General

Use of oral suprofen has been associated with a syndrome of acute flank pain and generally reversible renal insufficiency, which may present as acute uric acid nephropathy. This syndrome occurs in approximately 1 in 3500 patients and has been reported with as few as one to two doses of a 200 mg capsule. If PROFENAL 1% Ophthalmic Solution is applied as two drops (1 mg suprofen) to one eye five times on the day prior to surgery and three times on the day of surgery, the total applied dose over the two days would be about 25 times less than a single 200 mg oral dose. Do not touch dropper tip to any surface, as this may contaminate the solution.

Ocular

Patients with histories of herpes simplex keratitis should be monitored closely. PROFENAL is contraindicated in patients with active herpes simplex keratitis.

The possibility of increased ocular bleeding during surgery associated with nonsteroidal anti-inflammatory drugs should be considered.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In an 18-month study in mice, an increased incidence of benign hepatomas occurred in females at a dose of 40 mg/kg/day. Male mice, treated at doses of 2, 5, 10 and 40 mg/kg/day, also had an increased incidence of hepatomas when compared to control animals. No evidence of carcinogenicity was found in long term studies in doses as high as 40 mg/kg/day in the rat and mouse. Based on a battery of mutagenicity tests (Ames, micronucleus, and dominant lethal), suprofen does not appear to have mutagenic potential. Reproductive studies in rats at a dose of up to 40 mg/kg/day revealed no impairment of fertility and only slight reductions of fertility at doses of 80 mg/kg/day. However, testicular atrophy/hypoplasia was observed in a six-month dog study (at 80 mg/kg/day) and a 12-month rat study (at 40 mg/kg/day).

Pregnancy Category C

Reproductive studies have been performed in rabbits at doses up to 200 mg/kg/day and in rats at doses up to 80 mg/kg/day. In rats, doses of 40 mg/kg/day and above, and in rabbits, doses of 80 mg/kg/day and above, resulted in an increased incidence of fetal resorption associated with maternal toxicity. There was an increase in stillbirths and a decrease in postnatal survival in pregnant rats treated with suprofen at 2.5 mg/kg/day and above. An increased incidence of delayed parturition occurred in rats. As there are no adequate and well-controlled studies in pregnant women, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because of the known effect of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.

Nursing Mothers

Suprofen is excreted in human milk after a single oral dose. Based on measurements of plasma and milk levels in women taking oral suprofen, the milk concentration is about 1% of the plasma level. Because systemic absorption may occur from topical ocular administration, a decision should be considered to discontinue nursing while receiving PROFENAL®, since the safety of suprofen in human neonates has not been established.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Drug Interactions

Clinical studies with acetylcholine chloride revealed no interference, and there is no known pharmacological basis for such an interaction. However, with other topical nonsteroidal anti-inflammatory products, there have been reports that acetylcholine chloride and carbachol have been ineffective when used in patients treated with these agents.

Interaction of PROFENAL with other topical ophthalmic medications has not been fully investigated.

Ocular

The most frequent adverse reactions reported are burning and stinging of short duration. Instances of discomfort, itching and redness have been reported. Other reactions occurring in less than 0.5% of patients include allergy, iritis, pain, chemosis, photophobia, irritation, and punctate epithelial staining.

Systemic

Systemic reactions related to therapy were not reported in the clinical studies. It is known that some systemic absorption does occur with ocularly applied drugs, and that nonsteroidal anti-inflammatory drugs have been shown to increase bleeding time by interference with thrombocyte aggregation. It is recommended that PROFENAL be used with caution in patients with bleeding tendencies and those taking anticoagulants.