RESERPINE
DESCRIPTION:
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 re-
evaluated as conditions in each patient
warrant.
ADALPHEN-ESIDREX* (Reserpine-Chlorothiazide) combines two antihypertensives: DIURIL*
(Chlorothiazide) and reserpine.
Chlorothiazide
Chlorothiazide is a diuretic and antihypertensive. Its chemical name is 6-
chloro- 2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical
formula is C7H6ClN3O4S2.
Chlorothiazide is a white, or practically white, crystalline powder with a
molecular weight of 295.73, which is very slightly soluble in water, but readily
soluble in dilute aqueous sodium hydroxide. It is soluble in urine to the extent
of about 150 mg per 100 mL at pH 7.
Reserpine
The chemical name of reserpine is 11,17alpha- dimethoxy-18beta- ((3,4,5-
trimethoxybenzoyl)oxy)-3beta,20alpha- yohimban-16beta-carboxylic acid
methylester. It is a crystalline alkaloid derived from Rauwolfia serpentina. Its
empirical formula is C33H40N2O9.
Reserpine is a white or pale buff to slightly yellowish, odorless, crystalline
powder with a molecular weight of 608.69, is insoluble in water and freely
soluble in glacial acetic acid.
ACTIONS/CLINICAL PHARMACOLOGY:
Chlorothiazide
The mechanism of the antihypertensive effect of thiazides is unknown.
Chlorothiazide does not usually affect normal blood pressure.
Chlorothiazide affects the distal renal tubular mechanism of electrolyte
reabsorption. At maximal therapeutic dosage all thiazides are approximately
equal in their diuretic efficacy.
Chlorothiazide increases excretion of sodium and chloride in approximately
equivalent amounts. Natriuresis may be accompanied by some loss of potassium and
bicarbonate.
After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts
about 6 to 12 hours.
Reserpine
Reserpine has antihypertensive, bradycardic, and tranquilizing properties. It
lowers arterial blood pressure by depletion of catecholamines. Reserpine is
beneficial in relieving anxiety, tension, and headache in the hypertensive
patient. It acts at the hypothalamic level of the central nervous system to
promote relaxation without hypnosis or analgesia. The sleep pattern shown by the
electroencephalogram following barbiturates does not occur with this drug. In
laboratory animals spontaneous activity and response to external stimuli are
decreased, but confusion or difficulty of movement is not evident.
The bradycardic action of reserpine promotes relaxation and may eliminate sinus
tachycardia. It is most pronounced in subjects with sinus tachycardia and
usually is not prominent in persons with a normal pulse rate.
Miosis, relaxation of the nictitating membrane, ptosis, hypothermia, and
increased gastrointestinal activity are noted in animals given reserpine,
sometimes in subclinical doses. None of these effects, except increased
gastrointestinal activity, has been found to be clinically significant in man
with therapeutic doses.
Pharmacokinetics And Metabolism
Chlorothiazide
Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. The
plasma half-life of chlorothiazide is 45-120 minutes. After oral doses, 10-15
percent is excreted unchanged in the urine. Chlorothiazide crosses the placental
but not the blood-brain barrier and is excreted in breast milk.
Reserpine
Oral reserpine is rapidly absorbed from the gastrointestinal tract.
Methylreserpate and trimethoxybenzoic acid are the primary metabolites which
result from the hydrolytic cleavage of reserpine. Maximal blood levels are
achieved approximately 2 hours after the oral dosage of 3H-reserpine to six
normal volunteers; within 96 hours approximately 8 percent was excreted in urine
and 62 percent in feces. Reserpine appears in human breast milk. Reserpine
crosses the placental barrier in guinea pigs.
INDICATIONS AND USAGE:
Hypertension (see box warning).
CONTRAINDICATIONS:
Chlorothiazide is contraindicated in anuria.
ADALPHEN-ESIDREX is contraindicated in hypersensitivity to chlorothiazide or other
sulfonamide-derived drugs or to reserpine.
Electroshock therapy should not be given to patients while on reserpine, as
severe and even fatal reactions have been reported with minimal convulsive
electroshock dosage. After discontinuing reserpine, allow at least seven days
before starting electroshock therapy.
Reserpine is contraindicated in patients:
--with active peptic ulcer
--with ulcerative colitis
--with a history of mental depression, especially suicidal tendencies
--on therapy with monoamine oxidase (MAO) inhibitors.
WARNINGS:
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 re-
evaluated as conditions in each patient
warrant.
Chlorothiazide
Use with caution in severe renal disease. In patients with renal disease,
thiazides may precipitate azotemia. Cumulative effects of the drug may develop
in patients with impaired renal function.
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.
Thiazides may add to or potentiate the action of other antihypertensive drugs.
Sensitivity reactions may occur in patients with or without a history of allergy
or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus
has been reported.
Lithium generally should not be given with diuretics (see PRECAUTIONS, Drug
Interactions).
Reserpine
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.
The occurrence of mental depression due to reserpine in doses of 0.25 mg daily
or less is unusual. In any event, ADALPHEN-ESIDREX should be discontinued at the first
sign of depression.
PRECAUTIONS:
General
Chlorothiazide
All patients receiving diuretic therapy should be observed for evidence of fluid
or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and
hypokalemia. Serum and urine electrolyte determinations are particularly
important when the patient is vomiting excessively or receiving parenteral
fluids. Warning signs or symptoms of fluid and electrolyte imbalance,
irrespective of cause, include dryness of mouth, thirst, weakness, lethargy,
drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular
fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances
such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis
is present or after prolonged therapy.
Interference with adequate oral electrolyte intake will contribute to
hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or
exaggerate the response of the heart to the toxic effects of digitalis (e.g.,
increased ventricular irritability). Hypokalemia may be avoided or treated by
use of potassium sparing diuretics or potassium supplements such as foods with a
high potassium content.
Although any chloride deficit is generally mild and usually does not require
specific treatment except under extraordinary circumstances (as in liver disease
or renal disease), chloride replacement may be required in the treatment of
metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather.
Appropriate therapy is water restriction, rather than administration of salt,
except in rare instances when the hyponatremia is life threatening. In actual
salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or acute gout may be precipitated in certain patients
receiving thiazides.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents
may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent
diabetes mellitus may become manifest during thiazide therapy.
The antihypertensive effect of the drug may be enhanced in the postsympathectomy
patient.
If progressive renal impairment becomes evident, consider withholding or
discontinuing diuretic therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this
may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause
intermittent and slight elevation of serum calcium in the absence of known
disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden
hyperparathyroidism. Thiazides should be discontinued before carrying out tests
for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide
diuretic therapy.
Reserpine
Since reserpine may increase gastric secretion and motility, it should be used
cautiously in patients with a history of peptic ulcer, ulcerative colitis, or
other gastrointestinal disorder. This compound may precipitate biliary colic in
patients with gallstones, or bronchial asthma in susceptible persons.
Reserpine may cause hypotension including orthostatic hypotension.
Anxiety or depression, as well as psychosis, may develop during reserpine
therapy. If depression is present when therapy is begun, it may be aggravated.
Mental depression is unusual with reserpine doses of 0.25 mg daily or less. In
any case, ADALPHEN-ESIDREX should be discontinued at the first sign of depression.
Extreme caution should be used in treating patients with a history of mental
depression, and the possibility of suicide should be kept in mind.
As with most antihypertensive therapy, caution should be exercised when treating
hypertensive patients with renal insufficiency, since they adjust poorly to
lowered blood pressure.
When two or more antihypertensives are given, the individual dosages may have to
be reduced to prevent excessive drop in blood pressure. In hypertensive patients
with coronary artery disease, it is important to avoid a precipitous drop in
blood pressure.
Laboratory Tests
Periodic determination of serum electrolytes to detect possible electrolyte
imbalance should be done at appropriate intervals.
Drug Interactions
Chlorothiazide
When given concurrently the following drugs may interact with thiazide
diuretics.
Alcohol, Barbiturates, Or Narcotics--potentiation of orthostatic hypotension may
occur.
Antidiabetic Drugs (oral agents and insulin)--dosage adjustment of the
antidiabetic drug may be required.
Other Antihypertensive Drugs--additive effect or potentiation.
Cholestyramine And Colestipol Resins--Both cholestyramine and colestipol resins
have the potential of binding thiazide diuretics and reducing diuretic
absorption from the gastrointestinal tract.
Corticosteroids, ACTH--intensified electrolyte depletion, particularly
hypokalemia.
Pressor Amines (E.G., Norepinephrine)--possible decreased response to pressor
amines but not sufficient to preclude their use.
Skeletal Muscle Relaxants, Nondepolarizing (E.G., Tubocurarine)--possible
increased responsiveness to the muscle relaxant.
Lithium--generally should not be given with diuretics. Diuretic agents reduce
the renal clearance of lithium and add a high risk of lithium toxicity. Refer to
the package insert for lithium preparations before use of such preparations with
ADALPHEN-ESIDREX.
Non-steroidal Anti-inflammatory Drugs--In some patients, the administration of a
non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and
antihypertensive effects of loop, potassium-sparing and thiazide diuretics.
Therefore, when ADALPHEN-ESIDREX and non-steroidal anti- inflammatory agents are used
concomitantly, the patient should be observed closely to determine if the
desired effect of the diuretic is obtained.
Reserpine
In hypertensive patients on reserpine therapy significant hypotension and
bradycardia may develop during surgical anesthesia. The anesthesiologist should
be aware that reserpine has been taken, since it may be necessary to give vagal
blocking agents parenterally to prevent or reverse hypotension and/or
bradycardia.
Use reserpine cautiously with digitalis and quinidine; cardiac arrhythmias have
occurred with reserpine preparations.
Barbiturates enhance the central nervous system depressant effects of reserpine.
Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS.
Drug/Laboratory Test Interactions
Thiazides should be discontinued before carrying out tests for parathyroid
function (see PRECAUTIONS, General).
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity and mutagenicity studies have not been conducted with
combinations of reserpine/chlorothiazide.
In a two-litter study in the rat at an oral dose of 50.0/0.025 mg/kg, the
combination of chlorothiazide/reserpine did not impair fertility or produce
abnormalities in the fetus.
Chlorothiazide
Carcinogenicity studies have not been done with chlorothiazide.
Chlorothiazide was not mutagenic In Vitro in the Ames microbial mutagen test
(using a maximum concentration of 5 mg/plate and Salmonella Typhimurium strains
TA 98 and TA 100) and was not mutagenic and did not induce mitotic
nondisjunction in diploid-strains of Aspergillus Nidulans.
Chlorothiazide had no adverse effects on fertility in female rats at doses up to
60 mg/kg/day and no adverse effects on fertility in male rats at doses up to 40
mg/kg/day.
Reserpine
Reserpine at a concentration of 1 to 5000 mcg/plate had no mutagenic activity
against four strains of S. typhimurium In Vitro in the Ames microbial mutagen
test with or without metabolic activation. Reserpine did not induce malignant
transformation of mouse fibroblasts In Vitro at concentrations of 0.3 to 10
mcg/mL.
A few chromosomal aberrations were induced by reserpine In Vitro in cultured
mouse mammary carcinoma cells but were considered negative in this study. The
drug did not produce chromosomal aberrations in human peripheral leucocyte
cultures although an increase in mitotic figures occurred. One study reported
chromosomal aberrations and dominant lethal mutations in mice at doses up to 10
mg/kg of reserpine in the form of a pharmaceutical preparation. Another study
did not show dominant lethal mutations in mice at IP doses of 0.92 and 4.6 mg/kg
of reserpine.
Reserpine did not impair fertility in a two- litter study in the rat at an oral
dose of 0.025 mg/kg.
Rodent studies have shown that reserpine is an animal tumorigen, causing an
increased incidence of mammary fibroadenomas in female mice, malignant tumors of
the seminal vesicle in male mice, and malignant adrenal medullary tumors in male
rats. These findings arose in two year studies in which the drug was
administered in the feed at concentrations of 5 and 10 ppm--about 100 to 300
times the usual human dose. The breast neoplasms are thought to be related to
reserpine's prolactin-elevating effect. Several other prolactin-elevating drugs
have also been associated with an increased incidence of mammary neoplasia in
rodents.
The extent to which these findings indicate a risk to humans is uncertain.
Tissue culture experiments show that about one-third of human breast tumors are
prolactin-dependent In Vitro, a factor of considerable importance if the use of
the drug is contemplated in a patient with previously detected breast cancer.
The possibility of an increased risk of breast cancer in reserpine users has
been studied extensively; however, no firm conclusion has emerged. Although a
few epidemiologic studies have suggested a slightly increased risk (less than
twofold in all studies except one) in women who have used reserpine, other
studies of generally similar design have not confirmed this. Epidemiologic
studies conducted using other drugs (neuroleptic agents) that, like reserpine,
increase prolactin levels and therefore would be considered rodent mammary
carcinogens, have not shown an association between chronic administration of the
drug and human mammary tumorigenesis. While long- term clinical observation has
not suggested such an association, the available evidence is considered too
limited to be conclusive at this time. An association of reserpine intake with
pheochromocytoma or tumors of the seminal vesicles has not been explored.
Pregnancy
Use of diuretics during normal pregnancy is inappropriate and exposes mother and
fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of
pregnancy and there is no satisfactory evidence that they are useful in the
treatment of toxemia.
Teratogenic Effects--Pregnancy Category C: There are no adequate and well-
controlled studies with ADALPHEN-ESIDREX or other combinations of
reserpine/chlorothiazide in animals or pregnant women. ADALPHEN-ESIDREX may cause fetal
harm when given to a pregnant woman. ADALPHEN-ESIDREX should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
Reserpine: Reproduction studies in rats have shown that reserpine is teratogenic
at doses of 1-2 mg/kg (125-250 times the maximum recommended human dose) IM or
IP given early in pregnancy. A variety of abnormalities was produced including
anophthalmia, absence of the axial skeleton, hydronephrosis, etc. Pregnancy in
rabbits was interrupted when doses as low as 0.04 mg/kg (10 times the maximum
recommended human dose) were given early or late in pregnancy.
Chlorothiazide: Thiazides cross the placental barrier and appear in cord blood.
Although reproduction studies performed with chlorothiazide doses of 50
mg/kg/day in rabbits, 60 mg/kg/day in rats and 500 mg/kg/day in mice revealed no
external abnormalities of the fetus or impairment of growth and survival of the
fetus due to chlorothiazide, such studies did not include complete examinations
for visceral and skeletal abnormalities
Nonteratogenic Effects
Reserpine: Reserpine has been demonstrated to cross the placental barrier in
guinea pigs with depression of adrenal catecholamine stores in the newborn.
There is some evidence that side effects such as nasal congestion, lethargy,
depressed Moro reflex, and bradycardia may appear in infants born of reserpine-
treated mothers.
Chlorothiazide: Chlorothiazide may cause fetal or neonatal jaundice,
thrombocytopenia, and possibly other adverse reactions which have occurred in
the adult.
Nursing Mothers
Thiazides and reserpine appear in breast milk. Because of the potential for
serious adverse reactions in nursing infants from ADALPHEN-ESIDREX, 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 of ADALPHEN-ESIDREX in pediatric patients have not been
established.
DRUG INTERACTIONS:
Chlorothiazide
When given concurrently the following drugs may interact with thiazide
diuretics.
Alcohol, Barbiturates, Or Narcotics--potentiation of orthostatic hypotension may
occur.
Antidiabetic Drugs (oral agents and insulin)--dosage adjustment of the
antidiabetic drug may be required.
Other Antihypertensive Drugs--additive effect or potentiation.
Cholestyramine And Colestipol Resins--Both cholestyramine and colestipol resins
have the potential of binding thiazide diuretics and reducing diuretic
absorption from the gastrointestinal tract.
Corticosteroids, ACTH--intensified electrolyte depletion, particularly
hypokalemia.
Pressor Amines (E.G., Norepinephrine)--possible decreased response to pressor
amines but not sufficient to preclude their use.
Skeletal Muscle Relaxants, Nondepolarizing (E.G., Tubocurarine)--possible
increased responsiveness to the muscle relaxant.
Lithium--generally should not be given with diuretics. Diuretic agents reduce
the renal clearance of lithium and add a high risk of lithium toxicity. Refer to
the package insert for lithium preparations before use of such preparations with
ADALPHEN-ESIDREX.
Non-Steroidal Anti-Inflammatory Drugs--In some patients, the administration of a
non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and
antihypertensive effects of loop, potassium-sparing and thiazide diuretics.
Therefore, when ADALPHEN-ESIDREX and non-steroidal anti- inflammatory agents are used
concomitantly, the patient should be observed closely to determine if the
desired effect of the diuretic is obtained.
Reserpine
In hypertensive patients on reserpine therapy significant hypotension and
bradycardia may develop during surgical anesthesia. The anesthesiologist should
be aware that reserpine has been taken, since it may be necessary to give vagal
blocking agents parenterally to prevent or reverse hypotension and/or
bradycardia.
Use reserpine cautiously with digitalis and quinidine; cardiac arrhythmias have
occurred with reserpine preparations.
Barbiturates enhance the central nervous system depressant effects of reserpine.
Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The following adverse reactions have been reported and, within each category,
are listed in order of decreasing severity.
Chlorothiazide
Body As A Whole: Weakness.
Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated
by alcohol, barbiturates, narcotics or antihypertensive drugs).
Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea,
vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea,
anorexia.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia,
thrombocytopenia.
Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis and
cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary
edema, photosensitivity, fever, urticaria, rash, purpura.
Metabolic: Electrolyte imbalance (see PRECAUTIONS), hyperglycemia, glycosuria,
hyperuricemia.
Musculoskeletal: Muscle spasm.
Nervous System/Psychiatric: Vertigo, paresthesias, dizziness, headache,
restlessness.
Renal: Renal failure, renal dysfunction, interstitial nephritis. (See WARNINGS.)
Skin: Erythema multiforme including Stevens- Johnson syndrome, exfoliative
dermatitis including toxic epidermal necrolysis, alopecia.
Special Senses: Transient blurred vision, xanthopsia.
Urogenital: Impotence.
Reserpine
Cardiovascular: Angina pectoris, arrhythmia, premature ventricular contractions,
other direct cardiac effects (e.g., fluid retention, congestive heart failure),
bradycardia.
Digestive: Vomiting, diarrhea, nausea, hypersecretion and increased motility,
anorexia, dryness of mouth, increased salivation.
Hematologic: Thrombocytopenic purpura, excessive bleeding following prostatic
surgery.
Hypersensitivity: Pruritus, rash, flushing of skin.
Metabolic: Weight gain.
Musculoskeletal: Muscular aches.
Nervous System/Psychiatric: Mental depression, dull sensorium, syncope,
paradoxical anxiety, excessive sedation, nightmares, headache, dizziness,
nervousness, parkinsonism (usually reversible with decreased dosage or
discontinuance of therapy).
Respiratory: Dyspnea, epistaxis, nasal congestion, enhanced susceptibility to
colds.
Special Senses: Optic atrophy, uveitis, deafness, glaucoma, conjunctival
injection, blurred vision.
Urogenital: Dysuria, impotence, decreased libido, nonpuerperal lactation.
OVERDOSAGE:
Overdosage may lead to excessive sedation, mental depression, severe
hypotension, extrapyramidal reactions.
There is no specific antidote. In the event of overdosage, symptomatic and
supportive measures should be employed. Emesis should be induced or gastric
lavage performed. Correct dehydration, electrolyte imbalance, hepatic coma and
hypotension by established procedures. If required, give oxygen or artificial
respiration for respiratory impairment. In the event of severe hypotension from
the reserpine component, intravenous use of a vasopressor is indicated (e.g.,
ARAMINE* (Metaraminol Bitartrate), levarterenol, phenylephrine).
Anticholinergics may be needed to relieve gastrointestinal distress from
reserpine. Because the effects of the rauwolfia alkaloids are prolonged, the
patient should be closely observed for at least 72 hours.
Reserpine is not dialyzable. The degree to which chlorothiazide is removed by
hemodialysis has not been established.
The oral LD50 of chlorothiazide is 8.5 g/kg, greater than 10 g/kg, and greater
than 1 g/kg, in the mouse, rat and dog, respectively. The oral LD50 of reserpine
in the mouse is 390 mg/kg.
DOSAGE AND ADMINISTRATION:
The initial dosage of ADALPHEN-ESIDREX should conform to the dosages of the individual
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