Veregen
(sinecatechins)Dosage & Administration
Veregen Prescribing Information
Indication
Veregen® is indicated for the topical treatment of external genital and perianal warts (Condylomata acuminata) in immunocompetent patients 18 years and older.
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.
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.
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.
- Ointment, 15% w/w. Each gram of Veregen® Ointment, 15% contains 150 mg of sinecatechins in a brown ointment base.
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 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.
Lactation
Risk Summary
There are no data on the presence of sinecatechins in human or animal milk, the effects on the breastfed child, or the effects on milk production. After topical application, Veregen concentrations in plasma are low and therefore concentrations in human breast milk are likely to be low [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Veregen® and any potential adverse effects on the breast-fed child from Veregen® or from the underlying maternal condition.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
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.
None
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.
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.
Veregen® | Vehicle | |
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.
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.
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.
Pharmacodynamics
The pharmacodynamics of Veregen® is unknown.
Pharmacokinetics
- Systemic exposure to EGCg, EGC, ECg, and EC were evaluated following either topical application of Veregen® to subjects with external genital and perianal warts (250 mg applied 3 times a day for 7 days) or following oral ingestion of green tea beverage (500 mL ingested 3 times a day for 7 days). Following topical application of Veregen®, plasma concentration of all 4 catechins were below the limit of quantification (<5 ng/mL) on Day 1. After application of Veregen® for 7 days, plasma EGC, ECg, and EC concentrations were below the limit of quantification while plasma concentration of EGCg were measurable in 2 out of 20 subjects. The mean maximal plasma concentration (Cmax) of EGCg was 10.1 ng/mL and the mean area under the concentration versus time curve (AUC) of EGCg was 52.2 ng*h/mL in these 2 subjects. Oral ingestion of green tea beverage resulted in measurable concentration of EGCg in all subjects on both Day 1 and Day 7, with mean (SD) C max of 23.0 (12.0) ng/mL and AUC of 104.6 (39.0) ng*h/mL on Day 7.
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. 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.
Two randomized, double-blind, vehicle-controlled trials were performed to investigate the safety and efficacy of Veregen® in the treatment of immunocompetent subjects 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 trials 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 subjects 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.
Complete Clearance | |
All Countries | |
Veregen® 15% (N = 397) | 213 (53.6%) |
Vehicle (N = 207) | 73 (35.3%) |
United States | |
Veregen® 15% (N = 21) | 5 (23.8%) |
Vehicle (N = 9) | 0 (0.0%) |
Complete Clearance | |
Males | |
Veregen® 15% (N = 205) | 97 (47.3%) |
Vehicle (N = 118) | 34 (28.8%) |
Females | |
Veregen® 15% (N = 192) | 116 (60.4%) |
Vehicle (N = 89) | 39 (43.8%) |
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.
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 THE REACH OF CHILDREN.
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.