NIDAGEL

1 Dosing Considerations Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, NIDAGEL should be administered cautiously.

Pregnant patients should not be treated during the first trimester of pregnancy (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS). Use during menses is not recommended. 75% vaginal gel should be inserted into the vagina once daily at bedtime for 5 days, or twice daily at morning and bedtime for 5 days.

Controlled studies with alternate dosage schedules have not been conducted. If patients do not respond to initial therapy, it is recommended that appropriate laboratory measures be used to rule out other conditions before retreating with NIDAGEL.

Health Canada has not authorized an indication for pediatric use. 5 Missed Dose If you forget to take NIDAGEL, apply the product at your next scheduled time. Do not double dose.

2 Clinical Trial Adverse Reactions Based on a multi-center clinical trial involving 505 patients, comparing NIDAGEL twice-daily dosing to once-daily dosing, adverse event experiences are listed below, in descending order of frequency: vaginal discharge, descriptions of which varied in both color and consistency (12%), yeast infection (9%), vulval/vaginal irritative symptoms (9%), gastrointestinal discomfort which included patient descriptions of abdominal or stomach cramping, pain and discomfort (7%), headache (5%), nausea and vomiting (4%), pelvic discomfort (3%).

3 Less Common Clinical Trial Adverse Reactions The following reactions were seen at a frequency of 2%:  Gastrointestinal Disorders: cramping  General Disorders: unusual taste  Infections and Infestations: undocumented or self-diagnosed yeast infections  Nervous System Disorders: dizziness The following reactions were seen at a frequency of 1%:  Gastrointestinal Disorders: diarrhea, loose stools  General Disorders: decreased appetite  Infections and Infestations: urinary tract infection symptoms.

 Nervous System Disorders: fatigue PrNIDAGEL® Product Monograph Page 9 of 21  Renal and Urinary Disorders: medication leakage The following reactions were seen at a frequency of <1%:  Gastrointestinal Disorders: abdominal bloating/gas, constipation,  General Disorders: thirst/dry mouth  Nervous System Disorders: depression, irritability  Renal and Urinary Disorders: darkened urine  Reproductive System and Breast Disorders: menstrual discomfort, menstrual irregularities, vaginal numbness, vaginal spotting / bleeding, vulvovaginal burning sensation  Skin and Subcutaneous Tissue Disorders: itching Other reactions noted with oral or other systemic metronidazole therapy include :  Ear and Labyrinth Disorders: hearing impaired/hearing loss (including hypoacusis, deafness, deafness neurosensory), tinnitus, vertigo, incoordination  General Disorders: anorexia, insomnia, flushing, headache  Gastrointestinal Disorders: epigastric distress, nausea, vomiting, furry tongue, dry mouth, metallic taste, modification of taste of alcoholic beverages  Immune System Disorders: transient eosinophilia or neutropenia  Musculoskeletal and Connective Tissue Disorders: palpitation and chest pain.

General Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with NIDAGEL and requires treatment with a candicidal agent. No reports of alcohol interaction were received during clinical studies with NIDAGEL.

Despite the relatively low serum levels of metronidazole afforded by NIDAGEL, the possibility of a disulfiram-like reaction to alcohol while on NIDAGEL therapy cannot be excluded. Patients should be advised to abstain from alcohol during therapy and for one day followi ng therapy.

Carcinogenesis and Mutagenesis Metronidazole has shown evidence of carcinogenic activity following chronic oral administration in mice and rats. Pulmonary tumorigenesis has been reported in mice, and significant increases in the incidence of mammary and hepatic tumors have been found in female rats.

Lifetime tumorigenicity studies in hamsters have given negative results. 75% metronidazole vaginal gel (see NON-CLINICAL TOXICOLOGY). Hematologic Metronidazole is a nitroimidazole and should be used with care in patients with evidence of or history of blood dyscrasia.

A mild transient leukopenia has been observed during oral metronidazole administration. 75% metronidazole vaginal gel a mild, clinically insignificant leukopenia was observed in some patients. Relationship to therapy could not be determined.

75% p/p Vaginal Gel Carbomer 934P, Edetate Disodium, Methylparaben, Propylparaben, Propylene Glycol, Purified Water and Sodium Hydroxide PrNIDAGEL® Product Monograph Page 7 of 21 Hepatic/Biliary/Pancreatic Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in the plasma.

Accordingly, for such patients, NIDAGEL should be administered cautiously. Neurologic Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with oral metronidazole.

NIDAGEL is contraindicated in patients with a prior history of hypersensitivity to metronidazole, parabens, other ingredients of the formulation or other nitroimidazole derivatives. NIDAGEL is contraindicated during the first trimester of pregnancy (see WARNINGS AND PRECAUTIONS).

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