Dutoprol (Tablet, Film Coated)

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Dosing must be individualized considering baseline and target blood pressure as well as experience with individual agents. The side effects of metoprolol succinate extended release are a mixture of dose-dependent phenomena (primarily bradycardia and fatigue); 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 any combination of metoprolol succinate extended release and hydrochlorothiazide will be associated with both sets of dose independent side effects. To minimize the known dose-related tolerability and safety-related effects of the individual agents, consideration should be given to initiating treatment at less than their maximum doses. DUTOPROL may be administered with other antihypertensive agents. DUTOPROL may be administered with or without food. DUTOPROL is administered once daily. Hydrochlorothiazide is effective in doses of 12.5 mg to 50 mg once daily. Patients usually do not require doses in excess of 50 mg hydrochlorothiazide daily when used concomitantly with other antihypertensive agents. The usual initial dose of metoprolol succinate extended release is 25 to 100 mg daily in a single dose. Metoprolol succinate extended release doses greater than 400 mg have not been studied.<br/>Replacement Therapy: DUTOPROL may be substituted for treatment with individual components.<br/>Dose Titration by Clinical Effect: Use the dose necessary based on patient response once the need for combination product is established. Response rates are greater at higher doses. Patients with insufficient blood pressure effects with metoprolol succinate extended release or hydrochlorothiazide alone may be switched to DUTOPROL. The lowest DUTOPROL tablet available is 25/12.5 mg. A 50/6.25 mg dose can be achieved by splitting the 100/12.5 mg tablet. Subsequently titration may be carried out every 2 weeks up to a maximum of 200/25 mg (two DUTOPROL 100/12.5 mg tablets).<br/>Patients with Renal Impairment: The usual regimens of therapy with DUTOPROL may be followed as long as the patient's creatinine clearance is>30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so DUTOPROL is not recommended.<br/>Patients with Hepatic Impairment: The usual regimens of therapy with DUTOPROL may be followed in patients with mild hepatic impairment. In patients with moderate hepatic impairment, consideration should be given to initiation of TOPROL-XL with lower doses of hydrochlorothiazide.

General:: Metoprolol and hydrochlorothiazide have been used individually and in combination for the treatment of hypertension. The antihypertensive effects of these agents are additive. Metoprolol is a beta-selective (cardioselective) adrenergic receptor-blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction. Clinical pharmacology studies have confirmed the beta blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia. The relative beta-selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol is unable to reverse the beta-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol reduces FEVand FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta-receptor blocking doses. The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Using an Emodel, the maximum effect is a 30% reduction in exercise heart rate, which is attributed to beta-blockade. Beta-blocking effects in the range of 30���80% of the maximal effect (approximately 8���23% reduction in exercise heart rate) correspond to metoprolol plasma concentrations from 30-540 nmol/L. The relative beta-selectivity of metoprolol diminishes and blockade of beta-adrenoceptors increases at higher plasma concentrations above 300 nmol/L. Although beta-adrenergic receptor blockade is useful in the treatment of angina, hypertension, and heart failure there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta-blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equimolar amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.<br/>Pharmacokinetics:<br/>Metoprolol succinate extended release/hydrochlorothiazide: After single oral doses of DUTOPROL tablets, the peak plasma concentrations (Cmax) of metoprolol and hydrochlorothiazide are observed within 10-12 hours and 2.0 hours of dose intake, respectively. The rate and extent of absorption of metoprolol/ hydrochlorothiazide are similar in the fasting state and after a high-fat meal when given as DUTOPROL tablets. Single dose pharmacokinetics of metoprolol/hydrochlorothiazide given as DUTOPROL tablets is similar to that of each drug given individually as TOPROL-XL and a formulation of hydrochlorothiazide created for the clinical trial.<br/>Metoprolol: In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration of immediate release metoprolol tablets, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Metoprolol crosses the blood brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Plasma levels achieved are highly variable after oral administration of immediate release metoprolol. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S- enantiomers, and is primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours. Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have nobeta blocking activity. Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%. The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by a number of drugs. Concomitant use of inhibiting drugs in poor metabolizers will increase blood levels of metoprolol several-fold, decreasing metoprolol's cardioselectivity.<br/>Metoprolol succinate extended release: The metoprolol component of DUTOPROL is bioequivalent to TOPROL-XL. In comparison to immediate release metoprolol, the plasma metoprolol levels following administration of TOPROL-XL are characterized by lower peaks, longer time to peak and significantly lower peak to trough variation. The peak plasma levels following once-daily administration of TOPROL-XL average one-fourth to one-half the peak plasma levels obtained following a corresponding dose of immediate release metoprolol, administered once daily or in divided doses. At steady state the average bioavailability of metoprolol following administration of TOPROL-XL, across the dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or divided doses of immediate release metoprolol. Nevertheless, over the 24-hour dosing interval,��-blockade is similar and dose-related . The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose and is not significantly affected by food following TOPROL-XL administration.<br/>Hydrochlorothiazide: Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with a bioavailability of about 60-80%. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours. 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. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours . The bioavailability of hydrochlorothiazide is not significantly affected by food following DUTOPROL administration.<br/>Hypertension: The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity. The mechanism of the antihypertensive effect of thiazide is unknown.<br/>Clinical Trials:<br/>Metoprolol succinate extended release and hydrochlorothiazide: A randomized, double-blind, placebo-controlled, 8-week, unbalanced factorial study (N=1571) evaluated the antihypertensive effects of various doses 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 contribute to the antihypertensive effect, 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 24 hours post dosing retained approximately 96% of the peak (6 hours post dosing) effect. The antihypertensive effect was similar regardless of age or gender, and the response to the metoprolol succinate extended release and hydrochlorothiazide combination appears similar in black and non-black patients.

Metoprolol succinate extended release/hydrochlorothiazide is contraindicated in patients in cardiogenic shock, overt cardiac failure , second or third degree AV block, marked sinus bradycardia, anuria, and hypersensitivity to either component of this product or to other sulfonamide-derived drugs.

Ischemic Heart Disease: Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered DUTOPROL, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1���2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, DUTOPROL or beta-blocking agent administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may beprudent not to discontinue DUTOPROL therapy abruptly even in patients treated only for hypertension.

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Metoprolol succinate and hydrochlorothiazide

Metoprolol succinate extended release/hydrochlorothiazide: The metoprolol succinate extended release and hydrochlorothiazide combination was evaluated for safety in 891 patients treated for hypertension in clinical trials. In a placebo-controlled trial, 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). Overall, the incidence of adverse experiences reported with the combination was comparable to placebo. Adverse events, whether or not attributed to treatment, occurring in greater than 1% of patients treated with DUTOPROL and at a rate equal to or greater than with placebo were: nasopharyngitis (3.4% vs 1.3%), fatigue (2.6% vs 0.7%), dizziness (2.6% vs 2.6%), back pain (1.7% vs 1.3%), and nausea (1.4% vs 0.7%). Adverse experiences were usually mild and transient in nature and infrequently required discontinuation of therapy (2.7% vs 2.6% with placebo).<br/>Metoprolol: Most adverse effects have been mild and transient. The following adverse reactions have been reported for immediate release metoprolol tartrate. Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100 patients. Depression has been reported in about 5 of 100 patients. Mental confusion and short-term memory loss have been reported. Headache, somnolence, nightmares, and insomnia have also been reported. Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of 100 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; congestive heart failure; peripheral edema; syncope; chest pain; and hypotension have been reported in about 1 of 100 patients . Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100 patients . Gastrointestinal: Diarrhea has occurred in about 5 of 100 patients. Nausea, dry mouth, gastric pain, constipation, flatulence, digestive tract disorders, and heartburn have been reported in about 1 of 100 patients. Hypersensitive Reactions: Pruritus or rash have occurred in about 5 of 100 patients. Worsening of psoriasis has also been reported. Miscellaneous: Peyronie's disease has been reported in fewer than 1 of 100,000 patients. Musculoskeletal pain, blurred vision, decreased libido, and tinnitus have also been reported. There have been rare reports of reversible alopecia, agranulocytosis, and dry eyes. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with metoprolol.<br/>Potential Adverse Reactions: In addition, there are a variety of adverse reactions not listed above, which have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to DUTOPROL. Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. Cardiovascular: Intensification of AV block . Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm, and respiratory distress.<br/>Post-Marketing Experience: In addition, the following adverse reactions have been reported with metoprolol succinate in worldwide post-marketing use, regardless of causality: Cardiovascular: 2and 3degree heart block. Gastrointestinal: hepatitis, vomiting. Hematologic: thrombocytopenia. Musculoskeletal: arthralgia. Nervous System/Psychiatric: anxiety/nervousness, hallucinations, paresthesia. Reproductive, male: impotence. Skin: increased sweating, photosensitivity, urticaria. Special Sense Organs: taste disturbances.<br/>Hydrochlorothiazide: Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed below: Body As A Whole: weakness; Cardiovascular: hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics or antihypertensive drugs); Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia; Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia; Hypersensitivity: anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura; Metabolic: electrolyte imbalance, glycosuria; Musculoskeletal: muscle spasm; Nervous System/Psychiatric: Vertigo, paresthesias, dizziness, headache, restlessness; Renal: renal failure, renal dysfunction, interstitial nephritis; Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia; Special Senses: transient blurred vision, xanthopsia; Urogenital: impotence.

Hypertension: DUTOPROL is indicated for the management of hypertension. The fixed-dose combination is not indicated for initial therapy .

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