METHOXSALEN- methoxsalen capsule, liquid filled
Strides Pharma Science Limited
CAUTION: METHOXSALEN IS A POTENT DRUG. READ ENTIRE BROCHURE PRIOR TO PRESCRIBING OR DISPENSING THIS MEDICATION.
Methoxsalen with ultraviolet (UV) radiation should be used only by physicians who have special competence in the diagnosis and treatment of psoriasis and who have special training and experience in photochemotherapy. The use of Psoralen and ultraviolet radiation therapy should be under constant supervision of such a physician. For the treatment of patients with psoriasis, photochemotherapy should be restricted to patients with severe, recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, and only when the diagnosis is certain. Because of the possibilities of ocular damage, aging of the skin, and skin cancer (including melanoma), the patient should be fully informed by the physician of the risks inherent in this therapy.
CAUTION: Methoxsalen Capsules, USP 10 mg [Soft Gelatin Capsules]. This new dosage form of methoxsalen exhibits significantly greater bioavailability and earlier photosensitization onset time than previous methoxsalen dosage forms. Patient should be treated in accordance with the dosimetry specifically recommended for this product. The minimum phototoxic dose (MPD) and phototoxic peak time after drug administration prior to onset of photochemotherapy with this dosage form should be determined.
Methoxsalen Soft Gelatin Capsules USP contains 10mg methoxsalen. Methoxsalen occurs as white to pale yellow crystals and can be obtained naturally from seeds of Ammi majus and roots of Heracleum Candicans or through synthesis. Methoxsalen is practically insoluble in water, freely soluble in chloroform, soluble in boiling alcohol, in acetone, in acetic acid, in propylene glycol, and in benzene, sparingly soluble in boiling water and in ether. The chemical name of methoxsalen is 9-methoxy-7H-furo [3,2-g]  benzopyran-7-one; its empirical formula is C12 H8 O4 and the molecular weight is 216.19. The structural formula is:
Methoxsalen Capsules are available as soft gelatin capsules containing the following inactive ingredients: Citric acid anhydrous, D & C yellow 10, FD & C blue 1, Gelatin, Glycine, Glycerin, Isopropyl alcohol, Medium chain triglyceride, Polyethylene glycol 400, Polysorbate 80, Purified water, Titanium dioxide and Opacode black.
The opacode black contains Propylene glycol, Shellac glaze (Modified) IN SD-45, N-Butyl alcohol, Black iron oxide, Isopropyl alcohol and Ammonium hydroxide.
II. CLINICAL PHARMACOLOGY
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. In a well controlled bioavailability study, Methoxsalen Capsules, USP 10 mg [Soft Gelatin Capsules] reached peak drug levels in the blood of test subjects between 0.5 and 4 hours (Mean = 1.8 hours) as compared to between 1.5 and 6 hours (Mean = 3.0 hours) for regular hard gelatin capsule when administered with 8 ounces of milk. Peak drug levels were 2 to 3-fold greater when the overall extent of drug absorption was approximately 2-fold greater for Methoxsalen Capsules, USP 10 mg [Soft Gelatin Capsules] as compared to regular hard gelatin capsules. Detectable methoxsalen levels were observed up to 12 hours post dose. The drug half-life is approximately 2 hours. 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 hard gelatin capsules. In addition, the mean minimal erythema dose (MED), J/cm2 , for the Methoxsalen Capsules, USP 10 mg [Soft Gelatin Capsules] is substantially less than that required for regular hard gelatin capsule (Levins et al., 1984 and private communication1).
Methoxsalen is reversibly bound to serum albumin and is also preferentially taken up by epidermal cells (Artuc et al., 19792). At a dose which is 6 times larger than that used in humans, it induces mixed function oxidases in the liver of mice (Mandula et al., 19783). 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., 19774). 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 (crosslinking of psoralen to both strands of DNA) adducts (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 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.
III. INDICATIONS AND USAGE
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.
A. Patients exhibiting idiosyncratic reactions to psoralen compounds.
B. Patients possessing a specific history of light sensitive disease states should not initiate methoxsalen therapy except under special circumstances. Diseases associated with photosensitivity include lupus erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, variegate porphyria, xeroderma pigmentosum, and albinism.
C. Patients with melanoma or with a history of melanoma.
D. Patients with invasive squamous cell carcinomas.
E. Patients with aphakia, because of the significantly increased risk of retinal damage due to the absence of lenses.
V. WARNINGS — GENERAL
A. 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.
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).
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 have an elevated relative risk of contracting melanoma. The relative risk for melanoma in these patients was 2.3 (95% 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% 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.
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