Frivo

Drug overview for FRIVO (econazole nitrate/niacinamide):

Generic name: ECONAZOLE NITRATE/NIACINAMIDE
Drug class: Topical Antifungals
Therapeutic class: Dermatological

Econazole, an imidazole derivative, is a synthetic azole antifungal agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

No Image Available

The following indications for FRIVO (econazole nitrate/niacinamide) have been approved by the FDA:

Indications:
None.

Professional Synonyms:
None.

The following drug interaction information is available for FRIVO (econazole nitrate/niacinamide):

Contraindicated
Severe
Moderate

There are 0 contraindications.

There are 0 severe interactions.

There are 1 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Coumarin Anticoagulants/Econazole SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Econazole has been shown to be a potent inhibitor of CYP3A4.(1) If absorbed systemically, topical econazole may inhibit the metabolism of coumarin anticoagulants.(2-3) CLINICAL EFFECTS: The concurrent use of topical econazole and coumarin anticoagulants may increase international normalized ratio (INR) and result in an increased risk for bleeding.(2-4) PREDISPOSING FACTORS: This interaction may occur if topical econazole is absorbed systemically. Factors contributing to increased systemic absorption include exposure to large body surface areas, occlusion of the area, and application onto areas of thin, macerated or broken skin.(2-4) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 1/3, 2/2, 2/3, and 3/3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to achieve effective and safe anticoagulation than patients without these CYP2C9 variants. PATIENT MANAGEMENT: Patients with risk factors for increased systemic absorption of topical econazole and receiving concurrent therapy with a coumarin anticoagulant (e.g. warfarin) should have their INR closely monitored.(1) When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Topical econazole is typically minimally absorbed (less than 2%).(3,4) However absorption may be increased if it is applied to large areas of the body or to thin, macerated, or broken skin, or if the area is occluded.(2-4) A 79-year-old man on chronic warfarin therapy with stable INRs for 3 years developed severe bruising on his hip from a minor injury and bleeding for over 24 hours from a small, superficial cut on his hand. His INR was found to be 12. He had started econazole cream one week before for Candidal infection of his scrotum and thighs. He had no other medication or diet changes and no acute illnesses. He recovered after discontinuation of econazole and treatment with vitamin K.(3) An 84-year-old woman stable on acenocoumarol 4 mg daily for ten years developed a bilateral cervical hematoma causing upper airway obstruction, dyspnea and difficulty speaking. Her INR exceeded laboratory limits. She had started using econazole lotion 1% for extensive dermatitis over her axillary, inguinal, and breast areas 17 days prior. She had no other changes to her medications, diet, or other chronic conditions, and no acute illnesses. The patient was treated with prothrombin complex concentrate and vitamin K and recovered.(3)	DICUMAROL, JANTOVEN, WARFARIN SODIUM

Drug Interaction

Drug Names

Coumarin Anticoagulants/Econazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Econazole has been shown to be a potent inhibitor of CYP3A4.(1) If absorbed systemically, topical econazole may inhibit the metabolism of coumarin anticoagulants.(2-3)

CLINICAL EFFECTS: The concurrent use of topical econazole and coumarin anticoagulants may increase international normalized ratio (INR) and result in an increased risk for bleeding.(2-4)

PREDISPOSING FACTORS: This interaction may occur if topical econazole is absorbed systemically. Factors contributing to increased systemic absorption include exposure to large body surface areas, occlusion of the area, and application onto areas of thin, macerated or broken skin.(2-4) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia).

Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Patients with risk factors for increased systemic absorption of topical econazole and receiving concurrent therapy with a coumarin anticoagulant (e.g. warfarin) should have their INR closely monitored.(1) When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation.

Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Topical econazole is typically minimally absorbed (less than 2%).(3,4) However absorption may be increased if it is applied to large areas of the body or to thin, macerated, or broken skin, or if the area is occluded.(2-4) A 79-year-old man on chronic warfarin therapy with stable INRs for 3 years developed severe bruising on his hip from a minor injury and bleeding for over 24 hours from a small, superficial cut on his hand.

His INR was found to be 12. He had started econazole cream one week before for Candidal infection of his scrotum and thighs. He had no other medication or diet changes and no acute illnesses.

He recovered after discontinuation of econazole and treatment with vitamin K.(3) An 84-year-old woman stable on acenocoumarol 4 mg daily for ten years developed a bilateral cervical hematoma causing upper airway obstruction, dyspnea and difficulty speaking. Her INR exceeded laboratory limits.

She had started using econazole lotion 1% for extensive dermatitis over her axillary, inguinal, and breast areas 17 days prior. She had no other changes to her medications, diet, or other chronic conditions, and no acute illnesses. The patient was treated with prothrombin complex concentrate and vitamin K and recovered.(3)

DICUMAROL, JANTOVEN, WARFARIN SODIUM

Moderate List
No disease contraindications

More Frequent	Less Frequent
None.	Erythema Pruritus of skin Skin irritation Stinging of skin

Rare/Very Rare
None.

The following precautions are available for FRIVO (econazole nitrate/niacinamide):

Pediatric
Pregnant
Lactation
Geriatric

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Reproduction studies in mice, rabbits, and rats using orally administered econazole nitrate have not revealed evidence of teratogenicity; however, gestation has been reported to be prolonged in rats following oral administration of the drug. Prolonged gestation has not been reported following intravaginal administration of econazole nitrate in humans. Fetotoxic or embryotoxic effects were observed in reproduction studies in rats receiving oral econazole nitrate dosages 10-40 times the topical human dosage, and similar effects occurred in mice, rabbits, and/or rats receiving oral dosages 40 or 80 times the topical human dosage. Econazole nitrate 1% cream should be used during the first trimester of pregnancy only when considered essential to the welfare of the patient and during the second or third trimester of pregnancy only when clearly needed.

Following oral administration of econazole nitrate to lactating rats, econazole and/or its metabolites are distributed into milk and have been detected in nursing pups. In addition, in lactating rats receiving oral econazole nitrate dosages 40 or 80 times the topical human dosage, postpartum viability of pups and survival to weaning were reduced; however, at these dosages, maternal toxicity was present and may have been a contributing factor. Since it is not known whether econazole nitrate is distributed into human milk following topical application, econazole nitrate 1% cream should be used with caution in nursing women.

No enhanced Geriatric Use information available for this drug.