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Mechanism of Action
Everolimus inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes.
In cells, everolimus binds to a cytoplasmic protein, the FK506 Binding Protein-12 (FKBP-12), to form an immunosuppressive complex (everolimus: FKBP-12) that binds to and inhibits the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. In the presence of everolimus phosphorylation of p70 S6 ribosomal protein kinase (p70S6K), a substrate of mTOR, is inhibited. Consequently, phosphorylation of the ribosomal S6 protein and subsequent protein synthesis and cell proliferation are inhibited. The everolimus: FKBP-12 complex has no effect on calcineurin activity.
In rats and nonhuman primate models, everolimus effectively reduces kidney allograft rejection resulting in prolonged graft survival.
Everolimus pharmacokinetics have been characterized after oral administration of single and multiple doses to adult kidney transplant patients, hepatically-impaired patients, and healthy subjects.
After oral dosing, peak everolimus concentrations occur 1 to 2 h post dose. Over the dose range of 0.5 mg to 2 mg twice daily, everolimus Cmax and AUC are dose proportional in transplant patients at steady-state.
In 24 healthy subjects, a high-fat breakfast (44.5 g fat) reduced everolimus Cmax by 60%, delayed tmax by a median 1.3 hours, and reduced AUC by 16% compared with a fasting administration. To minimize variability, everolimus should be taken consistently with or without food. [See DOSAGE AND ADMINISTRATION]
The blood-to-plasma ratio of everolimus is concentration dependent ranging from 17% to 73% over the range of 5 ng/mL to 5000 ng/mL. Plasma protein binding is approximately 74% in healthy subjects and in patients with moderate hepatic impairment. The apparent distribution volume associated with the terminal phase (Vz/F) from a single-dose pharmacokinetic study in maintenance kidney transplant patients is 342 to 107 L (range 128 to 589 L).
Everolimus is a substrate of CYP3A4 and P-gp. The main metabolic pathways identified in man were monohydroxylations and O-dealkylations. Two main metabolites were formed by hydrolysis of the cyclic lactone. Everolimus was the main circulating component in blood. None of the main metabolites contribute significantly to the immunosuppressive activity of everolimus.
After a single dose of radiolabeled everolimus was given to transplant patients receiving cyclosporine, the majority (80%) of radioactivity was recovered from the feces and only a minor amount (5%) was excreted in urine. Parent drug was not detected in urine and feces.
Pharmacokinetics in Kidney Transplant Patients
Steady-state is reached by Day 4 with an accumulation in blood levels of 2- to 3-fold compared with the exposure after the first dose. Table 4 below provides a summary of the steady-state pharmacokinetic parameters.
Table 4: Steady-State Pharmacokinetic Parameters (mean
+/- SD) Following the Administration of 0.75 mg Twice Daily
|11.1 ± 4.6 ng/mL||1-2 h||75 ± 31 ng•h/mL||8.8 L/h||110 L||30 ± 11h|
|1population pharmacokinetic analysis|
The half-life estimates from 12 maintenance renal transplant patients who received single doses of everolimus capsules at 0.75 mg or 2.5 mg with their maintenance cyclosporine regimen indicate that the pharmacokinetics of everolimus are linear over the clinically-relevant dose range. Results indicate the half-life of everolimus in maintenance renal transplant patients receiving single doses of 0.75 mg or 2.5 mg Zortress during steady-state cyclosporine treatment was 30 ± 11 hours (range 19 to 53 hours).
Everolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between everolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below. [See WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS]
Cyclosporine (CYP3A4/P-gp inhibitor and CYP3A4 substrate)
Zortress should be taken concomitantly with cyclosporine in kidney transplant patients. Everolimus concentrations may decrease when doses of cyclosporine are reduced, unless the Zortress dose is increased. [See DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS]
In a single-dose study in healthy subjects, cyclosporine (Neoral) administered at a dose of 175 mg increased everolimus AUC by 168% (range, 46% to 365%) and Cmax by 82% (range, 25% to 158%) when administered with 2 mg Zortress compared with administration of Zortress alone. [See DRUG INTERACTIONS]
Ketoconazole and Other Strong CYP3A4 Inhibitors
Multiple-dose administration of 200 mg ketoconazole twice daily for 5 days to 12 healthy volunteers significantly increased everolimus Cmax, AUC, and half-life by 3.9-fold, 15-fold, and 89%, respectively, when co-administered with 2 mg Zortress. It is recommended that strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) should not be co-administered with Zortress. [See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]
Erythromycin (Moderate CYP3A4 Inhibitor)
Multiple-dose administration of 500 mg erythromycin three times daily for 5 days to 16 healthy volunteers significantly increased everolimus Cmax, AUC, and half-life by 2.0-fold, 4.4-fold, and 39%, respectively, when co-administered with 2 mg Zortress. If erythromycin is co-administered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary. [See DRUG INTERACTIONS]
Verapamil (CYP3A4 Inhibitor and P-gp Substrate)
Multiple-dose administration of 80 mg verapamil three times daily for 5 days to 16 healthy volunteers significantly increased everolimus Cmax and AUC by 2.3-fold and 3.5-fold, respectively, when co-administered with 2 mg Zortress. Everolimus half-life was not changed. If verapamil is coadministered, everolimus blood concentrations should be monitored and a dose adjustment made as necessary. [See DRUG INTERACTIONS]
Atorvastatin (CYP3A4 Substrate) and Pravastatin (P-gp Substrate)
Following administration of a single dose of 2 mg Zortress to 12 healthy subjects, the concomitant administration of a single oral dose administration of atorvastatin 20 mg or pravastatin 20 mg only slightly decreased everolimus Cmax and AUC by 9% and 10%, respectively. There was no apparent change in the mean T½ or median Tmax. In the same study, the concomitant Zortress dose slightly increased the mean Cmax of atorvastatin by 11% and slightly decreased the AUC by 7%. The concomitant Zortress dose decreased the mean Cmax and AUC of pravastatin by 10% and 5%, respectively. No dosage adjustments are needed for concomitant administration of Zortress and atorvastatin and pravastatin. [See DRUG INTERACTIONS]
Midazolam (CYP3A4/5 Substrate)
In 25 healthy male subjects, co-administration of a single dose of midazolam 4 mg oral solution with steady-state everolimus (10 mg daily dose for 5 days) resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC; whereas, the terminal half-life of midazolam and the metabolic AUC-ratio (1hydroxymidazolam/midazolam) were not affected. [See DRUG INTERACTIONS]
Rifampin (Strong CYP3A4 and P-gp Inducer)
Pretreatment of 12 healthy subjects with multiple-dose rifampin (600 mg once-daily for 8 days) followed by a single dose of 4 mg Zortress increased everolimus clearance nearly 3-fold, and decreased Cmax by 58% and AUC by 63%. Combination with rifampin is not recommended. [See DRUG INTERACTIONS]
Relative to the AUC of everolimus in subjects with normal hepatic function, the average AUC in 6 patients with mild hepatic impairment (Child-Pugh Class A) was 1.6-fold higher following administration of a 10 mg single-dose. In two independently studied groups of 8 and 9 patients with moderate hepatic impairment (Child-Pugh Class B) the average AUC was 2.1-fold and 3.3-fold higher following administration of a 2 mg or a 10 mg single-dose, respectively; and in 6 patients with severe hepatic impairment (Child-Pugh Class C) the average AUC was 3.6-fold higher following administration of a 10 mg single-dose. For patients with mild hepatic impairment (Child-Pugh Class A), the dose should be reduced by approximately one-third of the normally recommended daily dose. For patients with moderate or severe hepatic impairment (Child-Pugh B or C), the initial daily dose should be reduced to approximately one-half of the normally recommended daily dose. Further dose adjustment and/or dose titration should be made if a patient's whole blood trough concentration of everolimus, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3 to 8 ng/mL. [See DOSAGE AND ADMINISTRATION]
No pharmacokinetic studies in patients with renal impairment were conducted. Post-transplant renal function (creatinine clearance range 11 to 107 mL/min) did not affect the pharmacokinetics of everolimus, therefore, no dosage adjustments are needed in patients with renal impairment.
The safety and efficacy of Zortress has not been established in pediatric patients.
A limited reduction in everolimus oral CL of 0.33% per year was estimated in adults (age range studied was 16 to 70 years). There is no evidence to suggest that elderly patients will require a different dosage recommendation from younger adult patients.
Based on analysis of population pharmacokinetics, oral clearance (CL/F) is, on average, 20% higher in black transplant patients.
Everolimus Whole Blood Concentrations Observed in Kidney and in Liver Transplant Patients
Everolimus in Kidney Transplantation
Based on exposure-efficacy and exposure-safety analyses of clinical trials and using an LC/MS/MS assay method, kidney transplant patients achieving everolimus whole blood trough concentrations ≥ 3.0 ng/mL have been found to have a lower incidence of treated biopsy-proven acute rejection compared with patients whose trough concentrations were below 3.0 ng/mL. Patients who attained everolimus trough concentrations within the range of 6 to 12 ng/mL had similar efficacy and more adverse reactions than patients who attained lower trough concentrations between 3 to 8 ng/mL. [See DOSAGE AND ADMINISTRATION]
In the kidney clinical trial [See Clinical Studies], everolimus whole blood trough concentrations were measured at Days 3, 7, and 14 and Months 1, 2, 3, 4, 6, 7, 9, and 12. The proportion of patients receiving 0.75 mg twice daily Zortress treatment regimen who had everolimus whole blood trough concentrations within the protocol specified target range of 3 to 8 ng/mL at Days 3, 7, and 14 were 55%, 71% and 69%, respectively. Approximately 80% of patients had everolimus whole blood trough concentrations within the 3 to 8 ng/mL target range by Month 1 and remained stable within range through Month 12. The median everolimus trough concentration for the 0.75 mg twice daily treatment group was between 3 and 8 ng/mL throughout the study duration.
Everolimus in Liver Transplantation
In the liver clinical trial [See Clinical Studies] Zortress dosing was initiated after 30 days following transplantation. Whole blood trough everolimus concentrations were measured within 5 days after first dose, followed by weekly intervals for 3 to 4 weeks, and then monthly thereafter. Approximately 49%, 37%, and 18% of patients, respectively, were below 3 ng/mL at 1, 2, and 4 weeks after initiation of Zortress dosing. The majority of patients (approximately 70 to 80%) had everolimus trough blood concentrations within the target range of 3-8 ng/mL after Month 2 through Month 12.
Cyclosporine Concentrations Observed in Kidney Transplant Patients
In the kidney transplant clinical trial [See Clinical Studies], the target cyclosporine whole blood trough concentration for the Zortress treatment arm of 0.75 mg twice daily were 100 to 200 ng/mL through Month 1 post-transplant, 75 to 150 ng/mL at Months 2 and 3 post-transplant, 50 to 100 ng/mL at Month 4 post-transplant, and 25 to 50 ng/mL from Month 6 through Month 12 post-transplant. Table 5 below provides a summary of the observed cyclosporine whole blood trough concentrations during the study.
Table 5: Cyclosporine Trough Concentrations Over 12
Months – Kidney Study Median Values (ng/mL) with 10th and 90th
|Treatment group||Visit||N||Target (ng/mL)||Median||10th Percentile||90th Percentile|
|Zortress 0.75 mg twice daily||Day 3||242||100-200||172||46||388|
Tacrolimus Concentrations in Liver Transplant
In the liver transplant clinical trial [See Clinical Studies], the target tacrolimus whole blood trough concentrations were greater than or equal to 8 ng/mL in the first 30 days post-transplant. The protocol required that patients had a tacrolimus trough concentration of at least 8 ng/mL in the week prior to initiation of Zortress. Zortress was initiated after 30 days post-transplant. At that time, the target tacrolimus trough concentrations were reduced to 3 to 5 ng/mL. Table 6 below provides a summary of the tacrolimus whole blood trough concentrations observed during the study.
Table 6: Tacrolimus Trough
Concentrations Over 12 Months – Liver Study Median Values (ng/mL) with 10th
and 90th Percentiles
|Treatment group||Visit||N||Target (ng/mL)||Median||10th Percentile||90th Percentile|
Zortress 1.0 mg twice daily (initiated at month 1)
Prevention of Organ Rejection after Renal Transplantation
A 24-month, multi-national, open-label, randomized (1:1:1) trial was conducted comparing two concentration-controlled Zortress regimens of 1.5 mg per day starting dose (targeting 3 to 8 ng/mL using an LC/MS/MS assay method and 3.0 mg per day starting dose (targeting 6 to 12 ng/mL using an LC/MS/MS assay method) with reduced exposure cyclosporine and corticosteroids, to 1.44 g per day of mycophenolic acid with standard exposure cyclosporine and corticosteroids. The mean cyclosporine starting dose was 5.2, 5.0 and 5.7 mg/kg body weight/day in the Zortress 1.5 mg, 3.0 mg and in Zortress (everolimus) Mycophenolic Acid mycophenolic acid groups, respectively. The cyclosporine dose in the Zortress group was then adjusted to the blood trough concentration ranges indicated in Table 5, whereas in the mycophenolic acid group the target ranges were 200-300 ng/mL starting Day 5: 200-300 ng/mL, and 100-250 ng/mL from Month 2 to Month 12.
All patients received basiliximab induction therapy. The study population consisted of 18 to 70 year old male and female low to moderate risk renal transplant recipients undergoing their first transplant. Low to moderate immunologic risk was defined in the study as an ABO blood type compatible first organ or tissue transplant recipient with anti-HLA Class I PRA < 20% by a complement dependent cytotoxicity-based assay, or < 50% by a flow cytometry or ELISA-based assay, and with a negative T-cell cross match. Eight hundred thirty-three (833) patients were randomized after transplantation; 277 randomized to the Zortress 1.5 mg per day group, 279 to the Zortress 3.0 mg per day group and 277 to the mycophenolic acid 1.44 g per day group. The study was conducted at 79 renal transplant centers across Europe, South Africa, North and South America, and Asia-Pacific. There were no major baseline differences between treatment groups with regard to recipient or donor disease characteristics. The majority of transplant recipients in all groups (70% to 76%) had three or more HLA mismatches; mean percentage of panel reactive antibodies ranged from 1% to 2%. The rate of premature treatment discontinuation at 12 months was 30% and 22% in the Zortress 1.5 mg and control groups, respectively, (p=0.03, Fisher's exact test) and was more prominent between groups among female patients. Results at 12 months indicated that Zortress 1.5 mg per day is comparable to control with respect to efficacy failure, defined as treated biopsy-proven acute rejection*, graft loss, death or loss to follow-up. The percentage of patients experiencing this endpoint and each individual variable in the Zortress and control groups is shown in Table 7.
Table 7: Efficacy Failure by Treatment Group (ITT
Population) at 12 Months
|Zortress (everolimus) 1.5 mg per day With reduced exposure CsA
|Mycophenolic Acid 1.44 g per day With standard exposure CsA
|Efficacy Failure Endpoint2||70 (25.3)||67 (24.2)|
|Treated Biopsy Proven Acute Rejection||45 (16.2)||47 (17.0)|
|Death||7 (2.5)||6 (2.2)|
|Graft Loss||12 (4.3)||9 (3.2)|
|Loss to Follow-up||12 (4.3)||9 (3.2)|
|Graft Loss or Death or Loss to Follow-up3||32 (11.6)||26 (9.4)|
|Graft Loss or Death||18 (6.5)||15 (5.4)|
|Loss to Follow-up3||14 (5.1)||11 (4.0)|
|* Treated biopsy-proven acute
rejection (tBPAR) was defined as a histologically confirmed acute rejection
with a biopsy graded as IA, IB, IIA, IIB, or III according to 1997 Banff
criteria that was treated with anti-rejection medication.
1The difference in rates (Zortress–mycophenolic acid) with 95% CI for primary efficacy failure endpoint is 1.1% (-6.1%, 8.3%); and for the graft loss, death or loss to follow-up endpoint is 2.2% (-2.9%, 7.3%).
2Includes treated BPAR, graft loss, death or loss to follow-up by Month 12 where loss to follow-up represents patient who did not experience treated BPAR, graft loss or death and whose last contact date is prior to 12 month visit
3Loss to follow-up (for Graft Loss, Death, or Loss to Follow-up) represents patient who did not experience death or graft loss and whose last contact date is prior to 12 month visit
The estimated mean glomerular filtration rate (using the MDRD equation) for Zortress 1.5 mg (target trough concentrations 3 to 8 ng/mL) and mycophenolic acid groups were comparable at Month 12 in the ITT population (Table 8).
Table 8: Estimated
Glomerular Filtration Rates (mL/min/1.73m²) by MDRD at 12 Months
|Month 12 GFR (MDRD)||Zortress (everolimus) 1.5 mg per day with reduced exposure CsA
|Mycophenolic Acid 1.44 g per day with standard exposure CsA
|Mean (SD)**||54.6 (21.7)||52.3 (26.5)|
|Median (Range)||55.0 (0-140.9)||50.1 (0.0-366.4)|
|* Analysis based on using a
subject's last observation carried forward for missing data at 12 months due to
death or lost to follow-up data, a value of zero is used for subjects who
experienced a graft loss.
** SD=standard deviation
Two earlier studies compared fixed doses of Zortress 1.5 mg per day and 3 mg per day, without therapeutic drug monitoring, combined with standard exposure cyclosporine and corticosteroids to mycophenolate mofetil 2.0 g per day and corticosteroids. Antilymphocyte antibody induction was prohibited in both studies. Both were multicenter, double-blind (for first 12 months), randomized trials (1:1:1) of 588 and 583 de novo renal transplant patients, respectively. The 12 month analysis of GFR showed increased rates of renal impairment in both the Zortress groups compared to the mycophenolate mofetil group in both studies. Therefore, reduced exposure cyclosporine should be used in combination with Zortress in order to avoid renal dysfunction and everolimus trough concentrations should be adjusted using therapeutic drug monitoring to maintain trough concentrations between 3 to 8 ng/mL. [See BOXED WARNING, DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]
Prevention of Organ Rejection after Liver Transplantation
A 24-month, multinational, open-label, randomized (1:1:1) trial was conducted in liver transplant patients starting 30 days post-transplant. During the first 30 days, after transplant and prior to randomization, patients received tacrolimus and corticosteriods, with or without mycophenolate mofetil. No induction antibody was administered. Approximately 70 to 80% of patients received at least one dose of mycophenolate mofetil at a median total daily dose of 1.5 g during the first 30 days. For eligibility, patients had to have a tacrolimus trough concentration of at least 8 ng/mL in the week prior to randomization.
At randomization, mycophenolate mofetil was discontinued and patients were randomized to one of two Zortress treatment groups [initial dose of 1 mg twice per day (2 mg daily) and adjusted to target trough concentrations using an LC/MS/MS assay of 3 to 8 ng/mL] either with reduced exposure of tacrolimus (target trough whole blood concentrations of 3 to 5 ng/mL) or tacrolimus elimination. In the tacrolimus elimination group, at Month 4 post-transplant, once the everolimus trough concentrations were within the target range of 6 to 10 ng/mL, reduced exposure tacrolimus was eliminated. The Zortress with tacrolimus elimination group was discontinued early due to higher incidence of acute rejection. In the control group, patients received standard exposure tacrolimus (target trough whole blood concentrations of 8 to 12 ng/mL tapered to 6 to 10 ng/mL by month 4 post-transplant). All patients received corticosteroids during the trial.
The study population consisted of 18 to 70 year old male and female liver transplant recipients undergoing their first transplant, mean age was approximately 54 years, more than 70% of patients were male, and the majority of patients were Caucasian, with approximately 89% of patients per treatment group completing the study. Key stratification parameters of HCV status (31-32% HCV positive across groups) and renal function (mean baseline eGFR range 79-83 mL/min/1.73m²) were also balanced between groups.
A total of 1147 patients were enrolled into the run-in period of this trial. At 30 days post-transplant a total 719 patients, who were eligible according to study inclusion/exclusion criteria, were randomized into one of three treatment groups: Zortress with reduced exposure tacrolimus; N=245, Zortress with tacrolimus elimination (tacrolimus elimination group); N=231, or standard dose/exposure tacrolimus (tacrolimus control); N=243. The study was conducted at 89 liver transplant centers across Europe, including the United Kingdom and Ireland, North and South America, and Australia.
Key inclusion criteria were recipients 18-70 years of age, eGFR ≥ 30 mL/min/1.73m², tacrolimus trough level of ≥ 8 ng/mL in the week prior to randomization, and the ability to take oral medication.
Key exclusion criteria were recipients of multiple solid organ transplants, history of malignancy (except hepatocellular carcinoma within Milan criteria), human immunodeficiency virus, and any surgical or medical condition which significantly alter the absorption, distribution, metabolism and excretion of study drug.
There were no major baseline differences between treatment groups with regard to recipient or donor disease characteristics. Mean MELD scores at time of transplantation, cold ischemia times (CIT), and ABO matching were similar across groups. Overall the treatment groups were comparable with respect to the key determinants of liver transplantation.
The tacrolimus elimination group was stopped prematurely due to a higher incidence of acute rejection and adverse reactions leading to treatment discontinuation reported during the elimination phase of tacrolimus. Therefore, a treatment regimen of Zortress with tacrolimus elimination is not recommended.
Results at 12 months indicated that Zortress with reduced exposure tacrolimus is comparable to standard exposure tacrolimus with respect to efficacy failure, defined as treated biopsy-proven acute rejection, graft loss, death or loss to follow-up. The percentage of patients experiencing this endpoint and each individual variable in the Zortress and control group is shown in Table 9.
Table 9: Efficacy Failure by Treatment Group (ITT Population)
at 12 Months
|Zortress (everolimus) With reduced Exposure Tacrolimus
|Tacrolimus (standard exposure)
|Efficacy Failure Endpoint2||22 (9.0)||33 (13.6)|
|Treated Biopsy Proven Acute Rejection*||7 (2.9)||17 (7.0)|
|Death||13 (5.3)||7 (2.9)|
|Graft Loss||6 (2.4)||3 (1.2)|
|Loss to Follow-up||4 (1.6)||9 (3.7)|
|Graft Loss or Death or Loss to Follow-up3||18 (7.3)||18 (7.4)|
|Graft Loss or Death||14 (5.7)||8 (3.3)|
|Loss to Follow-up3||4 (1.6)||10 (4.1)|
|* Treated biopsy-proven acute
rejection (tBPAR) was defined as histologically confirmed acute rejection with
a rejection activity index (RAI) ≥ RAI score 3 that received
1The difference in rates (Zortress – control) with 97.5% CI for efficacy failure endpoint is -4.6% (-11.4%, 2.2%); and for the graft loss, death or loss to follow-up endpoint is -0.1% (-5.4%, 5.3%).
2Includes treated BPAR, graft loss, death or loss to follow-up by Month 12 where loss to follow-up represents patients who did not experience treated BPAR, graft loss or death and whose last contact date is prior to 12 month visit
3Loss to follow-up (for Graft Loss, Death, or Loss to Follow-up) represents patients who did not experience death or graft loss and whose last contact date is prior to 12 month visit
The estimated mean glomerular filtration rate (using the MDRD equation) for the Zortress group was 80.9 mL/min/1.73m² and the tacrolimus control was 70.3 mL/min/1.73m² at Month 12 for patients with estimated GFR (eGFR) in the ITT population (Table 10).
Table 10: Estimated Glomerular Filtration Rates
(mL/min/1.73m²) by MDRD at 12 Months Post-Transplant
|Month 12 GFR (MDRD)||Zortress (everolimus) with reduced exposure Tacrolimus
|Tacrolimus (standard exposure)
|Mean (SD)||80.9 (27.3)||70.3 (23.1)|
|Median* (Range)||78.3 (28.4-153.1)||66.4 (27.9-155.8)|
Figure 1: Mean and 95% CI of
eGFR (MDRD 4) [mL/min/1.73m²] by Visit Window and Treatment (ITT
population – 12 Month Analysis)*
* Zortress dosing was initiated 30 days after transplantation
Last reviewed on RxList: 3/6/2013
This monograph has been modified to include the generic and brand name in many instances.
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