Methoxsalen

8-MOP (Methoxsalen, 8-Methoxypsoralen) Capsules, 10 mg. Methoxsalen is a naturally occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant and in the roots of Heraclem Candicans. It belongs to a group of compounds known as psoralens, or furocoumarins. The chemical name of methoxsalen is 9-methoxy-7 H-furo[3, 2-g][1]-benzopyran-7-one; it has the following structure:

The combination treatment regimen of psoralen (P) and ultraviolet radiation of 320–400 nm wavelength commonly referred to as UVA is known by the acronym, PUVA. Skin reactivity to UVA (320–400 nm) radiation is markedly enhanced by the ingestion of methoxsalen. The drug reaches its maximum bioavailability 1 1/2–3 hours after oral administration and may last for up to 8 hours (Pathak et al. 1974)1. Methoxsalen is reversibly bound to serum albumin and is also preferentially taken up by epidermal cells (Artuc et al. 1979)2. At a dose which is six times larger than that used in humans, it induces mixed function oxidases in the liver of mice (Mandula et al. 1978)3. In both mice and man, methoxsalen is rapidly metabolized. Approximately 95% of the drug is excreted as a series of metabolites in the urine within 24 hours (Pathak et al. 1977)4.

The exact mechanism of action of methoxsalen with the epidermal melanocytes and keratinocytes is not known. The best known biochemical reaction of methoxsalen is with DNA. Methoxsalen, upon photoactivation, conjugates and forms covalent bonds with DNA which leads to the formation of both monofunctional (addition to a single strand of DNA) and bifunctional adducts (crosslinking of psoralen to both strands of DNA) (Dall'Acqua et al., 19715; Cole, 19706; Musajo et al., 19747; Dall'Acqua et al., 19798). Reactions with proteins have also been described (Yoshikawa, et al., 19799).

Methoxsalen acts as a photosensitizer. Administration of the drug and subsequent exposure to UVA can lead to cell injury. Orally administered methoxsalen reaches the skin via the blood and UVA penetrates well into the skin. If sufficient cell injury occurs in the skin, an inflammatory reaction occurs. The most obvious manifestation of this reaction is delayed erythema, which may not begin for several hours and peaks at 48–72 hours. The inflammation is followed, over several days to weeks, by repair which is manifested by increased melanization of the epidermis and thickening of the stratum corneum. The mechanisms of therapy are not known. In the treatment of vitiligo, it has been suggested that melanocytes in the hair follicle are stimulated to move up the follicle and to repopulate the epidermis (Ortonne et al, 197910). In the treatment of psoriasis, the mechanism is most often assumed to be DNA photodamage and resulting decrease in cell proliferation but other vascular, leukocyte, or cell regulatory mechanisms may also be playing some role. Psoriasis is a hyperproliferative disorder and other agents known to be therapeutic for psoriasis are known to inhibit DNA synthesis.

REFERENCES

1. Pathak, M. A., Kramer, D. M., Fitzpatrick, T. B.: Photobiology and Photochemistry of Furocoumarins (Psoralens), SUNLIGHT AND MAN: Normal and Abnormal Photobiologic Responses. Edited by M. A. Pathak, L. C. Harbor, M. Seiji et al. University of Tokyo Press. 1974, pp. 335-368.

2. Artuc, M., Stuettgen, G., Schalla, W., Schaefer, H., and Gazith, J.: Reversible binding of 5- and 8-methoxypsoralen to human serum proteins (albumin) and to epidermisin vitro:Brit. J. Dermat. 101, pp. 669-677 (1979).

3. Mandula, B. B., Pathak, M. A., Nakayama, Y., and Davidson, S. J.: Induction of mixed-function oxidases in mouse liver by psoralens, Ibid, 99, pp. 687-692 (1978).

4. Pathak, M. A., Fitzpatrick, T. B., Parrish, J. A.: PSORIASIS, Proceedings of the Second International Symposium. Edited by E. M. Farber, A. J. Cox, Yorke Medical Books, pp. 262–265 (1977).

5. Dall'Acqua, F., Marciani, S., Ciavatta, L., Rodighiero, G.: Formation of interstrand cross-linkings in the photoreactions between furocoumarins and DNA; Z Naturforsch (B), 26, pp. 561–569 (1971).

6. Cole, R. S.: Light-induced cross-linkings of DNA in the presence of a furocoumarin (psoralen), Biochem. Biophys. Acta. 217, pp. 30–39 (1970).

7. Musajo, L., Rodighiero, G., Carporale, G., Dall'Acqua, F., Marciani, S., Bordin, F., Baccichetti, F., Bevilacqua, R.: Photoreactions between Skin-Photosensitizing Furocoumarins and Nucleic Acids, SUNLIGHT AND MAN; Normal and Abnormal Photobiologic Responses. Edited by M. A. Pathak, L. C. Harber, M. Seiji et al., University of Tokyo Press, pp. 369–387 (1974).

8. Dall'Acqua, F., Vedaldi, D., Bordin, F., and Rodighiero, G.: New studies in the interaction between 8-methoxypsoralen and DNA in vitro; J. Investigative Dermat., 73, pp. 191–197 (1979).

9. Yoshikawa, K., Mori, N., Sakakibara, S., Mizuno, N., Song, P.: Photo-Conjugation of 8-methoxypsoralen with Proteins,Photochem & Photobiol. 29, pp. 1127–1133 (1979).

10. Ortonne, J. P., MacDonald, D. M., Micoud, A., Thivolet, J.: PUVA-induced repigmentation of vitiligo: a histochemical (split-DOPA) and ultra-structural study: Brit. J. of Dermat., 101, pp. 1–12 (1979).

Concomitant Therapy

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 may be at greater risk for photosensitivity reactions with UVADEX®.

Carcinogenicity, Mutagenesis, Impairment Of Fertility

Oral administration of methoxsalen followed by cutaneous UVA exposure (PUVA therapy) is carcinogenic. In a prospective study of 1380 patients given PUVA therapy for psoriasis, 237 patients developed 1422 cutaneous squamous cell cancers. This observed incidence of cutaneous carcinoma is 17.6 times that expected for the general population. Previous cutaneous exposure to tar and UVB treatment, ionizing radiation or arsenic increased the risk of developing skin carcinomas after PUVA therapy. Because the dose of methoxsalen with UVADEX® therapy is about 200 times less than with PUVA and the skin is not exposed to high cumulative doses of UVA light, the risk of developing skin cancer following UVADEX® therapy may be lower.

Methoxsalen was carcinogenic in male rats that were given the drug by oral gavage five days per week for 103 weeks at doses of 37.5 and 75 mg/kg. The 37.5 mg/kg dose is about 1900 times greater than a single human methoxsalen dose during extracorporeal photopheresis treatment on a body surface area basis. The neoplastic lesions in rats included adenomas and adenocarcinomas of the tubular epithelium of the kidneys, carcinoma or squamous cell carcinoma of the Zymbal gland and alveolar or bronchiolar adenomas. Topical or intraperitoneal methoxsalen is a potent photo-carcinogen in albino mice and hairless mice.

With S9 activation, methoxsalen is mutagenic in the Ames test. In the absence of S9 activation and UV light, methoxsalen is clastogenic in vitro (sister chromatid exchange and chromosome aberrations in Chinese hamster ovary cells). Methoxsalen also causes DNA damage, interstrand cross-links and errors in DNA repair.

Pregnancy

Methoxsalen may cause fetal harm when given to a pregnant woman. Doses of 80 to 160 mg/kg/day given during organogenesis caused significant fetal toxicity in rats. The lowest of these doses, 80 mg/kg/day, is over 4000 times greater than a single dose of UVADEX® on a mg/m² basis. Fetal toxicity was associated with significant maternal weight loss, anorexia and increased relative liver weight. Signs of fetal toxicity included increased fetal mortality, increased resorptions, late fetal death, fewer fetuses per litter, and decreased fetal weight. Methoxsalen caused an increase in skeletal malformation and variations at doses of 80 mg/kg/day and above. There are no adequate and well-controlled studies of methoxsalen in pregnant women. If UVADEX® is used during pregnancy, or if the patient becomes pregnant while receiving UVADEX®, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Methoxsalen is available in the following forms:

• Injectable Solution
• Oral Capsule
• Topical Lotion
• Topical Solution

Methoxsalen is a naturally occurring substance that is reactive to light. It works by enhancing the body's sensitivity to ultraviolet light A (UVA).

Methoxsalen is used in combination with UVA light therapy to treat severe psoriasis.

Methoxsalen is usually given after other psoriasis medications have been tried without successful treatment of symptoms.

Methoxsalen may also be used for purposes not listed in this medication guide.

• Oxsoralen

© Uvadex Patient Information is supplied by Cerner Multum, Inc. and Uvadex Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Avoid exposure to sunlight or artificial UV rays other than your scheduled light therapy treatments.

Usual Adult Dose for Psoriasis:

Initial dose: Based on patient weight.
115 kg = 70 mg

The initial UVA exposures are based on the patient's skin type and should be conducted according to the guidelines in professional literature.

Maintenance dose: Dose, schedule, and UVA exposure are based on the patients skin type, grades of erythema, and response to therapy per guidelines in professional literature.

Usual Adult Dose for Cutaneous T-cell Lymphoma:

Summary of UVAR photopheresis system (see the UVAR photopheresis system operator's manual for details of this process):
The UVAR system removes a portion of the patient's blood and separates the red blood cells from the white cell layer (buffy coat) by centrifugation. The red cells are returned to the patient and the methoxsalen sterile solution is then injected into the UVAR system and mixed with the buffy coat. The UVAR system then irradiates this drug-cell mixture with ultraviolet light (UVA light, 320 to 400 nm) and returns the treated cells to the patient.

Initial dose: 10 mL (200 mcg) of methoxsalen sterile solution is injected directly into the photoactivation bag during the first buffy coat collection cycle.

Maintenance: Treatment is given on two consecutive days every four weeks.

Duration: Minimum of seven treatment cycles (six months).

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with methoxsalen. Methoxsalen can make your skin even more sensitive to sunlight if you also use certain other medicines, especially:

• griseofulvin;

• nalidixic acid;

• an antibiotic (such as ciprofloxacin (Cipro), doxycycline, levofloxacin (Levaquin), minocycline, ofloxacin, tetracycline), and others;

• a bacteriostatic soap;

• coal tar applied to the skin or scalp (Neutrogena T/Gel, Psoriasin, Tegrin Medicated, and others);

• a diuretic or "water pill";

• medicine to treat mental illness (such as chlorpromazine, fluphenazine, prochlorperazine, thioridazine, and others);

• a staining dye such as methylene blue, toluene blue, rose bengal, or methyl orange; or

• a sulfa drug (Bactrim, SMX-TMP or SMZ-TMP, and others).

This list is not complete. Other drugs may interact with methoxsalen, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Methoxsalen belongs to the group of medicines called psoralens. It is used along with ultraviolet light (found in sunlight and some special lamps) in a treatment called PUVA to treat vitiligo, a disease in which skin color is lost, and psoriasis, a skin condition associated with red and scaly patches.

Methoxsalen is also used with ultraviolet light in the treatment of white blood cells. This treatment is called photopheresis and is used to treat the skin problems associated with mycosis fungoides, which is a type of lymphoma.

Methoxsalen may also be used for other conditions as determined by your doctor.

methoxsalen is available only with your doctor's prescription.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For methoxsalen, the following should be considered:

Methoxsalen is a very strong medicine that increases the skin's sensitivity to sunlight. In addition to causing serious sunburns if not properly used, it has been reported to increase the chance of skin cancer and cataracts. Also, like too much sunlight, PUVA can cause premature aging of the skin. Therefore, methoxsalen should be used only as directed and it should not be used simply for suntanning. Before using methoxsalen, be sure that you have discussed its use with your doctor.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to methoxsalen or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Some of the side effects are more likely to occur in children up to 12 years of age, since these children may be more sensitive to the effects of methoxsalen.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of methoxsalen in the elderly with use in other age groups.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking methoxsalen, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using methoxsalen with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Anagrelide
• Tegafur

Using methoxsalen with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Fosphenytoin
• Phenytoin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of methoxsalen. Make sure you tell your doctor if you have any other medical problems, especially:

• Allergy to sunlight (or family history of) or
• Infection or
• Lupus erythematosus or
• Porphyria or
• Skin cancer (history of) or
• Skin conditions (other) or
• Stomach problems—Use of PUVA may make the condition worse

• Eye problems, such as cataracts or loss of the lens of the eye—The light treatment may make the condition worse or may cause damage to the eye

• Heart or blood vessel disease (severe)—The heat or prolonged standing associated with each light treatment may make the condition worse

• Liver disease—Condition may cause increased blood levels of the medicine and cause an increase in side effects

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.

Applies to methoxsalen: oral capsule, oral capsule liquid filled

Other dosage forms:

• injection injectable, injection solution

Along with its needed effects, methoxsalen may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking methoxsalen:

• Blistering and peeling of skin
• reddened, sore skin
• swelling (especially of feet or lower legs)

Some side effects of methoxsalen may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Itching of skin
• nausea

• Dizziness
• headache
• mental depression
• nervousness
• trouble in sleeping

Treatment with this medicine usually causes a slight reddening of your skin 24 to 48 hours after the treatment. This is an expected effect and is no cause for concern. However, check with your doctor right away if your skin becomes sore and red or blistered.

There is an increased risk of developing skin cancer after use of methoxsalen. You should check your body regularly and show your doctor any skin sores that do not heal, new skin growths, and skin growths that have changed in the way they look or feel.

Premature aging of the skin may occur as a result of prolonged methoxsalen therapy. This effect is permanent and is similar to what happens when a person sunbathes for long periods of time.

Applies to methoxsalen: compounding powder, injectable solution, oral capsule

Dermatologic

Dermatologic side effects have included mild to serious skin burns, premature aging of the skin, pruritus, inflammation, erythema, rash (nonspecific), edema, extension of psoriasis, cutaneous tenderness, hypopigmentation, keratosis, folliculitis, dermal vessel damage, longer duration of epidermal and dermal abnormalities, miliaria, urticaria, vesiculation formation, and bullae formation. Postmarketing dermatologic side effects have included rash.[Ref]

Cardiovascular

Cardiovascular side effects are mostly associated with methoxsalen sterile solution and have included arrhythmia and serious (nonspecific) cardiovascular adverse experiences. Hypotension and dizziness have been associated with the sterile solution and the oral administration of methoxsalen.[Ref]

Immunologic

Immunologic side effects associated with the sterile solution have included infections (nonspecific) and hickman catheter infections. Immunologic side effect with oral administration of methoxsalen has been herpes simplex.[Ref]

Oncologic

Oncologic side effects have included cutaneous squamous cell cancers, malignant melanoma, and basal cell carcinoma.[Ref]

Psychiatric

Psychiatric side effects have included depression.[Ref]

Gastrointestinal

Gastrointestinal side effects have included unspecified gastrointestinal disturbances. Postmarketing gastrointestinal side effects have included nausea and dysgeusia.[Ref]

General

General side effects have included malaise and headache. Postmarketing general side effects have included pyrexia.[Ref]

Ocular

Ocular side effects have included cataracts.[Ref]

Hypersensitivity

Hypersensitivity side effects have included postmarketing reports of allergic reaction.[Ref]

Some side effects of methoxsalen may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Data not available