mycophenolate mofetil 200 MG/ML Oral Suspension
Generic Name: MYCOPHENOLATE MOFETIL
Brand Name: Mycophenolate mofetil
- Substance Name(s):
- MYCOPHENOLATE MOFETIL
DRUG INTERACTIONS
7 See FPI for drugs that may interfere with systemic exposure and reduce mycophenolate mofetil efficacy: antacids with magnesium or aluminum hydroxide, proton pump inhibitors, drugs that interfere with enterohepatic recirculation, telmisartan, calcium-free phosphate binders.
( 7.1 ) Mycophenolate mofetil may reduce effectiveness of oral contraceptives.
Use of additional barrier contraceptive methods is recommended.
( 7.2 ) See FPI for other important drug interactions.
( 7 ) 7.1 Effect of Other Drugs on Mycophenolate Mofetil Table 7.
Drug Interactions with Mycophenolate Mofetil that Affect Mycophenolic Acid (MPA) Exposure Antacids with Magnesium or Aluminum Hydroxide Clinical Impact Concomitant use with an antacid containing magnesium or aluminum hydroxide decreases MPA systemic exposure [see Clinical Pharmacology ( 12.3 )], which may reduce mycophenolate mofetil efficacy.
Prevention or Management Administer magnesium or aluminum hydroxide containing antacids at least 2h after mycophenolate mofetil administration.
Proton Pump Inhibitors (PPIs) Clinical Impact Concomitant use with PPIs decreases MPA systemic exposure [see Clinical Pharmacology ( 12.3 )], which may reduce mycophenolate mofetil efficacy Prevention or Management Monitor patients for alterations in efficacy when PPIs are co-administered with mycophenolate mofetil Examples Lansoprazole, pantoprazole Drugs that Interfere with Enterohepatic Recirculation Clinical Impact Concomitant use with drugs that directly interfere with enterohepatic recirculation, or indirectly interfere with enterohepatic recirculation by altering the gastrointestinal flora, can decrease MPA systemic exposure [see Clinical Pharmacology ( 12.3 )], which may reduce mycophenolate mofetil efficacy.
Prevention or Management Monitor patients for alterations in efficacy or mycophenolate mofetil related adverse reactions when these drugs are co-administered with mycophenolate mofetil Examples Cyclosporine A, trimethoprim/sulfamethoxazole, bile acid sequestrants (cholestyramine), rifampin as well as aminoglycoside, cephalosporin, fluoroquinolone and penicillin classes of antimicrobials Drugs Modulating Glucuronidation Clinical Impact Concomitant use with drugs inducing glucuronidation decreases MPA systemic exposure, potentially reducing mycophenolate mofetil efficacy, while use with drugs inhibiting glucuronidation increases MPA systemic exposure [see Clinical Pharmacology ( 12.3 )], which may increase the risk of mycophenolate mofetil related adverse reactions.
Prevention or Management Monitor patients for alterations in efficacy or mycophenolate mofetil related adverse reactions when these drugs are co-administered with mycophenolate mofetil Examples Telmisartan (induces glucuronidation); isavuconazole (inhibits glucuronidation).
Calcium Free Phosphate Binders Clinical Impact Concomitant use with calcium free phosphate binders decrease MPA systemic exposure [see Clinical Pharmacology ( 12.3 )], which may reduce mycophenolate mofetil efficacy.
Prevention or Management Administer calcium free phosphate binders at least 2 hours after mycophenolate mofetil Examples Sevelamer 7.2 Effect of Mycophenolate Mofetil on Other Drugs Table 8.
Drug Interactions with Mycophenolate Mofetil that Affect Other Drugs Drugs that Undergo Renal Tubular Secretion Clinical Impact When concomitantly used with mycophenolate mofetil, its metabolite MPAG, may compete with drugs eliminated by renal tubular secretion which may increase plasma concentrations and/or adverse reactions associated with these drugs Prevention or Management Monitor for drug-related adverse reactions in patients with renal impairment Examples Acyclovir, ganciclovir, probenecid, valacyclovir, valganciclovir Combination Oral Contraceptives Clinical Impact Concomitant use with mycophenolate mofetil decreased the systemic exposure to levonorgestrel, but did not affect the systemic exposure to ethinylestradiol [see Clinical Pharmacology ( 12.3 )], which may result in reduced combination oral contraceptive effectiveness.
Prevention or Management Use additional barrier contraceptive methods.
OVERDOSAGE
10 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 g/day.
In limited experience with heart and liver transplant patients in clinical trials, the highest doses used were 4 g/day or 5 g/day.
At doses of 4 g/day or 5 g/day, there appears to be a higher rate, compared to the use of 3 g/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 )].
DESCRIPTION
11 Mycophenolate mofetil is an antimetabolite immunosuppressant.
It is the 2morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor.
The chemical name for mycophenolate mofetil (MMF) is 2-morpholinoethyl (E)-6 (1,3dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate.
It has an empirical formula of C 23 H 31 NO 7 , a molecular weight of 433.50, and the following structural formula: Mycophenolate mofetil 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 MMF are 5.6 for the morpholino group and 8.5 for the phenolic group.
Mycophenolate mofetil USP for oral suspension is available for oral administration as a powder for oral suspension, which when constituted contains 200 mg/mL of mycophenolate mofetil Inactive ingredients in mycophenolate mofetil for oral solution 200 mg include Sorbitol, sodium citrate dehydrate, citric acid anhydrous, methylparaben, xanthan gum, aspartame, soybean lecithin and N &A gum fruit flavor.
FDA approved dissolution test specifications differ from USP.
mycophenolate-structure-.jpg
CLINICAL STUDIES
14 14.1 Kidney Transplantation Adults The three de novo kidney transplantation studies compared two dose levels of oral mycophenolate mofetil (1 g twice daily and 1.5 g twice daily) with azathioprine (2 studies) or placebo (1 study) to prevent acute rejection episodes.
One of the two studies with azathioprine (AZA) control arm also included anti-thymocyte globulin (ATGAM ® ) induction therapy.
The geographic location of the investigational sites of these studies are included in Table 13.
In all three de novo kidney transplantation studies, the primary efficacy endpoint was the proportion of patients in each treatment group who experienced treatment failure within the first 6 months after transplantation.
Treatment failure was defined as biopsy-proven acute rejection on treatment or the occurrence of death, graft loss or early termination from the study for any reason without prior biopsy-proven rejection.
Mycophenolate mofetil, in combination with corticosteroids and cyclosporine, reduced (statistically significant at 0.05 level) the incidence of treatment failure within the first 6 months following transplantation (Table 13).
Patients who prematurely discontinued treatment were followed for the occurrence of death or graft loss, and the cumulative incidence of graft loss and patient death combined are summarized in Table 14 .
Patients who prematurely discontinued treatment were not followed for the occurrence of acute rejection after termination.
Table 13.
Treatment Failure in De Novo Kidney Transplantation Studies USA Study (N=499 patients) Mycophenolate Mofetil 2g/day (n=167 patients) Mycophenolate Mofetil 3g/day (n=166 patients) AZA 1 to 2 mg/kg/day (n=166 patients) All 3 groups received anti-thymocyte globulin induction, cyclosporine and corticosteroids All treatment failures 31.1% 31.3% 47.6% Early termination without prior acute rejection 9.6% 12.7% 6.0% Biopsy-proven rejection episode on treatment 19.8% 17.5% 38.0% Europe/Canada/ Australia Study (N=503 patients) Mycophenolate Mofetil 2 g/day (n=173 patients) Mycophenolate Mofetil 3 g/day (n=164 patients) AZA 100 to 150 mg/day (n=166 patients) No induction treatment administered; all 3 groups received cyclosporine and corticosteroids.
All treatment failures 38.2% 34.8% 50.0% Early termination without prior acute rejection 13.9% 15.2% 10.2% Biopsy-proven rejection episode on treatment 19.7% 15.9% 35.5% Europe Study (N=491 patients) Mycophenolate Mofetil 2g/day (n=165 patients) Mycophenolate Mofetil 3g/day (n=160 patients) Placebo (n=166 patients) No induction treatment administered; all 3 groups received cyclosporine and corticosteroids.
All treatment failures 30.3% 38.8% 56.0% Early termination without prior acute rejection 11.5% 22.5% 7.2% Biopsy-proven rejection episode on treatment 17.0% 13.8% 46.4% * Does not include death and graft loss as reason for early termination No advantage of mycophenolate mofetil at 12 months with respect to graft loss or patient death (combined) was established ( Table 14 ).
Numerically, patients receiving mycophenolate mofetil 2 g/day and 3 g/day experienced a better outcome than controls in all three studies; patients receiving mycophenolate mofetil 2 g/day experienced a better outcome than mycophenolate mofetil 3 g/day in two of the three studies.
Patients in all treatment groups who terminated treatment early were found to have a poor outcome with respect to graft loss or patient death at 1 year.
Table 14.
De Novo Kidney Transplantation Studies Cumulative Incidence of Combined Graft Loss or Patient Death at 12 Months Study Mycophenolate Mofetil 2 g/day Mycophenolate Mofetil 3 g/day Control (AZA or Placebo) USA 8.5% 11.5% 12.2% Europe/Canada/Australia 11.7% 11.0% 13.6% Europe 8.5% 10.0% 11.5% Pediatrics-De Novo Kidney transplantation PK Study with Long Term Follow-Up One open-label, safety and pharmacokinetic study of mycophenolate mofetil for oral suspension 600 mg/m 2 twice daily (up to 1 g twice daily) in combination with cyclosporine and corticosteroids was performed at centers in the United States (9), Europe (5) and Australia (1) in 100 pediatric patients (3 months to 18 years of age) for the prevention of renal allograft rejection.
Mycophenolate mofetil was well tolerated in pediatric patients [see Adverse Reactions ( 6.1 )], and the pharmacokinetics profile was similar to that seen in adult patients dosed with 1 g twice daily mycophenolate mofetil capsules [see Clinical Pharmacology ( 12.3 )].
The rate of biopsy-proven rejection was similar across the age groups (3 months to less than 6 years, 6 years to less than 12 years, 12 years to 18 years).
The overall biopsy-proven rejection rate at 6 months was comparable to adults.
The combined incidence of graft loss (5%) and patient death (2%) at 12 months post-transplant was similar to that observed in adult kidney transplant patients.
14.2 Heart Transplantation A double-blind, randomized, comparative, parallel-group, multicenter study in primary de novo heart transplant recipients was performed at centers in the United States (20), in Canada (1), in Europe (5) and in Australia (2).
The total number of patients enrolled (ITT population) was 650; 72 never received study drug and 578 received study drug (Safety Population).
Patients received mycophenolate mofetil 1.5 g twice daily (n=289) or AZA 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine (Sandimmune ® or Neoral ® ) and corticosteroids as maintenance immunosuppressive therapy.
The two primary efficacy endpoints were: (1) the proportion of patients who, after transplantation, had at least one endomyocardial biopsy-proven rejection with hemodynamic compromise, or were re-transplanted or died, within the first 6 months, and (2) the proportion of patients who died or were re-transplanted during the first 12 months following transplantation.
Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection for up to 6 months and for the occurrence of death for 1 year.
The analyses of the endpoints showed: Rejection: No difference was established between mycophenolate mofetil and AZA with respect to biopsy-proven rejection with hemodynamic compromise.
Survival: Mycophenolate mofetil was shown to be at least as effective as AZA in preventing death or re-transplantation at 1 year (see Table 15 ).
Table 15.
De Novo Heart Transplantation Study Rejection at 6 Months/Death or Re-transplantation at 1 Year All Patients (ITT) Treated Patients AZA N = 323 Mycophenolate Mofetil N = 327 AZA N = 289 Mycophenolate Mofetil N = 289 Biopsy-proven rejection with hemodynamic compromise at 6 months a 121 (38%) 120 (37%) 100 (35%) 92 (32%) Death or re-transplantation at 1 year 49 (15.2%) 42 (12.8%) 33 (11.4%) 18 (6.2%) a Hemodynamic compromise occurred if any of the following criteria were met: pulmonary capillary wedge pressure ≥20 mm or a 25% increase; cardiac index less than 2.0 L/min/m 2 or a 25% decrease; ejection fraction ≤30%; pulmonary artery oxygen saturation ≤60% or a 25% decrease; presence of new S3 gallop; fractional shortening was ≤20% or a 25% decrease; inotropic support required to manage the clinical condition.
14.3 Liver Transplantation A double-blind, randomized, comparative, parallel-group, multicenter study in primary hepatic transplant recipients was performed at centers in the United States (16), in Canada (2), in Europe (4) and in Australia (1).
The total number of patients enrolled was 565.
Per protocol, patients received mycophenolate mofetil 1 g twice daily intravenously for up to 14 days followed by mycophenolate mofetil 1.5 g twice daily orally or AZA 1 to 2 mg/kg/day intravenously followed by AZA 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral ® ) and corticosteroids as maintenance immunosuppressive therapy.
The actual median oral dose of AZA on study was 1.5 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) initially and 1.26 mg/kg/day (range of 0.3 to 3.8 mg/kg/day) at 12 months.
The two primary endpoints were: (1) the proportion of patients who experienced, in the first 6 months post-transplantation, one or more episodes of biopsy-proven and treated rejection or death or re-transplantation, and (2) the proportion of patients who experienced graft loss (death or re-transplantation) during the first 12 months post-transplantation.
Patients who prematurely discontinued treatment were followed for the occurrence of allograft rejection and for the occurrence of graft loss (death or re-transplantation) for 1 year.
In combination with corticosteroids and cyclosporine, mycophenolate mofetil demonstrated a lower rate of acute rejection at 6 months and a similar rate of death or re-transplantation at 1 year compared to AZA ( Table 16 ) Table 16.
De Novo Liver Transplantation Study Rejection at 6 Months/Death or Retransplantation at 1 Year AZA N = 287 Mycophenolate Mofetil N = 278 Biopsy-proven, treated rejection at 6 months (includes death or re-transplantation) 137 (47.7%) 107 (38.5%) Death or re-transplantation at 1 year 42 (14.6%) 41 (14.7%)
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 Handling and Disposal Mycophenolate mofetil (MMF) has demonstrated teratogenic effects in humans [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )] .
Mycophenolate mofetil tablets should not be crushed and mycophenolate mofetil capsules should not be opened or crushed.
Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution.
Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in mycophenolate mofetil capsules, mycophenolate mofetil for oral suspension (before or after constitution), or mycophenolate mofetil intravenous (during or after preparation) [see Dosage and Administration ( 2.6 )].
Follow applicable special handling and disposal procedures 1 .
16.4 Mycophenolate Mofetil for Oral Suspension, USP Supplied as white to off white powder blend for constitution to white to off white mixed fruit flavor suspension.
Supplied in the following presentations: 225mL bottle with bottle adapter and 2 oral dispensers…………….
NDC 67877-230-22 Storage: Store dry powder at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) Store constituted suspension at 25°C (77°F); excursions permitted to 15° C to 30°C (59°F to 86°F) for up to 60 days.
Storage in a refrigerator at 2°C to 8°C (36°F to 46°F) is acceptable.
Do not freeze.
RECENT MAJOR CHANGES
Indications and Usage, Pediatric Heart or Liver Transplants ( 1 )…………… 6/2022 Dosage and Administration, Dosage Recommendations for Heart Transplant Patients ( 2.3 )………6/2022 Dosage and Administration, Dosage Recommendations for Liver Transplant Patients ( 2.4 )…6/2022 Warnings and Precautions, Serious Infections ( 5.3 )……..10/2021 Warnings and Precautions, Acute Inflammatory Syndrome Associated with Mycophenolate Products ( 5.7 )..10/2021
GERIATRIC USE
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 )].
DOSAGE FORMS AND STRENGTHS
3 Mycophenolate mofetil is available in the following dosage forms and strengths: • White to off-white powder, 200 mg/mL upon reconstitution.
35 g mycophenolate mofetil, powder for reconstitution
MECHANISM OF ACTION
12.1 Mechanism of Action Mycophenolate mofetil (MMF) is absorbed following oral administration and hydrolyzed to mycophenolic acid (MPA), the active metabolite.
MPA is a selective uncompetitive inhibitor of the two isoforms (type I and type II) of inosine monophosphate dehydrogenase (IMPDH) leading to inhibition of the de novo pathway of guanosine nucleotide synthesis and blocks DNA synthesis.
The mechanism of action of MPA is multifaceted and includes effects on cellular checkpoints responsible for metabolic programming of lymphocytes.
MPA shifts transcriptional activities in lymphocytes from a proliferative state to catabolic processes.
In vitro studies suggest that MPA modulates transcriptional activities in human CD4+ T-lymphocytes by suppressing the Akt/mTOR and STAT5 pathways that are relevant to metabolism and survival, leading to an anergic state of T-cells whereby the cells become less responsive to antigenic stimulation.
Additionally, MPA enhanced the expression of negative co-stimulators such as CD70, PD-1, CTLA-4, and transcription factor FoxP3 as well as decreased the expression of positive co-stimulators CD27 and CD28.
MPA decreases proliferative responses of T- and B-lymphocytes to both mitogenic and allo-antigenic stimulation, antibody responses, as well as the production of cytokines from lymphocytes and monocytes such as GM-CSF, IFN-Ɣ, IL-17, and TNF-α.
Additionally, 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.
Overall, the effect of MPA is cytostatic and reversible.
INDICATIONS AND USAGE
1 Mycophenolate mofetil (MMF) is indicated for the prophylaxis of organ rejection, in adult and pediatric recipients 3 months of age and older of allogeneic kidney [see Clinical Studies ( 14.1 )], heart [see Clinical Studies ( 14.2 )] or liver transplants [see Clinical Studies ( 14.3 )], in combination with other immunosuppressants.
Mycophenolate mofetil is an antimetabolite immunosuppressant indicated for the prophylaxis of organ rejection in adult and pediatric recipients 3 months of age and older of allogeneic kidney, heart or liver transplants, in combination with other immunosuppressants.
(1)
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness have been established in pediatric patients 3 months and older for the prophylaxis of organ rejection of allogenic kidney, heart or liver transplants.
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 (100 patients, 3 months to 18 years of age) [see Dosage and Administration ( 2.2 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.1 )] Heart Transplant and Liver Transplant Use of mycophenolate mofetil in pediatric heart transplant and liver transplant patients is supported by adequate and well-controlled studies and pharmacokinetic data in adult heart transplant and liver transplant patients.
Additional supportive data include pharmacokinetic data in pediatric kidney transplant and pediatric liver transplant patients (8 liver transplant patients, 9 months to 5 years of age, in an open-label, pharmacokinetic and safety study) and published evidence of clinical efficacy and safety in pediatric heart transplant and pediatric liver transplant patients [see Dosage and Administration ( 2.3 , 2.4 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.1 )].
PREGNANCY
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to mycophenolate during pregnancy and those becoming pregnant within 6 weeks of discontinuing mycophenolate mofetil treatment.
To report a pregnancy or obtain information about the registry, visit www.mycophenolateREMS.com or call 1-800-617-8191.
Risk Summary Use of mycophenolate mofetil (MMF) during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of multiple congenital malformations in multiple organ systems [see Human Data] .
Oral administration of mycophenolate to rats and rabbits during the period of organogenesis produced congenital malformations and pregnancy loss at doses less than the recommended clinical dose (0.01 to 0.05 times the recommended clinical doses in kidney and heart transplant patients) [see Animal Data].
Consider alternative immunosuppressants with less potential for embryofetal toxicity.
Risks and benefits of mycophenolate mofetil should be discussed with the pregnant woman.
The estimated background risk of pregnancy loss and congenital malformations in organ transplant populations is not clear .
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively Data Human Data A spectrum of congenital malformations (including multiple malformations in individual newborns) has been reported in 23 to 27% of live births in MMF exposed pregnancies, based on published data from pregnancy registries.
Malformations that have been documented include external ear, eye, and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney, and nervous system.
Based on published data from pregnancy registries, the risk of first trimester pregnancy loss has been reported at 45 to 49% following MMF exposure.
Animal Data In animal reproductive toxicology studies, there were increased rates of fetal resorptions and malformations in the absence of maternal toxicity.
Oral administration of MMF to pregnant rats from Gestational Day 7 to Day 16 produced increased embryofetal lethality and fetal malformations including anophthalmia, agnathia, and hydrocephaly at doses equivalent to 0.015 and 0.01 times the recommended human doses for renal and cardiac transplant patients, respectively, when corrected for BSA.
Oral administration of MMF to pregnant rabbits from Gestational Day 7 to Day 19 produced increased embryofetal lethality and fetal malformations included ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia at dose equivalents as low as 0.05 and 0.03 times the recommended human doses for renal and cardiac transplant patients, respectively, when corrected for BSA.
NUSRING MOTHERS
8.3 Females and Males of Reproductive Potential Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning.
Pregnancy Planning For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity whenever possible.
Risks and benefits of mycophenolate mofetil should be discussed with the patient.
Pregnancy Testing To prevent unplanned exposure during pregnancy, all females of reproductive potential should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL immediately before starting mycophenolate mofetil.
Another pregnancy test with the same sensitivity should be done 8 to 10 days later.
Repeat pregnancy tests should be performed during routine follow-up visits.
Results of all pregnancy tests should be discussed with the patient.
In the event of a positive pregnancy test, consider alternative immunosuppressants with less potential for embryofetal toxicity whenever possible.
Contraception Female Patients Females of reproductive potential taking mycophenolate mofetil must receive contraceptive counseling and use acceptable contraception (see Table 9 for acceptable contraception methods).
Patients must use acceptable birth control during the entire mycophenolate mofetil therapy, and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses abstinence.
Patients should be aware that mycophenolate mofetil reduces blood levels of the hormones from the oral contraceptive pill and could theoretically reduce its effectiveness [see Drug Interactions ( 7.2 )].
Table 9.
Acceptable Contraception Methods for Females of Reproductive Potential Pick from the following birth control options: Option 1 Methods to Use Alone Intrauterine devices (IUDs) Tubal sterilization Patient’s partner vasectomy OR Option 2 Hormone Methods choose 1 Barrier Methods choose 1 Choose One Hormone Method AND One Barrier Method Estrogen and Progesterone Oral Contraceptive Pill Transdermal patch Vaginal ring Progesterone-only Injection Implant AND Diaphragm with spermicide Cervical cap with spermicide Contraceptive sponge Male condom Female condom OR Option 3 Barrier Methods choose 1 Barrier Methods choose 1 Choose One Barrier Method from each column (must choose two methods) Diaphragm with spermicide Cervical cap with spermicide Contraceptive sponge AND Male condom Female condom Male Patients Genotoxic effects have been observed in animal studies at exposures exceeding the human therapeutic exposures by approximately 1.25 times.
Thus, the risk of genotoxic effects on sperm cells cannot be excluded.
Based on this potential risk, sexually active male patients and/or their female partners are recommended to use effective contraception during treatment of the male patient and for at least 90 days after cessation of treatment.
Also, based on the potential risk of genotoxic effects, male patients should not donate sperm during treatment with mycophenolate mofetil and for at least 90 days after cessation of treatment [see Use in Special Populations ( 8.1 ), Nonclinical Toxicology ( 13.1 ), Patient Counseling Information ( 17.9 )].
BOXED WARNING
WARNING: EMBRYOFETAL TOXICITY, MALIGNANCIES and SERIOUS INFECTIONS Use during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations.
Avoid if safer treatment options are available.
Females of reproductive potential must be counseled regarding pregnancy prevention and planning [see Warnings and Precautions ( 5.1 ), Use in Special Populations ( 8.1 , 8.3 )].
Increased risk of development of lymphoma and other malignancies, particularly of the skin [see Warnings and Precautions ( 5.2 )].
Increased susceptibility to bacterial, viral, fungal and protozoal infections, including opportunistic infections and viral reactivation of hepatitis B and C, which may lead to hospitalizations and fatal outcomes [see Warnings and Precautions ( 5.3 )].
WARNING: EMBRYOFETAL TOXICITY, MALIGNANCIES and SERIOUS INFECTIONS See full prescribing information for complete boxed warning Use during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations.
Avoid if safer treatment options are available.
Females of reproductive potential must be counseled regarding pregnancy prevention and planning [see Warnings and Precautions ( 5.1 )].
Increased risk of development of lymphoma and other malignancies, particularly of the skin [see Warnings and Precautions ( 5.2 )].
Increased susceptibility to infections, including opportunistic infections and severe infections with fatal outcomes [see Warnings and Precautions ( 5.3 )].
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Blood Dyscrasias (Neutropenia, Red Blood Cell Aplasia): Monitor with blood tests; consider treatment interruption or dose reduction.
( 5.4 ) Gastrointestinal Complications: Monitor for complications such as bleeding, ulceration and perforations, particularly in patients with underlying gastrointestinal disorders.
( 5.5 ) Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency: Avoid use of mycophenolate mofetil.
( 5.6 ) Acute Inflammatory Syndrome Associated with Mycophenolate Products: Monitor for this paradoxical inflammatory reaction.
( 5.7 ) Immunizations: Avoid live attenuated vaccines.
( 5.8 ) Local Reactions with Rapid Intravenous Administration: Mycophenolate mofetil Intravenous must not be administered by rapid or bolus intravenous injection.
( 5.9 ) Phenylketonurics: Oral suspension contains aspartame.
( 5.10) Blood Donation: Avoid during therapy and for 6 weeks thereafter.
( 5.11 ) Semen Donation: Avoid during therapy and for 90 days thereafter.
( 5.12 ) Potential Impairment on Driving and Use of Machinery: Mycophenolate mofetil may affect ability to drive or operate machinery.
( 5.14 ) 5.1 Embryofetal Toxicity Use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney and nervous system.
Females of reproductive potential must be made aware of these risks and must be counseled regarding pregnancy prevention and planning.
Avoid use of MMF during pregnancy if safer treatment options are available [see Use in Specific Populations ( 8.1 , 8.3 )].
5.2 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Adverse Reactions ( 6.1 )].
The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.
For patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen with a high protection factor.
Post-transplant lymphoproliferative disorder (PTLD) developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of kidney, heart and liver transplant patients [see Adverse Reactions ( 6.1 )].
The majority of PTLD cases appear to be related to Epstein Barr Virus (EBV) infection.
The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children.
In pediatric patients, no other malignancies besides PTLD were observed in clinical trials [see Adverse Reactions ( 6.1 )].
5.3 Serious Infections Patients receiving immunosuppressants, including mycophenolate mofetil, are at increased risk of developing bacterial, fungal, protozoal and new or reactivated viral infections, including opportunistic infections.
The risk increases with the total immunosuppressive load.
These infections may lead to serious outcomes, including hospitalizations and death [see Adverse Reactions ( 6.1 , 6.2 )].
Serious viral infections reported include: • Polyomavirus-associated nephropathy (PVAN), especially due to BK virus infection • JC virus-associated progressive multifocal leukoencephalopathy (PML), and • Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease.
• Viral reactivation in patients infected with Hepatitis B and C.
• COVID-19 Consider dose reduction or discontinuation of mycophenolate mofetil in patients who develop new infections or reactivate viral infections, weighing the risk that reduced immunosuppression represents to the functioning allograft.
PVAN, especially due to BK virus infection, is associated with serious outcomes, including deteriorating renal function and renal graft loss [see Adverse Reactions ( 6.2 )].
Patient monitoring may help detect patients at risk for PVAN.
PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia [see Adverse Reactions ( 6.2 )].
In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms.
The risk of CMV viremia and CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor.
Therapeutic approaches to limiting CMV disease exist and should be routinely provided.
Patient monitoring may help detect patients at risk for CMV disease.
Viral reactivation has been reported in patients infected with HBV or HCV.
Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended.
5.4 Blood Dyscrasias: Neutropenia and Pure Red Cell Aplasia (PRCA) Severe neutropenia [absolute neutrophil count (ANC) less than 0.5 x 103/mcL] developed in transplant patients receiving mycophenolate mofetil 3 g daily [see Adverse Reactions ( 6.1 )].
Patients receiving mycophenolate mofetil should be monitored for neutropenia.
Neutropenia has been observed most frequently in the period from 31 to 180 days post-transplant in patients treated for prevention of kidney, heart and liver rejection.
The development of neutropenia may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or a combination of these causes.
If neutropenia develops (ANC less than 1.3 x 103/mcL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately [see Dosage and Administration ( 2.5 )].
Patients receiving mycophenolate mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Consider monitoring with complete blood counts weekly for the first month, twice monthly for the second and third months, and monthly for the remainder of the first year.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents.
In some cases, PRCA was found to be reversible with dose reduction or cessation of mycophenolate mofetil therapy.
In transplant patients, however, reduced immunosuppression may place the graft at risk.
5.5 Gastrointestinal Complications Gastrointestinal bleeding requiring hospitalization, ulceration and perforations were observed in clinical trials.
Physicians should be aware of these serious adverse effects particularly when administering mycophenolate mofetil to patients with a gastrointestinal disease.
5.6 Patients with Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency (HGPRT) Mycophenolate mofetil is an inosine monophosphate dehydrogenase (IMPDH) inhibitor; therefore it should be avoided in patients with hereditary deficiencies of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndromes because it may cause an exacerbation of disease symptoms characterized by the overproduction and accumulation of uric acid leading to symptoms associated with gout such as acute arthritis, tophi, nephrolithiasis or urolithiasis and renal disease including renal failure.
5.7 Acute Inflammatory Syndrome Associated with Mycophenolate Products Acute inflammatory syndrome (AIS) has been reported with the use of MMF and mycophenolate products, and some cases have resulted in hospitalization.
AIS is a paradoxical pro-inflammatory reaction characterized by fever, arthralgias, arthritis, muscle pain and elevated inflammatory markers including, C-reactive protein and erythrocyte sedimentation rate, without evidence of infection or underlying disease recurrence.
Symptoms occur within weeks to months of initiation of treatment or a dose increase.
After discontinuation, improvement of symptoms and inflammatory markers are usually observed within 24 to 48 hours.
Monitor patients for symptoms and laboratory parameters of AIS when starting treatment with mycophenolate products or when increasing the dosage.
Discontinue treatment and consider other treatment alternatives based on the risk and benefit for the patient.
5.8 Immunizations During treatment with mycophenolate mofetil, the use of live attenuated vaccines should be avoided (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines) and patients should be advised that vaccinations may be less effective.
Advise patients to discuss with the physician before seeking any immunizations.
5.9 Local Reactions with Rapid Intravenous Administration Mycophenolate mofetil intravenous solution must not be administered by rapid or bolus intravenous injection as rapid infusion increases the risk of local adverse reactions such as phlebitis and thrombosis [see Adverse Reactions ( 6.1 )].
5.10 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU).
Mycophenolate mofetil for oral suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine/mL suspension).
Before prescribing mycophenolate mofetil for oral suspension to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including mycophenolate mofetil.
5.11 Blood Donation Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of mycophenolate mofetil because their blood or blood products might be administered to a female of reproductive potential or a pregnant woman.
5.12 Semen Donation Based on animal data, men should not donate semen during therapy and for 90 days following discontinuation of mycophenolate mofetil [see Use In Specific Populations ( 8.3 )].
5.13 Effect of Concomitant Medications on Mycophenolic Acid Concentrations A variety of drugs have potential to alter systemic MPA exposure when co-administered with mycophenolate mofetil.
Therefore, determination of MPA concentrations in plasma before and after making any changes to immunosuppressive therapy, or when adding or discontinuing concomitant medications, may be appropriate to ensure MPA concentrations remain stable.
5.14 Potential Impairment of Ability to Drive or Operate Machinery Mycophenolate mofetil may impact the ability to drive and use machines.
Patients should avoid driving or using machines if they experience somnolence, confusion, dizziness, tremor, or hypotension during treatment with mycophenolate mofetil [see Adverse Reactions ( 6.1 )].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) 17.1 Embryofetal Toxicity Pregnancy loss and malformations.
Inform females of reproductive potential and pregnant women that use of mycophenolate mofetil during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations.
Advise that they must use an acceptable form of contraception [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.1 , 8.3 ) ].
Encourage pregnant women to enroll in the Pregnancy Exposure Registry.
This registry monitors pregnancy outcomes in women exposed to mycophenolate [see Use in Specific Populations ( 8.1 )].
Contraception Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential [see Use in Specific Populations ( 8.3 )].
Females of reproductive potential must use an acceptable form of birth control during the entire mycophenolate mofetil therapy and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses abstinence.
Mycophenolate mofetil may reduce effectiveness of oral contraceptives.
Use of additional barrier contraceptive methods is recommended [see Use in Specific Populations ( 8.3 )].
For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryofetal toxicity.
Risks and benefits of mycophenolate mofetil should be discussed with the patient.
Advise sexually active male patients and/or their partners to use effective contraception during the treatment of the male patient and for at least 90 days after cessation of treatment.
This recommendation is based on findings of animal studies [see Use in Specific Populations ( 8.3 ), Nonclinical Toxicology ( 13.1 ) ].
17.2 Development of Lymphoma and Other Malignancies Inform patients that they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression [see Warnings and Precautions ( 5.2 )].
Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use of broad-spectrum sunscreen with high protection factor.
17.3 Increased Risk of Serious Infections Inform patients that they are at increased risk of developing a variety of infections due to immunosuppression.
Instruct them to contact their physician if they develop any of the signs and symptoms of infection explained in the Medication Guide [see Warnings and Precautions ( 5.3 )] .
17.4 Blood Dyscrasias Inform patients that they are at increased risk for developing blood adverse effects such as anemia or low white blood cells.
Advise patients to immediately contact their healthcare provider if they experience any evidence of infection, unexpected bruising, or bleeding, or any other manifestation of bone marrow suppression [see Warnings and Precautions ( 5.4 )].
17.5 Gastrointestinal Tract Complications Inform patients that mycophenolate mofetil can cause gastrointestinal tract complications including bleeding, intestinal perforations, and gastric or duodenal ulcers.
Advise the patient to contact their healthcare provider if they have symptoms of gastrointestinal bleeding, or sudden onset or persistent abdominal pain [see Warnings and Precautions ( 5.5 )].
17.6 Acute Inflammatory Syndrome Inform patients that acute inflammatory reactions have been reported in some patients who received mycophenolate mofetil.
Some reactions were severe, requiring hospitalization.
Advise patients to contact their physician if they develop fever, joint stiffness, joint pain or muscle pains [see Warnings and Precautions ( 5.7 )] .
17.7 Immunizations Inform patients that mycophenolate mofetil can interfere with the usual response to immunizations.
Before seeking vaccines on their own, advise patients to discuss first with their physician.
[see Warnings and Precautions ( 5.8 )].
17.8 Administration Instructions Advise patients not to crush mycophenolate mofetil tablets and not to open mycophenolate mofetil capsules.
Advise patients to avoid inhalation or contact of the skin or mucous membranes with the powder contained in mycophenolate mofetil capsules and with the oral suspension.
If such contact occurs, they must wash the area of contact thoroughly with soap and water.
In case of ocular contact, rinse eyes with plain water.
Advise patients to take a missed dose as soon as they remember, except if it is closer than 2 hours to the next scheduled dose; in this case they should continue to take mycophenolate mofetil at the usual times.
17.9 Blood Donation Advise patients not to donate blood during therapy and for at least 6 weeks following discontinuation of mycophenolate mofetil [see Warnings and Precautions ( 5.11 )].
17.10 Semen Donation Advise males of childbearing potential not to donate semen during therapy and for 90 days following discontinuation of mycophenolate mofetil [see Warnings and Precautions ( 5.12 )].
17.11 Potential to Impair Driving and Use of Machinery Advise patients that mycophenolate mofetil can affect the ability to drive or operate machines.
Patients should avoid driving or operating machines if they experience somnolence, confusion, dizziness, tremor or hypotension during treatment with mycophenolate mofetil [see Warnings and Precautions ( 5.14 )].
Manufactured by : Alkem Laboratories Ltd., INDIA.
Distributed by: Ascend Laboratories, LLC Parsippany, NJ 07054 Revised: October, 2023
DOSAGE AND ADMINISTRATION
2 ADULTS DOSAGE Kidney Transplant 1g twice daily, orally or intravenously (IV) over no less than 2h ( 2.2 ) Heart Transplant 1.5 g twice daily orally or IV, over no less than 2 h ( 2.3 ) Liver Transplant 1.5 g twice daily orally or 1 g twice daily IV over no less than 2 h ( 2.4 ) PEDIATRICS Kidney Transplant 600mg/m 2 orally twice daily, up to maximum of 2 g daily ( 2.2 ) Heart Transplant 600 mg/m 2 orally twice daily (starting dose) up to a maximum of 900 mg/m 2 twice daily (3 g or 15 mL of oral suspension) (2.3) Liver Transplant 600 mg/m 2 orally twice daily (starting dose) up to a maximum of 900 mg/m 2 twice daily (3 g or 15 mL of oral suspension) (2.4) Mycophenolate mofetil intravenous is an alternative when patients cannot tolerate oral medication.
Administer within 24 hours following transplantation, until patients can tolerate oral medication, up to 14 days.
( 2.1 ) Reduce or interrupt dosing in the event of neutropenia.
( 2.5 ) See full prescribing information (FPI) for: adjustments for renal impairment and neutropenia ( 2.5 ), preparation of oral suspension and IV solution.
( 2.6 ) 2.1 Important Administration Instructions Mycophenolate mofetil should not be used without the supervision of a physician with experience in immunosuppressive therapy.
Mycophenolate Mofetil Capsules, Tablets and Oral Suspension Mycophenolate mofetil oral dosage forms (capsules, tablets or oral suspension) should not be used interchangeably with mycophenolic acid delayed-release tablets without supervision of a physician with experience in immunosuppressive therapy because the rates of absorption following the administration of mycophenolate mofetil oral dosage forms and mycophenolic acid delayed-release tablets are not equivalent.
Mycophenolate mofetil tablets should not be crushed and mycophenolate mofetil capsules should not be opened or crushed.
Patients should avoid inhalation or contact of the skin or mucous membranes with the powder contained in mycophenolate mofetil capsules and oral suspension.
If such contact occurs, they must wash the area of contact thoroughly with soap and water.
In case of ocular contact, rinse eyes with plain water.
The initial oral dose of mycophenolate mofetil should be given as soon as possible following kidney, heart or liver transplant.
It is recommended that mycophenolate mofetil be administered on an empty stomach.
In stable transplant patients, however, mycophenolate mofetil may be administered with food if necessary [see Clinical Pharmacology ( 12.3 )].
Once reconstituted, mycophenolate mofetil for oral suspension must not be mixed with any liquids prior to dose administration.
If needed, mycophenolate mofetil for oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).
Patients should be instructed to take a missed dose as soon as they remember, except if it is closer than 2 hours to the next scheduled dose; in this case, they should continue to take mycophenolate mofetil at the usual times.
2.2 Dosage Recommendations for Kidney Transplant Patients Adults The recommended dosage for adult kidney transplant patients is 1 g orally or intravenously infused over no less than 2 hours, twice daily (total daily dose of 2 g).
Pediatrics (3 months and older) Pediatric dosing is based on body surface area (BSA).
The recommended dosage of mycophenolate mofetil for oral suspension for pediatric kidney transplant patients 3 months and older is 600 mg/m 2 , administered twice daily (maximum total daily dose of 2 g or 10 mL of the oral suspension).
Pediatric patients with BSA ≥ 1.25 m 2 may be dosed with capsules or tablets as follows: Table 1.
Pediatric Kidney Transplant: Dosage Using Capsules or Tablets Body Surface Area Dosage 1.25 m 2 to less than 1.5 m 2 Mycophenolate mofetil capsule 750 mg twice daily (1.5 g total daily dose) ≥ 1.5 m 2 Mycophenolate mofetil capsules or tablets 1 g twice daily (2 g total daily dose) 2.3 Dosage Recommendations for Heart Transplant Patients Adults The recommended dosage of mycophenolate mofetil for adult heart transplant patients is 1.5 g orally or intravenously infused over no less than 2 hours administered twice daily (total daily dose of 3 g).
Pediatrics (3 months and older) The recommended starting dosage of mycophenolate mofetil oral suspension for pediatric heart transplant patients 3 months and older is 600 mg/m 2 , administered twice daily.
If well tolerated, the dose can be increased to a maintenance dosage of 900 mg/m 2 twice daily (maximum total daily dose of 3 g or 15 mL of the oral suspension).
The dose may be individualized based on clinical assessment .
Pediatric patients with BSA ≥1.25 m 2 may be started on therapy with capsules or tablets as follows: Table 2 Pediatric Heart Transplant: Pediatric Starting Dosage Using Capsules or Tablets Body Surface Area Starting Dosage* 1.25 m 2 to less than 1.5 m 2 Mycophenolate mofetil capsule 750 mg twice daily (1.5 g total daily dose) ≥ 1.5 m 2 Mycophenolate mofetil capsules or tablets 1 g twice daily (2 g total daily dose) * Maximum maintenance dose: 3 g total daily.
2.4 Dosage Recommendations for Liver Transplant Patients Adults The recommended dosage of mycophenolate mofetil for adult liver transplant patients is 1.5 g administered orally twice daily (total daily dose of 3 g) or 1 g infused intravenously over no less than 2 hours, twice daily (total daily dose of 2 g).
Pediatrics (3 months and older) The recommended starting dosage of mycophenolate mofetil oral suspension for pediatric liver transplant patients 3 months of age and older is 600 mg/m 2 , administered twice daily.
If well tolerated, the dose can be increased to a maintenance dosage of 900 mg/m 2 twice daily (maximum total daily dose of 3 g or 15 mL of the oral suspension).
The dose may be individualized based on clinical assessment .
Pediatric patients with BSA ≥1.25 m 2 may be started on therapy with capsules or tablets as follows: Table 3 Pediatric Liver Transplant: Pediatric Starting Dosage Using Capsules or Tablets Body Surface Area Starting Dosage * 1.25 m 2 to less than 1.5 m 2 Mycophenolate mofetil capsule 750 mg twice daily (1.5 g total daily dose) ≥ 1.5 m 2 Mycophenolate mofetil capsules or tablets 1 g twice daily (2 g total daily dose) * Maximum maintenance dose: 3 g total daily.
2.5 Dosage Modifications: Patients with Renal Impairment, Neutropenia Renal Impairment No dosage modifications are needed in kidney transplant patients with delayed graft function postoperatively [see Clinical Pharmacology ( 12.3 )].
In kidney transplant patients with severe chronic impairment of the graft (GFR less than 25 mL/min/1.73 m 2 ), do not administer doses of mycophenolate mofetil greater than 1 g twice a day.
These patients should be carefully monitored [see Clinical Pharmacology ( 12.3 )].
Neutropenia If neutropenia develops (ANC less than 1.3 x 103/mcL), dosing with mycophenolate mofetil should be interrupted or reduced, appropriate diagnostic tests performed, and the patient managed appropriately [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 )].
2.6 Preparation Instructions of Oral Suspension and Intravenous for Pharmacists General Preparation Instructions Before Handling the Formulations Mycophenolate mofetil (MMF) has demonstrated teratogenic effects in humans.
Follow applicable special handling and disposal procedures 1 [see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.2 ), Use in Specific Populations ( 8.1 , 8.3 ), How Supplied/Storage and Handling ( 16.1 )].
Care should be taken to avoid inhalation or direct contact with skin or mucous membranes of the dry powder or the constituted suspension because MMF has demonstrated teratogenic effects in humans.
Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table surface after reconstitution.
If such contact occurs, wash hands thoroughly with soap and water; rinse eyes with water.
Alert patients that they and others should also avoid inhalation or contact of the skin or mucous membranes with the oral suspension.
Advise them to wash the area thoroughly with soap and water if such contact occurs; if ocular contact occurs, rinse eyes with plain water.
Mycophenolate Mofetil For Oral Suspension Mycophenolate mofetil for oral suspension must be reconstituted by the pharmacist prior to dispensing to the patient.
Mycophenolate mofetil for oral suspension should not be mixed with any other medication.
After reconstitution, the oral suspension contains 200 mg/mL MMF.
Before proceeding with the reconstitution steps read the general preparation instructions above [see General Preparation Instructions Before Handling the Formulations].
The following are the steps for reconstitution: 1.
Tap the closed bottle several times to loosen the powder.
2.
Measure 91 mL of water in a graduated cylinder.
3.
Add approximately half the total amount of water for reconstitution to the bottle and shake the closed bottle well for about 1 minute.
4.
Add the remainder of water and shake the closed bottle well for about 1 minute.
5.
Remove the child-resistant cap and push bottle adapter into neck of bottle.
6.
Close bottle with child-resistant cap tightly.
This will assure the proper seating of the bottle adapter in the bottle and child-resistant status of the cap.
7.
Write the date of expiration of the constituted suspension on the bottle label.
(The shelf-life of the constituted suspension is 60 days.) 8.
Dispense with the “Instruction for Use” and oral dispensers.
Alert patients to read the important handling information described in the instructions for use.
Store reconstituted suspension at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Storage in a refrigerator at 2°C to 8°C (36°F to 46°F) is acceptable.
Do not freeze.
Discard any unused portion 60 days after constitution.