Protopic


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tacrolimus

Advagraf, Prograf, Protopic

Pharmacologic class: Macrolide

Therapeutic class: Immunosuppressant

Pregnancy risk category C

FDA Box Warning

Immunosuppression may increase patient's susceptibility to infection and lymphoma development. Give under supervision of physician experienced in immunosuppressive therapy and management of organ transplant patients, in facility with adequate diagnostic and treatment resources. Physician responsible for maintenance therapy should have complete information needed for patient follow-up.

Be aware that long-term safety of topical calcineurin inhibitors hasn't been established.

Although a causal relationship hasn't been established, rare cases of malignancy (such as skin cancers and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including tacrolimus ointment. Therefore, continuous long-term use of tacrolimus ointment in any age-group should be avoided and application limited to areas of atopic dermatitis involvement. Tacrolimus ointment isn't indicated for use in children younger than age 2. Only 0.03% tacrolimus ointment is indicated for use in children ages 2 to 15.

Action

Unknown. Thought to inhibit T-lymphocyte activation.

Availability

Capsules: 0.5 mg, 1 mg, 5 mg

Injection: 5 mg/ml

Topical ointment: 0.03%, 0.1%

Indications and dosages

Prevention of organ rejection in patients with allogeneic liver transplants

Adults: Initially, 0.1 to 0.15 mg/kg/day P.O. in two divided doses q 12 hours. Alternatively, 0.03 to 0.05 mg/kg/day by continuous I.V. infusion.

Children: 0.15 to 0.2 mg/kg/day P.O. in two divided doses q 12 hours. Alternatively, 0.03 to 0.05 mg/kg/day by continuous I.V. infusion.

Prevention of organ rejection in patients with allogeneic kidney transplants

Adults: Initially, 0.2 mg/kg/day P.O. in two divided doses q 12 hours when used in combination with azathioprine, or 0.1 mg/kg/day P.O. when used in combination with mycophenolate mofetil (MMF). Alternatively, 0.03 to 0.05 mg/kg/day by continuous I.V. infusion until oral dosing can be tolerated.

Prevention of heart transplant rejection

Adults: Initially, 0.075 mg/kg/day P.O. q 12 hours in two divided doses in combination with azathioprine or MMF.

Moderate to severe atopic dermatitis

Adults: 0.03% or 0.1% ointment applied b.i.d. to affected area, continued 1 week after dermatitis symptoms resolve

Children ages 2 and older: 0.03% ointment applied b.i.d. to affected area, continued 1 week after dermatitis symptoms resolve

Dosage adjustment

• Hepatic or renal impairment

• Concurrent use of CYP3A inducers or inhibitors

• Black patients

Contraindications

• Hypersensitivity to drug or its components (including castor oil derivatives)

Precautions

Use cautiously in:

• severe hepatic disease, renal impairment, diabetes mellitus, hypertension, hyperkalemia, hyperuricemia, lymphoma, serious infections

• skin barrier defect with increased potential for systemic absorption of tacrolimus ointment

• premalignant and malignant skin conditions (avoid use)

• concurrent use of cyclosporine, nelfinavir, or live vaccines (avoid use)

• concurrent use of strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, itraconazole, ketoconazole, ritonavir, telaprevir, voriconazole,) and strong inducers (such as rifampin, rifabutin) (not recommended)

• concurrent use of other substrates or CYP3A4 inhibitors that also have potential to prolong QT interval

• concurrent use of sirolimus (not recommended in liver and heart transplant; use with sirolimus in kidney transplant not established)

• concurrent use of other nephrotoxic drugs or drugs that cause hyperkalemia

• prolonged exposure to ultraviolet (UV) light and sunlight (avoid)

• pregnant or breastfeeding patients

• children younger than age 12 (age 2 for ointment use).

Administration

• Give oral form consistently with or without food but not with grapefruit juice.

• Give I.V. doses by infusion only. Be aware that I.V. use is reserved for patients who can't tolerate capsules orally.

• Start therapy within 24 hours of kidney transplantation and no earlier than 6 hours after liver or heart transplantation. Switch to oral dosing as soon as tolerable, starting 8 to 12 hours after I.V. dosing ends.

Before giving I.V., ensure that epinephrine 1:1,000 and oxygen are at hand in case of emergency.

• For I.V. use, dilute in normal saline solution or dextrose 5% in water to a concentration of 0.004 to 0.02 mg/ml. Give by infusion only.

• Be aware that ointment is used only as second-line therapy for the short-term and noncontinuous treatment of moderate to severe atopic dermatitis in nonimmunocompromised patients who have failed to respond adequately to other topical prescription treatments for atopic dermatitis.

• After applying ointment, don't place occlusive dressing or wrapping over affected area.

Adverse reactions

CNS: tremor, headache, insomnia, paresthesia, delirium, asthenia, neurotoxicities (including posterior reversible encephalopathy syndrome, delirium, seizures, and coma)

CV: hypertension, peripheral edema, myocardial hypertrophy

GI: nausea, vomiting, diarrhea, constipation, abdominal pain, ascites, anorexia

GU: hematuria, proteinuria, urinary tract infection, albuminuria, abnormal renal function, oliguria, renal failure, nephrotoxicity

Hematologic: anemia, leukocytosis, thrombocytopenia, agranulocytosis, hemolytic anemia, pure red cell aplasia

Metabolic: new-onset diabetes mellitus, hyperglycemia, hypomagnesemia, hypokalemia, hyperkalemia

Musculoskeletal: back pain

Respiratory: dyspnea, pleural effusion, atelectasis

Skin: burning (with ointment), rash, flushing, pruritus, alopecia

Other: pain, fever, chills, lymphadenopathy, serious infections (including cytomegalovirus infections and polyoma virus infections), lymphoma and other malignancies, anaphylaxis

Interactions

Drug-drug. Bromocriptine, chloramphenicol, cimetidine, clarithromycin, clotrimazole, cyclosporine, danazol, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, methylprednisolone, metoclopramide, metronidazole, nicardipine, omeprazole, protease inhibitors, verapamil: increased tacrolimus blood level

Cyclosporine: increased risk of nephrotoxicity

CYP450 inducers (such as carbamazepine, phenobarbital, phenytoin, rifampin): decreased tacrolimus metabolism Immunosuppressants (except adrenocorticoids): immunologic oversuppression

Live-virus vaccines: interference with immune response to vaccine

Mycophenolate mofetil: increased mycophenolate blood level

Nephrotoxic drugs (such as aminoglycosides, amphotericin B, cisplatin, cyclosporine): additive or synergistic effects

Drug-diagnostic tests. Blood urea nitrogen, creatinine, glucose: increased levels

Hemoglobin, magnesium, platelets, white blood cells: decreased levels

Liver function tests: abnormal values

Potassium: increased or decreased level

Drug-food. Any food: inhibited drug absorption

Grapefruit or grapefruit juice: increased drug blood level

Drug-herbs. Astragalus, echinacea, melatonin: decreased immunosuppression

St. John's wort: decreased tacrolimus blood level

Patient monitoring

Once I.V. infusion starts, watch closely for signs and symptoms of anaphylaxis.

• Monitor cardiac, liver, and kidney function test results. Watch for signs and symptoms of cardiovascular disorder, nephrotoxicity, and hepatic dysfunction.

Assess neurologic status for evidence of neurotoxicity (including posterior encephalopathy syndrome and seizures).

• Monitor potassium level closely. Stay alert for signs and symptoms of hyperkalemia.

• Monitor blood glucose. Watch for indications of hyperglycemia.

• Evaluate respiratory status regularly.

Patient teaching

Teach patient to recognize and immediately report serious adverse reactions.

• Tell patient to take oral doses consistently with or without food, but not with grapefruit or grapefruit juice.

• Tell diabetic patient to expect increased blood glucose level, which may warrant further antidiabetic therapy. Advise him to monitor glucose level carefully.

• Instruct patient not to place occlusive dressings or wrappings over affected area after applying ointment. Tell him to use drug for 1 week after dermatitis symptoms resolve.

• Advise patient to avoid live vaccines and prolonged exposure to UV light or sunlight.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, foods, and herbs mentioned above.

tacrolimus (topical)

(ta-kroe-li-mus) ,

Protopic

(trade name)

Classification

Therapeutic: immunosuppressants
Pregnancy Category: C

Indications

Moderate to severe atopic dermatitis in non-immunocompromised patients who do not respond to or cannot tolerate conventional therapies.

Action

Inhibits T-lymphocyte activation.

Therapeutic effects

Improvement in signs/symptoms of atopic dermatitis.

Pharmacokinetics

Absorption: Minimal following topical use.
Distribution: Crosses the placenta and enters breast milk.
Protein Binding: 99%.
Metabolism and Excretion: 99% metabolized by the liver; <1% excreted unchanged in the urine.
Half-life: Healthy volunteers—21.2 hr.

Time/action profile (immunosuppression)

ROUTEONSETPEAKDURATION
Topical†unknown1–2 wkunknown
†Improvement in atopic dermatitis

Contraindications/Precautions

Contraindicated in: Hypersensitivity to tacrolimus or any component of the ointment; Weakened/compromised immune system; Malignant or pre-malignant skin conditions; Lactation: Breastfeeding should be avoided; Pediatric: Children <2 yr (safety not established).
Use Cautiously in: Exposure to sunlight/UV light (may ↑risk of malignant skin changes); Superficial skin infections; Obstetric: Hyperkalemia and renal impairment may occur in the newborn; use only if benefit to mother justifies risk to the fetus.

Adverse Reactions/Side Effects

Central nervous system

  • headache

Ear, Eye, Nose, Throat

  • sinusitis

Respiratory

  • cough
  • pharyngitis

Dermatologic

  • erythema (most frequent)
  • pruritis (most frequent)
  • skin infection (most frequent)
  • acne
  • folliculitis
  • rash

Local

  • burning

Musculoskeletal

  • back pain
  • myalgia

Miscellaneous

  • flu-like symptoms (most frequent)
  • fever
  • ↑ risk of lymphoma/skin cancer

Interactions

Noted primarily for PO and IV use, but should be considered for topical use

Drug-Drug interaction

Risk of nephrotoxicity is ↑ by concurrent use of aminoglycosides, amphotericin B, cisplatin, or cyclosporine (allow 24 hr to pass after stopping cyclosporine before starting tacrolimus).Concurrent use of potassium-sparing diuretics, ACE inhibitors, or angiotensin II receptor antagonists ↑ risk of hyperkalemia.The following drugs ↑ tacrolimus blood levels: azoleantifungals, bromocriptine, calcium channel blockers, chloramphenicol, cimetidine, clarithromycin, cyclosporine, danazol, erythromycin, lansoprazole, magnesium/aluminum hydroxidemethylprednisolone, omeprazole, nefazodone, metoclopramide, protease inhibitors, and voriconazole.Phenobarbital, phenytoin, caspofungin, sirolimuscarbamazepine, and rifamycins may ↓ tacrolimus blood levels.Vaccinations may be less effective if given concurrently with tacrolimus (avoid use of live-virus vaccines).Concomitant use with astragalus, echinacea, and melatonin may interfere with immunosuppression.St. John's wort may ↓ tacrolimus blood levels.

Route/Dosage

Topical (Adults) Apply 0.03% or 0.1% ointment twice daily. Discontinue when signs/symptoms of atopic dermatitis resolve.
Topical (Children ≥2–15 yr) Apply 0.03% ointment twice daily. Discontinue when signs/symptoms of atopic dermatitis resolve.

Availability

Ointment: 0.03%, 0.1%

Nursing implications

Nursing assessment

  • Atopic Dermatitis: Assess skin lesions prior to and periodically during therapy.
    • Use only for short time, not continuously, and in the minimum dose possible to decrease risk of developing skin cancer.

Potential Nursing Diagnoses

Risk for infection (Adverse Reactions)

Implementation

  • Do not use continuously for a long time.
  • Topical: Wash their hands before applying. Apply a thin layer of ointment twice daily to affected skin. Use smallest amount of ointment needed to control the signs and symptoms of eczema. Do not cover treated area with bandages, dressings or wraps. If not treating areas on hands, wash hands with soap and water after applying to remove any ointment on the hands.

Patient/Family Teaching

  • Instruct apply ointment as directed. Advise patient to read the Medication Guide prior to starting and with each Rx renewal; new information may be available.
  • Advise patient not to bathe, shower, or swim right after applying; may wash off ointment. May use moisturizers with ointment. Instruct patient to check with health care professional first about products to use. If moisturizers are used, apply them after application of ointment.
  • Advise patient to contact health care professional if their symptoms do not improve after 6 wk of treatment, if their symptoms get worse, or they develop a skin infection.
    • Instruct patient to use ointment only on areas of skin with atopic dermatitis.
    • Advise patient to stop using the ointment when the signs/symptoms of atopic dermatitis (itching, rash, redness) go away.
    • Advise patient to limit sun exposure during therapy.
    • Advise patient of the risk of using topical tacrolimus during pregnancy.
    • Inform patient of the risk of lymphoma or skin cancer with topical tacrolimus therapy.

Evaluation/Desired Outcomes

  • Management of atopic dermatitis.

Protopic

(prō-tŏp′ĭk)
A trademark for the drug tacrolimus.

Protopic

A brand name for TACROLIMUS.
References in periodicals archive ?
The distribution right of Protopic in Japan was transferred to Maruho Co.
- Protopic (Atopic Dermatitis) - Forecast and Market Analysis to 2022
Food and Drug Administration has approved two ointments--tacrolimus (Protopic) and pimecrolimus (Elidel)--to treat eczema.
To treat the lesions on his hands, we started the patient on tacrolimus (Protopic) 0.1% ointment once daily (to avoid using a topical steroid due to his skin fragility) and a skin protectant/moisturizer (Theraseal) 2 to 3 times daily to reduce irritation.
As an ointment (protopic), Tacrolimus has been recently used in the treatment of eczema particularly atopic dermatitis.
Two FDA-approved topical medications, tacrolimus (Protopic) and pimecrolimus (Elidel) are available for treatment of eczema.
Topical tacrolimus (Protopic) 0.1% ointment can be helpful, but this is an off-label use, and it should be applied sparingly as it may burn, she said.
Black boxes can be found on many other drugs, including the anti-depressant Prozac, Celebrex for arthritis, and eczema creams like Protopic.
Recently, Protopic (Tacrolimus ointment) and pimecrolimus were approved by the U.S.
The topical immunomodulators (a new class of drugs), pimecrolimus (Elidel) cream and tacrolimus (Protopic) ointment have been a boon to children with eczema (atopic dermatitis).
"Thomas was the first child to try the Protopic tacrolimus monohydrate ointment at the James Cook University Hospital.