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Tacrolimus (Topical)

Pronunciation

Pronunciation

(ta KROE li mus)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Ointment, External:

Protopic: 0.03% (30 g, 60 g, 100 g); 0.1% (30 g, 60 g, 100 g)

Generic: 0.03% (30 g, 60 g, 100 g); 0.1% (30 g, 60 g, 100 g)

Brand Names: U.S.

  • Protopic

Pharmacologic Category

  • Calcineurin Inhibitor
  • Immunosuppressant Agent
  • Topical Skin Product

Pharmacology

Suppresses cellular immunity (inhibits T-lymphocyte activation), by binding to an intracellular protein, FKBP-12 and complexes with calcineurin dependent proteins to inhibit calcineurin phosphatase activity

Absorption

Minimally absorbed; serum concentrations range from undetectable to 20 ng/mL (~2 ng/mL in majority of adult patients studied)

Use: Labeled Indications

Moderate-to-severe atopic dermatitis in immunocompetent patients not responsive to conventional therapy or when conventional therapy is not appropriate

Canadian labeling: Additional use (not in U.S. labeling): Maintenance therapy to prevent flares and extend flare-free intervals in patients with moderate-to-severe atopic dermatitis who are responsive to initial therapy and experiencing ≥5 flares per year

Contraindications

Hypersensitivity to tacrolimus or any component of the formulation

Dosing: Adult

Atopic dermatitis (moderate-to-severe): Topical:

Treatment: Apply thin layer of 0.03% or 0.1% ointment to affected area twice daily; rub in gently and completely. Discontinue use when symptoms have cleared. If no improvement within 6 weeks, patients should be re-examined to confirm diagnosis.

Maintenance therapy (Canadian labeling; not in U.S. labeling): Apply one application (thin layer of 0.03% or 0.1% ointment) to areas usually affected twice a week, allowing 2-3 days between applications (eg, one application on Monday and Thursday). Re-evaluate after 12 months. Safety of maintenance therapy >12 months has not been established.

Note: Patients experiencing flares should resume twice daily treatment.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Moderate-to-severe atopic dermatitis: Topical:

Treatment:

Children ≥2-15 years: Apply thin layer of 0.03% ointment to affected area twice daily; rub in gently and completely. Discontinue use when symptoms have cleared. If no improvement within 6 weeks, patients should be re-examined to confirm diagnosis.

Children >15 years: Refer to adult dosing.

Maintenance therapy (Canadian labeling; not in U.S. labeling):

Children ≥2-15 years: Apply one application (thin layer of 0.03% ointment) to areas usually affected twice a week, allowing 2-3 days between applications (eg, one application on Monday and Thursday). Re-evaluate after 12 months. Safety of maintenance therapy >12 months has not been established.

Children >15 years: Refer to adult dosing.

Note: Patients experiencing flares should resume twice daily treatment.

Administration

Do not use with occlusive dressings. Burning at the application site is most common in first few days; improves as atopic dermatitis improves. Limit application to involved areas. Continue as long as signs and symptoms persist; discontinue if resolution occurs; re-evaluate if symptoms persist >6 weeks.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Storage

Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alcohol (Ethyl): Tacrolimus (Topical) may enhance the dermatologic adverse effect of Alcohol (Ethyl). Monitor therapy

Antidepressants (Serotonin Reuptake Inhibitor/Antagonist): May decrease the metabolism of Tacrolimus (Topical). Exceptions: TraZODone. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Tacrolimus (Topical). Applicable Isavuconazonium considerations are addressed in separate monographs. Exceptions: Isavuconazonium Sulfate. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Tacrolimus (Topical). Exceptions: Bepridil. Monitor therapy

CycloSPORINE (Systemic): Tacrolimus (Topical) may enhance the nephrotoxic effect of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may enhance the nephrotoxic effect of Tacrolimus (Topical). Tacrolimus (Topical) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Tacrolimus (Topical). Avoid combination

Danazol: May increase the serum concentration of Tacrolimus (Topical). Monitor therapy

Grapefruit Juice: May decrease the metabolism of Tacrolimus (Topical). Monitor therapy

Immunosuppressants: Tacrolimus (Topical) may enhance the adverse/toxic effect of Immunosuppressants. Exceptions: Cytarabine (Liposomal). Avoid combination

Macrolide Antibiotics: May increase the serum concentration of Tacrolimus (Topical). Exceptions: Fidaxomicin; Roxithromycin; Spiramycin. Monitor therapy

Ombitasvir, Paritaprevir, and Ritonavir: May increase the serum concentration of Tacrolimus (Topical). Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May increase the serum concentration of Tacrolimus (Topical). Monitor therapy

Protease Inhibitors: May decrease the metabolism of Tacrolimus (Topical). Monitor therapy

Sirolimus: Tacrolimus (Topical) may enhance the adverse/toxic effect of Sirolimus. Sirolimus may enhance the adverse/toxic effect of Tacrolimus (Topical). Avoid combination

Temsirolimus: Tacrolimus (Topical) may enhance the adverse/toxic effect of Temsirolimus. Temsirolimus may enhance the adverse/toxic effect of Tacrolimus (Topical). Avoid combination

Adverse Reactions

As reported in children and adults, unless otherwise noted. Frequency not always defined.

Cardiovascular: Peripheral edema (adults 3% to 4%), hypertension (adults 1%)

Central nervous system: Headache (adults 19% to 20%), tingling of skin (2% to 8%), hyperesthesia (adults 3% to 7%), insomnia (adults 4%), paresthesia (adults 3%), depression (adults 2%), pain (1% to 2%)

Dermatologic: Burning sensation of skin (43% to 58%), pruritus (41% to 46%), erythema (25% to 28%), skin infection (adults 12%), acne vulgaris (adults 4% to 7%), urticaria (adults 3% to 6%), folliculitis (2% to 6%), skin rash (adults 2% to 5%), dermatological disease (children 4%), vesiculobullous dermatitis (children 4%), contact dermatitis (3% to 4%), pustular rash (adults 2% to 4%), contact eczema herpeticum (children 2%), fungal dermatitis (adults 1% to 2%), sunburn (adults 1% to 2%), alopecia (adults 1%), xeroderma (children 1%)

Gastrointestinal: Diarrhea (3% to 5%), dyspepsia (adults 1% to 4%), abdominal pain (children 3%), gastroenteritis (adults 2%), vomiting (adults 1%), nausea (children 1%)

Genitourinary: Dysmenorrhea (adults 4%), urinary tract infection (adults 1%)

Hematologic & oncologic: Lymphadenopathy (children 3%), malignant lymphoma, malignant neoplasm of skin

Hypersensitivity: Hypersensitivity reaction (adults 6% to 12%)

Infection: Herpes zoster (1% to 5%), varicella zoster infection (1% to 5%), infection (adults 1% to 2%)

Neuromuscular & skeletal: Myalgia (adults 2% to 3%), weakness (adults 2% to 3%), arthralgia (adults 1% to 3%), back pain (adults 2%)

Ocular: Conjunctivitis (adults 2%)

Otic: Otitis media (children 12%), otalgia (children 1%)

Respiratory: Flu-like symptoms (23% to 31%), increased cough (children 18%), asthma (adults 6%), rhinitis (children 6%), pharyngitis (adults 4%), sinusitis (adults 2% to 4%), bronchitis (adults 2%), pneumonia (adults 1%)

Miscellaneous: Fever (children 21%), allergic reaction (4% to 12%), alcohol intolerance (adults 3% to 7%), accidental injury (6%), cyst (adults 1% to 3%)

<1% (Limited to important or life-threatening): Abnormality in thinking, abscess, acne rosacea, acute renal failure, aggravated tooth caries, anaphylactoid reaction, anemia, anorexia, anxiety, application site edema, arthropathy, basal cell carcinoma, benign neoplasm (breast), blepharitis, bursitis, cataract, chest pain, chills, colitis, conjunctival edema, cutaneous candidiasis, cystitis, dehydration, dermal ulcer, diaphoresis, dry nose, dysgeusia, dyspnea, ecchymoses, edema, epistaxis, furunculosis, gastritis, heart valve disease, hernia, hyperbilirubinemia, hypercholesterolemia, hypertonia, hypothyroidism, impetigo (bullous), laryngitis, leukoderma, malaise, malignant lymphoma, malignant melanoma, migraine, muscle cramps, nail disease, neck pain, neoplasm (benign), oral candidiasis, osteoarthritis, osteomyelitis, otitis externa, pulmonary disease, rectal disease, renal insufficiency, seborrhea, seizure, septicemia, skin discoloration, skin photosensitivity, squamous cell carcinoma, stomatitis, syncope, tachycardia, tendon disease, unintended pregnancy, vaginitis, vasodilatation, vertigo, visual disturbance, vulvovaginal candidiasis, xerophthalmia, xerostomia

ALERT: U.S. Boxed Warning

Malignancy:

Although a causal relationship has not been established, rare cases of malignancy (ie, skin cancer and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including tacrolimus ointment. Avoid continuous long-term use of topical calcineurin inhibitors, including tacrolimus ointment, in any age group, and limit application to areas of involvement with atopic dermatitis.

Pediatrics:

Tacrolimus ointment is not indicated for use in children younger than 2 years of age. Only tacrolimus 0.03% ointment is indicated for use in children 2 to 15 years of age.

Warnings/Precautions

Concerns related to adverse events:

• Malignancy: [U.S. Boxed Warning]: Topical calcineurin inhibitors have been associated with rare cases of malignancy (including skin and lymphoma); therefore, it should be limited to short-term and intermittent treatment using the minimum amount necessary for the control of symptoms and only on involved areas. Avoid use on malignant or premalignant skin conditions (eg cutaneous T-cell lymphoma). Limit sun and ultraviolet light exposure; use appropriate sun protection.

• Infection: Do not apply to areas of active bacterial or viral infection; infections at the treatment site should be cleared prior to therapy. Patients with atopic dermatitis are predisposed to skin infections, and tacrolimus therapy has been associated with risk of developing eczema herpeticum, varicella zoster, and herpes simplex.

• Lymphadenopathy: May be associated with development of lymphadenopathy; possible infectious causes should be investigated. Discontinue use in patients with unknown cause of lymphadenopathy or acute infectious mononucleosis.

• Renal failure: Acute renal failure has been observed (rarely) with topical use.

Disease related concerns:

• Immunosuppression: Should not be used in immunocompromised patients. Safety and efficacy have not been evaluated.

• Skin diseases with altered absorption: Not recommended for use in patients with skin disease which may increase systemic absorption (eg, Netherton's syndrome).

Special populations:

• Pediatric: [U.S. Boxed Warning] Use in children <2 years of age is not recommended, only the 0.03% ointment should be used in children ages 2-15.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Other warnings/precautions:

• Appropriate use: Topical calcineurin agents are considered second-line therapies in the treatment of atopic dermatitis/eczema, and should be limited to use in patients who have failed treatment with other therapies. Safety not established in patients with generalized erythroderma. If atopic dermatitis is not improved in <6 weeks, re-evaluate to confirm diagnosis. Safety of intermittent use for >1 year has not been established, particularly since the effect on immune system development is unknown.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Tacrolimus crosses the human placenta and is measurable in the cord blood, amniotic fluid, and newborn serum following systemic use. Refer to the Tacrolimus (Systemic) monograph for additional information.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flu-like symptoms, itching, burning, stinging, skin tingling, temperature sensitivity, headache, cough, rhinitis, acne, hair bumps, or nausea. Have patient report immediately to prescriber ear pain, severe skin irritation, skin infection, skin growths, enlarged lymph nodes, muscle pain, urinary retention, or change in amount of urine passed (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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