Veregen

• PharmaDerm, A division of Fougera Pharmaceuticals Inc.

• Sandoz Inc.

External Genital and Perianal Human Papillomavirus Warts

Treatment of external genital and perianal warts (condylomata acuminata) caused by human papillomavirus (HPV) in immunocompetent patients.1 4

CDC recommends that external HPV genital warts be treated with a self-administered topical therapy (imiquimod, podofilox, sinecatechins), a topical therapy administered by a health-care provider (podophyllum resin, trichloroacetic acid [TCA], bichloroacetic acid [BCA]), or a surgical technique (cryotherapy, electrosurgery, surgical excision).4

Should not be used for treatment of urethral, intravaginal, cervical, rectal, or intra-anal HPV disease; safety and efficacy not established.1

This medicine may make your skin more sensitive to sunlight. Do not expose the area being treated with this medicine to sunlight, sunlamps, or tanning beds .

Avoid having genital, oral, or anal sex while the medicine is on your skin. Make sure you wash the ointment off your skin before you engage in any sexual activity. Also, the medicine contains oils that can weaken latex (rubber) condoms, or diaphragms causing them not to work properly .

Sinecatechins will not keep you from spreading genital warts to other people. Talk with your doctor about safe sex practices .

This medicine is not a cure for genital or anal warts. You may still develop new warts during or after your treatment .

This medicine may stain your clothes and bedding .

Do not use cosmetics or any other skin care products on the same skin area on which you use this medicine, unless directed otherwise by your doctor .

If your condition does not improve within 16 weeks, or if it becomes worse, check with your doctor .

Many patients experience redness, swelling, sores or blisters, burning, or itching after using this medicine. If you experience a severe skin reaction, remove the ointment by washing the area with mild soap and water and contact your doctor right away .

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad skin irritation.
• Blisters or sores.
• Oozing or bleeding.
• Pain when passing urine.
• Trouble passing urine.
• Groin or pelvic pain or swelling.

• Store at room temperature or in a refrigerator. Do not freeze.
• Protect from heat.
• Keep lid tightly closed.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

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.

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.

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.

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.

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.

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.

PATIENT INFORMATION

Veregen®
(sinecatechins)
Ointment, 15%

Read this leaflet carefully before you start using Veregen® Ointment 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 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?
Veregen® Ointment is a medicine for skin use only (topical) for the treatment of warts on the outside of the genitals and around the outside of the anus. It is not a treatment for warts in the vagina, cervix, or inside the anus. Your doctor may recommend examination and screening tests (such as a Pap smear) to evaluate these areas.

Who should not use Veregen® Ointment?
Do not use Veregen® Ointment if you are allergic to an ingredient in Veregen® Ointment. The list of ingredients is at the end of this leaflet.

What should I tell my doctor before using Veregen® Ointment?
Tell your doctor about all your health conditions and all the medicines you take including prescription, over-the-counter medicine, vitamins, supplements, and herbals. Be sure to tell your doctor if you are:

• pregnant or planning to become pregnant, as it is not known if Veregen® Ointment can harm your unborn baby. Your doctor will determine whether the benefit outweighs the risk.
• breastfeeding, as it is not known if Veregen® Ointment can pass into your milk and if it can harm your baby.
• using any other type of skin product or have open wounds on the area to be treated. Veregen® Ointment should not be used until your skin has healed from other treatments applied to the same area.
• immunocompromised. This means that your immune system cannot fight infections as well as it should.

How should I use Veregen® Ointment?

• Use Veregen® Ointment only on the area affected exactly as prescribed by your doctor.
• Wash your hands before and after application of Veregen® Ointment. A small amount of the ointment should be applied to all warts using your finger(s), dabbing it on to ensure complete coverage and leaving a thin layer of the ointment on the warts as directed by your doctor.
• Apply Veregen® Ointment three times per day --- in the morning, at noontime and in the evening.
• Do not wash off the ointment from the treated area before the next application. When you wash the treatment area or bathe, apply the ointment afterwards.
• Treatment with Veregen® Ointment should be continued until complete clearance of all warts, however no longer than 16 weeks. If your warts do not go away, or if they come back after treatment call your doctor.
• Veregen® Ointment is not a cure for warts on your genitals or around your anus with certainty. New warts may develop during or after treatment, and may need treatment.

What should I avoid while using Veregen® Ointment?

• Do not apply Veregen® Ointment on open wounds or into the vagina or into the anus.
• Genital warts are a sexually transmitted disease, and you may infect your partner.
• Avoid sexual contact (genital, anal or oral) when Veregen® Ointment is on your genital or perianal skin. If you do choose to have sexual contact, you must wash off the ointment carefully before having protected sexual contact as the ointment may weaken condoms and vaginal diaphragms. Talk to your doctor about safe sex practices.
• Avoid contact with your eyes, nostrils and mouth while ointment is on your finger(s).
• Women using tampons: insert the tampon before applying the ointment. If you need to change your tampon while the ointment is on your skin, avoid getting the ointment into the vagina.
• Uncircumcised men treating warts under the foreskin should retract the foreskin and clean the area daily.
• Do not expose the genital area treated with Veregen® Ointment to sunlight, sunlamps or tanning beds.
• Do not cover the treated area. Loose-fitting undergarments can be worn after applying Veregen® Ointment.
• Veregen® Ointment may stain your light colored clothes and bedding.

What are the possible side effects of Veregen® Ointment?

The most common side effects with Veregen® Ointment are local skin and application site reactions including:

• redness
• swelling
• sores or blisters
• burning
• itching
• pain

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, stop treatment and call your doctor right away.

You may experience other side effects of Veregen® Ointment 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 is not a cure.

How should I store Veregen® Ointment?

• Store Veregen® Ointment refrigerated or up to 77°F (25°C).
• Do not freeze.
• Make sure the cap on the tube is tightly closed.
• Safely throw away Veregen® Ointment tubes that are out of date or are empty.

Keep Veregen® Ointment and all medicines out of the reach of children.

General advice about prescription medicines
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Veregen® Ointment for a condition for which it was not prescribed. Do not give Veregen® Ointment to other people, even if they have the same symptoms you have. It may harm them. Do not use Veregen® Ointment after the expiration date on the tube.

This leaflet summarizes the most important information about Veregen® Ointment. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Veregen® Ointment that is written for the doctor.

For more information, go to www.pharmaderm.com or call 1-800-645-9833.

What are the ingredients in Veregen® Ointment?

Active ingredient:
A defined green tea extract named sinecatechins.

Inactive ingredients:
Isopropyl myristate, white petrolatum, cera alba (white wax), propylene glycol palmitostearate, and oleyl alcohol.

Veregen® is a registered trademark of Medigene AG, D-82152 Planegg/Martinsried, Germany.

This Patient Information has been approved by the U.S. Food and Drug Administration

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

IL331G R11/12

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