Veregen

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

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.

Indications

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.

Dosage And Administration

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.

How Supplied

Dosage Forms And Strengths

Ointment, 15% w/w. Each gram of Veregen® Ointment, 15% contains 150 mg of sinecatechins in a brown ointment base.

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 THE REACH OF CHILDREN.

Manufactured for: PharmaDerm®,  A Division of Fougera PHARMACEUTICALS INC, Melville, New York 11747. Manufactured by: C.P.M. Contract Pharma GmbH & Co. KG Frühlingstrasse 7 D-83620 Feldkirchen-Westerham, Germany, U.S. Patent Nos. 5795911 and 5968973 IL331H.Revised: Mar 2018

Side Effects

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 )

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 fa® in healthy volunteers, hypersensitivity (type IV) was observed in 5 out of 209 subjects (2.4%) under occlusive conditions.

Drug Interactions

No Information provided

WarningS

Included as part of the PRECAUTIONS section.

Precautions

Veregen® has not been evaluated for the treatment of urethral, intra-vaginal, cervical, rectal, or intraanal 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.

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

Nonclinical Toxicology

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]). 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).

Use In Specific Populations

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 F 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 treatmentrelated effects on pre- and post-natal development, growth, reproduction and fertility at any dose tested.

Nursing Mothers

It is not known whether topically applied Veregen® is excreted in breast milk.

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.

Overdose

No Information provided

Contraindications

None

Clinical Pharmacology

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) Cmax of 23.0 (12.0) ng/mL and AUC of 104.6 (39.0) ng*h/mL on Day 7.

Clinical Studies

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.

Table 2: Efficacy by Region

Table 3: Efficacy by Gender

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.