Herbesser 90 SR

Diltiazem HCl.

Diltiazem HCl is (2S,3S)-3-acetoxy-2,3-dihydro-2-(4-methoxyphenyl)-5-(2-dimethyl)-1-5-benzothiazepine-4(5H)-one monohydrochloride. It occurs as white crystals or crystalline powder and 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 dehydrated ethanol and in acetic anhydride, and practically insoluble in ether. Melting Point: 210-215°C (decomposition).

Calcium antagonist.
Pharmacology: The therapeutic benefits achieved with Herbesser 90 SR 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 vessels, etc.
Action on Blood Pressure: Lowers the elevated blood pressure gradually although hardly affects the normal blood pressure (rat, human). Suppresses the elevation of blood pressure induced by exercise load (human). Lowers blood pressure without decreasing cerebral and renal blood flow (dog, human). Suppresses myocardial and vascular hypertrophy together with lowering blood pressure (rat).
Effects on Myocardial Ischemia: Increases coronary blood flow into myocardial ischemic region by dilating the collateral channels and large coronary artery (dog). Suppresses coronary artery spasms (monkey, human). Decreases myocardial oxygen consumption without decreasing cardiac output by decreasing afterload and heart rate due to peripheral vasodilating effect (dog). Retains cardiac function and myocardial energy metabolism and reduces the infarct size by inhibiting extra calcium ion influx during myocardial ischemia (rat).
Action on Sinus Rhythm and Cardiac Conduction System: Slightly prolongs spontaneous sinus rhythm interval and atrioventricular node conduction time. Does not affect His-Purkinje conduction time (dog, human).
Pharmacokinetics: Plasma Level: When 1 capsule (90 mg as diltiazem HCl) of Herbesser 90 SR was orally administered to healthy adult men, its plasma level reached the peak (about 40 ng/mL) about 7 hrs after administration. The plasma elimination half-life was about 8.4 hrs. In case of repeated administration of Herbesser 90 SR twice a day to healthy adult men, plasma level at 1-10 hrs after administration was about 91 ng/mL.
Metabolism: When Herbesser 90 SR was administered to healthy adult men, deacetyl diltiazem, deacetyl-N-monodemethyl diltiazem, deacetyl-O-demethyl diltiazem, deacetyl-N,O-demethyl diltiazem and N-monodemethyl diltiazem were detected in urine as metabolites. A part of these metabolites are conjugated with glucuronic acid or sulfuric acid in body.
Clinical Studies:
Hypertension: Usefulness of Herbesser 90 SR in the treatment of essential hypertension was proved by 4 double-blind comparative studies with placebo, reserpine and propranolol as control drugs.
Angina Pectoris: Usefulness of Herbesser 90 SR in the treatment of anginal pain due to effort angina and old myocardial infarction was proved by 2 double-blind comparative studies including a placebo-controlled study.
Adverse Reactions: 432 cases (4.5%) of adverse reactions were reported out of total 9347 cases. The most common occurrences as well as their frequency of presentation are: Gastrointestinal system 1.3% (stomach discomfort 0.2%, constipation 0.2%, abdominal pain 0.1%, etc), cardiovascular system 1.3% (bradycardia 0.4%, dizziness 0.4%, hot flush of face 0.2%, atrioventricular block 0.2%, etc), hypersensitivity 1.2%, headache 0.2%, etc.
Toxicology: Preclinical Studies:
Acute Toxicity (LD₅₀ mg/kg): See table.

Click on icon to see table/diagram/image

Chronic Toxicity: When 2, 10 and 25 mg/kg/day each of diltiazem HCl were given orally to SD-strain rats and 5, 10 and 20 mg/kg/day to beagle dogs, for successive 6 months, respectively, general state as well as urinary and histopathological findings of these animals were not significantly different from those of the control. Hematological findings in dogs given orally 20 mg/kg of diltiazem HCl revealed a rise of GPT but it was transient and tended to recover the normal level at the end of experiment.
Teratogenicity: The effect of diltiazem HCl on the fetus was examined by the method as specified in "Policy for Assurance of Drug Safety" notified by the Ministry of Health and Welfare of Japan. At the oral dose level of >10 mg/kg in ICR-JCL-strain mice and >200 mg/kg in Wistar-strain rats, diltiazem HCl caused death of the fetus. At the oral dose level of >50 mg/kg in ICR-JCL-strain mice, diltiazem HCl provoked teratogenic effect. At an oral dose of 400 mg/kg in Wistar-strain rats, diltiazem HCl did not provoke teratogenic effect.

Hypertension. It may be used alone or in combination with other antihypertensive medications eg, diuretics. Angina pectoris, variant angina.

For adults, 1 cap (90 mg as diltiazem HCl) twice a day orally. The dosage may be increased or decreased according to the severity of symptoms. Diltiazem HCl has an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of diltiazem HCl or the concomitant antihypertensives may need to be adjusted when adding one to the other.
Swallow the capsules without chewing or opening.

Patients having atrioventricular block 2nd- and 3rd-degree or sinoatrial block; pregnant women and women suspected of being pregnant; patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker; hypotension (<90 mm Hg systolic); patients who have demonstrated hypersensitivity to the drug; those with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.

General: Since it is described in case reports that symptoms were aggravated after sudden withdrawal of calcium antagonists medication, reduce the dose gradually and observe the symptoms carefully if Herbesser 90 SR is to be withdrawn. Give patients precaution not to discontinue Herbesser 90 SR medication without physician's directions.
Herbesser 90 SR is to be carefully administered in the following cases:
Patients with severe bradycardia (<50 bpm) or 1st-degree atrioventricular block.
Experience with the use of diltiazem HCl in combination with β-blockers in patients with impaired ventricular function is limited. Caution should be exercised when using this combination.
Decreases in blood pressure associated with diltiazem HCl therapy may occasionally result in symptomatic hypotension.
Patients with impaired renal or hepatic function.
Use in pregnancy & lactation: Since animal experiments have proved teratogenic and feticidal, effects of diltiazem HCl, Herbesser 90 SR is contraindicated to pregnant women and women suspected of being pregnant.
It is not recommended to administer Herbesser 90 SR to nursing mothers since it is reported that diltiazem HCl is excreted in human milk. If administration is necessitated, nursing should be avoided.
Use in children: Safety of Herbesser 90 SR in children has not been established.

Cardiovascular System: Dizziness, bradycardia, flush, AV block may occasionally and palpitation, edema, ECG abnormality, hypotension may rarely occur. In such cases, the dose should be reduced or medication should be discontinued.
Central Nervous System: Lassitude, headache and heaviness of head may occasionally, and somnolence, insomnia, asthenia may rarely occur.
Liver: Jaundice and hepatomegaly may rarely occur. The drug should be withdrawn in such cases. Level of GOT, GPT and alkaline phosphatase may be elevated occasionally.
Hypersensitivity: Symptoms eg, eruption and multiform erythematous eruption may occur infrequently. In such cases, medication should be discontinued.
Gastrointestinal System: Stomach discomfort, constipation, abdominal pain, heartburn and anorexia may occasionally occur. Soft stool, nausea, diarrhea, thirst and dyspepsia may rarely occur.
Others: Polyuria may rarely occur.

Herbesser 90 SR should be carefully administered in case of concomitant use with the following drugs:
Antihypertensive Agents: Effect of antihypertensive agents is enhanced.
Beta-Blocking Agents or Rauwolfia Preparations: Bradycardia may occur.
Carbamazepine: Plasma level of carbamazepine may be increased and it may cause carbamazepine-induced toxic symptoms eg, sleepiness, nausea, vomiting, vertigo, etc.
Digoxin Preparations: Plasma level of digoxin is increased.
Cimetidine: Peak plasma level of diltiazem and area under the curve may be increased.
The depression of cardiac contractility, conductivity and automaticity, as well as the vascular dilation associated with anesthetics may be potentiated by calcium antagonists. When used concomitantly, anesthetics and calcium antagonists should be titrated carefully.

Store in a tight and light-resistant container at room temperature.

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