Veregen

1 INDICATIONS AND USAGE Veregen is a topical ointment indicated for the treatment of external genital and perianal warts (Condylomata acuminata) in immunocompetent patients 18 years and older (1.1) . Limitations of Use Safety and effectiveness of Veregen have not been established in immunosuppressed patients, in treatment of external genital and perianal warts beyond 16-weeks, or for multiple treatment courses (1.2) . 1.1 Indication Veregen is indicated for the topical treatment of external genital and perianal warts (Condylomata acuminata) in immunocompetent patients 18 years and older. 1.2 Limitations of Use The safety and effectiveness of Veregen have not been established for treatment beyond 16-weeks or for multiple treatment courses. The safety and effectiveness of Veregen in immunosuppressed patients have not been established.

2 DOSAGE AND ADMINISTRATION • Veregen is to be applied three times per day to all external genital and perianal warts (2.1) . • Apply about an 0.5 cm strand of ointment to each wart using the finger(s), dabbing it on to ensure complete coverage and leaving a thin layer of the ointment on the warts (2.1) . • Veregen is not for ophthalmic, oral, intravaginal, or intra-anal use (2.1) . 2.1 General Dosing Information Veregen is to be applied three times per day to all external genital and perianal warts. Apply about an 0.5 cm strand of the Veregen to each wart using the finger(s), dabbing it on to ensure complete coverage and leaving a thin layer of the ointment on the warts. Patients should wash their hands before and after application of Veregen. It is not necessary to wash off the ointment from the treated area prior to the next application. Veregen ® is not for ophthalmic, oral, intravaginal, or intra-anal use. 2.2 Treatment Period Treatment with Veregen should be continued until complete clearance of all warts, however no longer than 16 weeks. Local skin reactions (e.g. erythema) at the treatment site are frequent. Nevertheless, treatment should be continued when the severity of the local skin reaction is acceptable.

4 CONTRAINDICATIONS None None (4)

5 WARNINGS AND PRECAUTIONS Veregen has not been evaluated for the treatment of urethral, intra-vaginal, cervical, rectal, or intra-anal human papilloma viral disease and should not be used for the treatment of these conditions. Use of Veregen on open wounds should be avoided. Patients should be advised to avoid exposure of the genital and perianal area to sun/UV-light as Veregen has not been tested under these circumstances. • Veregen should not be used to treat urethral, intra-vaginal, cervical, rectal, or intra-anal human papilloma viral disease (5) . • Use of Veregen on open wounds should be avoided (5) . • Avoid exposure of Veregen treated areas to sun/UV-light as Veregen has not been tested under these circumstances (5) .

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Phase 3 clinical trials, a total of 397 subjects received Veregen three times per day topical application for the treatment of external genital and perianal warts for up to 16 weeks. Serious local adverse events of pain and inflammation were reported in two subjects (0.5%), both women. In clinical trials, the incidence of patients with local adverse events leading to discontinuation or dose interruption (reduction) was 5% (19/397). These included the following events: application site reactions (local pain, erythema, vesicles, skin erosion/ulceration), phimosis, inguinal lymphadenitis, urethral meatal stenosis, dysuria, genital herpes simplex, vulvitis, hypersensitivity, pruritus, pyodermitis, skin ulcer, erosions in the urethral meatus, and superinfection of warts and ulcers. Local and regional reactions (including adenopathy) occurring at >1% in the treated groups are presented in Table 1. Table 1: Local and Regional Adverse Reactions During Treatment (% Subjects) Veregen ® (N = 397) Vehicle (N = 207) Erythema 70 32 Pruritus 69 45 Burning 67 31 Pain/discomfort 56 14 Erosion/Ulceration 49 10 Edema 45 11 Induration 35 11 Rash vesicular 20 6 Regional Lymphadenitis 3 1 Desquamation 5 <1 Discharge 3 <1 Bleeding 2 <1 Reaction 2 0 Scar 1 0 Irritation 1 0 Rash 1 0 A total of 266/397 (67%) of subjects in the Veregen group had either a moderate or a severe reaction that was considered probably related to the drug, of which 120 (30%) subjects had a severe reaction. Severe reactions occurred in 37% (71/192) of women and in 24% (49/205) of men. The percentage of subjects with at least one severe, related adverse event was 26% (86/328) for subjects with genital warts only, 42% (19/45) in subjects with both genital and perianal warts and 48% (11/23) of subjects with perianal warts only. Phimosis occurred in 3% of uncircumcised male subjects (5/174) treated with Veregen and in 1% (1/99) in vehicle. The maximum mean severity of erythema, erosion, edema, and induration was observed by week 2 of treatment. Less common local adverse events included urethritis, perianal infection, pigmentation changes, dryness, eczema, hyperesthesia, necrosis, papules, and discoloration. Other less common adverse events included cervical dysplasia, pelvic pain, cutaneous facial rash, and staphylococcemia. In a dermal sensitization study of Veregen in healthy volunteers, hypersensitivity (type IV) was observed in 5 out of 209 subjects (2.4%) under occlusive conditions. Most common adverse reactions are local skin and application site reactions including (incidence ≥ 20%) erythema, pruritus, burning, pain/discomfort, erosion/ulceration, edema, induration, and rash vesicular (6) . To report SUSPECTED ADVERSE REACTIONS, ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Risk Summary There are no available data on Veregen use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, sinecatechins did not cause malformations, but did affect the developing fetus in the presence of maternal toxicity when given to pregnant rabbits and rats by intravaginal or systemic routes of administration during the period of organogenesis ( see Data ). The available data do not allow the calculation of relevant comparisons between the systemic exposure of sinecatechins observed in the animal studies to the systemic exposure that would be expected in humans after topical use of Veregen. Data Embryo-fetal development studies were conducted in rats and rabbits using intravaginal and systemic routes of administration, respectively. Oral administration of sinecatechins during the period of organogenesis (gestational Days 6 to 15 in rats or 6 to 18 in rabbits) did not cause treatment-related malformations or effects on embryo-fetal development at doses of up to 1,000 mg/kg/day. In the presence of maternal toxicity (characterized by marked local irritation at the administration sites and decreased body weight and food consumption) in pregnant female rabbits, subcutaneous doses of 12 and 36 mg/kg/day of sinecatechins during the period of organogenesis (gestational Days 6 to 19) resulted in corresponding influences on fetal development including reduced fetal body weights and delays in skeletal ossification. No treatment-related effects on embryo-fetal development were noted at 4 mg/kg/day. No malformations were noted at any of the doses evaluated in this study. A combined fertility and embryo-fetal development study using daily vaginal administration of Veregen to rats from Day 4 before mating and throughout mating until Day 17 of gestation did not show treatment-related effects on fertility, malformations, or embryo-fetal development at doses up to 0.15 mL/rat/day. This dose corresponds to approximately 150 mg/rat/day. A pre- and post-natal development study was conducted in rats using vaginal administration of Veregen at doses of 0.05, 0.10 and 0.15 mL/rat/day from Day 6 of gestation through parturition and lactation. The high and intermediate dose levels of 0.15 and 0.10 mL/rat/day resulted in an increased mortality of the F 0 dams, associated with indications of parturition complications. The high dose level of 0.15 mL/rat/day also resulted in an increased incidence of stillbirths. There were no other treatment-related effects on pre- and post-natal development, growth, reproduction and fertility at any dose tested.