Sirolimus (Rapamune) is a macrolide compound that inhibits the cytokine-mediated T-cell activation.

Sirolimus (Rapamune) Uses:

• Lymphangioleiomyomatosis:

  • It is indicated for treatment of lymphangioleiomyomatosis.

• For the prophylaxis of rejection in Renal transplantation:

  • It is used concurrently with cyclosporine and corticosteroids with cyclosporine withdrawn 2 to 4 months after transplant as prophylaxis of organ rejection in patients receiving renal transplants in low-/moderate immunologic risk patients
  • In high immunologic risk patients (black transplant recipients, repeat renal transplant recipients who lost a previous allograft based on an immunologic process and/or patient with high PRA (panel reactive antibodies; peak PRA level >80%),it is given with cyclosporine and corticosteroids for the first year after transplant.

• Off Label Use of Sirolimus in Adults:

  • Advanced Chordoma;
  • Graft-versus-host disease prevention;
  • Acute graft-versus-host disease treatment;
  • Chronic graft-versus-host disease treatment;
  • Prophylaxis of organ rejection and allograft vasculopathy in Heart transplant;
  • Prophylaxis of rejection in Lung transplantation
  • Renal angiomyolipoma

Sirolimus (Rapamune) dose in Adults

Sirolimus (Rapamune) dose for the treatment of Lymphangioleiomyomatosis:

• Initial: 2 mg per oral once daily.
• Obtain trough concentration in 10 to 20 days, adjust the dose to maintain a target concentration of 5 to 15 ng/mL.

• Dosage adjustment for lymphangioleiomyomatosis:

  • Further adjustments should be made at one to two intervals according to the long half-life of sirolimus after adjusting the maintenance.
  • New sirolimus dose = current dose x by target concentration divided by current concentration.
  • Trough concentrations should be assessed at least every 3 months after achieving a stable dose.

Sirolimus (Rapamune) Dose for the prophylaxis of rejection in the renal transplant:

• Low-to-moderate immunologic risk:

  • weight<40 kg:

    • Loading dose: 3 mg/m²  per oral on day 1
    • maintenance dose: of 1 mg/m once daily

  • weight ≥40 kg:

    • Loading dose: 6 mg  per oral on day 1
    • maintenance dose: 2 mg once daily

• High immunologic risk:

  • Loading dose: Up to 15 mg per oral on day 1
  • maintenance: 5 mg/day
  • Trough concentration should be achieved between days 5 to 7 and adjusted accordingly.
  • Concurrent cyclosporine/sirolimus/corticosteroid therapy should be continued for 1 year following transplantation.
  • Further adjustment of the regimen depends on clinical status.

• Dosage adjustment for renal transplantation:

  • Depending on the risk and concomitant therapy, the sirolimus dosage should be adjusted in small increments to maintain 24-hour trough concentrations within the desired range.
  • Dosage should be adjusted at intervals of 7 to 14 days to account for the long half-life of sirolimus.
  • Maximum loading dose: 40 mg/day (although typical loading doses are not generally this high).
  • Whole blood concentrations are not used as the sole basis for dosage adjustment (monitor clinical signs/symptoms, tissue biopsy, and laboratory parameters).

• Maintenance therapy after the withdrawal of cyclosporine:

  • Withdrawal of cyclosporine may be considered in low-to-moderate immunologic risk patients after 2-4 months of therapy but it should not be withdrawn in high-risk patients.
  • Sirolimus dose should be increased up to fourfold for maintaining adequate immunosuppressive effect after cyclosporine withdrawal over one to two months.
  • Dose adjusted trough target concentrations are typically 16 to 24 ng/mL for the first year post-transplant and 12 to 20 ng/mL thereafter (per the manufacturer; measured by chromatographic methodology).

Sirolimus (Rapamune) for the treatment of Graft-versus-host disease (GVHD):

• Prevention of GVHD:

  • 12 mg per oral loading dose on day -3 followed by 4 mg daily (target trough level: 3 to 12 ng/mL), taper off after 6 to 9 months.

• Treatment of refractory acute GVHD:

  • 4 to 5 mg/m² per oral for 2 weeks for 14 days without a loading dose.

• Treatment of chronic GVHD:

  • 6 mg per oral loading dose followed by 2 mg daily (target trough level: 7 to 12 ng/mL) for 6 to 9 months.

Sirolimus (Rapamune) dose for the prophylaxis of organ rejection and allograft vasculopathy in the Heart transplantation:

Note:

Sirolimus as primary immunosuppressant is not recommended due to adverse effects such as impaired wound healing/infection, however, patients may be converted to sirolimus from a calcineurin inhibitor after at least 6 months from time of transplant.

• Conversion from a calcineurin inhibitor (CNI) (ie, cyclosporine, tacrolimus):

  • Cyclosporine is reduced by 25 mg twice daily or tacrolimus by 1 mg twice daily followed by starting sirolimus 1 mg once daily, adjust sirolimus dose to target trough level of 8 to 14 ng/mL, biopsy should be repeated 2 weeks after calcineurin inhibitor withdrawal.
  • Alternatively, sirolimus 1 mg once daily for 1 week can be started with calcineurin inhibitor adjusting the target trough levels of 10 to 15 ng/mL over 2 weeks and 50% reduction of calcineurin inhibitor therapeutic concentrations and after 2 weeks evaluate for rejection.
  • The Same regimen can be continued for another month if there is no rejection, followed by a 25% reduction of CNI therapeutic concentrations with repeat biopsy 2 weeks later.

• Conversion from an antiproliferative immunosuppressive drug (ie, azathioprine or mycophenolate) while maintaining calcineurin inhibitor:

  • Sirolimus 6 mg loading dose after stopping antiproliferative followed by 2 mg once daily titrated to a target trough level of 4-15 ng/mL.

Sirolimus (Rapamune) dose for the prophylaxis of rejection in Lung transplantation:

• Initial loading dose: Sirolimus should not be given until bronchial anastomosis has completely healed (approximately 90 days) due to fatal airway dehiscence with earlier initiation.
• A Loading dose of 5 mg per oral once, followed by a maintenance dose of 3 mg once daily, titrated to a target trough level of 5 to 13 ng/mL.

Sirolimus (Rapamune) dose for the treatment of Renal angiomyolipoma:

• Initial: 0.5 mg/m² per oral once daily titrated to a target trough level of 3 to 6 ng/mL (may increase to a target trough level of 6 to 10 ng/mL if <10% reduction in lesion diameters at 2 months) for 2 years.

Sirolimus dose in children:

Note:

Dosage depends on monitoring of serum trough concentrations. The target range is variable and may depend upon type and length since transplantation type, rejection history, renal function, infection, drug combinations, and side effects of individual agents.

Sirolimus (Rapamune) Dose in the treatment of heart transplantation in children and adolescents:

• BSA/weight-directed dosing:

  • Loading dose:

    • 3 mg/m² per oral on day 1.

  • Maintenance dose:

    • Evaluate serum trough concentrations and adjust the dose to overall target range: 4-12 ng/mL.
    • In adolescents <40 kg, an initial maintenance dose of 1 mg/m /day in 1-2 divided doses has been suggested.

• Alternative fixed dosing:

  • Adolescents with weight ≥40 kg:

    • Loading dose: 6 mg per orally on day 1
    • maintenance: 2 mg once daily;
    • evaluate serum trough concentrations and adjust the dose to the overall target range: 4-12 ng/mL.

Sirolimus (Rapamune) Dose for the prophylaxis of organ rejection in Renal transplantation who are at a low to moderate immunologic risk:

• Conversion from tacrolimus in patients with stable graft function:

  • Initial maintenance dose: 3 mg/m²/day divided every 12 hours;
  • Adjust the dose to achieve target sirolimus serum trough concentration.

• Manufacturer's recommendations:

  • Adolescents:

    • Weight <40 kg:

      • Loading dose: 3 mg/m² on day 1
      • initial maintenance dose: 1 mg/m /day divided every 12 hours or once daily; adjust the dose to achieve target sirolimus trough blood concentration.

    • Weight ≥40 kg:

      • Loading dose: 6 mg on day 1.
      • maintenance: 2 mg once daily; adjust the dose to achieve target sirolimus trough blood concentration.

Note: If a large dose increase is required, consider loading dose calculated as: Loading dose = new maintenance dose - current maintenance dose  x  3

• Maximum daily dose:

  • 40 mg/day; if the required dose is >40 mg (due to loading dose), divide over 2 days.
  • Serum concentrations should not be used as the sole basis for dosage adjustment (monitor clinical signs/symptoms, tissue biopsy, and laboratory parameters).

• Maintenance therapy after the withdrawal of cyclosporine:

  • Same as adults.

Sirolimus (Rapamune) Dose for the treatment of refractory vascular anomalies/ tumors (eg, Kaposiform hemangioendothelioma):

• Infants ≥7 months, Children, and Adolescents ≤14 years:
  • Initial: 0.8 mg/m² of the oral solution twice daily (approximately every 12 hours), titrate to a serum trough concentration of 10-15 ng/mL.

Sirolimus pregnancy Risk Category: C

• Studies on animal reproduction showed sirolimus could cause harm to fetuses.
• Before sirolimus treatment begins, for the duration of treatment and for 12 weeks thereafter, females should use effective contraception.
• Treatment may result in both male and female fertility being affected, which can lead to amenorrhea/menorrhagia for females or azoospermia for males.

Use sirolimus during breastfeeding

• It is not known if sirolimus excretion occurs in breast milk.
• According to the manufacturer breastfeeding during therapy is a decision that should be made based on the risks and benefits to the infant as well as the benefits to the mother.

Sirolimus (Rapamune) Dose adjustment in renal disease:

No dosage adjustment is necessary. However reduction/ discontinuation of therapy is required when used concurrently with cyclosporine and increasing serum creatinine is noted.

Sirolimus (Rapamune) Dose adjustment in liver disease:

• Loading dose:

  • No dosage adjustment is necessary.

• Maintenance dose:

  • Mild to moderate impairment (Child-Pugh classes A and B):

    • Reduce maintenance dose by 33%.

  • Severe impairment (Child-Pugh class C):

    • Reduce maintenance dose by 50%.

Side effects of Sirolimus (Rapamune):

• Cardiovascular:

  • Peripheral Edema
  • Hypertension
  • Edema
  • Chest Pain
  • Deep Vein Thrombosis
  • Pulmonary Embolism
  • Tachycardia

• Central Nervous System:

  • Headache
  • Pain
  • Dizziness

• Dermatologic:

  • Acne Vulgaris
  • Skin Rash

• Endocrine & Metabolic:

  • Hypertriglyceridemia
  • Hypercholesterolemia
  • Amenorrhea
  • Diabetes Mellitus
  • Hypermenorrhea
  • Hypervolemia
  • Hypokalemia
  • Increased Lactate Dehydrogenase
  • Menstrual Disease
  • Ovarian Cyst

• Gastrointestinal:

  • Constipation
  • Abdominal Pain
  • Diarrhea
  • Nausea
  • Stomatitis

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Anemia
  • Thrombocytopenia
  • Lymphoproliferative Disorder
  • Skin Carcinoma
  • Hemolytic-Uremic Syndrome
  • Leukopenia
  • Lymphocele
  • Thrombotic Thrombocytopenic Purpura

• Infection:

  • Herpes Simplex Infection
  • Herpes Zoster
  • Sepsis

• Neuromuscular & Skeletal:

  • Arthralgia
  • Myalgia
  • Osteonecrosis

• Renal:

  • Increased Serum Creatinine
  • Pyelonephritis

• Respiratory:

  • Nasopharyngitis
  • Epistaxis
  • Pneumonia
  • Upper Respiratory Tract Infection

• Miscellaneous:

  • Wound Healing Impairment

Contraindication to Sirolimus (Rapamune):

Hypersensitivity to sirolimus and any component of the formulation

Warnings and precautions

• Anaphylactic/hypersensitivity reactions

  • Sirolimus can trigger hypersensitivity reactions like anaphylaxis and angioedema.

• Infections [US Boxed Warning]

  • The risk of infection is increased by immunosuppressive drugs, such as sirolimus. Immune suppression can also increase the chance of opportunistic infection, including activation or latent viral infections (PCP, CMV, JC virus causing Progressive multifocal Leukoencephalopathy).
  • Pneumocystis pneumonia (PCP), should be administered for one year after transplant, while prophylaxis against cytomegalovirus should be given for three months.
  • Clinical signs of PML include confusion, hemiparesis, cognitive deficit, confusion, and ataxia.

• Interstitial lung disease

  • Interstitial lung disease, which can include pneumonitis, bronchiolitis organizing pneumonia, and pulmonary fibrosis, may occur. Doses should be reduced or discontinued.

• Hyperlipidemia

  • Sirolimus can cause hypercholesterolemia or hypertriglyceridemia. Therefore, it is important to be vigilant.

• Lymphocele/fluid accumulation

  • Sirolimus can increase the risk of lymphocele, fluid accumulation, and peripheral edema.

• Malignancy: [US Boxed Warning]

  • I Sirolimus and other immunosuppressive drugs can increase the risk of skin cancer or lymphoma. Avoid sun/UV light exposure.

• Proteinuria

  • Nephrotic syndrome may cause proteinuria.

• Effects on the renal system:

  • Concurrent therapy with sirolimus or cyclosporine for long-term can raise serum creatinine and lower GFR.

• Wound healing/dehiscence:

  • In the postoperative period, wound dehiscence and impaired healing are more common. Patients with a BMI greater than 30 kg/m are at higher risk for abnormal wound healing.

• Limitations of Use (renal transplantation).:

  • Patients with high blood pressure, creatinine levels >4.5 mg/dL or patients with multi-organ/secondary transplants, black patients
  • Guidelines for the Kidney Disease Improving Global OutcomesFor the treatment of kidney transplant recipients, sirolimus should be stopped until graft function is established and wounds have healed.
  • Because of the increased risk for nephrotoxicity, it is best to avoid concurrent therapy with calcineurin inhibitors.

Sirolimus: Drug Interaction

Monitoring parameters:

• Complete blood count
• Liver function tests
• renal function tests/urinary protein
• Lipid profile
• BP

Monitoring Sirolimus levels is important in all patients, especially if sirolimus dosages are changed or reduced. Dose adjustments for patients undergoing renal transplant should be made 7 to 14 days after the loading dose. Drug concentrations should then be measured within 3 to 4 days.

How to administer Sirolimus (Rapamune)?

• Administer consistently with or without food.

Renal transplant:

• Sirolimus should be taken 4 hours after oral cyclosporin.
• Solution:
  • Mix with at least 60 mL of water or orange juice. No other liquids should be used for dilution.
  • The patient should drink a diluted solution immediately.
  • The cup should then be refilled with an additional 120 mL of water or orange juice, stirred vigorously, and the patient should drink the contents at once.
  • The tablet should not be crushed, split, or chewed.

Mechanism of action of Sirolimus (Rapamune):

• Sirolimus inhibits antibody production by inducing T-lymphocyte activation, proliferation and response to antigenic or cytokine stimulation.
• Its mechanism is different from that of other immunosuppressants. 
• It forms an immune suppressive complex by binding FKBP-12, an intracellular protein which inhibits the regulatory kinase mTOR (mechanistic Target of Rapamycin).
• This inhibits cytokine-mediated T cell proliferation and blocks the progression of the G1 phase. The inhibition of acute rejection is a key factor in prolonging graft survival.
• Lymphangioleiomyomatosis is characterized by activation of mTOR signaling pathways through the loss or function of the tuberous Sclerosis Complex (TSC) gene function.
• This results in cell proliferation and the release of lymphangiogenic growth factor.
• Sirolimus inhibits the mTOR pathway and prevents lymphangioleiomyomatosis cell proliferation

Absorption:

• Rapid

Protein binding:

• 92%, primarily to albumin

Metabolism:

• Extensive; in the intestinal wall via P-glycoprotein and hepatic via CYP3A4 to 7 major metabolites

Bioavailability:

• Oral solution: 14%
• Oral tablet: 27% higher relative to the oral solution
• oral solution and tablets are not bioequivalent, however, clinical equivalence is shown at 2 mg dose

Half-life elimination:

• Children: 13.7 ± 6.2 hours
• Adults: Mean: 62 hours (range: 46 to 78 hours)
• extended in hepatic impairment (Child-Pugh class A or B) to 113 hours

Time to peak serum concentration:

• Oral solution: 1 to 3 hours
• Tablet: 1 to 6 hours

Excretion:

• Occurs in feces (91% due to P-glycoprotein-mediated efflux into the gut lumen); urine (2%)

Sirolimus Brand Names (International):

• Rapamune
• Rapacan
• Rapalimus
• Siromune

Sirolimus Brand Names in Pakistan:

Sirolimus Brands in Pakistan will be updated later.