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Ser-Ap-Es®
C97-38 (Rev. 1/98) 666496
Ser-Ap-Es®
reserpine USP 0.1 mg
hydralazine hydrochloride USP 25 mg
hydrochlorothiazide USP 15 mg
Combination Tablets
Caution: Federal law prohibits dispensing without prescription.
Prescribing Information
WARNING
This fixed-combination drug is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. It 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
Ser-Ap-Es is an antihypertensive-diuretic combination, available as tablets for oral administration. Each tablet contains Serpasil (reserpine USP), 0.1 mg; Apresoline (hydralazine hydrochloride USP), 25 mg; and Esidrix (hydrochlorothiazide USP), 15 mg.
Reserpine is methyl 18β-hydroxy-11,17α-dimethoxy-3β,20α-yohimban-16β-carboxylate 3,4,5-trimethoxybenzoate (ester), and its structural formula is
Reserpine USP, a pure crystalline alkaloid of rauwolfia, is a white or pale buff to slightly yellowish, odorless crystalline powder. It darkens slowly on exposure to light, but more rapidly when in solution. It is insoluble in water, freely soluble in acetic acid and in chloroform, slightly soluble in benzene, and very slightly soluble in alcohol and in ether. Its molecular weight is 608.69.
Hydralazine hydrochloride is 1-hydrazinophthalazine monohydrochloride, and its structural formula is
Hydralazine hydrochloride USP is a white to off-white, odorless crystalline powder. It is soluble in water, slightly soluble in alcohol, and very slightly soluble in ether. It melts at about 275ºC, with decomposition, and has a molecular weight of 196.64.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, and its structural formula is
Hydrochlorothiazide USP is a white, or practically white, practically odorless crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Its molecular weight is 297.73.
Inactive Ingredients. Acacia, FD&C Blue No. 1, FD&C Green No. 3, FD&C Red No. 40, FD&C Yellow No. 6, lactose, polyethylene glycol, starch, stearic acid, and sucrose.
CLINICAL PHARMACOLOGY
Reserpine
Reserpine depletes stores of catecholamines and 5-hydroxytryptamine in many organs, including the brain and adrenal medulla. Most of its pharmacological effects have been attributed to this action. Depletion is slower and less complete in the adrenal medulla than in other tissues.
The depression of sympathetic nerve function results in a decreased heart rate and a lowering of arterial blood pressure. The sedative and tranquilizing properties of reserpine are thought to be related to depletion of catecholamines and 5-hydroxytryptamine from the brain.
Reserpine, like other rauwolfia compounds, is characterized by slow onset of action and sustained effects. Both cardiovascular and central nervous system effects may persist for a period of time following withdrawal of the drug.
Mean maximum plasma levels of 1.54 ng/ml were attained after a median of 3.5 hours in six normal subjects receiving a single oral dose of four 0.25-mg Serpasil tablets.
Bioavailability was approximately 50% of that of a corresponding intravenous dose. Plasma levels of reserpine after intravenous administration declined with a mean half-life of 33 hours. Reserpine is extensively bound (96%) to plasma proteins. No definitive studies on the human metabolism of reserpine have been made.
Hydralazine
Although the precise mechanism of action of hydralazine is not fully understood, the major effects are on the cardiovascular system. Hydralazine apparently lowers blood pressure by exerting a peripheral vasodilating effect through a direct relaxation of vascular smooth muscle. Hydralazine, by altering cellular calcium metabolism, interferes with the calcium movements within the vascular smooth muscle that are responsible for initiating or maintaining the contractile state.
The peripheral vasodilating effect of hydralazine results in decreased arterial blood pressure (diastolic more than systolic); decreased peripheral vascular resistance; and an increased heart rate, stroke volume, and cardiac output. The preferential dilatation of arterioles, as compared to veins, minimizes postural hypotension and promotes the increase in cardiac output. Hydralazine usually increases renin activity in plasma, presumably as a result of increased secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge. This increase in renin activity leads to the production of angiotensin II, which then causes stimulation of aldosterone and consequent sodium reabsorption. Hydralazine also maintains or increases renal and cerebral blood flow.
Hydralazine is rapidly absorbed after oral administration, and peak plasma levels are reached at 1-2 hours. Plasma levels decline with a half-life of 3-7 hours. Binding to human plasma protein is 87%. Plasma levels of hydralazine vary widely among individuals. Hydralazine is subject to polymorphic acetylation; slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism; it is excreted mainly in the form of metabolites in the urine.
Administration of hydralazine with food results in higher levels of the drug in plasma.
Hydrochlorothiazide
Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency. Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium.
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.
The onset of action of thiazides occurs in 2 hours, and the peak effect at about 4 hours. The action persists for approximately 6-12 hours. Hydrochlorothiazide is rapidly absorbed, as indicated by peak plasma concentrations 1-2.5 hours after oral administration. Plasma levels of the drug are proportional to dose; the concentration in whole blood is 1.6-1.8 times higher than in plasma. Thiazides are eliminated rapidly by the kidney. After oral administration of 25- to 100-mg doses of hydrochlorothiazide, 72%-97% of the dose is excreted in the urine, indicating dose-independent absorption. Hydrochlorothiazide is eliminated from plasma in a biphasic fashion with a terminal half-life of 10-17 hours. Plasma protein binding is 67.9%. Plasma clearance is 15.9-30.0 L/hr; volume of distribution is 3.6-7.8 L/kg.
Gastrointestinal absorption of hydrochlorothiazide is enhanced when administered with food. Absorption is decreased in patients with congestive heart failure, and the pharmacokinetics are considerably different in these patients.
INDICATIONS AND USAGE
Hypertension (see boxed WARNING).
CONTRAINDICATIONS
Reserpine
Hypersensitivity to reserpine; mental depression or history of mental depression (especially with suicidal tendencies); active peptic ulcer, ulcerative colitis; patients receiving electroconvulsive therapy.
Hydralazine
Hypersensitivity to hydralazine; coronary artery disease; mitral valvular rheumatic heart disease.
Hydrochlorothiazide
Anuria; hypersensitivity to this or other sulfonamide-derived drugs.
WARNINGS
Reserpine
Reserpine may cause mental depression. Recognition of depression may be difficult because this condition may often be disguised by somatic complaints. 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.
Hydralazine
In a few patients hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In such patients hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy with this drug. Signs and symptoms usually regress when the drug is discontinued, but residua have been detected many years later. Long-term treatment with steroids may be necessary. (See PRECAUTIONS, Laboratory Tests.)
Hydrochlorothiazide
Thiazides should be used with caution in patients with 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 imbalance may precipitate hepatic coma.
Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.
Sensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
PRECAUTIONS
General
Information for Patients
Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed.
Laboratory Tests
Drug/Drug Interactions
Drug/Laboratory Test Interactions
Thiazides may decrease serum levels of protein-bound iodine without signs of thyroid disturbance. Ser-Ap-Es should be discontinued before tests for parathyroid function are made (see General, Hydrochlorothiazide, Calcium excretion).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, mutagenicity, and fertility studies in animals have not been conducted with Ser-Ap-Es.
Reserpine
Pregnancy
Teratogenic Effects. Pregnancy Category C
Animal reproduction studies have not been conducted with Ser-Ap-Es.
Nonteratogenic Effects
Nursing Mothers
Reserpine is excreted in maternal breast milk, and increased respiratory tract secretions, nasal congestion, cyanosis, and anorexia may occur in breast-fed infants. Thiazides are also excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for reserpine in animal studies, a decision should be made whether to discontinue nursing or to discontinue Ser-Ap-Es, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness of the combination drug in pediatric patients have not been established.
ADVERSE REACTIONS
Adverse reactions are usually reversible upon reduction of dosage or discontinuation of Ser-Ap-Es. 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.
Reserpine
The following have been observed with rauwolfia preparations:
Digestive: Vomiting, diarrhea, nausea, anorexia, dryness of mouth, hypersecretion.
Cardiovascular: Arrhythmias (particularly when used concurrently with digitalis or quinidine), syncope, angina-like symptoms, bradycardia, edema.
Respiratory: Dyspnea, epistaxis, nasal congestion.
Neurologic: Rare parkinsonian syndrome and other extrapyramidal tract symptoms; dizziness; headache; paradoxical anxiety; depression; nervousness, nightmares; dull sensorium; drowsiness.
Musculoskeletal: Muscular aches.
Genitourinary: Pseudolactation, impotence, dysuria, gynecomastia, decreased libido, breast engorgement
Metabolic: Weight gain.
Special Senses: Deafness, optic atrophy, glaucoma, uveitis, conjunctival injection.
Hypersensitive Reactions: Purpura, rash, pruritus.
Hydralazine
Digestive: Hepatitis, paralytic ileus, vomiting, diarrhea, nausea, constipation, anorexia.
Cardiovascular: Angina pectoris, hypotension, paradoxical pressor response, tachycardia, palpitations, edema, flushing.
Respiratory: Dyspnea, nasal congestion.
Neurologic: Psychotic reactions characterized by depression, disorientation, or anxiety; peripheral neuritis, evidenced by paresthesia, numbness, and tingling; tremors; dizziness, headache.
Musculoskeletal: Muscle cramps, arthralgia.
Genitourinary: Difficulty in urination.
Hematologic: Blood dyscrasias, consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis; lymphadenopathy; splenomegaly, eosinophilia.
Special Senses: Conjunctivitis, lacrimation.
Hypersensitive Reactions: Purpura, fever, urticaria, rash, pruritus, chills.
Hydrochlorothiazide
Digestive: Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, anorexia.
Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics).
Neurologic: Vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, restlessness.
Musculoskeletal: Muscle spasm.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
Metabolic: Hyperglycemia, glycosuria, hyperuricemia.
Hypersensitive Reactions: Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress including pneumonitis and pulmonary edema, purpura, urticaria, rash, photosensitivity.
OVERDOSAGE
Acute Toxicity
No deaths due to acute poisoning with Ser-Ap-Es have been reported. Oral LD50’s in animals (mg/kg): rats, 397; mice, 272.
Signs and Symptoms
Treatment
There is no specific antidote.
The gastric spans should be evacuated, taking adequate precautions against aspiration and for protection of the airway. An activated charcoal slurry may be instilled if conditions permit. Dialysis may not be effective for elimination of Ser-Ap-Es because of its plasma protein binding (see CLINICAL PHARMACOLOGY).
These manipulations may have to be omitted or carried out after cardiovascular status has been stabilized, since they might precipitate cardiac arrhythmias or increase the depth of shock.
If hypotension or shock occurs, the patient's legs should be kept raised and lost fluid and electrolytes (potassium, sodium) should be replaced.
Support of the cardiovascular system is of primary importance in suspected hydralazine overdosage. If possible, vasopressors should not be given, but if a vasopressor is required, care should be taken not to precipitate or aggravate cardiac arrhythmia. Tachycardia responds to beta blockers. Digitalization may be necessary.
If hypotension is severe enough to require treatment with a vasopressor, one having a direct action upon vascular smooth muscle (e.g., phenylephrine, levarterenol, metaraminol) should be used to treat the symptomatic effects of reserpine overdosage.
Fluid and electrolyte balance (especially serum potassium) and renal function should be monitored until conditions become normal. Since reserpine is long-acting, the patient should be observed carefully for at least 72 hours.
DOSAGE AND ADMINISTRATION
Dosage should be determined by individual titration (see boxed WARNING). Dosage regimens that exceed 0.25 mg of reserpine per day are not recommended.
HOW SUPPLIED
Tablets – round, salmon pink, dry-coated (imprinted CIBA 71) 0.1 mg of reserpine, 25 mg of hydralazine hydrochloride, 15 mg of hydrochlorothiazide
Bottles of 100.......................................... NDC 0083-0071-30
Bottles of 1000.........................................NDC 0083-0071-40
Do not store above 30ºC (86ºF). Dispense in tight, light-resistant container (USP).
C97-38 (Rev. 1/98)
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936