Mycophenolate Mofetil (Page 6 of 10)

8.4 Pediatric Use

Safety and effectiveness of mycophenolate mofetil have been established in pediatric patients 3 months and older for the prophylaxis of kidney rejection after allogeneic kidney transplant. Use of mycophenolate mofetil in this population is supported by evidence from adequate and well-controlled studies of mycophenolate mofetil in adults with additional data from one open-label, pharmacokinetic and safety study of mycophenolate mofetil in pediatric patients after receiving allogeneic kidney transplant [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)].

Safety and effectiveness in pediatric patients receiving allogeneic heart or liver transplants have not been established.

8.5 Geriatric Use

Clinical studies of mycophenolate mofetil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between geriatric and younger patients. In general, dose selection for a geriatric patient should take into consideration the presence of decreased hepatic, renal or cardiac function and of concomitant drug therapies [see Adverse Reactions (6.1), Drug Interactions (7)].

8.6 Patients with Renal Impairment

Patients with Kidney Transplant

No dosage adjustments are needed in kidney transplant patients experiencing delayed graft function postoperatively but patients should be carefully monitored [see Clinical Pharmacology (12.3)]. In kidney transplant patients with severe chronic impairment of the graft (GFR <25 mL/min/1.73 m2), no dose adjustments are necessary; however, doses greater than 1 gram administered twice a day should be avoided.

Patients with Heart and Liver Transplant

No data are available for heart or liver transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for heart or liver transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.

8.7 Patients with Hepatic Impairment

Patients with Kidney Transplant

No dosage adjustments are recommended for kidney transplant patients with severe hepatic parenchymal disease. However, it is not known whether dosage adjustments are needed for hepatic disease with other etiologies [see Clinical Pharmacology (12.3)].

Patients with Heart Transplant

No data are available for heart transplant patients with severe hepatic parenchymal disease.

10 OVERDOSAGE

Possible signs and symptoms of acute overdose include hematological abnormalities such as leukopenia and neutropenia, and gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, vomiting, and dyspepsia.

The experience with overdose of mycophenolate mofetil in humans is limited. The reported effects associated with overdose fall within the known safety profile of the drug. The highest dose administered to kidney transplant patients in clinical trials has been 4 grams/day. In limited experience with heart and liver transplant patients in clinical trials, the highest doses used were 4 grams/day or 5 grams/day. At doses of 4 grams/day or 5 grams/day, there appears to be a higher rate, compared to the use of 3 grams/day or less, of gastrointestinal intolerance (nausea, vomiting, and/or diarrhea), and occasional hematologic abnormalities, particularly neutropenia [see Warnings and Precautions (5.4)].

Treatment and Management

MPA and the phenolic glucuronide metabolite of MPA (MPAG) are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 mcg/mL), small amounts of MPAG are removed. By increasing excretion of the drug, MPA can be removed by bile acid sequestrants, such as cholestyramine [see Clinical Pharmacology (12.3)].

11 DESCRIPTION

Mycophenolate mofetil, USP is an antimetabolite immunosuppressant. It is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor.

The chemical name for mycophenolate mofetil is 2-Morpholinoethyl (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl)-4-methyl-4-hexenoate. It has a molecular formula of C23 H31 NO7 , a molecular weight of 433.49, and the following structural formula:

1
(click image for full-size original)

Mycophenolate mofetil, USP is a white to off-white crystalline powder. It is slightly soluble in water (43 mcg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for mycophenolate mofetil are 5.6 for the morpholino group and 8.5 for the phenolic group.

Mycophenolate mofetil, USP is available for oral administration as a powder for oral suspension which, when reconstituted, contains 200 mg/mL of mycophenolate mofetil, USP.

Inactive ingredients in mycophenolate mofetil for oral suspension include aspartame, citric acid anhydrous, colloidal silicon dioxide, corn syrup, maltodextrin, methylparaben, modified corn starch, natural flavor, sodium citrate anhydrous, sorbitol, soybean lecithin, and xanthan gum.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mycophenolate mofetil is absorbed following oral administration and hydrolyzed to mycophenolic acid (MPA), the active metabolite. MPA is a selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation. Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes. MPA also suppresses antibody formation by B-lymphocytes. MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection. Mycophenolate mofetil did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of these events to DNA synthesis and proliferation.

12.2 Pharmacodynamics

There is a lack of information regarding the pharmacodynamic effects of mycophenolate mofetil.

12.3 Pharmacokinetics

Absorption

Following oral and intravenous administration, mycophenolate mofetil undergoes complete conversion to MPA, the active metabolite. In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil was 94%. Two 500 mg mycophenolate mofetil tablets have been shown to be bioequivalent to four 250 mg mycophenolate mofetil capsules. Five mL of the 200 mg/mL constituted mycophenolate mofetil for oral suspension have been shown to be bioequivalent to four 250 mg capsules.

The mean (±SD) pharmacokinetic parameters estimates for MPA following the administration of mycophenolate mofetil given as single doses to healthy volunteers, and multiple doses to kidney, heart, and liver transplant patients, are shown in Table 8. The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in kidney transplant patients receiving multiple oral doses of mycophenolate mofetil up to a daily dose of 3 grams (1.5 grams twice daily) (see Table 8).

Table 8: Pharmacokinetic Parameters for MPA [mean (±SD)] Following Administration of Mycophenolate Mofetil to Healthy Volunteers (Single Dose), and Kidney, Heart, and Liver Transplant Patients (Multiple Doses)

Healthy Volunteers

Dose/Route

Tmax

(h)

Cmax

(mcg/mL)

Total AUC (mcg•h/mL)

Single dose

1 gram/oral

0.80

(±0.36)

(n=129)

24.5

(±9.5)

(n=129)

63.9

(±16.2)

(n=117)

Kidney Transplant Patients (twice daily dosing) Time After Transplantation

Dose/Route

Tmax

(h)

Cmax

(mcg/mL)

Interdosing

Interval AUC(0-12h)

(mcg•h/mL)

5 days

1 gram/iv

1.58

(±0.46)

(n=31)

12.0

(±3.82)

(n=31)

40.8

(±11.4)

(n=31)

6 days

1 gram/oral

1.33

(±1.05)

(n=31)

10.7

(±4.83)

(n=31)

32.9

(±15.0)

(n=31)

Early (Less than 40 days)

1 gram/oral

1.31

(±0.76)

(n=25)

8.16

(±4.50)

(n=25)

27.3

(±10.9)

(n=25)

Early (Less than 40 days)

1.5 gram/oral

1.21

(±0.81)

(n=27)

13.5

(±8.18)

(n=27)

38.4

(±15.4)

(n=27)

Late (Greater than 3 months)

1.5 gram/oral

0.90

(±0.24)

(n=23)

24.1

(±12.1)

(n=23)

65.3

(±35.4)

(n=23)

Heart transplant Patients (twice daily dosing) Time After Transplantation

Dose/Route

Tmax

(h)

Cmax

(mcg/mL)

Interdosing

Interval AUC(0-12h)

(mcg•h/mL)

Early

(Day before discharge)

1.5 gram/oral

1.8

(±1.3)

(n=11)

11.5

(±6.8)

(n=11)

43.3

(±20.8)

(n=9)

Late (Greater than 6 months)

1.5 gram/oral

1.1

(±0.7)

(n=52)

20.0

(±9.4)

(n=52)

54.1a

(±20.4)

(n=49)

Liver transplant Patients (twice daily dosing) Time After Transplantation

Dose/Route

Tmax

(h)

Cmax

(mcg/mL)

Interdosing

Interval AUC(0-12h)

(mcg•h/mL)

4 to 9 days

1 gram/iv

1.50

(±0.517)

(n=22)

17.0

(±12.7)

(n=22)

34.0

(±17.4)

(n=22)

Early (5 to 8 days)

1.5 gram/oral

1.15

(±0.432)

(n=20)

13.1

(±6.76)

(n=20)

29.2

(±11.9)

(n=20)

Late (Greater than 6 months)

1.5 gram/oral

1.54

(±0.51)

(n=6)

19.3

(±11.7)

(n=6)

49.3

(±14.8)

(n=6)

a AUC(0-12h) values quoted are extrapolated from data from samples collected over 4 hours.

In the early post-transplant period (less than 40 days post-transplant), kidney, heart, and liver transplant patients had mean MPA AUCs approximately 20% to 41% lower and mean Cmax approximately 32% to 44% lower compared to the late transplant period (i.e., 3 to 6 months post-transplant) (non-stationarity in MPA pharmacokinetics).

Mean MPA AUC values following administration of 1 gram twice daily intravenous mycophenolate mofetil over 2 hours to kidney transplant patients for 5 days were about 24% higher than those observed after oral administration of a similar dose in the immediate post-transplant phase.

In liver transplant patients, administration of 1 gram twice daily intravenous mycophenolate mofetil followed by 1.5 grams twice daily oral mycophenolate mofetil resulted in mean MPA AUC estimates similar to those found in kidney transplant patients administered 1 gram mycophenolate mofetil twice daily.

Effect of Food

Food (27 grams fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 grams twice daily to kidney transplant patients. However, MPA Cmax was decreased by 40% in the presence of food [see Dosage and Administration (2.1)].

Distribution

The mean (±SD) apparent volume of distribution of MPA in 12 healthy volunteers was approximately 3.6 (±1.5) L/kg. At clinically relevant concentrations, MPA is 97% bound to plasma albumin. The phenolic glucuronide metabolite of MPA (MPAG) is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable kidney transplant patients; however, at higher MPAG concentrations (observed in patients with kidney impairment or delayed kidney graft function), the binding of MPA may be reduced as a result of competition between MPAG and MPA for protein binding. Mean blood to plasma ratio of radioactivity concentrations was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into the cellular fractions of blood.

In vitro studies to evaluate the effect of other agents on the binding of MPA to human serum albumin (HSA) or plasma proteins showed that salicylate (at 25 mg/dL with human serum albumin) and MPAG (at ≥460 mcg/mL with plasma proteins) increased the free fraction of MPA. MPA at concentrations as high as 100 mcg/mL had little effect on the binding of warfarin, digoxin or propranolol, but decreased the binding of theophylline from 53% to 45% and phenytoin from 90% to 87%.

Elimination

Mean (±SD) apparent half-life and plasma clearance of MPA are 17.9 (±6.5) hours and 193 (±48) mL/min following oral administration and 16.6 (±5.8) hours and 177 (±31) mL/min following intravenous administration, respectively.

Metabolism

The parent drug, mycophenolate mofetil, can be measured systemically during the intravenous infusion; however, approximately 5 minutes after the infusion is stopped or after oral administration, mycophenolate mofetil concentrations are below the limit of quantitation (0.4 mcg/mL).

Metabolism to MPA occurs pre-systemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form MPAG, which is not pharmacologically active. In vivo , MPAG is converted to MPA during enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.

Due to the enterohepatic recirculation of MPAG/MPA, secondary peaks in the plasma MPA concentration-time profile are usually observed 6 to 12 hours post-dose. Bile sequestrants, such as cholestyramine, reduce MPA AUC by interfering with this enterohepatic recirculation of the drug [see Overdosage (10) and Drug Interaction Studies below].

Excretion

Negligible amount of drug is excreted as MPA (less than 1% of dose) in the urine. Orally administered radiolabeled mycophenolate mofetil resulted in complete recovery of the administered dose, with 93% of the administered dose recovered in the urine and 6% recovered in feces. Most (about 87%) of the administered dose is excreted in the urine as MPAG. At clinically encountered concentrations, MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 mcg/mL), small amounts of MPAG are removed.

Increased plasma concentrations of mycophenolate mofetil metabolites (MPA 50% increase and MPAG about a 3-fold to 6-fold increase) are observed in patients with renal insufficiency [see Specific Populations].

Specific Populations

Patients with Renal Impairment

The mean (±SD) pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil given as single doses to non-transplant subjects with renal impairment are presented in Table 9.

In a single-dose study, mycophenolate mofetil was administered as a capsule or as an intravenous infusion over 40 minutes. Plasma MPA AUC observed after oral dosing to volunteers with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) was about 75% higher relative to that observed in healthy volunteers (GFR >80 mL/min/1.73 m2). In addition, the single-dose plasma MPAG AUC was 3-fold to 6-fold higher in volunteers with severe renal impairment than in volunteers with mild renal impairment or healthy volunteers, consistent with the known renal elimination of MPAG. No data are available on the safety of long-term exposure to this level of MPAG.

Plasma MPA AUC observed after single-dose (1 gram) intravenous dosing to volunteers (n=4) with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) was 62.4 mcg•h/mL (±19.3). Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied.

Patients with Delayed Graft Function or Nonfunction

In patients with delayed renal graft function post-transplant, mean MPA AUC(0-12h) was comparable to that seen in post-transplant patients without delayed renal graft function. There is a potential for a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. However, dose adjustment does not appear to be necessary in patients with delayed renal graft function. Mean plasma MPAG AUC(0-12h) was 2-fold to 3-fold higher than in post-transplant patients without delayed renal graft function [see Dosage and Administration (2.5)].

In eight patients with primary graft non-function following kidney transplantation, plasma concentrations of MPAG accumulated about 6-fold to 8-fold after multiple dosing for 28 days. Accumulation of MPA was about 1-fold to 2-fold.

The pharmacokinetics of mycophenolate mofetil are not altered by hemodialysis. Hemodialysis usually does not remove MPA or MPAG. At high concentrations of MPAG (>100 mcg/mL), hemodialysis removes only small amounts of MPAG.

Patients with Hepatic Impairment

The mean (± SD) pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil given as single doses to non-transplant subjects with hepatic impairment is presented in Table 9.

In a single-dose (1 gram oral) study of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this study were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this study had about a 50% lower AUC as compared to healthy volunteers in other studies, thus making comparisons between volunteers with alcoholic cirrhosis and healthy volunteers difficult. In a single-dose (1 gram intravenous) study of 6 volunteers with severe hepatic impairment (aminopyrine breath test less than 0.2% of dose) due to alcoholic cirrhosis, mycophenolate mofetil was rapidly converted to MPA. MPA AUC was 44.1 mcg•h/mL (±15.5).

Table 9: Pharmacokinetic Parameters for MPA [mean (±SD)] Following Single Doses of Mycophenolate Mofetil Capsules in Chronic Renal and Hepatic Impairment

Pharmacokinetic Parameters for Renal Impairment

Dose

Tmax

(h)

Cmax

(mcg/mL)

AUC(0-96h)

(mcg•h/mL)

Healthy Volunteers

GFR greater than 80 mL/min/1.73 m2

(n=6)

1 gram

0.75

(±0.27)

25.3

(±7.99)

45.0

(±22.6)

Mild Renal Impairment

GFR 50 to 80 mL/min/1.73 m2

(n=6)

1 gram

0.75

(±0.27)

26.0

(±3.82)

59.9

(±12.9)

Moderate Renal Impairment

GFR 25 to 49 mL/min/1.73 m2

(n=6)

1 gram

0.75

(±0.27)

19.0

(±13.2)

52.9

(±25.5)

Severe Renal Impairment

GFR less than 25 mL/min/1.73 m2

(n=7)

1 gram

1.00

(±0.41)

16.3

(±10.8)

78.6

(±46.4)

Pharmacokinetic Parameters for Hepatic Impairment

Dose

Tmax

(h)

Cmax

(mcg/mL)

AUC(0-48h)

(mcg•h/mL)

Healthy Volunteers

(n=6)

1 gram

0.63

(±0.14)

24.3

(±5.73)

29.0

(±5.78)

Alcoholic Cirrhosis

(n=18)

1 gram

0.85

(±0.58)

22.4

(±10.1)

29.8

(±10.7)

Pediatric Patients

The pharmacokinetic parameters of MPA and MPAG have been evaluated in 55 pediatric patients (ranging from 1 year to 18 years of age) receiving mycophenolate mofetil for oral suspension at a dose of 600 mg/m2 twice daily (up to a maximum of 1 gram twice daily) after allogeneic kidney transplantation. The pharmacokinetic data for MPA is provided in Table 10.

Table 10: Mean (±SD) Computed Pharmacokinetic Parameters for MPA by Age and Time after Allogeneic Kidney Transplantation

Age Group

(n)

Time

Tmax

(h)

Dose Adjusteda

Cmax

(mcg/mL)

Dose Adjusteda

AUC0-12

(mcg•h/mL)

Early (Day 7)

1 to less than 2 yr

(6)d

3.03

(4.70)

10.3

(5.80)

22.5

(6.66)

1 to less than 6 yr

(17)

1.63

(2.85)

13.2

(7.16)

27.4

(9.54)

6 to less than 12 yr

(16)

0.940

(0.546)

13.1

(6.30)

33.2

(12.1)

12 to 18 yr

(21)

1.16

(0.830)

11.7

(10.7)

26.3

(9.14)b

Late (Month 3)

1 to less than 2 yr

(4)d

0.725

(0.276)

23.8

(13.4)

47.4

(14.7)

1 to less than 6 yr

(15)

0.989

(0.511)

22.7

(10.1)

49.7

(18.2)

6 to less than 12 yr

(14)

1.21

(0.532)

27.8

(14.3)

61.9

(19.6)

12 to 18 yr

(17)

0.978

(0.484)

17.9

(9.57)

53.6

(20.3)c

Late (Month 9)

1 to less than 2 yr

(4)d

0.604

(0.208)

25.6

(4.25)

55.8

(11.6)

1 to less than 6 yr

(12)

0.869

(0.479)

30.4

(9.16)

61.0

(10.7)

6 to less than 12 yr

(11)

1.12

(0.462)

29.2

(12.6)

66.8

(21.2)

12 to 18 yr

(14)

1.09

(0.518)

18.1

(7.29)

56.7

(14.0)

a adjusted to a dose of 600 mg/m2

b n=20

c n=16

d a subset of 1 to <6 yr

The mycophenolate mofetil for oral suspension dose of 600 mg/m2 twice daily (up to a maximum of 1 gram twice daily) achieved mean MPA AUC values in pediatric patients similar to those seen in adult kidney transplant patients receiving mycophenolate mofetil capsules at a dose of 1 gram twice daily in the early post-transplant period. There was wide variability in the data. As observed in adults, early post-transplant MPA AUC values were approximately 45% to 53% lower than those observed in the later post-transplant period (>3 months). MPA AUC values were similar in the early and late post-transplant period across the 1 to 18-year age range.

Male and Female Patients

Data obtained from several studies were pooled to look at any gender-related differences in the pharmacokinetics of MPA (data were adjusted to 1 gram oral dose). Mean (±SD) MPA AUC(0-12h) for males (n=79) was 32.0 (±14.5) and for females (n=41) was 36.5 (±18.8) mcg•h/mL while mean (±SD) MPA Cmax was 9.96 (±6.19) in the males and 10.6 (±5.64) mcg/mL in the females. These differences are not of clinical significance.

Geriatric Patients

The pharmacokinetics of mycophenolate mofetil and its metabolites have not been found to be altered in elderly transplant patients when compared to younger transplant patients.

Drug Interaction Studies

Acyclovir

Coadministration of mycophenolate mofetil (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 AUCs were increased 10.6% and 21.9%, respectively.

Antacids with Magnesium and Aluminum Hydroxides

Absorption of a single dose of mycophenolate mofetil (2 grams) was decreased when administered to 10 rheumatoid arthritis patients also taking Maalox® TC (10 mL qid). The Cmax and AUC(0-24h) for MPA were 33% and 17% lower, respectively, than when mycophenolate mofetil was administered alone under fasting conditions.

Proton Pump Inhibitors (PPIs)

Coadministration of PPIs (e.g., lansoprazole, pantoprazole) in single doses to healthy volunteers and multiple doses to transplant patients receiving mycophenolate mofetil has been reported to reduce the exposure to MPA. An approximate reduction of 30 to 70% in the Cmax and 25% to 35% in the AUC of MPA has been observed, possibly due to a decrease in MPA solubility at an increased gastric pH.

Cholestyramine

Following single-dose administration of 1.5 grams mycophenolate mofetil to 12 healthy volunteers pretreated with 4 grams three times a day 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.

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 mycophenolate mofetil in 10 stable kidney transplant patients. The mean (±SD) AUC(0-12h) and Cmax of cyclosporine after 14 days of multiple doses of mycophenolate mofetil 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 mycophenolate mofetil.

Cyclosporine A interferes with MPA enterohepatic recirculation. In kidney transplant patients, mean MPA exposure (AUC(0-12h) ) was approximately 30% to 50% greater when mycophenolate mofetil was administered without cyclosporine compared with when mycophenolate mofetil was coadministered with cyclosporine. This interaction is due to cyclosporine inhibition of 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. This information should be taken into consideration when mycophenolate mofetil is used without cyclosporine.

Drugs Affecting Glucuronidation

Concomitant administration of drugs inhibiting glucuronidation of MPA may increase MPA exposure (e.g., increase of MPA AUC(0-∞) by 35% was observed with concomitant administration of isavuconazole).

Concomitant administration of telmisartan and mycophenolate mofetil resulted in an approximately 30% decrease in MPA concentrations. Telmisartan changes MPA’s elimination by enhancing PPAR gamma (peroxisome proliferator-activated receptor gamma) expression, which in turn results in an enhanced UGT1A9 expression and glucuronidation activity.

Ganciclovir

Following single-dose administration to 12 stable kidney transplant patients, no pharmacokinetic interaction was observed between mycophenolate mofetil (1.5 grams) and intravenous ganciclovir (5 mg/kg). Mean (±SD) ganciclovir AUC and Cmax (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 Cmax 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 mycophenolate mofetil alone.

Oral Contraceptives

A study of coadministration of mycophenolate mofetil (1 gram twice daily) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) was conducted in 18 women with psoriasis over 3 consecutive menstrual cycles. Mean serum levels of LH, FSH and progesterone were not significantly affected. Mean AUC(0-24h) was similar for ethinylestradiol and 3-keto desogestrel; however, mean levonorgestrel AUC(0-24h) significantly decreased by about 15%. There was large inter-patient variability (%CV in the range of 60% to 70%) in the data, especially for ethinylestradiol.

Sevelamer

Concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean MPA Cmax and AUC(0-12h) by 36% and 26% respectively.

Antimicrobials

Antimicrobials eliminating beta-glucuronidase-producing bacteria in the intestine (e.g. aminoglycoside, cephalosporin, fluoroquinolone, and penicillin classes of antimicrobials) may interfere with the MPAG/MPA enterohepatic recirculation thus leading to reduced systemic MPA exposure. Information concerning antibiotics is as follows:

  • Trimethoprim/Sulfamethoxazole: Following single-dose administration of mycophenolate mofetil (1.5 grams) to 12 healthy male volunteers on day 8 of a 10-day course of trimethoprim 160 mg/sulfamethoxazole 800 mg administered twice daily, no effect on the bioavailability of MPA was observed. The mean (±SD) AUC and Cmax of MPA after concomitant administration were 75.2 (±19.8) mcg•h/mL and 34.0 (±6.6) mcg/mL, respectively, compared to 79.2 (±27.9) mcg•h/mL and 34.2 (±10.7) mcg/mL, respectively, after administration of mycophenolate mofetil alone.
  • Norfloxacin and Metronidazole: Following single-dose administration of mycophenolate mofetil (1 gram) 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 significantly reduced by 33% compared to the administration of mycophenolate mofetil alone (p<0.05). The mean (±SD) MPA AUC(0-48h) after coadministration of mycophenolate mofetil 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 mycophenolate mofetil alone.
  • Ciprofloxacin and Amoxicillin Plus Clavulanic Acid: A total of 64 mycophenolate mofetil-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, respectively. Approximately 50% reductions in median trough MPA concentrations (pre-dose) from baseline (mycophenolate mofetil 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 antimicrobial therapy and ceased within 3 days of discontinuation of antibiotics.
  • Rifampin: In a single heart-lung transplant patient, after correction for dose, a 67% decrease in MPA exposure (AUC(0-12h) ) has been observed with concomitant administration of mycophenolate mofetil and rifampin.

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