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 not maintained.
- Animal Studies: Topical or intraperitoneal methoxsalen has been reported
to be a potent photocarcinogen in albino mice and hairless mice. However,
methoxsalen given by the oral route to albino mice or by any route in pigmented
mice is considerably less phototoxic or carcinogenic (Hakim et al. 196011,
Pathak et al. 195912).
- Human Studies: A prospective study of 1380 patients over 5 years
revealed an approximately nine-fold increase in risks of squamous cell carcinoma
among PUVA treated patients (Stern et al. 197913 and Stern et al.
198014). This increase in risk appears greatest among patients
who are fair skinned or had pre-PUVA exposure to 1) prolonged tar and UVB
treatment, 2) ionizing radiation, or 3) arsenic.
In addition, an approximately two-fold increase in the risk of basal cell carcinoma
was noted in this study. Roenigk et al. 198015 studied 690 patients
for up to 4 years and found no increase in the risk of non-melanoma skin cancer.
However, 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
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. 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
- 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
- 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 period20.
Patients should be told emphatically to wear UVA-absorbing, wraparound 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.13
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.
Actinic Degeneration: Exposure to sunlight and/or ultraviolet radiation
may result in “prematureaging” of the skin.
Basal Cell Carcinomas: Patients exhibiting multiple basal cell carcinomas
or having a history of basal cell carcinomas should be diligently observed and
Radiation Therapy: Patients having a history of previous x-ray therapy
or grenz ray therapy should be diligently observed for signs of carcinoma.
Arsenic Therapy: Patients having a history of previous arsenic therapy
should be diligently observed for signs of carcinoma.
Hepatic Diseases: Patients with hepatic insufficiency should be treated
with caution since hepatic biotransformation is necessary for drug urinary excretion.
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.
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.
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.
General - Applicable To Both Vitiligo And 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
- 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 for 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
- Unless affected by disease, male genitalia should be shielded.
After Combined Methoxsalen/Uva Therapy
- UVA-absorbing wrap-around sunglasses should be worn during the 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.
- The dosage of methoxsalen should not be increased above 0.6 mg/kg since
overdosage may result in serious burning of the skin.
- Eye and skin sun protection as described in the PRECAUTIONS — General
section should be observed.
Information for Patients
See accompanying Patient Package Insert.
Patients should have an ophthalmologic examination prior to start of therapy,
and thence yearly.
Patients should have the following tests prior to the start of therapy and
should be retested 6–12 months subsequently. Additional tests at more extended
time periods should be conducted as clinically indicated.
- Complete Blood Count (Hemoglobin or Hematocrit; White Blood Count—if abnormal,
a differential count).
- Anti-nuclear Antibodies.
- Liver Function Tests.
- Renal Function Tests (Creatinine or Blood Urea Nitrogen).
See WARNINGS Section.
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 only if clearly needed.
It is not known whether this drug is excreted in human milk. Because many
drugs are excreted in human milk, caution should be exercised when methoxsalen
is administered to a nursing woman.
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.
11. Hakim, R. E., 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).
12. 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).
13. Stern, R. S., Thibodeau, L. A., Kleinerman, R. A., Parrish,
J. A., Fitzpatrick, T. B., and 22 Participating Investigators: Risk of Cutaneous
Carcinoma in Patients Treated with Oral Methoxsalen Photochemotherapy for Psoriasis,
NEJM, 300 No. 15, pp. 809–813 (1979).
14. 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).
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. AbstractJID,
74 No. 4, p. 250 (April, 1980).
16. Stern et al, Malignant melanoma in patients treated for
psoriasis with methoxalen (psoralen) and ultraviolet A radiation (PUVA). The
PUVA Follow-Up Study. New England Journal of Medicine, 336:104-1045, (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
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; J. Invest. Dermat., 74, pp. 197–199
Included as part of the WARNINGS section.