DRUG INTERACTIONS
7 Sirolimus is known to be a substrate for both cytochrome P-450 3A4 (CYP3A4) and p-glycoprotein (P-gp).
Inducers of CYP3A4 and P-gp may decrease sirolimus concentrations whereas inhibitors of CYP3A4 and P-gp may increase sirolimus concentrations.
• Avoid concomitant use with strong CYP3A4/P-gp inducers or strong CYP3A4/P-gp inhibitors that decrease or increase sirolimus concentrations ( 7.4 , 12.3 ).
• See full prescribing information for complete list of clinically significant drug interactions ( 12.3 ).
7.1 Use with Cyclosporine Cyclosporine, a substrate and inhibitor of CYP3A4 and P-gp, was demonstrated to increase sirolimus concentrations when co-administered with sirolimus.
In order to diminish the effect of this interaction with cyclosporine, it is recommended that Rapamune be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED).
If cyclosporine is withdrawn from combination therapy with Rapamune, higher doses of Rapamune are needed to maintain the recommended sirolimus trough concentration ranges [ see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ].
7.2 Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of CYP3A4 and P-gp.
Alternative agents with lesser interaction potential with sirolimus should be considered [ see Warnings and Precautions (5.18) , Clinical Pharmacology (12.3) ].
7.3 Grapefruit Juice Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with or be used for dilution of Rapamune [ see Dosage and Administration (2.9) , Drug Interactions (7.3) , Clinical Pharmacology (12.3) ].
7.4 Weak and Moderate Inducers or Inhibitors of CYP3A4 and P-gp Exercise caution when using sirolimus with drugs or agents that are modulators of CYP3A4 and P-gp.
The dosage of Rapamune and/or the co-administered drug may need to be adjusted [ see Clinical Pharmacology (12.3) ].
• Drugs that could increase sirolimus blood concentrations: Bromocriptione, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, protease inhibitors (e.g., HIV and hepatitis C that include drugs such as ritonavir, indinavir, boceprevir, and telaprevir), metoclopramide, nicardipine, troleandomycin, verapamil • Drugs and other agents that could decrease sirolimus concentrations: Carbamazepine, phenobarbital, phenytoin, rifapentine, St.
John’s Wort ( Hypericum perforatum ) • Drugs with concentrations that could increase when given with Rapamune: Verapamil 7.5 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, the following: measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid.
OVERDOSAGE
10 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 LD 50 was greater than 800 mg/kg.
DESCRIPTION
11 Rapamune (sirolimus) is an immunosuppressive agent.
Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus .
The chemical name of sirolimus (also known as rapamycin) is (3 S ,6 R ,7 E ,9 R ,10 R ,12 R ,14 S ,15 E ,17 E ,19 E ,21 S ,23 S ,26 R ,27 R ,34a S )-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-[(1 R )-2-[(1 S ,3 R ,4 R )-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3 H -pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4 H ,6 H ,31 H )-pentone.
Its molecular formula is C 51 H 79 NO 13 and its molecular weight is 914.2.
The structural formula of sirolimus is illustrated as follows.
Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile.
Rapamune is available for administration as an oral solution containing 1 mg/mL sirolimus.
Rapamune is also available as a tan, triangular-shaped tablet containing 0.5 mg sirolimus, as a white, triangular-shaped tablet containing 1 mg sirolimus, and as a yellow-to-beige triangular-shaped tablet containing 2 mg sirolimus.
The inactive ingredients in Rapamune Oral Solution are Phosal 50 PG ® (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80.
Rapamune Oral Solution contains 1.5% – 2.5% ethanol.
The inactive ingredients in Rapamune Tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, dl -alpha tocopherol, and other ingredients.
The 0.5 mg and 2 mg dosage strengths also contain yellow iron (ferric) oxide and brown iron (ferric) oxide.
Chemical Structure
CLINICAL STUDIES
14 14.1 Prophylaxis of Organ Rejection in Renal Transplant Patients Rapamune Oral Solution 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.
These studies compared two dose levels of Rapamune Oral Solution (2 mg and 5 mg, once daily) with azathioprine (Study 1) or placebo (Study 2) when administered in combination with cyclosporine and corticosteroids.
Study 1 was conducted in the United States at 38 sites.
Seven hundred nineteen (719) patients were enrolled in this trial and randomized following transplantation; 284 were randomized to receive Rapamune Oral Solution 2 mg/day; 274 were randomized to receive Rapamune Oral Solution 5 mg/day, and 161 to receive azathioprine 2–3 mg/kg/day.
Study 2 was conducted in Australia, Canada, Europe, and the United States, at a total of 34 sites.
Five hundred seventy-six (576) patients were enrolled in this trial and randomized before transplantation; 227 were randomized to receive Rapamune Oral Solution 2 mg/day; 219 were randomized to receive Rapamune Oral Solution 5 mg/day, and 130 to receive placebo.
In both studies, the use of antilymphocyte antibody induction therapy was prohibited.
In both studies, the primary efficacy endpoint was the rate of efficacy failure in the first 6 months after transplantation.
Efficacy failure was defined as the first occurrence of an acute rejection episode (confirmed by biopsy), graft loss, or death.
The tables below summarize the results of the primary efficacy analyses from these trials.
Rapamune Oral Solution, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of efficacy failure (statistically significant at the < 0.025 level; nominal significance level adjusted for multiple [2] dose comparisons) at 6 months following transplantation compared with both azathioprine and placebo.
TABLE 8: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 24 MONTHS FOR STUDY 1 Patients received cyclosporine and corticosteroids.
, Includes patients who prematurely discontinued treatment.
Parameter Rapamune Oral Solution 2 mg/day (n = 284) Rapamune Oral Solution 5 mg/day (n = 274) Azathioprine 2–3 mg/kg/day (n = 161) Efficacy failure at 6 months Primary endpoint.
18.7 16.8 32.3 Components of efficacy failure Biopsy-proven acute rejection 16.5 11.3 29.2 Graft loss 1.1 2.9 2.5 Death 0.7 1.8 0 Lost to follow-up 0.4 0.7 0.6 Efficacy failure at 24 months 32.8 25.9 36.0 Components of efficacy failure Biopsy-proven acute rejection 23.6 17.5 32.3 Graft loss 3.9 4.7 3.1 Death 4.2 3.3 0 Lost to follow-up 1.1 0.4 0.6 TABLE 9: INCIDENCE (%) OF EFFICACY FAILURE AT 6 AND 36 MONTHS FOR STUDY 2 Patients received cyclosporine and corticosteroids.
, Includes patients who prematurely discontinued treatment.
Parameter Rapamune Oral Solution 2 mg/day (n = 227) Rapamune Oral Solution 5 mg/day (n = 219) Placebo (n = 130) Efficacy failure at 6 months Primary endpoint.
30.0 25.6 47.7 Components of efficacy failure Biopsy-proven acute rejection 24.7 19.2 41.5 Graft loss 3.1 3.7 3.9 Death 2.2 2.7 2.3 Lost to follow-up 0 0 0 Efficacy failure at 36 months 44.1 41.6 54.6 Components of efficacy failure Biopsy-proven acute rejection 32.2 27.4 43.9 Graft loss 6.2 7.3 4.6 Death 5.7 5.9 5.4 Lost to follow-up 0 0.9 0.8 Patient and graft survival at 1 year were co-primary endpoints.
The following table shows graft and patient survival at 1 and 2 years in Study 1, and 1 and 3 years in Study 2.
The graft and patient survival rates were similar in patients treated with Rapamune and comparator-treated patients.
TABLE 10: GRAFT AND PATIENT SURVIVAL (%) FOR STUDY 1 (12 AND 24 MONTHS) AND STUDY 2 (12 AND 36 MONTHS) Patients received cyclosporine and corticosteroids.
, Includes patients who prematurely discontinued treatment.
Parameter Rapamune Oral Solution 2 mg/day Rapamune Oral Solution 5 mg/day Azathioprine 2–3 mg/kg/day Placebo Study 1 (n = 284) (n = 274) (n = 161) Graft survival Month 12 94.7 92.7 93.8 Month 24 85.2 89.1 90.1 Patient survival Month 12 97.2 96.0 98.1 Month 24 92.6 94.9 96.3 Study 2 (n = 227) (n = 219) (n = 130) Graft survival Month 12 89.9 90.9 87.7 Month 36 81.1 79.9 80.8 Patient survival Month 12 96.5 95.0 94.6 Month 36 90.3 89.5 90.8 The reduction in the incidence of first biopsy-confirmed acute rejection episodes in patients treated with Rapamune compared with the control groups included a reduction in all grades of rejection.
In Study 1, which was prospectively stratified by race within center, efficacy failure was similar for Rapamune Oral Solution 2 mg/day and lower for Rapamune Oral Solution 5 mg/day compared with azathioprine in Black patients.
In Study 2, which was not prospectively stratified by race, efficacy failure was similar for both Rapamune Oral Solution doses compared with placebo in Black patients.
The decision to use the higher dose of Rapamune Oral Solution in Black patients must be weighed against the increased risk of dose-dependent adverse events that were observed with the Rapamune Oral Solution 5-mg dose [ see Adverse Reactions (6.1) ].
TABLE 11: PERCENTAGE OF EFFICACY FAILURE BY RACE AT 6 MONTHS Patients received cyclosporine and corticosteroids.
, Includes patients who prematurely discontinued treatment.
Parameter Rapamune Oral Solution 2 mg/day Rapamune Oral Solution 5 mg/day Azathioprine 2–3 mg/kg/day Placebo Study 1 Black (n = 166) 34.9 (n = 63) 18.0 (n = 61) 33.3 (n = 42) Non-Black 14.0 (n = 221) 16.4 (n = 213) 31.9 (n = 119) (n = 553) Study 2 Black (n = 66) 30.8 (n = 26) 33.7 (n = 27) 38.5 (n = 13) Non-Black 29.9 (n = 201) 24.5 (n = 192) 48.7 (n = 117) (n = 510) Mean glomerular filtration rates (GFR) post-transplant were calculated by using the Nankivell equation at 12 and 24 months for Study 1, and 12 and 36 months for Study 2.
Mean GFR was lower in patients treated with cyclosporine and Rapamune Oral Solution compared with those treated with cyclosporine and the respective azathioprine or placebo control.
TABLE 12: OVERALL CALCULATED GLOMERULAR FILTRATION RATES (Mean ± SEM, cc/min) BY NANKIVELL EQUATION POST-TRANSPLANT Includes patients who prematurely discontinued treatment.
, Patients who had a graft loss were included in the analysis with GFR set to 0.0.
Parameter Rapamune Oral Solution 2 mg/day Rapamune Oral Solution 5 mg/day Azathioprine 2–3 mg/kg/day Placebo Study 1 Month 12 57.4 ± 1.3 (n = 269) 54.6 ± 1.3 (n = 248) 64.1 ± 1.6) (n = 149) Month 24 58.4 ± 1.5 (n = 221) 52.6 ± 1.5 (n = 222) 62.4 ± 1.9 (n = 132) Study 2 Month 12 52.4 ± 1.5 (n = 211) 51.5 ± 1.5 (n = 199) 58.0 ± 2.1 (n = 117) Month 36 48.1 ± 1.8 (n = 183) 46.1 ± 2.0 (n = 177) 53.4 ± 2.7 (n = 102) Within each treatment group in Studies 1 and 2, mean GFR at one-year post-transplant was lower in patients who experienced at least one episode of biopsy-proven acute rejection, compared with those who did not.
Renal function should be monitored, and appropriate adjustment of the immunosuppressive regimen should be considered in patients with elevated or increasing serum creatinine levels [ see Warnings and Precautions (5.8) ].
Rapamune Tablets The safety and efficacy of Rapamune Oral Solution and Rapamune Tablets for the prevention of organ rejection following renal transplantation were demonstrated to be clinically equivalent in a randomized, multicenter, controlled trial [ see Clinical Pharmacology (12.3) ].
14.2 Cyclosporine Withdrawal Study in Renal Transplant Patients The safety and efficacy of Rapamune as a maintenance regimen were assessed following cyclosporine withdrawal at 3 to 4 months after renal transplantation.
Study 3 was a randomized, multicenter, controlled trial conducted at 57 centers in Australia, Canada, and Europe.
Five hundred twenty-five (525) patients were enrolled.
All patients in this study received the tablet formulation.
This study compared patients who were administered Rapamune, cyclosporine, and corticosteroids continuously with patients who received this same standardized therapy for the first 3 months after transplantation (pre-randomization period) followed by the withdrawal of cyclosporine.
During cyclosporine withdrawal, the Rapamune dosages were adjusted to achieve targeted sirolimus whole blood trough concentration ranges (16 to 24 ng/mL until month 12, then 12 to 20 ng/mL thereafter, expressed as chromatographic assay values).
At 3 months, 430 patients were equally randomized to either continue Rapamune with cyclosporine therapy or to receive Rapamune as a maintenance regimen following cyclosporine withdrawal.
Eligibility for randomization included no Banff Grade 3 acute rejection or vascular rejection episode in the 4 weeks before random assignment, serum creatinine ≤ 4.5 mg/dL, and adequate renal function to support cyclosporine withdrawal (in the opinion of the investigator).
The primary efficacy endpoint was graft survival at 12 months after transplantation.
Secondary efficacy endpoints were the rate of biopsy-confirmed acute rejection, patient survival, incidence of efficacy failure (defined as the first occurrence of either biopsy-proven acute rejection, graft loss, or death), and treatment failure (defined as the first occurrence of either discontinuation, acute rejection, graft loss, or death).
The following table summarizes the resulting graft and patient survival at 12, 24, and 36 months for this trial.
At 12, 24, and 36 months, graft and patient survival were similar for both groups.
TABLE 13: GRAFT AND PATIENT SURVIVAL (%): STUDY 3 Includes patients who prematurely discontinued treatment.
Parameter Rapamune with Cyclosporine Therapy (n = 215) Rapamune Following Cyclosporine Withdrawal (n = 215) Graft Survival Month 12 Primary efficacy endpoint.
95.3 Survival including loss to follow-up as an event.
97.2 Month 24 91.6 94.0 Month 36 Initial planned duration of the study.
87.0 91.6 Patient Survival Month 12 97.2 98.1 Month 24 94.4 95.8 Month 36 91.6 94.0 The following table summarizes the results of first biopsy-proven acute rejection at 12 and 36 months.
There was a significant difference in first biopsy-proven rejection rates between the two groups after randomization and through 12 months.
Most of the post-randomization acute rejections occurred in the first 3 months following randomization.
TABLE 14: INCIDENCE OF FIRST BIOPSY-PROVEN ACUTE REJECTION (%) BY TREATMENT GROUP AT 36 MONTHS: STUDY 3 Includes patients who prematurely discontinued treatment.
, All patients received corticosteroids.
Period Rapamune with Cyclosporine Therapy (n = 215) Rapamune Following Cyclosporine Withdrawal (n = 215) Pre-randomization Randomization occurred at 3 months ± 2 weeks.
9.3 10.2 Post-randomization through 12 months 4.2 9.8 Post-randomization from 12 to 36 months 1.4 0.5 Post-randomization through 36 months 5.6 10.2 Total at 36 months 14.9 20.5 Patients receiving renal allografts with ≥ 4 HLA mismatches experienced significantly higher rates of acute rejection following randomization to the cyclosporine withdrawal group, compared with patients who continued cyclosporine (15.3% versus 3.0%).
Patients receiving renal allografts with ≤ 3 HLA mismatches demonstrated similar rates of acute rejection between treatment groups (6.8% versus 7.7%) following randomization.
The following table summarizes the mean calculated GFR in Study 3 (cyclosporine withdrawal study).
TABLE 15: CALCULATED GLOMERULAR FILTRATION RATES (mL/min) BY NANKIVELL EQUATION AT 12, 24, AND 36 MONTHS POST-TRANSPLANT: STUDY 3 Includes patients who prematurely discontinued treatment.
, Patients who had a graft loss were included in the analysis and had their GFR set to 0.0.
, All patients received corticosteroids.
Parameter Rapamune with Cyclosporine Therapy Rapamune Following Cyclosporine Withdrawal Month 12 Mean ± SEM 53.2 ± 1.5 (n = 208) 59.3 ± 1.5 (n = 203) Month 24 Mean ± SEM 48.4 ± 1.7 (n = 203) 58.4 ± 1.6 (n = 201) Month 36 Mean ± SEM 47.0 ± 1.8 (n = 196) 58.5 ± 1.9 (n = 199) The mean GFR at 12, 24, and 36 months, calculated by the Nankivell equation, was significantly higher for patients receiving Rapamune as a maintenance regimen following cyclosporine withdrawal than for those in the Rapamune with cyclosporine therapy group.
Patients who had an acute rejection prior to randomization had a significantly higher GFR following cyclosporine withdrawal compared to those in the Rapamune with cyclosporine group.
There was no significant difference in GFR between groups for patients who experienced acute rejection post-randomization.
Although the initial protocol was designed for 36 months, there was a subsequent amendment to extend this study.
The results for the cyclosporine withdrawal group at months 48 and 60 were consistent with the results at month 36.
Fifty-two percent (112/215) of the patients in the Rapamune with cyclosporine withdrawal group remained on therapy to month 60 and showed sustained GFR.
14.3 High-Immunologic Risk Renal Transplant Patients Rapamune was studied in a one-year, clinical trial in high risk patients (Study 4) who were defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reasons and/or patients with high panel-reactive antibodies (PRA; peak PRA level > 80%).
Patients received concentration-controlled sirolimus and cyclosporine (MODIFIED), and corticosteroids per local practice.
The Rapamune dose was adjusted to achieve target whole blood trough sirolimus concentrations of 10–15 ng/mL (chromatographic method) throughout the 12-month study period.
The cyclosporine dose was adjusted to achieve target whole blood trough concentrations of 200–300 ng/mL through week 2, 150–200 ng/mL from week 2 to week 26, and 100–150 ng/mL from week 26 to week 52 [ see Clinical Pharmacology (12.3) ] for the observed trough concentrations ranges.
Antibody induction was allowed per protocol as prospectively defined at each transplant center, and was used in 88.4% of patients.
The study was conducted at 35 centers in the United States.
A total of 224 patients received a transplant and at least one dose of sirolimus and cyclosporine and was comprised of 77.2% Black patients, 24.1% repeat renal transplant recipients, and 13.5% patients with high PRA.
Efficacy was assessed with the following endpoints, measured at 12 months: efficacy failure (defined as the first occurrence of biopsy-confirmed acute rejection, graft loss, or death), first occurrence of graft loss or death, and renal function as measured by the calculated GFR using the Nankivell formula.
The table below summarizes the result of these endpoints.
TABLE 16: EFFICACY FAILURE, GRAFT LOSS OR DEATH AND CALCULATED GLOMERULAR FUNCTION RATES (mL/min) BY NANKIVELL EQUATION AT 12 MONTHS POST-TRANSPLANT: STUDY 4 Parameter Rapamune with Cyclosporine, Corticosteroids (n = 224) Efficacy Failure (%) 23.2 Graft Loss or Death (%) 9.8 Renal Function (mean ± SEM) Calculated glomerular filtration rate by Nankivell equation.
, Patients who had graft loss were included in this analysis with GFR set to 0.
52.6 ± 1.6 (n = 222) Patient survival at 12 months was 94.6%.
The incidence of biopsy-confirmed acute rejection was 17.4% and the majority of the episodes of acute rejection were mild in severity.
14.4 Conversion from Calcineurin Inhibitors to Rapamune in Maintenance Renal Transplant Patients Conversion from calcineurin inhibitors (CNI) to Rapamune was assessed in maintenance renal transplant patients 6 months to 10 years post-transplant (Study 5).
This study was a randomized, multicenter, controlled trial conducted at 111 centers globally, including US and Europe, and was intended to show that renal function was improved by conversion from CNI to Rapamune.
Eight hundred thirty (830) patients were enrolled and stratified by baseline calculated glomerular filtration rate (GFR, 20–40 mL/min versus greater than 40 mL/min).
In this trial 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.
In addition, enrollment of patients with baseline calculated GFR less than 40 mL/min was discontinued due to a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death [ see Adverse Reactions (6.4) ].
This study compared renal transplant patients (6–120 months after transplantation) who were converted from calcineurin inhibitors to Rapamune, with patients who continued to receive calcineurin inhibitors.
Concomitant immunosuppressive medications included mycophenolate mofetil (MMF), azathioprine (AZA), and corticosteroids.
Rapamune was initiated with a single loading dose of 12–20 mg, after which dosing was adjusted to achieve a target sirolimus whole blood trough concentration of 8–20 ng/mL (chromatographic method).
The efficacy endpoint was calculated GFR at 12 months post-randomization.
Additional endpoints included biopsy-confirmed acute rejection, graft loss, and death.
Findings in the patient stratum with baseline calculated GFR greater than 40 mL/min (Rapamune conversion, n = 497; CNI continuation, n = 246) are summarized below: There was no clinically or statistically significant improvement in Nankivell GFR compared to baseline.
TABLE 17: RENAL FUNCTION IN STABLE RENAL TRANSPLANT PATIENTS IN PATIENTS WITH BASELINE GFR > 40 mL/min THE RAPAMUNE CONVERSION STUDY (STUDY 5) Parameter Rapamune conversion N = 496 CNI continuation N = 245 Difference (95% CI) GFR mL/min (Nankivell) at 1 year 59.0 57.7 1.3 (-1.1, 3.7) GFR mL/min (Nankivell) at 2 year 53.7 52.1 1.6 (-1.4, 4.6) The rates of acute rejection, graft loss, and death were similar at 1 and 2 years.
Treatment-emergent adverse events occurred more frequently during the first 6 months after Rapamune conversion.
The rates of pneumonia were significantly higher for the sirolimus conversion group.
While the mean and median values for urinary protein to creatinine ratio were similar between treatment groups at baseline, significantly higher mean and median levels of urinary protein excretion were seen in the Rapamune conversion arm at 1 year and at 2 years, as shown in the table below [ see Warnings and Precautions (5.9) ].
In addition, when compared to patients who continued to receive calcineurin inhibitors, a higher percentage of patients had urinary protein to creatinine ratios > 1 at 1 and 2 years after sirolimus conversion.
This difference was seen in both patients who had a urinary protein to creatinine ratio ≤ 1 and those who had a protein to creatinine ratio > 1 at baseline.
More patients in the sirolimus conversion group developed nephrotic range proteinuria, as defined by a urinary protein to creatinine ratio > 3.5 (46/482 [9.5%] versus 9/239 [3.8%]), even when the patients with baseline nephrotic range proteinuria were excluded.
The rate of nephrotic range proteinuria was significantly higher in the sirolimus conversion group compared to the calcineurin inhibitor continuation group with baseline urinary protein to creatinine ratio > 1 (13/29 versus 1/14), excluding patients with baseline nephrotic range proteinuria.
TABLE 18: MEAN AND MEDIAN VALUES FOR URINARY PROTEIN TO CREATININE RATIO (mg/mg) BETWEEN TREATMENT GROUPS AT BASELINE, 1 AND 2 YEARS IN THE STRATUM WITH BASELINE CALCULATED GFR > 40 mL/min Study period Sirolimus Conversion CNI Continuation N Mean ± SD Median N Mean ± SD Median p-value Baseline 410 0.35 ± 0.76 0.13 207 0.28 ± 0.61 0.11 0.381 1 year 423 0.88 ± 1.61 0.31 203 0.37 ± 0.88 0.14 <0.001 2 years 373 0.86 ± 1.48 0.32 190 0.47 ± 0.98 0.13 <0.001 The above information should be taken into account when considering conversion from calcineurin inhibitors to Rapamune in stable renal transplant patients due to the lack of evidence showing that renal function improves following conversion, and the finding of a greater increment in urinary protein excretion, and an increased incidence of treatment-emergent nephrotic range proteinuria following conversion to Rapamune.
This was particularly true among patients with existing abnormal urinary protein excretion prior to conversion.
14.5 Conversion from a CNI-based Regimen to a Sirolimus-based Regimen in Liver Transplant Patients Conversion from a CNI-based regimen to a Rapamune-based regimen was assessed in stable liver transplant patients 6–144 months post-transplant.
The clinical study was a 2:1 randomized, multi-center, controlled trial conducted at 82 centers globally, including the US and Europe, and was intended to show that renal function was improved by conversion from a CNI to Rapamune without adversely impacting efficacy or safety.
A total of 607 patients were enrolled.
The study failed to demonstrate superiority of conversion to a Rapamune-based regimen compared to continuation of a CNI-based regimen in baseline-adjusted GFR, as estimated by Cockcroft-Gault, at 12 months (62 mL/min in the Rapamune conversion group and 63 mL/min in the CNI continuation group).
The study also failed to demonstrate non-inferiority, with respect to the composite endpoint consisting of graft loss and death (including patients with missing survival data) in the Rapamune conversion group compared to the CNI continuation group (6.6% versus 5.6%).
The number of deaths in the Rapamune conversion group (15/393, 3.8%) was higher than in the CNI continuation group (3/214, 1.4%), although the difference was not statistically significant.
The rates of premature study discontinuation (primarily due to adverse events or lack of efficacy), adverse events overall (infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all significantly greater in the Rapamune conversion group compared to the CNI continuation group.
14.6 Pediatric Renal Transplant Patients Rapamune was evaluated in a 36-month, open-label, randomized, controlled clinical trial at 14 North American centers in pediatric (aged 3 to < 18 years) renal transplant patients considered to be at high-immunologic risk for developing chronic allograft nephropathy, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy.
Seventy-eight (78) subjects were randomized in a 2:1 ratio to Rapamune (sirolimus target concentrations of 5 to 15 ng/mL, by chromatographic assay, n = 53) in combination with a calcineurin inhibitor and corticosteroids or to continue calcineurin-inhibitor-based immunosuppressive therapy (n = 25).
The primary endpoint of the study was efficacy failure as defined by the first occurrence of biopsy-confirmed acute rejection, graft loss, or death, and the trial was designed to show superiority of Rapamune added to a calcineurin-inhibitor-based immunosuppressive regimen compared to a calcineurin-inhibitor-based regimen.
The cumulative incidence of efficacy failure up to 36 months was 45.3% in the Rapamune group compared to 44.0% in the control group, and did not demonstrate superiority.
There was one death in each group.
The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections [ see Warnings and Precautions (5.8) ].
This study does not support the addition of Rapamune to calcineurin-inhibitor-based immunosuppressive therapy in this subpopulation of pediatric renal transplant patients.
14.7 Lymphangioleiomyomatosis Patients The safety and efficacy of Rapamune for treatment of lymphangioleiomyomatosis (LAM) were assessed in a randomized, double-blind, multicenter, controlled trial.
This study compared Rapamune (dose-adjusted to maintain blood trough concentrations between 5–15 ng/mL) with placebo for a 12-month treatment period, followed by a 12-month observation period.
Eighty-nine (89) patients were enrolled; 43 patients were randomized to receive placebo and 46 patients to receive Rapamune.
The primary endpoint was the difference between the groups in the rate of change (slope) per month in forced expiratory volume in 1 second (FEV1).
During the treatment period, the FEV1 slope was -12±2 mL per month in the placebo group and 1±2 mL per month in the Rapamune group (treatment difference = 13 mL (95% CI: 7, 18).
The absolute between-group difference in the mean change in FEV1 during the 12-month treatment period was 153 mL, or approximately 11% of the mean FEV1 at enrollment.
Similar improvements were seen for forced vital capacity (FVC).
After discontinuation of Rapamune, the decline in lung function resumed in the Rapamune group and paralleled that in the placebo group (see Figure 1 ).
FIGURE 1: CHANGE IN FORCED EXPIRATORY VOLUME IN 1 SECOND (FEV1) DURING THE TREATMENT AND OBSERVATION PHASES OF THE STUDY IN LAM PATIENTS The rate of change over 12 months of vascular endothelial growth factor-D (VEGF-D), a lymphangiogenic growth factor which has been shown to be elevated in patients with LAM, was significantly different in the Rapamune-treated group (-88.0 ± 16.6 pg/mL/month) compared to placebo (-2.42 ± 17.2 pg/mL/month) with a treatment difference of -86 pg/mL/month (95% CI: -133, -39).
The absolute between-group difference in the mean change in VEGF-D during the 12-month treatment period was -1017.2, or approximately 50% of the mean VEGF-D at enrollment.
Figure 1
HOW SUPPLIED
16 /STORAGE AND HANDLING Since Rapamune is not absorbed through the skin, there are no special precautions.
However, if direct contact of the oral solution occurs with the skin or eyes, wash skin thoroughly with soap and water; rinse eyes with plain water.
Do not use RAPAMUNE after the expiration date that is located on the blister and carton.
The expiration date refers to the last day of that month.
16.1 Rapamune Oral Solution Each Rapamune Oral Solution carton, NDC 0008-1030-06, contains one 2 oz (60 mL fill) amber glass bottle of sirolimus (concentration of 1 mg/mL), one oral syringe adapter for fitting into the neck of the bottle, sufficient disposable amber oral syringes and caps for daily dosing, and a carrying case.
Rapamune Oral Solution bottles should be stored protected from light and refrigerated at 2°C to 8°C (36°F to 46°F).
Once the bottle is opened, the contents should be used within one month.
If necessary, the patient may store the bottles at room temperatures up to 25°C (77°F) for a short period of time (e.g., not more than 15 days for the bottles).
An amber syringe and cap are provided for dosing, and the product may be kept in the syringe for a maximum of 24 hours at room temperatures up to 25°C (77°F) or refrigerated at 2°C to 8°C (36°F to 46°F).
The syringe should be discarded after one use.
After dilution, the preparation should be used immediately.
Rapamune Oral Solution provided in bottles may develop a slight haze when refrigerated.
If such a haze occurs, allow the product to stand at room temperature and shake gently until the haze disappears.
The presence of this haze does not affect the quality of the product.
16.2 Rapamune Tablets Rapamune Tablets are available as follows: • NDC 0008-1040-05, 0.5 mg, tan, triangular-shaped tablets marked “RAPAMUNE 0.5 mg” on one side; bottle containing 100 tablets.
• NDC 0008-1040-10, 0.5 mg, tan, triangular-shaped tablets marked “RAPAMUNE 0.5 mg” on one side; in Redipak ® cartons of 100 tablets (10 blister cards of 10 tablets each).
• NDC 0008-1041-05, 1 mg, white, triangular-shaped tablets marked “RAPAMUNE 1 mg” on one side; bottle containing 100 tablets.
• NDC 0008-1041-10, 1 mg, white, triangular-shaped tablets marked “RAPAMUNE 1 mg” on one side; in Redipak ® cartons of 100 tablets (10 blister cards of 10 tablets each).
• NDC 0008-1042-05, 2 mg, yellow-to-beige triangular-shaped tablets marked “RAPAMUNE 2 mg” on one side; bottle containing 100 tablets.
Rapamune Tablets should be stored at 20° to 25°C [USP Controlled Room Temperature] (68° to 77°F).
Use cartons to protect blister cards and strips from light.
Dispense in a tight, light-resistant container as defined in the USP.
RECENT MAJOR CHANGES
Warnings and Precautions, Angioedema ( 5.5 ) 4/2017 Warnings and Precautions, Embryo-Fetal Toxicity ( 5.15 ) 1/2018
GERIATRIC USE
8.5 Geriatric Use Clinical studies of Rapamune Oral Solution or Tablets did not include sufficient numbers of patients ≥ 65 years to determine whether they respond differently from younger patients.
Data pertaining to sirolimus trough concentrations suggest that dose adjustments based upon age in geriatric renal patients are not necessary.
Differences in responses between the elderly and younger patients have not been identified.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, or cardiac function, and of concomitant disease or other drug therapy.
MECHANISM OF ACTION
12.1 Mechanism of Action Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants.
Sirolimus also inhibits antibody production.
In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex.
The sirolimus:FKBP-12 complex has no effect on calcineurin activity.
This complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase.
This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G 1 to the S phase of the cell cycle.
Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates.
Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats.
In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy.
This tolerization effect is alloantigen-specific.
In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.
Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells).
Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors.
Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells.
INDICATIONS AND USAGE
1 Rapamune is an mTOR inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in patients aged ≥13 years receiving renal transplants.
3.
Patients at low- to moderate-immunologic risk: Use initially with cyclosporine (CsA) and corticosteroids.
CsA withdrawal is recommended 2–4 months after transplantation ( 1.1 ).
4.
Patients at high-immunologic risk: Use in combination with CsA and corticosteroids for the first 12 months following transplantation ( 1.1 ).
Safety and efficacy of CsA withdrawal has not been established in high risk patients ( 1.1 , 1.2 , 14.3 ).
Rapamune is an mTOR inhibitor indicated for the treatment of patients with lymphangioleiomyomatosis ( 1.3 ).
1.1 Prophylaxis of Organ Rejection in Renal Transplantation Rapamune (sirolimus) is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants.
In patients at low-to moderate-immunologic risk , it is recommended that Rapamune be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation [ see Dosage and Administration (2.2) ].
In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first year following transplantation [ see Dosage and Administration (2.3) , Clinical Studies (14.3) ].
1.2 Limitations of Use in Renal Transplantation Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those with serum creatinine > 4.5 mg/dL, Black patients, patients of multi-organ transplants, secondary transplants, or those with high levels of panel-reactive antibodies [ see Clinical Studies (14.2) ].
In patients at high-immunologic risk , the safety and efficacy of Rapamune used in combination with cyclosporine and corticosteroids has not been studied beyond one year; therefore after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient [ see Clinical Studies (14.3) ].
In pediatric patients , the safety and efficacy of Rapamune have not been established in patients < 13 years old, or in pediatric (< 18 years) renal transplant patients considered at high-immunologic risk [ see Adverse Reactions (6.5) , Clinical Studies (14.6) ].
The safety and efficacy of de novo use of Rapamune without cyclosporine have not been established in renal transplant patients [ see Warnings and Precautions (5.12) ].
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established [ see Clinical Studies (14.4) ].
1.3 Treatment of Patients with Lymphangioleiomyomatosis Rapamune (sirolimus) is indicated for the treatment of patients with lymphangioleiomyomatosis (LAM).
PEDIATRIC USE
8.4 Pediatric Use Renal Transplant The safety and efficacy of Rapamune in pediatric patients < 13 years have not been established.
The safety and efficacy of Rapamune Oral Solution and Rapamune Tablets have been established for prophylaxis of organ rejection in renal transplantation in children ≥ 13 years judged to be at low- to moderate-immunologic risk.
Use of Rapamune Oral Solution and Rapamune Tablets in this subpopulation of children ≥ 13 years is supported by evidence from adequate and well-controlled trials of Rapamune Oral Solution in adults with additional pharmacokinetic data in pediatric renal transplantation patients [ see Clinical Pharmacology (12.3) ].
Safety and efficacy information from a controlled clinical trial in pediatric and adolescent (< 18 years of age) renal transplant patients judged to be at high-immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of Rapamune Oral Solution or Tablets in combination with calcineurin inhibitors and corticosteroids, due to the higher incidence of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens compared to calcineurin inhibitors, without increased benefit with respect to acute rejection, graft survival, or patient survival [ see Clinical Studies (14.6) ].
Lymphangioleiomyomatosis The safety and efficacy of Rapamune in pediatric patients < 18 years have not been established.
PREGNANCY
8.1 Pregnancy Pregnancy Category C: Sirolimus was embryo/fetotoxic in rats when given in doses approximately 0.2 to 0.5 the human doses (adjusted for body surface area).
Embryo/fetotoxicity 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 with sirolimus alone.
There were no effects on rabbit development at a maternally toxic dosage approximately 0.3 to 0.8 times the human 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.
NUSRING MOTHERS
8.3 Nursing Mothers 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.
BOXED WARNING
WARNING: IMMUNOSUPPRESSION, USE IS NOT RECOMMENDED IN LIVER OR LUNG TRANSPLANT PATIENTS • Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression 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 ® for prophylaxis of organ rejection in patients receiving renal transplants.
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 [ see Warnings and Precautions (5.1) ] .
• The safety and efficacy of Rapamune (sirolimus) as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended [ see Warnings and Precautions (5.2 , 5.3) ] .
• Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis (HAT) The use of Rapamune in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients.
Many of these patients had evidence of infection at or near the time of death.
In this and another study in de novo liver transplant patients, the use of Rapamune in combination with cyclosporine or tacrolimus was associated with an increase in HAT; most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death [ see Warnings and Precautions (5.2) ].
• Lung Transplantation – Bronchial Anastomotic Dehiscence Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen [ see Warnings and Precautions (5.3) ].
WARNING: IMMUNOSUPPRESSION, USE IS NOT RECOMMENDED IN LIVER OR LUNG TRANSPLANT PATIENTS See Full Prescribing Information for complete Boxed Warning.
• Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression ( 5.1 ).
Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use Rapamune for prophylaxis of organ rejection in patients receiving renal transplants.
• The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended ( 5.2 , 5.3 ).
• Liver Transplantation – Excess mortality, graft loss, and hepatic artery thrombosis ( 5.2 ).
• Lung Transplantation – Bronchial anastomotic dehiscence ( 5.3 ).
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions ( 5.4 ) • Angioedema ( 5.5 ) • Fluid Accumulation and Impairment of Wound Healing ( 5.6 ) • Hyperlipidemia ( 5.7 ) • Decline in Renal Function ( 5.8 ) • Proteinuria ( 5.9 ) • Latent Viral Infections ( 5.10 ) • Interstitial Lung Disease/Non-Infectious Pneumonitis ( 5.11 ) • De Novo Use Without Cyclosporine ( 5.12 ) • Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic Syndrome/ Thrombotic Thrombocytopenic Purpura/ Thrombotic Microangiopathy ( 5.13 ) • Embryo-Fetal Toxicity ( 5.15 , 8.1 ) 5.1 Increased Susceptibility to Infection and the Possible Development of Lymphoma Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression.
The rates of lymphoma/lymphoproliferative disease observed in Studies 1 and 2 were 0.7–3.2% (for Rapamune-treated patients) versus 0.6–0.8% (azathioprine and placebo control) [ see Adverse Reactions (6.1) and (6.2) ].
Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections, and sepsis.
Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use Rapamune for prophylaxis of organ rejection in patients receiving renal transplants.
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.
5.2 Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended.
The use of Rapamune has been associated with adverse outcomes in patients following liver transplantation, including excess mortality, graft loss and hepatic artery thrombosis (HAT).
In a study in de novo liver transplant patients, the use of Rapamune in combination with tacrolimus was associated with excess mortality and graft loss (22% in combination versus 9% on tacrolimus alone).
Many of these patients had evidence of infection at or near the time of death.
In this and another study in de novo liver transplant patients, the use of Rapamune in combination with cyclosporine or tacrolimus was associated with an increase in HAT (7% in combination versus 2% in the control arm); most cases of HAT occurred within 30 days post-transplantation, and most led to graft loss or death.
In a clinical study in stable liver transplant patients 6–144 months post-liver transplantation and receiving a CNI-based regimen, an increased number of deaths was observed in the group converted to a Rapamune-based regimen compared to the group who was continued on a CNI-based regimen, although the difference was not statistically significant (3.8% versus 1.4%) [ see Clinical Studies (14.5) ].
5.3 Lung Transplantation – Bronchial Anastomotic Dehiscence Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen.
The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended.
5.4 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the administration of Rapamune [ see Adverse Reactions (6.7) ].
5.5 Angioedema Rapamune has been associated with the development of angioedema.
The concomitant use of Rapamune with other drugs known to cause angioedema, such as angiotensin-converting enzyme (ACE) inhibitors, may increase the risk of developing angioedema.
Elevated sirolimus levels (with/without concomitant ACE inhibitors) may also potentiate angioedema [ see Drug Interactions (7.2) ].
In some cases, the angioedema has resolved upon discontinuation or dose reduction of Rapamune.
5.6 Fluid Accumulation and Impairment of Wound Healing There have been reports of impaired or delayed wound healing in patients receiving Rapamune, including lymphocele and wound dehiscence [ see Adverse Reactions (6.1) ].
Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability.
Lymphocele, a known surgical complication of renal transplantation, occurred significantly more often in a dose-related fashion in patients treated with Rapamune [ see Adverse Reactions (6.1) ].
Appropriate measures should be considered to minimize such complications.
Patients with a body mass index (BMI) greater than 30 kg/m 2 may be at increased risk of abnormal wound healing based on data from the medical literature.
There have also been reports of fluid accumulation, including peripheral edema, lymphedema, pleural effusion, ascites, and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults), in patients receiving Rapamune.
5.7 Hyperlipidemia Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in patients treated with Rapamune compared with azathioprine or placebo controls in Studies 1 and 2 [ see Adverse Reactions (6.1) ].
There were increased incidences of hypercholesterolemia (43–46%) and/or hypertriglyceridemia (45–57%) in patients receiving Rapamune compared with placebo controls (each 23%).
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.
If detected, interventions such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines.
In clinical trials of patients receiving Rapamune plus cyclosporine or Rapamune after cyclosporine withdrawal, 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.
The concomitant administration of Rapamune and HMG-CoA reductase inhibitors resulted in adverse reactions such as CPK elevations (3%), myalgia (6.7%) and rhabdomyolysis (<1%).
In these trials, the number of patients was too small and duration of follow-up too short to evaluate the long-term impact of Rapamune on cardiovascular mortality.
During Rapamune therapy with or without cyclosporine, patients should be monitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents.
5.8 Decline in Renal Function Renal function should be closely monitored during the co-administration of Rapamune with cyclosporine, because long-term administration of the combination has been associated with deterioration of 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 (Studies 1 and 2).
The rate of decline in renal function in these studies was greater in patients receiving Rapamune and cyclosporine compared with control therapies.
Appropriate adjustment of the immunosuppressive regimen, including discontinuation of Rapamune and/or cyclosporine, should be considered in patients with elevated or increasing serum creatinine levels.
In patients at low- to moderate-immunologic risk, continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when the benefits outweigh the risks of this combination for the individual patients.
Caution should be exercised when using agents (e.g., aminoglycosides and amphotericin B) that are known to have a deleterious effect on renal function.
In patients with delayed graft function, Rapamune may delay recovery of renal function.
5.9 Proteinuria Periodic quantitative monitoring of urinary protein excretion is recommended.
In a study evaluating conversion from calcineurin inhibitors (CNI) to Rapamune in maintenance renal transplant patients 6–120 months post-transplant, increased urinary protein excretion was commonly observed from 6 through 24 months after conversion to Rapamune compared with CNI continuation [ see Clinical Studies (14.4) , Adverse Reactions (6.4) ].
Patients with the greatest amount of urinary protein excretion prior to Rapamune conversion were those whose protein excretion increased the most after conversion.
New onset nephrosis (nephrotic syndrome) was also reported as a treatment-emergent adverse reaction in 2.2% of the Rapamune conversion group patients in comparison to 0.4% in the CNI continuation group of patients.
Nephrotic range proteinuria (defined as urinary protein to creatinine ratio > 3.5) was also reported in 9.2% in the Rapamune conversion group of patients in comparison to 3.7% in the CNI continuation group of patients.
In some patients, reduction in the degree of urinary protein excretion was observed for individual patients following discontinuation of Rapamune.
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established.
5.10 Latent Viral Infections Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections.
These include BK virus-associated nephropathy, which has been observed in renal transplant patients receiving immunosuppressants, including Rapamune.
This infection may be associated with serious outcomes, including deteriorating renal function and renal graft loss [ see Adverse Reactions (6.7) ].
Patient monitoring may help detect patients at risk for BK virus-associated nephropathy.
Reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy.
Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been reported in patients treated with immunosuppressants, including Rapamune.
PML commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia.
Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function.
In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.
Consideration should be given to reducing the amount of immunosuppression in patients who develop PML.
In transplant patients, physicians should also consider the risk that reduced immunosuppression represents to the graft.
5.11 Interstitial Lung Disease/Non-Infectious Pneumonitis Cases of interstitial lung disease [ILD] (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 ILD was reported with pulmonary hypertension (including pulmonary arterial hypertension [PAH]) as a secondary event.
In some cases, the ILD has resolved upon discontinuation or dose reduction of Rapamune.
The risk may be increased as the trough sirolimus concentration increases [ see Adverse Reactions (6.7) ].
5.12 De Novo Use Without Cyclosporine The safety and efficacy of de novo use of Rapamune without cyclosporine is not established in renal transplant patients.
In a multicenter clinical study, de novo renal transplant patients treated with Rapamune, mycophenolate mofetil (MMF), steroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with cyclosporine, MMF, steroids, and IL-2 receptor antagonist.
A benefit, in terms of better renal function, was not apparent in the treatment arm with de novo use of Rapamune without cyclosporine.
These findings were also observed in a similar treatment group of another clinical trial.
5.13 Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura/Thrombotic Microangiopathy The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) [ see Adverse Reactions (6.7) ].
5.14 Antimicrobial Prophylaxis Cases of Pneumocystis carinii pneumonia have been reported in transplant 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.
5.15 Embryo-Fetal Toxicity Based on animal studies and the mechanism of action [ see Clinical Pharmacology (12.1) ], Rapamune may cause fetal harm when administered to a pregnant woman.
In animal studies, mTOR inhibitors caused embryo-fetal toxicity when administered during the period of organogenesis at maternal exposures that were equal to or less than human exposures at the recommended lowest starting dose.
Advise pregnant women of the potential risk to a fetus.
Advise women of childbearing potential to avoid becoming pregnant and to use effective contraception while using Rapamune and for 12 weeks after ending treatment [ see Use in Specific Populations (8.1) ] .
5.16 Different Sirolimus Trough Concentration Reported between Chromatographic and Immunoassay Methodologies Currently in clinical practice, sirolimus whole blood concentrations are being measured by various chromatographic and immunoassay methodologies.
Patient sample concentration values from different assays may not be interchangeable [ see Dosage and Administration (2.5) ].
5.17 Skin Cancer Events Patients on immunosuppressive therapy are at increased risk for skin cancer.
Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor [ see Adverse Reactions (6.1 , 6.2 , 6.7) ] .
5.18 Interaction with Strong Inhibitors and Inducers of CYP3A4 and/or P-gp Avoid concomitant use of Rapamune with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) [ see Drug Interactions (7.2) ].
DOSAGE AND ADMINISTRATION
2 Rapamune is to be administered orally once daily, consistently with or without food [ see Dosage and Administration (2.5) , Clinical Pharmacology (12.3) ].
Tablets should not be crushed, chewed or split.
Patients unable to take the tablets should be prescribed the solution and instructed in its use.
Renal Transplant Patients: • Administer once daily by mouth, consistently with or without food ( 2 ).
• Administer the initial dose as soon as possible after transplantation and 4 hours after CsA ( 2.1 , 7.1 ).
• Adjust the Rapamune maintenance dose to achieve sirolimus trough concentrations within the target-range ( 2.5 ).
• Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment ( 2.7 , 8.6 , 12.3 ).
In renal transplant patients at low-to moderate-immunologic risk : • Rapamune and CsA Combination Therapy: One loading dose of 6 mg on day 1, followed by daily maintenance doses of 2 mg ( 2.2 ).
• Rapamune Following CsA Withdrawal: 2–4 months post-transplantation, withdraw CsA over 4–8 weeks ( 2.2 ).
In renal transplant patients at high-immunologic risk: • Rapamune and CsA Combination Therapy (for the first 12 months post-transplantation): One loading dose of up to 15 mg on day 1, followed by daily maintenance doses of 5 mg ( 2.3 ).
Lymphangioleiomyomatosis Patients: • Administer once daily by mouth, consistently with or without food ( 2 ).
• Recommended initial Rapamune dose is 2 mg/day ( 2.4 ).
• Adjust the Rapamune dose to achieve sirolimus trough concentrations between 5–15 ng/mL ( 2.4 ).
• Hepatic impairment: Reduce maintenance dose in patients with hepatic impairment ( 2.7 , 8.6 , 12.3 ).
Therapeutic drug monitoring is recommended for all patients ( 2.5 , 5.16 ).
2.1 General Dosing Guidance for Renal Transplant Patients The initial dose of Rapamune should be administered as soon as possible after transplantation.
It is recommended that Rapamune be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED) [ see Drug Interactions (7.2) ].
Frequent Rapamune dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life.
Once Rapamune maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring.
In most patients, dose adjustments can be based on simple proportion: new Rapamune dose = current dose × (target concentration/current concentration).
A loading dose should be considered in addition to a new maintenance dose when it is necessary to increase sirolimus trough concentrations: Rapamune loading dose = 3 × (new maintenance dose – current maintenance dose).
The maximum Rapamune dose administered on any day should not exceed 40 mg.
If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days.
Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).
Two milligrams (2 mg) of Rapamune Oral Solution have been demonstrated to be clinically equivalent to 2 mg Rapamune Tablets; hence, at this dose these two formulations are interchangeable.
However, it is not known if higher doses of Rapamune Oral Solution are clinically equivalent to higher doses of Rapamune Tablets on a mg-to-mg basis [ see Clinical Pharmacology (12.3) ].
2.2 Renal Transplant Patients at Low- to Moderate-Immunologic Risk Rapamune and Cyclosporine Combination Therapy For de novo renal transplant patients, it is recommended that Rapamune Oral Solution and Tablets be used initially in a regimen with cyclosporine and corticosteroids.
A loading dose of Rapamune equivalent to 3 times the maintenance dose should be given, i.e.
a daily maintenance dose of 2 mg should be preceded with a loading dose of 6 mg.
Therapeutic drug monitoring should be used to maintain sirolimus drug concentrations within the target-range [ see Dosage and Administration (2.5) ].
Rapamune Following Cyclosporine Withdrawal At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the Rapamune dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range [ see Dosage and Administration (2.5) ].
Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the Rapamune dose is increased [ see Clinical Pharmacology (12.3) ].
2.3 Renal Transplant Patients at High-Immunologic Risk In patients with high-immunologic risk, it is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation [ see Clinical Studies (14.3) ].
The safety and efficacy of this combination in high-immunologic risk patients has not been studied beyond the first 12 months.
Therefore, after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient.
For patients receiving Rapamune with cyclosporine, Rapamune therapy should be initiated with a loading dose of up to 15 mg on day 1 post-transplantation.
Beginning on day 2, an initial maintenance dose of 5 mg/day should be given.
A trough level should be obtained between days 5 and 7, and the daily dose of Rapamune should thereafter be adjusted [ see Dosage and Administration (2.5) ].
The starting dose of cyclosporine should be up to 7 mg/kg/day in divided doses and the dose should subsequently be adjusted to achieve target whole blood trough concentrations [ see Dosage and Administration (2.5) ].
Prednisone should be administered at a minimum of 5 mg/day.
Antibody induction therapy may be used.
2.4 Dosing in Patients with Lymphangioleiomyomatosis For patients with lymphangioleiomyomatosis, the initial Rapamune dose should be 2 mg/day.
Sirolimus whole blood trough concentrations should be measured in 10–20 days, with dosage adjustment to maintain concentrations between 5–15 ng/mL [ see Dosage and Administration (2.5) ].
In most patients, dose adjustments can be based on simple proportion: new Rapamune dose = current dose × (target concentration/current concentration).
Frequent Rapamune dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or under dosing because sirolimus has a long half-life.
Once Rapamune maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring.
Once a stable dose is achieved, therapeutic drug monitoring should be performed at least every three months.
2.5 Therapeutic Drug Monitoring Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients ≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment, when a change in the Rapamune dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors [ see Drug Interactions (7) ].
Therapeutic drug monitoring should not be the sole basis for adjusting Rapamune therapy.
Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters.
When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range [ see Clinical Studies (14) , Clinical Pharmacology (12.3) ].
Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation.
Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL.
The above recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods.
Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies.
Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable [ see Warnings and Precautions (5.16) , Clinical Pharmacology (12.3) ].
Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations.
Since results are assay and laboratory dependent, and the results may change over time, adjustments to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used.
Therefore, communication should be maintained with the laboratory performing the assay.
A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000 [ see References (15) ].
2.6 Patients with Low Body Weight The initial dosage in patients ≥ 13 years who weigh less than 40 kg should be adjusted, based on body surface area, to 1 mg/m 2 /day.
The loading dose should be 3 mg/m 2 .
2.7 Patients with Hepatic Impairment It is recommended that the maintenance dose of Rapamune be reduced by approximately one third in patients with mild or moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment.
It is not necessary to modify the Rapamune loading dose [ see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ].
2.8 Patients with Renal Impairment Dosage adjustment is not needed in patients with impaired renal function [ see Use in Specific Populations (8.7) ].
2.9 Instructions for Dilution and Administration of Rapamune Oral Solution The amber oral dose syringe should be used to withdraw the prescribed amount of Rapamune Oral Solution from the bottle.
Empty the correct amount of Rapamune from the syringe into only a glass or plastic container holding at least two (2) ounces (1/4 cup, 60 mL) of water or orange juice.
No other liquids, including grapefruit juice, should be used for dilution [ see Drug Interactions (7.3) , Clinical Pharmacology (12.3) ].
Stir vigorously and drink at once.
Refill the container with an additional volume [minimum of four (4) ounces (1/2 cup, 120 mL)] of water or orange juice, stir vigorously, and drink at once.
Rapamune Oral Solution contains polysorbate 80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC).
This should be considered during the preparation and administration of Rapamune Oral Solution.
It is important that these recommendations be followed closely.