In the event of methoxsalen overdosage, induce emesis and keep the patient in a darkened room for at least 24 hours. Emesis is most beneficial within the first 2 to 3 hours after ingestion of methoxsalen, since maximum blood levels are reached by this time.
The most commonly reported side effect of methoxsalen alone is nausea, which occurs with approximately 10% of all patients. This effect may be minimized or avoided by instructing the patient to take methoxsalen in milk or food, or to divide the dose into two portions, taken approximately one-half hour apart. Other effects include nervousness, insomnia, and depression.
Combined Methoxsalen/Uva TherapyPhotochemotherapy (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.
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 2015
Serious skin burns from either UVA or sunlight (even through window glass) can result if recommended exposure schedule is exceeded and/or protective covering or sunscreens are not used. The blistering of the skin sometimes encountered after UV exposure generally heals without complication or scarring. (Farrington Daniels, Jr., M.D., personal communication). Suitable covering of the area of application or a topical sunblock should follow the therapeutic UVA exposure.
Carcinogenicity Animal StudiesTopical methoxsalen has been reported to be a potent photocarcinogen in certain strains of mice. (Pathak et al 1959)5.
Human StudiesNone of our clinical investigators reported skin cancer as a complication of topical treatment for vitiligo. However, it is recommended that caution be exercised when the patient is fair-skinned, has a history of prior coal tar UV treatment, or has had ionizing radiation or taken arsenical compounds. Such patients who subsequently have oral psoralen – UVA treatment (PUVA) are at increased risk for developing skin cancer.
Concomitant TherapySpecial care should be exercised in treating patients who are receiving concomitant therapy (either topically or systemically) with known photosensitizing agents such as anthralin, coal tar or coal tar derivatives, griseofulvin, phenothiazines, nalidixic acid, halogenated salicylanilides (bacteriostatic soaps), sulfonamides, tetracyclines, thiazides and certain organic staining dyes such as methylene blue, toluidine blue, rose bengal, and methyl orange.
REFERENCES
5. Pathak, M.A.; Daniels, F.; Hopkins, C.E.; Fitzpatrick, T.B.: Ultraviolet carcinogenesis in albino and pigmented mice receiving furocoumarins: psoralens and 8-methoxypsoralen, Nature, 183, pp. 728-730 (1959).
PRECAUTIONSThis product should be applied only in small well-defined lesions and preferably on lesions which can be protected by clothing or a sunscreen from subsequent exposure to radiant UVA. If this product is used to treat vitiligo of face or hands, be very emphatic when instructing patient to keep the treated areas protected from light by use of protective clothing or sunscreening agents. The area of application may be highly photosensitive for several days and may result in severe burn injury if exposed to additional UV or sunlight.
CarcinogenesisSee WARNING Section.
Pregnancy Category CAnimal reproduction studies have not been conducted with topical methoxsalen. It is also not known whether methoxsalen can cause fetal harm when used topically on a pregnant woman or affect reproductive capacity. It is not known to what degree, if any, topical methoxsalen is absorbed systemically. Topical methoxsalen should be used in women only when clearly indicated.
Nursing MothersIt is not known whether topical methoxsalen is absorbed or excreted in human milk. Caution is advised when topical methoxsalen is used in a nursing mother.
Pediatric UsageSafety and effectiveness in children below the age of 12 years have not been established.
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.
Psoriasis Therapy1. 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:
Patient's Weight
| Dose | ||
| (kg) | (lbs) | (mg) |
| < 30 | < 66 | 10 |
| 30-50 | 66-110 | 20 |
| 51-65 | 112-143 | 30 |
| 66-80 | 146-176 | 40 |
| 81-90 | 179-198 | 50 |
| 91-115 | 201-254 | 60 |
| > 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 |
| VI* | Blacks | 3.0 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:
The following specifications should be met with the window of the detector held in a vertical plane:
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 MeasurementsThe 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 DistributionThe 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. |
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:
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.
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).
Maintenance Schedules
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:
| Skin Types | Joules/cm²/treatment |
| I | 12 |
| II | 14 |
| III | 18 |
| IV | 22 |
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
| Grade | Erythema |
| 0 | No 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 |
The most commonly reported side effect of methoxsalen alone is nausea, which occurs with approximately 10% of all patients. This effect may be minimized or avoided by instructing the patient to take methoxsalen in milk or food, or to divide the dose into two portions, taken approximately one-half hour apart. Other effects include nervousness, insomnia, and depression.
Combined Methoxsalen/Uva TherapySee WARNINGS Section.
