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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Veregen® is indicated for the topical treatment of external genital and perianal warts (Condylomata acuminata) in immunocompetent patients 18 years and older.
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
Veregen® is a brown ointment and is supplied in aluminum tubes containing 15 grams (NDC # 10337-450-15) or 30 grams (NDC # 10337-450-03) of ointment per tube.
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.
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
Pregnancy Category C:
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.
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.
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.
The pharmacokinetics of topically applied Veregen® has not been sufficiently characterized at this time. However, data suggest that systemic exposure to catechins after repeated topical application of Veregen® is likely to be less than observed after a single oral intake of 400 mL green tea.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In an oral (gavage) carcinogenicity study, sinecatechins was administered daily for 26 weeks to p53 transgenic mice at doses up to 500 mg/kg/day (22-fold MRHD; [see Use in Specific Populations (8.1)]). Treatment with sinecatechins was not associated with an increased incidence of either neoplastic or non-neoplastic lesions in the organs and tissues examined. Veregen® has not been evaluated in a dermal carcinogenicity study.
Sinecatechins was negative in the Ames test, in vivo rat micronucleus assay, UDS test, and transgenic mouse mutation assay, but positive in the mouse lymphoma mutation assay.
Daily vaginal administration of Veregen® to rats from Day 4 before mating and throughout mating until Day 17 of gestation did not cause adverse effects on mating performance and fertility at doses up to 0.15 mL/rat/day. This dose corresponds to approximately 150 mg/rat/day (8-fold MRHD).
14 CLINICAL STUDIES
Two randomized, double-blind, vehicle-controlled studies were performed to investigate the safety and efficacy of Veregen® in the treatment of immunocompetent patients 18 years of age and older with external genital and perianal warts. The subjects applied the ointment 3 times daily for up to 16 weeks or until complete clearance of all warts (baseline and new warts occurring during treatment).
Over both studies the median baseline wart area was 51 mm2 (range 12 to 585 mm2), and the median baseline number of warts was 6 (range 2 to 30).
The primary efficacy outcome measure was the response rate defined as the proportion of patients with complete clinical (visual) clearance of all external genital and perianal warts (baseline and new) by week 16, presented in Tables 2 and 3 for all randomized subjects dispensed medication.
Median time to complete wart clearance was 16 weeks and 10 weeks, respectively, in the two phase 3 clinical trials.
The rate of recurrence of external genital and perianal warts 12 weeks after completion of treatment in subjects with complete clearance is 6.8% (14/206) for those treated with Veregen® and 5.8% (4/69) for those treated with vehicle.
16 HOW SUPPLIED/STORAGE AND HANDLING
Veregen® is a brown ointment and is supplied in aluminium tubes containing 15 grams (NDC # 10337-450-15) or 30 grams (NDC # 10337-450-03) of ointment per tube.
17 PATIENT COUNSELING INFORMATION
See FDA-approved Patient Labeling (17.2)
17.1 Instructions for Use
Patients using Veregen® should receive the following information and instructions:
17.2 FDA-Approved Patient Labeling
Read this leaflet carefully before you start using Veregen® Ointment, 15% and each time you refill your prescription. There may be new information. This information does not take the place of your doctor’s advice. If you have any questions about Veregen® Ointment, 15% or your condition ask your doctor or pharmacist. Only your doctor can prescribe Veregen® and determine if it is right for you.
What is Veregen® Ointment, 15%?
Who should not use Veregen® Ointment, 15%?
What should I tell my doctor before using Veregen® Ointment, 15%?
How should I use Veregen® Ointment, 15%?
What should I avoid while using Veregen® Ointment, 15%?
What are the possible side effects of Veregen® Ointment, 15%?
The most common side effects with Veregen® Ointment, 15% are local skin and application site reactions including:
Many patients experience itching, reddening or swelling on or around the application site during the course of treatment. Some of these side effects could be a sign of an allergic reaction. If you experience open sores or other severe reactions at the locations you applied Veregen® Ointment, 15%, stop treatment and call your doctor right away.
You may experience other side effects of Veregen® Ointment, 15%, which are not mentioned here. Ask your doctor or pharmacist for more information.
Patients should be aware that new warts may develop during treatment as Veregen® Ointment, 15% is not a cure.
How should I store Veregen® Ointment, 15%?
Keep Veregen® Ointment, 15% and all medicines out of the reach of children.
General advice about prescription medicines
This leaflet summarizes the most important information about Veregen® Ointment, 15%. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Veregen® Ointment, 15% that is written for the doctor.
What are the ingredients in Veregen® Ointment, 15%?
Veregen® is a trademark of MediGene AG, D-82152 Planegg/Martinsried, Germany.
Co-marketed with Kenwood Therapeutics, a division of Bradley Pharmaceuticals, Inc.
U.S. Patent Nos. 5795911 and 5968973
Revised: 10/2008 Bradley Pharmaceuticals, Inc.
Reproduced with permission of U.S. National Library of Medicine
Copyright © 2017
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