Rapamune

>10%

Peripheral edema, w/ corticosteroids (54-58%)

Hypertriglyceridemia (45-57%; up to 90% when used with or following cyclosporine)

Hypercholesterolemia (43-46%; up to 90% when used with or following cyclosporine)

Constipation (36-38%)

Arthralgia (25-31%)

Thrombocytopenia (14-30%)

Rash (10-20%)

Hypertension (45-49%)

Increased creatinine (39-40%)

Abdominal pain (29-36%)

Diarrhea (25-35%)

Headache (34%)

Fever (23-34%)

Urinary tract infection (26-33%)

Anemia (23-33%)

Nausea (25-31%)

Arthralgia (25-31%)

Pain (29-33%)

Acne (22%)

Edema (18-20%)

Sepsis (<20%)

Lymphocele (<20%)

Venous thromboembolism (<20%)

Tachycardia (<20%)

Stomatitis (<20%)

Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (<20%)

Leukopenia (<20%)

Abnormal healing (<20%)

Increased lactic dehydrogenase (<20%)

Hypokalemia (<20%)

Hypophoaphatemia (<20%)

Hyperglycemia (<20%)

Diabetes mellitus (<20%)

Bone necrosis (<20%)

Pneumonia (<20%)

Epistaxis (<20%)

Melanoma (<20%)

Squamous cell carcinoma (<20%)

Basal cell carcinoma (<20%)

Pyelonephritis (<20%)

Ovarian cysts (<20%)

Menstrual disorders (amenorrhea and menorrhagia) (<20%)

Postmarketing Reports

Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported

Posterior reversible encephalopathy syndrome

Neuroendocrine carcinoma of the skin (Merkel cell carcinoma)

Impairment of wound healing

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.

Tell your doctor if you become pregnant during treatment. Use effective birth control while you are using this medication and for at least 12 weeks after your treatment ends.

The oral liquid form of sirolimus must be mixed with water or orange juice only. Do not use any other liquids to mix this medicine. Do not mix this medicine with grapefruit juice or potentially dangerous effects may result. Avoid eating grapefruit or drinking grapefruit juice while you are taking sirolimus.

If you also take cyclosporine, take the sirolimus at least 4 hours after taking cyclosporine.

Sirolimus can lower the blood cells that help your body fight infections. Avoid contact with people who have colds, the flu, or other contagious illnesses. Do not receive any vaccines without your doctor's advice. Contact your doctor immediately if you develop signs of infection.

Avoid getting this medication on your skin, or around your nose and mouth. If it does get onto any of these areas, wash with soap and water. If this medicine gets into your eyes, rinse them with plain water.

Sirolimus may increase your risk of developing lymphoma or other forms of cancer. Talk with your doctor about your specific cancer risk.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

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 Impairment of 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 HUS/TTP/TMA [see WARNINGS AND PRECAUTIONS].

The most common ( ≥ 30%) adverse reactions observed with Rapamune in clinical studies for organ rejection prophylaxis in recipients of renal transplantation are: peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia.

The most common ( ≥ 20%) adverse reactions observed with Rapamune in the clinical study for the treatment of LAM are: stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia.

The following adverse reactions resulted in a rate of discontinuation of > 5% in clinical trials for renal transplant rejection prophylaxis: creatinine increased, hypertriglyceridemia, and TTP. In patients with LAM, 11% of subjects discontinued due to adverse reactions, with no single adverse reaction leading to discontinuation in more than one patient being treated with Rapamune.

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 Table 1 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.

TABLE 1: 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

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, diabetes mellitus.
• 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], ovarian cysts, menstrual disorders (including amenorrhea and menorrhagia).

Less frequently ( < 3%) occurring adverse reactions included: lymphoma/post-transplant lymphoproliferative disorder, mycobacterial infections (including M. tuberculosis), pancreatitis, cytomegalovirus (CMV), and Epstein-Barr virus.

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].

Abnormal healing events following transplant surgery include fascial dehiscence, incisional hernia, and anastomosis disruption (e.g., wound, vascular, airway, ureteral, biliary).

Table 2 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) post-transplant, there were no significant differences among treatment groups.

TABLE 2: INCIDENCE (%) OF MALIGNANCIES IN STUDY 1 (24 MONTHS) AND STUDY 2 (36 MONTHS) POST-TRANSPLANTa,b

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 Table 3.

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.

TABLE 3: INCIDENCE (%) OF MALIGNANCIES IN STUDY 3 (CYCLOSPORINE WITHDRAWAL STUDY) AT 36 MONTHS POST-TRANSPLANTa,b

High-Immunologic Risk Renal Transplant 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 reactions 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 25.9% (15/58) versus 13.8% (4/29), graft loss (excluding death with functioning graft loss) was 22.4% (13/58) versus 31.0% (9/29), and death was 15.5% (9/58) versus 3.4% (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 2.0% (11/551) and comparator 0.4% (1/273) treatment groups was observed with 2:1 randomization scheme.

Pediatric Renal Transplant Patients

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.

Patients With Lymphangioleiomyomatosis

Safety was assessed in a controlled trial involving 89 patients with lymphangioleiomyomatosis, 46 of whom were treated with Rapamune [see Clinical Studies]. The adverse drug reactions observed in this trial were consistent with the known safety profile for renal transplant patients receiving Rapamune, with the addition of weight decreased which was reported at a greater incidence with Rapamune when compared to placebo. Adverse reactions occurring at a frequency of ≥ 20% in the Rapamune treatment group and greater than placebo include stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Rapamune in transplant patients. 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 -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, diabetes mellitus.
• Nervous system -Posterior reversible encephalopathy syndrome.
• 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 - Neuroendocrine carcinoma of the skin (Merkel cell carcinoma)[see WARNINGS AND PRECAUTIONS], exfoliative dermatitis [see WARNINGS AND PRECAUTIONS].
• Urogenital - Nephrotic syndrome, proteinuria, focal segmental glomerulosclerosis, ovarian cysts, menstrual disorders (including amenorrhea and menorrhagia). 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)

Rapamune is part of the drug class:

• Selective immunosuppressants

Grapefruit and grapefruit juice may interact with Rapamune and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

Sirolimus may increase your risk of developing lymphoma or other forms of cancer. Talk with your doctor about your specific risk.

You should not use this medicine if you are allergic to sirolimus, or if you have ever had a lung transplant or liver transplant.

To make sure sirolimus is safe for you, tell your doctor if you have:

• high cholesterol or triglycerides;

• cytomegalovirus (CMV);

• liver disease; or

• a family history of skin cancer (melanoma).

It is not known whether this medicine will harm an unborn baby. Do not use sirolimus if you are pregnant. Use effective birth control to prevent pregnancy while you are taking sirolimus, and for at least 12 weeks after your last dose.

It is not known whether sirolimus passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Sirolimus should not be given to a child younger than 13 years old.

Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Sirolimus is usually taken once a day. If you also take cyclosporine, wait at least 4 hours after your cyclosporine dose before you take sirolimus.

You may take sirolimus with or without food, but take it the same way every time.

Do not crush, chew, or break a sirolimus tablet. Tell your doctor if you have trouble swallowing the tablet whole.

Sirolimus oral liquid must be mixed in a glass or plastic cup with at least 2 ounces (1/4 cup) of water or orange juice. Do not use any other juices or liquids to mix this medicine. Stir the mixture and drink all of it right away. Then add at least 4 ounces (1/2 cup) more water or orange juice to the same glass, stir again and drink right away.

Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Sirolimus can lower blood cells that help fight infection, and may cause you to produce too much of a certain type of white blood cell. This can lead to serious conditions including cancer, severe brain infection causing disability or death, or a viral infection causing kidney transplant failure. Your blood will need to be tested often. Your kidney function will also need to be tested. Your sirolimus dosing schedule may be delayed based on the results of these tests.

You should not stop using sirolimus without your doctor's advice. Stopping suddenly could make your condition worse.

Store sirolimus tablets at room temperature, away from heat, moisture, and light.

Store sirolimus liquid in the refrigerator. Do not freeze. You may notice a slight haze to the liquid after it has been refrigerated. This haze will not affect the medication, and should disappear when the liquid reaches room temperature.

If you are using sirolimus oral liquid with a disposable syringe, you may store a loaded syringe in the carrying case provided. Keep the case at room temperature and use the medicine within 24 hours. Use a disposable syringe only once and then throw it away.

Metabolized by CYP3A4;1 also a substrate for P-glycoprotein.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased blood concentrations of sirolimus).1

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased blood concentrations of sirolimus).1

Nephrotoxic Drugs

Possible increased risk of nephrotoxicity with concurrent use of nephrotoxic drugs (e.g., aminoglycosides, amphotericin B); use with caution.1

Specific Drugs and Foods

Storage

Oral

Tight, light-resistant container at 20–25°C.1

2–8°C for solution in bottles; protect from light.1 Discard bottle 1 month after opening.1 May store solution at room temperature (≤25°C) for up to 15 days.1 May store solution in the amber syringe provided by manufacturer for up to 24 hours at 2–8°C or room temperature (≤25°C).1 Use immediately after dilution.1

If slight haze develops when solution in bottles is refrigerated, allow to stand at room temperature and shake gently until haze disappears.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Sirolimus is used together with other medicines to prevent the body from rejecting a transplanted kidney. It belongs to a group of medicines known as immunosuppressive agents.

When a patient receives an organ transplant, the body's white blood cells will try to get rid of (reject) the transplanted organ. Sirolimus works by preventing the white blood cells from getting rid of the transplanted organ.

Sirolimus is a very strong medicine. It can cause side effects that can be very serious, such as kidney problems. It may also reduce the body's ability to fight infections. You and your doctor should talk about the benefits of this medicine as well as the risks.

Sirolimus is also used to treat lymphangioleiomyomatosis, a rare lung disease that affects predominantly women of childbearing age.

This medicine is available only with your doctor's prescription.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. The exact amount of medicine you need has been carefully worked out. Using too much will increase the risk of side effects, while using too little may lead to rejection of your transplanted kidney.

This medicine usually comes with a Medication Guide and patient directions. Read them carefully and make sure you understand them before taking this medicine. If you have any questions, ask your doctor.

Take this medicine the same way every day. This means take it at the same time and take it consistently, either with or without food.

Do not change your dose or stop taking this medicine without checking first with your doctor. You may have to take this medicine for the rest of your life to prevent your body from rejecting the kidney transplant.

Sirolimus is usually used along with a corticosteroid (cortisone-like medicine) and cyclosporine. Sirolimus should be taken 4 hours after cyclosporine modified oral solution or cyclosporine modified capsules (Neoral®). If you have any questions about this, ask your doctor.

If you have been taking sirolimus together with cyclosporine for 2 to 4 months after your transplant, your doctor may want you to stop using cyclosporine and increase the dose of sirolimus. However, some patients (eg, black patients or those with transplant rejection in the past) may need to continue using cyclosporine for up to one year after the transplant. Your doctor will tell you if you need to keep taking cyclosporine.

Swallow the tablet whole. Do not crush, break, or chew it. If you are unable to take the tablet form, your doctor will give you an oral liquid and be given instructions on how to take it.

To use the oral liquid:

• Open the solution bottle and insert the adapter tightly into the bottle.
• Insert the amber syringe that comes with the bottle to draw the right amount of medicine out of the bottle.
• Empty the medicine from the syringe into a glass or plastic cup.
• Mix the medicine with at least 2 ounces (¼ cup or 60 milliliters [mL]) of water or orange juice. Stir the mixture well and drink it immediately.
• Add at least 4 ounces (½ cup or 120 mL) of additional water or orange juice, stir it well, and drink it to make sure that all of the medicine is taken.
• If you have been instructed by your doctor to carry your medicine, you may keep your daily dose of sirolimus in a tightly-capped syringe for a maximum of 24 hours at room temperature or in the refrigerator. Throw away the used syringe after each use.

If this medicine gets into your skin, wash it with soap and water right away. If it gets in your eyes, rinse them with water.

You should not eat grapefruit or drink grapefruit juice while you are taking this medicine. Grapefruit and grapefruit juice may cause higher levels of sirolimus in the body. This could result in more unwanted effects.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage forms (oral solution or tablets):
  • For prevention of kidney transplant rejection:
    • Adults and children 13 years of age and older weighing 40 kilograms (kg) or more—2 milligrams (mg) per day after an initial one-time dose of 6 mg. Some patients may require a dose of up to 5 mg per day after an initial one-time dose of 15 mg. However, the dose is usually not more than 40 mg per day.
    • Children 13 years of age and older weighing less than 40 kg—Dose is based on body size as determined by your doctor. The dose is 1 milligram (mg) per square meter [m(2)] of body surface area once a day after an initial one-time dose of 3 mg per square meter [m(2)] of body surface area.
    • Children younger than 13 years of age—Use and dose must be determined by your doctor.
  • For treatment of lymphangioleiomyomatosis:
    • Adults—At first, 2 milligrams (mg) per day. Your doctor may adjust your dose as needed.
    • Children—Use and dose must be determined by your doctor.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the tablets at room temperature in a closed container, away from heat, moisture, and direct light.

Store the oral liquid in the refrigerator. Protect it from direct light and moisture. Do not freeze. You may store the oral liquid at room temperature for a short period of time (not more than 15 days). If you see a slight haze or cloudiness in the bottle, leave it out at room temperature and shake it until the haze disappears. Throw away any unused medicine after 30 days.

Reports of overdose with Rapamune have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section [see Adverse Reactions (6)].

General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD50 was greater than 800 mg/kg.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2 mg daily clinical dose (adjusted for body surface area), there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. In a second mouse study at dosages that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In the 104-week rat study at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for body surface area), there were no significant findings.

Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.

Fertility was diminished slightly in both male and female rats following oral administration of sirolimus at doses approximately 10 times or 2 times, respectively, the clinical dose of 2 mg daily (adjusted for body surface area). In male rats, atrophy of testes, epididymides, prostate, seminiferous tubules and/or reduction in sperm counts were observed. In female rats, reduced size of ovaries and uteri was observed. Reduction of sperm count in male rats was reversible upon cessation of dosing in one study. Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at doses that were approximately equal to the clinical dose (adjusted for body surface area).

Clinical Therapeutics, Volume 22, Supplement B, April 2000 [see Dosage and Administration (2.5)].

Advise patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of the document.

See FDA-Approved Medication Guide.

Dosage

Patients should be given complete dosage instructions [see FDA-Approved Medication Guide].

Skin Cancer Events

Patients should be told that exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor because of the increased risk for skin cancer [see Warnings and Precautions (5.16)].

Pregnancy Risks

Women of childbearing potential should be informed of the potential risks during pregnancy and told that they should use effective contraception prior to initiation of Rapamune therapy, during Rapamune therapy, and for 12 weeks after Rapamune therapy has been stopped [see Use in Specific Populations (8.1)].

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

LAB-0473-9.0

ALWAYS DISPENSE WITH MEDICATION GUIDE

Pfizer
NDC 0008-1040-10

Rapamune®
(sirolimus) Tablets

0.5 mg

For oral use only.

Unit Dose - 100 Tablets
(10 Blister Cards of 10 Tablets Each)

Rx only

Substance Name

Sirolimus

CAS Registry Number

53123-88-9

Drug Class

Immunosuppressive Agents