Pharm

Sirolimus

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Sirolimus, Rapamune, Rapamycin

  • See Also
  1. mTOR Inhibitor
  2. mTOR Pathway
  • Indications
  1. Solid Organ Transplant Immunosuppression (maintenance prevention of rejection)
    1. Renal Transplant
    2. Contraindicated in Liver Transplant and lung transplant (black box warning, see below)
  2. Lymphangioleiomyomatosis
  3. Ongoing research into mTOR Inhibitors as anti-aging drugs
    1. Resources
      1. Rapamycin (Peter Attia, Drive)
        1. https://peterattiamd.com/davidsabatini-mattkaeberlein/
    2. References
      1. Blagosklonny (2019) Aging 11(19):8048-67 +PMID: 31586989 [PubMed]
      2. Juricic (2022) Nat Aging 2(9):824-36 +PMID: 37118497 [PubMed]
      3. Lee (2024) Lancet Healthy Longev 5(2):e152-e162 +PMID: 38310895 [PubMed]
  • Mechanism
  1. mTOR Inhibitor
  2. See Mammalian Target of Rapamycin Pathway (mTOR Pathway)
  • Medications
  1. Sirolimus (Rapamune, Rapamycin)
    1. Tablets: 0.5 mg, 1 mg, 2 mg
    2. Solution: 1 mg/ml
  • Dosing
  1. See other references for specific dosing regimens per indication
  2. Prescribers are typically specialists knowledgeable about the risks and monitoring
  3. Decrease dose in renal dysfunction, and adjust doses based on serum levels
  • Adverse Effects
  1. Nephrotoxicity including Proteinuria
  2. Myelosuppression
  3. Rash
    1. Includes Exfoliative Dermatitis
  4. Delayed Wound Healing
  5. New Diabetes Mellitus
  6. Secondary Malignancy
    1. Lymphoma
    2. Skin Cancer (use sun protection)
  7. Male Infertility
  8. Cardiopulmonary
    1. Interstitial Lung Disease or Pulmonary fibrosis
    2. Hyperlipidemia
    3. Edema
    4. Thrombosis
      1. Hepatic artery thrombosis
      2. Kidney graft thrombosis
  9. Thrombotic Thrombocytopenic Purpura (TTP) or Hemolytic Uremic Syndrome (HUS)
    1. More common in combination with Cyclosporine
  10. Angioedema (and other serious Allergic Reactions including Anaphylaxis)
    1. More common in combination with ACE Inhibitors
  11. Serious Infections (including Polyoma Virus Infections)
    1. Latent Viral Infection activation
    2. BK virus associated nephropathy
  • Drug Interactions
  1. See Cytochrome P-450 3A4
  2. Agents that increase Purine Synthesis Inhibitor concentrations (strong CYP3A4 Inhibitors, and P-gp Inhibitors)
    1. Linezolid potentiates myelosuppression
    2. Erythromycin (and Clarithromycin to a lesser extent)
    3. Azole Antifungals (Ketoconazole, Voriconazole, Itraconazole)
  3. Agents that decrease Purine Synthesis Inhibitor concentrations (strong CYP3A4 Inducers, and P-gp Inducers)
    1. Rifampin
    2. Rifabutin
  4. Calcineurin Inhibitors (Cyclosporine, Tacrolimus)
    1. Increased risk of Hepatic Artery Thrombosis (HAT) when used with Sirolimus
    2. Increased risk of Bronchial anastomotic dehiscence in lung transplant
    3. Monitor Sirolimus drug levels closely after stopping Cyclosporine
  5. Cortocosteroids
    1. Increased risk of Bronchial anastomotic dehiscence in lung transplant
  • Safety
  1. Avoid in Lactation
  2. Avoid in Pregnancy (despite original Pregnancy Category C designation)
    1. Use reliable Contraception during treatment and for at least 12 weeks after completion
  3. Monitor Sirolimus serum trough levels
    1. Indications for more frequent monitoring (as often as every 1-2 weeks)
      1. Liver Impairment
      2. Altered Drug Metabolism
      3. Weight <40 kg in age >13 years
      4. Dose changes
      5. Drug Interactions (CYP3A4 or P-gp related)
  • Resources
  1. Sirolimus (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2e6130e5-fa94-dcf8-605c-817bf396e93d
  • References
  1. Hamilton (2020) Tarascon Pocket Pharmacopoeia
  2. Cimino (2016) Am Fam Physician 93(3): 203-10 [PubMed]
  3. Costanzo (2010) J Heart Lung Transplant 29(8): 914-56 [PubMed]