Metipranolol warnings and precautions

# Warnings
As with other topically applied ophthalmic drugs, this drug may be absorbed systemically. Thus, the same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely, death in association with cardiac failure, have been reported following topical application of beta-adrenergic blocking agents (see CONTRAINDICATIONS).
Since metipranolol ophthalmic solution had a minor effect on heart rate and blood pressure in clinical studies, caution should be observed in treating patients with a history of cardiac failure. Treatment with metipranolol ophthalmic solution should be discontinued at the first evidence of cardiac failure.
Metipranolol ophthalmic solution, or other beta-blockers, should not, in general, be administered to patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity (see CONTRAINDICATIONS). However, if the drug is necessary in such patients, then it should be administered with caution since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta2 receptors.

# Precautions

### General
Because of potential effects of beta-adrenergic receptor blocking agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with metipranolol ophthalmic solution, alternative therapy should be considered.
Some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents in patients undergoing elective surgery. If necessary during surgery, the effects of beta-adrenergic receptor blocking agents may be reversed by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or levarterenol.
While metipranolol ophthalmic solution has demonstrated a low potential for systemic effect, it should be used with caution in patients with diabetes (especially labile diabetes) because of possible masking of signs and symptoms of acute hypoglycemia.
Beta-adrenergic receptor blocking agents may mask certain signs and symptoms of hyperthyroidism, and their abrupt withdrawal might precipitate a thyroid storm.
Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness).
Risk of anaphylactic reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

### Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime studies with metipranolol have been conducted in mice at oral doses of 5, 50 and 100 mg/kg/day and in rats at oral doses of up to 70 mg/kg/day. Metipranolol demonstrated no carcinogenic effect. In the mouse study, female animals receiving the low, but not the intermediate or high dose, had an increased number of pulmonary adenomas. The significance of this observation is unknown. In a variety of in vitro and in vivo bacterial and mammalian cell assays, metipranolol was nonmutagenic.
Reproduction and fertility studies of metipranolol in rats and mice showed no adverse effect on male fertility at oral doses of up to 50 mg/kg/day, and female fertility at oral doses of up to 25 mg/kg/day.