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.
Metoprolol Succinate Extended Release/Hydrochlorothiazide
The metoprolol succinate extended release and hydrochlorothiazide combination was evaluated for safety in 891 patients with hypertension in clinical trials. In a randomized, double-blind, placebo-controlled, factorial trial (Study 1), 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) [see Clinical Studies]. Adverse events which occurred more than 1% more frequently in patients treated with DUTOPROL than placebo were: nasopharyngitis (3.4% vs 1.3%) and fatigue (2.6% vs 0.7%).
The adverse reactions of metoprolol succinate extended release are a mixture of dose-dependent phenomena (primarily bradycardia and fatigue) and 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 DUTOPROL will be associated with both sets of dose independent reactions.
Liver Enzyme Tests—Increases in liver enzymes or serum bilirubin.
The following adverse reactions have been identified during post-approval use of DUTOPROL, metoprolol succinate extended release, and/or hydrochlorothiazide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure.
The following adverse reactions have been reported for immediate release metoprolol tartrate. Most adverse reactions have been mild and transient.
Central Nervous System: Confusion, short-term memory loss, headache, somnolence, nightmares, insomnia, anxiety/nervousness, hallucinations, paresthesia, dizziness
Cardiovascular: Shortness of breath, bradycardia, cold extremities; arterial insufficiency (usually of the Raynaud type), palpitations, peripheral edema, syncope, chest pain
Gastrointestinal: Diarrhea, nausea, dry mouth, gastric pain, constipation, flatulence, heartburn, hepatitis, vomiting.
Hypersensitivity Reactions: Pruritus, rash
Miscellaneous: Musculoskeletal pain, arthralgia, blurred vision, decreased libido, male impotence, tinnitus, reversible alopecia, dry eyes, worsening of psoriasis, Peyronie's disease, sweating, photosensitivity, taste disturbance, depression
Other Beta-Adrenergic Blockers
In addition, adverse reactions not listed above, that have been reported with other beta-adrenoceptor blockers 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, emotional lability, clouded sensorium, and decreased performance on neuropsychometrics.
Hematologic: Non-thrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitivity Reactions: Laryngospasm, and respiratory distress.
Adverse reactions that have been reported with hydrochlorothiazide are listed below:
Body as a Whole: Weakness
Cardiovascular: Orthostatic hypotension
Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation, anorexia
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia
Hypersensitivity Reactions: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria
Musculoskeletal: Muscle spasm
Nervous System/Psychiatric: Vertigo, paresthesias, restlessness
Renal: Interstitial nephritis
Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis
Special Senses: Transient blurred vision, xanthopsia