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
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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%

Bone Sarcoma (Orphan)

Orphan sponsor

  • Merck Sharp & Dohme Corp; 126 E. Lincoln Avenue; Rahway, NJ 07065

Tuberous Sclerosis (Orphan)

Treatment of tuberous sclerosis complex

Orphan sponsor

  • OncoImmune, Inc; 333 Parkland Plaza, Suite 1000; Ann Arbor, MI 48103

Uveitis (Orphan)

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 (Orphan)

Orphan designation for treatment of pachyonychia congenita

Sponsor

  • TransDerm, Inc.; 2161 Delaware Avenue; Santa Cruz, CA 95060

Angiofibromas (Orphan)

Orphan designation for treatment of facial angiofibromas (FA) associated with tuberous sclerosis complex (TSC)

Sponsor

  • DSLP; 129 Hurstmere Road, Level 1, Nielsen Building; Auckland

Beta-Thalassemia (Orphan)

Orphan designation for treatment of beta-thalassemia

Sponsor

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

Pulmonary Arterial Hypertension (Orphan)

Orphan designation for treatment of pulmonary arterial hypertension

Sponsor

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

Dosage Forms & Strengths

tablet

  • 0.5mg
  • 1mg
  • 2mg

oral solution

  • 1mg/mL
more...

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

          Minor

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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

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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

            Ascites

            Not for liver or lung transplant

            Associated with increased renal dysfunction risk

            Dose-related incr risk of lymphocele

            Limit sun exposure because of increased skin cancer risk

            CYP3A4 inhibitors (including grapefruit juice) may increase whole blood levels

            Concomitant use with a calcineurin inhibitor (eg, cyclosporine, tacrolimus) may increase risk of calcineurin inhibitor induced HUS/TTP/TMA; pancytopenia, neutropenia

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

            Avoid pregnancy

            Lactation

            Increased risk of hypercholesterolemia and hypertriglyceridemia

            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

            Concomitant use of sirolimus with a calcineurin inhibitor may increase risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy

            Co-administration of sirolimus with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) not recommended

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            Pregnancy & Lactation

            Pregnancy Category: C

            Lactation: not known if excreted in breast milk; do not nurse

            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

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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