Myfortic

Before taking mycophenolate,

• tell your doctor and pharmacist if you are allergic to mycophenolate, mycophenolic acid, any other medications, or any of the ingredients in the mycophenolate or mycophenolic acid product you are taking. If you are taking mycophenolate liquid, tell your doctor and pharmacist if you are allergic to aspartame or sorbitol. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: activated charcoal; acyclovir (Zovirax); certain antibiotics such as amoxicillin and clavulanic acid (Augmentin), ciprofloxacin (Cipro),, and sulfamethoxazole/trimethoprim (Bactrim); azathioprine (Azasan, Imuran); cholestyramine (Prevalite); colestipol (Colestid); ganciclovir (Cytovene, Valcyte); other medications that suppress the immune system; probenecid (Probalan); rifampin (Rifadin, Rimactane); salicylate pain relievers such as aspirin, choline magnesium trisalicylate (Trisalate), choline salicylate (Arthropan), diflunisal, magnesium salicylate (Doan's, others) and salsalate (Argesic, Disalcid, Salgesic); sevelamer (Renagel, Renvela); valacyclovir (Valtrex); and valganciclovir (Valcyte). Also tell your doctor if you are taking a combination of both norfloxacin (Noroxin) and metronidazole (Flagyl). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• if you are taking antacids, take them 2 hours before or 4 hours after you take mycophenolate.
• tell your doctor if you have or have ever had Lesch-Nyhan syndrome or Kelley-Seegmiller syndrome (inherited diseases that cause high levels of a certain substance in the blood, joint pain, and problems with motion and behavior); anemia (a lower than normal number of red blood cells); neutropenia (less than normal number of white blood cells); ulcers or any disease that affects your stomach, intestines, or digestive system; any type of cancer; or kidney or liver disease.
• tell your doctor if you are breast-feeding.
• do not have any vaccinations without talking to your doctor. Ask your doctor if you should get a flu vaccine before or during your treatment because taking mycophenolate may increase your risk of infection.
• if you have phenylketonuria (PKU, an inherited condition in which a special diet must be followed to prevent mental retardation), you should know that mycophenolate suspension contains aspartame, a source of phenylalanine.

The following adverse reactions are discussed in greater detail in other sections of the label.

• Embryofetal Toxicity [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
• Lymphomas and Other Malignancies [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
• Serious Infections [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
• New or Reactivated Viral Infections [see WARNINGS AND PRECAUTIONS]
• Blood Dyscrasias Including Pure Red Cell Aplasia [see WARNINGS AND PRECAUTIONS]
• Serious GI Tract Complications [see WARNINGS AND PRECAUTIONS]
• Rare Hereditary Deficiencies [see WARNINGS AND PRECAUTIONS]

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below derive from two randomized, comparative, active-controlled, double-blind, double-dummy trials in prevention of acute rejection in de novo and converted stable kidney transplant patients.

In the de novo trial, patients were administered either Myfortic 1.44 grams per day (N=213) or MMF 2 grams per day (N=210) within 48 hours post-transplant for 12 months in combination with cyclosporine, USP MODIFIED and corticosteroids. Forty-one percent of patients also received antibody therapy as induction treatment. In the conversion trial, renal transplant patients who were at least 6 months post-transplant and receiving 2 grams per day MMF in combination with cyclosporine USP MODIFIED, with or without corticosteroids for at least two weeks prior to entry in the trial were randomized to Myfortic 1.44 grams per day (N=159) or MMF 2 grams per day (N=163) for 12 months.

The average age of patients in both studies was 47 years and 48 years (de novo study and conversion study, respectively), ranging from 22 to 75 years. Approximately 66% of patients were male; 82% were white, 12% were black, and 6% other races. About 40% of patients were from the United States and 60% from other countries.

In the de novo trial, the overall incidence of discontinuation due to adverse reactions was 18% (39/213) and 17% (35/210) in the Myfortic and MMF arms, respectively. The most common adverse reactions leading to discontinuation in the Myfortic arm were graft loss (2%), diarrhea (2%), vomiting (1%), renal impairment (1%), CMV infection (1%), and leukopenia (1%). The overall incidence of patients reporting dose reduction at least once during the 0 to 12 month study period was 59% and 60% in the Myfortic and MMF arms, respectively. The most frequent reasons for dose reduction in the Myfortic arm were adverse reactions (44%), dose reductions according to protocol guidelines (17%), dosing errors (11%) and missing data (2%).

The most common adverse reactions ( ≥ 20%) associated with the administration of Myfortic were anemia, leukopenia, constipation, nausea, diarrhea, vomiting, dyspepsia, urinary tract infection, CMV infection, insomnia, and postoperative pain.

The adverse reactions reported in ≥ 10% of patients in the de novo trial are presented in Table 2 below.

Table 2: Adverse Reactions (%) Reported in ≥ 10% of de novo Kidney Transplant Patients in Either Treatment Group

Table 3 summarizes the incidence of opportunistic infections in de novo transplant patients.

Table 3: Viral and Fungal Infections (%) Reported Over 0 to 12 Months

Lymphoma developed in 2 de novo patients (1%), (1 diagnosed 9 days after treatment initiation) and in 2 conversion patients (1%) receiving Myfortic with other immunosuppressive agents in the 12-month controlled clinical trials.

Nonmelanoma skin carcinoma occurred in 1% de novo and 12% conversion patients. Other types of malignancy occurred in 1% de novo and 1% conversion patients [see WARNINGS AND PRECAUTIONS].

The adverse reactions reported in < 10% of de novo or conversion patients treated with Myfortic in combination with cyclosporine and corticosteroids are listed in Table 4.

Table 4: Adverse Reactions Reported in < 10% of Patients Treated with Myfortic in Combination with Cyclosporine* and Corticosteroids

The following additional adverse reactions have been associated with the exposure to mycophenolic acid (MPA) when administered as a sodium salt or as mofetil ester:

Gastrointestinal: Intestinal perforation, gastrointestinal hemorrhage, gastric ulcers, duodenal ulcers [see WARNINGS AND PRECAUTIONS], colitis (including CMV colitis), pancreatitis, esophagitis, and ileus.

Infections: Serious life-threatening infections such as meningitis and infectious endocarditis, tuberculosis, and atypical mycobacterial infection [see WARNINGS AND PRECAUTIONS].

Respiratory: Interstitial lung disorders, including fatal pulmonary fibrosis.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Myfortic or other MPA derivatives. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Congenital malformations including ear, facial, cardiac and nervous system malformations and an increased incidence of first trimester pregnancy loss have been reported following exposure to MMF during pregnancy [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
• Infections [see WARNINGS AND PRECAUTIONS]
  • Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal.
  • Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection, associated with serious outcomes, including deteriorating renal function and renal graft loss.
  • Viral reactivation in patients infected with HBV or HCV.
• Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressive agents [see WARNINGS AND PRECAUTIONS].

The following additional adverse reactions have been identified during postapproval use of Myfortic: agranulocytosis, asthenia, osteomyelitis, lymphadenopathy, lymphopenia, wheezing, dry mouth, gastritis, peritonitis, anorexia, alopecia, pulmonary edema, Kaposi's sarcoma.

Myfortic can cause serious side effects:

• Possible loss of a pregnancy and higher risk of birth defects. Women who take Myfortic during pregnancy have a higher risk of losing a pregnancy (miscarriage) during the first 3 months (first trimester), and a higher risk that their baby will be born with birth defects
  If you are a female and are able to become pregnant
  • your healthcare provider must talk with you about effective birth control methods (contraceptive counseling)
  • you should have a negative pregnancy test within 1 week before you start to take Myfortic
  • you must use 2 different types of effective birth control at the same time, for 4 weeks before you start taking Myfortic, during your entire Myfortic therapy and for 6 weeks after stopping Myfortic, unless you choose to avoid sexual intercourse completely (abstinence). Myfortic decreases blood levels of the hormones in birth control pills that you take by mouth. Birth control pills may not work as well while you take Myfortic, and you could become pregnant
    If you plan to become pregnant, talk with your healthcare provider. Your healthcare provider will decide if other medicines to prevent rejection may be right for you. In certain situations, you and your healthcare provider may decide that taking Myfortic is more important to your health than the possible risks to your unborn baby.

• If you get pregnant while taking Myfortic do not stop taking Myfortic. Call your healthcare provider right away. You and your healthcare provider should report any cases of pregnancies to:
  • FDA MedWatch at 1-800-FDA-1088
  • Genentech at 1-888-835-2555

  Talk to your healthcare provider about joining the National Transplantation Pregnancy Registry at 1-877-955-6877.

• Increased risk of getting serious infections. Myfortic weakens the body's immune system and affects your ability to fight infections. Serious infections can happen with Myfortic and can lead to death. Types of infections can include:
  • Viral infections. Certain viruses can live in your body and cause active infections when your immune system is weak. Viral infections that can happen with Myfortic include:
    • Shingles, other herpes infections, and cytomegalovirus (CMV). CMV can cause serious tissue and blood infections.
    • BK virus. BK virus can affect how your kidney works and cause your transplanted kidney to fail.
  • A brain infection called Progressive Multifocal Leukoencephalopathy (PML). In some patients, Myfortic may cause an infection of the brain that may cause death. You are at risk for this brain infection because you have a weakened immune system. You should tell your healthcare provider right away if you have any of the following symptoms:
    • Weakness on one side of the body
    • You do not care about things that you usually care about (apathy)
    • You are confused or have problems thinking
    • You can not control your muscles
  • Fungal infections. Yeasts and other types of fungal infections can happen with Myfortic and can cause serious tissue and blood infections 

Call your healthcare provider right away if you have any of the following signs and symptoms of infection:

• Temperature of 100.5°F or greater
• Cold symptoms, such as a runny nose or sore throat
• Flu symptoms, such as an upset stomach, stomach pain, vomiting or diarrhea
• Earache or headache
• Pain during urination
• White patches in the mouth or throat
• Unexpected bruising or bleeding
• Cuts, scrapes or incisions that are red, warm and oozing pus

• Increased risk of getting certain cancers. People who take Myfortic have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Tell your healthcare provider if you have:
  • unexplained fever, prolonged tiredness, weight loss or lymph node swelling
  • a brown or black skin lesion with uneven borders, or one part of the lesion does not look like the other
  • a change in the size and color of a mole
  • a new skin lesion or bump
  • any other changes to your health

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

This medicine can cause a miscarriage or birth defects, especially if used during the first 3 months of pregnancy. If you are a woman of child-bearing potential, you must use specific types of birth control to prevent pregnancy before, during, and shortly after treatment with mycophenolic acid.

Mycophenolic acid is sometimes given to pregnant women. Although this medicine can affect pregnancy or fertility, it is sometimes given to women who are unable to use other needed transplant medications.

Using mycophenolic acid may increase your risk of developing serious infections or other types of cancer, such as lymphoma or skin cancer. You must remain under the care of a doctor while you are using mycophenolic acid.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of mycophenolate in children 5 years of age and older who had a kidney transplant at least 6 months before. However, safety and efficacy have not been established in children younger than 5 years of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of mycophenolate in the elderly. However, elderly patients are more likely to have age-related liver, kidney, or heart problems, which may require caution and an adjustment in the dose for patients receiving mycophenolate.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Activated Charcoal
• Adenovirus Vaccine Type 4, Live
• Adenovirus Vaccine Type 7, Live
• Aluminum Carbonate, Basic
• Aluminum Hydroxide
• Aluminum Phosphate
• Azathioprine
• Bacillus of Calmette and Guerin Vaccine, Live
• Cholestyramine
• Colesevelam
• Colestipol
• Cyclosporine
• Dexlansoprazole
• Dihydroxyaluminum Aminoacetate
• Dihydroxyaluminum Sodium Carbonate
• Influenza Virus Vaccine, Live
• Magaldrate
• Magnesium Carbonate
• Magnesium Hydroxide
• Magnesium Oxide
• Measles Virus Vaccine, Live
• Mercaptopurine
• Metronidazole
• Mumps Virus Vaccine, Live
• Norfloxacin
• Omeprazole
• Poliovirus Vaccine, Live
• Rifampin
• Rotavirus Vaccine, Live
• Rubella Virus Vaccine, Live
• Smallpox Vaccine
• Typhoid Vaccine
• Varicella Virus Vaccine
• Yellow Fever Vaccine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acyclovir
• Desogestrel
• Dienogest
• Drospirenone
• Estradiol Cypionate
• Estradiol Valerate
• Ethinyl Estradiol
• Ethynodiol Diacetate
• Etonogestrel
• Iron
• Levonorgestrel
• Medroxyprogesterone Acetate
• Mestranol
• Norelgestromin
• Norethindrone
• Norgestimate
• Norgestrel
• Sevelamer
• Valacyclovir

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bone marrow problems (eg, neutropenia) or
• Hepatitis B or C infection, history of or
• Stomach ulcers or bleeding—Use with caution. May make these conditions worse.

• Infection—May decrease your ability to fight an infection.

• Kelley-Seegmiller syndrome (rare genetic disease) or
• Lesch-Nyhan syndrome (rare genetic disease)—Should not be used in patients with these conditions.

• Kidney disease, severe—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• It is used to keep the body from harming the organ after an organ transplant.
• It may be given to you for other reasons. Talk with the doctor.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time Myfortic is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Myfortic (mycophenolic acid delayed-release tablets) or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Myfortic. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

     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.

     Pharmacokinetics

Myfortic exhibits linear and dose-proportional pharmacokinetics over the dose-range (360 to 2160 mg) evaluated. The absolute bioavailability of Myfortic 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 Myfortic tablet does 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 Myfortic 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 Myfortic delayed-release tablet was 93% and 72%, respectively. Myfortic pharmacokinetics is dose proportional over the dose range of 360 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 mycophenolic acid glucuronide (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, mycophenolic acid glucuronide (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 Myfortic 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 Myfortic 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 Myfortic 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 Myfortic 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 (Cmax), a 3.5-hour delay in the Tlag (range, -6 to 18 hours), and 5.0-hour delay in the Tmax (range, -9 to 20 hours) of MPA. To avoid the variability in MPA absorption between doses, Myfortic 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 Myfortic in renal transplant patients on cyclosporine, USP MODIFIED based immunosuppression are shown in Table 6. Single-dose Myfortic pharmacokinetics predicts multiple-dose pharmacokinetics. However, in the early post-transplant period, mean MPA AUC and Cmax were approximately one-half of those measured 6 months post-transplant.

After near equimolar dosing of Myfortic 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.

Specific Populations

Renal Insufficiency: No specific pharmacokinetic studies in individuals with renal impairment were conducted with Myfortic. 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 Myfortic 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.

Hepatic Insufficiency: No specific pharmacokinetic studies in individuals with hepatic impairment were conducted with Myfortic. In a single dose (MMF 1000 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.

Pediatrics: Limited data are available on the use of Myfortic at a dose of 450 mg/m2 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 Cmax 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)].

Gender: There are no significant gender differences in Myfortic pharmacokinetics.

Elderly: Pharmacokinetics in the elderly have not been formally studied.

Ethnicity: Following a single dose administration of 720 mg of Myfortic to 18 Japanese and 18 Caucasian healthy subjects, the exposure (AUCinf) for MPA and MPAG were 15% and 22% lower in Japanese subjects compared to Caucasians. The peak concentrations (Cmax) for MPAG were similar between the two populations, however, Japanese subjects had 9.6% higher Cmax for MPA. These results do not suggest any clinically relevant differences.

Drug Interactions:

Antacids with Magnesium and Aluminum Hydroxides:

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

Pantoprazole:

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

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

Cholestyramine:

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

Sevelamer:

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

Cyclosporine:

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

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

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

Norfloxacin and Metronidazole:

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

Rifampin:

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

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

Oral Contraceptives:

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

Acyclovir:

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

Ganciclovir:

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

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.