Nrr_c_epi_1311_10_02.pdf

Standard Commodity Classification No. of Japan - Long-acting isosorbide dinitrate preparation - Nitorol “ R Capsules 20mg
<Isosorbide dinitrate preparation> NITOROL R should be stored at room temperature. Date of listing in the NHI reimbursement price NITOROL R should be protected from moisture after opening the aluminum bag of the press through package, or the cap of the bottle Expiration date
NITOROL R should be used before the expiration date indicated on Caution : Use only as directed by a physician. CONTRAINDICATIONS (NITOROL R is contraindi-
INDICATIONS
cated in the following patients.)
Angina pectoris, myocardial infarction (excluding acute phase) 1. Patients with serious hypotension or cardiogenic shock [NITOROL R may lower blood pressure and aggravate <Precautions>
symptoms due to its vasodilator action.] NITOROL R is not a suitable drug for therapy aimed at reliev- ing anginal attacks. For the purpose of relief of attacks, rapid- [NITOROL R may increase intraocular pressure.] acting nitrate or nitrite ester preparations should be used. 3. Patients with a head injury or cerebral hemorrhage [NITOROL R may increase intracranial pressure.] DOSAGE AND ADMINISTRATION
The usual adult dosage for oral use is one capsule (20 mg of [Anemic symptoms (e.g. dizziness, dizziness on standing up) may be aggravated by a decrease in blood pressure.] The dose should be adjusted depending on the patient's age and 5. Patients with a history of hypersensitivity to nitrate or 6. Patients taking phosphodiesterase type 5 inhibitors (sil- PRECAUTIONS
denafil citrate, vardenafil hydrochloride hydrate or ta- 1. Careful Administration (NITOROL R should be admini-
stered with care in the following patients.)
[Combination therapy potentiates the hypotensive action and may induce an excessive decrease in blood pressure. [NITOROL R may lower blood pressure due to its (2) Patients with primary pulmonary hypertension
DESCRIPTION
[NITOROL R may decrease cardiac output and cause shock.] 1. Composition
(3) Patients with hypertrophic obstructive cardiomyopathy Each white, hard capsule contains 20 mg of isosorbide di- [NITOROL R may increase the ventricular internal pressure gradient and aggravate symptoms.] It also contains ethylcellulose, purified shellac, gelatin, (4) Patients with hepatic function disorder talc, corn starch, lactose hydrate, white soft sugar, and so- [Since high blood concentrations may continue, such dium lauryl sulfate as inactive ingredients. measures as reduction in dosage should be taken.] (5) The elderly [see “Use in the Elderly” section.] 2. Product description
2. Important Precautions
(1) Patients taking NITOROL R should be carefully ob- served for symptoms and course of disease. NITOROL R should be switched to other treatment when there is a lack of a satisfactory clinical response as indicated by (2) If an excessive decrease in blood pressure occurs, Precautions for coadministration (NITOROL R
treatment with NITOROL R should be discontinued, should be administered with care when coadminis-
and appropriate measures, such as raising the lower
tered with the following drugs.)
extremities or administration of a vasopressor, taken.
Signs, Symptoms, and
Mechanism and
(3) It has been reported that sudden withdrawal of nitrate Treatment
Risk Factors
or nitrite ester preparations resulted in the aggravation of symptoms. When NITOROL R is to be withdrawn, it
should be tapered off while being concomitantly
administered with an alternative drug. The patient
should be warned against discontinuing NITOROL R without the instruction of their attending physician. (4) Since orthostatic hypotension may occur, patients
should be made aware of this during treatment. (5) Like other nitrate and nitrite ester preparations, NI- TOROL R may cause adverse reactions such as head- ache due to its vasodilator action on the initiation of treatment. In the event of such symptoms, appropriate measures, such as administration of analgesics or re- duction in dosage or discontinuation of the medication, should be taken. These adverse reactions may cause a decrease in attention, concentration, reflex movement or other functions. In the event of any such changes, patients should be cautioned against engaging in poten- tially hazardous activities requiring alterness, such as 4. Adverse Reactions
Adverse reactions were reported in 463 of 10,098 patients (6) Since combination therapy with NITOROL and phos- (4.59%). (At the end of the reexamination period) phodiesterase type 5 inhibitors (sildenafil citrate, 5% > t0.1%
<0.1% Incidence
vardenafil hydrochloride hydrate or tadalafil) potenti- ates the hypotensive action and may induce an exces- sive decrease in blood pressure, it should be confirmed that such drugs have not been administered before treatment with NITOROL. During and after treatment with NITOROL, patients should be cautioned not to 3. Drug Interactions
(1) Contraindications for coadministration (NITOROL
R should not be coadministered with the following
Drugs Signs,
Symptoms,
Mechanism and Risk
Note) In the event of such symptoms, treatment should be and Treatment
5. Use in the Elderly
NITOROL R is metabolized primarily in the liver. Since the elderly generally have a lowered liver function, they should be carefully observed to avoid the risk of a high blood concentration continuing. It is advisable that NI- TOROL R is taken under careful supervision.
6. Use during Pregnancy, Delivery or Lactation
(1) NITOROL R should only be used for pregnant women or women suspected of being pregnant, if the expected therapeutic benefits are evaluated to outweigh the pos-sible risk of treatment. [The safety of NITOROL R during pregnancy has not been established.] (2) It is advisable to avoid administration to nursing moth- ers. When NITOROL R must be used, breast feeding should be discontinued during treatment. [It has been reported in an animal study (rats) that NI-
7. Pediatric Use
The safety in children has not been established (insufficient clinical experience).
8. Precautions concerning Use
Changes in plasma isosorbide dinitrate concentrations after oral
administration of a NITOROL R Capsules 20 mg and a
conventional Isosorbide dinitrate Tablets 5 mg
The patient should be instructed not to bite or chew the capsules, but to swallow them. If the capsule is Pharmacokinetic parameters after single administration of
crushed, the drug concentration in the blood may in- NITOROL R Capsules 20 mg
crease temporarily which is likely to cause a headache. For drugs that are dispensed in a press-through package (PTP), instruct the patient to remove the drug from the package prior to use. [It has been reported that, if the 2. Relationship between plasma concentration and clinical
PTP sheet is swallowed, the sharp corners of the sheet efficacy
may puncture the esophageal mucosa, causing perfora- The plasma concentrations reached 1.9 ng/mL at 1 hr after tion and resulting in serious complications such as me- oral administration of one NITOROL R capsule (20 mg of isosorbide dinitrate) to 5 patients with angina pectoris or myocardial infarction. Coronary arteriography conducted at 9. Other Precautions
this time point showed a mean expansion of the coronary (1) If NITOROL R is used continuously, tolerance to it and diameter by about 19%. The mean plasma concentration cross tolerance to other nitrate and nitrite ester prepara- remained at 2.36 ng/mL between 1 to 8 hr after administra- tions may be developed, with the result that their effi- tion. It was still at 2.0 ng/mL even 8 hr after administration. Pulmonary end-diastolic blood pressure decreased signifi- In controlled clinical trials conducted on effort angina cantly at 6 and 8 hr after administration (p<0.05). 1) outside of Japan, using transdermal preparations of an analog compound (nitroglycerin), it has been reported CLINICAL STUDIES
that an intermittent-dosing regimen could suppress tol- Clinical efficacy
(1) In double blind and open labeled clinical trials, NITOROL Methemoglobinemia has been reported in patients R was effective in 63.1% (321/509) of patients with ischemic heart diseases (effort angina, effort and rest an- gina, rest angina, myocardial infarction, etc.) treated with PHARMACOKINETICS
1. Blood concentrations
(2) In double blind and open labeled clinical trials conducted The stable plasma concentrations (about 2.0 ng/mL) were in patients with angina pectoris, the number of the attacks maintained over 1 to 6 hr after oral administration of one decreased significantly by about 1/2 in 2 weeks after ad- NITOROL R capsule (20 mg of isosorbide dinitrate) to 18 healthy adult male volunteers. Plasma concentrations of The requirement for symptomatic doses of nitrite also de- about 0.4 ng/mL were maintained at 12 hr after administra- creased significantly by about 1/3 to 1/2. 2, 3, 6, 7) tion. When a conventional Isosorbide dinitrate Tablets (5 mg) was administered orally, the peak plasma concentra- PHARMACOLOGY
tions (5.8 ng/mL) was reached 25.6 min after administra- 1. Reduction of cardiac preload and afterload
tion and decreased to 0.07 ng/mL at 6 hr after administra- In anesthetized dogs, isosorbide dinitrate decreases venous return, pulmonary wedge pressure and left ventricular NITOROL R was thus found to maintain plasma concen- end-diastolic blood pressure (reduction of preload) based trations of 0.4 ng/mL and over for about 4 times as long as on dilating venous capacitance vessels. It also decreases the conventional Isosorbide dinitrate Tablets. total peripheral vascular resistance (reduction of afterload) by dilating peripheral arteries. All these effects contribute to a decrease in myocardial oxygen demands. 8, 9) 2. Vasodilation of coronary arteries
REQUESTS FOR LITERATURE AND PRODUCT
In anesthetized dogs isosorbide dinitrate decreases coronary INFORMATION SHOULD BE MADE TO:
vascular resistance by dilating relatively thick coronary ar- teries (conductive vessels) and also dilates collateral vessels. Although the increase in coronary blood flow is slight, this contributes to the re-distribution of blood flow to ischemic myocardial areas, in particular in the lower layer of the in- Manufactured and marketed by:
tima, results in increases in myocardial oxygen supply. 10) 6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo, 112-8088 3. Production of cyclic GMP (cGMP)
When isosorbide dinitrate is added to isolated calf coronary artery previously contracted using potassium chloride, production of cGMP increases in proportion to the degree of relaxation of the coronary artery. 11) PHYSICOCHEMISTRY
Nonproprietary name: Isosorbide Dinitrate (JAN, INN)
Chemical name: 1,4:3,6-Dianhydro-D-glucitol dinitrate
Molecular formula: C6H8N2O8
Molecular weight: 236.14
Structural formula:
Description:
Isosorbide dinitrate occurs as white crystals or crystalline powder. It is odorless or has a faint odor like that of nitric acid. It is very soluble in N, N-dimethylformamide and in ace-tone, freely soluble in chloroform and in toluene, soluble in methanol, in ethanol (95) and in diethyl ether, and practi-cally insoluble in water. It explodes if heated quickly or subjected to percussion.
PACKAGING
NITOROL R Capsules 20 mg:
Boxes of 100, 140 (14 Caps. u 10), 700 (14 Caps. u 50) and 1,000 in press-through-packages, and bottles of 500
REFERENCES
1) Inoue K. et al.: J. Med. Pharm. Sci., 9, 247, 1983.
2) Maeda T. et al.: Jap. J. Clin. Exp. Med., 59, 255, 1982.
3) Abe H. et al.: ibid., 59, 1622, 1982.
4) Kashiwagi M. et al.: J. New Remed. Clin., 29, 1687,
5) Osamura Y. et al.: Med. Consult. New Remed., 17,
6) Nakano T. et al.: J. New Remed. Clin., 34, 1441, 1985.
7) Furukawa I. et al.: Jap. J. Clin. Exp. Med., 63, 2047,
8) Hirakawa S. et al.: Saishin Igaku, 29, 170, 1974.
9) Wendt R.L.: J. Pharmacol. Exp. Ther., 180, 732, 1972.
10) Takayama Y. et al.: J. Jpn. Coll. Angiol., 21, 351, 1981.
11) Matlib M. A. et al.: Am. Heart J., 110, 204, 1985.

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