Sirolimus

Sirolimus is an Immunosuppressive drug, belonging to the pharmacological class of "mTOR Inhibitors" or "mTOR Kinase Inhibitors".

Sirolimus has been approved to relieve symptoms and also for the treatment and maintenance of Chordoma, advanced Graft-versus-host disease, Heart transplantation, prophylaxis of rejection and allograft vasculopathy, Kidney transplantation, rejection prophylaxis, Liver transplantation, rejection prophylaxis, Lung transplantation, rejection prophylaxis, Lymphangioleiomyomatosis, Renal angiomyolipoma.

Sirolimus's systemic availability is approximately 14%. Mean sirolimus bioavailability after tablet administration is roughly 27% higher than that of the solution in healthy subjects. While sirolimus tablets and the solution are not bioequivalent, clinical equivalence has been shown at the 2 mg dose level. Sirolimus is extensively metabolized in the intestinal wall and liver, mainly by CYP3A4-mediated O-demethylation and/or hydroxylation, yielding pharmacologically inactive metabolites. After oral [14C] sirolimus administration in healthy subjects, about 91% of radioactivity was recovered from faeces, with only 2.2% detected in urine, and some metabolites were detectable in both faeces and urine.

The common side effects of Sirolimus include Diarrhea, Constipation, Nausea, Vomiting, Stomach pain, Joint pain, Shaking, Acne, Skin rash, Headache ,Trouble sleeping.

Sirolimus is available in the form of Oral tablets and oral solutions.

Sirolimus is approved in Germany, Japan, Malaysia, India, the U.K., and China.

Sirolimus, belonging to the pharmacological class of "mTOR Inhibitors" or "mTOR Kinase Inhibitors", acts as an Immunosuppressive Drugs.

Sirolimus exerts its immunosuppressive effects through the inhibition of T-lymphocyte activation and proliferation triggered by antigenic and cytokine stimuli (such as Interleukin [IL]-2, IL-4, and IL-15). Unlike other immunosuppressants, it utilizes a unique mechanism. Sirolimus also hampers antibody production. Within cells, sirolimus forms a complex with the immunophilin F.K. Binding Protein-12 (FKBP-12), creating an immunosuppressive entity. Notably, this sirolimus:FKBP-12 complex does not impact calcineurin activity. Instead, it binds to and hinders the activation of the mammalian Target Of Rapamycin (mTOR), a pivotal regulatory kinase. By doing so, it curtails cytokine-driven T-cell proliferation, thereby obstructing the transition from the G1 phase to the S phase of the cell cycle.

Sirolimus has been approved to relieve symptoms and also for the treatment and maintenance of Chordoma, advanced, Graft-versus-host disease, Heart transplantation, prophylaxis of rejection and allograft vasculopathy, Kidney transplantation, rejection prophylaxis, Liver transplantation, rejection prophylaxis, Lung transplantation, rejection prophylaxis, Lymphangioleiomyomatosis, Renal angiomyolipoma.

For adult renal transplant patients with low to moderate immunologic risk, taking 2 mg of sirolimus resulted in peak concentrations (Cmax) of 14.4 ± 5.3 ng/mL and 15.0 ± 4.9 ng/mL for oral solution and tablets, respectively. The time it took to reach peak concentrations (Tmax) was 2.1 ± 0.8 hours for oral solution and 3.5 ± 2.4 hours for tablets. Healthy individuals reached Tmax in approximately one hour. After six days of twice-daily administration without an initial loading dose, steady-state concentrations were achieved, resulting in an average 2-3 fold increase in sirolimus trough concentrations.

Sirolimus is found to be available in the form of Oral tablets, Oral solutions.

Sirolimus can be used in the following treatment:

• Chordoma, advanced
• Graft-versus-host disease
• Heart transplantation, prophylaxis of rejection as well as allograft vasculopathy
• Kidney transplantation, rejection prophylaxis
• Liver transplantation, rejection prophylaxis
• Lung transplantation, rejection prophylaxis
• Lymphangioleiomyomatosis
• Renal angiomyolipoma

Sirolimus can help to relieve symptoms and also for the treatment and maintenance of Chordoma, advanced, Graft-versus-host disease, Heart transplantation, prophylaxis of rejection and allograft vasculopathy, Kidney transplantation, rejection prophylaxis, Liver transplantation, rejection prophylaxis, Lung transplantation, rejection prophylaxis, Lymphangioleiomyomatosis, Renal angiomyolipoma.

Sirolimus is approved for use in the following clinical indications:

• Chordoma, advanced
• Graft-versus-host disease
• Heart transplantation, prophylaxis of rejection as well as allograft vasculopathy
• Kidney transplantation, rejection prophylaxis
• Liver transplantation, rejection prophylaxis
• Lung transplantation, rejection prophylaxis
• Lymphangioleiomyomatosis
• Renal angiomyolipoma

• Chordoma, Advanced

Chordoma in an advanced stage can be managed with oral sirolimus at a daily dose of 2 mg, which should be adjusted to maintain a therapeutic trough level ranging between 15 and 20 ng/mL. This treatment is typically combined with imatinib and is continued until disease progression or if unacceptable toxicity occurs.

• Graft-versus-Host Disease

Graft-versus-Host Disease Prevention

Sirolimus, in combination with other immunosuppressive therapies, is frequently used to prevent graft-versus-host disease. The recommended oral dose is 2 mg once daily, usually initiated three days prior to allogeneic hematopoietic cell transplant. Trough levels between three and twelve ng/mL are targeted through day 150, followed by a tapering regimen through day 180 or even day 365, based on the absence of graft-versus-host disease. Another option involves a 12 mg loading dose, followed by 4 mg daily. The latter strategy is often combined with tacrolimus and methotrexate and requires tapering off after 6 to 9 months.

Graft-versus-Host Disease Acute Treatment

For newly diagnosed standard-risk acute graft-versus-host disease, a loading dose of 6 mg is followed by maintenance dosing to maintain a target trough level between ten to fourteen ng/mL until resolution. Once acute GVHD resolves, the dose is titrated to achieve a target trough of 5 to 10 ng/mL by at least day 56, and subsequently tapered to discontinue by the third month from day 56. For refractory acute GVHD, an oral dose of 4 to 5 mg/m2 is administered daily for 14 days.

Graft-versus-Host Disease Chronic Treatment

In the context of chronic treatment for graft-versus-host disease, a loading dose of 6 mg is followed by a daily maintenance dose of two mg, with a target trough level between 7 and 12 ng/mL. This regimen is generally continued for 6 to 9 months.

• Heart Transplantation, Prophylaxis of Rejection and Allograft Vasculopathy

Sirolimus use in heart transplantation for prophylaxis of rejection and allograft vasculopathy, albeit off-label, necessitates highly individualized dosing. It's typically avoided within 30 days post-transplant to minimize adverse effects. Depending on the strategy employed, the initiation of sirolimus can involve minimizing calcineurin inhibitors or avoiding them altogether. Doses and target trough concentrations vary and should be guided by institutional protocols.

• Kidney Transplantation, Rejection Prophylaxis

Sirolimus use in kidney transplantation for rejection prophylaxis requires careful consideration of patient characteristics. It's generally avoided in patients with specific conditions such as hyperlipidemia, high serum creatinine, or significant proteinuria. Dosing strategies are tailored based on the time from transplant, assay method, and concurrent therapies. The following are examples of dosing regimens based on available literature:

• Calcineurin Inhibitor Minimization

Following an initial loading dose of 6 mg on day 1, a daily maintenance dose of 2 mg is administered in combination with a calcineurin inhibitor and "mTOR Inhibitors" or "mTOR Kinase Inhibitors.". The dose is adjusted to maintain trough concentrations between 3 and 8 ng/mL.

• Calcineurin Inhibitor Avoidance

For this approach, a loading dose of 12 to 15 mg is given within 4 to 24 hours after the last calcineurin inhibitor dose, followed by a daily dose of 4 to 8 mg. This regimen is combined with adjunctive agents and "mTOR Inhibitors" or "mTOR Kinase Inhibitors.", with the goal of maintaining trough concentrations between 8 and 12 ng/mL.

• Liver Transplantation, Rejection Prophylaxis

Off-label use of sirolimus in liver transplantation for rejection prophylaxis is guided by strategies that minimize or avoid calcineurin inhibitors. The initiation of sirolimus is usually deferred until more than 30 days post-transplant to mitigate hepatic artery thrombosis risk. Similar to other transplantation scenarios, dosing and target trough concentrations must be highly individualized.

• Calcineurin Inhibitor Minimization

A daily dose of 2 mg sirolimus is used in combination with a calcineurin inhibitor, with or without "mTOR Inhibitors" or "mTOR Kinase Inhibitors.". The calcineurin inhibitor dose is reduced by 50% when sirolimus is initiated. The sirolimus dose is adjusted to maintain target trough concentrations between 4 and 10 ng/mL.

• Calcineurin Inhibitor Avoidance

In cases where calcineurin inhibitors are avoided, an initial daily dose of 2 to 4 mg sirolimus is combined with mycophenolic acid derivatives, with or without "mTOR Inhibitors" or "mTOR Kinase Inhibitors.". Sirolimus is usually started within 24 hours after the last calcineurin inhibitor dose. The goal is to maintain sirolimus trough concentrations between 5 and 10 ng/mL.

• Lung Transplantation, Rejection Prophylaxis

Sirolimus use in lung transplantation for rejection prophylaxis is off-label and requires special considerations to ensure the safety of the patient. The initiation of sirolimus is delayed until after the bronchial anastomosis has fully healed (around 90 days) to avoid potential complications. Dosing strategies should account for the individual's circumstances.

• Calcineurin Inhibitor Minimization

An oral daily dose of 1 to 2 mg sirolimus is combined with a calcineurin inhibitor, with or without "mTOR Inhibitors" or "mTOR Kinase Inhibitors.". The dose of the calcineurin inhibitor is reduced once sirolimus is initiated. Sirolimus dose adjustments are made to maintain target trough concentrations between 6 and 10 ng/mL.

• Lymphangioleiomyomatosis

For lymphangioleiomyomatosis, an initial oral dose of 2 mg sirolimus is administered once daily. The first trough concentration is assessed between days 10 and 21, and the dose is adjusted to maintain a target concentration of 5 to 15 ng/mL.

• Renal Angiomyolipoma

Sirolimus is used off-label in the treatment of renal angiomyolipoma. The initial dose is determined by body surface area (0.5 mg/m2), with subsequent titration to achieve a target trough level of 3 to 6 ng/mL. This may be increased to a target trough level of 6 to 10 ng/mL if there is insufficient reduction in lesion diameters at 2 months. Treatment typically spans 2 years.

Sirolimus is available in the following dosage forms and strengths:

• Oral tablets :0.5mg, 1mg, 2mg
• Oral Solutions: 1mg/ml

Oral tablets, Oral solutions

• Dosage Adjustments in Kidney Patients:

The understanding of Sirolimus's pharmacokinetics in cases of kidney impairment is not extensively defined. 

• Dosage Adjustments in Hepatic Impairment Patients:

Loading Dosage: No alteration in dosage is required.

Continual Dosage:

For individuals with mild to moderate impairment (Child-Pugh classes A and B): Decrease the regular dosage by around 33%.

For individuals with severe impairment (Child-Pugh class C): Decrease the regular dosage by approximately 50%.

• Dosage Adjustments in Pediatric Patients:

Sirolimus Dosage Guidelines for Heart Transplantation, Renal Transplantation, and Vascular Anomalies/Tumors:

Heart Transplantation:

• Limited data available for children and adolescents.
• Not typically used as first-line therapy; often considered as an alternative immunosuppressant in combination with cyclosporine or tacrolimus.
• Loading dose: 3 mg/m2 on day 1.
• Maintenance dose: Adjusted based on serum trough concentrations, aiming for a target range of 4-12 ng/mL. Some trials suggest lower target ranges of 4-10 ng/mL. Specific maintenance doses for children are not widely reported.
• Alternative fixed dosing for adolescents with weight ≥40 kg: Loading dose: 6 mg on day 1; maintenance: 2 mg once daily. Consider adjustments for initial higher targets followed by reduction.

Renal Transplantation, Prophylaxis of Organ Rejection (Low to Moderate Immunologic Risk):

• Conversion from tacrolimus with stable graft function.
• Limited data available for children and adolescents.
• Initial maintenance dose: 3 mg/m2/day divided every 12 hours; adjust for target sirolimus serum trough concentration.
• Manufacturer's recommendations vary based on weight: Loading and maintenance doses provided accordingly.
• Dosage adjustment based on maintaining desired trough concentrations within the target range (maximum daily dose: 40 mg/day).

Maintenance Therapy after Withdrawal of Cyclosporine:

• Consider withdrawal of cyclosporine after combined therapy for 2-4 months in low to moderate risk patients.
• Discontinue cyclosporine gradually over 4-8 weeks.
• Anticipate an increase in sirolimus dosage (up to fourfold) due to the removal of cyclosporine's metabolic inhibition and to ensure continued immunosuppressive effects.

Vascular Anomalies/Tumors (Refractory):

• Limited data available for infants ≥7 months, children, and adolescents ≤14 years.
• Oral solution: Initial dose of 0.8 mg/m2 twice daily (approximately every 12 hours).
• Titrate to achieve a serum trough concentration of 10-15 ng/mL.
• Response time based on a pilot case series was around 25 days (range: 8-65 days).

When incorporating sirolimus into your medication regimen, it's important to be mindful of certain dietary precautions to ensure optimal treatment outcomes and minimize potential interactions. Here are some key points to bear in mind:

Sirolimus's effectiveness can be influenced by dietary factors, and adhering to specific guidelines can help ensure its proper absorption and efficacy. Grapefruit and grapefruit juice, for example, should be avoided entirely due to their ability to disrupt the metabolism of sirolimus, leading to elevated levels of the medication in the bloodstream. Additionally, while sirolimus can be taken with or without food, maintaining consistency in your meal choices is advisable. High-fat meals, in particular, can impact the absorption of sirolimus, potentially affecting its therapeutic levels.

Molecule Sirolimus may be contraindicated in the following conditions:

• Sirolimus should not be used by individuals with a known allergy to Sirolimus or any of its inactive components.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows :

Increased Susceptibility to Infection and Potential Lymphoma Development

Increased Vulnerability to Infection and Risk of Lymphoma:

Immunosuppression can heighten susceptibility to infections and the potential for lymphoma and other malignancies, particularly skin-related ones. In Studies 1 and 2, lymphoma/lymphoproliferative disease rates were observed at 0.7-3.2% in Sirolimus-treated patients versus 0.6-0.8% in azathioprine and placebo controls. Over-suppression of the immune system can raise susceptibility to infections, including serious ones like tuberculosis, fatal infections, and sepsis. Only physicians experienced in immunosuppressive therapy and transplant patient management should utilize Sirolimus for organ rejection prophylaxis in renal transplant patients. Adequate medical resources and laboratory support must be available for managing patients on Sirolimus.

Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis in Liver Transplantation:

Sirolimus's safety and effectiveness have not been established in liver transplant patients, making its use in this context not recommended. Studies involving liver transplant patients treated with Sirolimus have shown adverse outcomes, including higher mortality, graft loss, and hepatic artery thrombosis.

Hypersensitivity Reactions:

Sirolimus administration has been associated with hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis.

Angioedema and Interaction with ACE Inhibitors:

Sirolimus has been linked to angioedema, and its concomitant use with drugs known for causing angioedema, like angiotensin-converting enzyme (ACE) inhibitors, might heighten the risk. Elevated sirolimus levels, whether with or without ACE inhibitors, can also potentiate angioedema.

Fluid Accumulation and Impairment of Wound Healing:

Reports of delayed wound healing, including lymphocele and wound dehiscence, have been associated with Sirolimus use. Inhibition of growth factors related to angiogenesis and vascular permeability might contribute to this phenomenon.

Hyperlipidemia and Cardiovascular Risks:

Sirolimus treatment has been linked to increased serum cholesterol and triglycerides, often necessitating lipid-lowering interventions. Patients on Sirolimus plus cyclosporine have frequently required anti-lipid therapy due to elevated lipid levels.

Renal Function Decline:

Regular monitoring of renal function is advised during Sirolimus-cyclosporine co-administration. Long-term use of this combination has shown renal function deterioration. Serum creatinine levels and glomerular filtration rates were notably higher in patients receiving Sirolimus and cyclosporine compared to controls.

Proteinuria and Latent Viral Infections:

Periodic monitoring of urinary protein excretion is recommended. Sirolimus use might increase urinary protein excretion, potentially leading to nephrotic syndrome. Immunocompromised patients are at risk of latent viral infections like B.K. virus-associated nephropathy.

Interstitial Lung Disease and Non-Infectious Pneumonitis:

Cases of interstitial lung disease, including pneumonitis and pulmonary fibrosis, have occurred in patients treated with Sirolimus. The risk might be linked to higher trough sirolimus concentration.

De Novo Use Without Cyclosporine in Renal Transplants:

Sirolimus's safety and effectiveness without cyclosporine in renal transplant patients are uncertain, as studies have shown higher acute rejection and mortality rates in these cases.

Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura/Thrombotic Microangiopathy:

Combining Sirolimus with calcineurin inhibitors might increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy.

Antimicrobial Prophylaxis and Latent Viral Infections:

Prophylaxis against infections like Pneumocystis carinii pneumonia and cytomegalovirus is recommended due to the heightened risk in transplant patients.

Sirolimus Trough Concentration Variation:

Sirolimus concentration measurement discrepancies exist between chromatographic and immunoassay methodologies, requiring careful interpretation.

Skin Cancer Risk and Interaction with Strong Inhibitors and Inducers:

Transplant patients are at increased risk for skin cancer due to immunosuppression. Caution is needed with strong inhibitors or inducers of CYP3A4 and/or P-gp when co-administered with Sirolimus.

Sirolimus metabolism could be affected by alcohol, potentially impacting its efficacy and safety profile. Patients need to understand that their body's ability to process sirolimus might be influenced by alcohol consumption. Additionally, since both sirolimus and alcohol are processed by the liver, combining the two might place added strain on this organ. This could increase the risk of adverse effects, particularly in patients with pre-existing liver conditions.

Moreover, the immunosuppressive effects of sirolimus are fundamental in preventing organ rejection. Alcohol, known to suppress the immune system, could potentially compromise the desired outcomes of sirolimus therapy.

Sirolimus is found in minimal quantities in the milk of lactating rats. However, whether sirolimus is excreted in human milk remains uncertain. The pharmacokinetics and safety characteristics of sirolimus in infants are not established. As numerous drugs are excreted in human milk as well as considering the potential for adverse effects on nursing infants due to sirolimus, a choice should be made between discontinuing nursing or discontinuing the medication, with consideration of the drug's significance for the mother.

Pregnancy Category C

Sirolimus exhibited embryo/fetotoxic effects in rats at doses around 0.2 to 0.5 times the human doses (adjusted for body surface area). These effects were characterized by increased mortality and reduced fetal weights, along with delays in skeletal ossification. However, no instances of teratogenesis were observed. When administered in combination with cyclosporine, rats displayed greater embryo/fetal mortality compared to sirolimus alone. In rabbits, at a dose that was maternally toxic and approximately 0.3 to 0.8 times the human doses (adjusted for body surface area), there were no discernible impacts on development. Adequate and well-controlled studies involving pregnant women are lacking. To initiate Sirolimus therapy, during its course, and for 12 weeks following cessation of treatment, effective contraception should be implemented. The use of Sirolimus during pregnancy should only be considered if the potential benefits outweighs the potential risks to the embryo/fetus.

When incorporating sirolimus into your medication regimen, it's important to be mindful of certain dietary precautions to ensure optimal treatment outcomes and minimize potential interactions. Here are some key points to bear in mind:

Sirolimus's effectiveness can be influenced by dietary factors, and adhering to specific guidelines can help ensure its proper absorption and efficacy. Grapefruit and grapefruit juice, for example, should be avoided entirely due to their ability to disrupt the metabolism of sirolimus, leading to elevated levels of the medication in the bloodstream. Additionally, while sirolimus can be taken with or without food, maintaining consistency in your meal choices is advisable. High-fat meals, in particular, can impact the absorption of sirolimus, potentially affecting its therapeutic levels.

The adverse reactions related to Sirolimus can be categorized as follows:

Common

• Almost diarrhea
• Constipation
• Nausea
• Vomiting
• Stomach pain
• Joint pain
• Shaking
• Acne
• Skin rash
• Headache
• Trouble sleeping

Less Common

• Dizziness
• Swelling or fluid retention
• Increased blood pressure
• Changes in taste
• Fatigue
• Increased levels of cholesterol or triglycerides in the blood
• Increased blood sugar levels
• Changes in kidney function
• Changes in liver function
• Difficulty breathing
• Decreased appetite
• Increased levels of potassium in the blood
• Increased levels of protein in the urine

Rare

• Severe allergic reactions (e.g., rash, itching, swelling, severe dizziness, trouble breathing)
• Blood clot formation
• Wound healing complications
• Interstitial lung disease
• Infections
• Serious liver problems
• Changes in blood counts (e.g., low red blood cell count, low white blood cell count)
• Elevated levels of bilirubin in the blood
• Pancreatitis
• Changes in vision
• Abnormal heart rhythm
• Pericardial effusion (fluid around the heart)
• High levels of uric acid in the blood
• Increased risk of cancer, including skin cancer

The clinically relevant drug interactions of Sirolimus is briefly summarized here:

Using Cyclosporine

When sirolimus is co-administered with cyclosporine, which acts as a substrate and inhibitor of CYP3A4 and P-gp, there is an observed increase in sirolimus concentrations. To mitigate this interaction with cyclosporine, it is advised to take Sirolimus four hours after administering cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). If cyclosporine is discontinued from the combination therapy with Sirolimus, higher doses of Sirolimus are required to maintain the recommended sirolimus trough concentration ranges [refer to Dosage and Administration .

Strong CYP3A4 and P-gp Inducers and Inhibitors

Avoid concurrent usage of sirolimus with potent inducers (such as rifampin, rifabutin) and potent inhibitors (like ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of CYP3A4 and P-gp. It is advisable to consider alternative agents with lower potential for interaction with sirolimus .

Grapefruit Juice

Due to grapefruit juice's ability to inhibit CYP3A4-mediated metabolism of sirolimus, it should not be consumed concurrently with or used for dilution of Sirolimus.

The following are the side effects involving Sirolimus:

• Diarrhea
• Constipation
• Nausea
• Vomiting
• Stomach pain
• Joint pain
• Shaking
• Acne
• Skin rash
• Headache
• Trouble sleeping

The use of Sirolimus should be prudent in the following group of special populations:

Pregnancy:

Pregnancy Category C

Sirolimus exhibited embryo/fetotoxic effects in rats at doses around 0.2 to 0.5 times the human doses (adjusted for body surface area). These effects were characterized by increased mortality and reduced fetal weights, along with delays in skeletal ossification. However, no instances of teratogenesis were observed. When administered in combination with cyclosporine, rats displayed greater embryo/fetal mortality compared to sirolimus alone. In rabbits, at a dose that was maternally toxic and approximately 0.3 to 0.8 times the human doses (adjusted for body surface area), there were no discernible impacts on development. Adequate and well-controlled studies involving pregnant women are lacking. To initiate Sirolimus therapy, during its course, and for 12 weeks following cessation of treatment, effective contraception should be implemented. The use of Sirolimus during pregnancy should only be considered if the potential benefits outweighs the potential risks to the embryo/fetus.

Pediatric:

Renal Transplantation

The effectiveness and safety of Sirolimus in children under the age of 13 have not been verified.

For children aged 13 and above, who are categorized as having a low to moderate immunological risk, the use of Sirolimus Oral Solution as well as Sirolimus Tablets for the prevention of organ rejection in renal transplantation has been proven to be both safe and effective. This conclusion is supported by thorough and well-regulated trials conducted with Sirolimus Oral Solution in adults, supplemented by pharmacokinetic data acquired from pediatric renal transplant patients .

However, based on safety and efficacy data derived from a controlled clinical trial involving pediatric and adolescent patients (below 18 years of age) who were deemed to be at high immunological risk (defined by a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy), the continuous use of Sirolimus Oral Solution or Tablets in conjunction with calcineurin inhibitors and "mTOR Inhibitors" or "mTOR Kinase Inhibitors." is not endorsed. This is due to the heightened occurrence of lipid abnormalities and the deterioration of renal function that these immunosuppressive regimens entail when compared to calcineurin inhibitors alone. This increased risk does not lead to additional benefits in terms of acute rejection, graft survival, or patient survival .

Lymphangioleiomyomatosis

The safety and efficacy of Sirolimus have not been established for pediatric patients under the age of 18.

Geriatric Use:

The clinical trials involving Sirolimus Oral Solution or Tablets lacked a sufficient representation of patients aged 65 years and older to establish whether their response differs from that of younger patients. Sirolimus trough concentration data indicate that modifying dosages based on age is unnecessary for elderly renal patients. No discernible variations in reactions between older and younger patients have been observed. In the context of geriatric patients, it is recommended to exercise prudence when selecting doses, typically commencing at the lower end of the dosing spectrum. This approach acknowledges the higher occurrence of compromised hepatic or cardiac function, as well as the prevalence of concurrent ailments or other medication regimens.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Sirolimus.

Instances of excessive dosing with Sirolimus have been reported, although such occurrences have remained infrequent. The consequences of an overdose typically align with the adverse effects detailed in the adverse reactions section.In cases of overdose, it is advisable to implement general supportive measures. Given sirolimus's limited solubility in water and its significant binding to erythrocytes and plasma proteins, it is unlikely that substantial dialysis clearance of sirolimus would occur. In murine and rat models, the acute oral LD50 surpassed 800 mg/kg.

Pharmacodynamics:

Sirolimus is an immunosuppressive medication exhibiting antifungal and antitumor properties. In preclinical studies, sirolimus demonstrated the ability to extend allograft survival in diverse organ transplantation models and effectively reversed acute rejection of heart and kidney allografts in rat models. Administered orally at doses of 2 mg/day and 5 mg/day, sirolimus notably decreased the occurrence of organ rejection in renal transplant patients with low to moderate immunologic risk over a six-month post-transplantation period when compared to azathioprine or placebo. Noteworthy is the finding that, in certain investigations, the immunosuppressive impact of sirolimus persisted for up to six months after treatment discontinuation, showcasing an alloantigen-specific tolerization effect. Sirolimus exerts potent inhibition on the proliferation of T cells, B cells, and antibody production in response to antigens. Sirolimus has shown to have suppressive effects on immune-mediated events associated with autoimmune disorders in rodent models.

Pharmacokinetics:

● Absorption:

Upon administration of Sirolimus Oral Solution, sirolimus exhibits mean times to peak concentration (tmax) of approximately 1 hour in healthy subjects and 2 hours in renal transplant patients. The systemic availability of sirolimus is relatively low, with an estimated value of around 14% following the administration of Sirolimus Oral Solution. Comparatively, the mean bioavailability of sirolimus after tablet administration is approximately 27% higher than that of the solution. While sirolimus tablets are not bioequivalent to the solution, clinical equivalence has been established at the 2 mg dose level. Notably, the concentrations of sirolimus in stable renal transplant patients, following the administration of Sirolimus Oral Solution, demonstrate dose-proportional behavior within the range of 3 to 12 mg/m2.

● Distribution:

Sirolimus demonstrates a blood-to-plasma ratio mean of 36 ± 18 in stable renal allograft patients, indicating significant distribution within formed blood elements. The mean volume of distribution (Vss/F) for sirolimus is 12 ± 8 L/kg. Notably, sirolimus binds extensively (approximately 92%) to human plasma proteins, primarily serum albumin (97%), α1-acid glycoprotein, and lipoproteins.

● Metabolism:

Sirolimus serves as a substrate for both CYP3A4 and P-gp. It undergoes extensive metabolism within the intestinal wall and liver, with counter-transport occurring from enterocytes of the small intestine into the gut lumen. The presence of CYP3A4 and P-gp inhibitors leads to elevated sirolimus concentrations, while inducers of these enzymes result in decreased sirolimus concentrations [see Warnings and Precautions (5.17) and Drug Interactions (7)]. Sirolimus undergoes substantial metabolic processes involving O-demethylation and/or hydroxylation. A total of seven major metabolites, including hydroxy, demethyl, and hydroxydemethyl forms, are identifiable in whole blood. Several of these metabolites can also be detected in plasma, fecal, and urine samples. It is worth noting that sirolimus constitutes the predominant component in human whole blood and contributes to over 90% of its immunosuppressive activity.

● Excretion:

Following administration of a single dose of [14C] sirolimus oral solution in healthy volunteers, approximately 91% of radioactivity was recovered from feces, with only a minor fraction (approximately 2.2%) excreted in urine. The mean ± S.D. terminal elimination half-life (t1⁄2) of sirolimus, following multiple dosing in stable renal transplant patients, was estimated to be approximately 62 ± 16 hours.

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