Herbesser 90 SR/Herbesser R100/Herbesser R200

Herbesser 90 SR/Herbesser R100/Herbesser R200

diltiazem

Manufacturer:

Mitsubishi Tanabe Pharma

Distributor:

Pharmaforte
Full Prescribing Info
Contents
Diltiazem hydrochloride.
Description
Diltiazem hydrochloride occurs as white crystals or crystalline powder. It is odorless.
It is very soluble in formic acid, free 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).
Herbesser 90 SR: INN (name in J.P.): Diltiazem hydrochloride.
Chemical name: d-3-Acetoxy-cis-2,3-dihydro-5-[2-(dimethylamino) ethyl]-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride.
C22H26N2O4S.HCl: 450.99. (See Table 1.)

Click on icon to see table/diagram/image

Herbesser R100/Herbesser R200: (See Table 2.)

Click on icon to see table/diagram/image

Nonproprietary name: Diltiazem Hydrochloride (JAN); Diltiazem (INN).
Chemical name: (2S,3S)-5[2-(Dimethylamino) ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5- tetrahydro-1,5benzothiazepin-3-yl-acetate monohydrochloride.
C22H26N2O4S•HCl: 450.98.
Optical rotation [a]D20: + 115 to- + 120° (After drying. 0.20 g, water, 20 mL, 100 mm).
Action
Pharmacology: Herbesser 90 SR: Pharmacological Studies: The therapeutic benefits achieved with HERBESSER 90 SR 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 ion into coronary and peripheral vessels of smooth muscle cell.
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 after-load 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 A-V node conduction time. Does not affect on His-Purkinje conduction time (dog, human).
Herbesser R100/Herbesser R200: Diltiazem hydrochloride dilates blood vessels, improves myocardial ishemia, and exerts antihypertensive effect by inhibiting calcium channel influx to cells in vascular smooth muscles such as coronary vessels, peripheral vessels, etc.
Action on myocardial ishemia: Improvment of myocardial oxygen demand and supply balance: It dilates large coronary vessels and collateral channels, and increases blood flow to myocardial ischaemic lesion (dogs).
It inhibits coronary artery spasm (monkeys and humans).
It decreases myocardial oxygen consumption without decreasing cardiac output by afterload reduction due to peripheral vasodilation and decreased heart rate (dogs).
Myocardial protective action: It maintains cardiac function and myocardial energy metabolism, and reduces the extension of infarct lesions by inhibiting calcium channel influx to cells at the time of myocardial ischaemia (rats).
Action on blood pressure: It has almost no effect on normal blood pressure, while decreases high blood pressure gradually (rats and humans), and inhibits exercise-induced blood pressure elevation (humans).
It does not decrease cerebral and renal blood flow, while decreases blood pressure (dogs and humans).
It inhibits myocardial and vascular hypertrophies along with decreased blood pressure (rats).
Effects on cardiac stimulation and cardiac conduction: It slightly prolongs sinus node spontaneous cycle length and slows atrio-ventricular nodal conduction (AH interval), while it does not effect His-Purkinje system conduction (HV interval) (dogs and humans).
Pharmacodynamics: Herbesser 90 SR: Clinical Studies: Hypertension: Usefulness of HERBESSER 90 SR in the treatment of essential hypertension was proved by four 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 two double-blind comparative studies including a placebo-controlled study.
Adverse reactions: 432 cases (4.5%) of adverse reactions were reported out of total 9,347 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%, A-V block 0.2% etc.) hypersensitivity 1.2%; headache 0.2%, etc.
Herbesser R100/Herbesser R200: Clinical efficacy: The usefulness of this product was proven for essential hypertension, angina pectoris and variant angina in clinical studies including a double blind comparative clinical trials study using diltiazem hydrochloride (HERBESSER Tablets 30) as a control. (See Table 3.)

Click on icon to see table/diagram/image

Pharmacokinetics: Herbesser 90 SR: Plasma level: When 1 capsule (90 mg as diltiazem hydrochloride) of HERBESSER 90 SR was orally administered to healthy adult men, its plasma level reached the peak (about 40 ng/ml) about 7 hours after administration.
The plasma elimination half life was about 8.4 hours. In case of repeated administration of HERBESSER 90 SR twice a day to healthy adult men, plasma level at 1 to 10 hours 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.
Herbesser R100/Herbesser R200: Plasma concentration: Plasma concentration of this product after oral administration of one capsule HERBESSER Capsules 100 mg to healthy male adults reached maximum at about 14 hours after the administration, and the elimination half-life was about 7 hours. (See figure.)

Click on icon to see table/diagram/image

Metabolism: When this product was administered orally to healthy male adults, the main metabolic pathways were oxidative deaminization, oxidative demethylation, deacetylation, and conjugation.
Toxicology: Herbesser R100/Herbesser R200: Preclinical Studies: Toxicity: Acute toxicity (LD50 mg/kg): (See Table 4.)

Click on icon to see table/diagram/image

Chronic toxicity: When 2, 10 and 25 mg/kg/day each of diltiazem hydrochloride were given orally to SD-strain rats and 5, 10 and 20 mg/kg/day to beagle dogs, for successive six 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 hydrochloride revealed a rise of GPT but it was transient and tended to recover the normal level at the end of experiment.
Teratogenecity: The effect of diltiazem hydrochloride 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 more than 10 mg/kg in ICR-JCL-strain mice and more than 200 mg/kg in Wistar-strain rats, diltiazem hydrochloride caused death of the fetus. At the oral dose level of more than 50 mg/kg in ICR-JCL-strain mice, diltiazem hydrochloride provoked teratogenic effect. At an oral dose of 400 mg/kg in Wistar-strain rats, diltiazem hydrochloride did not provoke teratogenic effect.
Indications/Uses
Herbesser 90 SR: Hypertension: It may be used alone or in combination with other antihypertensive medications, such as diuretics.
Angina pectoris, Variant angina.
Herbesser R100/Herbesser R200: Essential hypertension (mild to moderate); Angina pectoris, variant angina pectoris.
Dosage/Direction for Use
Herbesser 90 SR: For adults, 1 capsule (90 mg as diltiazem hydrochloride) twice a day orally. The dosage may be increased or decreased according to the severity of symptoms. Diltiazem hydrochloride has an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of diltiazem hydrochloride or the concomitant antihypertensives may need to be adjusted when adding one to the other.
Herbesser R100/Herbesser R200: Essential hypertension (mild to moderate): Usually, for adults, 100 mg to 200 mg of diltiazem hydrochloride is orally administered once daily. The dosage may be adjusted according to the patient's age and symptoms.
Angina pectoris, variant angina pectoris: Usually, for adults, 100 mg of Diltiazem hydrochloride is orally administered once daily. If the effect is insufficient, the dosage may be increased to 200 mg once daily.
Overdosage
Herbesser R100/Herbesser R200: Symptoms: Bradycardia, complete atrioventricular block, cardiac failure, hypotension, etc. may occur after overdosage of HERBESSER. These symptoms have been also reported as adverse reactions.
Treatment: In case of overdosage, administration should be discontinued, and gastric lavage should be performed to remove the product as needed, and the following appropriate therapeutic measures should be taken.
Bradycardia, complete atrioventricular block: Atropine sulfate hydrate, isoprenaline, etc. should be administered or cardiac pacing should be taken.
Cardiac failure, hypotension: Cardiotonic drug, vasopressor, infusion, etc. should be administered or assisted circulation should be performed.
Contraindications
Herbesser 90 SR: Patients having atrioventricular block 2nd and 3rd degree or sinoatrial block; Pregnant women and women of pregnant suspicion; Patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker; Patients with hypotension (less than 90 mmHg systolic); Patients who have demonstrated hypersensitivty to the drug; Patients with acute myocardial infarction and pulmonary congestion documented by X-ray on admission.
Herbesser R100/Herbesser R200: Patients with severe congestive heart cardiac failure. [Symptoms of cardiac failure may be aggravated].
Patients with second or third degree atrioventricular block or sick sinus syndrome (persistent sinus bradycardia) (less than 50 beats/minute), sinus arrest, sinoatrial block, etc.) [Depression of cardiac stimulation and cardiac conduction may occur excessively].
Patients with a history of hypersensitivity to any of the ingredients of this product.
Pregnant women or women who may possibly be pregnant. [See Use in Pregnancy & Lactation].
Special Precautions
Herbesser 90 SR: 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 (below 50 beats/min.) or 1st degree atrioventricular block; Experience with the use of diltiazem hydrochloride in combination with beta-blockers in patients with impaired ventricular function is limited. Caution should be exercised when using this combination; Decreases in blood pressure associated with diltiazem hydrochloride therapy may occasionally result in symptomatic hypotension; Patients with impaired renal or hepatic function.
Administration to pregnant women and nursing mothers: Since animal experiments have proved teratogenic and feticidal effects of diltiazem hydrochloride, 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 hydrochloride is excreted in human milk. If administration is necessitated, nursing should be avoided.
Administration to children: Safety of HERBESSER 90 SR in children has not been established.
Herbesser R100/Herbesser R200: Patients with congestive cardiac failure. (Symptoms of cardiac failure may be aggravated].
Patients with severe bradycardia (less than 50 beats/min) or first grade atrioventricular block. [Depression of cardiac stimulation and cardiac conduction may occur excessively].
Patients with excessively low blood pressure. [Blood pressure may be further decreased].
Patients with severe hepatic or renal impairment. [The metabolism excretion of this product may be prolonged, and effects may be intensified].
It has been reported that abrupt cessation of calcium antagonist may aggravate the patient's symptoms. In case where cessation of this product is required, the dosage should be reduced gradually under careful observation of the patient. Patients should be instructed not to discontinue taking this product without consulting physicians.
Since dizzines, etc. may occur due to the antihypertensive action of this product, patients should be cautioned against engaging in potentially hazardous activities, such as working at altitude or driving motor vehicles.
Prolonged QT and ventricular arrhythmia have been reported in coadministration of terfenadine with other antiarrhythmic agents (disopyramide phosphate).
Pediatric Use: The safety of HERBESSER in children has not been established.
Use in the Elderly: Excessive decrease in blood pressure is generally considered undesirable in elderly patients. Therefore, HERBESSER should be administered with care such as starting from a lower dosage while carefully monitoring the patient's condition.
Use In Pregnancy & Lactation
Herbesser 90 SR: Since animal experiments have proved teratogenic and feticidal effects of diltiazem hydrochloride, 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 hydrochloride is excreted in human milk. If administration is necessitated, nursing should be avoided.
Herbesser R100/Herbesser R200: HERBESSER is contraindicated in pregnant women or women who may possibly be pregnant.
[Animal studies have shown teratogenicity (mice: skeletal abnormality, appearance abnormality) and embryotoxicity (mice, rats: fatality).]
Use of this product in lactating women is not recommended. If treatment with this product is judged to be essential, breastfeeding must be discontinued during treatment.
[It has been reported that diltiazem is excreted in human breast milk.]
Adverse Reactions
Herbesser 90 SR: Cardiovascular system: Dizziness, bradycardia, flush, A-V 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 occur, 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: Hypersensitivity symptoms eg, eruption and erythematous multiforme 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 R100/Herbesser R200: Adverse reactions were reported in 74 (2.1%) of 3,577 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 the time of completion of reexamination).
Clinically significant adverse reactions (rarely:<0.1%, incidence unknown because of spontaneous reports): Complete atrioventricular block, severe bradycardia (early symptom: bradycardia, dizziness, light-headedness, etc.) may occur rarely. If any abnormalities are observed, administration should be discontinued and atropine sulfate hydrate, isoprenaline, etc. should be administered or appropriate therapeutic measures such as cardiac pacing should be taken as needed.
Congestive cardiac failure may occur. If any abnormalities are observed, administration should be discontinued, and appropriate therapeutic measures such as administration of cardiotonic drug, etc. should be taken.
Oculomucocutaneous syndrome (Steven-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome), erythroderma (exfoliative dermatitis), acute generalized exanthematous pustulosis may occur. If erythema, blister, pustule, pruritus, fever, enanthema, etc. occur, administration should be discontinued, and appropriate therapeutic measures should be taken.
Hepatic function disorder or jaundice with increased AST (GOT), ALT (GPT) or γ-GTP may occur. The patient's conditions should be observed carefully. If any abnormalities are observed, administration should be discontinued, and appropriate therapeutic measures should be taken.
Other adverse reactions: If any adverse reactions are observed, appropriate therapeutic measures such as discontinuation of treatment should be taken. (See Table 5.)

Click on icon to see table/diagram/image
Drug Interactions
Herbesser 90 SR: 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.
Herbesser R100/Herbesser R200: This product is metabolized mainly by cytochrome P450 3A4 (CYP3A4) metabolizing enzyme. Precaution for coadministration (HERBESSER R should be administered with care when coadministered with the following drugs.) (See Table 6.)

Click on icon to see table/diagram/image
Caution For Usage
Herbesser 90 SR: Handling: Dispense by physician's prescription or direction.
Swallow the capsules without chewing or opening.
Herbesser R100/Herbesser R200: Precautions regarding dispensing: For drugs that are dispensed in a press-through package (PTP), instruct the patient to remove the drug from the PTP sheet prior to use. [It was 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 oral administration: This product should be taken without opening and chewing the capsule.
Storage
Herbesser 90 SR: Store in a tight and light-resistant container at below 30°C.
Herbesser R100/Herbesser R200: 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 90 SR cap 90 mg x 10 x 10's. Herbesser R100 cap 100 mg x 3 x 10's, 10 x 10's. Herbesser R200 cap 200 mg x 3 x 10's, 10 x 10's.
Exclusive offer for doctors
Register for a MIMS account and receive free medical publications worth $139 a year.
Sign up for free
Already a member? Sign in