VEREGEN

Veregen (sinecatechins) Ointment, 15% is a botanical drug product for topical use. The drug substance in Veregen is sinecatechins, which is a partially purified fraction of the water extract of green tea leaves from Camellia sinensis (L.) O Kuntze , and is a mixture of catechins and other green tea components. Catechins constitute 85 to 95% (by weight) of the total drug substance which includes more than 55% of Epigallocatechin gallate (EGCg), other catechin derivatives such as Epicatechin (EC), Epigallocatechin (EGC), Epicatechin gallate (ECg), and some additional minor catechin derivatives i.e. Gallocatechin gallate (GCg), Gallocatechin (GC), Catechin gallate (Cg), and Catechin (C). In addition to the known catechin components, it also contains gallic acid, caffeine, and theobromine which together constitute about 2.5% of the drug substance. The remaining amount of the drug substance contains undefined botanical constituents derived from green tea leaves. The structural formulae of catechins are shown below. General Structure of Catechins Each gram of the ointment contains 150 mg of sinecatechins in a water free ointment base consisting of isopropyl myristate, white petrolatum, cera alba (white wax), propylene glycol palmitostearate, and oleyl alcohol. Structure

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.

• 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.

None None (4)

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.

Prior to dispensing to the patient, store refrigerated 2°C to 8°C (36°F to 46°F). After dispensing, store refrigerated or up to 25°C (77°F). Do not freeze. KEEP OUT OF THE REACH OF CHILDREN.