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VASERETIC®
(ENALAPRIL MALEATE-HYDROCHLOROTHIAZIDE)
TABLETS
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, VASERETIC should be discontinued as soon as possible. See WARNINGS,Pregnancy, Enalapril Maleate, Fetal/Neonatal Morbidity and Mortality.
DESCRIPTION
VASERETIC® (Enalapril Maleate-Hydrochlorothiazide) combines an angiotensin converting enzyme inhibitor, enalapril maleate, and a diuretic, hydrochlorothiazide.
Enalapril maleate is the maleate salt of enalapril, the ethyl ester of a long-acting angiotensin converting enzyme inhibitor, enalaprilat. Enalapril maleate is chemically described as (S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline, (Z)-2-butenedioate salt (1:1). Its empirical formula is C20H28N2O5•C4H4O4, and its structural formula is:
Enalapril maleate is a white to off-white crystalline powder with a molecular weight of 492.53. It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol.
Enalapril is a pro-drug; following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin converting enzyme inhibitor.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8ClN3O4S2 and its structural formula is:
It is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
VASERETIC is available in two tablet combinations of enalapril maleate with hydrochlorothiazide: VASERETIC 5-12.5, containing 5 mg enalapril maleate and 12.5 mg hydrochlorothiazide and VASERETIC 10-25, containing 10 mg enalapril maleate and 25 mg hydrochlorothiazide. Inactive ingredients are: iron oxides, lactose, magnesium stearate, starch and other ingredients.
CLINICAL PHARMACOLOGY
As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium. Administration of enalapril maleate blocks the renin-angiotensin-aldosterone axis and tends to reverse the potassium loss associated with the diuretic.
In clinical studies, the extent of blood pressure reduction seen with the combination of enalapril maleate and hydrochlorothiazide was approximately additive. The antihypertensive effect of VASERETIC was usually sustained for at least 24 hours.
Concomitant administration of enalapril maleate and hydrochlorothiazide has little, or no effect on the bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of the separate entities.
Enalapril Maleate
Hydrochlorothiazide
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect normal blood pressure. Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular mechanism of electrolyte reabsorption. Hydrochlorothiazide 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 two hours, peaks in about four hours and lasts about 6 to 12 hours. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.
INDICATIONS AND USAGE
VASERETIC is indicated for the treatment of hypertension.
These fixed dose combinations are not indicated for initial treatment (See DOSAGE AND ADMINISTRATION).
In using VASERETIC, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that enalapril does not have a similar risk (see WARNINGS).
In considering use of VASERETIC, it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks (see WARNINGS,Angioedema).
CONTRAINDICATIONS
VASERETIC is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
WARNINGS
General
Enalapril Maleate
Pregnancy
PRECAUTIONS
General
Enalapril Maleate
Information for Patients
Drug Interactions
Enalapril Maleate
Carcinogenesis, Mutagenesis, Impairment of Fertility
Enalapril in combination with hydrochlorothiazide was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril-hydrochlorothiazide did not produce DNA single strand breaks in an in vitro alkaline elution assay in rat hepatocytes or chromosomal aberrations in an in vivo mouse bone marrow assay.
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters) (see WARNINGS, Pregnancy, Enalapril Maleate, Fetal/Neonatal Morbidity and Mortality).
Nursing Mothers
Enalapril, enalaprilat, and hydrochlorothiazide have been detected in human breast milk. Because of the potential for serious reactions in nursing infants from either drug, a decision should be made whether to discontinue nursing or to discontinue VASERETIC, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of VASERETIC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient should always include assessment of renal function (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
VASERETIC has been evaluated for safety in more than 1500 patients, including over 300 patients treated for one year or more. In clinical trials with VASERETIC no adverse experiences peculiar to this combination drug have been observed. Adverse experiences that have occurred, have been limited to those that have been previously reported with enalapril or hydrochlorothiazide.
The most frequent clinical adverse experiences in controlled trials were: dizziness (8.6 percent), headache (5.5 percent), fatigue (3.9 percent) and cough (3.5 percent). Generally, adverse experiences were mild and transient in nature. Adverse experiences occurring in greater than two percent of patients treated with VASERETIC in controlled clinical trials are shown below.
| Percent of Patients in Controlled Studies | ||
|---|---|---|
| VASERETIC (n=1580) Incidence (discontinuation) | Placebo (n=230) Incidence | |
| Dizziness | 8.6 (0.7) | 4.3 |
| Headache | 5.5 (0.4) | 9.1 |
| Fatigue | 3.9 (0.8) | 2.6 |
| Cough | 3.5 (0.4) | 0.9 |
| Muscle Cramps | 2.7 (0.2) | 0.9 |
| Nausea | 2.5 (0.4) | 1.7 |
| Asthenia | 2.4 (0.3) | 0.9 |
| Orthostatic Effects | 2.3 (<0.1) | 0.0 |
| Impotence | 2.2 (0.5) | 0.5 |
| Diarrhea | 2.1 (<0.1) | 1.7 |
Clinical adverse experiences occurring in 0.5 to 2.0 percent of patients in controlled trials included: Body As A Whole: Syncope, chest pain, abdominal pain; Cardiovascular: Orthostatic hypotension, palpitation, tachycardia; Digestive: Vomiting, dyspepsia, constipation, flatulence, dry mouth; Nervous/Psychiatric: Insomnia, nervousness, paresthesia, somnolence, vertigo; Skin: Pruritus, rash; Other: Dyspnea, gout, back pain, arthralgia, diaphoresis, decreased libido, tinnitus, urinary tract infection.
Angioedema: Angioedema has been reported in patients receiving VASERETIC, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with VASERETIC should be discontinued and appropriate therapy instituted immediately (see WARNINGS).
Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension (0.9 percent), orthostatic hypotension (1.5 percent), other orthostatic effects (2.3 percent). In addition syncope occurred in 1.3 percent of patients (see WARNINGS).
Cough: See PRECAUTIONS, Cough.
Clinical Laboratory Test Findings
OVERDOSAGE
No specific information is available on the treatment of overdosage with VASERETIC. Treatment is symptomatic and supportive. Therapy with VASERETIC should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.
Enalapril Maleate – Single oral doses of enalapril above 1,000 mg/kg and ≥ 1,775 mg/kg were associated with lethality in mice and rats, respectively. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis (see WARNINGS, Anaphylactoid reactions during membrane exposure).
Hydrochlorothiazide – Lethality was not observed after administration of an oral dose of 10 g/kg to mice and rats. The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.
DOSAGE AND ADMINISTRATION
Enalapril and hydrochlorothiazide are effective treatments for hypertension. The usual dosage range of enalapril is 10 to 40 mg per day administered in a single or two divided doses; hydrochlorothiazide is effective in doses of 12.5 to 50 mg daily. The side effects (see WARNINGS) of enalapril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of enalapril and hydrochlorothiazide will be associated with both sets of dose-independent side effects but the addition of enalapril in clinical trials blunted the hypokalemia normally seen with diuretics. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.
Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with either enalapril or hydrochlorothiazide monotherapy may be given VASERETIC 5-12.5 or VASERETIC 10-25. Further increases of enalapril, hydrochlorothiazide or both depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed. In general, patients do not require doses in excess of 20 mg of enalapril or 50 mg of hydrochlorothiazide. The daily dosage should not exceed four tablets of VASERETIC 5-12.5 or two tablets of VASERETIC 10-25.
Replacement Therapy: The combination may be substituted for the titrated components.
Use in Renal Impairment: The usual regimens of therapy with VASERETIC need not be adjusted as long as the patient's creatinine clearance is >30 mL/min/1.73m2 (serum creatinine approximately ≤ 3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so enalapril maleate-hydrochlorothiazide is not recommended (see WARNINGS, Anaphylactoid reactions during membrane exposure).
HOW SUPPLIED
VASERETIC Tablets 5-12.5 mg, are green, squared capsule-shaped compressed tablets, coded MSD on one side and 173 on the other. Each tablet contains 5 mg of enalapril maleate and 12.5 mg of hydrochlorothiazide. They are supplied as follows:
NDC 64455-145-01 bottles of 100 (with desiccant).
VASERETIC Tablets 10-25 mg, are rust, oval shaped tablets, with one side "MSD 720" and scored and the other side scored. Each tablet contains 10 mg of enalapril maleate and 25 mg of hydrochlorothiazide. They are supplied as follows:
NDC 64455-146-01 bottles of 100 (with desiccant).
Storage: Store below 30°C (86°F) and avoid transient temperatures above 50°C (122°F). Keep container tightly closed. Protect from moisture.
Dispense in a tight container as per USP, if product package is subdivided.
Vaseretic® is a registered trademark of Biovail Laboratories International SRL.
Manufactured by:
Merck Sharp & Dohme Ltd.
Cramlington, Northumberland UK NE23 3JU
Distributed by:
Biovail Pharmaceuticals, Inc.
Bridgewater, NJ 08807, USA
Tablets made in the United Kingdom.
Rev. 03/07
LB0027-04