Herbesser/Herbesser 60/Herbesser R100

Herbesser/Herbesser 60/Herbesser R100

diltiazem

Manufacturer:

Mitsubishi Tanabe

Distributor:

Toyota Tsusho
Full Prescribing Info
Contents
Diltiazem HCl.
Description
See Tables 1 and 2.

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It occurs as white crystals or crystalline powder, and it is odorless.
It is very soluble in formic acid, freely soluble in water, in methanol and in chloroform, sparingly soluble in acetonitrile, slightly soluble in acetic anhydride and in ethanol (99.5), and practically insoluble in diethyl ether.
Optical rotation [α]20D: +115 - +120° (after drying, 0.20 g, water, 20 mL, 100 mm)
Melting point: 210 - 215°C (decomposition)
Nonproprietary name: Diltiazem hydrochloride (JAN).
Diltiazem (INN).
Chemical name: (2S,3S)-3-acetoxy-2,3-dihydro-2-(4-methoxyphenyl)-5-(2-dimethylaminoethyl)-1,5-benzothiazepin-4 (5H)-one monohydrochloride.
Molecular formula: C22H26N2O4S·HCl: 450.99.
Action
Pharmacology: The therapeutic benefits achieved with diltiazem hydrochloride, such as improvement of myocardial ischemia and hypotensive effect, are believed to be related to its ability to dilate vessels by inhibiting the influx of calcium ions into the smooth muscle cells of the coronary and peripheral blood vessels.
Action on myocardial ischemia: Improving action on the balance of myocardial oxygen demand and supply: Diltiazem hydrochloride increases coronary blood flow into the myocardial ischemic region by dilating the large coronary artery and the collateral channels (dogs).
Diltiazem hydrochloride inhibits coronary artery spasms (monkeys, humans).
Diltiazem hydrochloride decreases myocardial oxygen consumption without decreasing cardiac output by decreasing the afterload and heart rate though peripheral vasodilation (dogs).
Action on myocardial protection: Diltiazem hydrochloride maintains cardiac function and myocardial energy metabolism, and reduces the infarct size by inhibiting excess calcium ion influx into the cells under myocardial ischemia (rats).
Action on blood pressure: Diltiazem hydrochloride lowers an elevated blood pressure gradually, although it hardly affects the normal blood pressure (rats, humans), and it suppresses the elevation of blood pressure induced by exercise load (humans).
Diltiazem hydrochloride lowers blood pressure without decreasing the cerebral and renal blood flow (dogs, humans).
Diltiazem hydrochloride suppresses myocardial and vascular hypertrophy while lowering blood pressure (rats).
Action on sinus rhythm and cardiac conduction system: Diltiazem hydrochloride prolongs slightly spontaneous sinus rhythm intervals and the A-H conduction time, but it does not affect the H-V conduction time (dogs, humans).
Clinical Studies: Angina pectoris, variant angina pectoris: The usefulness of HERBESSER and HERBESSER 60 in the treatment of angina pectoris was demonstrated by double blind comparative clinical trials, single blind comparative clinical trials, and open labeled clinical trials. The usefulness of the drug in the treatment of variant angina pectoris was demonstrated by open labeled clinical trials, including investigation with the Holter electrocardiogram.
Hypertension: The usefulness of HERBESSER and HERBESSER 60 in the treatment of essential hypertension was demonstrated by four double blind comparative clinical trials with a placebo, reserpine, and propranolol as the control drugs.
Pharmacokinetics: Blood concentration: When 2 tablets of HERBESSER (60 mg of diltiazem hydrochloride) were orally administered to healthy adult men, its plasma concentration reached a maximum 3 to 5 hours after administration, and decreased thereafter with a half-life of about 4.5 hours. On daily oral administrations, the plasma concentration of diltiazem reached a steady state 2 days after the start of administration. During the long-term, repeated oral administration of 90 mg (30 mg x 3)/day of diltiazem hydrochloride to patients, its plasma concentration 2 to 4 hours after administration was about 40 ng/mL. See figure.

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Metabolism: In case of oral administration to healthy adult men, diltiazem hydrochloride was metabolized mainly by oxidative deamination, oxidative demethylation, deacetylation, and conjugation.
Indications/Uses
Angina pectoris, variant angina pectoris. Essential hypertension (mild to moderate).
Dosage/Direction for Use
Herbesser/Herbesser 60: Angina pectoris, variant angina pectoris: The usual adult dosage for oral use is 30 mg of diltiazem hydrochloride three times a day (90 mg/day). The dosage may be increased to 60 mg three times a day (180 mg/day), if necessary.
Essential hypertension (mild to moderate): The usual adult dosage for oral use is 30 to 60 mg of diltiazem hydrochloride three times a day (90 - 180 mg/day). The dosage may be adjusted depending on the patient's age and symptoms.
Herbesser R100: Angina pectoris, variant angina pectoris: Usually, for adults, 100 mg to 200 mg of Diltiazem hydrochloride is orally administered once daily.
Essential Hypertension (mild to moderate): The dosage may be adjusted according to the patient's age and symptoms.
Overdosage
Symptoms: Overdosage may cause bradycardia, complete atrioventricular block, heart failure, hypotension, etc. These symptoms are also reported as adverse reactions.
Treatments: In the event of overdosage, the administration of HERBESSER and HERBESSER 60 should be discontinued and the following appropriate measures taken, while removing the drug by gastric lavage, etc. if necessary.
Bradycardia, complete atrioventricular block: Administer atropine sulfate, isoproterenol, etc., and/or apply cardiac pacing.
Heart failure, hypotension: Administer intravenous fluids, an inotropic agent, a pressor agent, etc., and/or institute assisted circulation.
Contraindications
HERBESSER, HERBESSER 60 and HERBESSER R100 are contraindicated in the following patients: Patients with severe congestive heart failure. [The symptoms of heart failure may be exacerbated.]; Patients with 2nd- or 3rd-degree atrioventricular block or sick sinus syndrome (continuous sinus bradycardia (less than 50 beats/minute), sinus arrest, sinoatrial block, etc.) [Excessive inhibition of sinus rhythm and cardiac conduction may occur.]; Patients with a history of hypersensitivity to any of the ingredients in the drug; Pregnant women or women who may possibly be pregnant, etc. [See Use during Pregnancy, Delivery or Lactation under Precautions.]
Special Precautions
Careful Administration (HERBESSER, HERBESSER 60 and HERBESSER R100 should be administered with care in the following patients.): Patients with congestive heart failure. [The symptoms of heart failure may be exacerbated.]
Patients with severe bradycardia (less than 50 beats/minute) or 1st-degree atrioventricular block. [Excessive inhibition of sinus rhythm and cardiac conduction may occur.]
Patients with severe hypotension. [The blood pressure may be further reduced.]
Patients with severe hepatic and renal dysfunction. [The action of the drug may be enhanced due to its delayed metabolism and excretion.]
Important Precautions: It has been reported that abrupt withdrawal of calcium antagonists may result in aggravation of symptoms. If HERBESSER, HERBESSER 60 and HERBESSER R100 are withdrawn, the dosage should be gradually reduced and the patient should be carefully monitored. The patient should be instructed not to discontinue taking the drug without consulting a physician.
Since dizziness, etc. due to hypotensive effect may occur, patients should be cautioned against engaging in potentially hazardous activities requiring alertness, such as driving a car, working at heights, or operating machinery, etc.
It has been reported that concomitant use of other antiarrhythmic agent (disopyramide phosphate with terfenadine may result in QT interval prolongation and ventricular arrhythmia.
Pediatric Use: The safety of HERBESSER and HERBESSER 60 in children has not been established.
Use in the Elderly: An excessive reduction in blood pressure is undesirable in elderly patients. Therapy should therefore be instituted with special care, starting at a reduced dosage with careful monitoring of the patient's condition.
Use In Pregnancy & Lactation
HERBESSER and HERBESSER 60 are contraindicated in pregnant women or women who may possibly be pregnant. [Animal studies have shown that the drug has teratogenic effects (mice: skeletal abnormalities, dysplasias) and embryotoxicity (mice, rats: death)
It is advisable to avoid using the drug in lactating mothers. If use of the drugs is judged to be essential, breast feeding should be discontinued during treatment. [It has been reported that diltiazem hydrochloride is excreted in breast milk.]
Adverse Reactions
Adverse reactions to HERBESSER and HERBESSER 60 were reported in 442 (4.6%) of 9,630 patients treated. The most frequent adverse reactions were observed in gastrointestinal system 1.4% (stomach discomfort 0.2%, constipation 0.2%, abdominal pain 0.1%, etc.), and in cardiovascular system 1.4% (dizziness 0.5%, bradycardia 0.4%, facial hot flushes 0.2%, atrioventricular block 0.2%, etc.), hypersensitivity 1.2%, headache 0.2%, etc. (Data collected from the time of approval up to December 1990).
Adverse reactions to Herbesser R100 were reported in 74 (2.1%) of 3,557 patients. The major adverse reactions were cardiovascular symptoms in 0.7% (bradycardia in 0.2%, atrioventricular block in 0.1%, facial flushing in 0.1%, etc.), gastrointestinal symptoms in 0.6% (constipation in 0.2%, nausea in 0.2%, stomach discomfort in 0.1%, etc.), headache and headache dull in 0.4%, hypersensitivity in 0.3%, etc. (at time of completion of reexamination).
Clinically significant adverse reactions (rarely: <0.1%, unknown: the incidence of adverse reactions on the basis of spontaneous reports is unknown.): Complete atrioventricular block, severe bradycardia (initial symptoms: bradycardia, dizziness, light-headed, etc.), etc., may occur rarely (<0.1 %). If any abnormalities are observed, the drug should be discontinued and appropriate measures, such as administration of atropine sulfate, isoproterenol, etc., and/or application of cardiac pacing, etc. if necessary, taken.
Congestive heart failure* may occur. If any abnormalities are observed, the drug should be discontinued and appropriate measures, such as administration of cardiac stimulants, taken.
Mucocutaneous-ocular syndrome (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome), erythroderma (exfoliative dermatitis)*, etc. may occur. If erythema, blisters, pruritus, fever, enanthema, etc. are observed, the drug should be discontinued and appropriate measures taken.
Other adverse reactions: If any adverse reactions are observed, appropriate measures, such as discontinuing administration, should be taken. (See Table 3.)

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Drug Interactions
This product is metabolized mainly by cytochrome P450 3A4 (CYP3A4) metabolizing enzyme.
Precautions for coadministration (HERBESSER, HERBESSER 60 and HERBESSER R should be administered with care when coadministered with the following drugs.) (See Tables 4 and 5.)

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Caution For Usage
Precautions Regarding Dispensing: When HERBESSER and HERBESSER 60 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 PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, resulting in severe complications such as mediastinitis.]
Precautions During Administration:
Patients should be instructed not to chew the tablets (Sustained release property may be reduced).
Use only pursuant to the prescription or directions of a physician, etc.
Storage
Store below 30°C. Avoid humidity after opening.
MIMS Class
ATC Classification
C08DB01 - diltiazem ; Belongs to the class of benzothiazepine derivative selective calcium-channel blockers with direct cardiac effects. Used in the treatment of cardiovascular diseases.
Presentation/Packing
Herbesser: Tab 30 mg (plain, white, imprinted with "TA 120" on one side) x 10 x 10's.
Herbesser 60: Tab 60 mg (plain, white, imprinted with "TA 125" on one side and "60" on the other side) x 10 x 10's.
Herbesser R100: Cap 100 mg (plain, white/white) x 10 x 10's.
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