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Rapamycin

Generic Name: Sirolimus

VA CLASSIFICATION
Primary: IM403

Commonly used brand name(s): Rapamune.

Another commonly used name is
rapamycin. Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Immunosuppressant —

Indications

Accepted

Transplant rejection, kidney (prophylaxis) —Sirolimus is indicated for the prevention of rejection of transplanted kidney allografts. It is recommended that sirolimus be used in a regimen with cyclosporine and corticosteroids.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Streptomyces hygroscopicus.{01}

Chemical group—
    Macrocyclic lactone{01}
Molecular weight—
    914.2.{01}
    Freely soluble in acetone, acetonitrile, benzyl alcohol, and chloroform; insoluble in water.{01}

Mechanism of action/Effect:

Immunosuppressant, systemic—Sirolimus inhibits cytokine (Interleukin (IL)–2, IL-4, and IL-15)— stimulated T lymphocyte activation and proliferation; it also inhibits antibody production. This may occur through formation of an immunosuppressive complex with FK Binding Protein-12 (FKBP-12). Although the sirolimus-(FKBP-12) complex is inactive against calcineurin activity, the complex binds to and inhibits activation of a key regulatory kinase, mammalian Target of Rapamycin (mTOR). This is believed to suppress cytokine-driven T-cell proliferation, inhibiting cell cycle progression from the G1 to S phase.{01}{02}{05}

Absorption:

Rapid, from the gastrointestinal tract. Bioavailability is approximately 14%. Rate of absorption is decreased in the presence of a high-fat diet.{01}The rate and extent of absorption is reduced in black patients.{03}

Distribution:

The volume of distribution (Vol D) of sirolimus is 12 ± 7.52 liters per kg of body weight; extensive uptake by formed blood elements is found{01}{03}{04}{05} (95% concentrated in red blood cells).{03}{04}{05}

Protein binding:

Very high (approximately 92%), primarily to serum albumin, 1—acid glycoprotein, and lipoproteins.
{01}
Biotransformation:

Hepatic, extensive, by cytochrome P450 3A enzymes{01}{04}{05}{06}{07}. Major metabolites include hydroxysirolimus, demethylsirolimus, and hydroxydemethylsirolimus.{01}{05}{07}

Elimination

57 to 63 hours.{03}{04}{05}{07} May be significantly increased (up to 72 hours) in males.{01} However, no adjustment in dosage is required.{01}

Time to peak concentration:

1 to 3 hours, after oral administration{01}{03}. A mean time-to-peak concentration of 2 hours after multiple oral doses in renal transplant patients.{01}

Peak blood concentration

12.2 ± 6.2 and 37.4 ± 21 nanograms per mL (ng/mL) in renal transplant patients administered 2 mg and 5 mg, respectively, of sirolimus in combination with cyclosporine and corticosteroids.{01}

Whole blood trough concentration

As measured by immunoassay—9 ng/mL in patients who received 2 mg of sirolimus per day; 17 ng/mL in patients who received 5 mg of sirolimus per day. Results from other assays may differ from those found with immunoassay.{01}

Duration of action:

The immunosuppressant effect of sirolimus lasted up to 6 months after discontinuation of therapy in some animal studies.{01}

Elimination:
    Only a minor amount (2.2%) is eliminated in urine; the majority of metabolites (91%) are recovered from the feces{01}


Precautions to Consider
{01}
Carcinogenicity/Tumorigenicity

Malignant lymphoma was statistically increased at dosages of 6 to 25 mg per kg of body weight (approximately 6 to 135 times the clinical dose based on body surface area) per day given for 86 weeks to female mice. There was a statistically significant increased incidence of testicular adenoma in rats given 0.2 mg per kg of body weight (approximately 0.4 to 1 times the clinical dose based on body surface area) per day for 104 weeks.{01}

Mutagenicity

Mutagenicity was not observed in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, nor with in vivo mouse micronucleus testing.{01}

Pregnancy/Reproduction
Fertility—
Adequate and well-controlled studies have not been conducted in humans. Sirolimus was not observed to affect fertility in female and male rats at doses of approximately 1 to 3 times (0.5 mg per kg of body weight) and 4 to 11 times (2 mg per kg of body weight) the clinical doses adjusted for body surface area, respectively. Reductions in testicular weights and/or histological lesions were observed in rats following dosages of 0.65 mg per kg of body weight (approximately 1 to 3 times the clinical dose based on body surface area) and above and in monkeys following dosages of 0.1 mg per kg of body weight (approximately 0.4 to 1 times the clinical dose based on body surface area) and above. Sperm counts were reduced following the administration of sirolimus at dosages of 6 mg per kg of body weight (approximately 12 to 32 times the clinical dose based on body surface area) for 13 weeks, but resolved 3 months after discontinuation of sirolimus in male rats.{01}

Pregnancy—
Adequate and well–controlled studies in humans have not been done.{01}

Sirolimus should be used during pregnancy only if the potential benefit outweighs the potential risk to the embryo/fetus. Effective contraception must be initiated before sirolimus therapy, during sirolimus therapy, and for 12 weeks after sirolimus therapy has been stopped.{01}

Sirolimus was associated with embryo and fetal toxicity in rats; there was no teratogenicity observed. Increased mortality and reduced fetal weights (with associated delays in skeletal ossification) occurred at dosages of 0.1 mg per kg of body weight and above (approximately 0.2 to 0.5 times the clinical doses adjusted for body surface area).{01} Embryo and fetal mortality increased in rats on combination sirolimus and cyclosporine compared to sirolimus alone. No effects on rabbit development at the maternally toxic dose of 0.05 mg per kg of body weight (approximately 0.3 to 0.8 times the clinical dose based on body surface area) were observed.{01}

FDA Pregnancy Category C{01}

Breast-feeding

It is not known whether sirolimus is distributed in human breast milk. However, trace amounts of sirolimus is excreted in the milk of lactating rats. Because similar drugs are known to be excreted in human milk, and because of the risk for adverse reactions in nursing infants, breast feeding is not recommended during sirolimus therapy{01}.

Pediatrics

Appropriate studies have not been performed on the relationship of age to the effects of sirolimus in the pediatric population in children up to 13 years of age. Safety and efficacy have not been established.{01}


Geriatrics


No information is available on the relationship of age to the effects of sirolimus in geriatric patients. Preliminary data pertaining to sirolimus trough concentrations infer that it is unnecessary to adjust doses based upon age in the geriatric renal transplant patient{01}.


Dental

The immunosuppressant effects of sirolimus may result in an increased incidence of microbial infection and delayed healing. Dental work, whenever possible, should be completed prior to initiation of therapy and undertaken with caution during therapy. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Antibiotics such as
rifabutin
rifapentine{01}

Anticonvulsants such as
carbamazepine or
phenobarbital or
phenytoin {01}    (may decrease sirolimus concentrations due to cytochrome P450 3A4 (CYP3 A4) isoenzyme induction.{01})



Antifungal agents such as
clotrimazole or
fluconazole or
itraconazole{01}
Bromocriptine{01}
Calcium channel blockers such as
nicardipine
verapamil{01}
Cimetidine{01}
Danazol{01}

Gastrointestinal prokinetic agents such as
cisapride
metoclopramide{01}

Macrolide antibiotics such as
clarithromycin or
erythromycin or
troleanodomycin{01}

Protease inhibitors, human immunodeficiency virus including
indinavir or
ritonavir {01}    (sirolimus is a known CYP3 A4 isoenzyme and P-glycoprotein substrate. Impairment of the CYP3 A4 enzyme-mediated metabolism of sirolimus, may lead to elevations in sirolimus blood concentrations and toxicity.{01})


» Cyclosporine {01}{06}{11}    (coadministration in renal transplantation patients increases the susceptibility to infection and possible developments of lymphomas and malignancy, especially of the skin. Patients should be monitored with adequate laboratory and supportive medical resources{11})

    (sirolimus is a known CYP3 A4 and P-glycoprotein substrate. Impairment of the CYP3 A4 enzyme-mediated metabolism of sirolimus, may lead to elevations in sirolimus blood concentrations and toxicity.{01}The drug interactions between sirolimus and cyclosporine have been observed clinically in either patients or healthy human subjects.{01}{06})

    (coadministration in liver transplant patients has resulted in excess mortality, graft loss and hepatic artery thrombosis [HAT], most cases of HAT occurred within 30 days post-transplantation {11})


» Diltiazem {01} or
» Ketoconazole {01}     (sirolimus is a known CYP3 A4 and P-glycoprotein substrate. Impairment of the CYP3 A4 enzyme-mediated metabolism of sirolimus, may lead to elevations in sirolimus blood concentrations and toxicity.{01}The drug interactions between sirolimus and diltiazem and ketoconazole have been observed clinically in either patients or healthy human subjects.{01}{06})


» Grapefruit juice{01}    (may inhibit CYP 3A4 enzymes, leading to decreased metabolism of sirolimus; must not be taken with or used to dilute sirolimus{01})


HMG-CoA reductase inhibitors{01}    (monitoring for rhabdomyolysis and other adverse effects as described in the respective labeling is recommended when these medications are administered concurrently with sirolimus and cyclosporine{01}{11})


Nephrotoxic medications{01} (see Appendix II), such as:
Aminoglycosides or
Amphotericin B     (may cause additive or synergistic impairment of renal function{01} )


» Rifampin{01}    (significant increases in sirolimus clearance occurs when administered with rifampin due to CYP3A4 induction by rifampin; an alternative antibacterial agent with less enzyme induction potential should be considered{01})


» St. John's wort    (because St. John's wort [hypericum perforatum] induces the activity of CYP3A4 and P-glycoprotein and sirolimus is a substrate of both, concurrent use of St. John's wort with sirolimus may result in decreased sirolimus concentrations{12}{13})


» Tacrolimus{11}    (may cause excess mortality, graft loss and hepatic artery thrombosis [HAT] in liver transplant patients, most cases of HAT occurred within 30 days post-transplantation {11})


Vaccines, killed virus    (immune response to vaccines may be decreased{01} )


» Vaccines, live virus    (avoid the use of live vaccines such as measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid.{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Cholesterol and
Triglycerides    (values may be increased;{01} in clinical trials, 42 to 52% of patients required treatment with lipid-lowering medications{01})


Creatinine, serum    (values may be increased. May indicate nephrotoxicity.{01})


Glomerular filtration rate{01} and
Hematocrit value and
Hemoglobin concentration    (may be decreased{01})


Leukocytes (neutrophils [WBC])    (blood counts may be increased or decreased {01})


Platelets    (blood counts may be decreased{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Hypersensitivity to sirolimus or its derivatives{01}
» Liver transplantation    (sirolimus not recommended for immunosuppressive therapy in liver transplants. Use in liver transplantation has resulted in excess mortality, graft loss and hepatic artery thrombosis.{11})


» Malignancy, current    (sirolimus use is associated with an increased susceptibility to lymphoma.{01})


Risk-benefit should be considered when the following medical problems exist
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


» Hepatic impairment    (prolonged half-life from 79 ± 12 hours to 113 ± 41 hours occurs in patients with impaired hepatic function. Dosage adjustment is necessary in patients with mild to moderate hepatic impairment.{01})


Hyperlipidemia{01}    (risk/benefit should be carefully considered before initiating therapy because renal transplant patients are at increased risk of developing clinically significant hyperlipidemia{01})


» Infection    (immunosuppression may exacerbate infections{01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood urea nitrogen (BUN) and
» Creatinine, serum    (recommended during administration of maintenance immunosuppression regimens; dosage adjustment may be necessary in patients with increased serum creatinine concentrations{01})


Cholesterol, serum and
Triglycerides, serum    (diet and exercise modifications and/or lipid-lowering agents may be required if cholesterol or triglyceride concentrations increase.{01})


Complete blood counts (CBCs)    (monitoring of CBC recommended to detect sirolimus-induced blood dyscrasias; changes in the neutrophil count may also indicate infection. )


» Sirolimus concentration, whole blood, trough    (recommended in patients likely to have altered drug metabolism, in patients ³ 13 years of age who weigh less than 40 kilograms, in patients with hepatic impairment, during concurrent administration of potent cytochrome P450 3A4 inducers and inhibitors, and/or if cyclosporine dosing is markedly reduced or discontinued. {01} )




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Anemia; (unusual bleeding or bruising; unusual tiredness or weakness; trouble breathing on exertion)
{01}    
atrial fibrillation (irregular heartbeat)
{01}    
chest pain {01}
{01}    
dyspnea {01}( shortness of breath)
{01}    
hypercholesteremia
{01}    
hyperkalemia (abdominal pain ; confusion; irregular or slow heartbeat ; nausea or vomiting ; numbness or tingling around lips, hands, or feet; shortness of breath or trouble breathing; unusual tiredness or weakness; weakness or heaviness of legs; unexplained anxiety)
{01}    
hyperlipidemia
{01}    
hypertension
{01}    
hypokalemia (convulsions ; decreased urine output; fast or irregular heartbeat ; increased thirst; loss of appetite; mood changes; muscle pain or cramps; nausea or vomiting; numbness or tingling in hands, feet, or lips; shortness of breath; unusual tiredness or weakness)
{01}    
hypophosphatemia (bone pain; convulsions ; loss of appetite; muscle weakness ; difficulty breathing; unusual tiredness or weakness)
{01}    
; lymphoma {01}( black, tarry stools; general feeling of illness; swollen glands ; weight loss, unusual; yellow skin and eyes)
    
peripheral edema (swelling of hands, ankles, feet, or lower legs), rash
thrombocytopenia (unusual bleeding or bruising)
{01}    
urinary tract infection (bloody or cloudy urine; difficult, burning, or painful urination ; frequent urge to urinate; lower back or side pain)
{01}
{01}Incidence less frequent
    
Hemolytic-uremic syndrome {01}
{01}    
hypotension {01}
{01}    
lymphocele {01}
{01}    
skin ulcer {01}
{01}
Note: To minimize the occurrence of lymphocele, appropriate post-operative measures should be employed.{01}


Incidence rare
    
Capillary leak syndrome (fever; low blood pressure; swelling of legs and feet; weight gain){08}

{01}Frequency unknown
    
Abnormal healing — fascial dehiscence and anastomotic disruption, including wound, vascular, airway, ureteral, biliary following transplant surgery{11}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal pain
{01}    
acne
{01}    
arthralgia (difficulty in moving ; muscle pain or stiffness; pain)
{01}    
asthenia {01}(loss of energy or weakness)
    
back pain {01}
    
constipation
{01}    
diarrhea
{01}    
fever
{01}    
headache
{01}    
insomnia ( trouble in sleeping)
{01}    
nausea {01}
    
tremor (shaking or trembling )
{01}    
vomiting
{01}    
weight gain, unusual

{01}Incidence less frequent
    
Epistaxis {01}(nosebleed)
{01}    
facial edema {01}(swelling of the face)
{01}
{01}



Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
There was minimal experience with overdose of sirolimus during clinical trials.

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Atrial fibrillation{01}. (irregular heartbeat)—transient

Treatment of overdose


Supportive care:
Treatment of overdose of sirolimus is generally symptomatic and supportive {01}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



To enhance elimination:
Due to the high erythrocyte binding and low aqueous solubility of sirolimus, dialysis is unlikely to offer any significant clinical benefit in the management of sirolimus overdose{01}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Sirolimus (Systemic).
Consider advising the patient on the following (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to sirolimus or its derivatives

Pregnancy—Effective contraception is recommended prior to, during and 12 weeks after sirolimus therapy. Increased embryo/fetal mortality has occurred in animal studies.





Breast-feeding—It is unknown if sirolimus is distributed into human breast milk. Breast feeding is not recommended during sirolimus therapy, due to risk of side effects in infants





Dental—Dental work should be completed prior to initiation of therapy whenever possible
Other medications, especially cyclosporine, diltiazem, ketoconazole, rifampin, St. John's wort, or tacrolimus
Other medical problems, especially chickenpox, current malignancy, hepatic impairment, herpes zoster infection, liver transplantation or other infection

Proper use of this medication
» Reading patient package insert carefully

» Taking medication only as directed by physician

Establishing the routine of taking medication at the same time each day

Taking medication consistently in relation to the timing of the intake of food to help increase compliance and maintain steady blood concentrations

» Checking with physician before discontinuing or changing medication; possible need for lifelong therapy

Taking sirolimus 4 hours after cyclosporine modified oral solution (Neoral, SangCya) or cyclosporine modified capsules (Neoral)

Mixing oral solution of sirolimus with at least 2 ounces (1/4 cup, 60 mL) of water or orange juice in a glass or plastic container, stirring well and drinking immediately, then rinsing the glass with at least 4 ounces (1/2 cup, 120 mL) of additional liquid, stirring well, and drinking that liquid also to make sure that all of the medication is taken

» Proper dosing
Taking as soon as possible if remembered within 12 hours; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Importance of close monitoring by physician

Maintaining good dental hygiene and seeing dentist regularly for teeth cleaning

» Not eating raw oysters or other shellfish; making sure they are fully cooked before eating

» Continuing recommended vaccination schedule (except for live vaccines)

Avoiding people with colds or other infections

» Not drinking grapefruit juice or eating grapefruit


Side/adverse effects
Signs of potential side effects, especially anemia, atrial fibrillation, chest pain, dyspnea, hypercholesteremia, hyperkalemia, hyperlipidemia, hypertension, hypokalemia, hypophosphatemia, leukopenia, lymphoma, peripheral edema, rash, thrombocytopenia, urinary tract infection, hemolytic-uremic syndrome, hypotension, lymphocele, skin ulcer, capillary leak syndrome, and abnormal healing following transplant surgery


General Dosing Information
Patients receiving sirolimus should be under the supervision of a physician experienced in immunosuppressive therapy for renal transplant patients{01}.

Sirolimus is indicated for use in conjunction with cyclosporine and corticosteroids. It is recommended that sirolimus be taken 4 hours after cyclosporine{01}.

Oral sirolimus is to be administered once daily. It is recommended that the initial dose be administered as soon as possible after transplantation{01}.

Because sirolimus is extensively metabolized by the liver, it is recommended that the maintenance dose be reduced by approximately one third in patients with impaired hepatic function{01}. However, adjustment of the loading dose is not necessary.{01}

Antimicrobial prophylaxis against Pneumocystis carinii pneumonia is recommended for 1 year following transplantation.{01}

Antiviral prophylaxis against cytomegalovirus (CMV) is recommended for 3 months following transplantation, especially in patients at increased risk for developing CMV disease.{01}

In clinical trials, maintenance doses of 5 milligrams (mg) per day provided no greater efficacy than 2 mg per day, and produced an overall less favorable safety profile than the 2 mg per day dose.{01}

Diet/Nutrition
It is recommended that sirolimus be taken consistently either with or without food, in order to minimize variability of absorption{01}.

Grapefruit juice significantly reduces the CYP3A4–mediated metabolism of sirolimus, and should not be taken with the drug nor used for dilution. Conversely, the rate of absorption of sirolimus is decreased in the presence of a high-fat diet{01}.

Bioequivalence information
Cyclosporine oral solution USP ( Sandimmune) is not bioequivalent to cyclosporine modified capsules (Neoral) and, therefore, these dosage forms cannot be used interchangeably.{01}

Safety considerations for handling this medication
Special precautions for handling sirolimus are unnecessary. However, wash thoroughly with soap and water, if direct contact with the skin or mucous membranes occurs; rinse eyes with plain water.{01}


Oral Dosage Forms

SIROLIMUS ORAL SOLUTION

Usual Adult and Adolescent Dose
Transplant rejection, kidney (prophylaxis)
Oral, loading dose of 6 mg and a maintenance dose of 2 mg once daily. For adolescents above the age of 13 years weighing less than 40 kg, the dose should be adjusted based upon body surface area, to 1 mg per square meter per day, following a 3 mg per square meter loading dose.{01}

Note: Reduce the dose by approximately one third in patients with hepatic impairment; an adjustment in the loading dose is unnecessary.{01}



Usual pediatric dose
Transplant rejection, kidney (prophylaxis)
Children up to 13 years of age—Safety and efficacy have not been established.{01}

Children 13 years of age or older—See Usual adult and adolescent dose.


Usual geriatric dose
See Usual adult and adolescent dose

Strength(s) usually available
U.S.—


1 mg per 1 mL (Rx) [Rapamune ( Phosal 50 PG® (phosphatidylcholine, propylene glycol, monodiglycerides, ethanol 1.5% —2.5%, soy fatty acids, and ascorbyl palmitate) and Polysorbate 80, NF){01}]

Packaging and storage:
Store between 2 and 8° Celsius (C) (36 and 46° Fahrenheit (F)). Brief periods of storage (less than 30 days) at room temperatures up to 25° C (77° F) are tolerated. The solution should be protected from light{01}.

Sirolimus oral solution may be stored in the syringe for up to 24 hours at room temperature up to 25 °C (77 °F) or refrigerated at temperatures between 2 and 8 °C (36 and 46 °F).{01}

Preparation of dosage form:
Oral sirolimus should be diluted in a glass or plastic container with at least 2 fluid ounces (1/4 cup, 60 mL) of water or orange juice. The drug should not be diluted in grapefruit juice or any other liquid{01}. See the manufacturer's package insert for instructions.

Stability:
Stable for up to 24 months in protected, unopened bottles and aluminum pouches. The solution should be used within one month after bottle opening. The solution should be used immediately after dilution{01}. The syringe should be discarded after one use.{01}

Note: When dispensing, include the calibrated oral dose syringes provided by the manufacturer.



SIROLIMUS TABLETS

Usual Adult and Adolescent Dose
Transplant rejection, kidney (prophylaxis)
Oral, loading dose of 6 mg and a maintenance dose of 2 mg once daily. For adolescents above the age of 13 years weighing less than 40 kg, the dose should be adjusted based upon body surface area, to 1 mg per square meter per day, following a 3 mg per square meter loading dose.{10}

Note: Reduce the maintenance dose by approximately one third in patients with hepatic impairment; an adjustment in the loading dose is unnecessary.{10}



Usual pediatric dose
Transplant rejection, kidney (prophylaxis)
Children up to 13 years of age—Safety and efficacy have not been established.{10}

Children 13 years of age or older—See Usual adult and adolescent dose.


Usual geriatric dose
See Usual adult and adolescent dose

Strength(s) usually available
U.S.—


1 mg (Rx) [Rapamune (sucrose) (lactose) (polyethylene glycol 8000 ) (calcium sulfate) ( microcrystalline cellulose) (pharmaceutical glaze ) (talc) (titanium dioxide ) (magnesium stearate) ( providone) (poloxamer 188) ( polyethylene glycol 20,000) (glycerol monoleate ) (carnauba wax) (and other ingredients){01}]

Packaging and storage:
Store between 20 and 25°C (68 and 77°F). {10}

Auxiliary labeling:
Protect from light.{10}



Developed: 04/06/2000
Revised: 07/28/2002



References
  1. Product Information: Rapamune sirolimus. Wyeth-Ayerst Laboratories, Philadelphia, PA, USA, (PI revised 9/99) reviewed 1/2000.
  1. Haczku A, Alexander A, Brown P et al: The effect of dexamethasone, cyclosporine, and rapamycin on T-lymphocyte proliferation in in vitro:comparison of cells from patients with glucocorticoid-sensitive and glucocorticoid-resistant chronic asthma. J Allergy Clin Immunol 1994; 93:510–519.
  1. Zimmerman JJ & Kahan BD: Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration . J Clin Pharmacol 1997; 37:405–415.
  1. Ferron GM,Mishina EV, Zimmerman JJ et al: Population pharmacokinetics of sirolimus in kidney transplant patients. Clin Pharmacol Ther 1997; 61:416–428.
  1. Kelly PA. Gruber SA. Behbod F et al: Sirolimus, a new, potent immunosuppressive agent. Pharmacotherapy 1997; 17:1148–1156.
  1. Kaplan B, Meier-Kriesche HU, Napoli KL et al: The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther 1998; 63:48–53.
  1. Yatscoff RW, Wang P, Chan K et al: Rapamycin: distribution, pharmacokinetics, and therapeutic range investigations. Ther Drug Monit 1995; 17:666–671.
  1. Kaplan MJ, Ellis CN, Bata-Csorgo Z et al: Systemic toxicity following administration of sirolimus (formerly rapamycin) for psoriasis. Arch Dermatol 1999; 135:553–557.
  1. Kahan BD & Napoli KL: Role of therapeutic drug monitoring of rapamycin. Transplant Proc 1998; 30:2189–2191.
  1. Product Information: Rapamune sirolimus. Wyeth-Ayerst Laboratories, Philadelphia, PA, USA, (PI revised 1/01) reviewed 3/2001.
  1. Product Information: Rapamune® sirolimus. Wyeth-Ayerst Laboratories, Philadelphia, PA, USA, (PI revised 4/2002) reviewed 6/2002.
  1. Reviewer comment, 06/27/2002.
  1. Product Information: Rapamune® sirolimus. Wyeth-Ayerst Laboratories, Philadelphia, PA, USA (PI revised 05/24/2002), reviewed 07/2002.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.