SIROLIMUS

SIROLIMUS
(sir-o-li'mus)
Rapamune
Classifications: immunomodulator; immunosuppressant;
Therapeutic: immunosuppressant

Prototype: Cyclosporine
Pregnancy Category: C

Availability

1 mg tablets; 1 mg/mL oral solution

Action

Macrolide antibiotic structurally related to tacrolimus with immunosuppressive activity. Active in reducing a transplant rejection by inhibiting the response of helper T-lymphocytes and B-lymphocytes to cytokinesis [(interleukin) IL-2, IL-4, and IL-5].

Therapeutic Effect

Inhibits antibody production and acute transplant rejection reaction in autoimmune disorders [e.g., systemic lupus erythematosus (SLE)]. Indicated by nonrejection of transplanted organ.

Uses

Prophylaxis of kidney transplant rejection.

Unlabeled Uses

Treatment of psoriasis.

Contraindications

Hypersensitivity to sirolimus; lung or liver transplant patients; soya lecithin (soy fatty acids) hypersensitivity; lymphoma, neoplastic disease; children <13 y; females of childbearing age; pregnancy (category C); lactation.

Cautious Use

Hypersensitivity to or concurrent administration with tacrolimus; impaired renal function; concurrent use of aminoglycosides, and amphotericin B; renal transplant patients; dialysis patients, UV exposure, retransplant patients, multiorgan transplant recipients, African American transplant patients; viral or bacterial infection; hypertriglyceridemia, hyperlipidemia, diabetic patients, atrial fibrillation, CHF, hypervolemia, palpitations; mild to moderate hepatic disease; coronary artery disease; myelosuppression; liver disease.

Route & Dosage

Kidney Transplant
Adult: PO 6 mg loading dose immediately after transplant, then 2 mg/d. Doses will need to be much higher (up to 40 mg/d) if not on cyclosporine.
Adolescent (≥13 y, <40 kg): PO 3 mg/m2 loading dose immediately after transplant, then 1 mg/m2/d. Doses will need to be much higher (up to 40 mg/d) if not on cyclosporine.

Hepatic Impairment
Reduce maintenance dose by 33%.

Administration

Oral
  • Give 4 h after oral cyclosporine.
  • Add prescribed amount of sirolimus to a glass containing ≥2 oz (60 mL) of water or orange juice (do not use any other type of liquid). Stir vigorously and administer immediately. Refill glass with ≥4 oz (120 mL) of water or orange juice. Stir vigorously and administer immediately.
  • Give consistently with respect to amount and type of food.
  • Refrigerate; protect from light; use multidose bottles within 1 mo of opening.

Adverse Effects (≥1%)

Body as a Whole: Asthenia, back pain, chest pain, fever, pain, arthralgia; flu-like syndrome; generalized edema; infection; lymphocele; malaise; sepsis, arthrosis, bone necrosis, leg cramps, myalgia, osteoporosis, tetany, abscess, ascites, cellulitis, chills, face edema, hernia, pelvic pain, peritonitis. CNS: Insomnia, tremor, headache, anxiety, confusion, depression, dizziness, emotional lability, hypertonia, hyperesthesia, hypotonia, neuropathy, paresthesia, somnolence. CV: Hypertension, atrial fibrillation, CHF, hypervolemia, hypotension, palpitation, peripheral vascular disorder, postural hypotension, syncope, tachycardia, thrombophlebitis, thrombosis, vasodilation. GI: Constipation, diarrhea, dyspepsia, nausea, vomiting, abdominal pain, anorexia, dysphagia, eructation, esophagitis, flatulence, gastritis, gastroenteritis, gingivitis, gum hyperplasia, ileus, mouth ulceration, oral moniliasis, stomatitis, abnormal liver function tests. Hematologic: Anemia, thrombocytopenia, leukopenia, hemorrhage, ecchymosis, leukocytosis, lymphadenopathy, polycythemia, thrombotic, thrombocytopenic purpura. Metabolic: Edema, hypercholesterolemia, hyperkalemia, hyperlipidemia, hypokalemia, hypophosphatemia, peripheral edema, weight gain, Cushing's syndrome, diabetes, acidosis, hypercalcemia, hyperglycemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia; increased LDH, alkaline phosphatase, BUN, creatine phosphokinase, ALT, or AST; weight loss. Respiratory: Dyspnea, pharyngitis, upper respiratory tract infection, asthma, atelectasis, bronchitis, cough, epistaxis, hypoxia, lung edema, pleural effusion, pneumonia, rhinitis, sinusitis. Skin: Acne, rash, fungal dermatitis, hirsutism, pruritus, skin hypertrophy, skin ulcer, sweating. Urogenital: UTI, albuminuria, bladder pain, dysuria, hematuria, hydronephrosis, impotence, kidney pain, nocturia, renal tubular necrosis, oliguria, pyuria, scrotal edema, incontinence, urinary retention, glycosuria. Special Senses: Abnormal vision, cataract, conjunctivitis, deafness, ear pain, otitis media, tinnitus.

Interactions

Drug: Sirolimus concentrations increased by clarithromycin, cyclosporine, diltiazem, erythromycin, ketoconazole, itraconazole, telithromycin; sirolimus concentrations decreased by rifabutin, rifampin; vaccines may be less effective with sirolimus; tacrolimus increases mortality, hepatic artery thrombosis, and graft loss. Food: Grapefruit juice significantly increases plasma levels. High fat meals increase levels. Herbal: St. John's wort decreases efficacy.

Pharmacokinetics

Absorption: Rapidly with 14% bioavailability. Peak: 2 h. Distribution: 92% protein bound, distributes in high concentrations to heart, intestines, kidneys, liver, lungs, muscle, spleen, and testes. Metabolism: In liver (CYP3A4). Elimination: 91% in feces, 2.2% in urine. Half-Life: 62 h.

Nursing Implications

Assessment & Drug Effects

  • Monitor for S&S of graft rejection.
  • Control hyperlipidemia prior to initiating drug.
  • Draw trough whole-blood sirolimus levels 1 h before a scheduled dose.
  • Lab tests: Obtain periodic lipid profile, CBC with differential, fasting plasma glucose, blood chemistry, BUN, and creatinine (especially with other drugs known to cause renal impairment).

Patient & Family Education

  • Avoid grapefruit juice within 2 h of taking sirolimus.
  • Limit exposure to sunlight (UV exposure).
  • Note: Decreased effectiveness possible for vaccines during therapy.
  • Use or add barrier contraceptive before, during, and for 12 wk after discontinuing therapy.

Common adverse effects in italic, life-threatening effects underlined; generic names in bold; classifications in SMALL CAPS; Canadian drug name; Prototype drug

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