Included as part of the "PRECAUTIONS" Section
Cardiac Ischemia After Abrupt Discontinuation
Following abrupt cessation of therapy with beta adrenergic blockers, exacerbations of angina pectoris and myocardial infarction may occur. When discontinuing chronically administered DUTOPROL,
particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1–2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly resume therapy and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without their physician’s advice. Because coronary artery disease is common and may be unrecognized, avoid abrupt discontinuation of DUTOPROL in patients treated only for hypertension.
Worsening cardiac failure may occur during up-titration of beta-blockers. If such symptoms occur, increase diuretics and restore clinical stability (compensated heart failure) before advancing the dose of DUTOPROL [see DOSAGE AND ADMINISTRATION]. It may be necessary to lower the dose of DUTOPROL or temporarily discontinue it [see BOX WARNING.] Such episodes do not preclude subsequent successful titration of DUTOPROL.
Beta adrenergic blockers can cause bronchospasm. Patients with bronchospastic disease should, in general, not receive beta adrenergic blockers. Because of its relative beta1 cardio-selectivity, however, metoprolol-containing products including DUTOPROL may be used in patients with bronchospastic disease who do not respond to or cannot tolerate other antihypertensive treatment. Because beta1selectivity
is not absolute, in such patients use the lowest possible DUTOPROL dose and have bronchodilators (e.g., beta2-agonists) readily available or administer concomitantly.
Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of Dutoprol. Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction disorders (including Wolff-Parkinson-White) may be at increased risk. The concomitant use of beta adrenergic blockers and non-dihydropyridine calcium channel blockers (e.g., verapamil and diltiazem), digoxin or clonidine increases the risk of significant bradycardia. Monitor heart rate and rhythm in patients receiving Dutoprol. If severe bradycardia develops, reduce or stop Dutoprol.
Risks Of Use In Major Surgery
Avoid initiation of high-dose regimen of DUTOPROL in patients with cardiovascular risk factors undergoing non-cardiac surgery, since use in such patients has been associated with bradycardia, hypotension, stroke and death.
Chronically administered beta adrenergic blockers should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures [see Cardiac Ischemia After Abrupt Discontinuation].
Masked Signs Of Hypoglycemia
Beta adrenergic blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
Electrolyte And Metabolic Effects
DUTOPROL contains hydrochlorothiazide which can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Monitor serum electrolytes periodically.
Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
Hydrochlorothiazide reduces clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.
Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.
Patients with chronic kidney disease, severe heart failure, or volume depletion may be at increased risk for developing acute renal failure on drugs containing hydrochlorothiazide, including DUTOPROL.
Exacerbated Symptoms Of Peripheral Vascular Disease
Beta adrenergic blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.
Increased Blood Pressure In Patients With Pheochromocytoma
Administration of beta adrenergic blockers alone in patients with pheochromocytoma has been associated with a paradoxical increase in blood pressure because of the attenuation of beta-mediated vasodilatation in skeletal muscle. If DUTOPROL is used in patients with pheochromocytoma, first initiate an alpha-blocker.
Thyrotoxicosis After Discontinuation In Patients With Hyperthyroidism
Beta adrenergic blockers may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of a beta adrenergic blocker may precipitate a thyroid storm. Therefore, in patients with hyperthyroidism discontinue DUTOPROL gradually.
Reduced Effectiveness Of Epinephrine In Treating Anaphylaxis
Beta adrenergic blocker-treated patients treated with epinephrine for a severe anaphylactic reaction may be less responsive to the typical doses of epinephrine. In these patients, consider other medications.
Acute Myopia And Secondary Angle-Closure Glaucoma
Hydrochlorothiazide, a sulfonamide, can cause acute transient myopia and acute angle-closure glaucoma (idiosyncratic reactions). Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of hydrochlorothiazide initiation. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Untreated acute angle-closure glaucoma can lead to permanent vision loss. Given that DUTOPROL contains hydrochlorothiazide, if these symptoms occur, discontinue DUTOPROL. Consider prompt medical or surgical treatment if the intraocular pressure remains uncontrolled.
Exacerbation Of Systemic Lupus Erythematosus
Hydrochlorothiazide can exacerbate or activate systemic lupus erythematosus.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity and mutagenicity studies have not been conducted with combinations of metoprolol and hydrochlorothiazide.
A combination of metoprolol tartrate and hydrochlorothiazide produced no adverse effects on the fertility and reproductive performance of male and female rats at doses of up to 200/50 mg/kg/day [about 10 and 20 times the maximum recommended human dose (MRHD) of metoprolol and hydrochlorothiazide, respectively, on a mg/m2 basis].
Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats at oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day (about 18 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.
All genotoxicity tests performed with metoprolol tartrate (a dominant lethal study in mice, chromosomal studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) and metoprolol succinate (a Salmonella/mammalian-microsome mutagenicity test) were negative.
No evidence of impaired fertility was observed in a study of metoprolol tartrate performed in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60 kg patient.
Two-year feeding studies in mice and rats uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice at doses of up to 600 mg/kg/day (about 120 times the MRHD of 25 mg/day) or in male and female rats at doses of up to 100 mg/kg/day (about 40 times the MRHD). However, there was equivocal evidence of hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in the Ames bacterial mutagenicity test or the in vitro 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 results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test, the Mouse Lymphoma Cell (mutagenicity) assay and the Aspergillus nidulans non-disjunction assay.
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 and 4 mg/kg/day (about 20 and 1.6 times the MRHD, on a mg/m2 basis), respectively, prior to mating and throughout gestation.
Use In Specific Populations
Pregnancy Category C
Oral administration of metoprolol tartrate/hydrochlorothiazide combinations to pregnant rats during organogenesis at doses up to 200/50 mg/kg/day (10 and 20 times the MRHD for metoprolol and hydrochlorothiazide, respectively) or to pregnant rabbits at doses up to 25/6.25 mg/kg/day (about 2.5 and 5 times the MRHD for metoprolol and hydrochlorothiazide, respectively) produced no teratogenic effects. A 200/50 mg/kg/day metoprolol tartrate/hydrochlorothiazide combination administered to rats from mid-late gestation through lactation produced increased post-implantation loss and decreased neonatal survival.
There are no adequate and well-controlled studies of metoprolol in pregnant women. Metoprolol tartrate has been shown to increase post-implantation loss and decrease neonatal survival in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60-kg patient. Distribution studies in mice confirm exposure of the fetus when metoprolol tartrate is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratogenicity. Because animal reproduction studies are not always predictive of human response, use this drug during pregnancy only if clearly needed.
The use of thiazide diuretics in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions, which have occurred in the adult. Hydrochlorothiazide administered to pregnant mice and rats during organogenesis at doses up to 3000 and 1000 mg/kg/day (600 and 400 times the MRHD), respectively, produced no harm to the fetus. Thiazides cross the placental barrier and appear in the cord blood.
Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of metoprolol. Thiazide diuretics appear in human milk. Consider possible infant exposure when DUTOPROL is administered to a nursing woman.
Safety and effectiveness in pediatric patients have not been established.
Of the 849 subjects randomized to treatment with both metoprolol succinate extended release and hydrochlorothiazide in a factorial clinical study, 129 (15%) were 65 and over, while 16 (2%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. In addition, patients 70 to 84 years of age were studied in two clinical outcome trials (n=3025), which included a treatment regimen of a thiazide diuretic or beta adrenergic blocker (metoprolol succinate extended release, atenolol or pindolol) or their combination have not identified differences in responses between the elderly and younger patients.
Hydrochlorothiazide 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.
Use In Patients With Hepatic Impairment
Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.
Use In Patients With Renal Impairment
Safety and effectiveness of DUTOPROL in patients with severe renal impairment (CrCL≤30 ml/min)
have not been established. No dose adjustment is required in patients with moderate renal impairment (CrCL 30-60 ml/min).