ROSIVER

Adverse Drug Reaction Overview During clinical trials, 2047 subjects with inflammatory lesions of rosacea received ROSIVER once daily. A total of 1555 subjects were treated once daily for at least 12 weeks, and 519 subjects were treated for approximately one year.

Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. 7) The safety profile remained stable under conditions of long-term use as observed in long-term treatment for up to one year.

Post-market Adverse Reactions Skin and Subcutaneous Tissue Disorders:

Application site erythema, dermatitis contact (allergic or irritant), rosacea aggravated, swelling face.

Hepatobiliary Disorder:

Transaminase increased. ROSIVER (ivermectin) Product Monograph Page 6 of

General Patients may experience aggravation of rosacea. In case of severe worsening, the treatment should be discontinued. The medicinal product contains: •Cetyl alcohol and stearyl alcohol, which may cause local skin reactions (eg. contact dermatitis), •Methyl parahydroxybenzoate (methyl paraben) and propyl parahydroxybenzoate (propyl paraben), which may cause allergic reactions (possibly delayed), •Propylene glycol, which may cause skin irritation.

Interactions with known irritants or photo-enhancers have not been studied. Concomitant use of potentially irritating topical products or procedures should be avoided. Immune Photosafety and sensitization potential were not specifically evaluated in humans.

Dermal studies in guinea pigs produced evidence of probable delayed sensitization and possible photoallergenicity. See TOXICOLOGY.

Special Populations Pregnant Women:

There are no adequate and well-controlled studies from the topical use of ivermectin in pregnant women. ROSIVER (ivermectin) Cream, 1% should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.

Reproductive toxicity studies have shown that ivermectin administered orally is teratogenic in rats and rabbits. 54 ng/mL) following an oral dose of 150 μg/kg). Excretion in human milk following topical administration has not been evaluated.

In oral studies in rats, ivermectin was excreted in the milk of dams at about 4-fold the maternal plasma concentrations; ivermectin related toxic central nervous system, physical and behavioral development effects and mortality were observed in the litters, which were attributed to the low p-glycoprotein activity of the blood-brain barrier of the rat pups.

Due to the potential for serious adverse reactions from ROSIVER in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ROSIVER (ivermectin) Product Monograph Page 5 of