Sirolimus (Rapamune) - Uses, Dose, Side effects

Sirolimus, also known by its trade name Rapamycin, is a medication that belongs to a class of drugs called mTOR inhibitors. It was originally discovered as a natural product produced by a bacterium called Streptomyces hygroscopicus found on Easter Island, also known as Rapa Nui. Sirolimus was initially developed as an immunosuppressant drug to prevent rejection in organ transplantation, particularly in kidney transplant recipients.

The primary mechanism of sirolimus is the inhibition of a protein called mammalian target of rapamycin (mTOR). This protein plays a crucial role in regulating cell growth, proliferation, and survival. By inhibiting mTOR, sirolimus slows down the growth of certain immune cells involved in the rejection of transplanted organs.

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    • It is used concurrently with cyclosporine and corticosteroids with cyclosporine withdrawn 2 to 4 months after transplant as prophylaxis of organ rejection in patients receiving renal transplants in low-/moderate immunologic risk patients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:

In the treatment of Lymphangioleiomyomatosis (LAM), the recommended dose of Sirolimus is as follows:

  • For adults: The initial dose is 2 mg taken orally once daily.
  • Within 10 to 20 days after starting the treatment, a blood test is done to measure the concentration of Sirolimus in the body (called trough concentration). This helps determine how the body is responding to the medication.
  • The dose is then adjusted based on the measured trough concentration to maintain a target concentration of 5 to 15 ng/mL.

Dosage adjustment for lymphangioleiomyomatosis:

  • Dosage adjustments for LAM should be made at intervals of 7 to 14 days because Sirolimus has a long half-life.
  • Generally, the dose can be adjusted proportionally based on the target concentration compared to the current concentration.
  • To calculate the new Sirolimus dose, multiply the current dose by (target concentration divided by current concentration).
  • Once a stable dose is achieved, trough concentrations should be monitored at least every 3 months to ensure the medication's effectiveness and safety.
  • It is essential to follow the guidance and instructions provided by your healthcare professional regarding the dosing and monitoring of Sirolimus in LAM treatment.

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

In renal transplant patients receiving Sirolimus for rejection prophylaxis, the recommended doses vary depending on the immunologic risk:

  • Low-to-moderate immunologic risk:
    • Patients weighing less than 40 kg: The loading dose is 3 mg/m² on day 1, followed by a maintenance dose of 1 mg/m² once daily.
    • Patients weighing 40 kg or more: The loading dose is 6 mg on day 1, followed by a maintenance dose of 2 mg once daily.
  • High immunologic risk:
    • The loading dose can be up to 15 mg on day 1, followed by a maintenance dose of 5 mg/day.
    • Trough concentration should be obtained between days 5 to 7 and adjusted accordingly.

Dosage adjustment for renal transplantation:

  • For dosage adjustments in renal transplantation, Sirolimus doses should be adjusted in small increments to maintain 24-hour trough concentrations within the desired range based on the risk and concomitant therapy.
  • Dosage adjustments should be made at intervals of 7 to 14 days due to the long half-life of Sirolimus.
  • It's important to note that maximum loading doses should not exceed 40 mg/day, although typical loading doses are generally lower.
  • Monitoring clinical signs/symptoms, tissue biopsy, and laboratory parameters should be considered alongside whole blood concentration measurements to guide dosage adjustments.

Regarding maintenance therapy after withdrawal of cyclosporine:

  • Cyclosporine withdrawal is generally not recommended in high immunologic risk renal transplant patients.
  • In low-to-moderate immunologic risk patients, withdrawal of cyclosporine may be considered after 2 to 4 months of combined therapy.
  • Cyclosporine should be gradually discontinued over 4 to 8 weeks, while anticipating an increase in Sirolimus dosage (up to fourfold) to compensate for the removal of metabolic inhibition by cyclosporine and maintain sufficient immunosuppressive effects.
  • Target trough concentrations are typically 16 to 24 ng/mL for the first-year post-transplant and 12 to 20 ng/mL thereafter, as per the manufacturer's recommendation. However, target trough concentrations of approximately 5 to 15 ng/mL are often used in clinical practice. It's essential to follow the specific institutional protocol for target Sirolimus trough concentrations.

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

In the off-label use of Sirolimus for the treatment of Graft-versus-host disease (GVHD), the recommended doses are as follows:

GVHD prevention:

  • Loading dose: 12 mg on day -3 (3 days before transplantation).
  • Maintenance dose: 4 mg daily.
  • The target trough level (concentration in the blood) is 3 to 12 ng/mL.
  • After 6 to 9 months, the dose should be tapered off.
  • It's important to note that further trials may be necessary to fully define the role of Sirolimus in GVHD prevention.

Treatment of refractory acute GVHD:

  • Dosage: 4 to 5 mg/m² for 14 days.
  • No loading dose is required.
  • Further trials may be necessary to better establish the role of Sirolimus in the treatment of refractory acute GVHD.

Treatment of chronic GVHD:

  • Loading dose: 6 mg.
  • Maintenance dose: 2 mg daily.
  • The target trough level is 7 to 12 ng/mL.
  • The duration of treatment is 6 to 9 months.
  • Additional trials may be necessary to further define the role of Sirolimus in the treatment of chronic GVHD.

It's important to note that the use of Sirolimus in GVHD is considered off-label, meaning it is not specifically approved by regulatory authorities for this indication. Therefore, careful monitoring and individualized treatment plans should be established.


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

In the off-label use of Sirolimus for heart transplantation, specifically for prophylaxis of organ rejection and allograft vasculopathy, the recommended doses and conversion guidelines are as follows:

Note: The use of Sirolimus as a primary immunosuppressant immediately after cardiac transplant (de novo heart transplant) has become less common due to adverse effects. However, patients who have undergone heart transplantation may be converted to Sirolimus from a calcineurin inhibitor (CNI) after at least 6 months from the time of transplant.

Conversion from a calcineurin inhibitor (CNI) (e.g., cyclosporine, tacrolimus):

  • Reduce cyclosporine by 25 mg twice daily or tacrolimus by 1 mg twice daily.
  • Initiate Sirolimus at 1 mg once daily.
  • Adjust the Sirolimus dose to achieve a target trough level of 8 to 14 ng/mL.
  • Withdraw the CNI and perform a repeat biopsy 2 weeks after CNI withdrawal.
  • Alternatively, maintain CNI concentrations while initiating Sirolimus at 1 mg once daily for 1 week.
  • Adjust Sirolimus to target trough levels of 10 to 15 ng/mL over 2 weeks.
  • Reduce the CNI to 50% of therapeutic concentrations and evaluate for rejection after 2 weeks.
  • If no rejection occurs, continue the same regimen for an additional month.
  • Then reduce the CNI to 25% of therapeutic concentrations with repeat biopsy 2 weeks later.
  • If no rejection occurs, the CNI may be discontinued after 2 weeks while maintaining Sirolimus trough levels of 10 to 15 ng/mL.
  • The actual doses required to maintain target levels may range from 1 to 8 mg daily.
  • Specific institutional protocols should be followed for target Sirolimus trough concentrations, as they may vary based on time from transplant, assay method, and concurrent or transitioning therapies.

Conversion from an antiproliferative immunosuppressive drug (e.g., azathioprine or mycophenolate) while maintaining a calcineurin inhibitor:

  • Upon discontinuation of the antiproliferative drug, administer a Sirolimus loading dose of 6 mg, followed by 2 mg once daily.
  • Titrate the Sirolimus dose to achieve a target trough level of 4 to 15 ng/mL or 4 to 12 ng/mL per ISHLT (International Society for Heart and Lung Transplantation) recommendations.

It's important to note that the use of Sirolimus in heart transplantation for these specific indications is considered off-label. Individualized treatment plans, careful monitoring, and adherence to specific institutional protocols are necessary when using Sirolimus


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

In the off-label use of Sirolimus for the treatment of Renal angiomyolipoma, the recommended dose is as follows:

  • Oral administration: The initial dose is 0.5 mg/m² once daily.
  • The dose is then titrated to achieve a target trough level (concentration in the blood) of 3 to 6 ng/mL.
  • If there is less than a 10% reduction in lesion diameters after 2 months of treatment, the target trough level may be increased to 6 to 10 ng/mL.
  • The treatment duration is typically 2 years.

It's important to note that the use of Sirolimus in the treatment of Renal angiomyolipoma is considered off-label, meaning it is not specifically approved by regulatory authorities for this indication. Therefore, careful monitoring and individualized treatment plans should be established


Sirolimus dose in children:

Note:

  • Please be aware that Sirolimus tablets and oral solution are not exactly the same in terms of how they are absorbed by the body.
  • However, studies have shown that they are clinically equivalent when using a dose of 2 mg.
  • The dosage of Sirolimus should be customized for each individual and determined by monitoring the concentration of the drug in the blood.
  • The target range for Sirolimus concentration can vary and may depend on factors such as the type of transplantation, the length of time since the transplant, kidney function, presence of infection, history of rejection, other medications being used in combination, and any side effects experienced with the medications.

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

The dosing of Sirolimus in children and adolescents is based on body surface area (BSA) or weight:

BSA/weight-directed dosing:

  • Loading dose: 3 mg/m² on the first day.
  • Maintenance dose:
    • The dosage is adjusted to achieve a target range of 4-12 ng/mL in serum trough concentrations.
    • Some trials suggest lower target ranges of 4-10 ng/mL.
    • The specific maintenance dose in children has not been reported widely.
    • In a study involving pediatric patients aged 2-18 years, the mean reported dose to reach a target serum concentration of 5-10 ng/mL was 7 mg/m² (or 0.25 mg/kg).
    • Another trial used an initial median dose of 1 mg once daily, adjusted to achieve a target concentration of 4-8 ng/mL.

Alternative fixed dosing:

  • Adolescents weighing ≥40 kg:
    • Loading dose of 6 mg on the first day, followed by a maintenance dose of 2 mg once daily.
    • The dosage is adjusted to achieve a target range of 4-12 ng/mL in serum trough concentrations.
    • Some studies suggest higher initial targets when initiating Sirolimus therapy, which can then be decreased to 4-8 ng/mL.

It's important to note that the use of Sirolimus in heart transplantation among children and adolescents is based on limited data. Individualized treatment plans and careful monitoring are necessary, taking into consideration the specific needs and response of each patient.


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:

  • Children and Adolescents: Limited data available.
    • Initial maintenance dose: 3 mg/m²/day divided every 12 hours.
    • Adjust the dose to achieve the target sirolimus serum trough concentration.
    • In one trial, a loading dose of 5 mg/m² on the first day was used, followed by maintenance doses of 3 mg/m²/day divided every 12 hours.

Manufacturer's Recommendations:

  • Adolescents:
    • Weight <40 kg:
      • Loading dose: 3 mg/m² on the first day.
      • Initial maintenance dose: 1 mg/m²/day divided every 12 hours or once daily.
      • Adjust the dose to achieve the target sirolimus trough blood concentration.
    • Weight ≥40 kg:
      • Loading dose: 6 mg on the first day.
      • Maintenance dose: 2 mg once daily.
      • Adjust the dose to achieve the target sirolimus trough blood concentration.

Dosage Adjustment:

  • Sirolimus dosages should be adjusted to maintain trough concentrations within the desired range based on the risk and concomitant therapy.
  • Maximum daily dose: 40 mg/day.
  • Dosage adjustment should be done at intervals of 7-14 days to account for the long half-life of sirolimus.
  • For children receiving twice-daily dosing, serum concentrations should be checked earlier due to pharmacokinetic differences.
  • In general, the dose can be calculated as follows: New sirolimus dose equals current dose multiplied by (target concentration/current concentration).
  • If a large dose increase is required, consider a loading dose calculated as: Loading dose equals (new maintenance dose minus current maintenance dose) multiplied by 3.
  • Maximum daily dose: 40 mg/day. If the required dose is greater than 40 mg (due to the loading dose), divide it over 2 days.
  • Serum concentrations should not be the sole basis for dosage adjustment; clinical signs/symptoms, tissue biopsy, and laboratory parameters should also be monitored.

Maintenance Therapy after Withdrawal of Cyclosporine:

  • After 2-4 months of combined therapy, withdrawal of cyclosporine may be considered in low to moderate risk patients.
  • Cyclosporine should be discontinued over 4-8 weeks.
  • An increase in the dosage of sirolimus (up to fourfold) should be anticipated to compensate for the removal of metabolic inhibition by cyclosporine and to maintain adequate immunosuppressive effects.

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

Infants ≥7 months, Children, and Adolescents ≤14 years: Oral solution.

  • Initial dose: 0.8 mg/m² twice daily (approximately every 12 hours).
  • Titrate the dose to achieve a serum trough concentration of 10-15 ng/mL.
  • The dosing is based on a pilot case series involving 6 patients.
  • The mean response time observed in the series was 25 days (range: 8-65 days).
  • Please note that additional data may be necessary to further establish the optimal dosing regimen for this indication.

Sirolimus pregnancy Risk Category: C

  • Based on available information, the use of sirolimus during pregnancy may potentially harm the fetus based on animal studies.
  • However, there is limited data regarding the use of sirolimus in pregnant women.
  • Therefore, women of reproductive age should use effective contraception before starting sirolimus treatment, during the treatment period, and for 12 weeks after discontinuing sirolimus.
  • Both male and female fertility may be affected while taking sirolimus.
  • Females may experience changes in menstrual periods, such as amenorrhea or menorrhagia, while males may have reduced sperm production, although this may be reversible.
  • If any pregnancies occur in female transplant recipients or are fathered by male transplant recipients, it is encouraged to report them to the Transplant Pregnancy Registry International for further study and monitoring.

Use sirolimus during breastfeeding

  • The presence of sirolimus in breast milk is currently unknown.
  • The manufacturer suggests that the decision to breastfeed while receiving sirolimus therapy should carefully consider the potential risk of exposing the infant to the medication, the benefits of breastfeeding for the infant, and the benefits of sirolimus treatment for 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 adjustment needed.

Maintenance dose:

  • For individuals with mild to moderate liver impairment (Child-Pugh classes A and B), the maintenance dose should be reduced by approximately 33%.
  • For individuals with severe liver impairment (Child-Pugh class C), the maintenance dose should be reduced by approximately 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):

If you have a known hypersensitivity or allergic reaction to sirolimus or any of the components in the formulation, it is important to avoid using sirolimus.

Allergic reactions can be serious and may include symptoms such as rash, itching, swelling, difficulty breathing, or dizziness.

Warnings and precautions

Anaphylactic/hypersensitivity reactions

  • Angioedema, which is swelling of deeper layers of the skin, has been reported with the use of sirolimus.
  • The risk of angioedema may be increased in patients with elevated levels of sirolimus or when sirolimus is used together with other medications known to cause angioedema, such as ACE inhibitors.
  • In some cases, angioedema has resolved when sirolimus was discontinued or the dose was reduced.
  • If you experience swelling of the face, lips, tongue, or throat, along with difficulty breathing or swallowing, seek immediate medical attention.

Infections [US Boxed Warning]

  • Please note that sirolimus, like other immunosuppressive agents, carries an important warning regarding the increased risk of infections.
  • Immune suppression caused by sirolimus can raise the chances of developing various infections, including opportunistic infections like reactivation of latent viral infections such as BK virus associated nephropathy, potentially fatal infections, and sepsis.
  • It is recommended to administer prophylactic treatment for Pneumocystis jirovecii pneumonia (PCP) for one year after transplantation and for cytomegalovirus (CMV) for three months post-transplant in patients at risk for CMV.
  • Progressive multifocal leukoencephalopathy (PML), a serious CNS infection caused by reactivation of the JC virus, has been reported in patients receiving immunosuppressive therapy, including sirolimus.
  • If you experience neurological changes such as apathy, ataxia, cognitive deficiency, confusion, or hemiparesis, it is important to seek prompt medical evaluation.
  • In certain cases, reducing the degree of immunosuppression may be considered, although the risk of organ rejection in transplant patients should also be taken into account.

Interstitial lung disease

  • Rare cases of interstitial lung disease (ILD), which includes conditions like pneumonitis, bronchiolitis obliterans organizing pneumonia (BOOP), and pulmonary fibrosis, have been reported in individuals taking sirolimus.
  • In some cases, ILD has been fatal.
  • There may also be a connection between ILD and pulmonary hypertension, including pulmonary arterial hypertension, with a higher risk seen in individuals with higher levels of sirolimus in their system.
  • If ILD is detected, it may improve with a reduction in dosage or by stopping sirolimus treatment altogether.

Hyperlipidemia

  • Sirolimus can raise levels of cholesterol and triglycerides in the blood, leading to hyperlipidemia.
  • It is important to be cautious when using sirolimus in patients who already have high lipid levels.
  • Regular monitoring of cholesterol and lipid levels is recommended.
  • If hyperlipidemia occurs, it should be managed according to current guidelines, which may involve lifestyle changes such as a healthy diet and exercise, as well as the use of lipid-lowering medications.

Lymphocele/fluid accumulation

  • Sirolimus use has been linked to a higher chance of fluid accumulation and the development of lymphocele.
  • This can manifest as peripheral edema, lymphedema, ascites, and the buildup of fluid around the lungs and heart (pleural and pericardial effusions), including more severe cases that can lead to tamponade.
  • It is important to exercise caution when using sirolimus in patients who may have difficulty tolerating fluid accumulation, especially those with cardiovascular conditions like heart failure or hypertension, as well as pulmonary disease.
  • Regular monitoring and appropriate management of fluid status are advised in these patients.

Malignancy: [US Boxed Warning]

  • There is a warning that immunosuppressive medications, including sirolimus, may increase the risk of developing certain types of cancer, including lymphoma and skin cancer.
  • It is important to take precautions to limit exposure to the sun and ultraviolet (UV) light and to use appropriate sun protection measures to reduce the risk of skin cancer.

Proteinuria

  • When switching renal transplant patients from calcineurin inhibitors to sirolimus as part of maintenance therapy, there have been reports of increased levels of protein in the urine, known as proteinuria.
  • The severity of proteinuria after the conversion to sirolimus may be higher in patients who had higher levels of proteinuria prior to the switch.
  • In some cases, the proteinuria can reach levels indicative of nephrotic syndrome.
  • It is important to monitor and manage proteinuria in these patients to ensure optimal kidney function and overall health.

Effects on the renal system:

  • Sirolimus, especially when used in combination with cyclosporine, may have effects on the kidneys.
  • It can increase levels of serum creatinine and decrease glomerular filtration rate (GFR) over the long term.
  • Additionally, immunosuppressed patients are at a higher risk of developing BK viral-associated nephropathy, which can further impair kidney function and potentially lead to graft loss.
  • If there are signs of worsening renal function, it may be necessary to reduce the overall burden of immunosuppressive therapy.
  • It is important to use sirolimus with caution in patients who are taking other medications that can affect renal function.
  • Regular monitoring of kidney function is crucial in these cases to ensure the best possible outcomes.

Wound healing/dehiscence:

  • Sirolimus use has been linked to the risk of wound dehiscence (the separation of wound edges) and impaired wound healing.
  • Therefore, caution should be exercised when using sirolimus in the perioperative period, particularly in patients with a body mass index (BMI) higher than 30 kg/m².
  • These individuals with a higher BMI are at an increased risk of experiencing abnormal wound healing.
  • Close monitoring and appropriate wound management strategies may be necessary to minimize complications and promote optimal healing in these patients.          

Sirolimus: Drug Interaction

Risk Factor C (Monitor therapy)

Angiotensin-Converting Enzyme Inhibitors

Sirolimus may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors.

Antidiabetic Agents

Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.

Bosentan

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Chloramphenicol (Ophthalmic)

May enhance the adverse/toxic effect of Myelosuppressive Agents.

Clofazimine

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Clotrimazole (Topical)

May increase the serum concentration of Sirolimus.

CloZAPine

Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.

Coccidioides immitis Skin Test

Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test.

CYP3A4 Inducers (Moderate)

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Deferasirox

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Denosumab

May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.

Erdafitinib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Erdafitinib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Erdafitinib

May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.

Fosaprepitant

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Ivosidenib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Larotrectinib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Mesalamine

May enhance the myelosuppressive effect of Myelosuppressive Agents.

Micafungin

May increase the serum concentration of Sirolimus.

Ocrelizumab

May enhance the immunosuppressive effect of Immunosuppressants.

Palbociclib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

P-glycoprotein/ABCB1 Inhibitors

May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of pglycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).

Pidotimod

Immunosuppressants may diminish the therapeutic effect of Pidotimod.

Promazine

May enhance the myelosuppressive effect of Myelosuppressive Agents.

Ranolazine

May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.

Rifabutin

May decrease the serum concentration of Sirolimus.

Sarilumab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Siltuximab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Siponimod

Immunosuppressants may enhance the immunosuppressive effect of Siponimod.

Tertomotide

Immunosuppressants may diminish the therapeutic effect of Tertomotide.

Tocilizumab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Trastuzumab

May enhance the neutropenic effect of Immunosuppressants.

Risk Factor D (Consider therapy modification)

Baricitinib

Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted.

CycloSPORINE (Systemic)

Sirolimus may enhance the adverse/toxic effect of CycloSPORINE (Systemic). An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described. CycloSPORINE (Systemic) may increase the serum concentration of Sirolimus. This is of specific concern with cyclosporine [MODIFIED]. Management: Administer oral doses of sirolimus 4 hours after doses of cyclosporine. Monitor for toxic effects of sirolimus if used with cyclosporine.

CYP3A4 Inducers (Strong)

May decrease the serum concentration of Sirolimus. Management: Avoid concomitant use of strong CYP3A4 inducers and sirolimus if possible. If combined, monitor for reduced serum sirolimus concentrations. Sirolimus dose increases will likely be necessary to prevent subtherapeutic sirolimus levels.

CYP3A4 Inhibitors (Moderate)

May increase the serum concentration of Sirolimus. Management: Monitor for increased serum concentrations of sirolimus if combined with a moderate CYP3A4 inhibitor. Lower initial sirolimus doses or sirolimus dose reductions will likely be required.

CYP3A4 Inhibitors (Strong)

May increase the serum concentration of Sirolimus. Management: Consider avoiding concurrent use of sirolimus with strong CYP3A4 inhibitors in order to minimize the risk for sirolimus toxicity. Concomitant use of sirolimus and voriconazole or posaconazole is contraindicated.

Dabrafenib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).

Deferiprone

Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely.

Echinacea

May diminish the therapeutic effect of Immunosuppressants.

Efavirenz

May decrease the serum concentration of Sirolimus. Management: Closely monitor sirolimus serum concentrations when starting, stopping, or changing doses of efavirenz, particularly during the first 2 weeks after any change. Dose adjustment of sirolimus may be required.

Erythromycin (Systemic)

May increase the serum concentration of Sirolimus. Sirolimus may increase the serum concentration of Erythromycin (Systemic). Management: Monitor for increased serum concentrations of sirolimus if combined with erythromycin. Lower initial sirolimus doses or sirolimus dose reductions will likely be required.

Fingolimod

Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections).

Fluconazole

May increase the serum concentration of Sirolimus. Management: Monitor for increased serum concentrations of sirolimus if combined with fluconazole. Lower initial sirolimus doses or sirolimus dose reductions will likely be required.

Itraconazole

May increase the serum concentration of Sirolimus. Management: Sirolimus dose adjustments will likely be needed when starting/stopping any azole antifungal. Clinical data suggest sirolimus (adult) dose reductions of 50-90% will be needed when starting an azole antifungal, but specific guidelines are lacking.

Ketoconazole (Systemic)

May increase the serum concentration of Sirolimus. Management: Sirolimus dose adjustments will likely be needed when starting/stopping any azole antifungal. Clinical data suggest sirolimus (adult) dose reductions of 50-90% will be needed when starting an azole antifungal, but specific guidelines are lacking.

Leflunomide

Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly.

Lorlatinib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.

Mitotane

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.

Nelfinavir

May increase the serum concentration of Sirolimus. Management: Carefully monitor the need for sirolimus dosage reductions when coadministered with nelfinavir. Sirolimus dosage reduction will probably be needed.

Nivolumab

Immunosuppressants may diminish the therapeutic effect of Nivolumab.

Roflumilast

May enhance the immunosuppressive effect of Immunosuppressants.

Sipuleucel-T

Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy.

St John's Wort

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.

Stiripentol

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring.

Tofacitinib

Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants.

Vaccines (Inactivated)

Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.

Venetoclax

May increase the serum concentration of Sirolimus. Management: Administer sirolimus at least 6 hours before venetoclax when concomitant therapy is required.

Risk Factor X (Avoid combination)

Antihepaciviral Combination Products

May increase the serum concentration of Sirolimus.

BCG (Intravesical)

Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).

BCG (Intravesical)

Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).

Cladribine

May enhance the immunosuppressive effect of Immunosuppressants.

Cladribine

May enhance the myelosuppressive effect of Myelosuppressive Agents.

Conivaptan

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Crizotinib

May increase the serum concentration of Sirolimus.

Dipyrone

May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased

Enzalutamide

May decrease the serum concentration of Sirolimus.

Fusidic Acid (Systemic)

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Grapefruit Juice

May increase the serum concentration of Sirolimus.

Idelalisib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

MiFEPRIStone

May increase the serum concentration of Sirolimus. Management: Avoid sirolimus during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically.

Natalizumab

Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.

Pimecrolimus

May enhance the adverse/toxic effect of Immunosuppressants.

Posaconazole

May increase the serum concentration of Sirolimus.

Tacrolimus (Systemic)

Sirolimus may enhance the adverse/toxic effect of Tacrolimus (Systemic). Tacrolimus (Systemic) may enhance the adverse/toxic effect of Sirolimus. Sirolimus may decrease the serum concentration of Tacrolimus (Systemic).

Tacrolimus (Topical)

Sirolimus may enhance the adverse/toxic effect of Tacrolimus (Topical). Tacrolimus (Topical) may enhance the adverse/toxic effect of Sirolimus.

Vaccines (Live)

Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants.

Voriconazole

May increase the serum concentration of Sirolimus.


Monitoring parameters:

  • Liver Function Tests (LFTs) and Complete Blood Count (CBC)

Sirolimus Levels:

  • Monitor sirolimus levels in all patients, especially:
    • Pediatric patients
    • Patients ≥13 years of age weighing <40 kg
    • Patients with hepatic impairment
    • Patients on concurrent potent inhibitors or inducers of CYP3A4 or P-gp
    • Patients with marked reduction or discontinuation of cyclosporine dosing
  • Monitor sirolimus levels when changing dosage forms of sirolimus

Serum Cholesterol and Triglycerides:

  • Monitor levels of cholesterol and triglycerides in the blood

Blood Pressure:

  • Regularly monitor blood pressure

Serum Creatinine:

  • Monitor serum creatinine levels, which indicate kidney function

Urinary Protein:

  • Monitor protein levels in urine

Serum Drug Concentrations:

  • Determine serum drug concentrations 3 to 4 days after loading doses and 7 to 14 days after dosage adjustments in renal transplant patients
  • Do not rely solely on drug concentrations for dosage adjustment, especially during cyclosporine withdrawal
  • Monitor clinical signs/symptoms, tissue biopsy, and laboratory parameters

Serum Trough Concentration:

  • Monitor serum trough concentration 10 to 20 days after initiating therapy for lymphangioleiomyomatosis and 7 to 14 days after dosage adjustments
  • Once a stable dose is achieved, assess trough concentrations at least every 3 months

Note: Concentrations and ranges may vary with assay methodology (chromatographic or immunoassay); assay methods are not interchangeable.


How to administer Sirolimus (Rapamune)?

Consistent Administration:

  • Sirolimus should be administered consistently, either with or without food.

Renal Transplant:

  • Take Sirolimus 4 hours after oral cyclosporine (Neoral or Gengraf) for renal transplant patients.

Solution:

  • Mix the prescribed dose of Sirolimus oral solution with at least 60 mL of water or orange juice.
  • Stir the mixture vigorously.
  • Do not use any other liquids for dilution.
  • Drink the diluted solution immediately.
  • Refill the cup with an additional 120 mL of water or orange juice.
  • Stir the contents vigorously.
  • Drink the entire contents at once.

Tablet:

  • Do not crush, split, or chew the Sirolimus tablet.

Mechanism of action of Sirolimus (Rapamune):

  • Sirolimus inhibits T-lymphocyte activation and proliferation in response to antigenic and cytokine stimulation.
  • It binds to FKBP-12, forming an immunosuppressive complex that inhibits the regulatory kinase mTOR (mechanistic target of rapamycin).
  • This inhibition of mTOR suppresses cytokine-mediated T-cell proliferation, preventing progression from the G1 to the S phase of the cell cycle.
  • Sirolimus's mechanism of action differs from other immunosuppressants.

Effects in Transplantation:

  • Sirolimus inhibits acute rejection of allografts and prolongs graft survival.
  • It prevents the activation of T-lymphocytes, reducing the immune response against the transplanted organ.

Effects in Lymphangioleiomyomatosis:

  • In lymphangioleiomyomatosis, the mTOR signaling pathway is activated due to the loss of the tuberous sclerosis complex (TSC) gene function.
  • This activation leads to cellular proliferation and the release of lymphangiogenic growth factors.
  • By inhibiting the mTOR pathway, sirolimus prevents the proliferation of lymphangioleiomyomatosis cells.
  • Sirolimus helps to manage lymphangioleiomyomatosis by targeting the underlying cellular mechanisms driving the disease.

Absorption:

  • Sirolimus is rapidly absorbed.

Distribution:

  • It has a distribution volume of 12 L/kg (with a range of 4 to 20 L/kg).

Protein binding:

  • Approximately 92% of sirolimus binds to albumin in the blood.

Metabolism:

  • Sirolimus undergoes extensive metabolism in the intestinal wall through P-glycoprotein and in the liver via CYP3A4, resulting in the formation of seven major metabolites.

Bioavailability:

  • The bioavailability of sirolimus is 14% for the oral solution and 27% higher for the oral tablet compared to the oral solution.
  • Although the oral solution and tablets are not bioequivalent, they have shown clinical equivalence at a dose of 2 mg.

Half-life elimination:

  • In children, the half-life elimination of sirolimus is approximately 13.7 ± 6.2 hours.
  • In adults, the mean half-life elimination is 62 hours (with a range of 46 to 78 hours), which is extended in individuals with hepatic impairment (Child-Pugh class A or B) to 113 hours.

Time to peak:

  • The time to reach peak concentration after administration is 1 to 3 hours for the oral solution and 1 to 6 hours for the tablet.

Excretion:

  • Sirolimus is primarily excreted in the feces (91%) through P-glycoprotein-mediated efflux into the gut lumen, and a small portion (2%) is excreted in the urine.

Sirolimus Brand Names (International):

  • Rapamune
  • Rapacan
  • Rapalimus
  • Siromune

Sirolimus Brand Names in Pakistan:

Sirolimus Brands in Pakistan will be updated later.

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