Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. In patients with impaired renal function, cumulative effects of the drug may develop.
Thiazides should also 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. Potentiation occurs with ganglionic or peripheral adrenergic-blocking drugs.
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.
Propranolol should be used with caution in patients with impaired hepatic or renal function. Inderide is not indicated for the treatment of hypertensive emergencies.
Hydrochlorothiazide
All patients receiving thiazide therapy should be observed for clinical signs 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. Medication such as digitalis may also influence serum electrolytes. Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis or when severe cirrhosis is present.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can 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 supplements or foods with a high potassium content.
Any chloride deficit is generally mild, and usually does not require specific treatment except under extraordinary circumstances (as in liver or renal disease). 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 frank gout may be precipitated in certain patients receiving thiazide therapy.
Diabetes mellitus which has been latent may become manifest during thiazide administration.
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.
Calcium excretion is decreased by thiazides. Pathologic changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulceration, have not been seen.
Information for Patients
Beta-adrenoreceptor blockade can cause reduction of intraocular pressure. Patients should be told that Inderide may interfere with the glaucoma screening test. Withdrawal may lead to a return of increased intraocular pressure.
Laboratory Tests
Propranolol hydrochloride (Inderal®)
Elevated blood urea levels in patients with severe heart disease, elevated serum transaminase, alkaline phosphatase, lactate dehydrogenase.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
Drug/Drug Interactions
Propranolol hydrochloride (Inderal®)
Patients receiving catecholamine-depleting drugs such as reserpine should be closely observed if Inderide is administered. The added catecholamine-blocking action may produce an excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.
Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel blocking drug, especially intravenous verapamil, for both agents may depress myocardial contractility or atrioventricular conduction. On rare occasions, the concomitant intravenous use of a beta blocker and verapamil has resulted in serious adverse reactions, especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by nonsteroidal anti-inflammatory drugs has been reported.
Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.
Aluminum hydroxide gel greatly reduces intestinal absorption of propranolol.
Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.
Phenytoin, phenobarbitone, and rifampin accelerate propranolol clearance.
Chlorpromazine, when used concomitantly with propranolol, results in increased plasma levels of both drugs.
Antipyrine and lidocaine have reduced clearance when used concomitantly with propranolol.
Thyroxine may result in a lower than expected T3 concentration when used concomitantly with propranolol.
Cimetidine decreases the hepatic metabolism of propranolol, delaying elimination and increasing blood levels.
Theophylline clearance is reduced when used concomitantly with propranolol.
Hydrochlorothiazide
Thiazide drugs may increase the responsiveness to tubocurarine.
Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Hypokalemia may develop during concomitant use of corticosteroids or ACTH.
Drug/Laboratory Test Interactions
Hydrochlorothiazide
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Thiazides should be discontinued before carrying out tests for parathyroid function (see “PRECAUTIONS—General”).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Combinations of propranolol and hydrochlorothiazide have not been evaluated for carcinogenic or mutagenic potential or for potential to adversely affect fertility.
Propranolol hydrochloride (Inderal®)
In dietary administration studies in which mice and rats were treated with propranolol for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. In a study in which both male and female rats were exposed to propranolol in their diets at concentrations of up to 0.05%, from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. Based on differing results from Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol in bacteria (S.typhimurium strain TA 1538).
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames bacterial mutagen assay (S.typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538) or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Nor was it genotoxic in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity), Mouse Lymphoma Cell (mutagenicity) and Aspergillus nidulans non-disjunction assays.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.
Pregnancy: Pregnancy Category C
Combinations of propranolol and hydrochlorothiazide have not been evaluated for effects on pregnancy in animals. Nor are there adequate and well-controlled studies of propranolol, hydrochlorothiazide, or Inderide in pregnant women. Inderide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Propranolol hydrochloride (Inderal®)
In a series of reproduction and developmental toxicology studies, propranolol was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day (>30 times the dose of propranolol contained in the maximum recommended human daily dose of Inderide), but not at doses of 80 mg/kg/day, treatment was associated with embryotoxicity (reduced litter size and increased resorption sites) as well as neonatal toxicity (deaths). Propranolol also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (>45 times the dose of propranolol contained in the maximum recommended daily human dose of Inderide). No evidence of embryo or neonatal toxicity was noted.
Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in human neonates whose mothers received propranolol during pregnancy. Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia and/or respiratory depression. Adequate facilities for monitoring these infants at birth should be available.
Hydrochlorothiazide
Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats at doses of up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.
Thiazides cross the placental barrier and appear in cord blood. The use of thiazides in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.
Nursing Mothers
Propranolol hydrochloride (Inderal®)
Propranolol is excreted in human milk. Caution should be exercised when Inderide is administered to a nursing woman.
Hydrochlorothiazide
Thiazides appear in breast milk. If the use of drug is deemed essential, the patient should stop nursing.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of Inderide 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.