Professional Drug Information > Tacrolimus

Tacrolimus (Topical)

VA CLASSIFICATION
Primary: DE900

Commonly used brand name(s): Protopic.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Immunomodulator (topical) —

Indications

Accepted

Dermatitis, atopic, moderate to severe (treatment)—Tacrolimus ointment is indicated for short-term and intermittent long-term therapy in the treatment of patients with moderate to severe atopic dermatitis in whom the use of alternative, conventional therapies are deemed inappropriate or inadequate.^{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    822.05
^{01}
Mechanism of action/Effect:

The exact mechanism of action of tacrolimus in atopic dermatitis is not known.Tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein FKBP-12, by forming a complex with FKBP-12, calcium, calmodulin, and calcineurin, inhibiting the phosphatase activity of calcineurin. This is believed to prevent the formation of lymphokines (IL-2, gamma interferon). ^{01}

Tacrolimus also inhibits the transcription of genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, inhibits the release of pre-formed mediators from skin mast cells and basophils, and downregulates Fc (epsilon) RI expression on Langerhans cells.^{01}

Absorption:

Absolute bioavailability is unknown. Using historial intravenous data for comparison, bioavailability is less than 0.5%.
^{01}
Peak blood concentration:

Blood—Range from undetectable to 20 ng per mL in adult patients and below 1.6 ng per mL in pediatric patients.
^{01}

Precautions to Consider

Carcinogenicity / Tumorigenicity

Application of tacrolimus ointment with concurrent UV exposure , in a 52-week photocarcinogenicity study (40 weeks of treatment followed by 12 weeks of observation) has been shown to decrease the median time to onset of skin tumor formation in hairless mice. Lymphomas were noted in the mouse dermal carcinogenicity study at a daily dose of 3.5 mg per kg (26 times the maximum recommended human dose [MRHD]) but none were noted with a daily dose of 1.1 mg per kg (10 times the MRHD). A 104 week dermal carcinogenicity study in which mice were given 1.1 to 118 mg per kg per day of tacrolimus ointment showed a significant elevation in the incidence of pleomorphic lymphoma in high dose male and female animals and in the incidence of undifferentiated lymphoma in high dose females. However, the incidenceof skin tumor formation was minimal and not associated with the topical application of tacrolimus, under ambient lighting.
^{01}
Mutagenicity

No evidence of genotoxicity was seen in bacterial or mammalian in vitro assays of mutagenicity, or in vivo clastogenicity assays performed in mice. Unscheduled DNA synthesis was not seen in rodent hepatocytes.
^{01}
Pregnancy/Reproduction
Fertility—
There are no adequate and well controlled studies on the effects of topical tacrolimus on fertility. However, studies in which tacrolimus was administered orally showed no reduction in fertility in male or female rats. Oral adminsitration at 1.0 mg/kg (0.12 times the MRHD) in rats was associated with embryolethality and adverse effects on female reproduction, indicated by a higher rate of pre-implantation loss andd increased numbers of undelivered and nonviable pups. Doses of 3.2 mg/kg (0.43 times the MRHD), was associated with maternal and paternal toxicity and reproductive toxiciy including marked effects on estrous cycles, parturition, pup viabiliy, and pup malformations.
^{01}
Pregnancy—
Tacrolimus crosses the placenta. There are no adequate and well-controlled studies of topically administered tacrolimus in pregnant women. Use of systemic tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Studies in animals have shown that orally administered tacrolimus causes adverse effects on the fetus. Tacrolimus ointment should be used during pregnancy only if the potential benefit to the mother justifies a potential risk to the fetus.
^{01}
FDA Pregnancy Category C.
^{01}
Breast-feeding

Systemic absorption of topical tacrolimus is minimal, although potential adverse effects on nursing infants exist. Tacrolimus is distributed in human breast milk following oral administration. A decision on the use of topical tacrolimus by nursing mothers should consider the benefit to the mother as well as the potential for adverse effects on the infant.
^{01}
Pediatrics

Appropriate studies have not been performed on the relationship of age to the effects of tacrolimus in children up to 2 years of age. Safety and efficacy in this age group have not been established.
^{01}
Tacrolimus ointment 0.03% may be used by pediatric patients 2 years of age or older.
^{01}

Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of tacrolimus ointment in the elderly.^{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Minimal systemic absorption of topically applied tacrolimus should preclude the potential for significant interactions with other oral medications.

CYP3A4 hepatic enzyme inhibitors, such as:
Erythromycin
Itraconazole
Ketoconazole
Fluconazole
Calcium channel blockers or
Cimetidine    (patients with widespread and/or erythrodermic disease should use caution^{01}; systemic absorption of topical tacrolimus is minimal, but drug interactions with these systemic drugs known to interact with systemic tacrolimus cannot be ruled out^{01}; may inhibit metabolism of tacrolimus, leading to increased tacrolimus blood concentrations and toxicity^{02})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to tacrolimus
» Netherton's syndrome    (potential for increased systemic absorption)

^{01}
Risk-benefit should be considered when the following medical problems exist
Eczema herpeticum
Herpes simplex virus infection
Varicella zoster virus infection    (increased risk may be associated with these conditions)

^{01}
Erythroderma, generalized    (safety and efficacy has not been established)

^{01}
Lymphoma    (increased risk for developing lymphoma in transplant patients receiving systemic immunosuppressant regimens, such as systemic tacrolimus; consider discontinuation of topical tacrolimus if lymphadenopathy without a clear etiology develops or in the presence of acute infectious mononucleosis^{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Alcohol intolerance ^{01}(skin flushing in areas of ointment application)
    
fever ^{01}—in pediatric patients
    
flu like symptoms ^{01}(cough; fever; headache; loss of appetite; general aches and pains; sneezing; weakness)
    
headache
    
pruritis ( itching skin)^{01}— in pediatric patients
    
skin burning

Incidence less frequent
    
Allergic reaction ( itching, pain, redness, or swelling of eye or eyelid; watering of eyes,; troubled breathing or wheezing ; severe skin rash or hives ; flushing ; headache; fever ; chills ; runny nose; increased sensitivity to sunlight; joint pain; swollen glands)^{01}
    
acne ^{01}
    
back pain ^{01}
    
cyst ^{01}
    
dyspepsia ( acid or sour stomach ; belching ; heartburn ; indigestion; stomach discomfort upset or pain)^{01}
    
folliculitis ( burning, itching, or pain in hairy areas; pus at root of hair)^{01}
    
hyperesthesia (increased skin sensitivity)^{01}
    
myalgia (muscle aches or pain)^{01}
    
rash ^{01}
    
skin tingling ^{01}
    
sinusitis ( pain or tenderness around eyes and cheekbones; fever; stuffy or runny nose ; headache ; cough; shortness of breath; troubled breathing; tightness of chest; wheezing)^{01}
    
vesiculobullous rash ^{01}(skin blisters)— in pediatric patients



Note: Other side effects have occurred, but have not been reasonably associated with the use of topical tacrolimus.^{01}{03}




Overdose
For specific information on the clinical effects of systemic tacrolimus overdose, see the Tacrolimus (Systemic) monograph.

For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).
^{01}
Treatment of overdose
Treatment is symptomatic and supportive ^{01}. Clearance of tacrolimus cannot be enhanced by dialysis because tacrolimus is extensively bound to erythrocytes and plasma proteins ^{02}.

If oral ingestion occurs, medical advice should be sought. Oral ingestion may lead to adverse effects associated with systemic administration of tacrolimus.^{01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tacrolimus (Topical).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to tacrolimus

Pregnancy—Crosses the placenta. Systemic tacrolimus associated with neonatal hyperkalemia and renal dysfunction





Breast-feeding—Distributed in human breast milk following oral administration





Use in children—Safety and efficacy not established in children up to 2 years of age

Other medical problems, especially Netherton's syndrome

Proper use of this medication
Clinical infections at treatment sites should be cleared before initiating topical tacrolimus treatment

Use on dry skin

Wash hands after application if hands are not an area for treatment

» Proper dosing
Using as soon as possible; not using if almost time for next scheduled dose; not doubling doses

Proper storage

Precautions while using this medication
» Importance of close monitoring by a physician

Report any adverse reactions to physician

Do not use tacrolimus ointment for any disorder other than that for which it was prescribed

» Minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment))


General Dosing Information
Skin should be completely dry prior to application^{01}

Showering, bathing, or swimming directly after application may wash off the ointment.^{03}

Tacrolimus ointments should not be used with occlusive dressings^{01}.

Tacrolimus ointments are not for oral use.^{01}

Treatment should continue for one week after clearing of signs and symptoms of atopic dermatitis.^{01}


Topical Dosage Forms

TACROLIMUS OINTMENT

Usual Adult Dose
Atopic dermatitis
Topical, as 0.03% or 0.1% ointment, rub gently into skin of the affected areas twice daily. Treatment should continue for one week after symptoms have ceased
^{01}

Usual Pediatric Dose
Atopic dermatitis
Children 2 to 15 years of age— Topical, as 0.03% ointment, rub gently into skin of the affected areas twice daily. Treatment should continue for one week after symptoms have ceased.
^{01}

Usual Geriatric Dose
See Usual adult dose.

Strength(s) usually available
U.S.—


0.03% (Rx) [Protopic (mineral oil ) (paraffin) (propylene carbonate) (white petrolatum) ( white wax)]^{01}


0.1% (Rx) [Protopic (mineral oil ) (paraffin) (propylene carbonate) (white petrolatum) ( white wax)]^{01}

Packaging and storage:
Store at 25 °C (77 °F), excursions permitted from 15 to 30°C (59 to 86°F).
^{01}
Auxiliary labeling:
   • Avoid direct exposure to sunlight^{01}

Developed: 05/24/2001
Revised: 07/16/2001

References

1. Product Information: Protopic ®, tacrolimus. Fujisawa, Deerfield, Illinois, (PI revised 12/2000) reviewed 4/2001.
   

2. Prograf package insert (Fujisawa—US), Rev 4/97, Rec 6/97.
   

3. Manufacturer comment, 7/9/01.
   

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