Oxsoralen-Ultra

Oxsoralen-Ultra

WARNINGS

General

  1. SKIN BURNING: Serious burns from either UVA or sunlight (even through window glass) can result if the recommended dosage of the drug and/or exposure schedules are exceeded.
  2. CARCINOGENICITY:
    1. ANIMAL STUDIES: Topical or intraperitoneal methoxsalen has been reported to be a potent photocarcinogen in albino mice and hairless mice (Hakim et al., 196010). However, methoxsalen given by the oral route to Swiss albino mice suggests this agent exerts a protective effect against ultraviolet carcinogenesis; mice given 8-methoxypsoralen in their diet showed 38% ear tumors 180 days after the start of ultraviolet therapy compared to 62% for controls (O'Neal et al., 195711).
    2. 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 had an elevated relative risk of contracting melanoma. The relative risk for melanoma in these patients was 2.3 (95 percent 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 percent 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.
  3. CATARACTOGENICITY:
    1. ANIMAL STUDIES: Exposure to large doses of UVA causes cataracts in animals, and this effect is enhanced by the administration of methoxsalen (Cloud et al., 196018; Cloud et al., 196119; Freeman et al., 196920).
    2. 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 twenty-four (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 five 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.
  4. ACTINIC DEGENERATION: Exposure to sunlight and/or ultraviolet radiation may result in "premature aging" of the skin.
  5. BASAL CELL CARCINOMAS: Patients exhibiting multiple basal cell carcinomas or having a history of basal cell carcinomas should be diligently observed and treated.
  6. RADIATION THERAPY: Patients having a history of previous x-ray therapy or grenz ray therapy should be diligently observed for signs of carcinoma.
  7. ARSENIC THERAPY: Patients having a history of previous arsenic therapy should be diligently observed for signs of carcinoma.
  8. HEPATIC DISEASES: Patients with hepatic insufficiency should be treated with caution since hepatic biotransformation is necessary for drug urinary excretion.
  9. CARDIAC DISEASES: Patients with cardiac diseases or others who may be unable to tolerate prolonged standing or exposure to heat stress should not be treated in a vertical UVA chamber.
  10. ELDERLY PATIENTS: Caution should be used in elderly patients, especially those with a pre-existing history of cataracts, cardiovascular conditions, kidney and/or liver dysfunction, or skin cancer.
  11. TOTAL DOSAGE: The total cumulative dose of UVA that can be given over long periods of time with safety has not as yet been established.
  12. CONCOMITANT THERAPY: Special 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, fluoroquinolone antibiotics, halogenated salicylanilides (bacteriostatic soaps), sulfonamides, tetracyclines, thiazides, and certain organic staining dyes such as methylene blue, toluidine blue, rose bengal, and methyl orange.

PRECAUTIONS

General - Applicable To Psoriasis Treatment

Before Methoxsalen Ingestion

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
  1. 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. b. 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
  1. 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.
  2. Abdominal skin, breasts, genitalia, and other sensitive areas should be protected for approximately 1/3 of the initial exposure time until tanning occurs.
  3. Unless affected by disease, male genitalia should be shielded.
After Combined Methoxsalen/UVA Therapy
  1. UVA-absorbing wrap-around sunglasses should be worn during daylight for 24 hours after combined methoxsalen/UVA therapy.
  2. Patients should not sunbathe for 48 hours after therapy. Erythema and/or burning due to photochemotherapy and sunburn due to sun exposure are additive.

Laboratory Tests

  1. Patients should have an ophthalmologic examination prior to start of therapy, and thence yearly.
  2. Patients should have routine laboratory tests prior to the start of therapy and at regular periods thereafter if patients are on extended treatments.

Carcinogenesis

See WARNINGS Section.

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with methoxsalen. It is also not known whether methoxsalen can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Methoxsalen should be given to a woman with reproductive capacity only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, either methoxsalen ingestion or nursing should be discontinued.

Pediatric Use

Safety in children has not been established. Potential hazards of long-term therapy include the possibilities of carcinogenicity and cataractogenicity as described in the Warnings Section as well as the probability of actinic degeneration which is also described in the Warnings Section.

Geriatric Use

Clinical studies with Oxsoralen-Ultra (methoxsalen capsules) capsules did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects responded differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

BIBLIOGRAPHY

10. Hakim, R.D., Griffin, A.C.: Knox, J.M.: Erythema and tumor formation in methoxsalen treated mice exposed to fluorescent light; Arch. Dermatol. 82, pp. 572-577 (1960).

11. O'Neal, M.A., Griffin, A.C.: The Effect of Oxypsoralen upon Ultraviolet Carcinogenesis in Albino Mice, Cancer Res., 17, pp. 911-916 (1957).

12. Stern, R.S., Unpublished personal communication.

13. Stern, R.S., Parrish, J.A., Zierler, S.: Skin Carcinoma in Patients with Psoriasis Treated with Topical Tar and Artificial Ultraviolet Radiation. Lancet, 1, pp. 732-735 (1980).

14. Stern, R.S., Laird, N., Melski, J., Parrish, J.A., Fitzpatrick, T.B., Bleich, H.L.: Cutaneous Squamous-Cell Carcinoma in Patients Treated with PUVA: NEJM, 310, No. 18, pp. 1156-1161 (1984).

15. Roenigk, Jr., H.H., and 12 Cooperating Investigators: Skin Cancer in the PUVA-48 Cooperative Study of Psoriasis. Program for Forty-First Annual Meeting for The Society of Investigative Dermatology, Inc., Sheraton Washington Hotel, Washington, D.C., May 12, 13, and 14, 1980. Abstracts JID, 74, No. 4, p. 250 (April, 1980).

16. Stern et al., Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-up Study. New England Journal of Medicine, 336:1041-1045, (April 10, 1997).

17. Mosher, D.B., Pathak, M.A., Harris, T.J., Fitzpatrick, T.B.: Development of Cutaneous Lesions in Vitiligo During Long-Term PUVA Therapy. Program for Forty-First Annual Meeting for The Society for Investigative Dermatology, Inc., Sheraton Washington Hotel, Washington, D.C., May 12, 13, and 14, 1980. Abstracts JID, 74, No. 4, p. 259 (April, 1980).

18. Cloud, T.M., Hakim, R., Griffin, A.C.: Photosensitization of the eye with methoxsalen. I. Acute effects; Arch. Ophthalmol. 64, pp. 346-352 (1960).

19. Cloud, T.M., Hakim, R., Griffin, A.C.: Photosensitization of the eye with methoxsalen. II. Chronic effects, Ibid, 66, pp. 689-694 (1961).

20. Freeman, R.G., Troll, D.: Photosensitization of the eye by 8-methoxypsoralen, JID, 53, pp. 449-453 (1969).

21. Lerman, S., Megaw, J., Willis, I.: Potential ocular complications from PUVA therapy and their prevention; JID 74, pp. 197-199 (1980).

22. Diffey, B.L., Medical Physics Handbook 11, Ultraviolet Radiation In Medicine, Adam Hilger, Ltd., Bristol, p. 86 (1982).

Last reviewed on RxList: 11/21/2008
This monograph has been modified to include the generic and brand name in many instances.

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