HomeNDC LookupIngredientsSirolimus › 55111-0654-01
Sirolimus 2 mg Tablet, 100-count — NDC 55111-0654-01 package photo

Sirolimus 2 mg Tablet, 100-count

by Dr. Reddy's Laboratories Limited · 100 TABLET in 1 BOTTLE (55111-654-01)
NDC 55111-0654-01
🏷️ FDA NDC (as labeled) 55111-654-01 billing pads the product segment with a zero
This package
Contains100-count Cost per ea$2.64 NADAC Per package$264.13 / 100 tablets Pack sizes2 compare ↓
Also priced by: Medicaid pays $7.45/unit · Part D plans $14.17/unit — full pricing hub ↓
Also comes in: 30 tablets 55111-0654-30
Rx only Generic 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 →
🚨
Active recall for this product.
Class III · May 1, 2024 — Failed Impurities/Degradation Specifications (Dr. Reddy's Laboratories, Inc.) · FDA recall D-0504-2024
Check your lot/expiration against the official notice — look up the recall number in the FDA recall database ↗

🆔 Identity & classification

FDA NDC (as labeled) 55111-654-01
Product NDC 55111-654
11-digit billing NDC 55111065401
NCPDP billing unit EA — each (per item)
RxCUI 349208, 360110
UNII W36ZG6FT64
UPC 0355111654018
Application # ANDA201578
SPL Set ID 2e6130e5-fa94-dcf8-605c-817bf396e93d
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 ANDA
Marketing status On market
FDA listing status Listed (active directory)
Marketing start 2014-10-27
Route ORAL
Dosage form TABLET
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 55111-654-01 — a 5-3-2 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 product segment → 55111-0654-01. 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

LabelerDr. Reddy's Laboratories Limited
Application holderDR REDDYS LABORATORIES LTD
FDA applicationANDA201578 (ANDA)
Labeler code55111
First marketedOct 2014
Product typeHuman Prescription Drug
Portfolio200 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.

🧪 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 H4N855PNZ1
    Alpha-tocopherol is a form of vitamin E, a fat-soluble antioxidant derived from natural or synthetic sources. In medicines, it prevents oils and fats from breaking down and becoming rancid, protecting the product's stability and shelf life.
  • UNII 5138Q19F1X
    Ammonia is a colorless gas made from nitrogen and hydrogen. It's used in medicines as a pH buffer to maintain the correct acidity level and help keep the product stable.
  • 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 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 7Z8S9VYZ4B
    Ethylcellulose is a plant-derived thickener and film-former made by chemically modifying cellulose. It's used as a binder to hold tablet ingredients together, a coating to control how quickly medicine is released, or a thickener in liquid formulations.
  • UNII WZB9127XOA
    A synthetic red dye used to color medications and make them easier to identify. It serves as a colorant in tablets, capsules, and liquid formulations.
  • UNII 1K09F3G675
    Ferric oxide red is an inorganic iron compound used as a colorant in medicines. It gives tablets, capsules, or other dosage forms a red or reddish tint for identification and appearance.
  • UNII EX438O2MRT
    Ferric oxide yellow is a naturally occurring iron compound used as a colorant in medications. It gives tablets, capsules, and other forms a yellow or golden hue for identification and appearance.
  • UNII R75537T0T4
    Hypromellose 2910 is a plant-derived thickening agent made from cellulose. It serves as a binder that holds tablet ingredients together, a film-coating for pills, and a viscosity controller in liquids.
  • 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 3OWL53L36A
    A natural sugar alcohol derived from seaweed or synthesized in the lab. It's used as a filler to add bulk, a sweetener in sugar-free formulas, and a disintegrant to help tablets break apart in the stomach.
  • 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 3WJQ0SDW1A
    Polyethylene glycol is a synthetic liquid or solid polymer used in medicines as a solvent, lubricant, and humectant. It helps dissolve active ingredients, reduces friction during manufacturing, and retains moisture in the final product.
  • UNII FZ989GH94E
    Povidone is a synthetic polymer made from a plastic-like material. It acts as a binder to hold tablet ingredients together and as a disintegrant to help the tablet break apart in your stomach so the medicine can be absorbed.
  • UNII 6DC9Q167V3
    Propylene glycol is a clear liquid derived from petroleum or vegetable sources. It acts as a solvent, humectant, and preservative in medicines, helping dissolve active ingredients and maintain product stability.
  • UNII 46N107B71O
    Shellac is a natural resin secreted by the lac beetle. It's used as a coating on tablets and capsules to control how quickly the medicine dissolves and to improve appearance and stability.
  • 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 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.

19 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 DailyMedingredient 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 $7.45 $744.74 / 100 tablets
Medicare drug plans payPart D · Q2 2026 $14.17 $1,417.38 / 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)55111-654-01
11-digit billing NDC55111-0654-01
Format5-3-2 as registered → padded to 5-4-2 for billing (zero added to the product 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 mgthis 55111-0654-01 Dr. 100 tablets $2.641 AB Availability likely
Sirolimus 2 mg 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 a generic version of the medicine. FDA equivalence ratings are shown when available, and 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 on the market
this product is a generic
This is a generic drug

This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.

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.

🗺️ Medicaid utilization & spend

📍 This exact package only: Medicaid data is reported per full 11-digit NDC — labeler, product and pack size — so every number here is for 55111-0654-01, not the drug overall. Other pack sizes report separately.
💊 Pharmacy benefit only: These are Medicaid outpatient pharmacy claims, billed by NDC. They exclude the medical benefit — clinic- or hospital-administered drugs billed under HCPCS J-codes — so drugs used mostly that way (e.g. Avastin, Lucentis, Keytruda) can look low or missing here. That’s expected, not an error.
📅 Q1 2025 – Q4 2025 · 4 quarters of data
ⓘ The newest quarter is usually incomplete when first published; states restate recent quarters in later CMS releases, so the latest figures typically revise upward. State coverage-policy changes can also shift quarter-to-quarter totals.
Prescriptions last 4 qtrs
1.5K
Units reimbursed last 4 qtrs
71.2K
Gross reimbursed last 4 qtrs
$530K
Avg / prescription
$357.41
Avg / unit
$7.4474
Latest quarter Q4 2025
322Rx
Medicaid pays / ea
$7.4474
gross reimbursed
vs
NADAC / ea
$2.6413
acquisition cost
=
Spread
+$4.8061
+182% vs cost
What Medicaid paid per ea (before rebates; includes the pharmacy’s dispensing fee) compared with NADAC — the average price pharmacies pay to buy the drug. A positive spread means Medicaid reimbursed more than the purchase price, before manufacturer rebates.
Fee-for-service vs managed care
40% FFS 60% MCO
Fee-for-service · 589 Rx Managed care · 894 Rx
State Medicaid map
Alaska: no data reported AK Maine: no data reported ME Washington: 1,590 units · 20.4 per 100k residents WA Idaho: no data reported ID Montana: no data reported MT North Dakota: no data reported ND Minnesota: no data reported MN Wisconsin: 3,390 units · 57.4 per 100k residents WI Michigan: 2,690 units · 26.8 per 100k residents MI New York: 4,689 units · 24.0 per 100k residents NY Vermont: no data reported VT New Hampshire: no data reported NH Oregon: no data reported OR Nevada: no data reported NV Wyoming: no data reported WY South Dakota: no data reported SD Iowa: no data reported IA Illinois: 5,416 units · 43.2 per 100k residents IL Indiana: no data reported IN Ohio: 540 units · 4.6 per 100k residents OH Pennsylvania: 3,068 units · 23.7 per 100k residents PA New Jersey: no data reported NJ Massachusetts: no data reported MA California: 11,942 units · 30.6 per 100k residents CA Utah: no data reported UT Colorado: 1,940 units · 33.0 per 100k residents CO Nebraska: no data reported NE Missouri: no data reported MO Kentucky: no data reported KY West Virginia: no data reported WV Virginia: 3,202 units · 36.7 per 100k residents VA Maryland: 3,423 units · 55.4 per 100k residents MD Connecticut: no data reported CT Rhode Island: no data reported RI Arizona: 2,424 units · 32.6 per 100k residents AZ New Mexico: no data reported NM Kansas: no data reported KS Arkansas: no data reported AR Tennessee: 2,443 units · 34.3 per 100k residents TN North Carolina: 3,832 units · 35.4 per 100k residents NC South Carolina: no data reported SC Delaware: no data reported DE Oklahoma: no data reported OK Louisiana: 1,604 units · 35.1 per 100k residents LA Mississippi: no data reported MS Alabama: 1,378 units · 27.0 per 100k residents AL Georgia: 3,037 units · 27.5 per 100k residents GA D.C.: no data reported DC Hawaii: no data reported HI Texas: 3,640 units · 11.9 per 100k residents TX Florida: 9,018 units · 39.9 per 100k residents FL
Units reimbursed · per 100k residents
4.657.4
gray = no data reported
Colors are per 100,000 residents, so big states don’t automatically dominate. Tap or hover a state for its actual totals.
Tap or hover a state
…for its Medicaid breakdown
🏆 Top states by units · per 100k residents
1 Wisconsin 57.4 /100k
2 Maryland 55.4 /100k
3 Illinois 43.2 /100k
4 Florida 39.9 /100k
5 Virginia 36.7 /100k
6 North Carolina 35.4 /100k
7 Louisiana 35.1 /100k
8 Tennessee 34.3 /100k
National units — by quarter
💵 About the dollar figures: “reimbursed” is what Medicaid paid pharmacies before confidential manufacturer rebates, so the program’s real net cost is lower than these numbers. Fee-for-service and managed-care claims are combined unless split above. Source: CMS State Drug Utilization Data; per-100k rates use 2023 Census population estimates.

💊 Medicaid utilization by pack size

Medicaid (SDUD) totals over the four most recent reported quarters for every package size of this drug — handy when a specific package (e.g. a starter/titration pack) carries little or no Medicaid volume on its own.
100 tablets this page55111-0654-01 1,483 Rx · $530,037
30 tablets55111-0654-30 No Medicaid data
Drug total (last 4 qtrs): 1,483 Rx · 71,171 units · $530,037 gross reimbursed
Tap a pack size to open its page. Source: CMS State Drug Utilization Data, last 4 quarters.

📊 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 Per unit Per pack Marketing startStatus
55111-0654-01 You're viewing this 100 TABLET in 1 BOTTLE (55111-654-01) $2.64 / ea $264.13 2014-10-27 Active
55111-0654-30 30 TABLET in 1 BOTTLE (55111-654-30) 2014-10-27 Active

You're viewing the largest of 2 pack sizes for this product.

In Medicaid, this is the most-dispensed pack of this product — about 100% of fills over the last four reported quarters. See all packs ↓

Pack size FAQ

What quantity is in NDC 55111-0654-01?
NDC 55111-0654-01 is a 100-count package — 100 tablet in 1 bottle.
What is the difference between NDC 55111-0654-01 and NDC 55111-0654-30?
Both are Sirolimus 2 mg Tablet — the drug itself is identical. NDC 55111-0654-01 is the 100-count package, while NDC 55111-0654-30 is the 30 tablets package.
What NDC number is used to bill for this package of Sirolimus 2 mg Tablet?
Bill NDC 55111-0654-01 — the 11-digit billing format is 55111065401. Pharmacy and medical claims use the 11-digit form; the FDA label may print a shorter form of the same code.

Prices are the latest CMS NADAC pharmacy acquisition cost per NDC; per-pack figures are per-unit × pack quantity, shown only when the pack is denominated in the same measure NADAC prices.

📄 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 ~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. O nly 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 to 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 tablets are 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets in maintenance renal transplant patients have not been established [see Clinical Studies ( 14.4 ) ].

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

⏱️ Dosage and Administration ~3 min read

2 DOSAGE AND ADMINISTRATION Sirolimus tablets are 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 to 4 months post-transplantation, withdraw CsA over 4 to 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 to 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 tablets should be administered as soon as possible after transplantation. It is recommended that sirolimus tablets be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [see Drug Interactions (7.2) ]. Frequent sirolimus tablets dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life.

Once sirolimus tablets 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 tablets 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 tablets loading dose = 3 x (new maintenance dose - current maintenance dose).

The maximum sirolimus tablets 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 Rapamune 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 Rapamune 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 Tablets and Cyclosporine Combination Therapy For de novo renal transplant patients, it is recommended that Rapamune Oral Solution and sirolimus tablets be used initially in a regimen with cyclosporine and corticosteroids. A loading dose of sirolimus tablets equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance dose of 2 mg should…

💊 Dosage Forms and Strengths 62 words

3 DOSAGE FORMS AND STRENGTHS Tablets: 1 mg, 2 mg (3.2) .

3.2Sirolimus Tablets Sirolimus tablets 1 mg are white, triangular shaped tablets imprinted with in red color on one side and plain on the other side. Sirolimus tablets 2 mg are creamish yellow, triangular shaped tablets imprinted with in red color on one side and plain on the other side.

Contraindications 26 words

4 CONTRAINDICATIONS Sirolimus tablets are 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 to 3.2% (for sirolimus-treated patients) versus 0.6 to 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 to 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 with the administration of sirolimus [s…

🤒 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 Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 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 Rapamune 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 Rapamune Oral Solution 2 mg/day, 208 received Rapamune 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 race was: White (78%), Black (11%), Asian (3…

🔄 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 ) and 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 to 4% and 15 to 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 to 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 to 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 hav…

🤰 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 to 4% and 15 to 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 to 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 to 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 218 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 Rapamune 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 Rapamune Oral Solution and sirolimus tablets in this subpopulation of children ≥13 years is supported by evidence from adequate and well-controlled trials of Rapamune 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 Rapamune Oral Solution or sirolimus 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 89 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 a,b 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) c 7.1 ± 3.5 7.6 ±

3.1CL/F (mL/h/kg) 173 ± 50 139 ± 63 a: In presence of cyclosporine administered 4 hours before sirolimus dosing. b: Based on data collected at months 1 and 3 post-transplantation. c: Average C min over 6 months. Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correlated…

🧬 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 153 words

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

16.2Sirolimus Tablets Sirolimus Tablets are available as follows: 1 mg, white, triangular shaped tablets imprinted with in red color on one side and plain on the other side. They are supplied in bottles of 30's and 100's. Bottles of 30 NDC 55111-653-30 Bottles of 100 NDC 55111-653-01 2 mg, creamish yellow, triangular shaped tablets imprinted with in red color on one side and plain on the other side.

They are supplied in bottles of 30's and 100's. Bottles of 30 NDC 55111-654-30 Bottles of 100 NDC 55111-654-01 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 213 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 (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)­9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2­ [(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26­ hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-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 chloroform, acetone and acetonitrile.

Sirolimus tablets are available as a white, triangular shaped tablet containing 1 mg sirolimus, and as a creamish yellow, triangular shaped tablet containing 2 mg sirolimus. The inactive ingredients in sirolimus tablets includes, carnauba wax, ethyl cellulose, hydroxypropyl methylcellulose 5 cps, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose (avicel pH 105), microcrystalline cellulose (avicel pH 200), poloxamer 188, polyethylene glycol 20000, polyethylene glycol 8000, sucrose, titanium dioxide, vitamin E preparation, seal coating agent opaglos clear NA 7150, and imprinting ink opacode red (S-1-15052).

The 2 mg dosage strength also contains iron oxide red and iron oxide yellow. Seal coating agent opaglos clear NA 7150 contains, acetylated monoglyceride, industrial methylated spirit 74 OP, povidone, and shellac. Imprinting ink opacode red (S-1-15052) contains, ammonium hydroxide, FD&C Red # 40, propylene glycol, shellac glaze, and titanium dioxide.

💬 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 Precaution s ( 5.16 ), Adverse Reactions ( 6.7 ), Use in Specific Populations ( 8.1 , 8.3 ), Nonclinical Toxicology ( 13.1 )] .

💬 Medication Guide ~3 min read

MEDICATION GUIDE Sirolimus(sir-OH-li-mus) Tablets What is the most important information I should know about sirolimus tablets? Sirolimus tablets 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 tablets.

2. Increased risk of getting certain cancers. People who take sirolimus tablets 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 tablets 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 tablets?” for information about other side effects of sirolimus tablets. 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 tablets are 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 l.ung disease that affects predominantly women of childbearing age. Who should not take sirolimus tablets? Do not take sirolimus tablets if you are allergic to sirolimus or any of the other ingredients in sirolimus tablets.

See the end of this leaflet for a complete list of ingredients in sirolimus tablets. What should I tell my doctor before taking sirolimus tablets? 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 tablets. 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 tablets. 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 tablets. 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 tablets.

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…

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗
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.