**Rapamune^®^**

(**sirolimus)**

**Oral Solution and Tablets**

\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*

\* 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. \*

**\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\*\***

**DESCRIPTION**

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 shown below.

![](media/image1.png){width="2.3in" height="1.98125in"}

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 and as a white, triangular-shaped tablet containing 1
mg sirolimus.

The inactive ingredients in Rapamune Oral Solution are Phosal 50 PG
(phosphatidylcholine, propylene glycol, monodiglycerides, 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, and other ingredients.

**CLINICAL PHARMACOLOGY**

**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
prolonged the graft survival in presensitized rats. In some studies, the
immunosuppressive effect of sirolimus lasted 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.

**Pharmacokinetics**

Sirolimus pharmacokinetic activity has been determined following oral
administration in healthy subjects, pediatric dialysis patients,
hepatically-impaired patients, and renal transplant patients.

**Absorption**

Following administration of Rapamune Oral Solution, sirolimus is rapidly
absorbed, with a mean time-to-peak concentration (t~max~) of
approximately 1 hour after a single dose in healthy subjects and
approximately 2 hours after multiple oral doses in renal transplant
recipients. The systemic availability of sirolimus was estimated to be
approximately 14% after the administration of Rapamune Oral Solution.
The mean bioavailability of sirolimus after administration of the tablet
is about 27% higher relative to the oral solution. Sirolimus oral
tablets are not bioequivalent to the oral solution; however, clinical
equivalence has been demonstrated at the 2-mg dose level. (See Clinical
Studies and Dosage and Administration). Sirolimus concentrations,
following the administration of Rapamune Oral Solution to stable renal
transplant patients, are dose proportional between 3 and 12 mg/m^2^.

***Food effects:*** In 22 healthy volunteers receiving Rapamune Oral
Solution, a high-fat meal (1.88 kcal, 54.7% fat) altered the
bioavailability characteristics of sirolimus. Compared to fasting, a 34%
decrease in the peak blood sirolimus concentration (C~max~), a 3.5-fold
increase in the time-to-peak concentration (t~max~), and a 35% increase
in total exposure (AUC) was observed. After administration of Rapamune
Tablets and a high-fat meal in 24 healthy volunteers, C~max~, t~max~,
and AUC showed increases of 65%, 32%, and 23%, respectively. To minimize
variability, both Rapamune Oral Solution and Tablets should be taken
consistently with or without food (See DOSAGE AND ADMINISTRATION).

**Distribution**

The mean ( SD) blood-to-plasma ratio of sirolimus was 36 ( 17.9) in
stable renal allograft recipients, indicating that sirolimus is
extensively partitioned into formed blood elements. The mean volume of
distribution (V~ss~/F) of sirolimus is 12 7.52 L/kg. Sirolimus is
extensively bound (approximately 92%) to human plasma proteins. In man,
the binding of sirolimus was shown mainly to be associated with serum
albumin (97%), ~1~-acid glycoprotein, and lipoproteins.

**Metabolism**

Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and
P-glycoprotein. Sirolimus is extensively metabolized by O-demethylation
and/or hydroxylation. Seven (7) major metabolites, including hydroxy,
demethyl, and hydroxydemethyl, are identifiable in whole blood. Some of
these metabolites are also detectable in plasma, fecal, and urine
samples. Glucuronide and sulfate conjugates are not present in any of
the biologic matrices. Sirolimus is the major component in human whole
blood and contributes to more than 90% of the immunosuppressive
activity.

**Excretion**

After a single dose of \[^14^C\]sirolimus in healthy volunteers, the
majority (91%) of radioactivity was recovered from the feces, and only a
minor amount (2.2%) was excreted in urine.

**Pharmacokinetics in renal transplant patients**

Rapamune Oral Solution: Pharmacokinetic parameters for sirolimus oral
solution given daily in combination with cyclosporine and
corticosteroids in renal transplant patients are summarized below based
on data collected at months 1, 3, and 6 after transplantation. There
were no significant differences in any of these parameters with respect
to treatment group or month.

+---------+--------+------------+------------+------------+---------+
| Si      |        |            |            |            |         |
| rolimus |        |            |            |            |         |
| P       |        |            |            |            |         |
| harmaco |        |            |            |            |         |
| kinetic |        |            |            |            |         |
| Par     |        |            |            |            |         |
| ameters |        |            |            |            |         |
| (MEAN   |        |            |            |            |         |
| sd) in  |        |            |            |            |         |
| Renal   |        |            |            |            |         |
| Tra     |        |            |            |            |         |
| nsplant |        |            |            |            |         |
| p       |        |            |            |            |         |
| atients |        |            |            |            |         |
| (       |        |            |            |            |         |
| M       |        |            |            |            |         |
| ULTIPLE |        |            |            |            |         |
| DOSE    |        |            |            |            |         |
| ORAL    |        |            |            |            |         |
| SO      |        |            |            |            |         |
| LUTION) |        |            |            |            |         |
| ^a,b^   |        |            |            |            |         |
+---------+--------+------------+------------+------------+---------+
| n       | Dose   | C~ma       | t~max,ss\  | AUC        | CL/F    |
|         |        | x,ss~^c^~\ | ~(h)       | ~,ss~^c^~\ | /WT^d^\ |
|         |        | ~(ng/mL)   |            | ~(ngh/mL)  | (m      |
|         |        |            |            |            | L/h/kg) |
+---------+--------+------------+------------+------------+---------+
| 19      | 2 mg   | 12.2 6.2   | 3.01 2.40  | 158 70     | 182 72  |
+---------+--------+------------+------------+------------+---------+
| 23      | 5 mg   | 37.4 21    | 1.84 1.30  | 396 193    | 221 143 |
+---------+--------+------------+------------+------------+---------+
| a:      |        |            |            |            |         |
| Si      |        |            |            |            |         |
| rolimus |        |            |            |            |         |
| admin   |        |            |            |            |         |
| istered |        |            |            |            |         |
| four    |        |            |            |            |         |
| hours   |        |            |            |            |         |
| after   |        |            |            |            |         |
| cyclo   |        |            |            |            |         |
| sporine |        |            |            |            |         |
| oral    |        |            |            |            |         |
| s       |        |            |            |            |         |
| olution |        |            |            |            |         |
| (MO     |        |            |            |            |         |
| DIFIED) |        |            |            |            |         |
| (e.g.,  |        |            |            |            |         |
| Neoral  |        |            |            |            |         |
| Oral    |        |            |            |            |         |
| So      |        |            |            |            |         |
| lution) |        |            |            |            |         |
| and/or  |        |            |            |            |         |
| cyclo   |        |            |            |            |         |
| sporine |        |            |            |            |         |
| c       |        |            |            |            |         |
| apsules |        |            |            |            |         |
| (MO     |        |            |            |            |         |
| DIFIED) |        |            |            |            |         |
| (e.g.,  |        |            |            |            |         |
| Ne      |        |            |            |            |         |
| oral^®^ |        |            |            |            |         |
| Soft    |        |            |            |            |         |
| Gelatin |        |            |            |            |         |
| Cap     |        |            |            |            |         |
| sules). |        |            |            |            |         |
|         |        |            |            |            |         |
| b: As   |        |            |            |            |         |
| m       |        |            |            |            |         |
| easured |        |            |            |            |         |
| by the  |        |            |            |            |         |
| Liquid  |        |            |            |            |         |
| C       |        |            |            |            |         |
| hromato |        |            |            |            |         |
| graphic |        |            |            |            |         |
| /Tandem |        |            |            |            |         |
| Mass    |        |            |            |            |         |
| Spectr  |        |            |            |            |         |
| ometric |        |            |            |            |         |
| Method  |        |            |            |            |         |
| (LC/    |        |            |            |            |         |
| MS/MS). |        |            |            |            |         |
|         |        |            |            |            |         |
| c:      |        |            |            |            |         |
| These   |        |            |            |            |         |
| par     |        |            |            |            |         |
| ameters |        |            |            |            |         |
| were    |        |            |            |            |         |
| dose    |        |            |            |            |         |
| nor     |        |            |            |            |         |
| malized |        |            |            |            |         |
| prior   |        |            |            |            |         |
| to the  |        |            |            |            |         |
| stat    |        |            |            |            |         |
| istical |        |            |            |            |         |
| comp    |        |            |            |            |         |
| arison. |        |            |            |            |         |
|         |        |            |            |            |         |
| d:      |        |            |            |            |         |
| CL/F/WT |        |            |            |            |         |
| = oral  |        |            |            |            |         |
| dose    |        |            |            |            |         |
| cle     |        |            |            |            |         |
| arance. |        |            |            |            |         |
+---------+--------+------------+------------+------------+---------+

Whole blood sirolimus trough concentrations, as measured by immunoassay,
(mean SD) for the 2 mg/day and 5 mg/day dose groups were 8.59 4.01 ng/mL
(n = 226) and 17.3 7.4 ng/mL (n = 219), respectively. Whole blood trough
sirolimus concentrations, as measured by LC/MS/MS, were significantly
correlated (r^2^ = 0.96) with AUC~,ss~. Upon repeated twice daily
administration without an initial loading dose in a multiple-dose study,
the average trough concentration of sirolimus increases approximately 2
to 3-fold over the initial 6 days of therapy at which time steady state
is reached. A loading dose of 3 times the maintenance dose will provide
near steady-state concentrations within 1 day in most patients. The mean
SD terminal elimination half life (t) of sirolimus after multiple dosing
in stable renal transplant patients was estimated to be about 62 16
hours.

Rapamune Tablets: Pharmacokinetic parameters for sirolimus tablets
administered daily in combination with cyclosporine and corticosteroids
in renal transplant patients are summarized below based on data
collected at months 1 and 3 after transplantation.

+-------+-----------+-----------+------------+------------+---------+
| Siro  |           |           |            |            |         |
| limus |           |           |            |            |         |
| Pharm |           |           |            |            |         |
| acoki |           |           |            |            |         |
| netic |           |           |            |            |         |
| Param |           |           |            |            |         |
| eters |           |           |            |            |         |
| (MEAN |           |           |            |            |         |
| sd)   |           |           |            |            |         |
| in    |           |           |            |            |         |
| Renal |           |           |            |            |         |
| Trans |           |           |            |            |         |
| plant |           |           |            |            |         |
| pat   |           |           |            |            |         |
| ients |           |           |            |            |         |
| (MUL  |           |           |            |            |         |
| TIPLE |           |           |            |            |         |
| DOSE  |           |           |            |            |         |
| tab   |           |           |            |            |         |
| lets) |           |           |            |            |         |
| ^a,b^ |           |           |            |            |         |
+-------+-----------+-----------+------------+------------+---------+
| n     | Dose\     | C~max     | t~max,ss\  | AUC        | CL/F    |
|       | (2        | ,ss~^c^~\ | ~(h)       | ~,ss~^c^~\ | /WT^d^\ |
|       | mg/day)   | ~(ng/mL)  |            | ~(ngh/mL)  | (m      |
|       |           |           |            |            | L/h/kg) |
+-------+-----------+-----------+------------+------------+---------+
| 17    | Oral      | 14.4 5.3  | 2.12 0.84  | 194 78     | 173 50  |
|       | solution  |           |            |            |         |
+-------+-----------+-----------+------------+------------+---------+
| 13    | Tablets   | 15.0 4.9  | 3.46 2.40  | 230 67     | 139 63  |
+-------+-----------+-----------+------------+------------+---------+
| a:    |           |           |            |            |         |
| Siro  |           |           |            |            |         |
| limus |           |           |            |            |         |
| ad    |           |           |            |            |         |
| minis |           |           |            |            |         |
| tered |           |           |            |            |         |
| four  |           |           |            |            |         |
| hours |           |           |            |            |         |
| after |           |           |            |            |         |
| cy    |           |           |            |            |         |
| closp |           |           |            |            |         |
| orine |           |           |            |            |         |
| oral  |           |           |            |            |         |
| sol   |           |           |            |            |         |
| ution |           |           |            |            |         |
| (MODI |           |           |            |            |         |
| FIED) |           |           |            |            |         |
| (     |           |           |            |            |         |
| e.g., |           |           |            |            |         |
| N     |           |           |            |            |         |
| eoral |           |           |            |            |         |
| Oral  |           |           |            |            |         |
| Solu  |           |           |            |            |         |
| tion) |           |           |            |            |         |
| a     |           |           |            |            |         |
| nd/or |           |           |            |            |         |
| cy    |           |           |            |            |         |
| closp |           |           |            |            |         |
| orine |           |           |            |            |         |
| cap   |           |           |            |            |         |
| sules |           |           |            |            |         |
| (MODI |           |           |            |            |         |
| FIED) |           |           |            |            |         |
| (     |           |           |            |            |         |
| e.g., |           |           |            |            |         |
| Neor  |           |           |            |            |         |
| al^®^ |           |           |            |            |         |
| Soft  |           |           |            |            |         |
| Ge    |           |           |            |            |         |
| latin |           |           |            |            |         |
| Capsu |           |           |            |            |         |
| les). |           |           |            |            |         |
|       |           |           |            |            |         |
| b: As |           |           |            |            |         |
| mea   |           |           |            |            |         |
| sured |           |           |            |            |         |
| by    |           |           |            |            |         |
| the   |           |           |            |            |         |
| L     |           |           |            |            |         |
| iquid |           |           |            |            |         |
| Ch    |           |           |            |            |         |
| romat |           |           |            |            |         |
| ograp |           |           |            |            |         |
| hic/T |           |           |            |            |         |
| andem |           |           |            |            |         |
| Mass  |           |           |            |            |         |
| Spe   |           |           |            |            |         |
| ctrom |           |           |            |            |         |
| etric |           |           |            |            |         |
| M     |           |           |            |            |         |
| ethod |           |           |            |            |         |
| (     |           |           |            |            |         |
| LC/MS |           |           |            |            |         |
| /MS). |           |           |            |            |         |
|       |           |           |            |            |         |
| c:    |           |           |            |            |         |
| These |           |           |            |            |         |
| param |           |           |            |            |         |
| eters |           |           |            |            |         |
| were  |           |           |            |            |         |
| dose  |           |           |            |            |         |
| norma |           |           |            |            |         |
| lized |           |           |            |            |         |
| prior |           |           |            |            |         |
| to    |           |           |            |            |         |
| the   |           |           |            |            |         |
| s     |           |           |            |            |         |
| tatis |           |           |            |            |         |
| tical |           |           |            |            |         |
| c     |           |           |            |            |         |
| ompar |           |           |            |            |         |
| ison. |           |           |            |            |         |
|       |           |           |            |            |         |
| d:    |           |           |            |            |         |
| CL    |           |           |            |            |         |
| /F/WT |           |           |            |            |         |
| =     |           |           |            |            |         |
| we    |           |           |            |            |         |
| ight- |           |           |            |            |         |
| norma |           |           |            |            |         |
| lized |           |           |            |            |         |
| oral  |           |           |            |            |         |
| dose  |           |           |            |            |         |
| clear |           |           |            |            |         |
| ance. |           |           |            |            |         |
+-------+-----------+-----------+------------+------------+---------+

Whole blood sirolimus trough concentrations (mean SD), as measured by
immunoassay, for the 2 mg oral solution and 2 mg tablets over 6 months,
were 8.94 4.36 ng/mL (n = 172) and 9.48 3.85 ng/mL (n = 179),
respectively. Whole blood trough sirolimus concentrations, as measured
by LC/MS/MS, were significantly correlated (r^2^ = 0.85) with AUC~,ss~.
Mean whole blood sirolimus trough concentrations in patients receiving
either Rapamune Oral Solution or Rapamune Tablets with a loading dose of
three times the maintenance dose achieved steady-state concentrations
within 24 hours after the start of dose administration.

**Special Populations**

***Hepatic impairment:*** Sirolimus (15 mg) was administered as a single
oral dose to 18 subjects with normal hepatic function and to 18 patients
with Child-Pugh classification A or B hepatic impairment, in which
hepatic impairment was primary and not related to an underlying systemic
disease. Shown below are the mean SD pharmacokinetic parameters
following the administration of sirolimus oral solution.

+-----------------+--------------+------------+------------+-----------+
| Sirolimus       |              |            |            |           |
| Pharmacokinetic |              |            |            |           |
| Parameters      |              |            |            |           |
| (MEAN sd) in 18 |              |            |            |           |
| HEALTHY         |              |            |            |           |
| SUBJECTS AND 18 |              |            |            |           |
| patients WITH   |              |            |            |           |
| HEPATIC         |              |            |            |           |
| IMPAIRMENT\     |              |            |            |           |
| (15 mg SINGLE   |              |            |            |           |
| DOSE -- Oral    |              |            |            |           |
| solution)       |              |            |            |           |
+-----------------+--------------+------------+------------+-----------+
| Population      | C~max,ss~^a^ | t~max~     | AUC~0-~    | CL/F/WT   |
|                 |              |            |            |           |
|                 | (ng/mL)      | \(h\)      | (ngh/mL)   | (mL/h/kg) |
+-----------------+--------------+------------+------------+-----------+
| Healthy         | 78.2 18.3    | 0.82 0.17  | 970 272    | 215 76    |
| subjects        |              |            |            |           |
+-----------------+--------------+------------+------------+-----------+
| Hepatic         | 77.9 23.1    | 0.84 0.17  | 1567 616   | 144 62    |
| impairment      |              |            |            |           |
+-----------------+--------------+------------+------------+-----------+
| a: As measured  |              |            |            |           |
| by LC/MS/MS.    |              |            |            |           |
+-----------------+--------------+------------+------------+-----------+

Compared with the values in the normal hepatic group, the hepatic
impairment group had higher mean values for sirolimus AUC (61%) and
t~1/2~ (43%) and had lower mean values for sirolimus CL/F/WT (33%). The
mean t~1/2~ increased from 79 12 hours in subjects with normal hepatic
function to 113 41 hours in patients with impaired hepatic function. The
rate of absorption of sirolimus was not altered by hepatic disease, as
evidenced by C~max~ and t~max~ values. However, hepatic diseases with
varying etiologies may show different effects and the pharmacokinetics
of sirolimus in patients with severe hepatic dysfunction is unknown.
Dosage adjustment is recommended for patients with mild to moderate
hepatic impairment (**see DOSAGE AND ADMINISTRATION**).

***Renal impairment:*** The effect of renal impairment on the
pharmacokinetics of sirolimus is not known. However, there is minimal
(2.2%) renal excretion of the drug or its metabolites.

***Pediatric:*** Limited pharmacokinetic data are available in pediatric
patients. The table below summarizes pharmacokinetic data obtained in
pediatric dialysis patients with chronically impaired renal function.

  ----------------- -------- --------------- --------------- -----------------
  SIROLIMUS                                                  
  PHARMACOKINETIC                                            
  PARAMETERS (MEAN                                           
  SD) IN PEDIATRIC                                           
  PATIENTS WITH                                              
  STABLE CHRONIC                                             
  RENAL FAILURE                                              
  MAINTAINED ON                                              
  HEMODIALYSIS OR                                            
  PERITONEAL                                                 
  DIALYSIS (1, 3,                                            
  9, 15 MG/M^2^                                              
  SINGLE DOSE)                                               

  Age Group (y)     n        t~max~ (h)      t~1/2~ (h)      CL/F/WT (mL/h/kg)

  5-11              9        1.1 0.5         71 40           580 450

  12-18             11       0.79 0.17       55 18           450 232
  ----------------- -------- --------------- --------------- -----------------

***Geriatric:*** Clinical studies of Rapamune did not include a
sufficient number of patients \> 65 years of age to determine whether
they will respond differently than younger patients. After the
administration of Rapamune Oral Solution, sirolimus trough concentration
data in 35 renal transplant patients \> 65 years of age were similar to
those in the adult population (n=822) 18 to 65 years of age. Similar
results were obtained after the administration of Rapamune Tablets to 12
renal transplant patients \> 65 years of age compared with adults
(n=167) 18 to 65 years of age.

***Gender:*** After the administration of Rapamune Oral Solution,
sirolimus oral dose clearance in males was 12% lower than that in
females; male subjects had a significantly longer t~1/2~ than did female
subjects (72.3 hours versus 61.3 hours). A similar trend in the effect
of gender on sirolimus oral dose clearance and t~½~ was observed after
the administration of Rapamune Tablets. Dose adjustments based on gender
are not recommended.

***Race:*** In large phase III trials using Rapamune Oral Solution and
cyclosporine oral solution (MODIFIED) (eg, Neoral Oral Solution) and/or
cyclosporine capsules (MODIFIED) (e.g., Neoral^®^ Soft Gelatin
Capsules), there were no significant differences in mean trough
sirolimus concentrations over time between black (n = 139) and non-black
(n = 724) patients during the first 6 months after transplantation at
sirolimus doses of 2 mg/day and 5 mg/day*.* Similarly, after
administration of Rapamune Tablets (2 mg/day) in a phase III trial, mean
sirolimus trough concentrations over 6 months were not significantly
different among black (n = 51) and non-black (n = 128) patients.

**CLINICAL STUDIES**

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 to both azathioprine and placebo.

+--------------------------+------------+--------------+--------------+
| INCIDENCE (%) OF THE     |            |              |              |
| PRIMARY ENDPOINT AT 6    |            |              |              |
| MONTHS: STUDY 1^a^       |            |              |              |
+--------------------------+------------+--------------+--------------+
| Parameter                | Rapamune^\ | Rapamune     | A            |
|                          | ^ Oral     |              | zathioprine\ |
|                          | Solution^\ | Oral         | 2-3          |
|                          | ^2 mg/day\ | Solution^\   | mg/kg/day\   |
|                          | (n = 284)  | ^5 mg/day\   | (n = 161)    |
|                          |            | (n = 274)    |              |
+--------------------------+------------+--------------+--------------+
| Efficacy failure at 6    | 18.7       | 16.8         | 32.3         |
| months                   |            |              |              |
+--------------------------+------------+--------------+--------------+
| *Components of efficacy  |            |              |              |
| failure*                 |            |              |              |
+--------------------------+------------+--------------+--------------+
| Biopsy-proven acute      | 16.5       | 11.3         | 29.2         |
| rejection                |            |              |              |
+--------------------------+------------+--------------+--------------+
| Graft loss               | 1.1        | 2.9          | 2.5          |
+--------------------------+------------+--------------+--------------+
| Death                    | 0.7        | 1.8          | 0            |
+--------------------------+------------+--------------+--------------+
| Lost to follow-up        | 0.4        | 0.7          | 0.6          |
+--------------------------+------------+--------------+--------------+
| a: Patients received     |            |              |              |
| cyclosporine and         |            |              |              |
| corticosteroids.         |            |              |              |
+--------------------------+------------+--------------+--------------+

  --------------------------- --------------- ---------------- -----------
  INCIDENCE (%) OF THE                                         
  PRIMARY ENDPOINT AT 6                                        
  MONTHS: STUDY 2 ^a^                                          

  Parameter                   Rapamune^\      Rapamune^\       Placebo\
                              ^ Oral          ^ Oral           (n = 130)
                              Solution^\      Solution^\       
                              ^2 mg/day\      ^5 mg/day\       
                              (n = 227)       (n = 219)        

  Efficacy failure at 6       30.0            25.6             47.7
  months                                                       

  *Components of efficacy                                      
  failure*                                                     

  Biopsy-proven acute         24.7            19.2             41.5
  rejection                                                    

  Graft loss                  3.1             3.7              3.9

  Death                       2.2             2.7              2.3

  Lost to follow-up           0               0                0

  a: Patients received                                         
  cyclosporine and                                             
  corticosteroids.                                             
  --------------------------- --------------- ---------------- -----------

Patient and graft survival at 1 year were co-primary endpoints. The
table below shows graft and patient survival at 1 year in Study 1 and
Study 2. The graft and patient survival rates at 1 year were similar in
the Rapamune- and comparator-treated patients.

  ------------------- ------------- ------------- --------------- -----------
  1-YEAR GRAFT AND                                                
  PATIENT SURVIVAL                                                
  (%)^a^                                                          

  Parameter           Rapamune\     Rapamune\     Azathioprine\   Placebo
                      Oral          Oral          2-3 mg/kg/day   
                      Solution^\    Solution^\                    
                      ^2 mg/day     ^5 mg/day                     

  Study 1             (n = 284)     (n = 274)     (n = 161)       

  Graft survival      94.7          92.7          93.8            

  Patient survival    97.2          96.0          98.1            

  Study 2             (n = 227)     (n = 219)                     (n = 130)

  Graft survival      89.9          90.9                          87.7

  Patient survival    96.5          95.0                          94.6

  a: Patients                                                     
  received                                                        
  cyclosporine and                                                
  corticosteroids.                                                
  ------------------- ------------- ------------- --------------- -----------

The reduction in the incidence of first biopsy-confirmed acute rejection
episodes in Rapamune-treated patients compared to the control groups
included a reduction in all grades of rejection.

+------------------+-------------+-------------+------------+----------+
| PERCENTAGE OF    |             |             |            |          |
| EFFICACY FAILURE |             |             |            |          |
| BY RACE AT 6     |             |             |            |          |
| MONTHS           |             |             |            |          |
+------------------+-------------+-------------+------------+----------+
| Parameter        | Rapamune\   | Rapamune\   | Az         | Placebo  |
|                  | Oral        | Oral        | athioprine |          |
|                  | Solution\   | Solution    |            |          |
|                  | 2 mg/day    |             | 2-3        |          |
|                  |             | 5 mg/day    | mg/kg/day  |          |
+------------------+-------------+-------------+------------+----------+
| Study 1          |             |             |            |          |
+------------------+-------------+-------------+------------+----------+
| Black (n=166)    | 34.9 (n=63) | 18.0 (n=61) | 33.3       |          |
|                  |             |             | (n=42)     |          |
+------------------+-------------+-------------+------------+----------+
| Nonblack (n=553) | 14.0        | 16.4 (      | 31.9       |          |
|                  | (n=221)     | n=213)      | (n=119)    |          |
+------------------+-------------+-------------+------------+----------+
| Study 2          |             |             |            |          |
+------------------+-------------+-------------+------------+----------+
| Black (n=66)     | 30.8 (n=26) | 33.7 (n=27) |            | 38.5     |
|                  |             |             |            | (n=13)   |
+------------------+-------------+-------------+------------+----------+
| Non-black        | 29.9        | 24.5        |            | 48.7     |
| (n=510)          | (n=201)     | (n=192)     |            | (n=117)  |
+------------------+-------------+-------------+------------+----------+

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 to 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 to 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).

+--------------+--------------+--------------+-------------+-----------+
| OVERALL      |              |              |             |           |
| CALCULATED   |              |              |             |           |
| GLOMERULAR   |              |              |             |           |
| FILTRATION   |              |              |             |           |
| RATES        |              |              |             |           |
| (CC/MIN) BY  |              |              |             |           |
| NANKIVELL    |              |              |             |           |
| EQUATION AT  |              |              |             |           |
| 12 MONTHS    |              |              |             |           |
| POST         |              |              |             |           |
| TRANSPLANT   |              |              |             |           |
+--------------+--------------+--------------+-------------+-----------+
| Parameter    | Rapamune\    | Rapamune^\   | A           | Placebo   |
|              | Oral         | ^Oral        | zathioprine |           |
|              | Solution\    | Solution\    |             |           |
|              | 2 mg/day     | 5 mg/day     | 2-3         |           |
|              |              |              | mg/kg/day   |           |
+--------------+--------------+--------------+-------------+-----------+
| Study 1      | (n=233)      | (n=226)      | (n=127)     |           |
+--------------+--------------+--------------+-------------+-----------+
| Mean (SE)    | 57.4 (1.28)  | 55.1 (1.28)  | 65.9 (1.69) |           |
+--------------+--------------+--------------+-------------+-----------+
| Study 2      | (n=190)      | (n=175)      |             | (n=101)   |
+--------------+--------------+--------------+-------------+-----------+
| Mean (SE)    | 54.9 (1.26)  | 52.9 (1.46)  |             | 61.7      |
|              |              |              |             | (1.81)    |
+--------------+--------------+--------------+-------------+-----------+

Mean glomerular filtration rates (GFR) at one year post transplant were
calculated by using the Nankivell equation for all subjects in Studies 1
and 2 who had serum creatinine measured at 12 months. In Studies 1 and 2
mean GFR, at 12 months, were lower in patients treated with cyclosporine
and Rapamune Oral Solution compared to those treated with cyclosporine
and the respective azathioprine or placebo control.

Within each treatment group in Studies 1 and 2, mean GFR at one year
post transplant was lower in patients who experienced at least 1 episode
of biopsy-proven acute rejection, compared to those who did not.

Renal function should be monitored and appropriate adjustment of the
immunosuppression regimen should be considered in patients with elevated
serum creatinine levels (see PRECAUTIONS).

**Rapamune Tablets**: The safety and efficacy of Rapamune Oral Solution
and Rapamune Tablets for the prevention of organ rejection following
renal transplantation were compared in a randomized multicenter
controlled trial (Study 3). This study compared a single dose level (2
mg, once daily) of Rapamune Oral Solution and Rapamune Tablets when
administered in combination with cyclosporine and corticosteroids. The
study was conducted at 30 centers in Australia, Canada, and the United
States. Four hundred seventy-seven (477) patients were enrolled in this
study and randomized before transplantation; 238 patients were
randomized to receive Rapamune Oral Solution 2 mg/day and 239 patients
were randomized to receive Rapamune Tablets 2 mg/day. In this study, the
use of antilymphocyte antibody induction therapy was prohibited. The
primary efficacy endpoint was the rate of efficacy failure in the first
3 months after transplantation. Efficacy failure was defined as the
first occurrence of an acute rejection episode (confirmed by biopsy),
graft loss, or death.

The table below summarizes the result of the primary efficacy analysis
at 3 months from this trial. The overall rate of efficacy failure in the
tablet treatment group was equivalent to the rate in the oral solution
treatment group.

+-------------------------------+-------------------+------------------+
| INCIDENCE (%) OF THE PRIMARY  |                   |                  |
| ENDPOINT AT 3 MONTHS: STUDY   |                   |                  |
| 3^a^                          |                   |                  |
+-------------------------------+-------------------+------------------+
|                               | Rapamune\         | Rapamune\        |
|                               | Oral Solution\    | Tablets\         |
|                               | (n = 238)         | (n = 239)        |
+-------------------------------+-------------------+------------------+
| Efficacy Failure at 3 months  | 23.5              | 24.7             |
+-------------------------------+-------------------+------------------+
| *Components of efficacy       |                   |                  |
| failure*                      |                   |                  |
+-------------------------------+-------------------+------------------+
| > Biopsy-proven acute         | 18.9              | 17.6             |
| > rejection                   |                   |                  |
+-------------------------------+-------------------+------------------+
| Graft loss                    | 3.4               | 6.3              |
+-------------------------------+-------------------+------------------+
| Death                         | 1.3               | 0.8              |
+-------------------------------+-------------------+------------------+
| a: Patients received          |                   |                  |
| cyclosporine and              |                   |                  |
| corticosteroids.              |                   |                  |
+-------------------------------+-------------------+------------------+

The table below summarizes the results of the primary efficacy analysis
at 6 months after transplantation.

+-------------------------------+-------------------+------------------+
| INCIDENCE (%) OF THE PRIMARY  |                   |                  |
| ENDPOINT AT 6 MONTHS: STUDY   |                   |                  |
| 3^a^                          |                   |                  |
+-------------------------------+-------------------+------------------+
|                               | Rapamune\         | Rapamune\        |
|                               | Oral Solution\    | Tablets\         |
|                               | (n = 238)         | (n = 239)        |
+-------------------------------+-------------------+------------------+
| Efficacy Failure at 6 months  | 26.1              | 27.2             |
+-------------------------------+-------------------+------------------+
| *Components of efficacy       |                   |                  |
| failure*                      |                   |                  |
+-------------------------------+-------------------+------------------+
| > Biopsy-proven acute         | 21.0              | 19.2             |
| > rejection                   |                   |                  |
+-------------------------------+-------------------+------------------+
| Graft loss                    | 3.4               | 6.3              |
+-------------------------------+-------------------+------------------+
| Death                         | 1.7               | 1.7              |
+-------------------------------+-------------------+------------------+
| a: Patients received          |                   |                  |
| cyclosporine and              |                   |                  |
| corticosteroids.              |                   |                  |
+-------------------------------+-------------------+------------------+

Graft and patient survival at 12 months were co-primary efficacy
endpoints. There was no significant difference between the oral solution
and tablet formulations for both graft and patient survival. Graft
survival was 92.0% and 88.7% for the oral solution and tablet treatment
groups, respectively. The patient survival rates in the oral solution
and tablet treatment groups were 95.8% and 96.2%, respectively.

The mean GFR at 12 months, calculated by the Nankivell equation, were
not significantly different for the oral solution group and for the
tablet group.

The table below summarizes the mean GFR at one-year post-transplantation
for all subjects in Study 3 who had serum creatinine measured at 12
months.

+--------------------+-----------------------------+------------------+
| OVERALL CALCULATED |                             |                  |
| GLOMERULAR         |                             |                  |
| FILTRATION RATES   |                             |                  |
| (CC/MIN) BY        |                             |                  |
| NANKIVELL EQUATION |                             |                  |
| AT 12 MONTHS POST  |                             |                  |
| TRANSPLANT: STUDY  |                             |                  |
| 3                  |                             |                  |
+--------------------+-----------------------------+------------------+
|                    | Rapamune\                   | Rapamune\        |
|                    | Oral Solution               | Tablets          |
+--------------------+-----------------------------+------------------+
| Mean (SE)          | 58.3 (1.64)                 | 58.5 (1.44)      |
|                    |                             |                  |
|                    | n=166                       | n=162            |
+--------------------+-----------------------------+------------------+

**INDICATIONS AND USAGE**

Rapamune is indicated for the prophylaxis of organ rejection in patients
receiving renal transplants. It is recommended that Rapamune be used in
a regimen with cyclosporine and corticosteroids.

**CONTRAINDICATIONS**

Rapamune is contraindicated in patients with a hypersensitivity to
sirolimus or its derivatives or any component of the drug product.

**WARNINGS**

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 a 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 azathioprine 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 to 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 (eg, 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 (400 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 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).

*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 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.

**ADVERSE REACTIONS**

**Rapamune Oral Solution:** The incidence of adverse reactions was
determined in two randomized, double-blind, multicenter controlled
trials in which 499 renal transplant patients received Rapamune Oral
Solution 2 mg/day, 477 received Rapamune Oral Solution 5 mg/day, 160
received azathioprine, and 124 received placebo. All patients were
treated with cyclosporine and corticosteroids. Data ( 12 months
post-transplant) presented in the table below show the adverse reactions
that occurred in any treatment group with an incidence of 20%.

Specific adverse reactions associated with the administration of
Rapamune Oral Solution occurred at a significantly higher frequency than
in the respective control group. For both Rapamune Oral Solution 2
mg/day and 5 mg/day these include hypercholesterolemia, hyperlipemia,
hypertension, and rash; for Rapamune Oral Solution 2 mg/day acne; and
for Rapamune Oral Solution 5 mg/day anemia, arthralgia, diarrhea,
hypokalemia, and thrombocytopenia. The elevations of triglycerides and
cholesterol and decreases in platelets and hemoglobin occurred in a dose
related manner in patients receiving Rapamune.

Patients maintained on Rapamune Oral Solution 5 mg/day, when compared to
patients on Rapamune Oral Solution 2 mg/day, demonstrated an increased
incidence of the following adverse events: anemia, leukopenia,
thrombocytopenia, hypokalemia, hyperlipemia, fever, and diarrhea.

<table style="width:100%;">
<colgroup>
<col style="width: 27%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 16%" />
<col style="width: 0%" />
<col style="width: 11%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="11">ADVERSE EVENTS OCCURRING AT A FREQUENCY OF 20% IN ANY
TREATMENT GROUP IN PREVENTION OF ACUTE RENAL REJECTION TRIALS
(%)<sup>a</sup> AT 12 MONTHS POST-TRANSPLANTATION FOR STUDIES 1 AND
2</th>
</tr>
<tr class="odd">
<th colspan="2"><strong>Body System</strong></th>
<th colspan="3">Rapamune<sup>®</sup><br />
Oral Solution<br />
------2 mg/day------</th>
<th colspan="3">Rapamune<sup>®<br />
</sup>Oral Solution<br />
-----5 mg/day-----</th>
<th colspan="2"><p>Azathioprine</p>
<p>2-3 mg/kg/day</p></th>
<th>Placebo</th>
</tr>
<tr class="header">
<th>Adverse Event</th>
<th colspan="2">Study 1<br />
(n = 281)</th>
<th>Study 2<br />
(n = 218)</th>
<th colspan="2">Study 1<br />
(n = 269)</th>
<th>Study 2<br />
(n = 208)</th>
<th colspan="2">Study 1<br />
(n = 160)</th>
<th colspan="2">Study 2<br />
(n = 124)</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><strong>Body As A Whole</strong></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Abdominal pain</td>
<td colspan="2">28</td>
<td>29</td>
<td colspan="2">30</td>
<td>36</td>
<td colspan="2">29</td>
<td colspan="2">30</td>
</tr>
<tr class="odd">
<td>Asthenia</td>
<td colspan="2">38</td>
<td>22</td>
<td colspan="2">40</td>
<td>28</td>
<td colspan="2">37</td>
<td colspan="2">28</td>
</tr>
<tr class="even">
<td>Back pain</td>
<td colspan="2">16</td>
<td>23</td>
<td colspan="2">26</td>
<td>22</td>
<td colspan="2">23</td>
<td colspan="2">20</td>
</tr>
<tr class="odd">
<td>Chest pain</td>
<td colspan="2">16</td>
<td>18</td>
<td colspan="2">19</td>
<td>24</td>
<td colspan="2">16</td>
<td colspan="2">19</td>
</tr>
<tr class="even">
<td>Fever</td>
<td colspan="2">27</td>
<td>23</td>
<td colspan="2">33</td>
<td>34</td>
<td colspan="2">33</td>
<td colspan="2">35</td>
</tr>
<tr class="odd">
<td>Headache</td>
<td colspan="2">23</td>
<td>34</td>
<td colspan="2">27</td>
<td>34</td>
<td colspan="2">21</td>
<td colspan="2">31</td>
</tr>
<tr class="even">
<td>Pain</td>
<td colspan="2">24</td>
<td>33</td>
<td colspan="2">29</td>
<td>29</td>
<td colspan="2">30</td>
<td colspan="2">25</td>
</tr>
<tr class="odd">
<td><strong>Cardiovascular System</strong></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Hypertension</td>
<td colspan="2">43</td>
<td>45</td>
<td colspan="2">39</td>
<td>49</td>
<td colspan="2">29</td>
<td colspan="2">48</td>
</tr>
<tr class="odd">
<td><strong>Digestive System</strong></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Constipation</td>
<td colspan="2">28</td>
<td>36</td>
<td colspan="2">34</td>
<td>38</td>
<td colspan="2">37</td>
<td colspan="2">31</td>
</tr>
<tr class="odd">
<td>Diarrhea</td>
<td colspan="2">32</td>
<td>25</td>
<td colspan="2">42</td>
<td>35</td>
<td colspan="2">28</td>
<td colspan="2">27</td>
</tr>
<tr class="even">
<td>Dyspepsia</td>
<td colspan="2">17</td>
<td>23</td>
<td colspan="2">23</td>
<td>25</td>
<td colspan="2">24</td>
<td colspan="2">34</td>
</tr>
<tr class="odd">
<td>Nausea</td>
<td colspan="2">31</td>
<td>25</td>
<td colspan="2">36</td>
<td>31</td>
<td colspan="2">39</td>
<td colspan="2">29</td>
</tr>
<tr class="even">
<td>Vomiting</td>
<td colspan="2">21</td>
<td>19</td>
<td colspan="2">25</td>
<td>25</td>
<td colspan="2">31</td>
<td colspan="2">21</td>
</tr>
<tr class="odd">
<td><strong>Hemic And Lymphatic System</strong></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Anemia</td>
<td colspan="2">27</td>
<td>23</td>
<td colspan="2">37</td>
<td>33</td>
<td colspan="2">29</td>
<td colspan="2">21</td>
</tr>
<tr class="odd">
<td>Leukopenia</td>
<td colspan="2">9</td>
<td>9</td>
<td colspan="2">15</td>
<td>13</td>
<td colspan="2">20</td>
<td colspan="2">8</td>
</tr>
<tr class="even">
<td>Thrombocytopenia</td>
<td colspan="2">13</td>
<td>14</td>
<td colspan="2">20</td>
<td>30</td>
<td colspan="2">9</td>
<td colspan="2">9</td>
</tr>
<tr class="odd">
<td><strong>Metabolic And Nutritional</strong></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Creatinine increased</td>
<td colspan="2">35</td>
<td>39</td>
<td colspan="2">37</td>
<td>40</td>
<td colspan="2">28</td>
<td colspan="2">38</td>
</tr>
<tr class="odd">
<td>Edema</td>
<td colspan="2">24</td>
<td>20</td>
<td colspan="2">16</td>
<td>18</td>
<td colspan="2">23</td>
<td colspan="2">15</td>
</tr>
<tr class="even">
<td>Hypercholesteremia<br />
(See WARNINGS and<br />
PRECAUTIONS)</td>
<td colspan="2">38</td>
<td>43</td>
<td colspan="2">42</td>
<td>46</td>
<td colspan="2">33</td>
<td colspan="2">23</td>
</tr>
<tr class="odd">
<td>Hyperkalemia</td>
<td colspan="2">15</td>
<td>17</td>
<td colspan="2">12</td>
<td>14</td>
<td colspan="2">24</td>
<td colspan="2">27</td>
</tr>
<tr class="even">
<td>Hyperlipemia<br />
(See WARNINGS and<br />
PRECAUTIONS)</td>
<td colspan="2">38</td>
<td>45</td>
<td colspan="2">44</td>
<td>57</td>
<td colspan="2">28</td>
<td colspan="2">23</td>
</tr>
<tr class="odd">
<td>Hypokalemia</td>
<td colspan="2">17</td>
<td>11</td>
<td colspan="2">21</td>
<td>17</td>
<td colspan="2">11</td>
<td colspan="2">9</td>
</tr>
<tr class="even">
<td>Hypophosphatemia</td>
<td colspan="2">20</td>
<td>15</td>
<td colspan="2">23</td>
<td>19</td>
<td colspan="2">20</td>
<td colspan="2">19</td>
</tr>
<tr class="odd">
<td>Peripheral edema</td>
<td colspan="2">60</td>
<td>54</td>
<td colspan="2">64</td>
<td>58</td>
<td colspan="2">58</td>
<td colspan="2">48</td>
</tr>
<tr class="even">
<td>Weight gain</td>
<td colspan="2">21</td>
<td>11</td>
<td colspan="2">15</td>
<td>8</td>
<td colspan="2">19</td>
<td colspan="2">15</td>
</tr>
<tr class="odd">
<td><strong>Musculoskeletal System</strong></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Arthralgia</td>
<td colspan="2">25</td>
<td>25</td>
<td colspan="2">27</td>
<td>31</td>
<td colspan="2">21</td>
<td colspan="2">18</td>
</tr>
<tr class="odd">
<td><strong>Nervous System</strong></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Insomnia</td>
<td colspan="2">14</td>
<td>13</td>
<td colspan="2">22</td>
<td>14</td>
<td colspan="2">18</td>
<td colspan="2">8</td>
</tr>
<tr class="odd">
<td>Tremor</td>
<td colspan="2">31</td>
<td>21</td>
<td colspan="2">30</td>
<td>22</td>
<td colspan="2">28</td>
<td colspan="2">19</td>
</tr>
<tr class="even">
<td><strong>Respiratory System</strong></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td>Dyspnea</td>
<td colspan="2">22</td>
<td>24</td>
<td colspan="2">28</td>
<td>30</td>
<td colspan="2">23</td>
<td colspan="2">30</td>
</tr>
<tr class="even">
<td>Pharyngitis</td>
<td colspan="2">17</td>
<td>16</td>
<td colspan="2">16</td>
<td>21</td>
<td colspan="2">17</td>
<td colspan="2">22</td>
</tr>
<tr class="odd">
<td>Upper respiratory infection</td>
<td colspan="2">20</td>
<td>26</td>
<td colspan="2">24</td>
<td>23</td>
<td colspan="2">13</td>
<td colspan="2">23</td>
</tr>
<tr class="even">
<td><strong>Skin And Appendages</strong></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td>Acne</td>
<td colspan="2">31</td>
<td>22</td>
<td colspan="2">20</td>
<td>22</td>
<td colspan="2">17</td>
<td colspan="2">19</td>
</tr>
<tr class="even">
<td>Rash</td>
<td colspan="2">12</td>
<td>10</td>
<td colspan="2">13</td>
<td>20</td>
<td colspan="2">6</td>
<td colspan="2">6</td>
</tr>
<tr class="odd">
<td>Urogenital System</td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Urinary tract infection</td>
<td colspan="2">20</td>
<td>26</td>
<td colspan="2">23</td>
<td>33</td>
<td colspan="2">31</td>
<td colspan="2">26</td>
</tr>
<tr class="odd">
<td colspan="11">a: Patients received cyclosporine and
corticosteroids.</td>
</tr>
</tbody>
</table>

At 12 months, there were no significant differences in incidence rates
for clinically important opportunistic or common transplant-related
infections across treatment groups, with the exception of mucosal
infections with *Herpes simplex*, which occurred at a significantly
greater rate in patients treated with Rapamune 5 mg/day than in both of
the comparator groups.

The table below summarizes the incidence of malignancies in the two
controlled trials for the prevention of acute rejection. At 12 months
following transplantation, there was a very low incidence of
malignancies and there were no significant differences among treatment
groups.

  --------------------------------------------------------------------------------------------
  INCIDENCE (%) OF MALIGNANCIES                                                     
  IN PREVENTION OF ACUTE RENAL                                                      
  REJECTION TRIALS: AT 12 MONTHS                                                    
  POST-TRANSPLANT ^a^                                                               
  ------------------------------ ----------- ----------- --------------- ---------- ----------
                                 Rapamune\   Rapamune\   Azathioprine\              Placebo
                                 Oral        Oral        2-3 mg/kg/day              
                                 Solution\   Solution\                              
                                 2 mg/day    5 mg/day                               

  Malignancy                     (n = 511)   (n = 493)                   (n = 161)  (n = 130)

  Lymphoma/lymphoproliferative   0.4         1.4                         0.6        0
  disease                                                                           

  Non-melanoma skin carcinoma    0.4         1.4                         1.2        3.1

  Other malignancy               0.6         0.6                         0          0

  a: Patients received                                                              
  cyclosporine and                                                                  
  corticosteroids                                                                   
  --------------------------------------------------------------------------------------------

Among the adverse events that were reported at a rate of 3% and \<20%,
the following were more prominent in patients maintained on Rapamune 5
mg/day, when compared to patients on Rapamune 2 mg/day: epistaxis,
lymphocele, insomnia, thrombotic thrombocytopenic purpura
(hemolytic-uremic syndrome), skin ulcer, increased LDH, hypotension,
facial edema.

The following adverse events were reported with 3% and \<20% incidence
in patients in any Rapamune treatment group in the two controlled
clinical trials for the prevention of acute rejection, BODY AS A WHOLE:
abdomen enlarged, abscess, ascites, cellulitis, chills, face edema, flu
syndrome, generalized edema, hernia, *Herpes zoster* infection,
lymphocele, malaise, pelvic pain, peritonitis, sepsis; CARDIOVASCULAR
SYSTEM: atrial fibrillation, congestive heart failure, hemorrhage,
hypervolemia, hypotension, palpitation, peripheral vascular disorder,
postural hypotension, syncope, tachycardia, thrombophlebitis,
thrombosis, vasodilatation; DIGESTIVE SYSTEM: anorexia, dysphagia,
eructation, esophagitis, flatulence, gastritis, gastroenteritis,
gingivitis, gum hyperplasia, ileus, liver function tests abnormal, mouth
ulceration, oral moniliasis, stomatitis; ENDOCRINE SYSTEM: Cushing's
syndrome, diabetes mellitus, glycosuria; HEMIC AND LYMPHATIC SYSTEM:
ecchymosis, leukocytosis, lymphadenopathy, polycythemia, thrombotic
thrombocytopenic purpura (hemolytic-uremic syndrome); METABOLIC AND
NUTRITIONAL: acidosis, alkaline phosphatase increased, BUN increased,
creatine phosphokinase increased, dehydration, healing abnormal,
hypercalcemia, hyperglycemia, hyperphosphatemia, hypocalcemia,
hypoglycemia, hypomagnesemia, hyponatremia, lactic dehydrogenase
increased, SGOT increased, SGPT increased, weight loss; MUSCULOSKELETAL
SYSTEM: arthrosis, bone necrosis, leg cramps, myalgia, osteoporosis,
tetany; NERVOUS SYSTEM: anxiety, confusion, depression, dizziness,
emotional lability, hypertonia, hypesthesia, hypotonia, insomnia,
neuropathy, paresthesia, somnolence; RESPIRATORY SYSTEM: asthma,
atelectasis, bronchitis, cough increased, epistaxis, hypoxia, lung
edema, pleural effusion, pneumonia, rhinitis, sinusitis; SKIN AND
APPENDAGES: fungal dermatitis, hirsutism, pruritus, skin hypertrophy,
skin ulcer, sweating; SPECIAL SENSES: abnormal vision, cataract,
conjunctivitis, deafness, ear pain, otitis media, tinnitus; UROGENITAL
SYSTEM: albuminuria, bladder pain, dysuria, hematuria, hydronephrosis,
impotence, kidney pain, kidney tubular necrosis, nocturia, oliguria,
pyelonephritis, pyuria, scrotal edema, testis disorder, toxic
nephropathy, urinary frequency, urinary incontinence, urinary retention.

Less frequently occurring adverse events included: mycobacterial
infections, Epstein-Barr virus infections, and pancreatitis.

**Rapamune Tablets:** The safety profile of the tablet did not differ
from that of the oral solution formulation. The incidence of adverse
reactions up to 12 months was determined in a randomized, multicenter
controlled trial (Study 3) in which 229 renal transplant patients
received Rapamune Oral Solution 2 mg once daily and 228 patients
received Rapamune Tablets 2 mg once daily. All patients were treated
with cyclosporine and corticosteroids. The adverse reactions that
occurred in either treatment group with an incidence of 20% in Study 3
are similar to those reported for Studies 1 & 2. There was no notable
difference in the incidence of these adverse events between treatment
groups (oral solution versus tablets) in Study 3, with the exception of
acne, which occurred more frequently in the oral solution group, and
tremor which occurred more frequently in the tablet group, particularly
in Black patients.

The adverse events that occurred in patients with an incidence of 3% and
\<20% in either treatment group in Study 3 were similar to those
reported in Studies 1 & 2. There was no notable difference in the
incidence of these adverse events between treatment groups (oral
solution versus tablets) in Study 3, with the exception of hypertonia,
which occurred more frequently in the oral solution group and diabetes
mellitus which occurred more frequently in the tablet group. Hispanic
patients in the tablet group experienced hyperglycemia more frequently
than Hispanic patients in the oral solution group. In Study 3 alone,
menorrhagia, metrorrhagia, and polyuria occurred with an incidence of 3%
and \<20%.

The clinically important opportunistic or common transplant-related
infections were identical in all three studies and the incidences of
these infections were similar in Study 3 compared with Studies 1&2. The
incidence rates of these infections were not significantly different
between the oral solution and tablet treatment groups in Study 3.

In Study 3 (at 12 months), there were two cases of
lymphoma/lymphoproliferative disorder in the oral solution treatment
group (0.8%) and two reported cases of lymphoma/lymphoproliferative
disorder in the tablet treatment group (0.8%). These differences were
not statistically significant and were similar to the incidences
observed in Studies 1 & 2.

**Other clinical experience:** Cases of pneumonitis with no identified
infectious etiology, sometimes with an interstitial pattern, have
occurred in patients receiving immunosuppressive regimens including
Rapamune. In some cases, the pneumonitis has resolved upon
discontinuation of Rapamune.

**OVERDOSAGE**

There is minimal experience with overdose. During clinical trials, there
were two accidental Rapamune ingestions, of 120 mg and 150 mg. One
patient, receiving 150 mg, experienced an episode of transient atrial
fibrillation. The other patient experienced no adverse effects. General
supportive measures should be followed in all cases of overdose. Based
on the poor aqueous solubility and high erythrocyte binding of Rapamune,
it is anticipated that Rapamune is not dialyzable to any significant
extent.

In mice and rats, the acute oral lethal dose was greater than 800 mg/kg.

# DOSAGE AND ADMINISTRATION 

It is recommended that Rapamune Oral Solution and Tablets be used in a
regimen with cyclosporine and corticosteroids. Two-mg Rapamune oral
solution has been demonstrated to be clinically equivalent to 2-mg
Rapamune oral tablets; hence, are interchangeable on a mg to mg basis.
However, it is not known if higher doses of Rapamune oral solution are
clinically equivalent to higher doses of tablets on a mg to mg basis.
(See Clinical Pharmacology: Absorption). Rapamune is to be administered
orally once daily. The initial dose of Rapamune should be administered
as soon as possible after transplantation. For de novo transplant
recipients, a loading dose of Rapamune of 3 times the maintenance dose
should be given. A daily maintenance dose of 2 mg is recommended for use
in renal transplant patients, with a loading dose of 6 mg. Although a
daily maintenance dose of 5 mg, with a loading dose of 15, mg was used
in clinical trials of the oral solution and was shown to be safe and
effective, no efficacy advantage over the 2 mg dose could be established
for renal transplant patients. Patients receiving 2 mg of Rapamune Oral
Solution per day demonstrated an overall better safety profile than did
patients receiving 5 mg of Rapamune Oral Solution per day.

To minimize the variability of exposure to Rapamune, this drug should be
taken consistently with or without food. Grapefruit juice reduces
CYP3A4-mediated metabolism of Rapamune and must not be administered with
Rapamune or used for dilution.

**It is recommended that sirolimus be taken 4 hours after administration
of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules
(MODIFIED).**

**Dosage Adjustments**

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^.

It is recommended that the maintenance dose of Rapamune be reduced by
approximately one third in patients with hepatic impairment. It is not
necessary to modify the Rapamune loading dose**.** Dosage need not be
adjusted because of impaired renal function.

**Blood Concentration Monitoring**

Routine therapeutic drug level monitoring is not required in most
patients. Blood sirolimus levels should be monitored in pediatric
patients, in patients with hepatic impairment, during concurrent
administration of strong CYP3A4 inducers and inhibitors, and/or if
cyclosporine dosing is markedly reduced or discontinued. In controlled
clinical trials with concomitant cyclosporine, mean sirolimus whole
blood trough levels, as measured by immunoassay, were 9 ng/mL (range 4.5
-- 14 ng/mL \[10^th^ to 90^th^ percentile\]) for the 2 mg/day treatment
group, and 17 ng/mL (range 10 - 28 ng/mL \[10^th^ to 90^th^
percentile\]) for the 5 mg/day dose.

Results from other assays may differ from those with an immunoassay. On
average, chromatographic methods (HPLC UV or LC/MS/MS) yield results
that are approximately 20% lower than the immunoassay for whole blood
concentration determinations. Adjustments to the targeted range should
be made according to the assay ultilized to determine sirolimus trough
concentrations. Therefore, comparison between concentrations in the
published literature and an individual patient concentration using
current assays must be made with detailed knowledge of the assay methods
employed. A discussion of the different assay methods is contained in
*Clinical Therapeutics*, Volume 22, Supplement B, April 2000.

**Instructions for Dilution and Administration of Rapamune Oral
Solution**

**Bottles**

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 (¼ cup, 60 mL) of water or
orange juice. No other liquids, including grapefruit juice, should be
used for dilution. Stir vigorously and drink at once. Refill the
container with an additional volume (minimum of four \[4\] ounces (½
cup, 120 mL)) of water or orange juice, stir vigorously, and drink at
once.

**Pouches**

When using the pouch, squeeze the entire contents of the pouch 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. Stir vigorously and drink at once.
Refill the container with an additional volume (minimum of four \[4\]
ounces (½ cup, 120 mL)) of water or orange juice, stir vigorously, and
drink at once.

**Handling and Disposal**

Since Rapamune is not absorbed through the skin, there are no special
precautions. However, if direct contact with the skin or mucous
membranes occurs, wash thoroughly with soap and water; rinse eyes with
plain water.

#  {#section .heading01}

**HOW SUPPLIED**

Rapamune Oral Solution is supplied at a concentration of 1 mg/mL in:

1\. Cartons:

> NDC \# 0008-1030-06, containing a 2 oz (60 mL fill) amber glass
> bottle.
>
> NDC \# 0008-1030-15, containing a 5 oz (150 mL fill) amber glass
> bottle.

In addition to the bottles, each carton is supplied with an 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.

2\. Cartons;

> NDC \# 0008-1030-03, containing 30 unit-of-use laminated aluminum
> pouches of 1 mL.
>
> NDC \# 0008-1030-07, containing 30 unit-of-use laminated aluminum
> pouches of 2 mL.
>
> NDC \# 0008-1030-08, containing 30 unit-of-use laminated aluminum
> pouches of 5 mL.

Rapamune Tablets are available as follows: 1 mg, white,
triangular-shaped tablets marked "RAPAMUNE 1 mg" on one side.

> NDC \# 0008-1031-05, bottle of 100 tablets.
>
> NDC \# 0008-1031-10, Redipak cartons of 100 tablets (10 blister cards
> of 10 tablets each).

# Storage

Rapamune^®^ Oral Solution bottles and pouches should be stored protected
from light and refrigerated at 2C to 8C (36F to 46F). Once the bottle is
opened, the contents should be used within one month. If necessary, the
patient may store both the pouches and the bottles at room temperatures
up to 25C (77 F) for a short period of time (e.g., several days, but not
longer than 30 days).

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
25C (77F) or refrigerated at 2C to 8C (36F to 46F). 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.

Rapamune Tablets should be stored at 20 to 25C (USP Controlled Room
Temperature) (68 - 77F). Use cartons to protect blister cards and strips
from light. Dispense in a tight, light-resistant container as defined in
the USP.

**R~x~ only.**

US Pat. Nos.: 5,100,899; 5,212,155; 5, 308,847; 5,403,833; 5,536,729.

Wyeth Laboratories

Division of Wyeth-Ayerst Pharmaceuticals Inc.

Philadelphia, PA 19101

25 August 2000

![](media/image2.png){width="2.2111111111111112in"
height="8.968055555555555in"}

![](media/image3.png){width="2.220833333333333in" height="4.2375in"}

![](media/image5.png){width="2.3618055555555557in"
height="6.243055555555555in"}