Prescription Drug Information: Mycophenolic Acid (Page 4 of 7)

8.4 Pediatric Use

The safety and effectiveness of mycophenolic acid delayed-release tablets have been established in pediatric kidney transplant patients 5 to 16 years of age who were initiated on mycophenolic acid delayed-release tablets at least 6 months post-transplant. Use of mycophenolic acid delayed-release tablets in this age group is supported by evidence from adequate and well-controlled studies of mycophenolic acid delayed-release tablets in a similar population of adult kidney transplant patients with additional pharmacokinetic data in pediatric kidney transplant patients [see Dosage and Administration ( 2.2, 2.3) , Clinical Pharmacology ( 12.3) ]. Pediatric doses for patients with BSA <1.19 m2 cannot be accurately administered using currently available formulations of mycophenolic acid delayed-release tablets.

The safety and effectiveness of mycophenolic acid delayed-release tablets in de novo pediatric kidney transplant patients and in pediatric kidney transplant patients below the age of 5 years have not been established.

8.5 Geriatric Use

Clinical studies of mycophenolic acid delayed-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 372 patients treated with mycophenolic acid delayed-release tablets in the clinical trials, 6 % (N=21) were 65 years of age and older and 0.3 % (N=1) were 75 years of age and older. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Signs and Symptoms

There have been anecdotal reports of deliberate or accidental overdoses with mycophenolic acid delayed-release tablets, whereas not all patients experienced related adverse reactions.

In those overdose cases in which adverse reactions were reported, the reactions fall within the known safety profile of the class. Accordingly, an overdose of mycophenolic acid delayed-release tablets could possibly result in oversuppression of the immune system and may increase the susceptibility to infection, including opportunistic infections, fatal infections and sepsis. If blood dyscrasias occur (e.g., neutropenia with absolute neutrophil count < 1.5 x 10 3 /mcL or anemia), it may be appropriate to interrupt or discontinue mycophenolic acid delayed-release tablets.

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

Treatment and Management

General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Although dialysis may be used to remove the inactive metabolite mycophenolic acid glucuronide (MPAG), it would not be expected to remove clinically significant amounts of the active moiety, mycophenolic acid, due to the 98% plasma protein binding of mycophenolic acid. By interfering with enterohepatic circulation of mycophenolic acid, activated charcoal or bile sequestrates, such as cholestyramine, may reduce the systemic mycophenolic acid exposure.

11 DESCRIPTION

Mycophenolic acid delayed-release tablets, USP are enteric formulation of mycophenolate sodium that delivers the active moiety mycophenolic acid (MPA). Mycophenolic acid is an immunosuppressive agent. As the sodium salt, MPA is chemically designated as (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid sodium salt.

Its empirical formula is C17 H19 O6 Na. The molecular weight is 342.32 g/mol and the structural formula is:

Chemical Structure

Mycophenolic acid as the sodium salt (mycophenolate sodium, USP), is a white to off-white, crystalline powder and is highly soluble in aqueous media at physiological pH and practically insoluble in 0.1N hydrochloric acid.

Mycophenolic acid is available for oral use as delayed-release tablets containing either 180 mg or 360 mg of mycophenolic acid.

Inactive ingredients include colloidal silicon dioxide, crospovidone, lactose anhydrous, magnesium stearate, maize starch and povidone (K-30).

The enteric coating of the tablet consists of FD & C Blue No. 2 Aluminum Lake (180 mg), ferric oxide red (360 mg), ferric oxide yellow, hypromellose phthalate and titanium dioxide.Contains no ingredient made from a gluten-containing grain (wheat, barley, or rye).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mycophenolic acid (MPA), an immunosuppressant, is an uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation to DNA. 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 cytostatic effects on lymphocytes.

Mycophenolate sodium has been shown to prevent the occurrence of acute rejection in rat models of kidney and heart allotransplantation. Mycophenolate sodium also decreases antibody production in mice.

12.3 Pharmacokinetics

Mycophenolic acid delayed-release tablets exhibit linear and dose-proportional pharmacokinetics over the dose-range (360 mg to 2160 mg) evaluated. The absolute bioavailability of mycophenolic acid delayed-release tablets in stable renal transplant patients on cyclosporine was 72%. MPA is highly protein bound (>98% bound to albumin). The predominant metabolite of MPA is the phenolic glucuronide (MPAG) which is pharmacologically inactive. A minor metabolite AcMPAG which is an acyl glucuronide of MPAG is also formed and has pharmacological activity comparable to MPA. MPAG undergoes renal elimination. A fraction of MPAG also undergoes biliary excretion, followed by deconjugation by gut flora and subsequent reabsorption as MPA. The mean elimination half-lives of MPA and MPAG ranged between 8 and 16 hours, and 13 and 17 hours, respectively.

Absorption

In vitro studies demonstrated that the enteric-coated mycophenolic acid delayed-release tablets do not release MPA under acidic conditions (pH < 5) as in the stomach but is highly soluble in neutral pH conditions as in the intestine. Following mycophenolic acid delayed-release tablets oral administration without food in several pharmacokinetic studies conducted in renal transplant patients, consistent with its enteric-coated formulation, the median delay (Tlag ) in the rise of MPA concentration ranged between 0.25 and 1.25 hours and the median time to maximum concentration (Tmax ) of MPA ranged between 1.5 and 2.75 hours. In comparison, following the administration of MMF, the median Tmax ranged between 0.5 and 1.0 hours. In stable renal transplant patients on cyclosporine, USP MODIFIED based immunosuppression, gastrointestinal absorption and absolute bioavailability of MPA following the administration of mycophenolic acid delayed-release tablets was 93% and 72%, respectively. Mycophenolic acid delayed-release tablets pharmacokinetics is dose proportional over the dose range of 360 mg to 2160 mg.

Distribution

The mean (± SD) volume of distribution at steady state and elimination phase for MPA is 54 (± 25) L and 112 (± 48) L, respectively. MPA is highly protein bound to albumin, >98%. The protein binding of MPAG is 82%. The free MPA concentration may increase under conditions of decreased protein binding (uremia, hepatic failure, and hypoalbuminemia).

Metabolism

MPA is metabolized principally by glucuronyl transferase to glucuronidated metabolites. The phenolic glucuronide of MPA, MPAG, is the predominant metabolite of MPA and does not manifest pharmacological activity. The acyl glucuronide is a minor metabolite and has comparable pharmacological activity to MPA. In stable renal transplant patients on cyclosporine, USP MODIFIED based immunosuppression, approximately 28% of the oral mycophenolic acid delayed-release tablets dose was converted to MPAG by presystemic metabolism. The AUC ratio of MPA:MPAG:acyl glucuronide is approximately 1:24:0.28 at steady state. The mean clearance of MPA was 140 (± 30) mL/min.

Elimination

The majority of MPA dose administered is eliminated in the urine primarily as MPAG (>60%) and approximately 3% as unchanged MPA following mycophenolic acid delayed-release tablets administration to stable renal transplant patients. The mean renal clearance of MPAG was 15.5 (± 5.9) mL/min. MPAG is also secreted in the bile and available for deconjugation by gut flora. MPA resulting from the deconjugation may then be reabsorbed and produce a second peak of MPA approximately 6 to 8 hours after mycophenolic acid delayed-release tablets dosing. The mean elimination half-life of MPA and MPAG ranged between 8 and 16 hours, and 13 and 17 hours, respectively.

Food Effect

Compared to the fasting state, administration of mycophenolic acid delayed-release tablets 720 mg with a high-fat meal (55 g fat, 1000 calories) had no effect on the systemic exposure (AUC) of MPA. However, there was a 33% decrease in the maximal concentration (C max ), a 3.5-hour delay in the T lag (range, -6 to 18 hours), and 5.0-hour delay in the T max (range, -9 to 20 hours) of MPA. To avoid the variability in MPA absorption between doses, mycophenolic acid delayed-release tablets should be taken on an empty stomach [see Dosage and Administration (2.3) ]

Pharmacokinetics in Renal Transplant Patients

The mean pharmacokinetic parameters for MPA following the administration of mycophenolic acid delayed-release tablets in renal transplant patients on cyclosporine, USP MODIFIED based immunosuppression are shown in Table 6. Single-dose mycophenolic acid delayed-release tablets pharmacokinetics predicts multiple-dose pharmacokinetics. However, in the early post-transplant period, mean MPA AUC and C max were approximately one-half of those measured 6 months post-transplant.

After near equimolar dosing of mycophenolic acid delayed-release tablets 720 mg twice daily and MMF 1000 mg twice daily (739 mg as MPA) in both the single- and multiple-dose cross-over trials, mean systemic MPA exposure (AUC) was similar.

Table 6 Mean ± SD Pharmacokinetic Parameters for MPA Following the Oral Administration of Mycophenolic Acid Delayed-Release Tablets to Renal Transplant Patients on Cyclosporine, USP MODIFIED Based Immunosuppression
Patient Mycophenolic Acid Delayed-Release tablets Dosing n Dose (mg) T max * (h) C max (mcg/mL) AUC (0 12h) (mcg*h/mL)
Adult Single 24 720 2 (0.8 to 8) 26.1 ± 12.0 66.5 ± 22.6**
Pediatric*** Single 10 450 /m2 2.5 (1.5 to 24) 36.3 ± 20.9 74.3 ± 22.5**
Adult Multiple x 6 days, twice daily 10 720 2 (1.5 to 3.0) 37.0 ± 13.3 67.9 ± 20.3
Adult Multiple x 28 days, twice daily 36 720 2.5 (1.5 to 8) 31.2 ± 18.1 71.2 ± 26.3
Adult Chronic, multiple-dose, twice daily
2 weeks post-transplant 12 720 1.8 (1.0 to 5.3) 15.0 ± 10.7 28.6 ± 11.5
3 months post-transplant 12 720 2 (0.5 to 2.5) 26.2 ± 12.7 52.3 ± 17.4
6 months post-transplant 12 720 2 (0 to 3) 24.1 ± 9.6 57.2 ± 15.3
Adult Chronic, multiple-dose, twice daily 18 720 1.5 (0 to 6) 18.9 ± 7.9 57.4 ± 15.0
*median (range) ** AUC inf *** age range of 5 to 16 years

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