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Label Changes for:

Toprol-XL (metoprolol succinate) extended release tablets

January 2010

Changes have been made to the WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) – January 2010

WARNINGS and PRECAUTIONS

Bronchospastic Disease
  • Because beta1-selectivity is not absolute, use the lowest possible dose of Toprol-XL. Bronchodilators, including beta2-agonists, should be readily available or administered concomitantly
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 Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and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.
Hepatic Impairment
  • Consider initiating 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.
Thyrotoxicosis
  • Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm.
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.

DRUG INTERACTIONS

Catecholamine Depleting Drugs (reworded)
  • Catecholamine-depleting drugs (eg, 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 depletory for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
Digitalis, Clonidine and Calcium Channel Blockers (reworded)
  • 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

ADVERSE REACTIONS

Clinical Trials Experience
  • 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.
  • 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.
Heart Failure (reworded)
  • 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.
Post-Marketing Experience
  • 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.

USE IN SPECIFIC POPULATIONS

Hepatic Impairment
  • No studies have been performed with TOPROL XL in patients with hepatic impairment. Because 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.
Nursing Mothers 
  • Consider possible infant exposure when TOPROL-XL is administered to a nursing woman.
Geriatric Use
  • 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.
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