Mycophenolate Mofetil 500 mg Tablet, Film Coated, 120-count — NDC 71610-033-70 (Billing 71610-0033-70)

WARNINGS (see boxed WARNING ) Embryofetal Toxicity Mycophenolate mofetil can cause fetal harm when administered to a pregnant female. Use of mycophenolate mofetil 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 (see PRECAUTIONS: Pregnancy ). Pregnancy Exposure Prevention and Planning 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.

For recommended pregnancy testing and contraception methods (see PRECAUTIONS: Pregnancy Exposure Prevention and Planning ). Lymphoma and Malignancy Patients receiving immunosuppressive regimens involving combinations of drugs, including mycophenolate mofetil, as part of an immunosuppressive regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see ADVERSE REACTIONS ). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Lymphoproliferative disease or lymphoma 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 renal, cardiac, and hepatic transplant patients (see ADVERSE REACTIONS ). In pediatric patients, no other malignancies besides lymphoproliferative disorder (2/148 patients) have been observed (see ADVERSE REACTIONS ).

Combination with Other Immunosuppressive Agents Mycophenolate mofetil has been administered in combination with the following agents in clinical trials: antithymocyte globulin (ATGAM ®† ), OKT3 (Orthoclone OKT ®† 3), cyclosporine (Sandimmune ®† , Neoral ®† ) and corticosteroids. The efficacy and safety of the use of mycophenolate mofetil in combination with other immunosuppressive agents have not been determined. 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.

These infections may lead to serious, including fatal outcomes. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution (see ADVERSE REACTIONS ). New or Reactivated Viral Infections Polyomavirus associated nephropathy (PVAN), JC virus associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including mycophenolate mofetil.

Reduction in immunosuppression should be considered for patients who develop evidence of new or reactivated viral infections. Physicians should also consider 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: Postmarketing Experience ).

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. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function (see ADVERSE REACTIONS: Postmarketing Experience ).

In immunosuppressed patients, physicians should consider PML in the differe… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS The principal adverse reactions associated with the administration of mycophenolate mofetil include diarrhea, leukopenia, sepsis, vomiting, and there is evidence of a higher frequency of certain types of infections e.g., opportunistic infection (see WARNINGS: Serious Infections and WARNINGS: New or Reactivated Viral Infections ). Mycophenolate Mofetil Oral The incidence of adverse events for mycophenolate mofetil was determined in randomized, comparative, double-blind trials in prevention of rejection in renal (two active, one placebo-controlled trials), cardiac (one active-controlled trial), and hepatic (one active-controlled trial) transplant patients.

Geriatrics Elderly patients (≥ 65 years), particularly those who are receiving mycophenolate mofetil as part of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus [CMV] tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema, compared to younger individuals (see PRECAUTIONS ). Safety data are summarized below for all active-controlled trials in renal (two trials), cardiac (one trial), and hepatic (one trial) transplant patients.

Approximately 53% of the renal patients, 65% of the cardiac patients, and 48% of the hepatic patients have been treated for more than one year. Adverse events reported in ≥ 20% of patients in the mycophenolate mofetil treatment groups are presented below. Table 9: Adverse Events in Controlled Studies in Prevention of Renal, Cardiac or Hepatic Allograft Rejection (Reported in ≥ 20% of Patients in the Mycophenolate Mofetil Group) Renal Studies Cardiac Study Hepatic Study Mycophenolate Mofetil 2 g/day Mycophenolate Mofetil 3 g/day Azathioprine 1 to 2 mg/kg/day or 100 to 150 mg/day Mycophenolate Mofetil 3 g/day Azathioprine 1.5 to 3 mg/kg/day Mycophenolate Mofetil 3 g/day Azathioprine 1 to 2 mg/kg/day (n = 336) (n = 330) (n = 326) (n = 289) (n = 289) (n = 277) (n = 287) % % % % % % % Body as a Whole Pain 33 31.2 32.2 75.8 74.7 74

77.7Abdominal pain 24.7 27.6 23 33.9 33.2 62.5

51.2Fever 21.4 23.3 23.3 47.4 46.4 52.3

56.1Headache 21.1 16.1 21.2 54.3 51.9 53.8

49.1Infection 18.2 20.9 19.9 25.6 19.4 27.1

25.1Sepsis - - - - - 27.4

26.5Asthenia - - - 43.3 36.3 35.4

33.8Chest pain - - - 26.3 26 - - Back pain - - - 34.6 28.4 46.6

47.4Ascites - - - - - 24.2

22.6Hematologic and Lymphatic Anemia 25.6 25.8 23.6 42.9 43.9 43 53 Leukopenia 23.2 34.5 24.8 30.4 39.1 45.8 39 Thrombocytopenia - - - 23.5 27 38.3

42.2Hypochromic anemia - - - 24.6 23.5 - - Leukocytosis - - - 40.5 35.6 22.4

21.3Urogenital Urinary tract infection 37.2 37 33.7 - - - - Kidney function abnormal - - - 21.8 26.3 25.6

28.9Cardiovascular Hypertension 32.4 28.2 32.2 77.5 72.3 62.1

59.6Hypotension - - - 32.5 36 - - Cardiovascular disorder - - - 25.6 24.2 - - Tachycardia - - - 20.1 18 22

15.7Metabolic and Nutritional Peripheral edema 28.6 27 28.2 64 53.3 48.4

47.7Hypercholesteremia - - - 41.2 38.4 - - Edema - - - 26.6 25.6 28.2

28.2Hypokalemia - - - 31.8 25.6 37.2

41.1 Hyperkalemia - - - - - 22

23.7Hyperglycemia - - - 46.7 52.6 43.7

48.8Creatinine increased - - - 39.4 36 - - BUN increased - - - 34.6 32.5 - - Lactic dehydrogenase increased - - - 23.2 17 - - Hypomagnesemia - - - - - 39

37.6Hypocalcemia - - - - - 30 30 Digestive Diarrhea 31 36.1 20.9 45.3 34.3 51.3

49.8Constipation 22.9 18.5 22.4 41.2 37.7 37.9

38.3Nausea 19.9 23.6 24.5 54 54.3 54.5

51.2Dyspepsia - - - - - 22.4

20.9Vomiting - - - 33.9 28.4 32.9

33.4Anorexia - - - - - 25.3

17.1Liver function tests abnormal - - - - - 24.9

19.2Respiratory Infection 22 23.9 19.6 37 35.3 - - Dyspnea - - - 36.7 36.3 31

30.3Cough increased - - - 31.1 25.6 - - Lung disorder - - - 30.1 29.1 22

18.8Sinusitis - - - 26 19 - - Pleural effusion - - - - - 34.3

35.9Skin and Appendages Rash - - - 22.1 18 - - Nervous System Tremor - - - 24.2 23.9 33.9

35.5Insomnia - - - 40.8 37.7 52.3 47 Dizziness - - - 28.7 27.7 - - Anxiety - - - 28.4… [Excerpted — this section continues on DailyMed.]

Drug Interactions Drug interaction studies with mycophenolate mofetil have been conducted with acyclovir, antacids, cholestyramine, cyclosporine, ganciclovir, oral contraceptives, sevelamer, trimethoprim/sulfamethoxazole, norfloxacin, and metronidazole. Drug interaction studies have not been conducted with other drugs that may be commonly administered to renal, cardiac or hepatic transplant patients. Mycophenolate mofetil has not been administered concomitantly with azathioprine.

Acyclovir Coadministration of mycophenolate mofetil (1 g) and acyclovir (800 mg) to 12 healthy volunteers resulted in no significant change in MPA AUC and C max . However, MPAG and acyclovir plasma AUCs were increased 10.6% and 21.9%, respectively. Because MPAG plasma concentrations are increased in the presence of renal 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.

Antacids with Magnesium and Aluminum Hydroxides Absorption of a single dose of mycophenolate mofetil (2 g) was decreased when administered to ten rheumatoid arthritis patients also taking Maalox ®† TC (10 mL qid). The C max and AUC (0-24h) for MPA were 33% and 17% lower, respectively, than when mycophenolate mofetil was administered alone under fasting conditions. Mycophenolate mofetil may be administered to patients who are also taking antacids containing magnesium and aluminum hydroxides; however, it is recommended that mycophenolate mofetil and the antacid not be administered simultaneously.

Proton Pump Inhibitors (PPIs) Coadministration of PPIs (e.g., lansoprazole, pantoprazole) in single doses to healthy volunteers and multiple doses to transplant patients receiving mycophenolate mofetil has been reported to reduce the exposure to mycophenolic acid (MPA). An approximate reduction of 30% to 70% in the C max and 25% to 35% in the AUC of MPA has been observed, possibly due to a decrease in MPA solubility at an increased gastric pH. The clinical impact of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and mycophenolate mofetil.

Because clinical relevance has not been established, PPIs should be used with caution when coadministered to transplant patients being treated with mycophenolate mofetil. Cholestyramine Following single-dose administration of 1.5 g mycophenolate mofetil to 12 healthy volunteers pretreated with 4 g tid 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.

Therefore, mycophenolate mofetil is not recommended to be given with cholestyramine or other agents that may interfere with enterohepatic recirculation. Cyclosporine Cyclosporine (Sandimmune ®† ) pharmacokinetics (at doses of 275 to 415 mg/day) were unaffected by single and multiple doses of 1.5 g bid of mycophenolate mofetil in ten stable renal transplant patients. The mean (± SD) AUC (0-12h) and C max of cyclosporine after 14 days of multiple doses of mycophenolate mofetil were 3290 (± 822) ng•h/mL and 753 (± 161) ng/mL, respectively, compared to 3245 (± 1088) ng•h/mL and 700 (± 246) ng/mL, respectively, one week before administration of mycophenolate mofetil.

Cyclosporine A interferes with MPA enterohepatic recirculation. In renal transplant patients, mean MPA exposure (AUC 0-12h ) was approximately 30% to 50% greater when mycophenolate mofetil is administered without cyclosporine compared with when mycophenolate mofetil is coadministered with cyclosporine. This interaction is due to cyclosporine inhibition of multidrug-resistance-associated protein 2 (MRP-2) transporter in the biliary tract, thereby preventing the excretion of MPAG into the bile that would lead to enterohepatic recirculation of MPA.

This infor… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS Pregnancy Exposure Prevention and Planning 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. Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not passed through menopause. Menopause is the permanent end of menstruation and fertility.

Menopause should be clinically confirmed by a patient’s healthcare practitioner. Some commonly used diagnostic criteria include 1) 12 months of spontaneous amenorrhea (not amenorrhea induced by a medical condition or medical therapy) or 2) postsurgical from a bilateral oophorectomy. Pregnancy Testing To prevent unplanned exposure during pregnancy, 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, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations. Contraception Females of reproductive potential taking mycophenolate mofetil must receive contraceptive counseling and use acceptable contraception (see Table 8 for acceptable contraception methods). Patients must use acceptable birth control during entire mycophenolate mofetil therapy, and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely).

Patients should be aware that mycophenolate mofetil reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness (see PRECAUTIONS: Information for Patients and PRECAUTIONS: Drug Interactions: Oral Contraceptives ). Table 8: 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 had a 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 Pregnancy Planning For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity.

Risks and benefits of mycophenolate mofetil should be discussed with the patient. Gastrointestinal Disorders Gastrointestinal bleeding (requiring hospitalization) has been observed in approximately 3% of renal, in 1.7% of cardiac, and in 5.4% of hepatic transplant patients treated with mycophenolate mofetil 3 g daily. In pediatric renal transplant patients, 5/148 cases of gastrointestinal bleeding (requiring hospitalization) were observed.

Gastrointestinal perforations have rarely been observed. Most patients receiving mycophenolate mofetil were also receiving other drugs known to be associated with these complications. Patients with active peptic ulcer disease were excluded from enrollment in studies with mycophenolate mofetil.

Because mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulcerat… [Excerpted — this section continues on DailyMed.]