Hypertension and Angina

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 (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).

Respiratory

Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100 patients (see WARNINGS).

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.

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 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, slightly clouded sensorium, and decreased performance on neuropsychometrics.

Cardiovascular

Intensification of AV block (see CONTRAINDICATIONS).

Hematologic

Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.

Hypersensitive Reactions

Fever combined with aching and sore throat, laryngospasm, and respiratory distress.

Heart Failure

In the MERIT-HF study, serious adverse events and adverse events leading to discontinuation of study medication were systematically collected. 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 events vs. 12.2% of placebo patients.

The table below lists adverse events in the MERIT-HF study that occurred at an incidence of equal to or greater than 1% in the TOPROL-XL group and greater than placebo by more than 0.5%, regardless of the assessment of causality.

Adverse Events Occurring in the MERIT-HF Study at an Incidence ≥1% in the TOPROL-XL Group and Greater Than Placebo by More Than 0.5%

Other adverse events with an incidence of > 1% on TOPROL-XL and as common on placebo (within 0.5%) included myocardial infarction, pneumonia, cerebrovascular disorder, chest pain, dyspnea/dyspnea aggravated, syncope, coronary artery disorder, ventricular tachycardia/arrhythmia aggravated, hypotension, diabetes mellitus/diabetes mellitus aggravated, abdominal pain, and fatigue.

Post-Marketing Experience

The following adverse reactions have been reported with TOPROL-XL in worldwide post-marketing use, regardless of causality:

Cardiovascular: 2nd and 3rd degree heart block, cardiogenic shock in patients with acute myocardial infarction.

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.

Catecholamine-depleting drugs (eg, reserpine, mono amine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Patients treated with TOPROL-XL plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

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.

Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Beta-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the beta blocker should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped.

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