IOPIDINE 1% apraclonidine hydrochloride ophthalmic solution 10 mg/mL Solution/ Drops — NDC 82667-200-01 (Billing 82667-0200-01)

WARNINGS FOR TOPICAL OPHTHALMIC USE ONLY. Not for injection or oral ingestion. Topical administration of apraclonidine have been reported to cause cardiovascular collapse requiring intubation and ventilation in pediatric patients 6 years and younger, including neonates.

Systemic adverse reactions such as prolonged lethargy and unresponsiveness, apnea, hypoxia, respiratory failure, bradycardia, hypertension, hypotension, hypothermia, hypotonia, pallor have also been reported. Appropriate monitoring in a clinical setting should be in place.

ADVERSE REACTIONS The following adverse events, occurring in less than 2% of patients, were reported in association with the use of IOPIDINE 1% Ophthalmic Solution in laser surgery: ocular injection, upper lid elevation, irregular heart rate, nasal decongestion, ocular inflammation, conjunctival blanching, and mydriasis. The following adverse events were observed in investigational studies dosing IOPIDINE 1% Ophthalmic Solution once or twice daily for up to 28 days in non‑laser studies: Ocular Conjunctival blanching, upper lid elevation, mydriasis, burning, discomfort, foreign body sensation, dryness, itching, hypotony, blurred or dimmed vision, allergic response, conjunctival microhemorrhage.

Gastrointestinal Abdominal pain, diarrhea, stomach discomfort, emesis Cardiovascular Bradycardia, vasovagal attack, palpitations, orthostatic episode Central Nervous System Insomnia, dream disturbances, irritability, decreased libido. Other Taste abnormalities, dry mouth, nasal burning or dryness, headache, head cold sensation, chest heaviness or burning, clammy or sweaty palms, body heat sensation, shortness of breath, increased pharyngeal secretion, extremity pain or numbness, fatigue, paresthesia, pruritus not associated with rash.

Clinical Practice The following events have been identified during postmarketing use of IOPIDINE 1% Ophthalmic Solution in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to IOPIDINE 1% Ophthalmic Solution, or a combination of these factors, include • Hypersensitivity. • Cardiovascular collapse requiring intubation and ventilation, prolonged lethargy and unresponsiveness, apnea, hypoxia, respiratory failure, hypertension, hypotension, hypothermia, hypotonia, and pallor have been reported in pediatric patients 6 years and younger, including neonates, following topical administration of apraclonidine.

DRUG INTERACTIONS Interactions with other agents have not been investigated.

PRECAUTIONS PRECAUTIONS GENERAL Since IOPIDINE* 1% Ophthalmic Solution is a potent depressor of IOP, patients who develop exaggerated reductions in IOP should be closely monitored. Although the acute administration of two drops of IOPIDINE 1% Ophthalmic Solution has minimal effect on heart rate or blood pressure in clinical studies evaluating patients undergoing anterior segment laser surgery, the preclinical pharmacologic profile of this drug suggests that caution should be observed in treating patients with severe cardiovascular disease including hypertension.

IOPIDINE 1% Ophthalmic Solution should also be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, Raynaud’s disease or thromboangiitis obliterans. The possibility of a vasovagal attack occurring during laser surgery should be considered and caution used in patients with history of such episodes. Topical ocular administration of two drops of 0.5%, 1%, and 1.5% IOPIDINE Ophthalmic Solution to New Zealand Albino rabbits three times daily for one month resulted in sporadic and transient instances of minimal corneal cloudiness in the 1.5% group only.

No histopathological changes were noted in those eyes. No adverse ocular effects were observed in cynomolgus monkeys treated with two drops of 1.5% IOPIDINE Ophthalmic Solution applied three times daily for three months. No corneal changes were observed in 320 humans given at least one dose of IOPIDINE 1% Ophthalmic Solution.

INFORMATION FOR PATIENTS Apraclonidine can cause dizziness and somnolence. Patients who engage in hazardous activities requiring mental alertness should be warned of the potential for a decrease in mental alertness on the day of surgery. DRUG INTERACTIONS Interactions with other agents have not been investigated.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY No significant change in tumor incidence or type was observed following two years of oral administration of apraclonidine HCl to rats and mice at dosages of 1 and 0.6 mg/kg/day, up to 50 and 30 times, respectively, the maximum dose recommended for human topical ocular use. Apraclonidine HCl was not mutagenic in a series of in vitro mutagenicity tests, including the Ames test, a mouse lymphoma forward mutation assay, a chromosome aberration assay in cultured Chinese hamster ovary (CHO) cells, a sister chromatid exchange assay in CHO cells, and a cell transformation assay.

An in vivo mouse micronucleus assay conducted with apraclonidine HCl also provided no evidence of mutagenicity. Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at a dose of 0.5 mg/kg/day (25 times the maximum recommended human dose). PREGNANCY Apraclonidine HCl has been shown to have an embryocidal effect in rabbits when given in an oral dose of 3 mg/kg/day (150 times the maximum recommended human dose).

Dose related maternal toxicity was observed in pregnant rats at 0.3 mg/kg/day (15 times the maximum recommended human dose). There are no adequate and well controlled studies in pregnant women. IOPIDINE* 1% Ophthalmic Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NURSING MOTHERS It is not known if topically applied IOPIDINE 1% Ophthalmic Solution is excreted in human milk. Decision should be made to discontinue nursing temporarily for the one day on which IOPIDINE 1% Ophthalmic Solution is used. PEDIATRIC USE Safety and effectiveness in pediatric patients have not been established.

During postmarketing surveillance, cardiovascular collapse requiring intubation and ventilation, prolonged lethargy and unresponsiveness, apnea, hypoxia, respiratory failure, bradycardia, hypertension, hypotension, hypothermia, hypotonia, and pallor have been reported in pediatric patients 6 years and younger, including neonates, following topical administration of apraclonidine (see WARNINGS). G… [Excerpted — this section continues on DailyMed.]