Beloc Zok Toprol XL 25 Mg Extended Release 20 Film Tablets Astra Zeneca

Beloc Zok Toprol XL 25 Mg Extended Release 20 Film Tablets Astra Zeneca

Brand:ASTRA ZENECA Pharmaceuticals
Product Code:114
Availability:In Stock

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: ISCHEMIC HEART DISEASE:

1 INDICATIONS AND USAGE

1.1 Hypertension

1.2 Angina Pectoris

1.3 Heart Failure

2 DOSAGE AND ADMINISTRATION

2.1 Hypertension

2.2 Angina Pectoris

2.3 Heart Failure

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Ischemic Heart Disease

5.2 Heart Failure

5.3 Bronchospastic Disease

5.4 Pheochromocytoma

5.5 Major Surgery

5.6 Diabetes and Hypoglycemia

5.7 Hepatic Impairment

5.8 Thyrotoxicosis

5.9 Anaphylactic Reaction

5.10 Peripheral Vascular Disease

5.11 Calcium Channel Blockers

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-Marketing Experience

6.3 Laboratory Test Findings

7 DRUG INTERACTIONS

7.1 Catecholamine Depleting Drugs

7.2 CYP2D6 Inhibitors

7.3 Digitalis, Clonidine, and Calcium Channel Blockers

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Angina Pectoris

14.2 Heart Failure

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: 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 Beloc Zoc (Toprol XL), 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, Beloc Zoc (Toprol XL) administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Warn patients against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue Beloc Zoc (Toprol XL) therapy abruptly even in patients treated only for hypertension (5.1).

1 INDICATIONS AND USAGE

1.1 Hypertension

Beloc Zoc (Toprol XL) is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including metoprolol.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (eg, on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Beloc Zoc (Toprol XL) may be administered with other antihypertensive agents.

1.2 Angina Pectoris

Beloc Zoc (Toprol XL) is indicated in the long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance.

1.3 Heart Failure

Beloc Zoc (Toprol XL) is indicated for the treatment of stable, symptomatic (NYHA Class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. It was studied in patients already receiving ACE inhibitors, diuretics, and, in the majority of cases, digitalis. In this population, Beloc Zoc (Toprol XL) decreased the rate of mortality plus hospitalization, largely through a reduction in cardiovascular mortality and hospitalizations for heart failure.

2 DOSAGE AND ADMINISTRATION

Beloc Zoc (Toprol XL) is an extended-release tablet intended for once daily administration. For treatment of hypertension and angina, when switching from immediate-release metoprolol to Beloc Zoc (Toprol XL), use the same total daily dose of Beloc Zoc (Toprol XL). Individualize the dosage of Beloc Zoc (Toprol XL). Titration may be needed in some patients.

Beloc Zoc (Toprol XL) tablets are scored and can be divided; however, do not crush or chew the whole or half tablet.

2.1 Hypertension

Adults: The usual initial dosage is 25 to 100 mg daily in a single dose. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved. In general, the maximum effect of any given dosage level will be apparent after 1 week of therapy. Dosages above 400 mg per day have not been studied.

Pediatric Hypertensive Patients ≥ 6 Years of age: A pediatric clinical hypertension study in patients 6 to 16 years of age did not meet its primary endpoint (dose response for reduction in SBP); however some other endpoints demonstrated effectiveness [see Use in Specific Populations (8.4)]. If selected for treatment, the recommended starting dose of Beloc Zoc (Toprol XL) is 1 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily. Dosage should be adjusted according to blood pressure response. Doses above 2 mg/kg (or in excess of 200 mg) once daily have not been studied in pediatric patients [see Clinical Pharmacology (12.3)].

Beloc Zoc (Toprol XL) is not recommended in pediatric patients < 6 years of age [see Use in Specific Populations (8.4)].

2.2 Angina Pectoris

Individualize the dosage of Beloc Zoc (Toprol XL). The usual initial dosage is 100 mg daily, given in a single dose. Gradually increase the dosage at weekly intervals until optimum clinical response has been obtained or there is a pronounced slowing of the heart rate. Dosages above 400 mg per day have not been studied. If treatment is to be discontinued, reduce the dosage gradually over a period of 1 - 2 weeks [see Warnings and Precautions (5)].

2.3 Heart Failure

Dosage must be individualized and closely monitored during up-titration. Prior to initiation of Beloc Zoc (Toprol XL), stabilize the dose of other heart failure drug therapy. The recommended starting dose of Beloc Zoc (Toprol XL) is 25 mg once daily for two weeks in patients with NYHA Class II heart failure and 12.5 mg once daily in patients with more severe heart failure. Double the dose every two weeks to the highest dosage level tolerated by the patient or up to 200 mg of Beloc Zoc (Toprol XL). Initial difficulty with titration should not preclude later attempts to introduce Beloc Zoc (Toprol XL). If patients experience symptomatic bradycardia, reduce the dose of Beloc Zoc (Toprol XL). If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of Beloc Zoc (Toprol XL) or temporarily discontinuing it. The dose of Beloc Zoc (Toprol XL) should not be increased until symptoms of worsening heart failure have been stabilized.

3 DOSAGE FORMS AND STRENGTHS

25 mg tablets White, oval, biconvex, film-coated scored tablet engraved with “A/β”.

50 mg tablets: White, round, biconvex, film-coated scored tablet engraved with “A/mo”.

100 mg tablets: White, round, biconvex, film-coated scored tablet engraved with “A/ms”.

200 mg tablets: White, oval, biconvex, film-coated scored tablet engraved with “A/my”.

4 CONTRAINDICATIONS

Beloc Zoc (Toprol XL) is contraindicated in severe bradycardia, second or third degree heart block, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product.

5 WARNINGS AND PRECAUTIONS

5.1 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 Beloc Zoc (Toprol XL), 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 reinstate Beloc Zoc (Toprol XL), 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 abruptly discontinuing Beloc Zoc (Toprol XL) in patients treated only for hypertension.

5.2 Heart Failure

Worsening cardiac failure may occur during up-titration of Beloc Zoc (Toprol XL). If such symptoms occur, increase diuretics and restore clinical stability before advancing the dose of Beloc Zoc (Toprol XL)[see Dosage and Administration (2)]. It may be necessary to lower the dose of Beloc Zoc (Toprol XL) or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of Beloc Zoc (Toprol XL).

5.3 Bronchospastic Disease

PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1 cardio-selectivity, however, Beloc Zoc (Toprol XL) 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, use the lowest possible dose of Beloc Zoc (Toprol XL). Bronchodilators, including beta2-agonists, should be readily available or administered concomitantly [see Dosage and Administration (2)].

5.4 Pheochromocytoma

If Beloc Zoc (Toprol XL) is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.

5.5 Major Surgery

Avoid initiation of a high-dose regimen of extended-release metoprolol in patients undergoing non-cardiac surgery, since such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke and death.

Chronically administered beta-blocking therapy 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.

5.6 Diabetes and Hypoglycemia

Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.

5.7 Hepatic Impairment

Consider initiating Beloc Zoc (Toprol XL) therapy at doses lower than those recommended for a given indication; gradually increase dosage to optimize therapy, while monitoring closely for adverse events.

5.8 Thyrotoxicosis

Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.

5.9 Anaphylactic Reaction

While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.

5.10 Peripheral Vascular Disease

Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

5.11 Calcium Channel Blockers

Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly.

6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in labeling:

•Worsening angina or myocardial infarction. [see Warnings and Precautions (5)]

•Worsening heart failure. [see Warnings and Precautions (5)]

•Worsening AV block. [see Contraindications (4)]

6.1 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.

Hypertension and Angina: Most adverse reactions have been mild and transient. The most common (>2%) adverse reactions are tiredness, dizziness, depression, diarrhea, shortness of breath, bradycardia, and rash.

Heart Failure: In the MERIT-HF study comparing Beloc Zoc (Toprol XL) in daily doses up to 200 mg (mean dose 159 mg once-daily; n=1990) to placebo (n=2001), 10.3% of Beloc Zoc (Toprol XL) patients discontinued for adverse reactions vs. 12.2% of placebo patients.

The table below lists adverse reactions in the MERIT-HF study that occurred at an incidence of ≥ 1% in the Beloc Zoc (Toprol XL) group and greater than placebo by more than 0.5%, regardless of the assessment of causality.

Post-operative Adverse Events: In a randomized, double-blind, placebo-controlled trial of 8351 patients with or at risk for atherosclerotic disease undergoing non-vascular surgery and who were not taking beta–blocker therapy, Beloc Zoc (Toprol XL) 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. Beloc Zoc (Toprol XL) use was associated with a higher incidence of bradycardia (6.6% vs. 2.4%; HR, 2.74; 95% CI 2.19, 3.43), hypotension (15% vs. 9.7%; HR 1.55; 95% CI 1.37, 1.74), stroke (1.0% vs. 0.5%; HR 2.17; 95% CI 1.26, 3.74) and death (3.1% vs. 2.3%; HR 1.33; 95% CI 1.03, 1.74) compared to placebo.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Beloc Zoc (Toprol XL) or immediate-release metoprolol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular: Cold extremities, arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, chest pain and hypotension.

Respiratory: Wheezing (bronchospasm), dyspnea.

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

Gastrointestinal: Nausea, dry mouth, constipation, flatulence, heartburn, hepatitis, vomiting.

Hypersensitive Reactions: Pruritus.

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

Potential Adverse Reactions: In addition, there are adverse reactions not listed above that have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to Beloc Zoc (Toprol XL).

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, clouded sensorium, and decreased performance on neuropsychometrics.

Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.

Hypersensitive Reactions: Laryngospasm, respiratory distress.

6.3 Laboratory Test Findings

Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.

7 DRUG INTERACTIONS

7.1 Catecholamine Depleting Drugs

Catecholamine depleting drugs (eg, reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with Beloc Zoc (Toprol XL) plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

7.2 CYP2D6 Inhibitors

Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to increase metoprolol concentration. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg and immediate-release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release metoprolol 50 mg t.i.d. resulted in two- to five-fold increases in the steady-state concentration of metoprolol. These increases in plasma concentration would decrease the cardioselectivity of metoprolol.

7.3 Digitalis, Clonidine, and Calcium Channel Blockers

Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia.

If clonidine and a beta blocker, such as metoprolol are coadministered, withdraw the beta-blocker several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped [see Warnings and Precautions (5.11)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

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. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, use this drug during pregnancy only if clearly needed.

8.3 Nursing Mothers

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 the drug. Consider possible infant exposure when Beloc Zoc (Toprol XL) is administered to a nursing woman.

8.4 Pediatric Use

One hundred forty-four hypertensive pediatric patients aged 6 to 16 years were randomized to placebo or to one of three dose levels of Beloc Zoc (Toprol XL) (0.2, 1.0 or 2.0 mg/kg once daily) and followed for 4 weeks. The study did not meet its primary endpoint (dose response for reduction in SBP). Some pre-specified secondary endpoints demonstrated effectiveness including:

•Dose-response for reduction in DBP,

•1 mg/kg vs. placebo for change in SBP, and

•2 mg/kg vs. placebo for change in SBP and DBP.

The mean placebo corrected reductions in SBP ranged from 3 to 6 mmHg, and DBP from 1 to 5 mmHg. Mean reduction in heart rate ranged from 5 to 7 bpm but considerably greater reductions were seen in some individuals [see Dosage and Administration (2.1)].

No clinically relevant differences in the adverse event profile were observed for pediatric patients aged 6 to 16 years as compared with adult patients.

Safety and effectiveness of Beloc Zoc (Toprol XL) have not been established in patients < 6 years of age.

8.5 Geriatric Use

Clinical studies of Beloc Zoc (Toprol XL) in hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in hypertensive patients has not identified differences in responses between elderly and younger patients.

Of the 1,990 patients with heart failure randomized to Beloc Zoc (Toprol XL) in the MERIT-HF trial, 50% (990) were 65 years of age and older and 12% (238) were 75 years of age and older. There were no notable differences in efficacy or the rate of adverse reactions between older and younger patients.

In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

No studies have been performed with Beloc Zoc (Toprol XL) in patients with hepatic impairment. Because Beloc Zoc (Toprol XL) is metabolized by the liver, metoprolol blood levels are likely to increase substantially with poor hepatic function. Therefore, initiate therapy at doses lower than those recommended for a given indication; and increase doses gradually in patients with impaired hepatic function.

8.7 Renal Impairment

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. No reduction in dosage is needed in patients with chronic renal failure [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Signs and Symptoms - Overdosage of Beloc Zoc (Toprol XL) may lead to severe bradycardia, hypotension, and cardiogenic shock. Clinical presentation can also include: atrioventricular block, heart failure, bronchospasm, hypoxia, impairment of consciousness/coma, nausea and vomiting.

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