1 INDICATIONS AND USAGE

Curaderm is indicated for the topical treatment of actinic keratosis, keratoacanthoma, basal cell carcinoma and cutaneous superficial squamous cell carcinoma.

2 DOSAGE AND ADMINISTRATION

For topical use only; Curaderm is not for oral, ophthalmic, or intravaginal use.

For the treatment of actinic keratosis, Curaderm should be applied to the affected area with an occlusive dressing twice daily for 3 consecutive days.

For the treatment of keratoacanthoma, basal cell carcinoma and cutaneous superficial squamous cell carcinoma, Curaderm should be applied to the affected area with an occlusive dressing, such as Micropore Paper Tape, twice daily until the lesion is completely cleared. The treatment period depends on the type and size of the lesion.

After spreading Curaderm thinly and evenly over the treatment area, the lesion should be covered with Micropore Paper Tape to avoid drying out. Patients should wash their hands immediately after applying Curaderm and take care not to transfer the applied drug to other areas, including the eyes.

3 DOSAGE FORM AND STRENGTH

Curaderm, 0.005% BEC in a white cream.

4 HOW TO USE CURADERM

Wash the lesion and the surrounding area with a mild non-irritating soap.

Rinse with water.

Dry thoroughly.

Unscrew the lid of the Curaderm tube and remove the protective foil that covers the hole in the lid of the tube.

Apply Curaderm to the lesion, just enough to cover the lesion.

Spread evenly over lesion only. Do not apply the cream in large quantity and do not extend the cream more than 0.5cm onto the apparently normal skin surrounding the edge of the lesion.

Apply the cream to the lesion by gently squeezing the tube.

Cover each lesion with an occlusive dressing (for example paper tape) until the next application of Curaderm.

Apply the cream to the lesion at least twice daily, i.e. at least every 12 hours. However, up to 10 applications with at least 0.5 hour spans can be done daily to remove the lesion more rapidly.

Stop treatment only when the lesion has been completely cleared and replaced with normal skin.

5 WHAT TO EXPECT DURING CURADERM TREATMENT

Curaderm contains the exfoliants salicylic acid and urea. The purpose for these exfoliants is to remove the mass of dead cells, including the keratin layer, that pile up above skin cancer that has not yet pushed itself up on the surface of the skin. Cancer cells are alive and originate in the living, dividing skin cells and are generally, but not always, covered by the superficially dead skin cells. Salicylic acid and urea help remove the outer layer surface of dead cells so that BEC is accessible to interact and kill the cancer cells. BEC at the concentration used, does not kill normal cells.

In the initial stages of Curaderm therapy, which may vary from one day to several weeks depending on size and type of cancer, the treated lesion will become larger. The reaction of the tumor treated with Curaderm may be unsightly at the initial stages during treatment. The reason for the initial increase in lesion size is that Curaderm is seeking and destroying the cancer cells that are originally not visible to the bare eyes.

At this stage some patients may be discouraged to continue treatment because the cancer seems to be getting worse and not better. In addition, some patients may experience pain or a burning sensation for some time after Curaderm is applied to the lesion. These possible observations are all part of the treatment regime. Don’t forget we are dealing with cancer. The possible pain experienced, is due to the salicylic and urea contents and not the active ingredient BEC. Salicylic acid and urea help with the penetration of BEC to kill the deep-seated cancer cells.

After some time during the treatment, the lesion will start to reduce in size. At this stage most of the cancer cells are eliminated by the treatment. Treatment should continue and because the lesion is becoming smaller, less Curaderm cream is applied to the lesion.

Treatment should continue until the lesion is completely gone and replaced with normal skin. If treatment is stopped too early, some residual cancer cells may remain and over time will become a lesion again. Studies have shown if the procedure is followed diligently, all cancer cells are removed and the lesion will be cured with no recurrences for over 5 and 10 years.

6 CONTRAINDICATIONS

None.

7 WARNINGS AND PRECAUTIONS

7.1 Local Skin Reactions

Severe skin reactions in the treated area, including erythema, crusting, swelling, vesiculation/postulation, and erosion/ulceration, can occur after topical application of Curaderm BEC5 [see Adverse Reactions (8)].

8 ADVERSE REACTIONS

8.1 Clinical Trials Experience and Clinical Practice Experience

Adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates observed in clinical practice. However, a small but significant number of patients in the clinical trials as well as in clinical practice have experienced burning sensations that have lasted for several minutes after application of Curaderm. Other skin reactions are erythema, pruritis, swelling, postulation and ulceration.

9 USE IN SPECIFIC POPULATIONS

9.1 Pregnancy

There are no adequate and well-controlled studies of Curaderm in pregnant women. Curaderm BEC5 should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

9.2 Pediatric Use

Actinic keratosis, keratoacanthoma, basal cell carcinoma and cutaneous superficial squamous cell carcinoma, are not conditions generally seen within the pediatric population. The safety and effectiveness of Curaderm for actinic keratosis, keratoacanthoma, basal cell carcinoma and cutaneous superficial squamous cell carcinoma, in patients less than 18 years of age have not been established.

9.3 Geriatric Use

No overall differences in safety or effectiveness of patients over 65 years were observed between these subjects and younger subjects.

10 OVERDOSAGE

Topical overdosing of Curaderm could result in an increased incidence of local skin reactions.

11 DESCRIPTION

Curaderm is a white cream for topical application, which contains the active substance BEC, an inducer of cell death.

BEC is a standardized mixture of Solamargine (33%), Solasonine (33%) and di-and monoglycosides of solasodine (34%) extracted from S. sodomaeum, now reclassified as S. linnaeanum.

Solamargine has the molecular formula C45H73NO15 with the mass of 868.04 Da. Its systematic name is (22R, 25R)-spiro-5-ene-3ß-yl–L-rhamnopyranosyl-(12glu)-0–L-rhamnopyranosyl-(14glu)-ß-D-glucopyranose.

Solasonine has the molecular formula C45H73NO16 with the mass of 884.04 Da. Its systematic name is (22R, 25R)-spiro-5-ene-3ß-yl–L-rhamnopyranosyl-(12gal)-0-ß-D-glucopyranosyl-(1 3gal)-ß-D-galactopyranose.

 BEC is a white crystalline powder.

Curaderm cream contains 50 micrograms of BEC in each gram of cream.

Curaderm is a white cream and supplied in 20 grams tubes. The tubes should be discarded after use.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action by which Curaderm induces cell death in treating actinic keratosis, keratoacanthoma, basal cell carcinoma and superficial squamous cell carcinoma lesions is by apoptosis (programmed cell death).

12.2 Pharmacodynamics

In humans the plasma biological half-life of Solamargine is 8.4±2h and for Solasonine this is 5.57±1.27 h.
The clearance is 3.0±0.7 L/h for Solamargine and 5.6±1.6 L/h for Solasonine. Plasma protein binding for both Solamargine and Solasonine is consistent in human, rat and dog. Solamargine protein binding ranges from 76.7-96.3%, for Solasonine it is 76.4-97.3%. Solamargine and Solasonine are essentially stable
when incubated with human, rat and dog cryopreserved hepatocytes indicating that Solamargine and Solasonine are metabolically stable.

12.3 Pharmacokinetics

Absorption
- The systemic exposure to Curaderm BEC5 was assessed in subjects with basal cell carcinoma following application of Curaderm to lesions for 8 weeks with two applications per day. In these studies, blood levels of BEC were measured. Blood levels of BEC were below the
lower limit of quantification (0.1 ng/mL) in all the blood samples of the subjects evaluated.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis

BEC therapy lacks mutagenic and carcinogenic properties. Solamargine does not exert any mutagenic effect, but Solamargine also significantly reduces the frequency of chromosomal aberrations induced by the chemotherapeutic agent doxorubicin in both V79 cells and micronuclei in Swiss mice. So, in addition of not having mutagenic effects,

Solamargine displays antimutagenic properties. BEC was also negative in the Ames.

Test in vitro mouse lymphoma assay.

14 CLINICAL STUDIES

14.1 Keratosis

In 1987 it was reported that 10% BEC in a topical cream formulation obtained regression in 23 of 23 keratotic lesions in patients. In an open study in 1991 clinical and histological observations indicated that 56 keratoses were cleared with very low concentrations (0.005%) of BEC in a cream formulation Curaderm. In both 1987 and 1991 studies, it was reported that no adverse effects in the liver, kidneys or hematopoietic system was observed. In 2011 it was reported that SR-T100 extracted from S. incanum containing mainly Solamargine, as the main active ingredient was effective against actinic keratoses. The treatment period for actinic keratoses was for 16 weeks and there were negligible discomforts. In 2013 a single-blind, randomized, placebo-controlled, parallel group study revealed that Curaderm BEC5 cream applied topically twice daily for 3 days was effective for the treatment of actinic keratoses.

14.2 Keratoacanthoma

Two patients with a total of 9 keratoacantomas treated with BEC in a topical cream formulation for 3-5 weeks resulted in regression of all lesions.

14.3 Basal Cell Carcinoma

In 1987 it was first reported in an open controlled clinical trial that BEC in a topical cream formulation was effective in treating 20 of 24 basal cell carcinomas. There were no serious adverse effects within the treatment period and there were no recurrences after 5 years.

In a subsequent open study in 1991 with Curaderm BEC5 39 of 39 cases with basal cell carcinomas were effectively removed. In this study the treatment period necessary to obtain complete removal of the lesions by Curaderm BEC5 ranged from several weeks to 12 weeks. Eight weeks of treatment with Curaderm resulted in 75% success rates and with the study it was shown that 12 weeks of treatment was required to obtain virtually 100% success rates.

This observation was confirmed in a double-blind, randomized, placebo-controlled, parallel group, multicentre study with Zycure (which essentially is Curaderm), for the treatment of basal cell carcinoma. In this trial the patients were treated for 8 weeks. Sixty six percent of patients treated with Curaderm and
25% of patients on placebo appeared to be treated successfully.

Follow-up for 1 year revealed histologically that 78% who were treated with Curaderm remained cancer-free, whereas, in the placebo group there was a 50% recurrence rate. When calculated overall, Curaderm treatment of basal cell carcinoma was five-fold superior to the placebo. Regeneration of new epidermis at the application site during treatment of skin cancers with Curaderm supports the preclinical and clinical observations that BEC is preferential in its action towards transformed cells. This also explains the impressive cosmetic outcomes with Curaderm therapy.

Further clinical studies showed that Curaderm eliminated basal cell carcinoma in areas that were difficult to treat by any modality. Very large basal cell carcinomas were shown to be successfully treatable with Curaderm.

14.4 Cutaneous Superficial Squamous Cell Carcinoma

Cell culture and whole animal studies showed that BEC recognized and interacted with rhamnose binding protein (RBP) receptors in squamous cell carcinoma. After internalization, BEC caused apoptosis in the cancer cells. These observations also applied to cutaneous squamous cell carcinoma. Specificity of BEC towards cutaneous squamous cell carcinoma resulted in clearing of squamous cell carcinoma. Normal skin cells were not affected by BEC.

In 1987 it was shown that topical application of BEC in a cream formulation in 5 patients with 6 squamous cell carcinoma lesions resulted in 83% complete regression with no recurrences after 3 years. The BEC treatment period ranged from 4-12 weeks with a mean of 6.2±2.7 weeks. Normal skin was not affected with topical BEC treatment. Plasma biochemical profiles, full blood count and differential and urinalysis indicated that these parameters were unaltered by BEC therapy. Mild pruritis and modest burning sensation surrounding the treated lesions occurred in a few cases. Curaderm causes apoptosis in cutaneous
squamous cell carcinoma, in agreement with cell culture studies.

In an open study in 1991, clinical and histological observations indicated that all 29 squamous cell carcinomas treated with Curaderm had regressed. A placebo formulation had no effect on a smaller number of treated lesions. Curaderm had no adverse effects on the liver, kidneys or hematopoietic system.

In 2007 an open clinical study with 11 patients who had squamous cell carcinoma determined that Curaderm therapy resulted in complete regression of all lesions as shown histologically by analyses of biopsies at the completion of treatment period and clinical assessment 5 years post treatment.

The mean treatmentperiods were 9 weeks (range 5-16 weeks). The duration of Curaderm therapy varied depending on size of the particular lesions. The period of treatment was longer than previously reported because the treated squamous cell carcinoma lesions were much larger than those previously reported.

In 2011, a case report of a large squamous cell carcinoma was presented. The lesion was confirmed histologically as a squamous cell carcinoma and was 4cm in diameter. Before treatment with Curaderm the lesion sometimes oozed exudates.

After 3 weeks of Curaderm treatment the lesion appeared larger.

Another 3 weeks of treatment the lesion appeared much “cleaner” an was starting to fill in with normal tissue and this continued until after 14 weeks of treatment, the lesion had regressed and normal skin tissue had replaced the squamous cell carcinoma. There was no scar tissue at the completion of the treatment. The patient experienced itching and moderate transient stinging surrounding the treated lesion for the first week of Curaderm therapy. There were no recurrences 5 years after treatment.

14.5 Tissue-sparing and preservation of functionality

Tissue-sparing and preservation of functionality with topical application of Curaderm have been reported in various studies. Treatment of tumors on the penis with Curaderm BEC5 is superior to other more destructive treatment options for Bowen’s disease of the penis. After treatment with Curaderm functionality was completely restored and it was difficult to locate where the lesions once were.

14.6 Periocular Skin Cancers

In 2013 studies showed that treatment with Curaderm was very effective for basal cell carcinoma and squamous cell carcinoma around the eyes without the need for reconstructive surgery.

15 HOW SUPPLIED/STORAGE AND HANDLING

Curaderm is a white cream and is supplied in tubes containing a nominal fill weight of 20 grams. Curaderm should be stored below 25°C, preferably in the refrigerator under adequate security. If the cream is exposed to high temperature eg above 35°C the cream may separate to a liquid form and cannot be used further. The tubes should be discarded after use. Store in refrigerator at 36°F-46°F (2°C-8°C); excursions permitted between 32°F-86°F (0°C-30°C). Protect from freezing or at temperatures above 30°C.

16 PATIENT COUNSELING INFORMATION

Curaderm should be used as directed by a physician. Curaderm is for external use only. Inform patients that treatment with Curaderm may lead to local skin reactions (see Warnings and Precautions (7)]. Patients should avoid inadvertent transfer of Curaderm to other areas, or to another person. Instruct patients to follow the How To Use Curaderm (4) and What To Expect During Curaderm Treatment (5). Keep out of the reach of children.