Metoprolol Succinate and Hydrochlorothiazide

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 Metoprolol Succinate Extended Release/Hydrochlorothiazide, 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 Metoprolol Succinate Extended Release/Hydrochlorothiazide in patients treated only for hypertension.

Heart Failure

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 Metoprolol Succinate Extended Release/Hydrochlorothiazide [see Dosage and Administration (2)]. It may be necessary to lower the dose of Metoprolol Succinate Extended Release/Hydrochlorothiazide or temporarily discontinue it [see Boxed Warning.] Such episodes do not preclude subsequent successful titration of Metoprolol Succinate Extended Release/Hydrochlorothiazide.

Bronchospasm

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 Metoprolol Succinate Extended Release/Hydrochlorothiazide may be used in patients with bronchospastic disease who do not respond to or cannot tolerate other antihypertensive treatment. Because beta1-selectivity is not absolute, in such patients use the lowest possible Metoprolol Succinate Extended Release/Hydrochlorothiazide dose and have bronchodilators (e.g., beta2-agonists) readily available or administer concomitantly.

Bradycardia

Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of Metoprolol Succinate Extended Release/Hydrochlorothiazide. 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 Metoprolol Succinate Extended Release/Hydrochlorothiazide. If severe bradycardia develops, reduce or stop Metoprolol Succinate Extended Release/Hydrochlorothiazide.

Risks of Use in Major Surgery

Avoid initiation of high-dose regimen of Metoprolol Succinate Extended Release/Hydrochlorothiazide 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 Warnings and Precautions (5.1)].

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

Metoprolol Succinate Extended Release/Hydrochlorothiazide 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.

Renal Impairment

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 Metoprolol Succinate Extended Release/Hydrochlorothiazide.

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 Metoprolol Succinate Extended Release/Hydrochlorothiazide 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 Metoprolol Succinate Extended Release/Hydrochlorothiazide 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 Metoprolol Succinate Extended Release/Hydrochlorothiazide contains hydrochlorothiazide, if these symptoms occur, discontinue Metoprolol Succinate Extended Release/Hydrochlorothiazide. 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Metoprolol succinate extended release/hydrochlorothiazide

The metoprolol succinate extended release and hydrochlorothiazide combination was evaluated for safety in 891 patients with hypertension in clinical trials. In a randomized, double-blind, placebo-controlled, factorial trial (Study 1), 843 patients were treated with various combinations of metoprolol succinate (doses of 25 to 200 mg) and hydrochlorothiazide (doses of 6.25 to 25 mg) [see Clinical Studies (14)]. Adverse events which occurred more than 1% more frequently in patients treated with Metoprolol Succinate Extended Release/Hydrochlorothiazide than placebo were: nasopharyngitis (3.4% vs 1.3%) and fatigue (2.6% vs 0.7%).

The adverse reactions of metoprolol succinate extended release are a mixture of dose-dependent phenomena (primarily bradycardia and fatigue) and those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with Metoprolol Succinate Extended Release/Hydrochlorothiazide will be associated with both sets of dose independent reactions.

Laboratory Abnormalities

Liver Enzyme TestsIncreases in liver enzymes or serum bilirubin.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Metoprolol Succinate Extended Release/Hydrochlorothiazide, metoprolol succinate extended release, and/or hydrochlorothiazide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure.

Metoprolol

The following adverse reactions have been reported for immediate release metoprolol tartrate. Most adverse reactions have been mild and transient.

Central Nervous System: Confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia, dizziness

Cardiovascular: Shortness of breath, bradycardia, cold extremities; arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, chest pain

Respiratory: Dyspnea

Gastrointestinal: Diarrhea, nausea, dry mouth, gastric pain, constipation, flatulence, heartburn, hepatitis, vomiting.

Hypersensitivity Reactions: Pruritus, rash

Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, dry eyes, worsening of psoriasis, Peyronie’s disease, sweating, photosensitivity, taste disturbance, depression

Other Beta-Adrenergic Blockers

In addition, adverse reactions not listed above, that have been reported with other beta-adrenoceptor blockers and should be considered potential adverse reactions to Metoprolol Succinate Extended Release/Hydrochlorothiazide.

Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics

Hematologic: Non-thrombocytopenic purpura, thrombocytopenic purpura

Hypersensitivity Reactions: Laryngospasm, and respiratory distress

Hydrochlorothiazide

Adverse reactions that have been reported with hydrochlorothiazide are listed below:

Body as a Whole: Weakness

Cardiovascular: Orthostatic hypotension

Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation, anorexia

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia

Hypersensitivity Reactions: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria

Metabolic: Glycosuria

Musculoskeletal: Muscle spasm

Nervous System/Psychiatric: Vertigo, paresthesias, restlessness

Renal: Interstitial nephritis

Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis

Special Senses: Transient blurred vision, xanthopsia

Drug Interactions with Metoprolol

Reserpine, monoamine oxidase (MAO) inhibitors: The concomitant use of catecholamine-depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors) with beta adrenergic blockers may have an additive affect and increase the risk of hypotension or bradycardia. Observe patients treated with Metoprolol Succinate Extended Release/Hydrochlorothiazide plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

CYP2D6 Inhibitors: Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to increase metoprolol concentration [see Clinical Pharmacology (12.3)].

Nondihydropyridine Calcium Channel Blockers: [See Warnings and Precautions (5.4)].

Digoxin: Digitalis glycosides slow atrioventricular conduction and decrease heart rate. Concomitant use of digoxin with beta adrenergic blockers increases the risk of bradycardia.

Clonidine: Clonidine slows conduction and decrease heart rate. Concomitant use with beta adrenergic blockers increases the risk of bradycardia. If clonidine and Metoprolol Succinate Extended Release/Hydrochlorothiazide are to both be discontinued, withdraw Metoprolol Succinate Extended Release/Hydrochlorothiazide several days before the gradual withdrawal of clonidine to reduce the risk of rebound hypertension following the clonidine withdrawal. If a patient is to switch from clonidine to Metoprolol Succinate Extended Release/Hydrochlorothiazide, delay the introduction of Metoprolol Succinate Extended Release/Hydrochlorothiazide for several days after discontinuation of clonidine.

Epinephrine: [See Warnings and Precautions (5.12)].

Drug Interactions with Hydrochlorothiazide

Antidiabetic drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required.

Ion exchange resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. Stagger the dosage of hydrochlorothiazide and ion exchange resins (e.g., cholestyramine and colestipol resins) such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins to minimize the interaction.

Lithium: Diuretics reduce the renal clearance of lithium and increase the risk of lithium toxicity. Monitor serum lithium concentrations during concurrent use.

Non-Steroidal Anti-Inflammatory Drugs: NSAIDs can reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Metoprolol/hydrochlorothiazide

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].

Metoprolol

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.

Hydrochlorothiazide

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.

A randomized, double-blind, placebo-controlled, 8-week, factorial study (Study 1) (N=1571) evaluated the antihypertensive effects of various doses (given once daily) of metoprolol succinate extended release (25, 50, 100 and 200 mg) and hydrochlorothiazide (6.25, 12.5 and 25 mg), and 9 of their combinations. The trial established that metoprolol succinate extended release and hydrochlorothiazide both contributed to the antihypertensive effect, as measured by the change from baseline to week 8 in sitting diastolic (p= 0.0015) and systolic (p=0.0006) blood pressure. The predicted values for the drugs’ effects are shown in Table 1.

Blood pressure declines were apparent within 2 weeks and were maintained throughout the 8-week study. The blood pressure lowering effect 24 hours post-dosing retained approximately 96% of the peak effect (6 hours post-dosing). The antihypertensive effect was similar regardless of age or gender, and the blood pressure response to the metoprolol succinate extended release and hydrochlorothiazide combination appears similar in black and non-black patients.

Metoprolol Succinate Extended Release/Hydrochlorothiazide is supplied as circular, biconvex, film-coated tablets engraved on one side.

Store at 25°C (77°F). Excursions permitted to 15-30°C (59‑86°F). (See USP Controlled Room Temperature.)