Toprol Xl Drug Information

Hypertension Adults

The usual initial dosage is 25 to 100 mg daily in a single dose. Adjust dosage 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: The recommended starting dose of TOPROL-XL is 1 mg/kg once daily, but the maximum initial dose should not exceed 50 mg once daily. Adjust dosage 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. TOPROL-XL has not been studied in pediatric patients < 6 years of age .

Angina Pectoris Individualize the dosage of

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.

Heart Failure Dosage must be individualized and closely monitored during up-titration.

Prior to initiation of TOPROL-XL, stabilize the dose of other heart failure drug therapy. The recommended starting dose of 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 TOPROL-XL. Initial difficulty with titration should not preclude later attempts to introduce TOPROL-XL. If patients experience symptomatic bradycardia, reduce the dose of TOPROL-XL. If transient worsening of heart failure occurs, consider treating with increased doses of diuretics, lowering the dose of TOPROL-XL, or temporarily discontinuing it.

The dose of TOPROL-XL should not be increased until symptoms of worsening heart failure have been stabilized.

Administration

TOPROL-XL tablets are scored and can be divided; however, do not crush or chew the whole or half tablet.

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 TOPROL-XL in daily doses up to 200 mg (mean dose 159 mg once- daily; n=1990) to placebo (n=2001), 10.3% of 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 TOPROL-XL group and greater than placebo by more than 0.5%, regardless of the assessment of causality.

Adverse Reactions Occurring in the MERIT-HF Study at an Incidence ≥1% in the TOPROL-XL Group and Greater Than Placebo by More Than 0.5% TOPROL-XL n=1990 % of patients Placebo n=2001 % of patients Dizziness/vertigo 1.8

Bradycardia 1.5 0.4 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, TOPROL-XL 100 mg was started 2 to 4 hours prior to surgery then continued for 30 days at 200 mg per day. 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.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of 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, 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 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.

Catecholamine Depleting Drugs Catecholamine depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors)

may have an additive effect when given with beta-blocking agents. Observe patients treated with TOPROL-XL plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

CYP2D6 Inhibitors Drugs that are strong inhibitors of

CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone were shown to double metoprolol concentrations. While there is no information about moderate or weak inhibitors, these too are likely to increase metoprolol concentration. Increases in plasma concentration decrease the cardioselectivity of metoprolol.

Monitor patients closely when the combination cannot be avoided.

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 co-administered, 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.

Pregnancy Risk Summary Untreated hypertension and heart failure during pregnancy can lead to adverse outcomes for the mother and the fetus (see Clinical Considerations ). Available data from published observational studies have not demonstrated a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with metoprolol use during pregnancy. However, there are inconsistent reports of intrauterine growth restriction, preterm birth, and perinatal mortality with maternal use of beta-blockers, including metoprolol, during pregnancy (see Data ). In animal reproduction studies, metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, approximately 24 times the daily dose of 200 mg in a 60-kg patient on a mg/m 2 basis. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical consideration Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Pregnant women with hypertension should be carefully monitored and managed accordingly. Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. There is a risk for preterm birth with pregnant women with chronic heart failure in 3rd trimester of pregnancy.

Fetal/Neonatal adverse reactions Metoprolol crosses the placenta. Neonates born to mothers who are receiving metoprolol during pregnancy, may be at risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Observe neonates and manage accordingly.

Data Human Data Data from published observational studies did not demonstrate an association of major congenital malformations and use of metoprolol in pregnancy. The published literature has reported inconsistent findings of intrauterine growth retardation, preterm birth, and perinatal mortality with maternal use of metoprolol during pregnancy; however, these studies have methodological limitations hindering interpretation. Methodological limitations include retrospective design, concomitant use of other medications, and other unadjusted confounders that may account for the study findings including the underlying disease in the mother.

These observational studies cannot definitively establish or exclude any drug-associated risk during pregnancy. Animal Data Metoprolol has been shown to increase post-implantation loss and decrease neonatal survival in rats at oral dosages of 500 mg/kg/day, i.e., 24 times, on a mg/m 2 basis, the daily dose of 200 mg in a 60-kg patient. No fetal abnormalities were observed when pregnant rats received metoprolol orally up to a dose of 200 mg/kg/day, i.e., 10 times, the daily dose of 200 mg in a 60-kg patient.

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 TOPROL-XL (0.2, 1or 2 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 . 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 TOPROL-XL have not been established in patients < 6 years of age.

TOPROL-XL is contraindicated in severe bradycardia, second- or third-degree heart block, cardiogenic shock, decompensated heart failure, sick sinus syndrome (unless a permanent pacemaker is in place), and in patients who are hypersensitive to any component of this product. Known hypersensitivity to product components. Severe bradycardia: Greater than first degree heart block, or sick sinus syndrome without a pacemaker.

Cardiogenic shock or decompensated heart failure.

Signs and Symptoms - Overdosage of 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. Treatment – Consider treating the patient with intensive care.

Patients with myocardial infarction or heart failure may be prone to significant hemodynamic instability. Beta-blocker overdose may result in significant resistance to resuscitation with adrenergic agents, including beta-agonists. On the basis of the pharmacologic actions of metoprolol, employ the following measures: Hemodialysis is unlikely to make a useful contribution to metoprolol elimination.

Bradycardia: Evaluate the need for atropine, adrenergic-stimulating drugs, or pacemaker to treat bradycardia and conduction disorders. Hypotension: Treat underlying bradycardia. Consider intravenous vasopressor infusion, such as dopamine or norepinephrine.

Heart failure and shock: May be treated when appropriate with suitable volume expansion, injection of glucagon (if necessary, followed by an intravenous infusion of glucagon), intravenous administration of adrenergic drugs such as dobutamine, with α 1 receptor agonistic drugs added in presence of vasodilation. Bronchospasm: Can usually be reversed by bronchodilators.