Rapamune


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sirolimus

Rapamune

Pharmacologic class: Macrocyclic lactone

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 renal transplant patients, in facility with adequate diagnostic and treatment resources. Physician responsible for maintenance therapy should have complete information needed for patient follow-up.

• Safety and efficacy of sirolimus as an immunosuppressant haven't been established in liver or lung transplant patients; therefore, such use isn't recommended.

• Sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients. Many of these patients had evidence of infection at or near time of death. In this and another study in de novo liver transplant patients, sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in hepatic artery thrombosis (HAT); most cases of HAT occurred within 30 days after transplantation and most led to graft loss or death.

• Cases of bronchial anastomotic dehiscence, most fatal, have occurred in de novo lung transplant patients when sirolimus was used as part of an immunosuppressive regimen.

Action

Inhibits early activation and proliferation of T lymphocytes and inhibits cell cycle progression at a later stage

Availability

Oral solution: 1 mg/ml

Tablets: 1 mg, 2 mg

Indications and dosages

Prevention of organ rejection in patients with kidney transplants

Adults and adolescents older than age 13 who weigh more than 40 kg (88 lb): Initially, 6 mg P.O. as a single dose as soon as possible after transplantation, then a maintenance dosage of 2 mg P.O. once daily. Usually given with cyclosporine and corticosteroids.

Dosage adjustment

• Mild to moderate hepatic failure

Contraindications

• Hypersensitivity to drug or its components

Precautions

Use cautiously in:
• renal or hepatic disease, cancer, diabetes mellitus, hyperlipidemia, infectious complications
• patients with liver or lung transplants (use not recommended)
• concurrent use of aminoglycosides, amphotericin B, and other nephrotoxic agents
• concurrent use of strong CYP3A4 inhibitors such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin or strong CYP3A4 inducers such as rifampin or rifabutin (use not recommended)
• pregnant or breastfeeding patients
• children younger than age 13.

Administration

• Administer consistently either with or without food.
• Use syringe provided to withdraw prescribed amount. Dilute oral solution in a glass or plastic (not Styrofoam) cup containing at least 2 oz of water or orange juice. Don't use other fluids, especially grapefruit juice.
• Swirl cup to mix drug thoroughly; discard syringe. Administer diluted drug right away. Then fill cup with 4 oz of water or orange juice, and have patient drink fluid right away.

If solution touches skin or mucous membranes, immediately wash affected area with soap and water.
• Wait 4 hours after the cyclosporine dose (if prescribed) before giving sirolimus.

Adverse reactions

CNS: headache, drowsiness, paresthesia, hypoesthesia, hypertonia, hypertonia, emotional lability, dizziness, confusion, syncope, malaise, asthenia, depression, anxiety, tremor, insomnia

CV: hypertension, hypotension, tachycardia, chest pain, edema, palpitations, vasodilation, peripheral edema, peripheral vascular disorders, thrombophlebitis, thrombosis, heart failure, atrial fibrillation, hemorrhage, pericardial effusion

EENT: abnormal vision, cataract, conjunctivitis, hearing loss, ear pain, otitis media, tinnitus, epistaxis, rhinitis, sinusitis, pharyngitis

GI: nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, hernia, enlarged abdomen, ascites, esophagitis, eructation, flatulence, gastritis, gastroenteritis, dysphagia, stomatitis, mouth ulcers, oral candidiasis, anorexia, peritonitis

GU: dysuria, nocturia, pyuria, urinary retention, hematuria, albuminuria, urinary frequency or incontinence, urinary tract infection, pelvic pain, kidney or bladder pain, hydronephrosis, erectile dysfunction, scrotal edema, testes disorders, oliguria, GU tract hemorrhage, renal tubular necrosis, toxic nephropathy

Hematologic: anemia, bruising, poly-cythemia, leukocytosis, thrombocytopenia, leukopenia, thrombotic thrombocytopenia

Metabolic: hyperlipidemia, glycosuria, hyperglycemia, diabetes mellitus, hypokalemia, hypophosphatemia, hypovolemia, hypercalcemia, dehydration, Cushing's syndrome, acidosis

Respiratory: dyspnea, cough, upper respiratory infection, bronchitis, hypoxia, pneumonia, atelectasis, pleural effusion, pulmonary edema, asthma, interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia, pulmonary fibrosis)

Skin: skin ulcers, skin hypertrophy, pruritus, fungal dermatitis, hirsutism, rash, acne, cellulites, non-melanoma skin cancer

Other: gingivitis, gum hyperplasia, weight changes, neck pain, fever, abscess, chills, facial edema, flulike symptoms, infection, lymphadenopathy, abnormal healing, lymphocele, fluid accumulation (including lymphedema, ascites), opportunistic infections (such as tuberculosis, fatal infections, sepsis), hypersensitivity reactions (including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, hypersensitivity vasculitis) lymphoma

Interactions

Drug-drug.Aminoglycosides, amphotericin, other nephrotoxic drugs: increased risk of nephrotoxicity

Bromocriptine, cimetidine, clarithromycin, danazol, erythromycin, fluconazole, indinavir, itraconazole, metoclopramide, nicardipine, ritonavir, verapamil, other CYP3A4 inhibitors: decreased sirolimus metabolism and increased blood level

Carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, other CYP3A4 inducers: decreased sirolimus blood level

Cyclosporine, diltiazem: increased sirolimus blood level

Live-virus vaccines: reduced vaccine efficacy

Drug-diagnostic tests.Blood urea nitrogen, cholesterol, creatinine, hepatic enzymes, lipids, red blood cells: increased levels

Calcium, glucose, phosphate, white blood cells: increased or decreased levels

Hemoglobin, magnesium, platelets, sodium: decreased levels

Drug-food.Grapefruit juice: decreased sirolimus metabolism and increased blood level

Drug-herbs.Astragalus, echinacea, melatonin, St. John's wort: decreased sirolimus efficacy

Patient monitoring

• Watch closely for signs and symptoms of infection and hypersensitivity reactions.
• Monitor renal function tests, lipid panel, electrolyte levels, blood chemistry studies, and sirolimus blood level.
• Evaluate all body systems carefully, especially cardiovascular, respiratory, and renal.
• Assess neurologic status closely. Implement safety precautions as needed to prevent injury.
• Be aware that cases of Pneumocystis carinii pneumonia have occurred in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for P. carinii pneumonia should be administered for 1 year following transplantation. In addition, cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.
• Watch for abnormal wound healing, especially in patients with body mass index greater than 30 kg/m2.

Patient teaching

• Teach patient correct procedure for taking drug.
• Advise patient to take consistently either with or without food, but not with grapefruit juice.
• Instruct patient to wait 4 hours after cyclosporine dose (if prescribed) before taking sirolimus.

Tell patient to wash affected area with soap and water immediately if drug touches his skin or mucous membranes.
• Inform patient that drug affects almost every body system. Advise him to report significant adverse reactions.

Advise patient that drug lowers resistance to infection. Instruct him to immediately report fever, cough, breathing problems, sore throat, or other signs and symptoms of infection.
• Caution patient to avoid driving and other hazardous activities until he knows how drug affects concentration and alertness.

Instruct patient to immediately report unusual bleeding or bruising.

Advise female patient to use effective contraception before and during therapy and for 12 weeks after discontinuation.

Caution patient to limit exposure to sunlight and ultraviolet light. Advise him to wear protective clothing and to use sunscreen with a high protection factor to help prevent skin cancer.
• 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.

sirolimus

(sir-oh-li-mus) ,

Rapamune

(trade name)

Classification

Therapeutic: immunosuppressants
Pregnancy Category: C

Indications

Prevention of organ rejection in allogenic kidney transplantation (with corticosteroids and cyclosporine).Sirolimus is also eluted from the Cypher coronary stent used in angioplasty procedures.

Action

Inhibits T-lymphocyte activation/proliferation, which occurs as a response to antigenic and cytokine stimulation; antibody production is also inhibited.

Therapeutic effects

Decreased incidence and severity of organ rejection.

Pharmacokinetics

Absorption: Rapidly absorbed following oral administration (14% bioavailability).
Distribution: Concentrates in erythrocytes; distributes to heart, intestines, kidneys, liver, lungs, muscle, spleen, and testes in high concentrations.
Protein Binding: 92%.
Metabolism and Excretion: Extensively metabolized (some metabolism by P450 3A4 system); 91% excreted in feces.
Half-life: 62 hr.

Time/action profile (blood levels)

ROUTEONSETPEAKDURATION
POrapid1–2 hr24 hr

Contraindications/Precautions

Contraindicated in: Hypersensitivity;Alcohol intolerance/sensitivity (solution contains ethanol);Concurrent ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin, rifampin, rifabutin, or grapefruit juice;Severe hepatic impairment; Obstetric / Lactation: Pregnancy and lactation.
Use Cautiously in: Mild to moderate hepatic impairment; Obstetric: Women with childbearing potential; Pediatric: Children <13 yr (safety not established).

Adverse Reactions/Side Effects

Reflects combined therapy with corticosteroids and cyclosporine

Central nervous system

  • progressive multifocal leukoencephalopathy (PML) (life-threatening)
  • insomnia (most frequent)

Respiratory

  • interstitial lung disease

Cardiovascular

  • edema
  • hypotension
  • pericardial effusion

Gastrointestinal

  • ascites
  • hepatotoxicity

Genitourinary

  • amenorrhea
  • menorrhagia
  • ovarian cysts
  • renal impairment

Dermatologic

  • acne (most frequent)
  • rash (most frequent)
  • thrombocytopenic purpura

Fluid and Electrolyte

  • hypokalemia

Hematologic

  • leukopenia (most frequent)
  • thrombocytopenia (most frequent)
  • anemia

Metabolic

  • hypercholesterolemia (most frequent)
  • hypertriglyceridemia (most frequent)

Musculoskeletal

  • arthralgias (most frequent)

Neurologic

  • tremor (most frequent)

Miscellaneous

  • infection (including activation of latent viral infections such as BK virus-associated nephropathy, pseudomembranous colitis)
  • lymphocele
  • lymphoma
  • ↓ wound healing

Interactions

Drug-Drug interaction

Cyclosporine (modified) greatly ↑ blood levels (administer sirolimus 4 hr after cyclosporine).Drugs that inhibit the CYP3A4 enzyme system may be expected to ↑ blood levels and the risk of adverse reactions.Ketoconazole, voriconazole, itraconazole, clarithromycin, erythromycin, telithromycin significantly ↑ blood levels (concurrent use is contraindicated).Blood levels are also ↑ by diltiazem and verapamil (monitor sirolimus levels and adjust dose as necessary) and may be ↑ by nicardipine, verapamil, clotrimazole, fluconazole, troleandomycin, metoclopramide, cimetidine, danazol, and protease inhibitors.Rifampin and rifabutin ↑ metabolism by stimulating the CYP3A4 enzyme system and significantly ↓ blood levels.Blood levels may also be ↓ by carbamazepine, phenobarbital, phenytoin, and rifapentine.Risk of renal impairment may be ↑ by concurrent use of other nephrotoxic agents.Concurrent use with tacrolimus and corticosteroids in lung transplantation may ↑ risk of anastamotic dehiscence; fatalites have been reported (not approved for this use).Concurrent use with tacrolimus and corticosteroids in liver transplantation may ↑ risk of hepatic artery thrombosis; fatalites have been reported (not approved for this use).May ↓ antibody response to and ↑ risk of adverse reactions to live-virus vaccines (avoid vaccination).Concomitant use with echinacea and melatonin may interfere with immunosuppression.St. John's wort may ↑ blood levels and the risk of toxicity.Grapefruit juice ↓ CYP3A4 metabolism and ↑ levels; do not use as a diluent and avoid concurrent ingestion.

Route/Dosage

Oral (Adults and Children ≥13 yr) 6-mg loading dose, followed by 2 mg/day maintenance dose. Dosing following cyclosporine withdrawal—Patients at low to moderate risk for rejection after transplantation may be withdrawn from cyclosporine over 4–8 wk beginning 2–4 mo after transplant. Thereafter, sirolimus dose should be titrated upward to maintain a whole blood trough level of 12–14 ng/mL. Clinical assessment should also be used to gauge dose. Dose changes can be made at 7–14 day intervals. The following formula may also be used: sirolimus maintenance dose = current dose × (target concentration/current concentration). If a large ↑ is needed, a loading dose may be given and blood levels reassessed 3–4 days later. Loading dose may be calculated by the following formula: sirolimus loading dose = 3 × (new maintenance dose-current maintenance dose). Loading doses >40 mg should be spread over 2 days.
Oral (Adults and Children ≥13 yr and <40 kg) 3 mg/m2 loading dose, followed by 1 mg/m2/day maintenance dose. See adjustments above for doses following cyclosporine withdrawal.

Hepatic Impairment

Oral (Adults and Children ≥13 yr and <40 kg) ↓ maintenance dose by 33%; loading dose is unchanged.

Availability

Tablet: 0.5 mg, 1 mg, 2 mg
Oral solution: 1 mg/mL

Nursing implications

Nursing assessment

  • Monitor BP closely during therapy. Hypertension is a common complication of sirolimus therapy and should be treated.
  • Assess for any new signs or symptoms that may be suggestive of PML, an opportunistic infection of the brain that leads to death or severe disability; withhold dose and notify health care professional promptly. Symptoms of PML may include hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia. Consider decreasing the amount of immunosuppression in these patients.
  • Lab Test Considerations: Monitor sirolimus blood levels when dose forms are changed and in patients likely to have altered drug metabolism, patients ≥13 yr who weigh <40 kg, patients with hepatic impairment, and during concurrent administration of drugs that may interact with sirolimus. Trough concentrations of ≥15 ng/mL are associated with an ↑ in adverse effects.
    • Monitor patients for hyperlipidemia. May require additional interventions to treat hyperlipidemia.
    • May cause anemia, leukopenia, thrombocytopenia, and hypokalemia.
    • May cause ↑ AST, ↑ ALT, hypophosphatemia, and hyperglycemia.

Potential Nursing Diagnoses

Risk for infection (Adverse Reactions)

Implementation

  • Therapy with sirolimus should be started as soon as possible post-transplant. Concurrent therapy with cyclosporine and corticosteroids is recommended. Sirolimus should be taken 4 hr after cyclosporine (MODIFIED, Neoral).
    • Sirolimus should be ordered only by physicians skilled in immunosuppressive therapy, with the staff and facilities to manage renal transplant patients.
    • Antimicrobial prophylaxis for Pneumocystis jirovecii pneumonia for 1 yr and for cytomegalovirus protection for 3 mo post-transplant are recommended.
  • Oral: Administer consistently with or without food. Swallow tablet whole; do not crush, break, or chew. Do not administer with or mix with grapefruit juice.
    • To dilute from bottle, use amber oral dose syringe to withdraw prescribed amount. Empty sirolimus from syringe into a glass or plastic container holding at least 2 oz (60 mL) of water or orange juice; do not use other liquids. Stir vigorously and drink at once. Refill container with at least 4 oz of additional liquid, stir vigorously, and drink at once.
    • If using the pouch, empty entire contents of pouch into at least 2 oz of water or orange juice; do not use other liquids. Stir vigorously and drink at once. Refill container with at least 4 oz of additional liquid, stir vigorously, and drink at once.
    • Store bottles and pouches in refrigerator. Protect from light. Solution may develop a slight haze when refrigerated; allow to stand at room temperature and shake gently until haze disappears. Sirolimus may remain in syringe at room temperature or refrigerated for up to 24 hr. Discard syringe after 1 use. Oral solution must be used within 1 mo of opening bottle.

Patient/Family Teaching

  • Instruct patient to take sirolimus at the same time each day, as directed. Advise patient to avoid taking with or diluting with grapefruit juice. Do not skip or double up on missed doses. Do not discontinue medication without advice of health care professional.
    • Advise patient to avoid grapefruit and grapefruit juice during therapy.
    • Reinforce the need for lifelong therapy to prevent transplant rejection. Review symptoms of rejection for transplanted organ and stress need to notify health care professional immediately if they occur.
    • Advise patient to notify health care professional if swelling of your face, eyes, or mouth; trouble breathing or wheezing; throat tightness; chest pain or tightness; feeling dizzy or faint; rash or peeling of skin; swelling of hands or feet; or symptoms of PML occur.
    • Advise patient to wear sunscreen and protective clothing and limit time in sunlight and UV light due to increased risk of skin cancer.
    • Caution patient to notify health care professional if signs of infection occur.
    • Advise patient to avoid vaccinations with a live virus during therapy.
    • Advise patient of the risk of taking sirolimus during pregnancy. Caution women of childbearing age to use effective contraception prior to, during, and for 12 wk following therapy.
    • Emphasize the importance of repeated lab tests during sirolimus therapy.

Evaluation/Desired Outcomes

  • Prevention of transplanted kidney rejection.

Rapamune

(răp′ə-myo͞on′)
A trademark for the drug sirolimus.

sirolimus

A macrolide immunosuppressant that is structurally similar to tacrolimus. It suppresses B- and T-cell proliferation, lymphokine synthesis, and T-cell response to IL2 by acting on target of rapamycin (TOR).
References in periodicals archive ?
Do not take Rapamune if you know you are allergic to sirolimus or any of the other ingredients in Rapamune.
Rapamune is indicated for the prophylaxis of organ rejection in patients 13 years or older receiving kidney transplants, with specific regimens recommended for use in patients at low to moderate immunologic risk and in patients at high immunologic risk.
District Court for the Eastern District of Pennsylvania, led to an investigation by the Justice Department and multiple states into abusive marketing practices related to Rapamune, which is primarily approved by the FDA for individuals following kidney transplants to help the body prevent organ rejection.
With the Court ruling in Pfizer's favor, Actavis will not be able to launch its generic version of Rapamune before the patent expires unless the company appeals the ruling and wins.
The companies stress patients receiving Rapamune should be managed at facilities equipped and staffed with adequate laboratory and support medical resources.
Sirolimus, which is marketed as Rapamune by Wyeth Pharmaceuticals, Madison, NJ, was developed from a naturally occurring substance first isolated from soil samples in Easter Island in the South Pacific.
Wyeth Pharmaceuticals, Madison, NJ, announced the US Food and Drug Administration (FDA) has approved a new indication for its immunosuppressive drug Rapamune.
The warning letter was issued following the deaths of 4 lung transplant recipients who were being treated with Rapamune.
Madison, NJ, warned transplant professionals in late April that findings from a recent study indicated that Rapamune (sirolimus) should not be used in combination with Fujisawa Pharmaceutical's Prograf (tacrolimus) in treating liver transplant patients.
Wyeth-Ayerst Laboratories, Madison, NJ announced that a US Food and Drug Administration (FDA) panel of experts recommended against its request to change the indication of Rapamune (sirolimus) to allow physicians to eliminate cyclosporine 2 to 4 months after the patient receives a kidney transplant.
Wyeth-Ayerst Laboratories, Philadelphia, PA, announced that the first solid formulation of its transplant immunosuppressent, Rapamune (sirolimus), is now available in the US.
Wyeth-Ayerst Laboratories, Madison, NJ, the pharmaceutical division of American Home Products, Philadelphia, PA, announced that Rapamune (sirolimus) has received marketing authorization from the European Commission (EU).