep dokter"

No.Reg. : DKL10041315I0A1

Manufactured by:
Toray Industries. Inc. Tokyo, Japan

Imported by :
PT. Combiphar, Padalarang, Indonesia

Repacked by:
PT. Combiphar, Padalarang, Indonesia

Share this :