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Sirolimus 2 mg Tablet, Sugar Coated, 100-count — NDC 59762-1003-01 package photo

Sirolimus 2 mg Tablet, Sugar Coated, 100-count

by Mylan Pharmaceuticals Inc. · 100 TABLET, SUGAR COATED in 1 BOTTLE (59762-1003-1)
NDC 59762-1003-01
🏷️ FDA NDC (as labeled) 59762-1003-1 billing pads the package segment with a zero
Rx only Brand On market Non-controlled
🗂️ Data synced Jul 24, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

This page is curated, coded, and maintained by

Compiled from public FDA, CMS, DailyMed, NADAC, and related drug data sources. Editorial policy

⚠️
Other active recalls for Sirolimus (different manufacturers) — 1 · tap to view
These affect other manufacturers’ products for the same ingredient — not necessarily the exact NDC on this page.
Class III · May 1, 2024 — Failed Impurities/Degradation Specifications (Dr. Reddy's Laboratories, Inc.) · FDA recall D-0504-2024
Each entry is an official FDA enforcement report — look up any recall number in the FDA recall database ↗

🆔 Identity & classification

FDA NDC (as labeled) 59762-1003-1
Product NDC 59762-1003
11-digit billing NDC 59762100301
NCPDP billing unit EA — each (per item)
RxCUI 349208, 360110, 905158
UNII W36ZG6FT64
Application # NDA021110
SPL Set ID 5908cd1a-fc5a-462f-99ed-1d8983e253c9
Established class (EPC) mTOR Inhibitor Immunosuppressant; Kinase Inhibitor
Mechanism of action mTOR Inhibitors; Protein Kinase Inhibitors
Physiologic effect Decreased Immunologic Activity
DEA schedule Non-controlled
Marketing category NDA AUTHORIZED GENERIC
Marketing status On market
FDA listing status Listed (active directory)
Marketing start 2014-10-27
Route ORAL
Dosage form TABLET, SUGAR COATED
Substance SIROLIMUS
GPI-14 99404070000330
GPI class Sirolimus
GCN Seq No 051878
GCN 19299
HICL code 020519
Ingredient (HICL) Sirolimus
HIC1 code Z
Therapeutic class — broad (HIC1) Body As A Whole
HIC2 code Z2
Therapeutic class — intermediate (HIC2) Antihistamines, Antiserotonins, Immunosuppressants
HIC3 code Z2E
Therapeutic class — specific (HIC3) Immunosuppressives
AHFS code 84:06.28.00
AHFS class Immunomodulatory Agents (84:06)
FDB label name SIROLIMUS 2 MG TABLET
FDB brand name Sirolimus
Legend status F — Federal legend — prescription drug or device
TE code (Orange Book) AB · RLD · RS
Why two NDCs? The FDA registers this code as 59762-1003-1 — a 5-4-1 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the package segment → 59762-1003-01. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

🏷️ RxNorm drug class

This medicine belongs to the Kinase Inhibitor class.

Pharmacologic class Kinase Inhibitor, mTOR Inhibitor Immunosuppressant
Drug family (ATC) Mammalian target of rapamycin (mTOR) kinase inhibitors, Mammalian target of rapamycin (mTOR) kinase inhibitors, Other ophthalmologicals
How it works Protein Kinase Inhibitors, mTOR Inhibitors
Where does this data come from?
Therapeutic classes from RxNorm RxClass (U.S. National Library of Medicine) — Established Pharmacologic Class (FDA), ATC drug family (WHO) and mechanism of action, matched by this product’s RxCUI.

🏭 Manufacturer & labeler

LabelerMylan Pharmaceuticals Inc.
Application holderPF PRISM CV
FDA applicationNDA021110 (NDA AUTHORIZED GENERIC)
Labeler code59762
First marketedOct 2014
Product typeHuman Prescription Drug
Portfolio473 products on file
The labeler markets the product; the application holder owns the FDA approval. They’re often the same company but can differ (e.g. a repackager or an authorized generic). A mailing address / phone appears here when the manufacturer includes it in the product’s FDA label (not all do).
Where does this data come from?
Labeler, application holder and registered establishment from the FDA openFDA NDC Directory and Drugs@FDA; address/contact from the product’s FDA label.

🩺 Clinical

Label name SIROLIMUS 2 MG TABLET Ingredient Sirolimus
📖 What it is MedlinePlus · NLM

Sirolimus is used in combination with other medications to prevent rejection of kidney transplants. It is also used to treat lymphangioleiomyomatosis (LAM; a rare lung condition). Sirolimus is in a class of medications called immunosuppressants. It works by suppressing the body's immune system.

Read the full MedlinePlus article ↗
📗 Our plain-language guide HelloPharmacist
  • Sirolimus comes in a few different forms, and each one has its own approved use. The oral tablets and liquid are mainly used to prevent kidney transplant rejection and to treat a r...
  • What exactly is sirolimus being used for — I've seen it listed for so many different things?
  • Yes, it matters — but not in the way you might think. You don't have to eat with it, but you do need to be consistent. Food, especially a high-fat meal, can increase how much sirol...
  • Does it matter if I take my oral sirolimus with food or without?
📖 Read our full Sirolimus guide →
Where does this data come from?
Plain-language summary from MedlinePlus (U.S. National Library of Medicine); supplement & herbal interactions and nutrient depletion data from the Natural Medicines database; our full guide is HelloPharmacist editorial content.

💊 What it looks like

Color Brown / White / Yellow
ShapeTriangle
ImprintRAPAMUNE;2;MG
Size8 mm
ScoringNot scored
One label can cover several strengths, so colors may be combined — always confirm a loose pill against the dispensed prescription label or a pharmacist.
Where does this data come from?
Physical description (imprint, shape, color, scoring, coating) from this product’s FDA Structured Product Labeling (SPL), mirrored from DailyMed / openFDA.

🧪 Inactive Ingredients / Excipients

Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.

💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.

  • UNII 9E8X80D2L0
    A synthetic form of vitamin E used as an antioxidant and preservative in medications. It helps prevent the active ingredients from degrading when exposed to oxygen or light.
  • UNII WAT0DDB505
    Calcium sulfate is a mineral compound used as a filler and binder in tablets and capsules. It helps give the medicine its solid structure and ensures consistent dosing.
  • UNII R12CBM0EIZ
    A natural wax derived from a Brazilian palm tree, used as a coating and polish on tablets and capsules. It creates a smooth, shiny finish that protects the medicine and improves appearance.
  • UNII 4PC054V79P
    A fatty acid derived from glycerin and oleic acid (a natural oil component). It acts as an emulsifier to help mix oil and water-based ingredients, and serves as a lubricant and surfactant in the formulation.
  • UNII EWQ57Q8I5X
    Lactose monohydrate is a natural sugar derived from milk. It serves as a filler and binder in tablets and capsules, helping create the proper size, texture, and consistency of the medicine.
  • UNII 70097M6I30
    Magnesium stearate is a salt made from magnesium and stearic acid, a fatty substance. It's used in tablets and capsules as a lubricant and glidant to help ingredients flow smoothly during manufacturing and prevent sticking.
  • UNII OP1R32D61U
    Microcrystalline cellulose is a purified form of cellulose, a natural fiber from plant sources. It acts as a binder and filler in tablets and capsules, helping hold ingredients together and give the medicine its shape and size.
  • UNII LQA7B6G8JG
    A synthetic polymer made by combining water-soluble compounds. It acts as a surfactant and solubilizer to help mix oil and water-based ingredients, improving the medicine's texture and how active ingredients dissolve.
  • UNII Q662QK8M3B
    Polyethylene glycol 8000 is a synthetic polymer made from ethylene oxide. It acts as a binder and filler in tablets and capsules, helping hold ingredients together and add bulk to the medicine.
  • UNII U725QWY32X
    Povidone K30 is a synthetic polymer made from petroleum. It acts as a binder to hold tablet ingredients together and as a disintegrant to help the tablet break apart in the stomach so the medicine can be absorbed.
  • UNII C151H8M554
    A natural sugar derived from sugar cane or sugar beets. It's used as a sweetener, filler, and binder to improve taste, add bulk, and help hold tablet or capsule ingredients together.
  • UNII 7SEV7J4R1U
    A powder made from a naturally occurring mineral. In medicines, talc works as a glidant and anti-caking agent, helping tablets and capsules flow smoothly during manufacturing and preventing clumping.
  • UNII 15FIX9V2JP
    Titanium dioxide is a bright white mineral powder commonly used as a colorant and opacifying agent. It makes pills and tablets white or lighter in color and helps make coatings non-transparent.

13 inactive ingredients listed in the exact product block matched to this NDC.

Where does this data come from?
Data sourced from official FDA Structured Product Labeling (SPL) via DailyMed — ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.

Inactive ingredient FAQ

Are inactive ingredients the same for every manufacturer?
No. Inactive ingredients can differ by manufacturer, dosage form, strength, and package / product version.
Why might an inactive ingredient be missing?
Some SPLs do not provide a complete structured inactive-ingredient list, and older or unusual labels may only include the information in narrative text.
Can inactive ingredients matter?
Yes. They can matter for allergies, intolerances, dyes, gluten / lactose concerns, preservatives, and formulation differences — but confirm with a pharmacist or the manufacturer when it’s clinically important.

💲 Pricing

A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.

Price systemPer eaPer package
Retail pharmacies payNADAC · weekly $2.641 $264.13 / 100 tablets
Medicaid paysCMS SDUD · 12 mo No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data.
Medicare drug plans payPart D · Q2 2026 $3.75 $375.42 / 100 tablets
Medicare Part B allowsASP · J7520 $0.744 / J7520 unit —
NADAC price history (per ea) — tap or hover for the price & month
Dec 2023 Feb 2026 May 2026 Aug 2026 $4.938 $2.641
▼ Down 47% over the last 10 months.
Where does this data come from?
NADAC (National Average Drug Acquisition Cost) is the CMS weekly pharmacy-acquisition-cost survey — what pharmacies pay. ASP (Average Sales Price) is the CMS Medicare Part B drug-payment file, published quarterly. Medicaid pays is computed by us from CMS State Drug Utilization Data (total reimbursed ÷ units, trailing 12 months) — gross of rebates and inclusive of dispensing fees, so it reflects what Medicaid paid, not an acquisition cost. Medicare drug plans pay is the median negotiated point-of-sale unit cost across plans listing this NDC in the CMS quarterly Prescription Drug Plan pricing files, before rebates. The VA pays is the federal contract price (FSS, and the statutory Big 4 ceiling where listed) from the VA National Acquisition Center pharmaceutical price file. All are free public government data; each measures a different payer, so the figures are not directly comparable.

🧾 Billing & reimbursement

FDA NDC (as labeled)59762-1003-1
11-digit billing NDC59762-1003-01
Format5-4-1 as registered → padded to 5-4-2 for billing (zero added to the package segment)
HCPCS J-codeJ7520
DescriptorSIROLIMUS, ORAL, 1 MG
Billing units / pkg2 units
Crosswalk sourcePDAC NDC-HCPCS crosswalk (DME MAC / DMEPOS)
Where does this data come from?
The HCPCS J-code crosswalk comes from the CMS ASP NDC-HCPCS crosswalk and the DMEPDAC (DME MAC) NDC-HCPCS crosswalk — free public CMS data. Billing units are derived from the code’s descriptor and the package amount.

🔁 Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
sirolimus 2 mg 16714-0189-01 NORTHSTAR 100 tablets $2.641 AB Availability likely —
Sirolimus 2 mg 55111-0654-01 Dr. 100 tablets $2.641 AB Availability likely —
Sirolimus 2 mgthis 59762-1003-01 Mylan 100 tablets $2.641 AB Availability likely —
Sirolimus 2 mg 67877-0748-01 Ascend 100 tablets $2.641 AB Availability likely —
sirolimus 2 mg 68382-0352-01 Zydus 100 tablets $2.641 AB Availability likely —
sirolimus 2 mg 68462-0684-01 Glenmark 100 tablets $2.641 AB Availability likely —
sirolimus 2 mg 65841-0773-01 Zydus 100 tablets — AB FDA listed —
About this product: this is an authorized generic — the brand-name product marketed without its brand name. Other versions are listed above, least expensive first.
Where does this data come from?
Equivalents are other NDCs of the same ingredient, form and route from the openFDA NDC Directory, ranked least-expensive-first by NADAC. Therapeutic-equivalence (AB) ratings come from the FDA Orange Book; biologics use the FDA Purple Book for biosimilar & interchangeable status.

⏳ Availability & generic status

🏛️
2014
On the market since
Oct 2014
📍
2026
Currently FDA-listed
12 years listed
🔓
·
Generic versions listed
see equivalents
✅Generic appears available

FDA-approved generic versions are listed, and recent pricing/market data suggests they may be available — see Therapeutic equivalents.

Where does this data come from?
Patents and exclusivity from the FDA Orange Book (small-molecule drugs), refreshed from public FDA data. Generic launch timing is an estimate, not a guarantee.

📊 Medicare Part D spend CMS · PART D · 2026 (Q1)

Medicare Part D (outpatient prescription) spending for Sirolimus — the program that covers self-administered drugs. 11 manufacturers.
⚠️ Drug-level data: CMS publishes Part D spending by drug, not by NDC — these figures combine every manufacturer, strength and package size sold under the name Sirolimus. That’s a different level of aggregation than the Medicaid card above, which is specific to this exact 11-digit NDC (pack size included), so the two aren’t directly comparable.
Period
Total Part D spend
$3.98M
Claims incl. refills
12.6K
Beneficiaries
6.3K
Spend / beneficiary
$630.81
Spend / claim
$314.93
Trend by period
💵 About the dollar figures: spending is what Part D plans paid before confidential manufacturer rebates, so the program’s real net cost is lower. A blank patient count means fewer than 11 people — CMS hides counts that small to protect privacy. Source: CMS Medicare Quarterly Part D Spending by Drug (data.cms.gov), updated quarterly.

🔬 Reported adverse events (FAERS)

Read carefully: FAERS reports are voluntary and unverified. Counts are not incidence, do not establish causation, are subject to reporting bias, and cannot be used to compare one drug to another. Shown for signal context only. Reports for Sirolimus — the ingredient across all brands.

Top reported reactions

Pyrexia525
Diarrhoea515
Pneumonia487
Drug Interaction448
Acute Kidney Injury435
Thrombotic Microangiopathy376
Transplant Rejection372

Age at onset

Neonate67
Infant167
Child317
Adolescent188
Adult1,256
Elderly309

Reporter sex

13,394 reports
Male · 57%
Female · 43%
Unknown · 0%

Serious outcomes

Hospitalization4,563
Death2,151
Life-threatening976
Disabling94
Reports over time (by year) — tap or hover for the count & year
2019 2021 2023 2026 1,239 0
Most recent year is provisional (FAERS lags ~3 months).
Where does this data come from?
Adverse-event reports from the FDA Adverse Event Reporting System (FAERS) via openFDA. FAERS reports are voluntary and unverified — counts are not incidence and don’t establish causation.

📦 Packaging — all sizes for this product

Package NDCDescription Marketing startStatus
59762-1003-01 You're viewing this 100 TABLET, SUGAR COATED in 1 BOTTLE (59762-1003-1) 2014-10-27 Active

📄 Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. Jump with a chip, search within the label, or expand everything.
🚨 Boxed Warning 🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 🔄 Drug Interactions 👥 Use in Specific Populations 🤰 Pregnancy 🧒 Pediatric Use 🧓 Geriatric Use 🆘 Overdosage 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📦 Storage and Handling 📋 Description 💬 Information for Patients 💬 Medication Guide
🚨 Boxed Warning ~2 min read ▾

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 ).

🎯 Indications and Usage ~2 min read ▾

1 INDICATIONS AND USAGE Sirolimus 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 is an mTOR inhibitor indicated for the treatment of patients with lymphangioleiomyomatosis ( 1.3 ).

1.1Prophylaxis of Organ Rejection in Renal Transplantation Sirolimus 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 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 be used in combination with cyclosporine and corticosteroids for the first year following transplantation [ see Dosage and Administration (2.3) , Clinical Studies (14.3) ].

1.2Limitations 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 calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established [ see Clinical Studies (14.4) ].

1.3Treatment of Patients with Lymphangioleiomyomatosis Sirolimus is indicated for the treatment of patients with lymphangioleiomyomatosis (LAM).

⏱️ Dosage and Administration ~3 min read ▾

2 DOSAGE AND ADMINISTRATION Sirolimus is to be administered orally once daily, consistently with or without food [ see Dosage and Administration (2.5) , Clinical Pharmacology (12.3) ]. Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be prescribed the solution and instructed in its use.

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 and CsA Combination Therapy: One loading dose of 6 mg on day 1, followed by daily maintenance doses of 2 mg ( 2.2 ). • Sirolimus 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 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 dose is 2 mg/day ( 2.4 ). • Adjust the sirolimus 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 ).

2.1General Dosing Guidance for Renal Transplant Patients The initial dose of sirolimus 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 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 dose = current dose × (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 loading dose = 3 × (new maintenance dose - current maintenance dose).

The maximum sirolimus 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 administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).

Two milligrams (2 mg) of sirolimus oral solution have been demonstrated to be clinically equivalent to 2 mg sirolimus tablets; hence, at this dose these two formulations are interchangeable. However, it is not known if higher doses of sirolimus oral solution are clinically equivalent to higher doses of sirolimus tablets on a mg-to-mg basis [ see Clinical Pharmacology (12.3) ].

2.2Renal Transplant Patients at Low- to Moderate-Immunologic Risk Sirolimus and Cyclosporine Combination Therapy For de novo renal transplant patients, it is recommended that sirolimus tablets be used initially in a regimen with cyclosporine and corticosteroids. A loading dose of sirolimus equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance dose of 2 mg should be preceded with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain siroli…

💊 Dosage Forms and Strengths 58 words ▾

3 DOSAGE FORMS AND STRENGTHS • Tablets: 0.5 mg, 1 mg, 2 mg ( 3.1 ).

3.1Sirolimus Tablets • 0.5 mg, tan, triangular-shaped tablets marked "RAPAMUNE 0.5 mg" on one side. • 1 mg, white, triangular-shaped tablets marked "RAPAMUNE 1 mg" on one side. • 2 mg, yellow-to-beige triangular-shaped tablets marked "RAPAMUNE 2 mg" on one side.

⛔ Contraindications 25 words ▾

4 CONTRAINDICATIONS Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus [ see Warnings and Precautions (5.4) ]. Hypersensitivity to sirolimus ( 4 ).

⚠️ Warnings and Cautions ~3 min read ▾

5 WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions ( 5.4 ) • Angioedema ( 5.5 ) • Fluid Accumulation and Impairment of Wound Healing ( 5.6 ) • Hyperlipidemia ( 5.7 ) • Decline in Renal Function ( 5.8 ) • Proteinuria ( 5.9 ) • Latent Viral Infections ( 5.10 ) • Interstitial Lung Disease/Non-Infectious Pneumonitis ( 5.11 ) • De Novo Use Without Cyclosporine ( 5.12 ) • Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic Syndrome/ Thrombotic Thrombocytopenic Purpura/ Thrombotic Microangiopathy ( 5.13 ) • Embryo-Fetal Toxicity: Can cause fetal harm.

Use of highly effective contraception is recommended for females of reproductive potential during treatment and for 12 weeks after final dose of sirolimus ( 5.15 , 8.1 ) • Male Infertility: Azoospermia or oligospermia may occur ( 5.16 , 13.1 ) • Immunizations: Avoid live vaccines ( 5.19 )

5.1Increased Susceptibility to Infection and the Possible Development of Lymphoma Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression. The rates of lymphoma/lymphoproliferative disease observed in Studies 1 and 2 were 0.7–3.2% (for sirolimus -treated patients) versus 0.6–0.8% (azathioprine and placebo control) [ see Adverse Reactions (6.1) and (6.2) ]. Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections, and sepsis.

Only physicians experienced in immunosuppressive therapy and management of organ 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.

5.2Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended. The use of sirolimus has been associated with adverse outcomes in patients following liver transplantation, including excess mortality, graft loss and hepatic artery thrombosis (HAT). In a study in de novo liver transplant patients, the use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss (22% in combination versus 9% on tacrolimus alone).

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 (7% in combination versus 2% in the control arm); most cases of HAT occurred within 30 days post-transplantation, and most led to graft loss or death. In a clinical study in stable liver transplant patients 6–144 months post-liver transplantation and receiving a CNI-based regimen, an increased number of deaths was observed in the group converted to a sirolimus-based regimen compared to the group who was continued on a CNI-based regimen, although the difference was not statistically significant (3.8% versus 1.4%) [ see Clinical Studies (14.5) ].

5.3Lung 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. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended.

5.4Hypersensitivity Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, have been associated w…

🤒 Adverse Reactions ~2 min read ▾

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 Greenstone LLC Professional Information Services at 1-877-446-3679 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1Clinical 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 th…

🔄 Drug Interactions ~2 min read ▾

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 ).

7.1Use 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) ].

7.2Strong 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) ].

7.3Grapefruit Juice Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with sirolimus [ see Clinical Pharmacology (12.3) ].

7.4Weak 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) ]. • Drugs that could increase sirolimus blood concentrations: Bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, letermovir, protease inhibitors (e.g., HIV and hepatitis C that include drugs such as ritonavir, indinavir, boceprevir, and telaprevir), metoclopramide, nicardipine, troleandomycin, verapamil • Drugs and other agents that could decrease sirolimus concentrations: Carbamazepine, phenobarbital, phenytoin, rifapentine, St.

John's Wort ( Hypericum perforatum ) • Drugs with concentrations that could increase when given with sirolimus: Verapamil

7.5Cannabidiol The blood levels of sirolimus may increase upon concomitant use with cannabidiol. When cannabidiol and sirolimus are co-administered, closely monitor for an increase in sirolimus blood levels and for adverse reactions suggestive of sirolimus toxicity. A dose reduction of sirolimus should be considered as needed when sirolimus is co-administered with cannabidiol [ see Dosage and Administration (2.5) , Warnings and Precautions (5.21) ].

👥 Use in Specific Populations ~3 min read ▾

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data can cause fetal harm ( 5.15 , 8.1 ). • Lactation: Potential for serious adverse effects in breastfed infants based on mechanism of action ( 8.2 ). • Females and Males of Reproductive Potential: May impair fertility ( 8.1 , 8.3 , 13.1 ).

8.1Pregnancy 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., embryo-fetal abortion or early resorption).

Maternal toxicity (decreased body weight) was observed at 0.05 mg/kg. The NOAEL for maternal toxicity was 0.025 mg/kg (0.25-fold the clinical dose of 2 mg). In a pre- and post-natal development study in rats, pregnant females were dosed during gestation and lactation (Gestational Day 6 through Lactation Day 20).

An increased incidence of dead pups, resulting in reduced live litter size, occurred at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg/kg on a body surface area basis). At 0.1 mg/kg (0.5-fold the clinical dose of 2 mg), there were no adverse effects on offspring. Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg, the highest dose tested.

8.2Lactation Risk Summary It is not known whether sirolimus is present in human milk. There are no data on its effects on the breastfed infant or milk production. The pharmacokinetic and safety profiles of sirolimus in infants are not known.

Sirolimus is present in the milk of lactating rats. There is potential for serious adverse effects from sirolimus in breastfed infants based on mechanism of action [ see Clinical Pharmacology (12.1) ] . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for sirolimus and any potential adverse effects on the breastfed child from sirolimus.

8.3Females and Males of Reproductive Potential Contraception Females should not be pregnant or become pregnant while receiving sirolimus. Advise females of reproductive potential that animal studies have been…

🤰 Pregnancy ~2 min read ▾

8.1Pregnancy 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., embryo-fetal abortion or early resorption).

Maternal toxicity (decreased body weight) was observed at 0.05 mg/kg. The NOAEL for maternal toxicity was 0.025 mg/kg (0.25-fold the clinical dose of 2 mg). In a pre- and post-natal development study in rats, pregnant females were dosed during gestation and lactation (Gestational Day 6 through Lactation Day 20).

An increased incidence of dead pups, resulting in reduced live litter size, occurred at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg/kg on a body surface area basis). At 0.1 mg/kg (0.5-fold the clinical dose of 2 mg), there were no adverse effects on offspring. Sirolimus did not cause maternal toxicity or affect developmental parameters in the surviving offspring (morphological development, motor activity, learning, or fertility assessment) at 0.5 mg/kg, the highest dose tested.

🧒 Pediatric Use 219 words ▾

8.4Pediatric Use Renal Transplant The safety and efficacy of sirolimus in pediatric patients <13 years have not been established. The safety and efficacy of sirolimus oral solution and sirolimus tablets have been established for prophylaxis of organ rejection in renal transplantation in children ≥13 years judged to be at low- to moderate-immunologic risk. Use of sirolimus oral solution and sirolimus tablets in this subpopulation of children ≥13 years is supported by evidence from adequate and well-controlled trials of sirolimus oral solution in adults with additional pharmacokinetic data in pediatric renal transplantation patients [ see Clinical Pharmacology (12.3) ].

Safety and efficacy information from a controlled clinical trial in pediatric and adolescent (<18 years of age) renal transplant patients judged to be at high-immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of sirolimus oral solution or tablets in combination with calcineurin inhibitors and corticosteroids, due to the higher incidence of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens compared to calcineurin inhibitors, without increased benefit with respect to acute rejection, graft survival, or patient survival [ see Clinical Studies (14.6) ].

Lymphangioleiomyomatosis The safety and efficacy of Sirolimus in pediatric patients <18 years have not been established.

🧓 Geriatric Use 101 words ▾

8.5Geriatric Use Clinical studies of sirolimus oral solution or tablets did not include sufficient numbers of patients ≥65 years to determine whether they respond differently from younger patients. Data pertaining to sirolimus trough concentrations suggest that dose adjustments based upon age in geriatric renal patients are not necessary. Differences in responses between the elderly and younger patients have not been identified.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, or cardiac function, and of concomitant disease or other drug therapy.

🆘 Overdosage 90 words ▾

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.

🧬 Clinical Pharmacology ~3 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex.

The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G 1 to the S phase of the cell cycle.

Mammalian target of rapamycin (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. Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats.

In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen-specific. In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.

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.

12.2Pharmacodynamics Orally-administered sirolimus, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of organ rejection in low-to moderate-immunologic risk renal transplant patients at 6 months following transplantation compared with either azathioprine or placebo [ see Clinical Studies (14.1) ]. There was no demonstrable efficacy advantage of a daily maintenance dose of 5 mg with a loading dose of 15 mg over a daily maintenance dose of 2 mg with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug levels within the target-range [ see Dosage and Administration (2.5) ].

12.3Pharmacokinetics Sirolimus pharmacokinetics activity have been determined following oral administration in healthy subjects, pediatric patients, hepatically impaired patients, and renal transplant patients. The pharmacokinetic parameters of sirolimus in low- to moderate-immunologic risk adult renal transplant patients following multiple dosing with sirolimus 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in Table 4. TABLE 4: MEAN ± SD STEADY STATE SIROLIMUS PHARMACOKINETIC PARAMETERS IN LOW- TO MODERATE-IMMUNOLOGIC RISK ADULT RENAL TRANSPLANT PATIENTS FOLLOWING SIROLIMUS 2 MG DAILY In presence of cyclosporine administered 4 hours before sirolimus dosing. , Based on data collected at months 1 and 3 post-transplantation.

Multiple Dose (daily dose) Solution Tablets C max (ng/mL) 14.4 ± 5.3 15.0 ± 4.9 t max (hr) 2.1 ± 0.8 3.5 ±

2.4AUC (ng∙h/mL) 194 ± 78 230 ± 67 C min (ng/mL) Average C min over 6 months. 7.1 ± 3.5 7.6 ±

3.1CL/F (mL/h/kg) 173 ± 50 139 ± 63 Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correlated with AUC τ,…

🧬 Mechanism of Action ~1 min read ▾

12.1Mechanism of Action Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex.

The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G 1 to the S phase of the cell cycle.

Mammalian target of rapamycin (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. Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats.

In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen-specific. In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.

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.

📦 How Supplied / Storage and Handling 130 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING Since sirolimus is not absorbed through the skin, there are no special precautions. Do not use sirolimus after the expiration date. The expiration date refers to the last day of that month.

16.1Sirolimus Tablets Sirolimus Tablets are available as follows: • NDC 59762-1001-1, 0.5 mg, tan, triangular-shaped tablets marked "RAPAMUNE 0.5 mg" on one side; bottle containing 100 tablets. • NDC 59762-1002-1, 1 mg, white, triangular-shaped tablets marked "RAPAMUNE 1 mg" on one side; bottle containing 100 tablets. • NDC 59762-1003-1, 2 mg, yellow-to-beige triangular-shaped tablets marked "RAPAMUNE 2 mg" on one side; bottle containing 100 tablets. Sirolimus Tablets should be stored at 20°C to 25°C [USP Controlled Room Temperature] (68°F to 77°F).

Dispense in a tight, light-resistant container as defined in the USP.

📦 Storage and Handling 27 words ▾

Sirolimus Tablets should be stored at 20°C to 25°C [USP Controlled Room Temperature] (68°F to 77°F). Dispense in a tight, light-resistant container as defined in the USP.

📋 Description 217 words ▾

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 )-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3 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 and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile.

Sirolimus is available as a tan, triangular-shaped tablet containing 0.5 mg sirolimus, as a white, triangular-shaped tablet containing 1 mg sirolimus, and as a yellow-to-beige triangular-shaped tablet containing 2 mg sirolimus. The inactive ingredients in sirolimus tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, dl -alpha tocopherol, and other ingredients.

The 0.5 mg and 2 mg dosage strengths also contain yellow iron (ferric) oxide and brown iron (ferric) oxide. Chemical structure

💬 Information for Patients ~1 min read ▾

17 PATIENT COUNSELING INFORMATION Advise patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of the document. See FDA-Approved Medication Guide .

17.1Dosage Patients should be given complete dosage instructions [ see FDA-Approved Medication Guide ].

17.2Skin Cancer Events Advise patients that 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 because of the increased risk for skin cancer [ see Warnings and Precautions (5.18) ].

17.3Pregnancy and Lactation Advise female patients of reproductive potential to avoid becoming pregnant throughout treatment and for 12 weeks after sirolimus therapy has stopped. Sirolimus can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to her fetus.

Before making a decision to breastfeed, inform the patient that the effects of breastfeeding in infants while taking this drug are unknown, but there is potential for serious adverse effects [ see Warnings and Precautions (5.15) , Use in Specific Populations (8.1 , 8.2 , 8.3) ].

17.4Infertility Inform male and female patients that sirolimus may impair fertility [ see Warnings and Precautions (5.16) , Adverse Reactions (6.7) , Use in Specific Populations (8.1 , 8.3) , Nonclinical Toxicology (13.1) ].

💬 Medication Guide ~3 min read ▾

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised Nov 2024 MEDICATION GUIDE Sirolimus Tablets What is the most important information I should know about sirolimus?

Sirolimus can cause serious side effects, including: 1. Increased risk of getting infections. Serious infections can happen including infections caused by viruses, bacteria, and fungi (yeast).

Your doctor may put you on medicine to help prevent some of these infections. Call your doctor right away if you have symptoms of infection including fever or chills while taking sirolimus. 2.

Increased risk of getting certain cancers. People who take sirolimus have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Talk with your doctor about your risk for cancer.

Sirolimus has not been shown to be safe and effective in people who have had liver or lung transplants. Serious complications and death may happen in people who take sirolimus after a liver or lung transplant. You should not take sirolimus if you have had a liver or lung transplant without talking with your doctor.

See the section " What are the possible side effects of sirolimus? " for information about other side effects of sirolimus. What is sirolimus? Sirolimus is a prescription medicine used to prevent rejection (anti-rejection medicine) in people 13 years of age and older who have received a kidney transplant.

Rejection is when your body's immune system recognizes the new organ as a "foreign" threat and attacks it. Sirolimus is used with other medicines called cyclosporine (Gengraf, Neoral, Sandimmune), and corticosteroids. Your doctor will decide: • if sirolimus is right for you, and • how to best use it with cyclosporine and corticosteroids after your transplant.

It is not known if sirolimus is safe and effective in children under 13 years of age. Sirolimus is a prescription medicine also used to treat lymphangioleiomyomatosis (LAM). LAM is a rare progressive lung disease that affects predominantly women of childbearing age.

Who should not take sirolimus? Do not take sirolimus if you are allergic to sirolimus or any of the other ingredients in sirolimus. See the end of this leaflet for a complete list of ingredients in sirolimus.

What should I tell my doctor before taking sirolimus? • have liver problems • have skin cancer or it runs in your family • have high cholesterol or triglycerides (fat in your blood) • are pregnant or are a female who can become pregnant. Sirolimus can harm your unborn baby. You should not become pregnant during treatment with sirolimus and for 12 weeks after ending treatment with sirolimus.

In order to avoid pregnancy, a female who can get pregnant should use effective birth control during treatment and for 12 weeks after your final dose of sirolimus. Talk with your doctor about what birth control method is right for you during this time. Tell your doctor right away if you become pregnant or think you are pregnant during treatment with sirolimus or within 12 weeks after your final dose of sirolimus. • It is not known whether sirolimus passes into breast milk; however, there is a risk of serious side effects in breastfed infants.

You and your doctor should decide about the best way to feed your baby if you take sirolimus. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Using sirolimus with certain medicines may affect each other causing serious side effects.

Sirolimus may affect the way other medicines work, and other medicines may affect how sirolimus works. Especially tell your doctor if you take: • a medicine to lower your cholesterol or triglycerides • cyclosporine (including Gengraf, Neoral, Sandimmune) or tacrolimus (Prograf) or other medicines that suppress the immune system • an antibiotic • an antifungal medicine • a medicine for high blood pressure or heart problems • an anti-seizure medicine • medicines used to treat…

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗
← 59762-1002-01 · Mylan 59762-1005-01 · Mylan →
For educational and professional reference only — not medical advice. Pricing reflects published NADAC and CMS ASP (free public data) and may differ from your acquisition cost; always verify before billing or dispensing.