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Sinecatechins Ointment

TABLE OF CONTENTS

1. DESCRIPTION 6. ADVERSE REACTIONS
2. INDICATIONS AND USAGE 7. USE IN SPECIFIC POPULATIONS
3. DOSAGE AND ADMINISTRATION 8. MECHANISM OF ACTION
4. CONTRAINDICATIONS 9. PHARMACOKINETICS
5. WARNINGS AND PRECAUTIONS 10. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Sinecatechins ointment, 15% is a botanical drug product for topical use. The drug substance in sinecatechins 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.

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.

2. INDICATIONS AND USAGE

2.1 Indication

Sinecatechins is indicated for the topical treatment of external genital and perianal warts (Condylomata acuminata) in immunocompetent patients 18 years and older.

2.2 Limitations of Use

The safety and effectiveness of sinecatechins have not been established for treatment beyond 16 weeks or for multiple treatment courses.

The safety and effectiveness of sinecatechins in immunosuppressed patients have not been established.

3. DOSAGE AND ADMINISTRATION

3.1 General Dosing Information

Sinecatechins is to be applied three times per day to all external genital and perianal warts.

Apply about an 0.5 cm strand of the sinecatechins 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 sinecatechins.

It is not necessary to wash off the ointment from the treated area prior to the next application.

Sinecatechins is not for ophthalmic, oral, intravaginal, or intra-anal use.

3.2 Treatment Period

Treatment with sinecatechins 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.

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

Sinecatechins 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 sinecatechins on open wounds should be avoided.

Patients should be advised to avoid exposure of the genital and perianal area to sun/UV-light as sinecatechins 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 sinecatechins 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 sinecatechins 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 sinecatechins 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 sinecatechins in healthy volunteers, hypersensitivity (type IV) was observed in 5 out of 209 subjects (2.4%) under occlusive conditions.

7. USE IN SPECIFIC POPULATIONS

7.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies in pregnant women. Sinecatechins should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The Maximum Recommended Human Dose (MRHD) of sinecatechins 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 sinecatechins 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 sinecatechins 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.

7.2 Nursing Mothers

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

7.3 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

7.4 Geriatric Use

Seven patients (1.4%), older than 65 years of age were treated with sinecatechins in clinical studies. This, however, is an insufficient number of subjects to determine whether they respond differently from younger subjects.

8. MECHANISM OF ACTION

The mode of action of sinecatechins 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.

9. PHARMACOKINETICS

Systemic exposure to EGCg, EGC, ECg, and EC were evaluated following either topical application of sinecatechins 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 sinecatechins, plasma concentration of all 4 catechins were below the limit of quantification (< 5 ng/mL) on Day 1. After application of sinecatechins 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.

10. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: VEREGEN, by Medigene AG.

b) Generic drugs: None.

2) How Supplied:

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.

3) Storage and Handling:

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.

Rx only

Rev 11/12