sirolimus (Rx)

Brand and Other Names:Rapamune
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 0.5mg
  • 1mg
  • 2mg

oral solution

  • 1mg/mL

Prophylaxis of Renal Transplant Rejection

Initiate with concomitant cyclosporine and corticosteroids

Oral solution and tablets interchangeable on a mg per mg basis

Target whole blood trough concentrations: 16-24 ng/mL for the first year following transplantation; thereafter, 12-20 ng/mL

High immunologic risk

  • <40 kg: 3 mg/m² loading dose
  • ≥40 kg: 15 mg PO loading dose
  • Maintenance: 5 mg/day PO if >40 kg and 1 mg/m²/day if <40 kg on day 2 and thereafter; obtain trough levels between days 5 and 7
  • Dose adjustments: Dose should be adjusted to maintain trough concentrations within desired range based on clinical state and concomitant therapy; further dose adjustment should not be done sooner than 7-14 days following a dose adjustment
  • Concomitant therapy: For the first year, following transplantation, sirolimus should be used in combination with cyclosporine and corticosteroids; cyclosporine may be initiated at 7 mg/kg/day in divided doses with the dose adjusted to achieve trough concentrations; prednisone should be given at a dose of 5 mg/day

Low-to-moderate immunologic risk

  • <40 kg: 3 mg/m² loading dose
  • ≥40 kg: 6 mg PO loading dose
  • Maintenance: 2 mg/day PO if ≥ 40 kg and 1 mg/m²/day if <40 kg on day 2 and thereafter; obtain trough levels between days 5 and 7
  • Dose adjustments: Dose should be adjusted to maintain trough concentrations within desired range based on clinical state and concomitant therapy; further dose adjustment should not be done sooner than 7-14 days following a dose adjustment
  • Concomitant therapy: Following transplantation, sirolimus should be used in combination with cyclosporine and corticosteroids; may discontinue cyclosporine gradually over 4-8 weeks two to four months after transplant in patients with low immunologic risk, & sirolimus dose increased (serum concentrations of sirolimus may decrease following cyclosporine withdrawal)

Lymphangioleiomyomatosis

Indicated for treatment of lymphangioleiomyomatosis (LAM)

Initial: 2 mg/day PO x10-20 days and then measure whole blood trough level

Therapeutic drug monitoring (LAM)

  • Adjust dose to maintain target concentrations between 5-15 ng/mL
  • Calculate dose adjustment: New sirolimus dose = current dose x (target concentration/current concentration)
  • Frequent dose adjustments based on nonsteady-state sirolimus concentrations can lead to overdosing or under dosing because sirolimus has a long half-life
  • Once maintenance dose is adjusted, continue on the new maintenance dose for at least 7-14 days before further dosage adjustment with concentration monitoring
  • Once a stable dose is achieved, monitor whole blood trough levels at least every 3 months

Dosage Modifications

Renal impairment

  • Dose adjusment not necessary
  • Adust dose of discontinue if serum creatinine increases when used in combination with cyclosporine

Hepatic impairment

  • Loading dose: Dosage adjustment not required
  • Maintenance dose
    • Mild-to-moderate (Child Pugh A or B): Reduce dose by 33%
    • Severe (Child Pugh C): Reduce dose by 50%

Orphan Designations

Bone sarcoma

  • Sponsor: Merck; 126 E. Lincoln Avenue; Rahway, NJ 07065

Tuberous sclerosis complex

  • Orphan designation for tuberous sclerosis complex-related facial angiofibromas
  • Sponsors
    • OncoImmune, Inc; 333 Parkland Plaza, Suite 1000; Ann Arbor, MI 48103
    • Aucta Pharmaceuticals, LLC; 675 US Highway One; North Brunswick, New Jersey 08902
    • AI Therapeutics, Inc; 530 Old Whitfield Street; Guilford, Connecticut 06437

Uveitis

  • Ophthalmic: Orphan designation for treatment of chronic/refractory anterior noninfectious uvetits afffecting the posterior segment of the eye
  • Sponsor: Santen Pharmaceutical Co, Ltd; 2100 Powell Street, Suite 1600; Emeryville, California 94608

Pachyonychia congenita

  • Sponsor: Santen Pharmaceutical Co, Ltd; 2100 Powell Street, Suite 1600; Emeryville, California 94608

Angiofibromas

  • Orphan designation for treatment of facial angiofibromas (FA) associated with tuberous sclerosis complex (TSC)
  • DSLP; 129 Hurstmere Road, Level 1, Nielsen Building; Auckland

Beta-thalassemia

  • Sponsor: Rare Partners srl Impresa Sociale; 31 Corso Magenta; Milano, Italy

Pulmonary arterial hypertension

  • Sponsor: Lam Therapeutics; 530 Old Whitfield Street; Guilford, Connecticut 06437

Sickle cell disease

  • Sponsor: Rare Partners srl Impresa Sociale; 31 Corso Magenta Milano, Italy

Familial adenomatous polyposis

  • Orphan designation for encapsulated formulation (Erapa) for treatment of familial adenomatous polyposis
  • Orphan sponsor: Emtora Biosciences Inc; 16601 Blanco Road, Suite 120; San Antonio, Texas 78232

Dosage Forms & Strengths

tablet

  • 0.5mg
  • 1mg
  • 2mg

oral solution

  • 1mg/mL

Prophylaxis of Renal Transplant Rejection

<13 years: Not recommended

≥13 years:

High Immunologic Risk

  • Loading dose: <40 kg: 3 mg/m² PO
  • Loading dose ≥40 kg: 15 mg PO
  • Maintenance: 5 mg/day PO if >40 kg and 1 mg/m²/day if <40 kg on day 2 and thereafter; obtain trough levels between days 5 and 7
  • Dose adjustments: Dose should be adjusted to maintain trough concentrations within desired range based on clinical state and concomitant therapy; further dose adjustment should not be done sooner than 7-14 days following a dose adjustment
  • Concomitant therapy: For the first year, following transplantation, sirolimus should be used in combination with cyclosporine and corticosteroids; cyclosporine may be initiated at 7 mg/kg/day in divided doses with the dose adjusted to achieve trough concentrations; prednisone should be given at a dose of 5 mg/day

Low-to-moderate Immunologic risk

  • Loading dose <40 kg: 3 mg/m² PO
  • Loading dose ≥40 kg: 6 mg PO
  • Maintenance: 2 mg/day PO if ≥ 40 kg and 1 mg/m²/day if <40 kg on day 2 and thereafter; obtain trough levels between days 5 and 7
  • Dose adjustments: Dose should be adjusted to maintain trough concentrations within desired range based on clinical state and concomitant therapy; further dose adjustment should not be done sooner than 7-14 days following a dose adjustment
  • Concomitant therapy: Following transplantation, sirolimus should be used in combination with cyclosporine and corticosteroids; may discontinue cyclosporine gradually over 4-8 weeks two to four months after transplant in patients with low immunologic risk, & sirolimus dose increased (serum concentrations of sirolimus may decrease following cyclosporine withdrawal)
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Interactions

Interaction Checker

and sirolimus

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            Peripheral edema, w/ corticosteroids (54-58%)

            Hypertriglyceridemia (45-57%; up to 90% when used with or following cyclosporine)

            Hypercholesterolemia (43-46%; up to 90% when used with or following cyclosporine)

            Constipation (36-38%)

            Arthralgia (25-31%)

            Thrombocytopenia (14-30%)

            Rash (10-20%)

            Hypertension (45-49%)

            Increased creatinine (39-40%)

            Abdominal pain (29-36%)

            Diarrhea (25-35%)

            Headache (34%)

            Fever (23-34%)

            Urinary tract infection (26-33%)

            Anemia (23-33%)

            Nausea (25-31%)

            Arthralgia (25-31%)

            Pain (29-33%)

            Acne (22%)

            Edema (18-20%)

            Sepsis (<20%)

            Lymphocele (<20%)

            Venous thromboembolism (<20%)

            Tachycardia (<20%)

            Stomatitis (<20%)

            Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (<20%)

            Leukopenia (<20%)

            Abnormal healing (<20%)

            Increased lactic dehydrogenase (<20%)

            Hypokalemia (<20%)

            Hypophoaphatemia (<20%)

            Hyperglycemia (<20%)

            Diabetes mellitus (<20%)

            Bone necrosis (<20%)

            Pneumonia (<20%)

            Epistaxis (<20%)

            Melanoma (<20%)

            Squamous cell carcinoma (<20%)

            Basal cell carcinoma (<20%)

            Pyelonephritis (<20%)

            Ovarian cysts (<20%)

            Menstrual disorders (amenorrhea and menorrhagia) (<20%)

            Postmarketing Reports

            Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported

            Posterior reversible encephalopathy syndrome

            Neuroendocrine carcinoma of the skin (Merkel cell carcinoma)

            Impairment of wound healing

            Embryo-fetal toxicity

            Male infertility

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            Warnings

            Black Box Warnings

            Do not use in liver or lung transplantation as safety and efficacy is not established

            Excess mortality, graft loss, and hepatic artery thrombosis have been observed in liver transplant recipients

            Bronchial anastomotic dehiscence has been observed in lung transplant recipients

            Should be prescribed only by physicians who have experience with immunosuppression in organ transplant recipients and can provide necessary follow-up and appropriate monitoring

            Increased risk of infection, lymphoma, and other malignancies due to increased immunosuppression

            Contraindications

            Hypersensitivity to sirolimus or macrolide antibiotics

            Concomitant live vaccines

            Cautions

            Increased risk of lymphoma or infections, including latent virus activation, eg, BK virus-induced nephropathy

            Fluid accumulation reported, including peripheral edema, lymphedema, pleural effusion, ascites, and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults), in patients receiving therapy

            Not for liver or lung transplant

            Impaired or delayed wound healing reported in patients receiving therapy, including lymphocele and wound dehiscence mTOR inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability; lymphocele, a known surgical complication of renal transplantation, reported to occur significantly more often in dose-related fashion in patients receiving therapy; appropriate measures should be considered to minimize complications; patients with body mass index (BMI) >30 kg/m² may be at increased risk of abnormal wound healing based on data from medical literature

            Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a broad spectrum sunscreen with a high protection factor

            Progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported; commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia

            Based on animal studies and mechanism of action, therapy may cause fetal harm when administered to a pregnant woman; in animal studies, mTOR inhibitors caused embryo- fetal toxicity when administered during period of organogenesis at maternal exposures that were equal to or less than human exposures at recommended lowest starting dose; advise pregnant women of potential risk to a fetus; advise women of childbearing potential to avoid becoming pregnant and to use effective contraception while on therapy and for 12 weeks after ending treatment

            Associated with development of angioedema; concomitant use of other drugs known to cause angioedema, such as angiotensin-converting enzyme (ACE) inhibitors, may increase risk of developing angioedema; elevated sirolimus levels (with/without concomitant ACE inhibitors) may potentiate angioedema; in some cases, angioedema has resolved upon discontinuation or therapy dose reduction

            Any patient receiving therapy should be monitored for hyperlipidemia; if detected, interventions such as diet, exercise, and lipid-lowering agents should be initiated as outlined by National Cholesterol Education Program guidelines

            Hyperlipidemia: In clinical trials of patients receiving sirolimus plus cyclosporine or after cyclosporine withdrawal, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy; despite antilipid management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and triglycerides above recommended target levels

            Consult lab regarding type of assay for drug monitoring; whole blood concentrations are being measured by various chromatographic and immunoassay methodologies; sample concentration values from different assays may not be interchangeable

            Cases of interstitial lung disease [ILD] (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including sirolimus; in some cases, was reported with pulmonary hypertension (including pulmonary arterial hypertension as a secondary event; in some cases, the ILD has resolved upon discontinuation or dose reduction; risk may be increased as trough sirolimus concentration increases

            Safety and efficacy of de novo use of sirolimus without cyclosporine is not established in renal transplant patients; in a multicenter clinical study significantly higher acute rejection rates and numerically higher death rates compared to patients treated with cyclosporine, MMF, steroids, and IL-2 receptor antagonist reported; a benefit, in terms of better renal function, was not apparent in the treatment arm with de novo use of sirolimus without cyclosporine

            Drug interaction overview

            • Coadministration with live virus vaccines is contraindicated (see Black Box Warnings)
            • CYP3A4 inhibitors (including grapefruit juice) may increase whole blood levels
            • Coadministration of sirolimus with strong inhibitors of CYP3A4 and/or P-gp (eg, ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (eg, rifampin or rifabutin) not recommended
            • Concomitant use with a calcineurin inhibitor (eg, cyclosporine, tacrolimus, sirolimus) may increase risk of calcineurin inhibitor-induced hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, thrombotic microangiopathy, pancytopenia, or neutropenia
            • Live vaccines should be avoided during treatment; live vaccines may include, but are not limited to, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid; immunosuppressants may affect response to vaccination; during treatment, vaccination may be less effective
            • Renal function should be closely monitored during the coadministration with cyclosporine, because long-term administration of the combination has been associated with deterioration of renal function; appropriate adjustment of immunosuppressive regimen, including discontinuation of therapy and/or cyclosporine, should be considered in patients with elevated or increasing serum creatinine levels; in patients at low- to moderate-immunologic risk, continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when benefits outweigh risks of this combination for individual patients; exercise caution when using agents (eg, aminoglycosides and amphotericin B) that are known to have a deleterious effect on renal function; in patients with delayed graft function, therapy may delay recovery of renal function
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            Pregnancy & Lactation

            Pregnancy

            Can cause fetal harm when administered to pregnant women based on animal studies and the mechanism of action

            Animal studies

            • Reproductive studies in animals have demonstrated that sirolimus showed embryo/fetotoxicity manifested as mortality and reduced fetal weights (with associated delays in skeletal ossification) in rats when given doses ~0.2-0.5 the human dose

            Contraception

            • Females should not be pregnant or become pregnant while receiving sirolimus
            • Females of reproductive potential are recommended to use highly effective contraception methods during treatment and for 12 weeks after treatment has been stopped

            Infertility

            • Based on clinical findings and findings in animals, male and female fertility may be compromised by the treatment; ovarian cysts and menstrual disorders (including amenorrhea and menorrhagia) reported in females; azoospermia reported in males and has been reversible upon discontinuation in most cases

            Lactation

            Data are not available regarding the presence in human milk, the effects on breastfed infants, or the effects on milk production

            Sirolimus is excreted in trace amounts in milk of lactating rats Because many drugs are excreted in human milk, and because of the potential for adverse reactions in nursing infants from sirolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Inhibits T-cell activation and proliferation and inhibits antibody production that occurs in response to antigenic and cytokine stimulation; inhibits T- cell proliferation by inhibiting progression from the G1 to the S phase of the cell cycle

            Lymphangioleiomyomatosis

            • Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells)
            • Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors
            • Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells

            Absorption

            Bioavailability: 14% (oral solution); 41% (tablet)

            Peak Plasma Time: 1-3 hr (oral solution); 1-6 hr (tablet)

            Distribution

            Protein Bound: 92%

            Vd:12 L/kg

            Metabolism

            CYP3A4

            Elimination

            Half-Life: 2.5 days

            Excretion: feces (91%)

            Pharmacogenomics

            Rapamycins form complexes with an intracellular immunophillin (FKBP), which bind to a kinase called the mammalian target of rapamycin (mTOR)

            Intrinsic rapamycin resistance may be caused by genetic mutations identified for FKBP and mTOR genes

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            Administration

            Instructions

            Take consistently either with or without food

            Take 4 hr after cyclosporine

            Renal transplantation: Not to exceed 40 mg/day

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            Formulary

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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