Sirolimus
FDA Drug Information • Also known as: Fyarro, Hyftor, Sirolimus
- Brand Names
- Fyarro, Hyftor, Sirolimus
- Dosage Form
- POWDER
- Product Type
- BULK INGREDIENT
⚠ Boxed Warning (Black Box)
WARNING: IMMUNOSUPPRESSION, USE IS NOT RECOMMENDED IN LIVER OR LUNG TRANSPLANT PATIENTS Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus for prophylaxis of organ rejection in patients receiving renal transplants. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [ see Warnings and Precautions (5.1 ) ] . The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended [ see Warnings and Precautions ( 5.2 , 5.3 ) ] . Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis (HAT) The use of 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 the time of death. In this and another study in de novo liver transplant patients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT; most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death [ see Warnings and Precautions (5.2 ) ]. Lung Transplantation – Bronchial Anastomotic Dehiscence Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen [ see Warnings and Precautions ( 5.3 ) ]. WARNING: IMMUNOSUPPRESSION, USE IS NOT RECOMMENDED IN LIVER OR LUNG TRANSPLANT PATIENTS See full prescribing information for complete boxed warning. Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression ( 5.1 ). Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus for prophylaxis of organ rejection in patients receiving renal transplants. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended ( 5.2 , 5.3 ). – Liver Transplantation – Excess mortality, graft loss, and hepatic artery thrombosis ( 5.2 ). – Lung Transplantation – Bronchial anastomotic dehiscence ( 5.3 ).
Description
11 DESCRIPTION Sirolimus is an mTOR inhibitor immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus . The chemical name of sirolimus (also known as rapamycin) is (3 S ,6 R ,7 E ,9 R ,10 R ,12 R ,14 S ,15 E ,17 E ,19 E ,21 S ,23 S ,26 R ,27 R ,34a S )-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1 R )-2-[(1 S ,3 R ,4 R )-4hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy3 H -pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4 H ,6 H ,31 H )-pentone. Its molecular formula is C 51 H 79 NO 13 and its molecular weight is 914.2. The structural formula of sirolimus is illustrated as follows. Sirolimus is a white to off-white powder Freely soluble in Chloroform, acetone, methanol, methylene dichloride and acetonitrile. Soluble in ethanol and ethyl acetate. Insoluble in water. Sirolimus is available for administration as an oral solution containing 1 mg/mL sirolimus. The inactive ingredients in sirolimus oral solution are Phosal 50 PG ® (phosphatidylcholine, propylene glycol, sunflower seed oil glyceride, ethanol, soy fatty acids, ascorbyl palmitate and tocopherol) and polysorbate 80. Sirolimus oral solution contains 1.5% - 2.5% ethanol. sirolimus-structure
What Is Sirolimus Used For?
1 INDICATIONS AND USAGE Sirolimus oral solution is an mTOR inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in patients aged ≥13 years receiving renal transplants: Patients at low- to moderate-immunologic risk: Use initially with cyclosporine (CsA) and corticosteroids. CsA withdrawal is recommended 2-4 months after transplantation ( 1.1 ). Patients at high-immunologic risk: Use in combination with CsA and corticosteroids for the first 12 months following transplantation ( 1.1 ). Safety and efficacy of CsA withdrawal has not been established in high risk patients ( 1.1 , 1.2 , 14.3 ). Sirolimus oral solution is an mTOR inhibitor indicated for the treatment of patients with lymphangioleiomyomatosis ( 1.3 ). 1.1 Prophylaxis of Organ Rejection in Renal Transplantation Sirolimus oral solution is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. In patients at low-to moderate-immunologic risk , it is recommended that sirolimus oral solution be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation [ see Dosage and Administration ( 2.2 ) ]. In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level >80%]), it is recommended that sirolimus oral solution be used in combination with cyclosporine and corticosteroids for the first year following transplantation [ see Dosage and Administration ( 2.3 ) , Clinical Studies ( 14.3 ) ]. 1.2 Limitations of Use in Renal Transplantation Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those with serum creatinine >4.5 mg/dL, Black patients, patients of multi-organ transplants, secondary transplants, or those with high levels of panel-reactive antibodies [ see Clinical Studies ( 14.2 ) ]. In patients at high-immunologic risk , the safety and efficacy of sirolimus used in combination with cyclosporine and corticosteroids has not been studied beyond one year; therefore after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient [ see Clinical Studies ( 14.3 ) ]. In pediatric patients , the safety and efficacy of sirolimus have not been established in patients <13 years old, or in pediatric (<18 years) renal transplant patients considered at high-immunologic risk [ see Adverse Reactions ( 6.5 ), Clinical Studies ( 14.6 ) ]. The safety and efficacy of de novo use of sirolimus without cyclosporine have not been established in renal transplant patients [ see Warnings and Precautions ( 5.12 ) ]. The safety and efficacy of conversion from...
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Sirolimus oral solution is to be administered orally once daily, consistently with or without food [ see Dosage and Administration ( 2.5 ), Clinical Pharmacology ( 12.3 ) ]. Renal Transplant Patients: Administer once daily by mouth, consistently with or without food ( 2 ). Administer the initial dose as soon as possible after transplantation and 4 hours after CsA ( 2.1 , 7.1 ). Adjust the sirolimus maintenance dose to achieve sirolimus trough concentrations within the target-range ( 2.5 ). Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment ( 2.7 , 8.6 , 12.3 ). In renal transplant patients at low-to moderate-immunologic risk : Sirolimus oral solution and CsA Combination Therapy: One loading dose of 6 mg on day 1, followed by daily maintenance doses of 2 mg ( 2.2 ). Sirolimus oral solution Following CsA Withdrawal: 2-4 months post-transplantation, withdraw CsA over 4-8 weeks ( 2.2 ). In renal transplant patients at high-immunologic risk: Sirolimus oral solution and CsA Combination Therapy (for the first 12 months post-transplantation): One loading dose of up to 15 mg on day 1, followed by daily maintenance doses of 5 mg ( 2.3 ). Lymphangioleiomyomatosis Patients: Administer once daily by mouth, consistently with or without food ( 2 ). Recommended initial sirolimus oral solution dose is 2 mg/day ( 2.4 ). Adjust the sirolimus oral solution dose to achieve sirolimus trough concentrations between 5-15 ng/mL ( 2.4 ). Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment ( 2.7 , 8.6 , 12.3 ). Therapeutic drug monitoring is recommended for all patients ( 2.5 , 5.17 ). 2.1 General Dosing Guidance for Renal Transplant Patients The initial dose of sirolimus oral solution should be administered as soon as possible after transplantation. It is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [ see Drug Interactions ( 7.2 ) ]. Frequent sirolimus oral solution dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. In most patients, dose adjustments can be based on simple proportion: new sirolimus oral solution dose = current dose x (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dose when it is necessary to increase sirolimus trough concentrations: sirolimus oral solution loading dose = 3 x (new maintenance dose - current maintenance dose). The maximum sirolimus oral solution dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label. Increased susceptibility to infection, lymphoma, and malignancy [ see Boxed Warning , Warnings and Precautions ( 5.1 ) ] Excess mortality, graft loss, and hepatic artery thrombosis in liver transplant patients [ see Boxed Warning , Warnings and Precautions ( 5.2 ) ] Bronchial anastomotic dehiscence in lung transplant patients [ see Boxed Warning , Warnings and Precautions ( 5.3 ) ] Hypersensitivity reactions [ see Warnings and Precautions ( 5.4 ) ] Exfoliative dermatitis [ see Warnings and Precautions ( 5.4 ) ] Angioedema [ see Warnings and Precautions ( 5.5 ) ] Fluid accumulation and impairment of wound healing [ see Warnings and Precautions ( 5.6 ) ] Hypertriglyceridemia, hypercholesterolemia [ see Warnings and Precautions ( 5.7 ) ] Decline in renal function in long-term combination of cyclosporine with sirolimus [ see Warnings and Precautions ( 5.8 ) ] Proteinuria [ see Warnings and Precautions ( 5.9 ) ] Interstitial lung disease [ see Warnings and Precautions ( 5.11 ) ] Increased risk of calcineurin inhibitor-induced HUS/TTP/TMA [ see Warnings and Precautions ( 5.13 ) ] Embryo-fetal toxicity [ see Warnings and Precautions ( 5.15 ) ] Male infertility [ see Warnings and Precautions ( 5.16 ) ] The most common (≥30%) adverse reactions observed with sirolimus in clinical studies for organ rejection prophylaxis in recipients of renal transplantation are: peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia. The most common (≥20%) adverse reactions observed with sirolimus in the clinical study for the treatment of LAM are: stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia. The following adverse reactions resulted in a rate of discontinuation of >5% in clinical trials for renal transplant rejection prophylaxis: creatinine increased, hypertriglyceridemia, and TTP. In patients with LAM, 11% of subjects discontinued due to adverse reactions, with no single adverse reaction leading to discontinuation in more than one patient being treated with sirolimus. Prophylaxis of organ rejection in patients receiving renal transplants: Most common adverse reactions (incidence ≥30%) are peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia ( 6 ). Lymphangioleiomyomatosis: Most common adverse reactions (incidence ≥20%) are stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia ( 6.6 ). To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience in Prophylaxis of Organ Rejection Following Renal Transplantation The safety and efficacy of Sirolimus oral solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials [ see Clinical Studies ( 14.1 ) ]. The safety profiles in the two studies were similar. The incidence of adverse reactions in the randomized, double-blind, multicenter, placebo-controlled trial (Study 2) in which 219 renal transplant patients received sirolimus oral solution 2 mg/day, 208 received sirolimus oral solution 5 mg/day, and 124 received placebo is presented in Table 1 below. The study population had a mean age of 46 years (range 15 to 71 years), the distribution was 67% male, and the composition by...
Drug Interactions
7 DRUG INTERACTIONS Sirolimus is known to be a substrate for both cytochrome P-450 3A4 (CYP3A4) and p-glycoprotein (P-gp). Inducers of CYP3A4 and P-gp may decrease sirolimus concentrations whereas inhibitors of CYP3A4 and P-gp may increase sirolimus concentrations. Avoid concomitant use with strong CYP3A4/P-gp inducers or strong CYP3A4/P-gp inhibitors that decrease or increase sirolimus concentrations ( 7.4 , 12.3 ). Therapeutic drug monitoring and dose reduction for sirolimus should be considered when sirolimus is co-administered with cannabidiol ( 5.21 , 7.5 ). See full prescribing information for complete list of clinically significant drug interactions ( 12.3 ). 7.1 Use with Cyclosporine Cyclosporine, a substrate and inhibitor of CYP3A4 and P-gp, was demonstrated to increase sirolimus concentrations when co-administered with sirolimus. In order to diminish the effect of this interaction with cyclosporine, it is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). If cyclosporine is withdrawn from combination therapy with sirolimus, higher doses of sirolimus are needed to maintain the recommended sirolimus trough concentration ranges [ see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 ) ]. 7.2 Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of CYP3A4 and P-gp. Alternative agents with lesser interaction potential with sirolimus should be considered [ see Warnings and Precautions ( 5.20 ), Clinical Pharmacology ( 12.3 ) ]. 7.3 Grapefruit Juice Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with or be used for dilution of sirolimus [ see Dosage and Administration ( 2.9 ), Drug Interactions ( 7.3 ), Clinical Pharmacology ( 12.3 ) ]. 7.4 Weak and Moderate Inducers or Inhibitors of CYP3A4 and P-gp Exercise caution when using sirolimus with drugs or agents that are modulators of CYP3A4 and P-gp. The dosage of sirolimus and/or the co-administered drug may need to be adjusted [see Clinical Pharmacology ( 12.3 )].
Contraindications
4 CONTRAINDICATIONS Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus [ see Warnings and Precautions ( 5.4 ) ].
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Based on animal studies and the mechanism of action, sirolimus can cause fetal harm when administered to a pregnant woman [ see Data, Clinical Pharmacology ( 12.1 ) ]. There are limited data on the use of sirolimus during pregnancy; however, these data are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal studies, sirolimus was embryo/fetotoxic in rats at sub-therapeutic doses [ see Data ]. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Sirolimus crossed the placenta and was toxic to the conceptus. In rat embryo-fetal development studies, pregnant rats were administered sirolimus orally during the period of organogenesis (Gestational Day 6-15). Sirolimus produced embryo-fetal lethality at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg, on a body surface area basis) and reduced fetal weight at 1 mg/kg (5-fold the clinical dose of 2 mg). The no observed adverse effect level (NOAEL) for fetal toxicity in rats was 0.1 mg/kg (0.5-fold the clinical dose of 2 mg). Maternal toxicity (weight loss) was observed at 2 mg/kg (10-fold the clinical dose of 2 mg). The NOAEL for maternal toxicity was 1 mg/kg. In combination with cyclosporine, rats had increased embryo-fetal mortality compared with sirolimus alone. In rabbit embryo-fetal development studies, pregnant rabbits were administered sirolimus orally during the period of organogenesis (Gestational Day 6-18). There were no effects on embryo-fetal development at doses up to 0.05 mg/kg (0.5-fold the clinical dose of 2 mg, on a body surface area basis); however, at doses of 0.05 mg/kg and above, the ability to sustain a successful pregnancy was impaired (i.e.,...
Overdosage
10 OVERDOSAGE Reports of overdose with sirolimus have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section [ see Adverse Reactions ( 6 ) ]. General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD 50 was greater than 800 mg/kg.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Since sirolimus oral solution is not absorbed through the skin, there are no special precautions. However, if direct contact of the oral solution occurs with the skin or eyes, wash skin thoroughly with soap and water; rinse eyes with plain water. Do not use sirolimus oral solution after the expiration date. The expiration date refers to the last day of that month. 16.1 Sirolimus Oral Solution Sirolimus oral solution, 1 mg/mL is available as a yellow or yellow to brown liquid. Each sirolimus oral solution carton, NDC 72205-099-78, contains one 2 oz (60 mL fill) amber glass bottle of sirolimus (concentration of 1 mg/mL), one oral syringe adapter for fitting into the neck of the bottle, sufficient disposable oral syringes (amber color) and caps for daily dosing, and a carrying case. Sirolimus oral solution bottles should be stored protected from light and refrigerated at 2°C to 8°C (36°F to 46°F). Once the bottle is opened, the contents should be used within one month. If necessary, the patient may store the bottles at room temperatures up to 25°C (77°F) for a short period of time (e.g., not more than 15 days for the bottles). A syringe (amber color) and cap are provided for dosing, and the product may be kept in the syringe for a maximum of 24 hours at room temperatures up to 25°C (77°F) or refrigerated at 2°C to 8°C (36°F to 46°F). The syringe should be discarded after one use. After dilution, the preparation should be used immediately. Sirolimus oral solution provided in bottles may develop a slight haze when refrigerated. If such a haze occurs, allow the product to stand at room temperature and shake gently until the haze disappears. The presence of this haze does not affect the quality of the product.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.