Names and pronunciation
(seer-oh-lie′mus) Fyarro, Rapamune
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Drug reference
(seer-oh-lie′mus) Fyarro, Rapamune
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Func. class.: Immunosuppressant
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Chem. class.: Macrolide
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ACTION: Produces immunosuppres- sion by inhibiting T-lymphocyte activation and proliferation
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USES: Organ transplants to prevent rejection; recommended use is with cycloSPORINE and corticosteroids
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CONTRAINDICATIONS: Breast- feeding, hypersensitivity to this product, components of product Precautions: Pregnancy, children <13 yr, severe cardiac/renal/hepatic disease; diabetes mellitus, hyperkalemia, hyper- uricemia, hypertension, interstitial lung disease, hyperlipidemia, soya lecithin hypersensitivity
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Black Box Warning: Lymphomas, infec- S tion, other malignancies, liver transplant, lung transplant; requires a specialized setting; requires an experienced clinician Black Box Warning: Only those expe- rienced in immunosuppressant therapy and transplant should use this drug; must use in a specialized care setting with ad- equate medical equipment Black Box Warning: Infection: immuno- suppression may lead to susceptibility to infection, assess for infection Black Box Warning: Neoplastic dis- ease: lymphoma, skin cancer may occur; limit UV exposure; use protective cloth- ing, sunscreen Black Box Warning: Liver/lung trans- plant: not recommended; mortality and graft loss may occur • Pulmonary fibrosis, pulmonary effu- sion, pneumonitis: dyspnea, cough, hy- poxia; some fatal cases have occurred • Wound dehiscence and anastomotic disruption: wound, vascular, airway, ureteral, biliary, inhibition of growth factors; do not combine with corticosteroids, not recom- mended in lung or liver transplant • Anaphylaxis, angioedema, exfolia- tive dermatitis: more common when given with ACE inhibitors; do not use if a hypersensitivity reaction occurs • Bone marrow suppression: HB, WBC, platelets during treatment each month; if leu- kocytes <3000/mm3 or platelets <100,000/ mm3, product should be discontinued or re- duced; decreased hemoglobin level • Hepatotoxicity: alk phos, AST, ALT, am- ylase, bilirubin, dark urine, jaundice, itch- ing, light-colored stools; product should be discontinued • Pregnancy/breastfeeding: avoid use in pregnancy; obtain pregnancy test at baseline; use effective form of contracep- tion, continue for 12 wk after discontinu- ing; notify prescriber if pregnancy occurs; unknown breastfeeding effects; weigh benefits, risks with prescriber
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SIDE EFFECTS CNS: Tremors, headache, insomnia, paresthesia, chills, fever, progressive mul- tifocal leukoencephalopathy (PML) CV: Hypertension, atrial fibrillation, HF, hypotension, palpitation, tachycardia, peripheral edema, thrombosis EENT: Blurred vision, photophobia GI: Nausea, vomiting, diarrhea, constipa- tion, hepatotoxicity, CDAD GU: UTIs, albuminuria, hematuria, pro- teinuria, renal failure, nephrotic syndrome, increased creatinine, amenorrhea HEMA: Anemia, leukopenia, thrombocy- topenia INTEG: Rash, acne, photosensitivity, exfoliative dermatitis META: Hyperglycemia, increased creati- nine, edema, hypercholesterolemia, hyper lipemia, hypophosphatemia, weight gain, hypo/hyperkalemia, hyperuricemia, hypo- magnesemia, hypertriglyceridemia MS: Arthralgia RESP: Pleural effusion, atelectasis, dys- pnea, pneumonitis, pulmonary embolism/ fibrosis, pulmonary hypertension, interstitial lung disease SYST: Lymphoma
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INTERACTIONS • Increase: Sirolimus metabolism strong CYP3A4 or P-gp inducers, avoid use Increase: angioedema—ACE inhibitors, angiotensin II–receptor antagonists, cephalosporins, iodine-containing radi- opaque contrast media, neuromuscular blockers, NSAIDs, penicillins, salicylates, thrombolytics Increase: blood levels—antifungals, cal- cium channel blockers, cimetidine, dan- azol, erythromycin, cycloSPORINE, meto clopramide, bromocriptine, HIV-protease inhibitors Decrease: Sirolimus metabolism causing toxicity, CYP3A4 inhibitors, avoid use Decrease: blood levels—carBAMaze- pine, PHENobarbital, phenytoin, rifamy- cin, rifapentine Decrease: effect of vaccines Drug/Herb • St. John’s wort: may decrease the ef- fect of sirolimus Drug/Food • Alters bioavailability; use consistently with/without food; do not use with grape- fruit juice Drug/Lab Test Increase: LFTs, alk phos, lipids, triglycer- ides, total cholesterol, BUN, creatinine, LDH, phosphate Decrease: platelets, sodium Increase or decrease: magnesium, glu- cose, calcium
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DOSAGE AND ROUTES Kidney transplant • Adult/adolescent ≥40 kg: PO 2 mg/ day with 6-mg loading dose; IV infusion 100 mg/m2 over 30 min on days 1 and 8 of each 21-day cycle until disease pro- gression or unacceptable toxicity • Child <13 yr weighing <40 kg (88 lb): PO 1 mg/m2/day, 3 mg/m2 loading dose Hepatic dose • Adult/child ≥13 yr/<40 kg: PO re- duce by 33% for maintenance dose (mild to moderate hepatic impairment); reduce by 50% for maintenance dose (severe hepatic impairment) Lymphangioleimyotosis Adult: PO 2 mg daily trough level (whole blood) after 10-20 days, titrate to 5-15 ng/mL, then monitor trough q3mo
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Available forms: Oral sol 1 mg/mL; tabs 0.5 mg, 1 mg, 2 mg; lyophilized powder for injectable suspension 100 mg
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Administer: • Prophylaxis for Pneumocystis jiroveci pneumonia for 1 yr after transplantation; prophylaxis for CMV is recommended for 90 days after transplantation in those at increased risk for CMV • All medications PO if possible; avoid IM inj; bleeding may occur • For 3 days before transplant surgery; place in protective isolation; give at same time of day; give 4 hr after cycloSPORINE oral sol or caps; do not give with grapefruit juice • Use amber oral syringe and withdraw amount needed; empty dose into plastic/ glass container holding 60 mL of water/ orange juice; stir vigorously and have pa- tient drink at once; refill container with additional 120-mL water/orange juice; stir, have patient drink; if using a pouch, squeeze entire contents into container; follow above directions • Store protected from light, refrigerate; stable for 30 days after opening (sol) • Do not crush, chew; store tabs at room temperature
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Assess: • High risk: those with Banff grade 3 acute rejection or vascular rejection before cycloSPORINE withdrawal, dialy- sis dependent, creatinine >4.5 mg/dL, African descent, retransplants, multior- gan transplant, high panel of reactive antibodies • Blood levels in patients who may have altered metabolism, trough level ≥15 ng/ mL is associated with increased adverse reactions; monitor trough concentrations in all patients • Renal status: monitor fluid imbalance, edema, electrolytes, creatinine/BUN, CBC, serum potassium • Lipid profile: cholesterol, triglycerides; lipid-lowering agent may be needed
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Evaluate: • Therapeutic response: absence of graft rejection; immunosuppression with auto- immune disorders
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CLINICAL CONSIDERATIONS
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Patient and caregiver information: • To report fever, rash, severe diarrhea, chills, sore throat, fatigue; serious infec- tions may occur; clay-colored stools, cramping (hepatotoxicity); fever, chills, sore throat (infection) • To avoid crowds, persons with known S infections to reduce risk for infection • To use sunscreen, protective clothing to prevent burns, skin cancer • Not to use with grapefruit juice • To avoid live virus vaccines during treatment • That lifelong use will be required to prevent rejection • That continuing follow-up exams and blood work will be required • To take with or without regard to food, at same time, consistently • Take 4 hr after oral cycloSPORINE when used for renal transplant • Pregnancy/breastfeeding: to use con- traception before, during, for 12 wk after product discontinued; to avoid breastfeeding HIGH ALERT
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PHARMACOKINETICS Rapidly absorbed; peak 1 hr single dose, 2 hr multiple dosing; protein binding 92%; distribution to major organs, exten- sively metabolized by CYP3A4 excretion 91% feces, half-life 57-63 hr
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• Adult/adolescent ≥40 kg: PO 2 mg/ day with 6-mg loading dose; IV infusion 100 mg/m2 over 30 min on days 1 and 8 of each 21-day cycle until disease pro- gression or unacceptable toxicity
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• Child <13 yr weighing <40 kg (88 lb): PO 1 mg/m2/day, 3 mg/m2 loading dose Hepatic dose
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• Adult/child ≥13 yr/<40 kg: PO re- duce by 33% for maintenance dose (mild to moderate hepatic impairment); reduce by 50% for maintenance dose (severe hepatic impairment) Lymphangioleimyotosis Adult: PO 2 mg daily trough level (whole blood) after 10-20 days, titrate to 5-15 ng/mL, then monitor trough q3mo
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