VEREGEN- sinecatechins ointment
PharmaDerm a division of Fougera Pharmaceuticals Inc.
1 INDICATIONS AND USAGE
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
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.
3 DOSAGE FORMS AND STRENGTHS
Ointment, 15% w/w. Each gram of Veregen� Ointment, 15% contains 150 mg of sinecatechins in a brown ointment base.
4 CONTRAINDICATIONS
None
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.
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.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C: There are no adequate and well controlled studies in pregnant women. Veregen� should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The Maximum Recommended Human Dose (MRHD) of Veregen� was set at three times daily topical administration of 250 mg, 750 mg total, containing 112.5 mg sinecatechins for the animal multiple of human exposure calculations presented in this labelling. Dose multiples were calculated based on the human equivalent dose (HED).
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 effects on embryo-fetal development or teratogenicity at doses of up to 1,000 mg/kg/day (86-fold MRHD in rats; 173-fold MRHD in rabbits).
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 (0.7-fold MRHD). There was no evidence of teratogenic effects at any of the doses evaluated in this study.
A combined fertility / 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 embryo-fetal development or teratogenicity at doses up to 0.15 mL/rat/day (8-fold MRHD).
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 (8-fold MRHD) and 0.10 mL/rat/day resulted in an increased mortality of the F0 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.
8.3 Nursing Mothers
It is not known whether topically applied Veregen� is excreted in breast milk.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Seven patients (1.4%), older than 65 years of age were treated with Veregen� in clinical studies. This, however, is an insufficient number of subjects to determine whether they respond differently from younger subjects.
11 DESCRIPTION
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
General Structure of Catechins
(click image for full-size original)
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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mode of action of Veregen� involved in the clearance of genital and perianal warts is unknown. In vitro, sinecatechins had anti-oxidative activity; the clinical significance of this finding is unknown
HOW SUPPLIED/STORAGE AND HANDLING
Veregen� is a brown ointment and is supplied in an aluminum tube containing 15 grams (NDC # 10337-450-15) of ointment per tube or 30 grams (NDC # 10337-450-03) of ointment per tube.
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 reach of children.
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information)
Patients using Veregen� should receive the following information and instructions:
This medication is only to be used as directed by a physician. It is for external use only. Eye contact should be avoided as well as application into the vagina or anus.
It is not necessary to wash off Veregen� prior to the next application. When the treatment area is washed or a bath is taken, the ointment should be applied afterwards.
It is common for patients to experience local skin reactions such as erythema, erosion, edema, itching, and burning at the site of application. Severe skin reactions can occur and should be promptly reported to the healthcare provider. Should severe local skin reaction occur, the ointment should be removed by washing the treatment area with mild soap and water, and further doses withheld.
Sexual (genital, anal or oral) contact should be avoided while the ointment is on the skin, or the ointment should be washed off prior to these activities. Veregen� may weaken condoms and vaginal diaphragms. Therefore, the use in combination with Veregen� is not recommended.
Female patients using tampons should insert the tampon before applying the ointment. If the tampon is changed while the ointment is on the skin, accidental application of the ointment into the vagina must be avoided.
Veregen� may stain clothing and bedding.
Veregen� is not a cure and new warts might develop during or after a course of therapy. If new warts develop during the 16-week treatment period, these should also be treated with Veregen�.
The effect of Veregen� on the transmission of genital/perianal warts is unknown.
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.
The treatment area should not be bandaged or otherwise covered or wrapped as to be occlusive.
Uncircumcised males treating warts under the foreskin should retract the foreskin and clean the area daily.
