Names and pronunciation
Protopic
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Drug reference
Protopic
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Func. class.: Immunosuppressant, calcineurin inhibitor
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Chem. class.: Macrolide, calcineurin inhibitor
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Do not confuse: Prograf/PROzac Proscar tacrolimus/tamsulosin
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ACTION: Produces immunosuppression by inhibiting T-lymphocytes
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USES: Organ transplants to prevent rejection; topical: atopic dermatitis
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CONTRAINDICATIONS: Children <2 yr (topical); hypersensitivity to this product or to some kinds of castor oil (IV); long-term use (topical) Precautions: Pregnancy, breastfeeding, severe renal/hepatic disease; diabetes mellitus, hyperkalemia, hyperuricemia, hypertension, acute bronchospasm, African-American patients, heart failure, seizures, QT prolongation
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Black Box Warning: Children <12, lym- phomas, infection, neoplastic disease, neonates, infants, requires a specialized setting, requires an experienced clinician; liver transplant (ext rel) DOSAGE AND ROUTES—NTI Kidney transplant rejection prophylaxis • Adult: IV 0.03-0.05 mg/kg/day as CONT INFUSION, begin within 24 hr of transplantation, delay until renal func- tion has recovered; PO 0.2 mg/kg/day in 2 divided doses q12hr with azaTHIO- prine and corticosteroids, may give first dose within 24 hr of transplantation, delay until renal function has recov- ered; EXT REL CAPS 0.1 mg/kg daily preoperatively on empty stomach, 1st dose 12 hr before reperfusion and 0.2 mg/kg once daily postoperatively, 1st dose within 12 hr of reperfusion but ≥4 hr after preoperative dose in combina- tion with mycophenolate and cortico- steroids Liver transplant rejection prophylaxis • Adult: PO 0.1-0.15 mg/kg/day in 2 divided doses q12hr; give no sooner than 6 hr after transplantation; IV 0.03-0.05 mg/kg/day as CONT INFUSION; give no sooner than 6 hr after transplantation Heart transplant rejection prophylaxis • Adult: PO 0.075 mg/kg/day in 2 di- vided doses q12hr; give no sooner than 6 hr after transplantation; IV 0.01 mg/kg/ day as CONT INFUSION; give no sooner than 6 hr after transplantation Atopic dermatitis • Adult: TOP use 0.03% or 0.1% oint- ment; apply bid × 7 days after clearing of signs • Child ≥2-15 yr: TOP 0.03% ointment; apply bid × 7 days after clearing of signs Graft-versus-host disease (orphan drug) (unlabeled) • Adult/adolescent: IV 0.1 mg/kg/day in 2 divided doses given with other immu- T nosuppressants or PO 0.3 mg/kg/day in 2 divided doses • Child: CONT IV INFUSION 0.1 mg/kg/day Black Box Warning: Liver transplant: ext rel product should not be used be- cause of increased female mortality rate Black Box Warning: Specialized care setting, experienced clinician: only use when equipped and staffed with adequate supportive services and by those experienced in immunosup- pressive therapy and organ transplan- tation Black Box Warning: Children, infants, neonates: not approved use of ointment in those <2 yr, ext rel in those <16 yr; not approved for pediatric kidney/heart transplant • Pregnancy/breastfeeding: use only if benefits outweigh fetal risk; do not breastfeed, excretion unknown Black Box Warning: To report symp- toms of lymphoma, skin cancer; to avoid crowds, persons with known infections to reduce risk for infection; to avoid eating raw shellfish Topical route • To stop using topical product when atopic dermatitis is resolved; not to use >6 wk if symptoms do not improve; not to shower or swim after applying • To report if pregnancy is planned or suspected
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SIDE EFFECTS CNS: Tremors, headache, insomnia, paresthesia, chills, fever, seizures, BK virus–associated nephropathy, coma, posttransplant lymphoproliferative disor der (PTLD) CV: Hypertension, myocardial hypertro- phy, prolonged QTc, cardiomyopathy EENT: Blurred vision, photophobia GI: Nausea, vomiting, diarrhea, constipa- tion, GI bleeding, GI perforation GU: UTIs, albuminuria, hematuria, pro teinuria, renal failure, hemolytic uremic syndrome HEMA: Anemia, leukocytosis, thrombocy topenia, purpura INTEG: Rash, flushing, itching, alopecia META: Hyperglycemia, hyperuricemia, hypo kalemia, hypomagnesemia, hyperkalemia MS: Back pain, muscle spasms RESP: Pleural effusion, atelectasis, dys- pnea, interstitial lung disease SYST: Anaphylaxis, infection, malignancy
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INTERACTIONS Increase: QT prolongation—class IA/III antidysrhythmics, some phenothiazines, β agonists, local anesthetics, tricyclics, haloperidol, chloroquine, droperidol, pentamidine; CYP3A4 inhibitors (ami odarone, clarithromycin, erythromycin, telithromycin, troleandomycin), arsenic trioxide; CYP3A4 substrates (metha done, pimozide, QUEtiapine, quiNIDine, risperiDONE, ziprasidone); do not use together Increase: toxicity—aminoglycosides, CISplatin, cycloSPORINE Increase: blood levels—antifungals, cal- cium channel blockers, cimetidine, dan- azol, mycophenolate, mofetil Decrease: blood levels—carBAMazepine, PHENobarbital, phenytoin, rifamycin Decrease: effect of live virus vaccines Drug/Herb Decrease: immunosuppression—astragalus, echinacea, melatonin, ginseng, St. John’s wort Drug/Food Increase: effect—grapefruit juice Decreased absorption: food Drug/Lab Test Increase: glucose, BUN, creatinine Increase or decrease: LFTs, potassium T Decrease: magnesium, HB, platelets
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Available forms: Inj 5 mg/mL; caps 0.5, 1, 5 mg; ext rel cap (Astragraf XL) 0.5, 1, 3, 5 mg; ointment 0.03%, 0.1%; ext rel cap (Envarsus XR) 0.75, 1.4 mg Administer PO route Conventional immediate-release capsules • Give consistently with or without food Extended-release capsules (Astagraf XL) • Take in the AM, preferably on an empty stomach at least 1 hr before a meal or at least 2 hr after a meal • Swallow whole; do not chew, divide, or crush capsules • Do not administer with an alcoholic beverage • If a dose is missed up to 14 hr from the scheduled time, take the dose; if a dose is missed at >14 hr from the scheduled time, skip the dose and take the next dose at the regularly scheduled time Extended-release tablets (Envarsus XR) • Take in the AM, preferably on an empty stomach at least 1 hr before a meal or at least 2 hr after a meal • Swallow whole; do not chew, divide, or crush capsules • Do not administer with an alcoholic beverage • If a dose is missed up to 15 hr from the scheduled time, take the dose; if a dose is missed at >15 hr from the scheduled time, skip the dose and take the next dose at the regularly sched- uled time Topical route • Apply thin layers to affected skin only; rub in gently • Do not use occlusive dressings • Use on small area of skin • Topical ointment carries risk of devel oping cancer; use only when other op tions have failed IV route • Visually inspect for particulate matter and discoloration before use • Because of the risk of hypersensitivity reactions, IV use should be reserved for those who cannot take tacrolimus orally. PO should replace IV therapy as soon as possible • Observe patients for 30 min after beginning the infusion and frequently there- after for possible hypersensitivity reactions • Do not mix or infuse with solutions with a pH of 9 or more (acyclovir or ganciclovir) Dilution • The concentrate for injection must be diluted with NS or D5W injection to a final concentration between 0.004 mg/mL and 0.02 mg/mL • Prepare solutions in polyethylene or glass containers to allow storage for 24 hr; do not use polyvinyl chloride (PVC) containers, stability is decreased and the polyoxyl 60 hydrogenated castor oil in the formulation may leach phthalates from PVC containers Continuous IV infusion • Give through non-PVC tubing to mini- mize the potential for drug adsorption onto the tubing • Infuse the required daily dose of the diluted IV solution over 24 hr compatibilities: Alemtuzumab, Y-site alfentanil, amifostine, amikacin, amino- phylline, amiodarone, amphotericin B colloidal, amphotericin B liposome, anid- ulafungin, argatroban, atracurium, aztreo- nam, benztropine, bivalirudin, bleomycin, bumetanide, buprenorphine, busulfan, butorphanol, calcium acetate/chloride/ gluconate, CARBOplatin, carmustine, caspofungin, ceFAZolin, cefoperazone, cefotaxime, cefoTEtan, cefOXitin, cefTAZi- dime, ceftizoxime, cefTRIAXone, cefurox- ime, chloramphenicol, chlorproMAZINE, cimetidine, ciprofloxacin, cisatracurium, CISplatin, clindamycin, cyclophospha- mide, cycloSPORINE, cytarabine, DACTI- Nomycin, DAPTOmycin, dexamethasone, dexmedetomidine, dexrazoxane, digoxin, diltiaZEM, diphenhydrAMINE, DOBUTa- mine, DOCEtaxel, dolasetron, DOPamine, doripenem, doxacurium, DOXOrubicin hydrochloride, doxycycline, droperidol, enalaprilat, ePHEDrine, EPINEPHrine, epiRUBicin, ertapenem, erythromycin, esmolol, etoposide, etoposide phosphate, famotidine, fenoldopam, fentaNYL, flucon- azole, fludarabine, foscarnet, fosphenyt- oin, gemcitabine, gentamicin, glycopyrro- late, granisetron, haloperidol, heparin, hydrALAZINE, hydrocortisone, HYDRO- morphone, IDArubicin, ifosfamide, imipe- nem/cilastatin, inamrinone, insulin, isoproterenol, ketorolac, labetalol, leu- covorin, levoFLOXacin, levorphanol, lido- caine, linezolid, LORazepam, magnesium sulfate, mannitol, mechlorethamine, meperidine, meropenem, mesna, meta- raminol, methotrexate, methyldopate, methylPREDNISolone, metoclopramide, metoprolol, metroNIDAZOLE, micafungin, midazolam, milrinone, mitoMYcin, mito- XANTRONE, mivacurium, morphine, mul- tivitamins, nafcillin, nalbuphine, nalox- one, nesiritide, niCARdipine, nitroglycerin, nitroprusside, norepinephrine, octreo- tide, ondansetron, oxacillin, oxaliplatin, oxytocin, PACLitaxel, palonosetron, pan- curonium, PEMEtrexed, penicillin G, pent- amidine, pentazocine, perphenazine, phentolamine, phenylephrine, piperacil- lin/tazobactam, potassium chloride/ phosphates, procainamide, prochlor- perazine, promethazine, propranolol, quinupristin/dalfopristin, raNITIdine, remifentanil, rocuronium, sodium ace- tate/bicarbonate/phosphates, streptozo- cin, succinylcholine, SUFentanil, tenipo- side, theophylline, thiotepa, ticarcillin/ clavulanate, tigecycline, tirofiban, tobra- mycin, tolazoline, trimethobenzamide, vancomycin, vasopressin, vecuronium, verapamil, vinCRIStine, vinorelbine, vori- conazole, zidovudine, zoledronic acid
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Assess: • Blood studies: HB, WBC, platelets dur ing treatment monthly; if leukocytes <3000/mm3 or platelets <100,000/mm3, discontinue or reduce; decreased hemo globin level may indicate bone marrow suppression • Hepatic studies: alk phos, AST, ALT, amylase, bilirubin; for hepatotoxicity: dark urine, jaundice, itching, light-colored stools; product should be discontinued • Atopic dermatitis: Check lesions base- line and during treatment • Assess for castor oil allergy (HCO-60); do not use if present • Serum creatinine/BUN, serum electro- lytes, lipid profile, serum tacrolimus con- centration • Anaphylaxis: rash, pruritus, wheezing, laryngeal edema; stop infusion, initiate emergency procedures • QT prolongation: ECG, ejection frac tion; assess for chest pain, palpitations, dyspnea • PTLD: Malaise, fever, weight loss, night sweats, decreased appetite can be fatal, allogenic hematopoietic stem cell trans plant (HSCT) may be required • Blood level monitoring: maintain ta crolimus whole blood (7-20 ng/mL) then 5-15 ng/mL for 1 yr in kidney transplant; 1-3 mo maintain whole blood at 8-20 ng/ mL, then 6-18 ng/mL 3-18 mo after trans plant (heart)
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Evaluate: • Therapeutic response: absence of graft rejection; immunosuppression in pa- tients with autoimmune disorders
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CLINICAL CONSIDERATIONS
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Patient and caregiver information: PO route • To report fever, rash, severe diarrhea, chills, sore throat, fatigue; that serious infections may occur; to report clay- colored stools, cramping (hepatotoxicity), nephrotoxicity, signs of diabetes mellitus • To avoid exposure to natural or artifi- cial sunlight • Not to breastfeed while taking product • That repeated lab tests will be needed during treatment • To avoid vaccines • Not to use with alcohol, grapefruit, grapefruit juice • Organ rejection: B/P, provide treat- ment for hypertension to help prevent rejection
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PHARMACOKINETICS PO: Extensively metabolized, half-life 10 hr, 75% protein binding
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