of moral Sirolimus the reality
Photo :Sirolimus cut [40:<10% reduction in lesion diameters at 2 months) for 2 years (Davies 2011) Dosing: Geriatric Refer to adult dosing. Dosing: Pediatric Renal transplant (rejection prophylaxis): Low-to-moderate immunologic risk: Adolescents 13 years: Oral: Refer to adult dosing. Dosing: Renal Impairment No dosage adjustment is necessary. However, adjustment of regimen (including discontinuation of therapy) should be considered when used concurrently with cyclosporine and elevated or increasing serum creatinine is noted. Dosing: Hepatic Impairment 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%. Administration Administer consistently (either with or without food). Renal transplant: Sirolimus should be taken 4 hours after oral cyclosporine (Neoral or Gengraf). Solution: Mix (by stirring vigorously) with at least 60 mL of water or orange juice. No other liquids should be used for dilution. Patient should drink 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. Tablet: Do not crush, split, or chew. Storage Oral solution: Store at 2 C to 8 C (36 F to 46 F). Protect from light. A slight haze may develop in refrigerated solutions, but the quality of the product is not affected. After opening, solution should be used within 1 month. If necessary, may be stored at temperatures up to 25 C (77 F) for 15 days after opening. Product may be stored in amber syringe for a maximum of 24 hours (at room temperature or refrigerated). Discard syringe after single use. Solution should be used immediately following dilution. Tablet: Store at 20 C to 25 C (68 F to 77 F). Protect from light. Drug Interactions Angiotensin-Converting Enzyme Inhibitors: Sirolimus may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy Antihepaciviral Combination Products: May increase the serum concentration of Sirolimus. Avoid combination Aprepitant: May increase the serum concentration of Sirolimus. Monitor therapy BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination Boceprevir: May increase the serum concentration of Sirolimus. Management: Significant sirolimus dose reductions may be required if used with boceprevir. Concurrent use should be performed with great caution and close monitoring of both sirolimus concentrations and clinical response. Consider therapy modification Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy Clotrimazole (Topical): May increase the serum concentration of Sirolimus. Monitor therapy CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination Crizotinib: May increase the serum concentration of Sirolimus. Avoid combination 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. Consider therapy modification CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy 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. Consider therapy modification CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy 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. Consider therapy modification 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). Consider therapy modification Dasatinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy DilTIAZem: May increase the serum concentration of Sirolimus. Monitor therapy Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification 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. Consider therapy modification Enzalutamide: May decrease the serum concentration of Sirolimus. Avoid combination Erythromycin (Systemic): May increase the serum concentration of Sirolimus. Sirolimus may increase the serum concentration of Erythromycin (Systemic). Avoid combination 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). Consider therapy modification Fluconazole: 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. Consider therapy modification Fosaprepitant: May increase the serum concentration of Sirolimus. Monitor therapy Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination Grapefruit Juice: May increase the serum concentration of Sirolimus. Avoid combination Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination Isavuconazonium Sulfate: May increase the serum concentration of Sirolimus. Monitor therapy 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. Consider therapy modification 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. Consider therapy modification 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. Consider therapy modification Letermovir: May increase the serum concentration of Sirolimus. Monitor therapy Micafungin: May increase the serum concentration of Sirolimus. Monitor therapy 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. Avoid combination 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. Consider therapy modification Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination 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. Consider therapy modification Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification Posaconazole: May increase the serum concentration of Sirolimus. Avoid combination Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor 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. Consider therapy modification 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. Consider therapy modification Tacrolimus (Systemic): May enhance the adverse/toxic effect of Sirolimus. Sirolimus may enhance the adverse/toxic effect of Tacrolimus (Systemic). Sirolimus may decrease the serum concentration of Tacrolimus (Systemic). Avoid combination Tacrolimus (Topical): May enhance the adverse/toxic effect of Sirolimus. Sirolimus may enhance the adverse/toxic effect of Tacrolimus (Topical). Avoid combination Telaprevir: May increase the serum concentration of Sirolimus. Management: Significant sirolimus dose reductions are likely to be required if used with telaprevir. Concurrent use should be performed with great caution and close monitoring of both sirolimus concentrations and clinical response. Consider therapy modification Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy 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. Consider therapy modification Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy 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. Consider therapy modification 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. Avoid combination Venetoclax: May increase the serum concentration of Sirolimus. Management: Administer sirolimus at least 6 hours before venetoclax when concomitant therapy is required. Consider therapy modification Verapamil: May increase the serum concentration of Sirolimus. Sirolimus may increase the serum concentration of Verapamil. Monitor therapy Voriconazole: May increase the serum concentration of Sirolimus. Avoid combination Adverse Reactions Incidence of many adverse effects is dose related. Reported events exclusive to renal transplant patients unless otherwise noted. Frequency not always defined. Cardiovascular: Peripheral edema ( 20% to 58%, LAM and renal transplants), hypertension (49%), edema (18% to 20%), chest pain (LAM), deep vein thrombosis, pulmonary embolism, tachycardia Central nervous system: Headache ( 20% to 34%, LAM and renal transplants), pain (29% to 33%), dizziness (LAM) Dermatologic: Acne vulgaris ( 20% to 22%, LAM and renal transplants), skin rash (10% to 20%) Endocrine & metabolic: Hypertriglyceridemia (45% to 57%), hypercholesterolemia ( 20% to 46%, LAM and renal transplants), amenorrhea, diabetes mellitus, hypermenorrhea, hypervolemia, hypokalemia, increased lactate dehydrogenase, menstrual disease, ovarian cyst Gastrointestinal: Constipation (36% to 38%), abdominal pain ( 20% to 36%, LAM and renal transplants), diarrhea ( 20% to 35%, LAM and renal transplants), nausea ( 20% to 31%, LAM and renal transplants), stomatitis (3% to> 20%) Genitourinary: Urinary tract infection (33%) Hematologic & oncologic: Anemia (23% to 33%), thrombocytopenia (14% to 30%), lymphoproliferative disorder ( 3%; including lymphoma), skin carcinoma ( 3%; includes basal cell carcinoma, squamous cell carcinoma, melanoma), hemolytic-uremic syndrome, leukopenia, lymphocele, thrombotic thrombocytopenic purpura Infection: Herpes simplex infection, herpes zoster, sepsis Neuromuscular & skeletal: Arthralgia (25% to 31%), myalgia (LAM), osteonecrosis Renal: Increased serum creatinine (39% to 40%), pyelonephritis Respiratory: Nasopharyngitis (LAM), epistaxis, pneumonia, upper respiratory tract infection (LAM) Miscellaneous: Wound healing impairment <3% (Limited to important or life-threatening): Ascites, azoospermia, cardiac tamponade, cytomegalovirus, dehiscence (fascial), Epstein-Barr infection, exfoliative dermatitis, focal segmental glomerulosclerosis, hepatic necrosis, hepatotoxicity, hyperglycemia, hypersensitivity angiitis, hypersensitivity reaction, hypophosphatemia, incisional hernia, interstitial pulmonary disease (dose related; includes pneumonitis, pulmonary fibrosis, and bronchiolitis obliterans organizing pneumonia with no identified infectious etiology), lymphedema, Merkel cell carcinoma, mycobacterium infection, nephrotic syndrome, neutropenia, pancreatitis, pancytopenia, pericardial effusion, pleural effusion, pneumonia due to Pneumocystis carinii , progressive multifocal leukoencephalopathy, proteinuria, pseudomembranous colitis, pulmonary alveolitis, pulmonary hemorrhage, renal disease (BK virus-associated), reversible posterior leukoencephalopathy syndrome, tuberculosis, weight loss, wound dehiscence ALERT: U.S. Boxed Warning Immunosuppression: Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression. Experienced physician: Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus for prophylaxis of organ rejection in patients receiving renal transplants. Patients receiving sirolimus should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The health care provider responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Liver transplantation: The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients. Many of these patients had evidence of infection at or near the time of death. In this and another study in de novo liver transplant recipients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in hepatic artery thrombosis; most cases of hepatic artery thrombosis occurred within 30 days post-transplantation, and most led to graft loss or death. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver transplant patients; therefore, use in these patients is not recommended. Lung transplantation: Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in lung transplant patients; therefore, use in these patients is not recommended. Warnings/Precautions Concerns related to adverse effects: Anaphylactic/hypersensitivity reactions: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis have been reported. Angioedema: Has been reported; risk is increased in patients with elevated sirolimus levels and/or concurrent use with other drugs known to cause angioedema (eg, ACE inhibitors). Angioedema resolved following discontinuation or dose reduction in some cases. Infections: [US Boxed Warning]: Immunosuppressive agents, including sirolimus, increase the risk of infection. Immune suppression may also increase the risk of opportunistic infections including activation of latent viral infections (including BK virus-associated nephropathy), fatal infections, and sepsis. Prophylactic treatment for Pneumocystis jirovecii pneumonia (PCP) should be administered for 1 year post-transplant; prophylaxis for cytomegalovirus (CMV) should be taken for 3 months post-transplant in patients at risk for CMV. Progressive multifocal leukoencephalopathy (PML), an opportunistic CNS infection caused by reactivation of the JC virus, has been reported in patients receiving immunosuppressive therapy, including sirolimus. Clinical findings of PML include apathy, ataxia, cognitive deficiency, confusion, and hemiparesis; promptly evaluate any patient presenting with neurological changes; consider decreasing the degree of immunosuppression with consideration to the risk of organ rejection in transplant patients. Interstitial lung disease: Cases of interstitial lung disease (ILD) (eg, pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], pulmonary fibrosis) have been observed (some fatal); may be associated with pulmonary hypertension (including pulmonary arterial hypertension) and risk may be increased with higher trough levels. ILD may resolve with dose reduction or discontinuation of therapy. Hyperlipidemia: May increase serum lipids (cholesterol and triglycerides). Use with caution in patients with hyperlipidemia. Monitor cholesterol/lipids; if hyperlipidemia occurs, follow current guidelines for management (diet, exercise, lipid lowering agents). Antihyperlipidemic therapy may not be effective in normalizing levels. Lymphocele/fluid accumulation: Use has been associated with an increased risk of fluid accumulation and lymphocele. Peripheral edema, lymphedema, ascites, and pleural and pericardial effusions (including significant effusions and tamponade) were reported; use with caution in patients in whom fluid accumulation may be poorly tolerated, such as in cardiovascular disease (heart failure or hypertension) and pulmonary disease. Malignancy: [US Boxed Warning]: Immunosuppressive agents, including sirolimus, may be associated with the development of lymphoma and other malignancies, including an increased risk of skin cancer; limit sun and ultraviolet light exposure; use appropriate sun protection. Proteinuria: Increased urinary protein excretion has been observed when converting renal transplant patients from calcineurin inhibitors to sirolimus during maintenance therapy. A higher level of proteinuria prior to sirolimus conversion correlates with a higher degree of proteinuria after conversion. In some patients, proteinuria may reach nephrotic levels; nephrotic syndrome (new onset) has been reported. Renal effects: May increase serum creatinine and decrease GFR with long-term combination use of sirolimus and cyclosporine. Immunosuppressed patients are at an increased risk of BK viral-associated nephropathy which may impair renal function and cause graft loss; consider decreasing immunosuppressive burden if evidence of deteriorating renal function. Use with caution in patients concurrently taking medications which may alter renal function. Wound dehiscence/healing: May be associated with wound dehiscence and impaired healing; use caution in the perioperative period. Patients with a body mass index (BMI)> 30 kg/m 2 are at increased risk for abnormal wound healing. Disease-related concerns: Hepatic impairment: Use with caution in patients with hepatic impairment; a reduction in the maintenance dose is recommended. Concurrent drug therapy issues: Calcineurin inhibitors: Concurrent use with a calcineurin inhibitor (cyclosporine, tacrolimus) may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA). Cyclosporine: Safety and efficacy of combination therapy with cyclosporine in high immunologic risk patients have not been studied beyond 12 months of treatment. Monitor renal function closely when combined with cyclosporine; consider dosage adjustment or discontinue in patients with increasing serum creatinine. Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Vaccines: Immunosuppressants may affect response to vaccination. Therefore, during treatment with sirolimus, vaccination may be less effective. The use of live vaccines should be avoided. Special populations: Liver transplants: [US Boxed Warning]: Sirolimus is not recommended for use in liver transplantation; studies indicate an association with an increased risk of hepatic artery thrombosis (HAT), graft failure, and increased mortality (with evidence of infection) in these patients when sirolimus is used in combination with cyclosporine and/or tacrolimus. Most cases of HAT occurred within 30 days of transplant. Lung transplants: [US Boxed Warning]: Sirolimus is not recommended for use in lung transplantation. Bronchial anastomotic dehiscence cases have been reported in lung transplant patients when sirolimus was used as part of an immunosuppressive regimen; most of these reactions were fatal. Renal transplant: In renal transplant patients, de novo use without cyclosporine has been associated with higher rates of acute rejection. Sirolimus may delay recovery of renal function in patients with delayed allograft function. Dosage form specific issues: Product interchangeability: Sirolimus tablets and oral solution are not bioequivalent, due to differences in absorption. Clinical equivalence was seen using 2 mg tablet and 2 mg solution. It is not known if higher doses are also clinically equivalent. Monitor sirolimus levels if changes in dosage forms are made. Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP, 1997; Zar 2007). Other warnings/precautions: Appropriate use: In renal transplant patients, sirolimus should be used in combination with cyclosporine (and corticosteroids) initially. Cyclosporine may be withdrawn in low-to-moderate immunologic risk patients after 2 to 4 months, in conjunction with an increase in sirolimus dosage. In high immunologic risk patients, use in combination with cyclosporine and corticosteroids is recommended for the first year. Adjustment of immunosuppressive therapy beyond 12 months should be considered based on clinical judgment. Experienced physician: [US Boxed Warning]: Should only be used by physicians experienced in immunosuppressive therapy and management of transplant patients. Adequate laboratory and supportive medical resources must be readily available. Laboratory monitoring: Sirolimus concentrations are dependent on the assay method (eg, chromatographic and immunoassay) used; assay methods are not interchangeable. Variations in methods to determine sirolimus whole blood concentrations, as well as interlaboratory variations, may result in improper dosage adjustments, which may lead to subtherapeutic or toxic levels. Determine the assay method used to assure consistency (or accommodations if changes occur), and for monitoring purposes, be aware of alterations to assay method or reference range and that values from different assays may not be interchangeable. Monitoring Parameters Monitor LFTs and CBC during treatment. Monitor sirolimus levels in all patients (especially in pediatric patients, patients 13 years of age weighing <40 kg, patients with hepatic impairment, or on concurrent potent inhibitors or inducers of CYP3A4 or P-gp, and/or if cyclosporine dosing is markedly reduced or discontinued), and when changing dosage forms of sirolimus. Also monitor serum cholesterol and triglycerides, blood pressure, serum creatinine, and urinary protein. Serum drug concentrations should be determined 3 to 4 days after loading doses and 7 to 14 days after dosage adjustments for renal transplant patients; however, these concentrations should not be used as the sole basis for dosage adjustment, especially during withdrawal of cyclosporine (monitor clinical signs/symptoms, tissue biopsy, and laboratory parameters). 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, trough concentrations should be assessed at least every 3 months. Note: Concentrations and ranges are dependent on and will vary with assay methodology (chromatographic or immunoassay); assay methods are not interchangeable. Pregnancy Risk Factor C Pregnancy Considerations Adverse events have been observed in animal reproduction studies. Effective contraception must be initiated before therapy with sirolimus and continued for 12 weeks after discontinuation. The National Transplantation Pregnancy Registry (NTPR) is a registry which follows pregnancies which occur in maternal transplant recipients or those fathered by male transplant recipients. The NTPR encourages reporting of pregnancies following solid organ transplant by contacting them at 877-955-6877 or NTPR@giftoflifeinstitute.org. Patient Education Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?) Patient may experience abdominal pain, constipation, diarrhea, nausea, rhinitis, pharyngitis, acne, or joint pain. Have patient report immediately to prescriber signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of infection, signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, coughing up blood, swollen glands, excessive weight loss, severe dizziness, passing out, tachycardia, night sweats, severe headache, skin growths, mole changes, severe loss of strength and energy, wound healing impairment, bruising, bleeding, swelling of arms or legs, menstrual changes, signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of progressive multifocal leukoencephalopathy (confusion, depression, memory impairment, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes), or signs of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (bruising or bleeding; loss of strength and energy; dark urine or jaundice; pale skin; change in amount of urine passed; vision changes; change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance; or fever) (HCAHPS). Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional q in all fairness
confer with Sirolimus become older
