Methoxsalen (Monograph)

Drug class: Pigmenting Agents
ATC class: D05AD02
VA class: DE900
CAS number: 298-81-7

Medically reviewed by Drugs.com on Oct 22, 2024. Written by ASHP.

Introduction

Methoxsalen, a psoralen derivative, when activated by long wavelength ultraviolet light (UVA) is strongly erythemogenic, melanogenic, and cytotoxic in the epidermis.

Uses for Methoxsalen

Idiopathic Vitiligo

Methoxsalen is used orally (as conventional capsules) or topically in conjunction with controlled exposure to long wavelength ultraviolet radiation (UVA) or sunlight to repigment vitiliginous skin in patients with idiopathic vitiligo. The liquid-filled capsules currently are not approved by the US Food and Drug Administration for this use. Clinical response to methoxsalen is erratic and unpredictable and is cosmetically acceptable in only a small percentage of patients with vitiligo. Complete cures following psoralen therapy are infrequent; only about one-third of patients with vitiligo have an appreciable amount of pigmentation restored. In one study of 20 patients treated with topical methoxsalen and blacklight, complete repigmentation occurred in only 3 patients. In one study using UVA light and oral methoxsalen or oral trioxsalen for 12–14 months, 73% of vitiligo patients had some pigmentation restored and, in 23% of patients, pigmentation improved by about 73%. Repigmentation varies among patients in completeness, time of onset, and duration. Methoxsalen-induced repigmentation occurs more rapidly on fleshy areas such as the face, abdomen, and buttocks than on bony areas such as the dorsa of the hands and feet. To retain new pigment, periodic treatment with the drug and some form of UVA light is often required; however, in one study, 90% or more of the new pigment established during oral methoxsalen and conventional UV light therapy remained in 85% of patients 8–14 years after methoxsalen treatment was discontinued.

When oral psoralens are used for vitiligo, most studies have shown that results are most successful but adverse effects are more serious and frequent when a high-intensity UVA light source, rather than a conventional light source, is used. Although there are no well-controlled studies comparing methoxsalen with trioxsalen in the treatment of vitiligo, some clinicians prefer oral trioxsalen to oral methoxsalen because trioxsalen produces fewer adverse GI effects and erythemic reactions. For small, well-defined, vitiliginous lesions (less than 10 cm²) some clinicians prefer topical methoxsalen to oral trioxsalen; topical methoxsalen should be used only when vitiliginous lesions are small and well defined.

Psoriasis

Methoxsalen is used orally (as conventional or liquid-filled capsules) in conjunction with controlled exposure to long wavelength ultraviolet radiation (UVA) for the symptomatic treatment of severe, recalcitrant, disabling psoriasis that is refractory to other forms of therapy and when the diagnosis has been confirmed by biopsy. In several studies, psoriatic lesions cleared in about 90% of patients treated with a mean of 10–20 exposures to a psoralen and UVA light (PUVA therapy). For extensive or refractory psoriasis, some clinicians consider PUVA therapy to be more acceptable and effective than other therapies (e.g., corticosteroids, hydroxyurea, total body tar application) and safer than methotrexate; however, the role of PUVA therapy in the treatment of psoriasis remains to be clearly established. In one controlled study, PUVA therapy was effective in most patients who had previously required methotrexate to control the disease and in some patients whose disease did not respond to a topical anthralin regimen. Limited data indicate that PUVA with liquid-filled methoxsalen capsules is effective in clearing psoriatic lesions in many patients whose disease is refractory to PUVA therapy with conventional methoxsalen capsules.¹⁰² Because of more rapid and extensive absorption and a substantially lower minimum phototoxic dose (MPD) associated with the liquid-filled capsules, use of these capsules may substantially decrease the number of PUVA treatments necessary in many patients compared with use of the conventional capsules.¹⁰² The role of PUVA maintenance therapy to prevent recurrence of psoriatic lesions remains to be determined.

Psoralens have been used topically^{† [off-label]} in conjunction with UVA light for the treatment of psoriasis, but the use of topical methoxsalen largely has been abandoned because it produces a greater incidence of adverse effects and is less cosmetically acceptable than oral psoralens.

Cutaneous T-cell Lymphoma

Oral methoxsalen is used in conjunction with photopheresis with the UVAR instrument (Therakos, King of Prussia, PA) for the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL; e.g., mycosis fungoides, Sézary syndrome). Limited evidence indicates that photopheresis therapy (e.g., administered once daily for 2 consecutive days per month) can produce reductions in the size and/or severity of skin lesions without serious toxicity; sustained responses (2 years or longer) have occurred in some patients. For detailed information on the use of oral methoxsalen in conjunction with photopheresis in patients with cutaneous T-cell lymphoma, clinicians should consult the manufacturer’s labeling for methoxsalen and the UVAR instrument and other specialized references and published protocols.

Methoxsalen Dosage and Administration

Administration

Methoxsalen is usually administered orally. Oral methoxsalen may be administered as a single dose with milk or after a meal, or in 2 divided doses approximately 30 minutes apart, to minimize adverse GI effects.

Methoxsalen may also be applied topically in the form of a 1% lotion; occasionally, the lotion may need to be diluted 10- or 100-fold to avoid excessive reactions. Methoxsalen lotion should be applied only to small, well-defined, vitiliginous lesions (less than 10 cm²) by a physician. Methoxsalen lotion should not be dispensed to a patient for home use. The hands and fingers of the individual applying the lotion should be protected by gloves or finger cots to avoid photosensitization and possible burns. The lotion may be applied with a cotton swab, allowed to dry for 1–2 minutes, then reapplied. The borders of the vitiliginous lesion being treated should be protected with petrolatum and a sunscreen to prevent hyperpigmentation.

Dosage

Methoxsalen therapy must be accompanied by some form of UVA irradiation. Use of sunlight or conventional artificial UV light sources (e.g., hot or cold quartz lamps, fluorescent sunlamps, blacklights) is preferred by some clinicians but others prefer to use light from sources that provide high-intensity UVA light. Following topical methoxsalen application, conventional UV light sources are used by most clinicians; sunlight is used rarely.

Initial UV light exposure times should be based on the minimum phototoxic dose (MPD) for the specific light source being used. MPD can be determined by irradiating several skin areas 2 cm in diameter with varying light exposure times and determining the exposure time that produces erythema at 72 hours. When sunlight is used as the UV light source, initial sunlight exposure following methoxsalen administration should not exceed 15, 20, or 25 minutes for patients with light, medium, or dark skin colors, respectively; subsequent exposure may be increased 5 minutes each day, depending on the degree of erythema and tenderness. Exposure time should be reduced for noontime sun and for high-altitude or low-latitude (0–20°) exposure. Following topical application of methoxsalen, initial exposure to sunlight should not exceed 1 minute; subsequent exposure time may be increased cautiously depending on erythemic response. If a conventional artificial light source is used, exposure time should usually be 50% of that producing erythema after sunlight exposure or should be adjusted according to the MPD and the directions of the manufacturer of the device. Clinicians should consult published protocols and specialized references for information on the use of high-intensity UVA light sources.

To prevent serious burns following administration of methoxsalen, patients should be carefully instructed not to exceed the recommended dosage and UV light exposure time; the appropriate precautions associated with psoralen therapy and protective measures must be employed. (See Cautions: Precautions and Contraindications.)

Methoxsalen conventional and liquid-filled capsules should not be used interchangeably in the treatment of psoriasis.¹⁰⁰ The liquid-filled capsules are absorbed more rapidly and extensively, have earlier peak photosensitivity times, and have substantially lower minimum phototoxic doses (MPD) than the conventional capsules.^{100 101} Dosages of these preparations are not interchangeable. Patients must be treated in accordance with the dosimetry specifically recommended for the dosage form employed.¹⁰⁰ Before using PUVA therapy with the liquid-filled capsules, the MPD and peak photosensitivity time after drug administration should be evaluated in each patient.¹⁰⁰

Idiopathic Vitiligo

To repigment vitiliginous areas in adults and children older than 12 years of age, the oral dosage of methoxsalen as conventional capsules recommended by the manufacturer is 20 mg daily, given as a single dose with milk or food 2–4 hours before measured periods of sunlight or UVA exposure. Therapy should be on alternate days and never on 2 consecutive days. Oral dosages greater than 0.6 mg/kg should not be used, since severe burns may result.

Alternatively, small, well-defined lesions may be treated with 1% methoxsalen lotion. Some clinicians suggest that for optimum effect, the lotion should be applied about 1–2 hours before exposure to UV light. The treated area may be exposed to UV light for a limited time, then washed with soap and water. Although the manufacturer states that treatments with topical methoxsalen and UV light exposure should be no more frequent than once weekly, some clinicians recommend treatment every 3–5 days, depending on response.

Repigmentation of vitiliginous lesions may begin after a few weeks of treatment, but substantial changes usually require 6–9 months of therapy. If follicular repigmentation is not apparent after 3 months of treatment, methoxsalen therapy should be discontinued.

Psoriasis

For the symptomatic treatment of severe, recalcitrant, disabling psoriasis not adequately responsive to other forms of therapy, the appropriate oral dose of methoxsalen is administered as conventional capsules with milk or food 2 hours before exposure to high-intensity UVA light or as liquid-filled capsules with low-fat milk or food 1.5–2 hours before exposure to high-intensity UVA light. Treatments may be administered 2 or 3 times weekly (at least 48 hours apart) or as necessary. The initial dose of methoxsalen as conventional capsules or liquid-filled capsules is based on the patient’s weight according to the following schedule:

The number of methoxsalen doses per week is determined by the patient’s schedule of UVA exposures. PUVA therapy should not be administered more frequently than once every other day, since the full extent of phototoxic reactions to therapy may not be evident until 48 hours after each exposure. If the weight of the patient changes during therapy such that the patient would be in a different weight range/dose category, a dosage change is usually not necessary; however, if the change in weight is considered sufficiently great, adjustment of methoxsalen dosage and exposure to UVA light should be made accordingly. If there is no response or only minimal response after 15 PUVA treatments, the dose of methoxsalen may be increased by 10 mg (a one-time increase); the increased dose may be continued for the remainder of the course of treatment but should not be exceeded.

For detailed information on the PUVA treatment protocol, maintenance PUVA therapy, and management of psoriatic flares during maintenance PUVA therapy, the manufacturer’s labeling and specialized references should be consulted.

Cutaneous T-Cell Lymphoma

When used in conjunction with photopheresis with the UVAR instrument (Therakos, King of Prussia, PA) in patients with cutaneous T-cell lymphoma (CTCL; e.g., mycosis fungoides, Sézary syndrome), the appropriate dose of methoxsalen is given orally as conventional capsules 2 hours before obtaining blood for extracorporeal exposure of extracted leukocytes to high-intensity UVA light. The UVAR manufacturer states that the oral dose of methoxsalen should be adequate to achieve a serum concentration of at least 50 ng/mL 2 hours after the dose; an initial dose of 0.6 mg/kg is recommended. If the serum methoxsalen concentration is less than 50 ng/mL with this dose, the initial dose plus 10 mg may be administered after 24 hours. Clinicians should consult the UVAR photopheresis procedural guide and other published protocols and specialized references for specific information on administration and dosage of methoxsalen in patients with cutaneous T-cell lymphoma.

Cautions for Methoxsalen

Dermatologic Effects

Phototoxic reactions including severe edema and erythema, and painful blistering, burning, and peeling of skin may occur with methoxsalen and conventional UV light. In addition, PUVA therapy has produced severe burns requiring hospitalization, and marked hyperpigmentation and aging of skin. When peeling or blistering occurs, the skin becomes more sensitive to UV light. Phototoxic reactions to methoxsalen occur most commonly when the skin is overexposed to UV light or when dosage is excessive. Severe burns may occur if treated skin is accidentally exposed to additional UV light. Some reports indicate that the incidence of psoralen-induced phototoxicity may be slightly reduced by concurrent application of benzophenone sunscreens.

Pruritus occurs in about 10% of patients treated with PUVA therapy utilizing methoxsalen. In most cases, pruritus is relieved by frequent application of bland emollients or other topical agents; severe pruritus may require systemic treatment. When pruritus is unresponsive to these measures, pruritic areas should be shielded from further UVA exposure until the condition resolves. If pruritus refractory to treatment is generalized, PUVA therapy should be discontinued until the pruritus disappears.

Other adverse dermatologic effects associated with PUVA therapy include skin freckling, hypopigmentation, uneven or excessive tanning, dry skin, vesiculation and bullae formation, generalized exfoliation, nonspecific rash, urticaria, miliaria, folliculitis, acneiform eruption, aggravation or extension of psoriasis, hyperpigmentation of psoriatic lesions, cutaneous tenderness, severe skin pain (lasting 1–2 months), onycholysis, pigmentation of the nails, and exacerbation of latent photosensitive dermatoses (e.g., lupus erythematosus). Kaposi’s varicelliform eruption was reported in one patient with a history of recurrent localized herpes infection after the initiation of PUVA therapy. Contact allergy, confirmed by patch testing, has been reported with the use of topical methoxsalen.

GI Effects

Nausea is the most common adverse effect of oral methoxsalen, occurring in about 10% of patients. GI disturbances may also occur with PUVA therapy utilizing methoxsalen. Nausea and other adverse GI effects may be minimized by administering methoxsalen with milk or food, or in 2 divided doses approximately 30 minutes apart, or by reducing dosage.

CNS Effects

Nervousness, vertigo, insomnia, and mental depression or excitation have occurred with oral methoxsalen. Dizziness, headache, and mental depression have occurred with PUVA therapy utilizing methoxsalen.

Other Adverse Effects

Cheilitis and transient loss of muscle coordination have reportedly occurred in patients receiving oral methoxsalen. Although abnormal liver function test results were reported in a few patients receiving oral methoxsalen, this observation has not been confirmed by others and a causal relationship has not been established. Edema, malaise, leg cramps, and hypotension have occurred with PUVA therapy utilizing methoxsalen.

The potential adverse effects of long-term PUVA therapy remain to be clearly established but may include accelerated aging of the skin, cutaneous carcinogenesis (see Cautions: Carcinogenicity), cataract formation (See Cautions: Precautions and Contraindications), and systemic immune effects.

Precautions and Contraindications

Methoxsalen conventional capsules and liquid-filled capsules exhibit substantially different rates and extents of absorption, minimum phototoxic doses (MPDs), and peak photosensitivity times and should not be used interchangeably in the treatment of psoriasis.^{100 104} (See Dosage and Administration: Dosage.) Patients must be treated in accordance with the dosimetry specifically recommended for the dosage form employed.¹⁰⁰

Since methoxsalen is a strong photosensitizer capable of producing severe burns if used improperly, the drug should be used only under the supervision of a physician with special training and experience in photochemotherapy. Methoxsalen lotion should be applied only by a physician under controlled conditions for light exposure and subsequent light shielding; the lotion should not be dispensed to a patient for home use. Methoxsalen lotion should be applied only to small, well-defined vitiliginous lesions, preferably those lesions that can be protected by clothing or a sunscreen from subsequent exposure to UVA light. Because of the potential for serious adverse effects (e.g., ocular damage, aging of the skin, and skin cancer [including melanoma]) resulting from PUVA therapy, the patient should be fully informed by the physician of the risks associated with the treatment. To prevent serious adverse effects, the physician should carefully instruct the patient to adhere to the prescribed methoxsalen dosage regimen and schedules for UVA exposure. When oral methoxsalen is used in the treatment of vitiligo, the dosage should not exceed 0.6 mg/kg.

Mild, transient erythema occurring 24–48 hours after PUVA therapy is an expected cutaneous reaction, and indicates that a therapeutic interaction between methoxsalen and UVA has occurred. Areas of skin showing fiery erythema with edema should be shielded during subsequent UVA exposures until the erythema has resolved. Fiery erythema with edema which occurs within 24 hours following UVA exposure may indicate a potentially severe burn, since the peak erythemal reaction usually occurs 48–72 hours following PUVA therapy. If burning or blistering of skin or intractable generalized pruritus occurs, therapy should be discontinued until these effects subside.

Prior to methoxsalen administration and UVA exposure, patients should not sunbathe for at least 24 hours, since the presence of sunburn may prevent an accurate evaluation of patient response to photochemotherapy. Following methoxsalen ingestion and controlled exposure to UVA or sunlight, patients must avoid additional, direct or indirect (through window glass or cloud cover) exposure to sunlight for at least 8 hours; following topical treatment with methoxsalen, additional exposure to UV light should be avoided for at least 12–48 hours. If exposure to sunlight cannot be avoided, the patient should wear protective clothing (e.g., hat, gloves) and/or apply sunscreens that filter out UVA radiation (e.g., sunscreens with a sun protective factor greater than or equal to 15). Sunscreens should be applied to all areas of the body that may be exposed to the sun (including lips). Skin of the abdomen, breasts, genitalia, and other sensitive areas should be protected during PUVA therapy for about one-third of the initial exposure time until sufficient tanning occurs; unless affected by disease, male genitalia should be shielded. Sunscreens should not be applied to areas affected by psoriasis until the patient has been treated with controlled exposure to UVA. Following PUVA therapy, patients should not sunbathe for 48 hours, since erythema and/or burning resulting from photochemotherapy and sunburn are additive. If methoxsalen is used topically to treat vitiligo of the face or hands, the patient must be carefully instructed to keep the treated areas protected from light with the use of clothing or sunscreens; the treated areas may be highly photosensitive for several days and severe burns could result from additional exposure to UVA or sunlight.

Following ingestion of methoxsalen and after combined oral methoxsalen and UVA therapy, wrap-around sunglasses with UVA-absorbing properties should be worn by patients during daylight hours for 24 hours. The protective eyewear must be designed to prevent entry of stray radiation into the eyes, including that which may enter from the sides of eyeglasses. Protective eyewear is used to prevent irreversible binding of methoxsalen to proteins and DNA components of the lens. Total UVA-absorbing/blocking goggles must be worn during PUVA therapy. Failure to do so may increase the risk of cataract formation. A radiometer may be used to verify elimination of UVA transmission through the protective goggles.

Exposure of animals to large doses of UVA without eye protection has produced cataracts and this effect is enhanced by methoxsalen; however, in patients receiving PUVA therapy who use appropriate eye protection, there is no evidence to date for an increased risk of cataract formation. Prior to the initiation of PUVA therapy and yearly thereafter, patients should have an ophthalmologic examination because of the cataractogenic potential of psoralens.

Before and 6–12 months after oral methoxsalen therapy is initiated, a complete blood count, antinuclear antibody titer, and hepatic and renal function tests should be performed. If the leukocyte count is abnormal, a differential cell count should be performed. Additional laboratory tests at more extended time periods should be performed as clinically indicated. The manufacturer states that oral methoxsalen should be used with caution in patients with hepatic insufficiency.

Exposure to sunlight and/or UVA may result in premature aging of the skin or skin cancer. In patients with multiple basal cell carcinomas or history of basal cell carcinomas, careful observation during treatment with methoxsalen is recommended. Patients with a history of radiation therapy or treatment with arsenic should be carefully observed for signs of carcinoma. The total cumulative dose of UVA that can be given over long periods of time with safety has not been established. Since exposure to extensive PUVA therapy has been associated with increased risk of malignant melanoma, patients with substantial exposure to PUVA should be observed carefully for the development of both malignant melanoma and other forms of skin cancer.¹⁰⁵

Patients with cardiac disease or those unable to tolerate prolonged standing or exposure to heat stress should not be treated in a vertical UVA chamber.

Because psoralens have caused photoallergic contact dermatitis and may precipitate sunlight allergy, methoxsalen should be used with caution in patients with a family history of sunlight allergy. The drug should also be used with caution in patients with GI diseases or chronic infection. Oral or topical methoxsalen should be used with particular caution in patients receiving topical or systemic therapy with known photosensitizing agents. (See Drug Interactions: Photosensitizing Agents.)

Oral or topical methoxsalen is contraindicated in patients exhibiting idiosyncratic reactions to psoralens or with a history of a sensitivity reaction to the drugs; in patients with diseases associated with photosensitivity (e.g., lupus erythematosus, porphyria cutanea tarda, erythropoietic protoprophyria, variegate porphyria, xeroderma pigmentosum, albinism, hydroa vacciniforme, leukoderma of infectious origin, polymorphous light eruptions), except under special circumstances; in patients with melanoma or history of melanoma; and in patients with invasive squamous cell carcinoma. Oral methoxsalen is also contraindicated in patients with aphakia (absence of lenses) because of the increased risk of retinal damage.

Pediatric Precautions

Safe use of methoxsalen in children younger than 12 years of age has not been established, and the drug is contraindicated in this age group. The Committee on Drugs of the American Academy of Pediatrics recommends that under no circumstance should children receive PUVA therapy, except under established investigational new drug (IND) protocols.

Carcinogenicity

Possible long-term effects of PUVA therapy include an increased risk of cutaneous carcinoma, especially in patients with predisposing risk factors. Topical or intraperitoneal methoxsalen is reportedly a potent photocarcinogen in albino mice and in hairless mice; however, methoxsalen given orally to albino mice or by any route to pigmented mice is considerably less phototoxic or carcinogenic.

In one long-term prospective study in patients with psoriasis receiving PUVA therapy, the overall incidence of basal cell carcinoma was about 1.7 times higher than expected, and the overall incidence of cutaneous squamous cell carcinoma was about 9 times higher.¹⁰³ Increased risk of cutaneous squamous cell carcinoma appears to be greatest in fair-skinned patients; in patients with previous exposure to ionizing radiation, prolonged therapy with coal tar and high-energy middle wavelength ultraviolet radiation (UVB), or arsenic therapy; in patients with a history of cutaneous carcinoma; and in patients with higher exposure to PUVA. The risk of cutaneous squamous cell carcinoma developing at least 22 months after the initial PUVA exposure was approximately 12.8 times higher in patients receiving high-dose PUVA than in those receiving low-dose PUVA.^{100 103} The dose-related increase was observed in patients without a history of cutaneous carcinoma or substantial exposure to cutaneous carcinogens.^{100 103} Reduction in PUVA dose substantially reduces the risk.^{100 103} A substantial dose-related increase in the risk of basal cell carcinoma was not observed.^{100 103} Other long-term studies have not revealed an increased risk of nonmelanoma skin cancer in patients treated with PUVA; however, some of these patients had substantially less exposure to PUVA than patients in previous studies. Although data are lacking, topical methoxsalen should be used with caution in patients with predisposing risk factors.

Malignant melanoma has been reported in some patients receiving PUVA therapy. Macular pigmented lesions on the buttocks have developed in more than 20% of patients in one study. Results of a long-term (about 21 years), multicenter, prospective study in patients with psoriasis receiving PUVA therapy, indicate that the risk of malignant melanoma increases with prolonged PUVA therapy and with time elapsed after the first PUVA treatment.¹⁰⁵ The relative risk of malignant melanoma developing at least 15 years after the initial PUVA exposure was approximately 5.4 times higher than expected and such risk increased further to 8.9 times higher in patients who received at least 250 PUVA treatments.¹⁰⁵ No increased risk of malignant melanoma was found in patients receiving PUVA therapy for about 15 years.¹⁰⁵ Patients with substantial exposure to PUVA should be observed carefully for the development of both malignant melanoma and other forms of skin cancer.¹⁰⁵

Some clinicians have suggested that the effect of PUVA on DNA synthesis may lead to hematologic malignancies through damage to circulating multipotential stem cells; acute myeloid leukemia and preleukemia have been reported in patients receiving PUVA therapy. Potentially premalignant epidermal changes (e.g., epidermal dystrophy, actinic keratoses) have been reported in psoriatic patients receiving PUVA therapy. Further evaluation of the carcinogenic potential of PUVA therapy is necessary.

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies have not been performed with oral or topical methoxsalen. It is not known whether methoxsalen can cause fetal harm when administered orally or topically to pregnant women. Methoxsalen should be used during pregnancy only when clearly needed.

Fertility

It is not known whether methoxsalen affects fertility in humans.

Lactation

Since it is not known whether methoxsalen is distributed into milk, the drug should be used with caution in nursing women.

Drug Interactions

Photosensitizing Agents

Concomitant therapy with methoxsalen and other systemic or topical photosensitizing agents (e.g., anthralin, coal tar or coal tar derivatives, griseofulvin, phenothiazines, nalidixic acid, halogenated salicylanilides [bacteriostatic soaps], sulfonamides, tetracyclines, thiazides, or certain organic staining dyes such as methylene blue, toluidine blue, rose bengal, and methyl orange) may produce additive photosensitizing effects. Particular caution is necessary if methoxsalen is administered concomitantly with any topical or systemic photosensitizing agent.

Food

When oral methoxsalen is administered with food, the extent of absorption and the peak serum concentration appear to be increased. The mechanism of this interaction is not known but may involve the effect of food on dissolution or hepatic metabolism of methoxsalen. Since the photosensitizing effect may be related to the serum concentration of methoxsalen, it has been suggested that the drug be administered in a consistent manner with regard to food intake.

Acute Toxicity

Overdosage of methoxsalen or overexposure to UV light following methoxsalen administration may result in serious burning and blistering of skin. In acute oral methoxsalen overdose, the stomach should be emptied immediately by inducing emesis; emesis is beneficial only with the first 2–3 hours after the ingestion. The patient should be placed in a darkened room for at least 24 hours or until cutaneous reactions subside, and supportive measures for the treatment of burns initiated.

Pharmacology

Methoxsalen, when activated by long wavelength ultraviolet light (UVA) in the range of 320–400 nm, is strongly erythemogenic, melanogenic, and cytotoxic in the epidermis; the maximal erythemogenic activity occurs in the range of 330–360 nm. The mechanisms of action of methoxsalen in inducing repigmentation of vitiliginous skin have not been established. Repigmentation depends on the presence of functioning melanocytes and UV light. Methoxsalen may activate the few functional and dihydroxyphenylalanine-positive melanocytes present in vitiliginous skin. An increase in the activity of tyrosinase, the enzyme that catalyzes the conversion of tyrosine to dihydroxyphenylalanine (a precursor of melanin), has been shown in melanin-producing cells exposed in vitro to trioxsalen and UVA light. In addition, binding of photoactivated psoralens (in triplet states) to pyrimidine bases of nucleic acids, with subsequent inhibition of DNA synthesis, cell division, and epidermal turnover, has been demonstrated. Following photoactivation, methoxsalen forms covalent bonds with DNA to produce monofunctional (addition to a single strand of DNA) and bifunctional adducts (crosslinking to both strands of DNA). Reactions with other proteins also occur. Psoralens may also increase melanin formation by producing an inflammatory reaction in the skin. Other mechanisms of increased pigmentation may include an increase in the number of functional melanocytes (and possibly activation of dormant melanocytes); enhancement of melanin granule synthesis; stimulation of the movement of melanocytes up hair follicles resulting in melanocytic repopulation of the epidermis; and/or hypertrophy of melanocytes and increased arborization of their dendrites.

Since psoriasis is a hyperproliferative disorder and other agents effective in the treatment of psoriasis are known to inhibit DNA synthesis, the therapeutic effect of methoxsalen in the treatment of psoriasis probably involves binding to DNA and inhibition of DNA synthesis resulting in decreased cell proliferation; other vascular, leukocyte, or cell regulatory mechanisms may also be involved.

When administered orally, methoxsalen produces a more intense erythemic and melanogenic response than does trioxsalen. Topical psoralens produce a more intense photosensitizing response than do oral psoralens. Tolerance to the effects of psoralens may occur when pigmentation occurs much more rapidly than does erythema.

Erythema resulting from therapy with a psoralen (P) and UVA radiation (PUVA) differs from sunburn or the erythema produced by middle wavelength ultraviolet radiation (UVB) in the range of 290–320 nm, since UVA radiation penetrates more deeply into the skin and the photochemical reaction occurs deeper within skin tissue. Since the maximum erythemogenic activity of psoralens occurs in the range of 330–360 nm, the drugs increase the patient’s sensitivity to UVA light but not to UVB light. PUVA-induced DNA lesions differ from UV-induced DNA lesions (thymine dimers) and are probably more lethal to cells; DNA synthesis is suppressed longer after PUVA. Compared with histologic changes induced by equally erythemogenic doses of UVB, histologic changes resulting from PUVA involve greater damage to dermal vessels and increased duration of epidermal and dermal abnormalities. Erythema resulting from PUVA is delayed compared with UVB-induced erythema and may not involve the usual mediators of the inflammatory process for sunburn. PUVA-induced erythema may begin to appear 24 hours after therapy; however, exposure to UVB radiation may produce erythema which reaches its peak effect at 24 hours.

Methoxsalen Pharmacokinetics

Absorption

Methoxsalen appears to be well, but variably, absorbed from the GI tract following oral administration. The extent to which topically applied methoxsalen is absorbed has not been determined. When oral methoxsalen is administered with food, the extent of absorption and the peak serum concentration appear to be increased. (See Drug Interactions: Food.) Considerable interindividual variations in peak serum concentrations of methoxsalen have been reported. Following oral administration of a single dose of methoxsalen as conventional capsules or liquid-filled capsules with low-fat milk, peak serum drug concentrations occur within 3 hours (range: 1.5–6 hours) or 1.8 hours (range: 0.5–4 hours), respectively,^{100 101} and serum concentrations decline to low levels within 8–10 hours.¹⁰¹ Peak serum methoxsalen concentrations are approximately 2–3 times higher and the area under the serum concentration-time curve is approximately 1.5–2 times greater with the liquid-filled capsules than with the conventional capsules.^{100 101}

Serum concentrations of methoxsalen required for photosensitizing effects are not known; however, in one study, maximum photosensitivity appeared to correlate with the time of peak serum concentration. Following a single oral dose of methoxsalen, skin sensitivity to UVA light occurs within 1–2 hours, is maximal within about 1–4 hours, and persists about 3–8 hours. Peak photosensitivity occurs within about 1.5–2.1 or 3.9–4.25 hours after administration of the liquid-filled or conventional capsules, respectively.^{100 101} The minimum phototoxic dose (MPD) for the liquid-filled capsules is substantially less than that for the conventional capsules.¹⁰⁰ Following topical application of methoxsalen, skin sensitivity to UVA light occurs within 1–2 hours and persists for several days; erythema may not be maximal until 2 days after treatment.

Distribution

Distribution of methoxsalen into human tissues and fluids has not been fully characterized. The drug appears to be preferentially taken up by epidermal cells. Methoxsalen distributes into the lens of the eye in concentrations proportional to the serum concentrations.¹⁰⁰ It is not known if methoxsalen crosses the placenta or is distributed into milk. The drug is reportedly 75–91% bound to serum proteins, principally albumin.

Elimination

The elimination half-life of methoxsalen is reportedly about 0.75–2.4 hours.

Although the exact metabolic fate of methoxsalen has not been fully established, the drug is rapidly and apparently almost completely metabolized. Methoxsalen is demethylated to 8-hydroxypsoralen (8-HOP), and methoxsalen and 8-HOP are conjugated with glucuronic acid and sulfate; other unidentified metabolites have also been detected. Methoxsalen and 8-hydroxypsoralen and their conjugates are excreted in urine. Following oral administration of methoxsalen, 80–90% of the drug is excreted in urine within 8 hours as hydroxylated, glucuronide, and sulfate metabolites; less than 0.1% of a dose is excreted in urine as unchanged drug. About 95% of the drug is excreted in urine within 24 hours as metabolites.

Chemistry and Stability

Chemistry

Methoxsalen is a psoralen derivative that is structurally and pharmacologically related to trioxsalen. Methoxsalen occurs naturally in several different plants including Ammi majus (Umbelliferae), Psorales coryfolia, and Ruta chalepensis, but is prepared synthetically for commercial use. Methoxsalen occurs as white to cream-colored, fluffy, odorless, needle-like crystals. The drug is practically insoluble in water, slightly soluble in alcohol, and soluble in propylene glycol.

Stability

Methoxsalen conventional capsules and topical lotion should be protected from light and stored in well-closed, light-resistant containers at 15–30°C.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Medical Disclaimer