Dosing and uses of Rapamune (sirolimus)
Adult dosage forms and 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 load
- ≥40 kg: 15 mg PO load
- 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 load
- ≥40 kg: 6 mg PO load
- 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
Pediatric dosage forms and 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)
Rapamune (sirolimus) adverse (side) 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
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
Pregnancy and 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.
Pharmacology of Rapamune (sirolimus)
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
Administration
Instructions
Take consistently either with or without food
Take 4 hr after cyclosporine
Renal transplantation: Not to exceed 40 mg/day
