Myhibbin Drug Information

is 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. MYHIBBIN 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.

• The following adverse reactions are discussed in greater detail in other sections of the label:
• Embryofetal Toxicity [see Warnings and Precautions (5.1) ]
• Lymphomas and Other Malignancies [see Warnings and Precautions (5.2) ]
• Serious Infections [see Warnings and Precautions (5.3) ]
• Blood Dyscrasias: Neutropenia, Pure Red Cell Aplasia [see Warnings and Precautions (5.4) ]
• Gastrointestinal Complications [see Warnings and Precautions (5.5) ]
• Acute Inflammatory Syndrome Associated with Mycophenolate Products [see Warnings and Precautions (5.7) ]
• Hypersensitivity Reactions [see Warnings and Precautions (5.8) ] The most common adverse reactions in clinical trials (20 % or greater) include diarrhea, leukopenia, infection, vomiting, and there is evidence of a higher frequency of certain types of infections e.g., opportunistic infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. An estimated total of 1557 adult patients received mycophenolate mofetil during pivotal clinical trials in the prevention of acute organ rejection. Of these, 991 were included in the three renal studies, 277 were included in one hepatic study, and 289 were included in one cardiac study. Patients in all study arms also received cyclosporine and corticosteroids. The data described below primarily derive from five randomized, active-controlled double-blind 12-month trials of mycophenolate mofetil in de novo kidney (3) heart (1) and liver (1) transplant patients [see Clinical Studies ( 14.1 , 14.2 , and 14.3 )] . Oral Mycophenolate Mofetil The incidence of adverse reactions for mycophenolate mofetil was determined in five randomized, comparative, double- blind trials in the prevention of rejection in kidney, heart and liver transplant patients (two active- and one placebo- controlled trials, one active-controlled trial, and one active-controlled trial, respectively) [see Clinical Studies ( 14.1 , 14.2 and 14.3 )] . The three de novo kidney studies with 12-month duration 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) when administered in combination with cyclosporine (Sandimmune ® ) and corticosteroids to prevent acute rejection episodes. One study also included anti-thymocyte globulin (ATGAM ® ) induction therapy. In the de novo heart transplantation study with 12-month duration, patients received mycophenolate mofetil 1.5 g twice daily (n=289) or azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine (Sandimmune ® or Neoral ® ) and corticosteroids as maintenance immunosuppressive therapy. In the de novo liver transplantation study with 12-month duration, patients received mycophenolate mofetil 1.5 g twice daily orally or azathioprine 1 to 2 mg/kg/day orally, in combination with cyclosporine (Neoral ® ) and corticosteroids as maintenance immunosuppressive therapy. The total number of patients enrolled was 565. Approximately 53% of the kidney transplant patients, 65% of the heart transplant patients, and 48% of the liver transplant patients were treated for more than 1 year. Adverse reactions reported in ≥ 20% of patients in the mycophenolate mofetil treatment groups are presented below. The safety data of three kidney transplantation studies are pooled together. Table 1 Adverse Reactions in Controlled Studies of De Novo Kidney, Heart or Liver Transplantation Reported in ≥20% of Patients in the Mycophenolate Mofetil (MMF) Group System Organ Class Kidney Studies Heart Study Liver Study MMF 2 g/day (n=501) or 3 g/day (n=490) AZA 1 to 2 mg/kg/day or 100 to 150 mg/day Placebo MMF 3 g/day AZA 1.5 to 3 mg/kg/day MMF 3g/day AZA 1 to 2 mg/kg/day Adverse Drug Reaction (n=991) (n=326) (n=166) (n=289) (n=289) (n=277) (n=287) % % % % % % % Infections and infestations Bacterial infections 39.9 33.7 37.3 - - 27.4 26.5 Viral infections -a - - 31.1 24.9 - - Blood and lymphatic system disorders Anemia 20.0 23.6 2.4 45.0 47.1 43.0 53.0 Ecchymosis - - - 20.1 9.7 - - Leukocytosis - - - 42.6 37.4 22.4 21.3 Leukopenia 28.6 24.8 4.2 34.3 43.3 45.8 39.0 Thrombocytopenia - - - 24.2 28.0 38.3 42.2 Metabolism and nutrition disorders Hypercholesterolemia - - - 46.0 43.9 - - Hyperglycemia - - - 48.4 53.3 43.7 48.8 Hyperkalemia - - - - - 22.0 23.7 Hypocalcemia - - - - - 30.0 30.0 Hypokalemia - - - 32.5 26.3 37.2 41.1 Hypomagnesemia - - - 20.1 14.2 39.0 37.6 Psychiatric disorders Depression - - - 20.1 15.2 - - Insomnia - - - 43.3 39.8 52.3 47.0 Nervous system disorders Dizziness - - - 34.3 33.9 - - Headache - - - 58.5 55.4 53.8 49.1 Tremor - - - 26.3 25.6 33.9 35.5 Cardiac disorders Tachycardia - - - 22.8 21.8 22.0 15.7 Vascular disorders Hypertension 27.5 32.2 19.3 78.9 74.0 62.1 59.6 Hypotension - - - 34.3 40.1 - - Respiratory, thoracic and mediastinal disorders Cough - - - 40.5 32.2 - - Dyspnea - - - 44.3 44.3 31.0 30.3 Pleural effusion - - - - - 34.3 35.9 Gastrointestinal disorders Abdominal pain 22.4 23.0 11.4 41.9 39.4 62.5 51.2 Constipation - - - 43.6 38.8 37.9 38.3 Decreased appetite - - - - - 25.3 17.1 Diarrhea 30.4 20.9 13.9 52.6 39.4 51.3 49.8 Dyspepsia - - - 22.1 22.1 22.4 20.9 Nausea - - - 56.1 60.2 54.5 51.2 Vomiting - - - 39.1 34.6 32.9 33.4 Hepatobiliary disorders Blood lactate dehydrogenase increased - - - 23.5 18.3 - - Hepatic enzyme increased - - - - - 24.9 19.2 Skin and subcutaneous tissues disorders Rash - - - 26.0 20.8 - - Renal and urinary disorders Blood creatinine increased - - - 42.2 39.8 - - Blood urea increased - - - 36.7 34.3 - - General disorders and administration site conditions Asthenia - - - 49.1 41.2 35.4 33.8 Edema b 21.0 28.2 8.4 67.5 55.7 48.4 47.7 Pain c 24.8 32.2 9.6 79.2 77.5 74.0 77.5 Pyrexia - - - 56.4 53.6 52.3 56.1 a:“-” Indicates that the incidence was below the cutoff value of 20% for inclusion in the table. b:“Edema” includes peripheral edema, facial edema, scrotal edema. c:“Pain” includes musculoskeletal pain (myalgia, neck pain, back pain). In the three de novo kidney studies, patients receiving 2 g/day of mycophenolate mofetil had an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil. Post-transplant lymphoproliferative disease (PTLD, pseudolymphoma) developed in 0.4% to 1% of patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressive agents in controlled clinical trials of kidney, heart and liver transplant patients followed for at least 1 year [see Warnings and Precautions ( 5.2 )]. Non-melanoma skin carcinomas occurred in 1.6% to 4.2% of patients, other types of malignancy in 0.7% to 2.1% of patients. Three-year safety data in kidney and heart transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. In pediatric patients, PTLD was observed in 1.35% (2/148) by 12 months post-transplant. Cytopenias, including leukopenia, anemia, thrombocytopenia and pancytopenia are a known risk associated with mycophenolate and may lead or contribute to the occurrence of infections and hemorrhages [see Warnings and Precautions ( 5.3 )] . Severe neutropenia (ANC <0.5 x 103/µL) developed in up to 2% of kidney transplant patients, up to 2.8% of heart transplant patients and up to 3.6% of liver transplant patients receiving mycophenolate mofetil 3 g daily [see Warnings and Precautions ( 5.4 ) and Dosage and Administration ( 2.5 )]. The most common opportunistic infections in patients receiving mycophenolate mofetil with other immunosuppressants were mucocutaneous candida, CMV viremia/syndrome, and herpes simplex. The proportion of patients with CMV viremia/syndrome was 13.5%. In patients receiving mycophenolate mofetil (2 g or 3 g) in controlled studies for prevention of kidney, heart or liver rejection, fatal infection/sepsis occurred in approximately 2% of kidney and heart patients and in 5% of liver patients [see Warnings and Precautions ( 5.3 )]. The most serious gastrointestinal disorders reported were ulceration and hemorrhage, which are known risks associated with mycophenolate mofetil. Mouth, esophageal, gastric, duodenal, and intestinal ulcers often complicated by hemorrhage, as well as hematemesis, melena, and hemorrhagic forms of gastritis and colitis were commonly reported during the pivotal clinical trials, while the most common gastrointestinal disorders were diarrhea, nausea and vomiting. Endoscopic investigation of patients with mycophenolate mofetil-related diarrhea revealed isolated cases of intestinal villous atrophy [see Warnings and Precautions ( 5.5 )] . The following adverse reactions were reported with 3% to <20% incidence in kidney, heart, and liver transplant patients treated with mycophenolate mofetil, in combination with cyclosporine and corticosteroids. Table 2 Adverse Reactions in Controlled Studies of De Novo Kidney, Heart or Liver Transplantation Reported in 3% to <20% of Patients Treated with Mycophenolate Mofetil in Combination with Cyclosporine and Corticosteroids System Organ Class Adverse Reactions Body as a Whole cellulitis, chills, hernia, malaise Infections and Infestations fungal infections Hematologic and Lymphatic coagulation disorder, ecchymosis, pancytopenia Urogenital hematuria Cardiovascular hypotension Metabolic and Nutritional acidosis, alkaline phosphatase increased, hyperlipemia, hypophosphatemia, weight loss Digestive esophagitis, flatulence, gastritis, gastrointestinal hemorrhage, hepatitis, ileus, nausea and vomiting, stomach ulcer, stomatitis Neoplasm benign, malignant and unspecified neoplasm Skin and Appendages skin benign neoplasm, skin carcinoma Psychiatric confusional state Nervous hypertonia, paresthesia, somnolence Musculoskeletal arthralgia, myasthenia Pediatrics The type and frequency of adverse events in a clinical study for prevention of kidney allograft rejection in 100 pediatric patients 3 months to 18 years of age dosed with mycophenolate mofetil oral suspension 600 mg/m2 twice daily (up to 1 g twice daily) were generally similar to those observed in adult patients dosed with mycophenolate mofetil capsules at a dose of 1 g twice daily with the exception of abdominal pain, fever, infection, pain, sepsis, diarrhea, vomiting, pharyngitis, respiratory tract infection, hypertension, leukopenia, and anemia, which were observed in a higher proportion in pediatric patients. Safety information in pediatric heart transplant or pediatric liver transplant patients treated with mycophenolate mofetil is supported by an open-label study in pediatric liver transplant patients and publications; the type and frequency of the reported adverse reactions are consistent with those observed in pediatric patients following renal transplant and in adults. Geriatrics Geriatric 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 Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.1 )]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of mycophenolate mofetil. 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: Embryo-Fetal Toxicity : Congenital malformations and spontaneous abortions, mainly in the first trimester, have been reported following exposure to mycophenolate mofetil (MMF) in combination with other immunosuppressants during pregnancy [see Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 ), ( 8.3 )]. Congenital malformations include: - Facial malformations: cleft lip, cleft palate, micrognathia, hypertelorism of the orbits - Abnormalities of the ear and eye: abnormally formed or absent external/middle ear, coloboma, microphthalmos - Malformations of the fingers: polydactyly, syndactyly, brachydactyly - Cardiac abnormalities: atrial and ventricular septal defects - Esophageal malformations: esophageal atresia - Nervous system malformations: such as spina bifida . Digestive : Colitis, pancreatitis Hematologic and Lymphatic : Bone marrow failure, cases of pure red cell aplasia (PRCA) and hypogammaglobulinemia have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents [see Warnings and Precautions ( 5.4 )] . Immune : Hypersensitivity reactions, including anaphylaxis and angioedema [see Warnings and Precautions ( 5.8 )] , hypogammaglobinemia. Infections : Meningitis, infectious endocarditis, tuberculosis, atypical mycobacterial infection, progressive multifocal leukoencephalopathy, BK virus infection, viral reactivation of hepatitis B and hepatitis C, protozoal infections [see Warnings and Precautions ( 5.3 )] . Respiratory : Bronchiectasis, interstitial lung disease, fatal pulmonary fibrosis, have been reported rarely and should be considered in the differential diagnosis of pulmonary symptoms ranging from dyspnea to respiratory failure in post-transplant patients receiving mycophenolate mofetil. Vascular: Lymphocele

Effect of Other Drugs on

MYHIBBIN Table 3 Drug Interactions with MYHIBBIN 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 , which may reduce MYHIBBIN efficacy. Prevention or Management Administer magnesium or aluminum hydroxide containing antacids at least 2h after MYHIBBIN. Proton Pump Inhibitors (PPIs) Clinical Impact Concomitant use with PPIs decreases MPA systemic exposure , which may reduce MYHIBBIN efficacy. Prevention or Management Monitor patients for alterations in efficacy when PPIs are co- administered with MYHIBBIN. 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 , which may reduce MYHIBBIN efficacy.

Prevention or Management Monitor patients for alterations in efficacy or MYHIBBIN-related adverse reactions when these drugs are co-administered with MYHIBBIN. 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 MYHIBBIN efficacy, while use with drugs inhibiting glucuronidation increases MPA systemic exposure , which may increase the risk of MYHIBBIN-related adverse reactions. Prevention or Management Monitor patients for alterations in efficacy or MYHIBBIN-related adverse reactions when these drugs are co-administered with MYHIBBIN. Examples Telmisartan (induces glucuronidation); isavuconazole (inhibits glucuronidation). Calcium Free Phosphate Binders Clinical Impact Concomitant use with calcium free phosphate binders decrease MPA systemic exposure , which may reduce MYHIBBIN efficacy. Prevention or Management Administer calcium free phosphate binders at least 2 hours after MYHIBBIN. Examples Sevelamer

Effect of

MYHIBBIN on Other Drugs Table 4 Drug Interactions with MYHIBBIN that Affect Other Drugs Drugs that Undergo Renal Tubular Secretion Clinical Impact When concomitantly used with MYHIBBIN, 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 , which may result in reduced combination oral contraceptive effectiveness.

Prevention or Management Use additional barrier contraceptive methods.

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 MYHIBBIN treatment. To report a pregnancy or obtain information about the registry, visit the Mycophenolate Pregnancy Registry at 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 MYHIBBIN should be discussed with the pregnant woman.

The 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.

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 MYHIBBIN 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). Heart Transplant and Liver Transplant Use of MYHIBBIN 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.

The combination of inactive ingredients (e.g., simethicone, sodium phosphate monobasic dihydrate, sodium phosphate dibasic dihydrate, glycerin) in MYHIBBIN have the potential to impact gastrointestinal tolerability. Monitor pediatric patients receiving MYHIBBIN for signs and symptoms of gastrointestinal intolerance.

is contraindicated in patients with a history of hypersensitivity, including anaphylaxis, to mycophenolate mofetil (MMF), mycophenolic acid (MPA), polysorbate 80 (TWEEN) or any other component of the drug product . History of hypersensitivity, including anaphylaxis, to mycophenolate mofetil, mycophenolic acid, polysorbate 80 or any component of the drug product

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 . 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 µg/mL), small amounts of MPAG are removed. By increasing excretion of the drug, MPA can be removed by bile acid sequestrants, such as cholestyramine.