"The U.S. Food and Drug Administration today approved Liposorber LA-15 System to treat pediatric patients with primary focal segmental glomerulosclerosis (FSGS) either before transplant, or after renal (kidney) transplantation in which there is re"...
Rapamune Side Effects Center
Medical Editor: John P. Cunha, DO, FACOEP
Rapamune (sirolimus) is used to prevent your body from rejecting a transplanted kidney. Rapamune is sometimes used in a combination treatment with cyclosporine and a steroid medicine such as prednisone. It is an immunosuppressive agent. Common side effects include diarrhea, joint pain, shaking, acne, or trouble sleeping.
Rapamune is taken orally once daily, and the initial dose should be given as soon as possible after transplantation. Dose depends on the patient's immunologic risk, among other factors. Rapamune may interact with amphotericin B, bromocriptine, cimetidine, cisapride, danazol, metoclopramide, rifampin, rifabutin, rifapentine, St. John's wort, tacrolimus, ACE inhibitors, antibiotics, antifungal medications, calcium channel blockers, or HIV medicines. Tell your doctor all medications you are taking. Rapamune is not recommended for use during pregnancy. It is recommended that men and women using this medication use two forms of birth control (e.g., condoms and birth control pills) before starting this medication, while taking this medication, and for 12 weeks after stopping this medication. This drug may pass into breast milk and could have undesirable effects on a nursing infant. Breast-feeding is not recommended while using this drug.
Our Rapamune (sirolimus) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What is Patient Information in Detail?
Easy-to-read and understand detailed drug information and pill images for the patient or caregiver from Cerner Multum.
Rapamune in Detail - Patient Information: Side Effects
Sirolimus may cause a serious viral infection of the brain that can lead to disability or death. This risk is higher if you have a weak immune system or are receiving certain medicines. Call your doctor right away if you have any change in your mental state, problems with speech or walking, or decreased vision. These symptoms may start gradually and get worse quickly.
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Call your doctor at once if you have a serious side effect such as:
- fast heart rate;
- pain when you breathe, feeling short of breath;
- chest pain, feeling weak or tired;
- coughing up blood or mucus;
- feeling like you might pass out;
- pale skin, easy bruising or bleeding, weakness;
- fever, chills, body aches, flu symptoms;
- night sweats, weight loss;
- swelling in your face, stomach, hands or feet;
- rapid weight gain;
- pain or burning when you urinate; or
- slow healing of a wound.
Less serious side effects may include:
- joint pain;
- nausea, vomiting, diarrhea, constipation, stomach pain;
- headache; or
- acne or skin rash.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Read the entire detailed patient monograph for Rapamune (Sirolimus) »
What is Patient Information Overview?
A concise overview of the drug for the patient or caregiver from First DataBank.
Rapamune Overview - Patient Information: Side Effects
Diarrhea, joint pain, shaking, acne, or trouble sleeping may occur. If any of these effects persist or worsen, notify your doctor promptly.
Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.
Tell your doctor immediately if any of these unlikely but serious side effects occur: muscle pain/cramps, bone pain, increased thirst/hunger, frequent urination, vision changes, hearing problems (e.g., hearing loss, ringing in the ears), unusual tiredness/weakness, fast/slow/irregular heartbeat, easy bruising/bleeding, mental/mood changes, swelling ankles/feet, severe headache, dizziness, stomach/abdominal pain, missed/heavy/painful periods.
This drug increases the risk of a possibly fatal brain infection (PML - progressive multifocal leukoencephalopathy). Tell your doctor right away if you have any of these symptoms: clumsiness, sudden change in your thinking (such as confusion, difficulty concentrating), difficulty moving muscles, seizure, difficulty speaking.
Tell your doctor immediately if any of these rare but very serious side effects occur: change in the amount of urine, frothy urine, chest pain, shortness of breath, pain/redness/swelling of arms or legs, swelling abdomen, dark urine, yellowing eyes/skin, persistent nausea/vomiting.
Sirolimus may slow wound healing after surgery. Tell your doctor immediately if you have signs that your surgery wound is not healing well (e.g., redness, swelling, pain). The risk of poor wound healing is higher if you are obese.
Sirolimus may cause your cholesterol/triglycerides to increase. You may be required to have your cholesterol/triglycerides checked periodically and/or take another medication to control your cholesterol/triglycerides.
A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.
Sirolimus can commonly cause a mild rash that is usually not serious. However, you may not be able to tell it apart from a rare rash that could be a sign of a severe allergic reaction. Therefore, seek immediate medical attention if you develop any rash.
This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.
In the US -
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.
Read the entire patient information overview for Rapamune (Sirolimus)»
What is Prescribing information?
The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.
Rapamune FDA Prescribing Information: Side Effects
The following adverse reactions are discussed in greater detail in other sections of the label.
- Increased susceptibility to infection, lymphoma, and malignancy [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Excess mortality, graft loss, and hepatic artery thrombosis in liver transplant patients [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Bronchial anastomotic dehiscence in lung transplant patients [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
- Exfoliative dermatitis [see WARNINGS AND PRECAUTIONS]
- Angioedema [see WARNINGS AND PRECAUTIONS]
- Fluid Accumulation and Wound Healing [see WARNINGS AND PRECAUTIONS]
- Hypertriglyceridemia, hypercholesterolemia [see WARNINGS AND PRECAUTIONS]
- Decline in renal function in long-term combination of cyclosporine with Rapamune [see WARNINGS AND PRECAUTIONS]
- Proteinuria [see WARNINGS AND PRECAUTIONS]
- Interstitial lung disease [see WARNINGS AND PRECAUTIONS]
- Increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) [see WARNINGS AND PRECAUTIONS].
The most common ( ≥ 30%) adverse reactions observed with Rapamune in clinical studies are: peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia.
The following adverse reactions resulted in a rate of discontinuation of > 5% in clinical trials: creatinine increased, hypertriglyceridemia, and thrombotic thrombocytopenic purpura (TTP).
Clinical Studies Experience in Prophylaxis of Organ Rejection Following Renal Transplantation
The safety and efficacy of Rapamune Oral Solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials [see Clinical Studies]. The safety profiles in the two studies were similar.
The incidence of adverse reactions in the randomized, double-blind, multicenter, placebo-controlled trial (Study 2) in which 219 renal transplant patients received Rapamune Oral Solution 2 mg/day, 208 received Rapamune Oral Solution 5 mg/day, and 124 received placebo is presented in the table below. The study population had a mean age of 46 years (range 15 to 71 years), the distribution was 67% male, and the composition by race was: White (78%), Black (11%), Asian (3%), Hispanic (2%), and Other (5%). All patients were treated with cyclosporine and corticosteroids. Data ( ≥ 12 months post-transplant) presented in the following table show the adverse reactions that occurred in at least one of the Rapamune treatment groups with an incidence of ≥ 20%.
The safety profile of the tablet did not differ from that of the oral solution formulation [see Clinical Studies].
In general, adverse reactions related to the administration of Rapamune were dependent on dose/concentration. Although a daily maintenance dose of 5 mg, with a loading dose of 15 mg, was shown to be safe and effective, no efficacy advantage over the 2 mg dose could be established for renal transplant patients. Patients receiving 2 mg of Rapamune Oral Solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of Rapamune Oral Solution per day.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice.
ADVERSE REACTIONS OCCURRING AT A FREQUENCY OF ≥
20% IN AT LEAST ONE OF THE RAPAMUNE TREATMENT GROUPS IN A STUDY OF PROPHYLAXIS
OF ORGAN REJECTION FOLLOWING RENAL TRANSPLANTATION (%) AT ≥ 12 MONTHS
POST-TRANSPLANTATION (STUDY 2)a
|Adverse Reaction||-Rapamune Oral Solution-||Placebo
(n = 124)
| 2 mg/day
(n = 218)
| 5 mg/day
(n = 208)
|Urinary tract infection||26||33||26|
|a Patients received cyclosporine and corticosteroids.|
The following adverse reactions were reported less frequently ( ≥ 3%, but < 20%)
- Body as a Whole - Sepsis, lymphocele, herpes zoster, herpes simplex.
- Cardiovascular - Venous thromboembolism (including pulmonary embolism, deep venous thrombosis), tachycardia.
- Digestive System - Stomatitis.
- Hematologic and Lymphatic System - Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia.
- Metabolic/Nutritional - Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia.
- Musculoskeletal System - Bone necrosis.
- Respiratory System - Pneumonia, epistaxis.
- Skin - Melanoma, squamous cell carcinoma, basal cell carcinoma.
- Urogenital System - Pyelonephritis, decline in renal function (creatinine increased) in long-term combination of cyclosporine with Rapamune [see WARNINGS AND PRECAUTIONS].
Less frequently ( < 3%) occurring adverse reactions included: lymphoma/post-transplant lymphoproliferative disorder, mycobacterial infections (including M. tuberculosis), pancreatitis, cytomegalovirus (CMV), and Epstein-Barr virus.
Increased Serum Cholesterol and Triglycerides
The use of Rapamune in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment.
In Studies 1 and 2, in de novo renal transplant patients who began the study with fasting, total serum cholesterol < 200 mg/dL or fasting, total serum triglycerides < 200 mg/dL, there was an increased incidence of hypercholesterolemia (fasting serum cholesterol > 240 mg/dL) or hypertriglyceridemia (fasting serum triglycerides > 500 mg/dL), respectively, in patients receiving both Rapamune 2 mg and Rapamune 5 mg compared with azathioprine and placebo controls.
Treatment of new-onset hypercholesterolemia with lipid-lowering agents was required in 42-52% of patients enrolled in the Rapamune arms of Studies 1 and 2 compared with 16% of patients in the placebo arm and 22% of patients in the azathioprine arm. In other Rapamune renal transplant studies, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels > 240 mg/dL and triglycerides above recommended target levels [see WARNINGS AND PRECAUTIONS].
The table below summarizes the incidence of malignancies in the two controlled trials (Studies 1 and 2) for the prevention of acute rejection [see Clinical Studies].
At 24 months (Study 1) and 36 months (Study 2), there were no significant differences among treatment groups.
INCIDENCE (%) OF MALIGNANCIES IN STUDY 1 (24 MONTHS)
AND STUDY 2 (36 MONTHS) POST-TRANSPLANTa,b
|Malignancy||Rapamune Oral Solution 2 mg/day||Rapamune Oral Solution 5 mg/day||Azathioprine 2-3 mg/kg/day||Placebo|
(n = 284)
(n = 227)
(n = 274)
(n = 219)
(n = 161)
(n = 130)
|Lymphoma/ lymphoproliferative disease||0.7||1.8||1.1||3.2||0.6||0.8|
|Any Squamous Cellc||0.4||2.7||2.2||0.9||3.8||3.0|
|Any Basal Cellc||0.7||2.2||1.5||1.8||2.5||5.3|
|a : Patients received
cyclosporine and corticosteroids.
b : Includes patients who prematurely discontinued treatment.
c : Patients may be counted in more than one category.
Rapamune Following Cyclosporine Withdrawal
The incidence of adverse reactions was determined through 36 months in a randomized, multicenter, controlled trial (Study 3) in which 215 renal transplant patients received Rapamune as a maintenance regimen following cyclosporine withdrawal, and 215 patients received Rapamune with cyclosporine therapy [see Clinical Studies]. All patients were treated with corticosteroids. The safety profile prior to randomization (start of cyclosporine withdrawal) was similar to that of the 2 mg Rapamune groups in Studies 1 and 2.
Following randomization (at 3 months), patients who had cyclosporine eliminated from their therapy experienced higher incidences of the following adverse reactions: abnormal liver function tests (including increased AST/SGOT and increased ALT/SGPT), hypokalemia, thrombocytopenia, and abnormal healing. Conversely, the incidence of the following adverse events was higher in patients who remained on cyclosporine than those who had cyclosporine withdrawn from therapy: hypertension, cyclosporine toxicity, increased creatinine, abnormal kidney function, toxic nephropathy, edema, hyperkalemia, hyperuricemia, and gum hyperplasia. Mean systolic and diastolic blood pressure improved significantly following cyclosporine withdrawal.
The incidence of malignancies in Study 3 [see Clinical Studies] is presented in the table following.
In Study 3, the incidence of lymphoma/lymphoproliferative disease was similar in all treatment groups. The overall incidence of malignancy was higher in patients receiving Rapamune plus cyclosporine compared with patients who had cyclosporine withdrawn. Conclusions regarding these differences in the incidence of malignancy could not be made because Study 3 was not designed to consider malignancy risk factors or systematically screen subjects for malignancy. In addition, more patients in the Rapamune with cyclosporine group had a pretransplantation history of skin carcinoma.
INCIDENCE (%) OF MALIGNANCIES IN STUDY 3 (CYCLOSPORINE
WITHDRAWAL STUDY) AT 36 MONTHS POST-TRANSPLANTa,b
(n = 95)
|Rapamune with Cyclosporine Therapy
(n = 215)
|Rapamune Following Cyclosporine Withdrawal
(n = 215)
|Lymphoma/ lymphoproliferative disease||1.1||1.4||0.5|
|Any Squamous Cellc||3.2||3.3||2.3|
|Any Basal Cellc||3.2||6.5||2.3|
|a: Patients received
cyclosporine and corticosteroids.
b: Includes patients who prematurely discontinued treatment.
c: Patients may be counted in more than one category.
High-Immunologic Risk Patients
Safety was assessed in 224 patients who received at least one dose of sirolimus with cyclosporine [see Clinical Studies]. Overall, the incidence and nature of adverse events was similar to those seen in previous combination studies with Rapamune. The incidence of malignancy was 1.3% at 12 months.
Conversion from Calcineurin Inhibitors to Rapamune in Maintenance Renal Transplant Population
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant population have not been established [see Clinical Studies]. In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to Rapamune (initial target sirolimus concentrations of 12-20 ng/mL, and then 8-20 ng/mL, by chromatographic assay) in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n = 87) with a baseline glomerular filtration rate of less than 40 mL/min. There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death, in this stratum of the Rapamune treatment arm.
The subset of patients with a baseline glomerular filtration rate of less than 40 mL/min had 2 years of follow-up after randomization. In this population, the rate of pneumonia was 15/58 vs. 4/29, graft loss (excluding death with functioning graft loss) was 13/58 vs. 9/29, and death was 9/58 vs. 1/29 in the sirolimus conversion group and CNI continuation group, respectively.
In the subset of patients with a baseline glomerular filtration rate of greater than 40 mL/min, there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the Rapamune conversion arm.
Overall in this study, a 5-fold increase in the reports of tuberculosis among sirolimus (11/551) and comparator (1/273) treatment groups was observed with 2:1 randomization scheme.
Safety was assessed in a controlled clinical trial in pediatric ( < 18 years of age) renal transplant patients considered at high-immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy [see Clinical Studies]. The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with a higher incidence of deterioration of renal function (creatinine increased) compared to calcineurin inhibitor-based therapy, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections.
The following adverse reactions have been identified during post-approval use of Rapamune. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Body as a Whole - Lymphedema.
- Cardiovascular - Pericardial effusion (including hemodynamically significant effusions and tamponade requiring intervention in children and adults) and fluid accumulation.
- Digestive System - Ascites.
- Hematological/Lymphatic - The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA [see WARNINGS AND PRECAUTIONS]; pancytopenia, neutropenia.
- Hepatobiliary Disorders - Hepatotoxicity, including fatal hepatic necrosis, with elevated sirolimus trough concentrations.
- Immune System - Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, and hypersensitivity vasculitis [see WARNINGS AND PRECAUTIONS].
- Infections - Tuberculosis. BK virus associated nephropathy has been observed in patients receiving immunosuppressants, including Rapamune. This infection may be associated with serious outcomes, including deteriorating renal function and renal graft loss. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with immunosuppressants, including Rapamune [see WARNINGS AND PRECAUTIONS]. Clostridium difficile enterocolitis.
- Metabolic/Nutritional - Liver function test abnormal, AST/SGOT increased, ALT/SGPT increased, hypophosphatemia, hyperglycemia.
- Respiratory - Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of Rapamune. The risk may be increased as the sirolimus trough concentration increases [see WARNINGS AND PRECAUTIONS]; pulmonary hemorrhage; pleural effusion; alveolar proteinosis.
- Skin - Exfoliative dermatitis [see WARNINGS AND PRECAUTIONS].
- Urogenital - Nephrotic syndrome, proteinuria, focal segmental glomerulosclerosis. Azoospermia has been reported with the use of Rapamune and has been reversible upon discontinuation of Rapamune in most cases.
Read the entire FDA prescribing information for Rapamune (Sirolimus) »
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