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Serious adverse reactions are uncommon when verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil. The following reactions to orally administered COVERA-HS occurred at rates greater than 2.0% or occurred at lower rates but appeared drug-related in clinical trials in hypertension and angina:

  Placebo
n=261
%
All doses studied
n=572
%
Constipation 2.7 11.7*
Headache 7.3 6.6
Upper respiratory infection 4.6 5.4
Dizziness 2.7 4.7
Fatigue 3.8 4.5
Edema 3.1 3.0
Nausea 1.9 2.1
AV block (1°) 0.0 1.7
Elevated liver enzymes (see WARNINGS) 0.8 1.4
Bradycardia 0.4 1.4
Paresthesia 0.0 1.0
Flushing 0.3 0.8
Hypotension 0.0 0.7
Postural hypotension 0.3 0.4
* Constipation was typically mild, easily manageable, and the incidence usually diminished within about one week. At a typical once-daily dose of 240 mg, the observed incidence was 7.2%.

In previous experience with other formulations of verapamil, the following reactions occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug related in clinical trials in 4,954 patients.

Constipation 7.3% Dyspnea 1.4%
Dizziness 3.3% Bradycardia (HR < 50/min) 1.4%
Nausea 2.7% AV Block total (1°,2°,3°) 1.2%
Hypotension 2.5% AV Block 2° and 3° 0.8%
Headache 2.2% Rash 1.2%
Edema 1.9% Flushing 0.6%
CHF/Pulmonary Edema 1.8%    
Fatigue 1.7%    
Elevated liver enzymes (see WARNINGS)

The following reactions, reported with orally administered verapamil in 2% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Cardiovascular: angina pectoris, AV block (2° & 3°), atrioventricular dissociation, CHF, pulmonary edema, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope.

Digestive system: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia.

Hemic and lymphatic: ecchymosis or bruising.

Nervous system: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, psychotic symptoms, shakiness, somnolence, extrapyramidal symptoms.

Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme.

Special senses: blurred vision, tinnitus.

Urogenital: gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation, impotence.

Other: allergy aggravated, dyspnea.

Treatment of acute cardiovascular adverse reactions

The frequency of cardiovascular adverse reactions that require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately; e.g., intravenously administered norepinephrine bitartrate, atropine sulfate, isoproterenol HCl (all in usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine HCl, metaraminol bitartrate, or methoxamine HCl) should be used to maintain blood pressure, and isoproterenol and norepinephrine should be avoided. If further support is necessary, dopamine HCl or dobutamine HCl may be administered. Actual treatment and dosage should depend on the severity of the clinical situation and the judgement and experience of the treating physician.