"(Reuters) - Valeant Pharmaceuticals International Inc's experimental drug to treat psoriasis carries a potential risk of suicide that is challenging to assess due to limited data, a preliminary review by the U.S. Food and Drug Administration said"...
Photochemotherapy (Methoxsalen with long wave UVA radiation) is indicated for the symptomatic control of severe, recalcitrant, disabling psoriasis not adequately responsive to other forms of therapy and when the diagnosis has been supported by biopsy. Methoxsalen is intended to be administered only in conjunction with a schedule of controlled doses of long wave ultraviolet radiation.
DOSAGE AND ADMINISTRATION
CAUTION: Oxsoralen-Ultra represents a new dose form of methoxsalen. This new dosage form of methoxsalen exhibits significantly greater bioavailability and earlier photosensitization onset time than previous methoxsalen dosage forms. Each patient should be evaluated by determining the minimum phototoxic dose (MPD) and phototoxic peak time after drug administration prior to onset of photochemotherapy with this dosage form. Human bioavailability studies have indicated the following drug dosage and administration directions are to be used as a guideline only.
1. DRUG DOSAGE - INITIAL THERAPY: The methoxsalen capsules should be taken 1 ½ to 2 hours before UVA exposure with some low fat food or milk according to the following table:
|< 30||< 66||10|
|> 115||> 254||70|
Elderly patients should generally be started at the low end of the dose recommended according to body weight and closely monitored during PUVA therapy. Although clinical experience has not identified differences in response between elderly and younger patients, the use of methoxsalen in older individuals may be affected by the presence or pre-existing medical conditions.
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:
|Skin Type||Historv||Recommended Joules/cm²|
|I||Always burn, never tan (patients with erythrodermic psoriasis are to be classed as Type I for determination of UVA dosage.)||0.5 J/cm²|
|II||Always burn, but sometimes tan||1.0 J/cm²|
|III||Sometimes burn, but always tan||1.5 J/cm²|
|IV||Never burn, always tan||2.0 J/cm²|
|Skin Type||Physician Examination||Joules/cm²|
|V*||Moderately pigmented||2.5 J/cm²|
|(*Patients with natural pigmentation of these types should be classified into a lower skin type category if the sunburning history so indicates.)|
If the MPD is done, start at ½ MPD.
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 fifteenth treatment under the conditions outlined in section XI.B.4.b.
Uva Radiation Source Specifications & Information
The following specifications should be met with the window of the detector held in a vertical plane:
- 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 percent of the highest reading.
- Horizontal variation: Throughout any specific horizontal plane, the lowest reading must be at least 80 percent of the highest reading, excluding the peripheral 3 cm of the patient treatment space.
Patient Safety Features
The following safety features should be present: (1) Protection from electrical hazard: All units should be grounded and conform to applicable electrical codes. The patient or operator should not be able to touch any live electrical parts. There should be ground fault protection. (2) Protective shielding of lamps: The patient should not be able to come in contact with the bare lamps. In the event of lamp breakage, the patient should not be exposed to broken lamp components. (3) Hand rails and hand holds: Appropriate supports should be available to the patient. (4) Patient viewing window: A window which blocks UV should be provided for viewing the patient during treatment. (5) Door and latches: Patients should be able to open the door from the inside with only slight pressure to the door. (6) Non-skid floor: The floor should be of a non-skid nature. (7) Thermoregulation: Sufficient air flow should be provided for patient safety and comfort, limiting temperature within the UVA radiator cabinet to approximately less than 100° F. (8) Timer: The irradiator should be equipped with an automatic timer which terminates the exposure at the conclusion of a pre-set time interval. (9) Patient alarm device: An alarm device within the UVA irradiator chamber should be accessible to the patient for emergency activation. (10) Danger label: The unit should have a label prominently displayed which reads as follows:
DANGER - Ultraviolet Radiation - Follow your physician's instructions - Failure to use protective eyewear may result in eye injury.
Uva Exposure Dosimetry Measurements
The maximum radiant exposure or irradiance (within ± 15 percent) of UVA (320-400 nm) delivered to the patient should be determined by using an appropriate radiometer calibrated to be read in Joules/cm² or mW/cm². In the absence of a standard measuring technique approved by the National Bureau of Standards, the system should use a detector corrected to a cosine spatial response. The use and recalibration frequency of such a radiometer for a specific UVA irradiator chamber should be specified by the manufacturer because the UVA dose (exposure) is determined by the design of the irradiator, the number of lamps, and the age of the lamp. If irradiance is measured, the radiometer reading in mW/cm² is used to calculate the exposure time in minutes to deliver the required UVA in Joules/cm² to a patient in the UVA irradiator cabinet. The equation is:
Exposure Time (minutes) = Desired UVA Dose (J/cm²)/ 0.06x 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.
Uva Spectral Output Distribution
The spectral distributions of the lamps should meet the following specifications:
|Wavelength band (nanometers)||Output1|
|< 310||< 1|
|310 to 320||1 to 3|
|320 to 330||4 to 8|
|330 to 340||11 to 17|
|340 to 350||18 to 25|
|350 to 360||19 to 28|
|360 to 370||15 to 23|
|370 to 380||8 to 12|
|380 to 390||3 to 7|
|390 to 400||1 to 3|
|1 As a percentage of total irradiance between 320 and 400 nanometers.|
Puva Treatment Protocol
The Oxsoralen-Ultra® Capsules reach their maximum bioavailability in 1 ½ to 2 hours after ingestion.
On average, the serum level achieved with Oxsoralen-Ultra is twice that obtained with 8-MOP (formerly Oxsoralen) and reach their peak concentration in less than ½ the time of the 8-MOP capsules.
As a result the mean MED J/cm² for the Oxsoralen-Ultra Capsules is substantially less than that required for 8-MOP (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.
Initial Exposure: The initial UVA exposures should be conducted according to the guidelines presented previously under IX., Psoriasis Therapy, Drug Dosage-Initial Therapy and Initial Exposure.
Clearing Phase: Specific recommendations for patient treatment are as follows:
- 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 Joule/cm 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 section for additional information.
- 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 Joules/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 treatmentrelated 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 Joules/cm² above the prior incremental increases for each treatment. (Example: a patient whose exposure dosage is being increased by 1.0 Joule/cm² may now have all subsequent doses increased by 1.5-2.0 Joules/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 Joules/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 percent 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.
Alternative Exposure Schedule
As an alternative to increasing the UVA exposure at each treatment, the following schedule may be followed; this schedule may reduce the total number of Joules/cm² received by the patient over the entire course of therapy.
- Incremental increases in UVA exposure for all patients may range from 0.5 to 1.5 Joules/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 Joules/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 (Joules/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.
The goal of maintenance treatment is to keep the patient as symptom-free as possible with the least amount of UVA exposure.
1. SCHEDULE OF EXPOSURES: When patients have achieved 95 percent 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).
M - once/week
M - once/2 weeks
M - once/3 weeks
M - p.r.n. (i.e., for flares)
2. LENGTH OF EXPOSURE: The UVA exposure for the first maintenance treatment of any schedule (except M4 as noted below) is the same as that of the patient's last treatment under the previous schedule. For skin types I-IV, however, it is recommended that the maximum UVA dosage during maintenance treatments not exceed the following:
If the patient develops erythema or new lesions of psoriasis, proceed as follows: a. Erythema: During maintenance therapy, the patient's tan and threshold dose for erythema may gradually decrease. If maintenance treatments produce significant erythema, the exposure to UVA should be decreased by 25 percent until further treatments no longer produce erythema. 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 Joules/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.
3. FLARES DURING MAINTENANCE: If the patient flares during maintenance treatment (i.e., develops psoriasis on more than 5 percent of the originally involved areas of the body), his maintenance treatment schedule may be changed to the preceding maintenance or clearing schedule. The patient may be kept on his schedule until again 95 percent 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 percent 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 percent 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.
Table 1: Grades of Erythema
|1||Minimally perceptible erythema - faint pink|
|2||Marked erythema but with no edema|
|3||Fiery erythema with edema|
|4||Fiery erythema with edema and blistering|
Table 2: Response To Therapy
|Grade Criteria||Percent Improvement (compared to original extent of disease)|
|-1 Psoriasis worse||0|
|0 No change||0|
|1 Minimal improvement. - slightly less scale and/or erythema||5-20|
|2 Definite improvement - partial flattening of all plaques - less scaling and less erythema||20-50|
|3 Considerable improvement - nearly complete flattening of all plaques but borders of plaques still palpable||50-95|
|4 Clearing; complete flattening of plaques including borders; plaques may be outlined by pigmentation||95|
Oxsoralen-Ultra Capsules, each containing 10 mg of methoxsalen (8-methoxypsoralen) are available in green soft gelatin capsules in white plastic bottles of 50 (NDC 0187-0650-42), with VRX imprinted on one side of the capsule and 650 imprinted on the other side.
Store at 25°C (77°F); excursions permitted to 15°C- 30°C (59°F- 86°F).
Manufactured for: Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807 USA. By:Heritage Pharma Labs Inc., East Brunswick, NJ 08816 USA. Revised: Feb 2015This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 5/5/2016
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