Herbesser R 100/Herbesser R 200

Diltiazem HCl.

Herbesser R 100: Tablet Size: Length 14.2 mm, thickness 5.4 mm, weight 0.17 g. Identification Code: TA303.
Herbesser R 200: Tablet Size: Length 17.7 mm, thickness 6.4 mm, weight 0.32 g. Identification Code: TA304.
Herbesser R200 also contains FD&C Red No.3 (erythrosine) as inactive ingredient.
Diltiazem HCl is (2S,3S)-3-acetoxy-2,3-dihydro-2-(4-methoxyphenyl)-5-(2-dimethyl)-1, 5-benzothiazepine-4(5H)-one monohydrochloride. Molecular Formula: C₂₂H₂₆N₂O₄S·HCl. Molecular Weight: 450.99. 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: +115 to +120° (after drying, 0.2 g, water, 20 mL, 100 mm). Melting Point: 210-215°C (decomposition).

Calcium antagonist.
Pharmacology: The therapeutic benefits achieved with diltiazem HCl eg, improvement of myocardial ischemia and hypotensive effect are believed to be related to its ability to dilate vessels by inhibiting the influx of calcium ion into smooth muscle cells of the coronary and peripheral blood vessels, etc.
Action on Myocardial Ischemia:
Improving action on the balance of myocardial oxygen demand and supply:
To increase coronary blood flow into the myocardial ischemic region by dilating the collateral channels and the large coronary artery (dogs).
To inhibit coronary artery spasms (monkeys, humans).
To decrease myocardial oxygen consumption without decreasing afterload and heart rate due to peripheral vasodilator (dogs).
Action on Myocardial Protection: To retain cardiac function and myocardial energy metabolism and reduce the infarct size by inhibiting excess calcium ion influx into cells under myocardial ischemia (rats).
Action on Blood Pressure:
To lower elevated blood pressure gradually although it hardly affects normal blood pressure (rats, humans). To suppress the elevation of blood pressure induced by exercise load (humans).
To lower blood pressure without decreasing cerebral and renal blood flow (dogs, humans).
To suppress myocardial and vascular hypertrophy while lowering blood pressure (rats).
Action on Sinus Rhythm and Cardiac Conduction System: To prolong slightly spontaneous sinus rhythm intervals and A-H conduction time. Not to affect the H-V conduction time (dogs, humans).
Pharmacokinetics: Blood Concentration: When 1 capsule of Herbesser R 100 was administered to healthy adult men at a single oral dosage, its plasma concentration reached the peak about 14 hrs after the administration. The half-life was about 7 hrs.
Metabolism: In case of oral administration to healthy adult men, diltiazem HCl was mainly metabolised by oxidative deamination, oxidative demethylation, deacetylation and conjugation.
Clinical Studies: Clinical Efficacy: The usefulness of Herbesser R 100/R 200 in the treatment of essential hypertension, angina pectoris and variant angina pectoris was demonstrated by clinical studies including double-blind comparative clinical trials using Herbesser R 100/R 200 as a control. See Table 1.

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Essential hypertension (mild to moderate).
Angina pectoris, variant angina pectoris.

Essential Hypertension (mild to moderate): Usual Adult Dosage: 100-200 mg once a day. The dosage may be adjusted depending on the patient's age and symptoms.
Angina Pectoris, Variant Angina Pectoris: Usual Adult Dosage: 100 mg once a day. In case of insufficient efficacy, the dosage may be increased to 200 mg once a day.
Patients should be instructed not to open or chew the capsules.

Symptoms:Overdosage may cause bradycardia, complete atrioventricular block, heart failure, hypotension, etc. The symptoms are also reported as adverse reactions.
Treatment: In overdosage, the administration of Herbesser R 100/R 200 should be discontinued and the following appropriate measures taken while removing the drug by gastrolavage etc, if necessary.
Bradycardia, Complete Atrioventricular Block: Administer atropine sulfate, isoproterenol, etc or insert an artificial cardiac pacemaker.
Heart Failure, Hypotension: Administer IV fluids, a cardiac stimulant, pressor agent, etc or institute assisted circulation.

Patients with a history of hypersensitivity to any of the ingredients of Herbesser R 100/R 200.
Patients with severe congestive heart failure. (The symptoms may be exacerbated.)
Patients with 2nd- or 3rd-degree atrioventricular block or sick sinus syndrome [continuous sinus bradycardia (<50 beats/min), sinus arrest, sinoatrial block, etc]. (The inhibitory action on sinus rhythm and cardiac conduction of the drug may occur excessively.)
Use in pregnancy: Herbesser R 100/R 200 is contraindicated to pregnant women and women who may possibly be pregnant. [Animal studies have shown that the drug has teratogenic effects (mice: Abnormality of skeleton, dysplasia) and embryotoxicity (mice, rats: Lethality)].

Herbesser R 100/R 200 should be administered with care in the following patients:
Patients with congestive heart failure. (The symptoms may be exacerbated.)
Patients with severe bradycardia (<50 beats/min) or with 1st degree atrioventricular block. (The inhibitory action on sinus rhythm and cardiac conduction of the drug may occur excessively.)
Patients with severe hypotension. (The blood pressure may be reduced further.)
Patients with severe hepatic and renal dysfunction. (The action of Herbesser R 100/R 200 may be enhanced due to the delayed metabolism and excretion.)
It has been reported that abrupt withdrawal of Herbesser R 100/R 200 may result in aggravation of symptoms in patients receiving treatment with calcium antagonists. If the drug is withdrawn, the dosage should be gradually reduced and the patients should be closely monitored. The patients should be instructed not to discontinue taking the drug without consulting a physician.
It has been reported that concomitant use of other antiarrhythmic agents (disopyramide phosphate) with terfenadine may result in QT interval prolongation and ventricular arrhythmia including torsades de pointes.
Effects on the Ability to Drive or Operate Machinery: Since dizziness, etc due to hypotensive effect may occur, the patients should be cautioned against engaging in potentially hazardous activities requiring alertness eg, driving a car, working at heights or operating machinery, etc.
Use in lactation: It is advisable to avoid using Herbesser R 100/R 200 in lactating mothers. If use of the drug is judged to be essential, breastfeeding must be discontinued during treatment. (It has been reported that Herbesser R 100/R 200 is excreted in breast milk.)
Use in children: The safety of Herbesser R 100/R 200 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.

Adverse reactions to Herbesser R100/R200 were reported in 74 (2.1%) of 3577 patients treated. The most frequently observed adverse reactions were cardiovascular system 0.7% (bradycardia 0.2%, atrioventricular block 0.1%, facial hot flushes 0.1%, etc), gastrointestinal system 0.6% (constipation 0.2%, vomiting 0.2%, stomach discomfort 0.1%, etc), headache/dull headache 0.4%, hypersensitivity 0.3%, etc (at the end of the re-examination period).
Clinically Significant Adverse Reactions: (Rarely: <0.1%; Unknown: Incidence of adverse reactions on the basis of spontaneous reports is unknown).
Since complete atrioventricular block, advanced bradycardia (initial symptoms are bradycardia, dizziness, lightheadedness, etc) may occur rarely. If any abnormalities are observed, Herbesser R 100/R 200 should be discontinued and appropriate measures eg, administration of atropine sulfate, isoproterenol, etc or application of cardiac pacing, etc, if necessary, can be taken.
Congestive heart failure may occur. If any abnormalities are observed, Herbesser R 100/R 200 should be discontinued and appropriate measures eg, administration of cardiac stimulants be 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, Herbesser R 100/R 200 should be discontinued and appropriate measures taken.
Other Adverse Reactions: If any adverse reactions are observed, appropriate measures eg, discontinuing administration, should be taken. See Table 2.

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Herbesser R 100/R 200 should be administered with care when co-administered with the following drugs: See Tables 3a and 3b.

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Since Herbesser R 100/R 200 is 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 eg, mediastinitis.)

Store at room temperature. Avoid humidity after opening.

Calcium Antagonists / Anti-Anginal Drugs

C08DB01 - diltiazem ; Belongs to the class of benzothiazepine derivative selective calcium-channel blockers with direct cardiac effects. Used in the treatment of cardiovascular diseases.

P₁S₁S₃