A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rapamune Warnings, Precautions, Pregnancy, Nursing, Abuse - Sirolimus
Rapamune Warnings, Precautions, Pregnancy, Nursing, Abuse - Sirolimus
WARNINGS
WARNING:
Increased susceptibility to infection and the possible development of
lymphoma may result from immunosuppression. Only physicians experienced
in immunosuppressive therapy and management of renal transplant patients
should use Rapamune®. Patients receiving the drug should be managed in
facilities equipped and staffed with adequate laboratory and supportive
medical resources. The physician responsible for maintenance therapy should
have complete information requisite for the follow-up of the patient.
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Increased susceptibility to infection and the possible development of lymphoma
and other malignancies, particularly of the skin, may result from immunosuppression
(see ADVERSE REACTIONS). Oversuppression of the immune system can also
increase susceptibility to infection including opportunistic infections, fatal
infections, and sepsis. Only physicians experienced in immunosuppressive therapy
and management of organ transplant patients should use Rapamune. Patients receiving
the drug should be managed in facilities equipped and staffed with adequate
laboratory and supportive medical resources. The physician responsible for maintenance
therapy should have complete information requisite for the follow-up of the
patient. As usual for patients with increased risk for skin cancer, exposure
to sunlight and UV light should be limited by wearing protective clothing and
using a sunscreen with a high protection factor.
Increased serum cholesterol and triglycerides, that may require treatment,
occurred more frequently in patients treated with Rapamune compared to azathioprine
or placebo controls (see PRECAUTIONS
).
In phase III studies, mean serum creatinine was increased and mean glomerular
filtration rate was decreased in patients treated with Rapamune and cyclosporine
compared to those treated with cyclosporine and placebo or azathioprine controls
(see CLINICAL STUDIES ). Renal function should be monitored during the
administration of maintenance immunosuppression regimens including Rapamune
in combination with cyclosporine, and appropriate adjustment of the immunosuppression
regimen should be considered in patients with elevated serum creatinine levels.
Caution should be exercised when using agents which are known to impair renal
function (see PRECAUTIONS
).
In clinical trials, Rapamune has been administered concurrently with corticosteroids
and with the following formulations of cyclosporine:
Sandimmune® Injection (cyclosporine injection)
Sandimmune® Oral Solution (cyclosporine oral solution)
Sandimmune® Soft Gelatin Capsules (cyclosporine capsules)
Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED])
Neoral® Oral Solution (cyclosporine oral solution [MODIFIED])
The efficacy and safety of the use of Rapamune in combination with other immunosuppressive
agents has not been determined.
PRECAUTIONS
General
Rapamune is intended for oral administration only.
Lymphocele, a known surgical complication of renal transplantation, occurred
significantly more often in dose-related fashion in Rapamune-treated patients.
Appropriate post-operative measures should be considered to minimize this complication.
Lipids
The use of Rapamune® in renal transplant patients was associated with increased
serum cholesterol and triglycerides that may require treatment.
In phase III clinical trials, in de novo renal transplant recipients
who began the study with normal, fasting, total serum cholesterol (fasting serum
cholesterol < 200 mg/dL), there was an increased incidence of hypercholesterolemia
(fasting serum cholesterol > 240 mg/dL) in patients receiving both Rapamune®
2 mg and Rapamune® 5 mg compared to azathiopine and placebo controls.
In phase III clinical trials, in de novo renal transplant recipients
who began the study with normal, fasting, total serum triglycerides (fasting
serum triglycerides < 200 mg/dL), there was an increased incidence of hypertriglyceridemia
(fasting serum triglycerides > 500 mg/dL) in patients receiving Rapamune®
2 mg and Rapamune® 5 mg compared to 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 the study compared
to 16% of patients in the placebo arm and 22% of patients in the azathioprine
arm.
Renal transplant patients have a higher prevalence of clinically significant
hyperlipidemia. Accordingly, the risk/benefit should be carefully considered
in patients with established hyperlipidemia before initiating an immunosuppressive
regimen including Rapamune.
Any patient who is administered Rapamune should be monitored for hyperlipidemia
using laboratory tests and if hyperlipidemia is detected, subsequent interventions
such as diet, exercise, and lipid-lowering agents, as outlined by the National
Cholesterol Education Program guidelines, should be initiated.
In the limited number of patients studied, the concomitant administration of
Rapamune and HMG-CoA reductase inhibitors and/or fibrates appeared to be well
tolerated. Nevertheless, all patients administered Rapamune with cyclosporine,
in conjunction with an HMG-CoA reductase inhibitor, should be monitored for
the development of rhabdomyolysis.
Renal Function
Patients treated with cyclosporine and Rapamune were noted to have higher serum
creatinine levels and lower glomerular filtration rates compared with patients
treated with cyclosporine and placebo or azathioprine controls. Renal function
should be monitored during the administration of maintenance immunosuppression
regimens including Rapamune in combination with cyclosporine, and appropriate
adjustment of the immunosuppression regimen should be considered in patients
with elevated serum creatinine levels. Caution should be exercised when using
agents (e.g., aminoglycosides, and amphotericin B) that are known to have a
deleterious effect on renal function.
Antimicrobial Prophylaxis
Cases of Pneumocystis carinii pneumonia have been reported in patients
not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis
for Pneumocystis carinii pneumonia should be administered for 1 year
following transplantation. Cytomegalovirus (CMV) prophylaxis is recommended
for 3 months after transplantation, particularly for patients at increased risk
for CMV disease.
Information for Patients
Patients should be given complete dosage instructions (see Patient Instructions
). Women of childbearing potential should be informed of the potential risks
during pregnancy and 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 PRECAUTIONS
: Pregnancy ).
Patients should be told that exposure to sunlight and 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
).
Laboratory Tests
It is prudent to monitor blood sirolimus levels in patients likely to have
altered drug metabolism, in patients ≥13 years who weigh less than 40 kg,
in patients with hepatic impairment, and during concurrent administration of
potent CYP3A4 inducers and inhibitors (see PRECAUTIONS
: Drug
Interactions ).
Drug Interactions
Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-glycoprotein.
The pharmacokinetic interaction between sirolimus and concomitantly administered
drugs is discussed below. Drug interaction studies have not been conducted with
drugs other than those described below.
Cyclosporine capsules MODIFIED:
Rapamune Oral Solution: In a single dose drug-drug interaction
study, 24 healthy volunteers were administered 10 mg sirolimus either simultaneously
or 4 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine
capsules [MODIFIED]). For simultaneous administration, the mean C max and
AUC of sirolimus were increased by 116% and 230%, respectively, relative to
administration of sirolimus alone. However, when given 4 hours after Neoral®
Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus
C max and AUC were increased by 37% and 80%, respectively, compared
to administration of sirolimus alone.
Mean cyclosporine C max and AUC were not significantly affected
when sirolimus was given simultaneously or when administered 4 hours after Neoral®
Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). However, after multiple-dose
administration of sirolimus given 4 hours after Neoral® in renal post-transplant
patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower
doses of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) were
needed to maintain target cyclosporine concentration.
Rapamune Tablets: In a single-dose drug-drug interaction
study, 24 healthy volunteers were administered 10 mg sirolimus (Rapamune Tablets)
either simultaneously or 4 hours after a 300 mg dose of Neoral® Soft Gelatin
Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration,
mean C max and AUC were increased by 512% and 148%, respectively,
relative to administration of sirolimus alone. However, when given 4 hours after
cyclosporine administration, sirolimus C max and AUC were both increased
by only 33% compared with administration of sirolimus alone.
Because of the effect of cyclosporine capsules (MODIFIED), it is recommended
that sirolimus should be taken 4 hours after administration of cyclosporine
oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED), (see DOSAGE
AND ADMINISTRATION ).
Cyclosporine oral solution: In a multiple-dose study in
150 psoriasis patients, sirolimus 0.5, 1.5, and 3 mg/m 2 /day was
administered simultaneously with Sandimmune® Oral Solution (cyclosporine Oral
Solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations
ranged between 67% to 86% relative to when sirolimus was administered without
cyclosporine. The intersubject variability (%CV) for sirolimus trough concentrations
ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose
sirolimus on cyclosporine trough concentrations following Sandimmune® Oral Solution
(cyclosporine oral solution) administration. However, the %CV was higher (range
85.9%-165%) than those from previous studies.
Sandimmune® Oral Solution (cyclosporine oral solution) is not bioequivalent
to Neoral® Oral Solution (cyclosporine oral solution MODIFIED), and should not
be used interchangeably. Although there is no published data comparing Sandimmune®
Oral Solution (cyclosporine oral solution) to SangCya® Oral Solution (cyclosporine
oral solution [MODIFIED]), they should not be used interchangeably. Likewise,
Sandimmune® Soft Gelatin Capsules (cyclosporine capsules) are not bioequivalent
to Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) and should
not be used interchangeably.
Diltiazem: The simultaneous oral administration of 10 mg
of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers
significantly affected the bioavailability of sirolimus. Sirolimus C max
, t max , and AUC were increased 1.4-, 1.3-, and 1.6-fold,
respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem
or its metabolites desacetyldiltiazem and desmethyldiltiazem. If diltiazem is
administered, sirolimus should be monitored and a dose adjustment may be necessary.
Ketoconazole: Multiple-dose ketoconazole administration
significantly affected the rate and extent of absorption and sirolimus exposure
after administration of Rapamune Oral Solution, as reflected by increases in
sirolimus C max , t max , and AUC of 4.3-fold, 38%, and
10.9-fold, respectively. However, the terminal t 1/2 of sirolimus
was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma
ketoconazole concentrations. It is recommended that sirolimus oral solution
and oral tablets should not be administered with ketoconazole.
Rifampin: Pretreatment of 14 healthy volunteers with multiple
doses of rifampin, 600 mg daily for 14 days, followed by a single 20 mg-dose
of sirolimus, greatly increased sirolimus oral-dose clearance by 5.5-fold (range
= 2.8 to 10), which represents mean decreases in AUC and C max of
about 82% and 71%, respectively. In patients where rifampin is indicated, alternative
therapeutic agents with less enzyme induction potential should be considered.
Drugs which may be coadministered without dose adjustment
Clinically significant pharmacokinetic drug-drug interactions were not observed
in studies of drugs listed below. A synopsis of the type of study performed
for each drug is provided. Sirolimus and these drugs may be coadministered without
dose adjustments.
Acyclovir: Acyclovir, 200 mg, was administered once daily
for 3 days followed by a single 10-mg dose of sirolimus oral solution on day
3 in 20 adult healthy volunteers.
Digoxin: Digoxin, 0.25 mg, was administered daily for 8
days and a single 10-mg dose of sirolimus oral solution was given on day 8 to
24 healthy volunteers.
Glyburide: A single 5-mg dose of glyburide and a single
10-mg dose of sirolimus oral solution were administered to 24 healthy volunteers.
Sirolimus did not affect the hypoglycemic action of glyburide.
Nifedipine: A single 60-mg dose of nifedipine and a single
10-mg dose of sirolimus oral solution were administered to 24 healthy volunteers.
Norgestrel/ethinyl estradiol (Lo/Ovral®): Sirolimus oral
solution, 2 mg, was given daily for 7 days to 21 healthy female volunteers on
norgestrel/ethinyl estradiol.
Prednisolone: Pharmacokinetic information was obtained from
42 stable renal transplant patients receiving daily doses of prednisone (5-20
mg/day) and either single or multiple doses of sirolimus oral solution (0.5-5
mg/m 2 q 12h).
Sulfamethoxazole/trimethoprim (Bactrim®): A single oral
dose of sulfamethoxazole (40 mg)/trimethoprim, (80 mg) was given to 15 renal
transplant patients receiving daily oral doses of sirolimus (8 to 25 mg/m 2
).
Other drug interactions
Sirolimus is extensively metabolized by the CYP3A4 isoenzyme in the gut wall
and liver. Therefore, absorption and the subsequent elimination of systemically
absorbed sirolimus may be influenced by drugs that affect this isoenzyme. Inhibitors
of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus levels,
while inducers of CYP3A4 may increase the metabolism of sirolimus and decrease
sirolimus levels.
Drugs that may increase sirolimus blood concentrations include:
Calcium channel blockers: nicardipine, verapamil.
Antifungal agents: clotrimazole, fluconazole, itraconazole.
Macrolide antibiotics: clarithromycin, erythromycin, troleandomycin.
Gastrointestinal prokinetic agents: cisapride, metoclopramide.
Other drugs: bromocriptine, cimetidine, danazol, HIV-protease inhibitors
(e.g., ritonavir, indinavir).
Drugs that may decrease sirolimus levels include:
Anticonvulsants: carbamazepine, phenobarbital, phenytoin.
Antibiotics: rifabutin, rifapentine.
This list is not all inclusive.
Care should be exercised when drugs or other substances that are metabolized
by CYP3A4 are administered concomitantly with Rapamune. Grapefruit juice reduces
CYP3A4-mediated metabolism of Rapamune and must not be used for dilution (see
DOSAGE AND ADMINISTRATION ).
Herbal Preparations
St. John's Wort ( hypericum perforatum ) induces CYP3A4 and P-glycoprotein.
Since sirolimus is a substrate for both cytochrome CYP3A4 and P-glycoprotein,
there is the potential that the use of St. John's Wort in patients receiving
Rapamune could result in reduced sirolimus levels.
Vaccination
Immunosuppressants may affect response to vaccination. Therefore, during treatment
with Rapamune, vaccination may be less effective. The use of live vaccines should
be avoided; live vaccines may include, but are not limited to measles, mumps,
rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid.
Drug-Laboratory Test Interactions
There are no studies on the interactions of sirolimus in commonly employed
clinical laboratory tests.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
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.
Carcinogenicity studies were conducted in mice and rats. In an 86-week female
mouse study at dosages of 0, 12.5, 25 and 50/6 (dosage lowered from 50 to 6
mg/kg/day at week 31 due to infection secondary to immunosuppression) there
was a statistically significant increase in malignant lymphoma at all dose levels
(approximately 16 to 135 times the clinical doses adjusted for body surface
area) compared to controls. In a second mouse study at dosages of 0, 1, 3 and
6 mg/kg (approximately 3 to 16 times the clinical dose adjusted for body surface
area), hepatocellular adenoma and carcinoma (males), were considered Rapamune
related. In the 104-week rat study at dosages of 0, 0.05, 0.1, and 0.2 mg/kg/day
(approximately 0.4 to 1 times the clinical dose adjusted for body surface area),
there was a statistically significant increased incidence of testicular adenoma
in the 0.2 mg/kg/day group.
There was no effect on fertility in female rats following the administration
of sirolimus at dosages up to 0.5 mg/kg (approximately 1 to 3 times the clinical
doses adjusted for body surface area). In male rats, there was no significant
difference in fertility rate compared to controls at a dosage of 2 mg/kg (approximately
4 to 11 times the clinical doses adjusted for body surface area). Reductions
in testicular weights and/or histological lesions (e.g., tubular atrophy and
tubular giant cells) were observed in rats following dosages of 0.65 mg/kg (approximately
1 to 3 times the clinical doses adjusted for body surface area) and above and
in a monkey study at 0.1 mg/kg (approximately 0.4 to 1 times the clinical doses
adjusted for body surface area) and above. Sperm counts were reduced in male
rats following the administration of sirolimus for 13 weeks at a dosage of 6
mg/kg (approximately 12 to 32 times the clinical doses adjusted for body surface
area), but showed improvement by 3 months after dosing was stopped.
Pregnancy
Pregnancy Category C: Sirolimus was embryo/feto toxic in
rats at dosages of 0.1 mg/kg and above (approximately 0.2 to 0.5 the clinical
doses adjusted for body surface area). Embryo/feto toxicity was manifested as
mortality and reduced fetal weights (with associated delays in skeletal ossification).
However, no teratogenesis was evident. In combination with cyclosporine, rats
had increased embryo/feto mortality compared to Rapamune alone. There were no
effects on rabbit development at the maternally toxic dosage of 0.05 mg/kg (approximately
0.3 to 0.8 times the clinical doses adjusted for body surface area). There are
no adequate and well controlled studies in pregnant women. Effective contraception
must be initiated before Rapamune therapy, during Rapamune therapy, and for
12 weeks after Rapamune therapy has been stopped. Rapamune should be used during
pregnancy only if the potential benefit outweighs the potential risk to the
embryo/fetus.
Use during lactation
Sirolimus is excreted in trace amounts in milk of lactating rats. It is not
known whether sirolimus is excreted in human milk. The pharmacokinetic and safety
profiles of sirolimus in infants are not known. Because many drugs are excreted
in human milk and because of the potential for adverse reactions in nursing
infants from sirolimus, a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the importance of the drug to
the mother.
Pediatric use
The safety and efficacy of Rapamune in pediatric patients below the age of
13 years have not been established.
Geriatric use
Clinical studies of Rapamune Oral Solution or Tablets did not include sufficient
numbers of patients aged 65 years and over to determine whether safety and efficacy
differ in this population from younger patients. Data pertaining to sirolimus
trough concentrations suggest that dose adjustments based upon age in geriatric
renal patients are not necessary.
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