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ENDURONYL®
(methyclothiazide and deserpidine)
tablets
oral
thiazide-rauwolfia therapy for hypertension.
WARNING:
This
fixed combination drug is not indicated for initial therapy of hypertension.
Hypertension requires therapy titrated to the individual patient. If the
fixed combination represents the dosage so determined, its use may be more
convenient in patient management. The treatment of hypertension is not static,
but must be reevaluated as conditions in each patient warrant.
DESCRIPTION
ENDURONYL tablets are an orally administered combination of Enduron® (methyclothiazide) and deserpidine. ENDURONYL tablets are available in two dosage strengths. ENDURONYL tablets contain methyclothiazide 5 mg and deserpidine 0.25 mg. ENDURONYL FORTE tablets contain methyclothiazide 5 mg and deserpidine 0.5 mg.
Inactive Ingredients
ENDURONYL FORTE Tablets
Corn starch, iron oxide, lactose, magnesium stearate and talc.
Methyclothiazide is an oral diuretic-antihypertensive of the benzothiadiazine (thiazide) class of drugs. It occurs as a white to practically white crystalline powder which is basically odorless and has a molecular weight of 360.25. Methyclothiazide is very slightly soluble in water and chloroform, and slightly soluble in alcohol. Chemically, methyclothiazide is represented as 6-chloro-3-(chloromethyl)-3,4-dihydro-2-methyl-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.
Deserpidine is a purified rauwolfia alkaloid. It occurs as a white to light yellow crystalline powder and has a molecular weight of 578.64. Deserpidine is insoluble in water and very slightly soluble in alcohol. Chemically, deserpidine is identified as 17α-methoxy-18β-[(3,4,5-trimethoxybenzoyl)oxy]-3β,20α-yohimban-16β-carboxylic acid methyl ester. The structural formulas are:
 | |
| Methyclothiazide | Deserpidine |
CLINICAL PHARMACOLOGY
The combined antihypertensive actions of methyclothiazide and deserpidine result in a total clinical antihypertensive effect which is greater than can ordinarily be achieved by either drug given individually.
Methyclothiazide
The diuretic and saluretic effects of methyclothiazide result from a drug-induced inhibition of the renal tubular reabsorption of electrolytes. The excretion of sodium and chloride is greatly enhanced. Potassium excretion is also enhanced to a variable degree, as it is with the other thiazides. Although urinary excretion of bicarbonate is increased slightly, there is usually no significant change in urinary pH. Methyclothiazide has a per mg natriuretic activity approximately 100 times that of the prototype thiazide, chlorothiazide. At maximal therapeutic dosages, all thiazides are approximately equal in their diuretic/natriuretic effects.
There is significant natriuresis and diuresis within 2 hours after administration of a single dose of methyclothiazide. These effects reach a peak in about 6 hours and persist for 24 hours following oral administration of single dose.
Like other benzothiadiazines, methyclothiazide also has antihypertensive properties, and may be used for this purpose either alone or to enhance the antihypertensive action of other drugs. The mechanism by which the benzothiadiazines, including methyclothiazide, produce a reduction of elevated blood pressure is not known. However, sodium depletion appears to be involved.
Deserpidine
The pharmacologic actions of deserpidine are essentially the same as those of other active rauwolfia alkaloids. Deserpidine probably produces its antihypertensive effects through depletion of tissue stores of catecholamines (epinephrine and norepinephrine) from peripheral sites. By contrast, its sedative and tranquilizing properties are thought to be related to depletion of 5-hydroxytryptamine from the brain. The antihypertensive effect is often accompanied by bradycardia. There is no significant alteration in cardiac output or renal blood flow. The carotid sinus reflex is inhibited, but postural hypotension is rarely seen with the use of conventional doses of deserpidine alone.
Deserpidine, like other rauwolfia alkaloids, is characterized by slow onset of action and sustained effect which may persist following withdrawal of the drug.
Pharmacokinetics and Metabolism
INDICATIONS AND USAGE
ENDURONYL (methyclothiazide and deserpidine) is indicated in the treatment of mild to moderately severe hypertension (see BOXED WARNING). In many cases ENDURONYL tablets alone produces an adequate reduction of blood pressure. In resistant or unusually severe cases ENDURONYL tablets also may be supplemented with more potent antihypertensive agents. When administered with ENDURONYL tablets, more potent agents can be given at reduced dosage to minimize undesirable side effects.
CONTRAINDICATIONS
Methyclothiazide is contraindicated in patients with anuria and in patients with a history of hypersensitivity to this or other sulfonamide-derived drugs.
Deserpidine is contraindicated in patients with known hypersensitivity, history of mental depression especially with suicidal tendencies, active peptic ulcer, and ulcerative colitis. It is also contraindicated in patients receiving electroconvulsive therapy.
WARNINGS
Methyclothiazide
Methyclothiazide shares with other thiazides the propensity to deplete potassium reserves to an unpredictable degree.
There have been isolated reports that certain nonedematous individuals developed severe fluid and electrolyte derangements after only brief exposure to normal doses of thiazide and nonthiazide diuretics.
Thiazides should be used with caution in patients with renal disease or significant impairment of renal function, since azotemia may be precipitated and cumulative drug effects may occur.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
Deserpidine
Deserpidine differs slightly in chemical structure from reserpine; however, its actions, indications, cautions, and adverse reactions are common to the class of rauwolfia alkaloids. Reserpine may cause mental depression. Recognition of depression may be difficult because this condition may often be disguised by somatic complaints (Masked Depression). The drug should be discontinued at first signs of depression such as despondency, early morning insomnia, loss of appetite, impotence, or self-deprecation. Drug-induced depression may persist for several months after drug withdrawal and may be severe enough to result in suicide.
PRECAUTIONS
General
Information for Patients
Patients should inform their doctor if they have: 1) had an allergic reaction to methyclothiazide, other diuretics, or deserpidine; 2) asthma; 3) kidney disease; 4) liver disease; 5) gout; 6) systemic lupus erythematosus; or 7) been taking other drugs such as cortisone, digitalis, lithium carbonate, or drugs for diabetes.
The physician should inform patients of possible side effects and caution the patient to report any of the following symptoms of electrolyte imbalance: dryness of mouth, thirst, weakness, tiredness, drowsiness, restlessness, muscle pains or cramps, nausea, vomiting, or increased heart rate.
The patient and his family should be warned of the possibility of depression. If signs of despondency, early morning insomnia, loss of appetite, impotence, or self-deprecation appear, the drug should be discontinued and the physician consulted.
Patients who engage in potentially hazardous activities such as operating machinery or driving motor vehicles should be warned about possible central nervous system (CNS) side effects.
The physician should advise the patient to take this medication every day as directed. Physicians should also caution patients that drinking alcohol can increase the chance of dizziness and other CNS-depressant effects.
Laboratory Tests
Initial and periodic determination of serum electrolytes should be performed at appropriate intervals for the purpose of detecting possible electrolyte imbalances such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when a patient is vomiting excessively or receiving parenteral fluids.
Drug Interactions
Drug/Laboratory Test Interactions
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Thiazides should be discontinued before carrying out tests for parathyroid function.
Rauwolfia alkaloids have been reported to interfere with assay procedures for the determination of urinary 17-hydroxycorticosteroids and 17-ketosteroids.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term data are available for methyclothiazide or deserpidine concerning the potential for carcinogenicity. No adequate studies have been done to determine the mutagenic potential of methyclothiazide or deserpidine, or their effects on fertility.
Pregnancy Category C
Animal reproduction studies have not been conducted with methyclothiazide or deserpidine. It is also not known whether methyclothiazide or deserpidine can cause fetal harm when administered to a pregnant woman. Methyclothiazide and deserpidine should be given to a pregnant woman only if clearly needed.
Nonteratogenic Effects
Nursing Mothers
Methyclothiazide and deserpidine are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ENDURONYL tablets, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in children have not been established.
ADVERSE REACTIONS
Adverse reactions are usually reversible upon reduction of dosage or discontinuation of ENDURONYL tablets. Whenever adverse reactions are moderate or severe, it may be necessary to discontinue the drug.
The following adverse reactions have been observed, but there has not been enough systematic collection of data to support an estimate of their frequency. Consequently, the reactions are categorized by organ system and are uled in decreasing order of severity and not frequency.
Methyclothiazide
Deserpidine
OVERDOSAGE
Symptoms of thiazide overdosage include electrolyte imbalance and signs of potassium deficiency such as confusion, dizziness, muscular weakness, and gastrointestinal disturbances. General supportive measures including replacement of fluids and electrolytes may be indicated in treatment of overdosage.
An overdosage of deserpidine is characterized by flushing of the skin, conjunctival injection, and pupillary constriction. Sedation ranging from drowsiness to coma may occur. Hypotension, hypothermia, central respiratory depression, and bradycardia may develop in cases of severe overdosage. Treatment consists of the careful evacuation of stomach spans followed by the usual procedures for the symptomatic management of CNS depressant overdosage. If severe hypotension occurs, it should be treated with a direct-acting vasopressor (e.g., norepinephrine). If bradycardia becomes marked, especially with cardiac arrhythmia, consider use of atropine or other anticholinergic drug. Because of prolonged effects of deserpidine, the patient should be closely observed for at least 72 hours.
DOSAGE AND ADMINISTRATION
Dosage should be determined by individual titration of ingredients (see BOXED WARNING).
Dosage of both components should be carefully adjusted to the needs of the individual patient. Since at least 10 days to 2 weeks may elapse before the full effects of the drugs become manifest, the dosage of the drugs should not be adjusted more frequently.
Two tablet strengths, ENDURONYL (methyclothiazide 5 mg, deserpidine 0.25 mg) and ENDURONYL FORTE (methyclothiazide 5 mg, deserpidine 0.5 mg), each grooved, are provided to permit considerable latitude in meeting the dosage requirements of individual patients.
The following table will help in determining which dose of ENDURONYL or ENDURONYL FORTE tablets best represents the equivalent of the titrated dose.
| Daily Dosage of ENDURONYL | Methyclothiazide | Deserpidine |
| ½ tablet | 2.5 mg | 0.125 mg |
| 1 tablet | 5.0 mg | 0.250 mg |
| 1½ tablets | 7.5 mg | 0.375 mg |
| 2 tablets | 10.0 mg | 0.500 mg |
| Daily Dosage of ENDURONYL FORTE | Methyclothiazide | Deserpidine |
| ½ tablet | 2.5 mg | 0.250 mg |
| 1 tablet | 5.0 mg | 0.500 mg |
| 1½ tablets | 7.5 mg | 0.750 mg |
| 2 tablets | 10.0 mg | 1.000 mg |
The appropriate dose of ENDURONYL tablets is administered orally, once daily. The usual adult dosage is one lower-strength ENDURONYL tablet daily. Debilitated and elderly patients may require lower doses.
There is no contraindication to combining ENDURONYL tablets with other antihypertensive agents. When other antihypertensive agents are to be added to the regimen, this should be accomplished gradually. Ganglionic blocking agents should be given at only half the usual dose since their effect is potentiated by pretreatment with ENDURONYL tablets.
HOW SUPPLIED
ENDURONYL (methyclothiazide and deserpidine) is supplied as monogrammed, grooved, square-shaped tablets in the following dosage sizes and quantities:
ENDURONYL (5 mg of methyclothiazide and 0.25 mg of deserpidine) yellow tablets bearing the Abbott“A” logo and Abbo-Code LS for product identification in bottles of 100 (NDC 0074-6838-01).
ENDURONYL FORTE (5 mg of methyclothiazide and 0.5 mg of deserpidine) gray-colored tablets bearing the Abbott “A” logo and Abbo-Code LT for product identification in bottles of 100 (NDC 0074-6854-01).
Recommended Storage
Store below 86°F (30°C).
Abbott Laboratories
North Chicago, IL 60064, U.S.A.
Printed in U.S.A.