Prescription Drug Information: Mycophenolic Acid (Page 5 of 7)

Specific Populations

Patients with Renal Insufficiency : No specific pharmacokinetic studies in individuals with renal impairment were conducted with mycophenolic acid delayed-release tablets. However, based on studies of renal impairment with MMF, MPA exposure is not expected to be appreciably increased over the range of normal to severely impaired renal function following mycophenolic acid delayed-release tablets administration. In contrast, MPAG exposure would be increased markedly with decreased renal function; MPAG exposure being approximately 8-fold higher in the setting of anuria. Although dialysis may be used to remove the inactive metabolite MPAG, it would not be expected to remove clinically significant amounts of the active moiety MPA. This is in large part due to the high plasma protein binding of MPA.

Patients Hepatic Insufficiency: No specific pharmacokinetic studies in individuals with hepatic impairment were conducted with mycophenolic acid delayed-release tablets. In a single dose (MMF 1,000 mg) trial of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when the pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this trial were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this trial had about a 50% lower AUC compared to healthy volunteers in other studies, thus making comparison between volunteers with alcoholic cirrhosis and healthy volunteers difficult. Effects of hepatic disease on this process probably depend on the particular disease. Hepatic disease, such as primary biliary cirrhosis, with other etiologies may show a different effect.

Pediatric Patients: Limited data are available on the use of mycophenolic acid delayed-release tablets at a dose of 450 mg/m 2 body surface area in children. The mean MPA pharmacokinetic parameters for stable pediatric renal transplant patients, 5 to 16 years, on cyclosporine, USP MODIFIED are shown in Table 6. At the same dose administered based on body surface area, the respective mean C max and AUC of MPA determined in children were higher by 33% and 18% than those determined for adults. The clinical impact of the increase in MPA exposure is not known [see Dosage and Administration ( 2.2, 2.3) ].

Male and Female Patients: There are no significant gender differences in mycophenolic acid delayed-release tablets pharmacokinetics.

Geriatric Pateints: Pharmacokinetics in the elderly have not been formally studied.

Racial or Ethnic Groups: Following a single dose administration of 720 mg of mycophenolic acid delayed-release tablets to 18 Japanese and 18 Caucasian healthy subjects, the exposure (AUC inf ) for MPA and MPAG were 15% and 22% lower in Japanese subjects compared to Caucasians. The peak concentrations (C max ) for MPAG were similar between the two populations, however, Japanese subjects had 9.6% higher C max for MPA. These results do not suggest any clinically relevant differences.

Drug Interactions:

Antacids With Magnesium and Aluminum Hydroxides:

Absorption of a single dose of mycophenolic acid delayed-release tablets was decreased when administered to 12 stable kidney transplant patients also taking magnesium-aluminum-containing antacids (30 mL): the mean C max and AUC (0-t) values for MPA were 25% and 37% lower, respectively, than when mycophenolic acid delayed-release tablets were administered alone under fasting conditions [see Drug Interactions ( 7.1) ].

Pantoprazole:

In a trial conducted in 12 healthy volunteers, the pharmacokinetics of MPA were observed to be similar when a single dose of 720 mg of mycophenolic acid delayed-release tablets was administered alone and following concomitant administration of mycophenolic acid delayed-release tablets and pantoprazole, which was administered at a dose of 40 mg twice daily for 4 days [see Drug Interactions ( 7.11) ].

The following drug interaction studies were conducted following the administration of MMF:

Cholestyramine:

Following single-dose oral administration of 1.5 grams MMF to 12 healthy volunteers pretreated with 4 grams three times daily of cholestyramine for 4 days, MPA AUC decreased approximately 40%. This decrease is consistent with interruption of enterohepatic recirculation which may be due to binding of recirculating MPAG with cholestyramine in the intestine [see Drug Interactions ( 7.3) ].

Sevelamer:

Concomitant administration of sevelamer and MMF in stable adult and pediatric kidney transplant patients decreased the mean MPA C max and AUC (0-12h) by 36% and 26% respectively [see Drug Interactions ( 7.4) ].

Cyclosporine:

Cyclosporine (Sandimmune ®) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 grams twice daily of MMF in 10 stable kidney transplant patients. The mean (±SD) AUC(0-12h) and C max of cyclosporine after 14 days of multiple doses of MMF were 3290 (±822) ng•h/mL and 753 (±161) ng/mL, respectively, compared to 3245 (±1088) ng•h/mL and 700 (±246) ng/mL, respectively, 1 week before administration of MMF.

A total of 73 de novo kidney allograft recipients on MMF therapy received either low dose cyclosporine withdrawal by 6 months post-transplant (50 to 100 ng/mL for up to 3 months post-transplant followed by complete withdrawal at month 6 post-transplant) or standard dose cyclosporine (150 to 300 ng/mL from baseline through to month 4 post-transplant and 100 to 200 ng/mL thereafter). At month 12 post-transplant, the mean MPA (AUC (0-12h) ) in the cyclosporine withdrawal group was approximately 40% higher, than that of the standard dose cyclosporine group.

Cyclosporine inhibits multidrug-resistance-associated protein 2 (MRP-2) transporter in the biliary tract, thereby preventing the excretion of MPAG into the bile that would lead to enterohepatic recirculation of MPA [see Drug Interactions ( 7.5) ].

Norfloxacin and Metronidazole:

Following single-dose administration of MMF (1 g) to 11 healthy volunteers on Day 4 of a 5 day course of a combination of norfloxacin and metronidazole, the mean MPA AUC (0-48h) was reduced by 33% compared to the administration of MMF alone (p<0.05). There was no significant effect on mean MPA AUC (0-48h) when MMF was concomitantly administered with norfloxacin or metronidazole separately. The mean (±SD) MPA AUC (0-48h) after coadministration of MMF with norfloxacin or metronidazole separately was 48.3 (±24) mcg•h/mL and 42.7 (±23) mcg•h/mL, respectively, compared with 56.2 (±24) mcg•h/mL after administration of MMF alone [see Drug Interactions ( 7.6) ].

Rifampin:

In a single heart-lung transplant patient on MMF therapy (1 gram twice daily), a 67% decrease in MPA exposure (AUC (0-12h) ) was observed with concomitant administration of MMF and 600 mg rifampin daily.

In 8 kidney transplant patients on stable MMF therapy (1 gram twice daily), administration of 300 mg rifampin twice daily resulted in a 17.5% decrease in MPA AUC (0-12h) due to inhibition of enterohepatic recirculation of MPAG by rifampin. Rifampin coadministration also resulted in a 22.4% increase in MPAG AUC (0-12h) [see Drug Interactions ( 7.7) ].

Oral Contraceptives:

In a drug-drug interaction trial, mean AUCs were similar for ethinyl estradiol and norethindrone, when coadministered with MMF as compared to administration of the oral contraceptives alone [see Drug Interactions ( 7.8) ].

Acyclovir:

Coadministration of MMF (1 gram) and acyclovir (800 mg) to 12 healthy volunteers resulted in no significant change in MPA AUC and Cmax. However, MPAG and acyclovir plasma mean AUC(0-24h) were increased 10% and 18%, respectively. Because MPAG plasma concentrations are increased in the presence of kidney impairment, as are acyclovir concentrations, the potential exists for mycophenolate and acyclovir or its prodrug (e.g., valacyclovir) to compete for tubular secretion, further increasing the concentrations of both drugs [see Drug Interactions ( 7.9) ].

Ganciclovir:

Following single-dose administration to 12 stable kidney transplant patients, no pharmacokinetic interaction was observed between MMF (1.5 grams) and intravenous ganciclovir (5 mg per kg). Mean (±SD) ganciclovir AUC and C max (n=10) were 54.3 (±19.0) mcg•h/mL and 11.5 (±1.8) mcg/mL, respectively, after coadministration of the two drugs, compared to 51.0 (±17.0) mcg•h/mL and 10.6 (±2.0) mcg/mL, respectively, after administration of intravenous ganciclovir alone. The mean (±SD) AUC and C max of MPA (n=12) after coadministration were 80.9 (±21.6) mcg•h/mL and 27.8 (±13.9) mcg/mL, respectively, compared to values of 80.3 (±16.4) mcg•h/mL and 30.9 (±11.2) mcg/mL, respectively, after administration of MMF alone.

Because MPAG plasma concentrations are increased in the presence of renal impairment, as are ganciclovir concentrations, the two drugs will compete for tubular secretion and thus further increases in concentrations of both drugs may occur. In patients with renal impairment in which MMF and ganciclovir or its prodrug (e.g., valganciclovir) are coadministered, patients should be monitored carefully [see Drug Interactions ( 7.9) ].

Ciprofloxacin and Amoxicillin Plus Clavulanic Acid: :

A total of 64 MMF-treated kidney transplant recipients received either oral ciprofloxacin 500 mg twice daily or amoxicillin plus clavulanic acid 375 mg three times daily for 7 or at least 14 days. Approximately 50% reductions in median trough MPA concentrations (predose) from baseline (MMF alone) were observed in 3 days following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. These reductions in trough MPA concentrations tended to diminish within 14 days of antibiotic therapy and ceased within 3 days after discontinuation of antibiotics. The postulated mechanism for this interaction is an antibiotic-induced reduction in glucuronidase-possessing enteric organisms leading to a decrease in enterohepatic recirculation of MPA. The change in trough level may not accurately represent changes in overall MPA exposure; therefore, clinical relevance of these observations is unclear [see Drug Interactions ( 7.10) ].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week oral carcinogenicity study in rats, mycophenolate sodium was not tumorigenic at daily doses up to 9 mg per kg, the highest dose tested. This dose resulted in approximately 0.6 to 1.2 times the systemic exposure (based on plasma AUC) observed in renal transplant patients at the recommended dose of 1,440 mg per day. Similar results were observed in a parallel study in rats performed with MMF. In a 104-week oral carcinogenicity study in mice, MMF was not tumorigenic at a daily dose level as high as 180 mg per kg (which corresponds to 0.6 times the recommended mycophenolate sodium therapeutic dose, based on body surface area).

The genotoxic potential of mycophenolate sodium was determined in five assays. Mycophenolate sodium was genotoxic in the mouse lymphoma/thymidine kinase assay, the micronucleus test in V79 Chinese hamster cells, and the in vivo mouse micronucleus assay. Mycophenolate sodium was not genotoxic in the bacterial mutation assay (Salmonella typhimurium TA 1535, 97a, 98, 100, and 102) or the chromosomal aberration assay in human lymphocytes.

Mycophenolate mofetil generated similar genotoxic activity. The genotoxic activity of mycophenolic acid (MPA) is probably due to the depletion of the nucleotide pool required for DNA synthesis as a result of the pharmacodynamic mode of action of MPA (inhibition of nucleotide synthesis).

Mycophenolate sodium had no effect on male rat fertility at daily oral doses as high as 18 mg per kg and exhibited no testicular or spermatogenic effects at daily oral doses of 20 mg per kg for 13 weeks (approximately 2 times the systemic exposure of MPA at the recommended therapeutic dose). No effects on female fertility were seen up to a daily dose of 20 mg per kg (approximately 3 times the systemic exposure of MPA at the recommended therapeutic dose).

14 CLINICAL STUDIES

14.1 Prophylaxis of Organ Rejection in Patients Receiving Allogeneic Renal Transplants

The safety and efficacy of mycophenolic acid delayed-release tablets in combination with cyclosporine, USP MODIFIED and corticosteroids for the prevention of organ rejection was assessed in two multicenter, randomized, double-blind, active-controlled trials in de novo and conversion renal transplant patients compared to MMF.

The de novo trial was conducted in 423 renal transplant patients (ages 18 to 75 years) in Austria, Canada, Germany, Hungary, Italy, Norway, Spain, UK, and USA. Eighty-four percent of randomized patients received kidneys from deceased donors. Patients were excluded if they had second or multiorgan (e.g., kidney and pancreas) transplants, or previous transplant with any other organs; kidneys from non-heart beating donors; panel reactive antibodies (PRA) of >50% at last assessment prior to transplantation, and presence of severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus. Patients were administered either mycophenolic acid delayed-release tablets 1.44 grams per day or MMF 2 grams per day within 48 hours post-transplant for 12 months in combination with cyclosporine, USP MODIFIED and corticosteroids. Forty-one percent of patients received antibody therapy as induction treatment. Treatment failure was defined as the first occurrence of biopsy-proven acute rejection, graft loss, death or lost to follow-up at 6 months.

The incidence of treatment failure was similar in mycophenolic acid delayed-release tablets and MMF-treated patients at 6 and 12 months (Table 7). The cumulative incidence of graft loss, death and lost to follow-up at 12 months is also shown in Table 7.

Table 7 Treatment Failure in de novo Renal Transplant Patients (Percentage of Patients) at 6 and 12 Months of Treatment when Administered in Combination With Cyclosporine* and Corticosteroids
Mycophenolic Acid Delayed-Release Tablets 1.44 grams per day (n=213) mycophenolate mofetil (MMF) 2 grams per day (n=210)
6 Months n (%) n (%)
Treatment failure # 55 (25.8) 55 (26.2)
Biopsy-proven acute rejection 46 (21.6) 48 (22.9)
Graft loss 7 (3.3) 9 (4.3)
Death 1 (0.5) 2 (1.0)
Lost to follow-up** 3 (1.4) 0
12 Months n (%) n (%)
Graft loss or death or lost to follow-up*** 20 (9.4) 18 (8.6)
Treatment failure ## 61 (28.6) 59 (28.1)
Biopsy-proven acute rejection 48 (22.5) 51 (24.3)
Graft loss 9 (4.2) 9 (4.3)
Death 2 (0.9) 5 (2.4)
Lost to follow-up** 5 (2.3) 0
*USP MODIFIED. **Lost to follow-up indicates patients who were lost to follow-up without prior biopsy-proven acute rejection, graft loss or death.***Lost to follow-up indicates patients who were lost to follow-up without prior graft loss or death (9 mycophenolic acid patients and 4 MMF patients).# 95% confidence interval of the difference in treatment failure at 6 months (mycophenolic acid – MMF) is (-8.7%, 8.0%). ## 95% confidence interval of the difference in treatment failure at 12 months (mycophenolic acid – MMF) is (-8.0%, 9.1%).

The conversion trial was conducted in 322 renal transplant patients (ages 18 to 75 years), who were at least 6 months post-transplant and had undergone primary or secondary, deceased donor, living related, or unrelated donor kidney transplant, stable graft function (serum creatinine <2.3 mg/mL), no change in immunosuppressive regimen due to graft malfunction, and no known clinically significant physical and/or laboratory changes for at least 2 months prior to enrollment. Patients were excluded if they had 3 or more kidney transplants, multiorgan transplants (e.g., kidney and pancreas), previous organ transplants, evidence of graft rejection or who had been treated for acute rejection within 2 months prior to screening, clinically significant infections requiring continued therapy, presence of severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus.

Patients received 2 grams per day MMF in combination with cyclosporine USP MODIFIED, with or without corticosteroids for at least two weeks prior to entry in the trial. Patients were randomized to mycophenolic acid delayed-release tablets 1.44 grams per day or MMF 2 grams per day for 12 months. The trial was conducted in Austria, Belgium, Canada, Germany, Italy, Spain, and USA. Treatment failure was defined as the first occurrence of biopsy-proven acute rejection, graft loss, death, or lost to follow-up at 6 and 12 months.

The incidences of treatment failure at 6 and 12 months were similar between mycophenolic acid delayed-release tablets and MMF-treated patients (Table 8). The cumulative incidence of graft loss, death and lost to follow-up at 12 months is also shown in Table 8.

Table 8: Treatment Failure in Conversion Transplant Patients (Percentage of Patients) at 6 and 12 Months of Treatment When Administered in Combination With Cyclosporine* and With or Without Corticosteroids
Mycophenolic Acid Delayed-Release Tablets 1.44 grams per day (n = 159) Mycophenolate mofetil (MMF) 2 grams per day (n = 163)
6 Months n (%) n (%)
Treatment failure # 7 (4.4) 11 (6.7)
Biopsy-proven acute rejection 2 (1.3) 2 (1.2)
Graft loss 0 1 (0.6)
Death 0 1 (0.6)
Lost to follow-up** 5 (3.1) 7 (4.3)
12 Months n (%) n (%)
Graft loss or death or lost to follow-up*** 10 (6.3) 17 (10.4)
Treatment failure ## 12 (7.5) 20 (12.3)
Biopsy-proven acute rejection 2 (1.3) 5 (3.1)
Graft loss 0 1 (0.6)
Death 2 (1.3) 4 (2.5)
Lost to follow-up** 8 (5.0) 10 (6.1)
*USP MODIFIED. **Lost to follow-up indicates patients who were lost to follow-up without prior biopsy-proven acute rejection, graft loss, or death.***Lost to follow-up indicates patients who were lost to follow-up without prior graft loss or death (8 mycophenolic acid patients and 12 MMF patients).# 95% confidence interval of the difference in treatment failure at 6 months (mycophenolic acid – MMF) is (-7.3%, 2.7%). ## 95% confidence interval of the difference in treatment failure at 12 months (mycophenolic acid – MMF) is (-11.2%,1.8%).

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