A. SKIN BURNING:

B. CARCINOGENICITY:

HUMAN STUDIES: A 5.7 year prospective study of 1380 psoriasis patients treated with oral methoxsalen and ultraviolet A photochemotherapy (PUVA) demonstrated that the risk of cutaneous squamous-cell carcinoma developing at least 22 months following the first PUVA exposure was approximately 12.8 times higher in the high dose patients than in the low dose patients (Stern et al., 197912, Stern et al., 198013, and Stern et al., 198414). The substantial dose-dependent increase was observed in patients with neither a prior history of skin cancer nor significant exposure to cutaneous carcinogens. Reduction in PUVA dosage significantly reduces the risk. No substantial dose-related increase was noted for basal cell carcinoma according to Stern et al., 198414. Increases appear greatest in patients who have pre-PUVA exposure to 1) prolonged tar and UVB treatment, 2) ionizing radiation, or 3) arsenic. Roenigk et al., 198015, studied 690 patients for up to 4 years and found no increase in the risk of non-melanoma skin cancer, although patients in this cohort had significantly less exposure to PUVA than in the Stern et al. study. Recent analysis of new data in the Stern et al cohort (Stern et al., 199716) has shown that these patients have an elevated relative risk of contracting melanoma. The relative risk for melanoma in these patients was 2.3 (95% confidence interval 1.1 to 4.1). The risk is particularly higher in those patients who have received more than 250 PUVA treatments and in those whose treatment has spanned greater than 15 years earlier. Some patients developing melanoma did so even after having ceased PUVA therapy over 5 years earlier. These observations indicate the need for monitoring of PUVA patients for skin tumors throughout their lives. In a study in Indian patients treated for 4 years for vitiligo, 12% developed keratoses, but not cancer, in the depigmented, vitiliginous areas (Mosher, 198017). Clinically, the keratoses were keratotic papules, actinic keratosis-like macules, nonscaling dome-shaped papules, and lichenoid porokeratotic-like papules.

C. CATARACTOGENICITY:

HUMAN STUDIES: It has been found that the concentration of methoxsalen in the lens is proportional to the serum level. If the lens is exposed to UVA during the time methoxsalen is present in the lens, photochemical action may lead to irreversible binding of methoxsalen to proteins and the DNA components of the lens (Lerman et al., 198021). However, if the lens is shielded from UVA, the methoxsalen will diffuse out of the lens in a 24-hour period (Lerman et al., 198021). Patients should be told emphatically to wear UVA absorbing, wrap-around sunglasses for the 24-hour period following ingestion of methoxsalen whether exposed to direct or indirect sunlight in the open or through a window glass. Among patients using proper eye protection, there is no evidence for a significantly increased risk of cataracts in association with PUVA therapy (Stern et al., 197912). Thirty-five of 1380 patients have developed cataracts in the 5 years since their first PUVA treatment. This incidence is comparable to that expected in a population of this size and age distribution. No relationship between PUVA dose and cataract risk in this group has been noted.

D. ACTINIC DEGENERATION:

E. BASAL CELL CARCINOMAS:

F. RADIATION THERAPY:

G. ARSENIC THERAPY:

H. HEPATIC DISEASES:

I. CARDIAC DISEASES:

J. GERIATRIC PATIENTS:

K. TOTAL DOSAGE:

L. CONCOMITANT THERAPY:

A. GENERAL - APPLICABLE TO PSORIASIS TREATMENT:

Patients must not sunbathe during the 24 hours prior to methoxsalen ingestion and UV exposure. The presence of a sunburn may prevent an accurate evaluation of the patient's response to photochemotherapy.

AFTER METHOXSALEN INGESTION

UVA-absorbing wrap-around sunglasses should be worn during daylight for 24 hours after methoxsalen ingestion. The protective eyewear must be designed to prevent entry of stray radiation to the eyes, including that which may enter from the sides of the eyewear. The protective eyewear is used to prevent the irreversible binding of methoxsalen to the proteins and DNA components of the lens. Cataracts form when enough of the binding occurs. Visual discrimination should be permitted by the eyewear of patient well-being and comfort.

Patients must avoid sun exposure, even through window glass or cloud cover, for at least 8 hours after methoxsalen ingestion. If sun exposure cannot be avoided, the patient should wear protective devices such as a hat and gloves, and/or apply sunscreens which contain ingredients that filter out UVA radiation (e.g., sunscreens containing benzophenone and/or PABA esters which exhibit a sun protective factor equal to or greater than 15). These chemical sunscreens should be applied to all areas that might be exposed to the sun (including lips). Sunscreens should not be applied to areas affected by psoriasis until after the patient has been treated in the UVA chamber.

DURING PUVA THERAPY

Total UVA-absorbing/blocking goggles mechanically designed to give maximal ocular protection must be worn. Failure to do so may increase the risk of cataract formation. A reliable radiometer can be used to verify elimination of UVA transmission through the goggles.

Abdominal skin, breasts, genitalia, and other sensitive areas should be protected for approximately 1/3 of the initial exposure time until tanning occurs.

Unless affected by disease, male genitalia should be shielded.

AFTER COMBINED METHOXSALEN/UVA THERAPY

UVA-absorbing wrap-around sunglasses should be worn during daylight for 24 hours after combined methoxsalen/UVA therapy.

Patients should not sunbathe for 48 hours after therapy. Erythema and/or burning due to photochemotherapy and sunburn due to sun exposure are additive.

A. METHOXSALEN:

B. COMBINED METHOXSALEN/UVA THERAPY:

ERYTHEMA: Mild, transient erythema at 24-48 hours after PUVA therapy is an expected reaction and indicates that a therapeutic interaction between methoxsalen and UVA occurred. Any area showing moderate erythema (greater than Grade 2 - See Table 1 for grades of erythema) should be shielded during subsequent UVA exposures until the erythema has resolved. Erythema greater than Grade 2 which appears within 24 hours after UVA treatment may signal a potentially severe burn. Erythema may become progressively worse over the next 24 hours, since the peak erythemal reaction characteristically occurs 48 hours or later after methoxsalen ingestion. The patient should be protected from further UVA exposures and sunlight, and should be monitored closely.

IMPORTANT DIFFERENCES BETWEEN PUVA ERYTHEMA AND SUNBURN: PUVA-induced inflammation differs from sunburn or UVB phototherapy in several ways. The % transmission of UVB varies between 0% to 34% through skin whereas UVA varies between 1% to 80% transmission; thus, UVA is transmitted to a larger % through the skin. (Diffey, 198222). The DNA lesions induced by PUVA are very different from UV-induced thymine dimers and may lead to a DNA crosslink. This DNA lesion may be more problematic to the cell because crosslinks are more lethal and psoralen-DNA photoproducts may be "new" or unfamiliar substrates for DNA repair enzymes. DNA synthesis is also suppressed longer after PUVA. The time course of delayed erythema is different with PUVA and may not involve the usual mediators seen in sunburn. PUVA-induced redness may be just beginning at 24 hours, when UVB erythema has already passed its peak. The erythema dose-response curve is also steeper for PUVA. Compared to equally erythemogenic doses of UVB, the histologic alterations induced by PUVA show more dermal vessel damage and longer duration of epidermal and dermal abnormalities.

OTHER ADVERSE REACTIONS: Those reported include edema, dizziness, headache, malaise, depression, hypopigmentation, vesiculation and bullae formation, non-specific rash, herpes simplex, miliaria, urticaria, folliculitis, gastrointestinal disturbances, cutaneous tenderness, leg cramps, hypotension, and extension of psoriasis.

To report SUSPECTED ADVERSE REACTION, contact Strides Pharma Inc. at 1-877-244-9825 or go to www.strides.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

PSORIASIS THERAPY

2. INITIAL EXPOSURE: The initial UVA exposure energy level and corresponding time of exposure is determined by the patient's skin characteristics for sun burning and tanning as follows:

Additional drug dosage directions are as follows:

Weight Change: In the event that the weight of a patient changes during treatment such that he/she falls into an adjacent weight range/dose category, no change in the dose of methoxsalen is usually required. If, in the physician's opinion, however, a weight change is sufficiently great to modify the drug dose, then an adjustment in the time of exposure to UVA should be made.

Dose/Week: The number of doses per week of methoxsalen capsules will be determined by the patient's schedule of UVA exposures. In no case should treatments be given more often than once every other day because the full extent of phototoxic reactions may not be evident until 48 hours after each exposure.

Dosage Increase: Dosage may be increased by 10 mg. after the 15th treatment under the conditions outlined in section XI.B.4.b.

X. UVA RADIATION SOURCE SPECIFICATIONS AND INFORMATION

A. IRRADIANCE UNIFORMITY

Vertical Variation: For readings taken at any point along the vertical center axis of the chamber (to within 15 cm from the top and bottom), the lowest reading should not be less than 70 % of the highest reading.

Horizontal Variation: Throughout any specific horizontal plane, the lowest reading must be at least 80 % of the highest reading, excluding the peripheral 3 cm of the patient treatment space.

B. PATIENT SAFETY FEATURES:

DANGER - Ultraviolet radiation - Follow your physicians instructions - Failure to use protective eyewear may result in eye injury.

C. UVA EXPOSURE DOSIMETRY MEASUREMENTS:

Exposure Time Desired UVA Dose (J/cm2)

(minutes) = -------------------------------------

0.06 x Irradiance (mW/cm2)

Overexposure due to human error should be minimized by using an accurate automatic timing device, which is set by the operator and controlled by energizing and de-energizing the UVA irradiator lamp. The timing device calibration interval should be specified by the manufacturer. Safety systems should be included to minimize the possibility of delivering a UVA exposure which exceeds the prescribed dose, in the event the timer or radiometer should malfunction.

D. UVA SPECTRAL OUTPUT DISTRIBUTION:

XI. PUVA TREATMENT PROTOCOL:

INTRODUCTION:

On average, the serum level achieved with Methoxsalen Capsules, USP 10 mg [Soft Gelatin Capsules] is twice that obtained with hard gelatin capsules and reach their peak concentration in less than half the time of the hard gelatin capsules.

As a result the mean MED J/cm2 for the Methoxsalen Capsules, USP 10 mg [Soft Gelatin Capsules] is substantially less than that required for hard gelatin capsules (Levins et al., 1984 and private communication1).

Photosensitivity studies demonstrate a shorter time of peak photosensitivity of 1.5 to 2.1 hours vs. 3.9 to 4.25 hours for regular methoxsalen capsules.

A. INITIAL EXPOSURE:

B. CLEARING PHASE:

SKIN TYPES I, II, & III. Patients with skin types I, II, and III may be treated 2 or 3 times per week. UVA exposure may be held constant or increased by up to 1.0 J/cm2 at each treatment, according to the patient's response. If erythema occurs, however, do not increase exposure time until erythema resolves. The severity and extent of the patient's erythema may be used to determine whether the next exposure should be shortened, omitted, or maintained at the previous dosage. (See ADVERSE REACTIONS.)

SKIN TYPES IV, V, & VI. Patients with skin types IV, V, and VI may be treated 2 or 3 times per week. UVA exposure may be held constant or increased by up to 1.5 J/cm2 at each treatment unless erythema occurs. If erythema occurs, follow instructions outlined above in the procedures for patients with skin types I, II, and III.

ERYTHRODERMIC PSORIASIS. Patients with erythrodermic psoriasis should be treated with special attention because pre-existing erythema may obscure observations of possible treatment-related phototoxic erythema. These patients may be treated 2 or 3 times per week, as a Type I patient.

MISCELLANEOUS SITUATIONS:

If there is no response after a total of 10 treatments, the exposure of UVA energy may be increased by an additional 0.5–1.0 J/cm2 above the prior incremental increases for each treatment. (Example: a patient whose exposure dosage is being increased by 1.0 J/cm2 may now have all subsequent doses increased by 1.5–2.0 J/cm2.)

If there is no response, or only minimal response, after 15 treatments, the dosage of methoxsalen may be increased by 10 mg (a one-time increase in dosage). This increased dosage may be continued for the remainder of the course of treatment but should not be exceeded.

If a patient misses a treatment, the UVA exposure time of the next treatment should not be increased. If more than one treatment is missed, reduce the exposure by 0.5 J/cm2 for each treatment missed.

If the lower extremities are not responding as well as the rest of the body and do not show erythema, cover all other body areas and give 25 % of the present exposure dose as an additional exposure to the lower extremities. This additional exposure to the lower extremities should be terminated if erythema develops on these areas.

Non-responsive psoriasis: If a patient's generalized psoriasis is not responding, or if the condition appears to be worsening during treatment, the possibility of a generalized phototoxic reaction should be considered. This may be confirmed by the improvement of the condition following temporary discontinuance of this therapy for two weeks. If no improvement occurs during the interruption of treatment, this patient may be considered a treatment failure.

C. ALTERNATIVE EXPOSURE SCHEDULE:

Incremental increases in UVA exposure for all patients may range from 0.5 to 1.5 J/cm2, according to the patient's response to therapy.

Once Grade 2 clearing (see Table 2) has been reached and the patient is progressing adequately, UVA dosage is held constant. This dosage is maintained until Grade 4 clearing is reached.

If the rate of clearing significantly decreases, exposure dosage may be increased at each treatment (0.1-1.5 J/cm2) until Grade 3 clearing and a satisfactory progress rate is attained. The UVA exposure will be held constant again until Grade 4 clearing is attained. These increases may be used also if the rate of clearing significantly decreases between Grade 3 and Grade 4 response. However, the possibility of a phototoxic reaction should be considered; see Non-responsive Psoriasis, above.

In summary, this schedule raises slightly the increments (J/cm2) of UVA dosage, but limits these increases to those periods when the patient is not responding adequately. Otherwise, the UVA exposure is held at the lowest effective dose.

D. MAINTENANCE PHASE:

SCHEDULE OF EXPOSURES: When patients have achieved 95% clearing, or Grade 4 response (Table 2), they may be placed on the following maintenance schedules (M1 – M4), in sequence. It is recommended that each maintenance schedule be adhered to for at least 2 treatments (unless erythema or psoriatic flare occurs, in which case see (2a) and (2b) below).

b. Psoriasis: If the patient develops new areas of psoriasis during maintenance therapy (but still is classified as having a Grade 4 response), the exposure to UVA may be increased by 0.5-1.5 J/cm2 at each treatment; this is appropriate for all types of patients. These increases are continued until the psoriasis is brought under control and the patient is again clear. The exposure being administered when this clearing is reached should be used for further maintenance treatment.

FLARES DURING MAINTENANCE: If the patient flares during maintenance treatment (i.e., develops psoriasis on more than 5% of the originally involved areas of the body), this maintenance treatment schedule may be changed to the preceding maintenance or clearing schedule. The patient may be kept on his schedule until again 95 % clear. If the original maintenance treatment schedule is unable to control the psoriasis, the schedule may be changed to a more frequent regimen. If a flare occurs less than 6 weeks after the last treatment, 25 % of the maximum exposure received during the clearing phase, with the clearing schedule received during the clearing phase, may be used and then proceed with the clearing schedule previously followed for this patient. (At 95% clearing, follow regular maintenance until the optimum maintenance schedule is determined for the patient.) If more than 6 weeks have elapsed since the last treatment was given, treat patients as if they were beginning therapy insofar as exposure dosages are concerned, since their threshold for erythema may have decreased.