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.
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.
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:
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).
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.
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.
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.
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).
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.
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.
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) ]
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.
|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|
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.
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) ].
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:
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) ].
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 (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) ].
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) ].
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) ].
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) ].
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) ].
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