Kefunova (fluorouracil/calcipotriene)

At equivalent concentrations, the solutions are considered more effective than the creams.

Safety and efficacy of calcipotriene alone or in fixed combination with betamethasone dipropionate in pediatric patients have not been established.

For the management of plaque psoriasis, calcipotriene 0.005% cream is applied as a thin film and rubbed gently and completely into the affected area twice daily. Safety and efficacy of calcipotriene cream have been demonstrated in patients receiving the drug for 8 weeks.

For the topical treatment of plaque psoriasis, the fixed-combination ointment containing calcipotriene 0.005% and betamethasone 0.05% should be applied and rubbed gently into the affected area(s), until absorbed, once daily. The fixed-combination ointment should not be applied to greater than 30% of body surface area. The manufacturer states that dosage of the fixed-combination ointment should not exceed 100 g of ointment per week, and duration of therapy should not exceed 4 consecutive weeks. Occlusive dressings should not be used with the fixed-combination preparation, unless directed by a clinician. The fixed-combination ointment should not be used in patients with erythrodermic, exfoliative, and pustular psoriasis or in patients with preexisting skin atrophy at the treatment site.

For chronic, moderately severe psoriasis of the scalp, the hair should be combed to remove scaly debris and, after the hair has been parted to reveal the affected area, the 0.005% solution should be applied only to the affected area and rubbed gently and completely into the scalp twice daily. Care should be taken to avoid contact of the drug with the forehead or uninvolved scalp margins. The solution should not be used in patients with acute psoriatic eruptions of the scalp.

For the topical treatment of moderate to severe plaque psoriasis of the scalp, the fixed-combination suspension containing calcipotriene 0.005% and betamethasone 0.05% should be applied to the affected area(s) on the scalp once daily for 2 weeks or until clearing of psoriatic lesions occurs. The bottle should be shaken prior to each use. The manufacturer states that dosage of the combination suspension should not exceed 100 g of suspension per week, and duration of therapy should not exceed 8 weeks. Occlusive dressings should not be used with the combination preparation, unless directed by a clinician. In addition, the combination suspension should not be used in patients with preexisting skin atrophy at the treatment site.

Most patients with psoriasis received topical calcipotriene 0.005% cream or solution in adequate well-controlled clinical trials of 8 weeks' duration. Results of controlled clinical studies indicate that twice-daily topical application of calcipotriene 0.005% cream or solution usually results in apparent improvement within 2 weeks; after 8 weeks of therapy, continued improvement was observed in 50 or 31% of patients receiving the cream or solution, respectively, while only 4 or 14% of patients showed complete clearing of lesions receiving calcipotriene cream or solution, respectively.

In a multicenter, double-blind, controlled study in patients with mild to very severe plaque psoriasis, absent or very mild disease after 4 weeks of treatment was reported in 48, 16.5, 26.3, and 7.6%, respectively, of patients receiving fixed-combination ointment containing calcipotriene and betamethasone dipropionate, calcipotriene alone, betamethasone dipropionate alone, and vehicle alone. In multicenter, randomized, double-blind studies in patients with moderate to very severe scalp psoriasis, clear or almost clear disease after 8 weeks of once-daily treatment was observed in 67.2-70, 59.6-63.1, and 36.7-41%, of patients receiving fixed-combination suspension containing calcipotriene and betamethasone dipropionate, betamethasone dipropionate monotherapy, and calcipotriene monotherapy, respectively.

Topically applied calcipotriene may be absorbed in sufficient amounts to produce systemic effects; elevated serum calcium concentrations have been observed with use of topical calcipotriene. If elevations in serum calcium concentration occur, use of calcipotriene preparations should be discontinued until normal serum calcium concentrations have been restored. Preparations containing calcipotriene should not be used in patients with demonstrated hypercalcemia or evidence of vitamin D toxicity (hypervitaminosis D) or in patients with known or suspected disorders of calcium metabolism.

Calcipotriene may increase the effect of ultraviolet radiation to induce skin tumors; patients who apply calcipotriene to exposed areas of the body should minimize exposure to sunlight or artificial ultraviolet light (e.g., sunlamps, tanning booths). In addition, the manufacturer states that clinicians may want to limit or avoid use of phototherapy in patients using calcipotriene alone or in fixed combination with betamethasone dipropionate.

Fluorouracil cream or solution is applied topically with a nonmetallic applicator, clean fingertips, or gloved fingers in an amount sufficient to cover the lesions. If the fingers are used to apply the drug, the hands should be washed immediately afterward.

Calcipotriene alone or in fixed combination with betamethasone dipropionate is applied topically to the skin as a cream or ointment, respectively; calcipotriene also is applied as a solution or as a fixed-combination suspension containing calcipotriene and betamethasone dipropionate to the scalp. The topical cream and solution are for external use only and should not be applied to the face, eyes, or mucous membranes. The topical fixed-combination ointment and suspension also are for external use onlyand should not be applied to the face, eyes, axillae, or groin area. The hands should be washed thoroughly after application of topical calcipotriene preparations.

No dosing information is available for this tab.

No dosing information is available for this tab.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Fluorouracil & Fluorouracil Prodrugs/Brivudine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Brivudine is an irreversible inhibitor of dihydropyrimidine dehydrogenase, which catalyzes the rate-limiting step in the catabolism of fluorouracil.(1-5) Brivudine may decrease the clearance and increase the toxicity of fluorouracil.

CLINICAL EFFECTS: Concurrent use of brivudine with fluorouracil or fluorouracil prodrugs (e.g., capecitabine, tegafur) may result in elevated levels of fluorouracil and serious toxicity, including melenic diarrhea, mucositis, hand-foot syndrome, pancytopenia, and death.(1-5)

PREDISPOSING FACTORS: Patients who are intermediate or poor dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no DPYD function. Since DPYD is the rate-limiting enzyme involved in fluoropyrimidine metabolism, these patients may be more susceptible to the effects of this interaction.(3)

PATIENT MANAGEMENT: The use of fluorouracil or fluorouracil prodrugs is contraindicated during and for 4 weeks after therapy with brivudine. Treatment with brivudine can be started 24 hours after the last dose of fluorouracil or fluorouracil prodrug. If brivudine is coadministered with fluorouracil or fluorouracil prodrugs, immediate hospitalization is recommended and effective measures should be taken to reduce the toxicity of capecitabine, including prevention of systemic infections and dehydration.(1)

DISCUSSION: Brivudine inhibition of dihydropyrimidine dehydrogenase has been reported to cause a 5- to 15-fold increase in 5-fluorouracil (5-FU) concentrations.(2) In June 2012, the Spanish Agency of Medicines and Health Products (AEMPS) reported that 29 cases of concomitant use of a fluoropyrimidine and brivudine had occurred in Europe, with 23 of the cases resulting in death.(6) In September 2017, the AEMPS issued an update that an additional 7 fatalities had occurred since 2012 as a result of this drug combination.(7) In a case report, an 80-year-old woman with metastatic colon cancer on capecitabine was given brivudine for herpes zoster. She took two doses of brivudine prior to stopping therapy due to rash and mucositis. Nevertheless, two weeks later, she was hospitalized with skin lesions that progressed to Stevens-Johnson Syndrome, leukopenia, and thrombocytopenia. She developed septic shock and ultimately died.(2) Another two case reports describe similar patients with metastatic colon cancer who received combinations of brivudine with 5-FU. One patient had overlapping therapy for one day, and the other received 5-FU four days after stopping brivudine. Both developed mucositis, pancytopenia, and respiratory failure and died.(3,4) A 66-year-old woman with metastatic breast cancer took brivudine on the last 4 days of a chemotherapy cycle that included capecitabine. She was hospitalized for over 3 weeks with hand-foot syndrome, severe mucositis requiring parenteral nutrition, pancytopenia requiring filgrastim, platelet transfusion, and blood transfusion, and sepsis. She recovered from symptoms of hand-food syndrome and mucositis after about 6 weeks.(5)

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

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• Dihydropyrimidine dehydrogenase deficiency
• Hypervitaminosis D
• Lactation
• Pregnancy

• Hypercalcemia
• Hypercalcinuria

There are no moderate contraindications for this drug.

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More Frequent

• Dermatitis due to topical drug
• Dermatitis due to topical drug
• Pruritus of skin
• Skin rash
• Skin rash

Rare or Very Rare

• Eosinophilia
• Folliculitis
• Hypercalcemia
• Hypercalcinuria
• Leukocytosis
• Skin atrophy
• Thrombocytopenic disorder

More Frequent

• Abnormal desquamation
• Dry skin
• Dry skin
• Erythema
• Erythema
• Paresthesia
• Pruritus of skin
• Skin irritation
• Skin photosensitivity
• Stinging of skin

Less Frequent

• Acute pain at drug application site
• Drug-exacerbated psoriasis
• Headache disorder
• Ocular irritation
• Pain
• Skin irritation
• Skin swelling

Rare or Very Rare

• Acquired ichthyosis
• Alopecia
• Basal cell carcinoma of skin
• Blistering skin
• Conjunctivitis
• Dyschromia
• Dyschromia
• Dysgeusia
• Eye tearing
• Miliaria
• Skin hypopigmentation
• Skin photosensitivity
• Skin scaling
• Skin thickening
• Skin ulcer
• Squamous cell carcinoma of skin
• Telangiectasia
• Urticaria

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No enhanced messaging available.

Safe use of fluorouracil topical solution or cream during pregnancy has not been established.

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No enhanced messaging available.