mycophenolic acid 360 MG Delayed Release Oral Tablet [Myfortic]

INDICATIONS AND USAGE • Mycophenolic acid delayed-release tablets are an antimetabolite immunosuppressant indicated for prophylaxis of organ rejection in adult patients receiving kidney transplants and in pediatric patients at least 5 years of age and older who are at least 6 months post kidney transplant. ( 1.1 ) • Use in combination with cyclosporine and corticosteroids. ( 1.1 ) Limitations of Use: • Mycophenolic acid delayed-release tablets and mycophenolate mofetil tablets and capsules should not be used interchangeably. ( 1.2 ) 1.1 Prophylaxis of Organ Rejection in Kidney Transplant Mycophenolic acid delayed-release tablets are indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. Mycophenolic acid delayed-release tablets are indicated for the prophylaxis of organ rejection in pediatric patients 5 years of age and older who are at least 6 months post kidney transplant. Mycophenolic acid delayed-release tablets are to be used in combination with cyclosporine and corticosteroids. 1.2 Limitations of Use Mycophenolic acid delayed-release tablets and mycophenolate mofetil (MMF) tablets and capsules should not be used interchangeably without physician supervision because the rate of absorption following the administration of these two products is not equivalent.

DOSAGE AND ADMINISTRATION • In adults: 720 mg by mouth, twice daily (1,440 mg total daily dose) on an empty stomach, 1 hour before or 2 hours after food intake. ( 2.1 ) • In children: 5 years of age and older (who are at least 6 months post kidney transplant), 400 mg/m 2 by mouth, twice daily (up to a maximum of 720 mg twice daily). ( 2.2 ) • Do not crush, chew, or cut tablet prior to ingestion. ( 2.3 ) 2.1 Dosage in Adult Kidney Transplant Patients The recommended dose of mycophenolic acid delayed-release tablets are 720 mg administered twice daily (1,440 mg total daily dose). 2.2 Dosage in Pediatric Kidney Transplant Patients The recommended dose of mycophenolic acid delayed-release tablets in conversion (at least 6 months post-transplant) pediatric patients age 5 years and older is 400 mg/m 2 body surface area (BSA) administered twice daily (up to a maximum dose of 720 mg administered twice daily). 2.3 Administration Mycophenolic acid delayed-release tablets should be taken on an empty stomach, 1 hour before or 2 hours after food intake [see Clinical Pharmacology ( 12.3 ) ]. Mycophenolic acid delayed-release tablets should not be crushed, chewed, or cut prior to ingesting. The tablets should be swallowed whole in order to maintain the integrity of the enteric coating. Pediatric patients with a BSA of 1.19 m 2 to 1.58 m 2 may be dosed either with three mycophenolic acid delayed-release 180 mg tablets, or one 180 mg tablet plus one 360 mg tablet twice daily (1,080 mg daily dose). Patients with a BSA of greater than 1.58 m 2 may be dosed either with four mycophenolic acid delayed-release 180 mg tablets, or two mycophenolic acid delayed-release 360 mg tablets twice daily (1,440 mg daily dose). Pediatric doses for patients with BSA less than 1.19 m 2 cannot be accurately administered using currently available formulations of mycophenolic acid delayed-release tablets.

WARNINGS AND PRECAUTIONS New or Reactivated Viral Infections: Consider reducing immunosuppression. (5.5) Blood Dyscrasias including Pure Red Cell Aplasia (PRCA): Monitor for neutropenia or anemia; consider treatment interruption or dose reduction. (5.6) Serious GI Tract Complications (gastrointestinal bleeding, perforations and ulcers): Administer with caution to patients with active digestive system disease. (5.7) Immunizations: Avoid live attenuated vaccines. (5.9) Patients with Hereditary Deficiency of Hypoxanthine-guanine Phosphoribosyl-transferase (HGPRT): May cause exacerbation of disease symptoms; avoid use. (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) 5.1 Embryo-Fetal Toxicity Use of mycophenolic acid delayed-release tablets 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 aware of these risks and must be counseled regarding pregnancy prevention and planning. Avoid use of mycophenolic acid delayed-release tablets during pregnancy if safer treatment options are available [see Use in Specific Populations (8.1 , 8.3) ]. 5.2 Management of Immunosuppression Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe mycophenolic acid delayed-release tablets. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physicians responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see Boxed Warning ]. 5.3 Lymphoma and Other Malignancies Patients receiving immunosuppressants, including mycophenolic acid delayed-release tablets, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Adverse Reactions (6) ]. 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 broad-spectrum sunscreen with a high protection factor. Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear 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. 5.4 Serious Infections Patients receiving immunosuppressants, including mycophenolic acid delayed-release tablets, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, and new or reactivated viral infections, including opportunistic infections [see Warnings and Precautions (5.5) ]. 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. 5.5 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), SARS-CoV-2 infection, have been reported in patients treated with immunosuppressants, including MPA derivatives mycophenolic acid delayed-release tablets and MMF. 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. 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. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. 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 [see Adverse Reactions (6.1) ]. 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. 5.6 Blood Dyscrasias, Including Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressive agents. The mechanism for MPA derivatives induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppressive regimen is also unknown. In some cases, PRCA was found to be reversible with dose reduction or cessation of therapy with MPA derivatives. In transplant patients, however, reduced immunosuppression may place the graft at risk. Changes to mycophenolic acid therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimize the risk of graft rejection. Patients receiving mycophenolic acid should be monitored for blood dyscrasias (e.g., neutropenia or anemia). The development of neutropenia may be related to mycophenolic acid itself, concomitant medications, viral infections, or some combination of these reactions. Complete blood count should be performed weekly during the first month, twice monthly for the second and the third month of treatment, then monthly through the first year. If blood dyscrasias occur [ neutropenia develops (ANC < 1.3 × 10 3 /mcL) or anemia ] , dosing with mycophenolic acid should be interrupted or the dose reduced, appropriate tests performed, and the patient managed accordingly. 5.7 Serious GI Tract Complications Gastrointestinal bleeding (requiring hospitalization), intestinal perforations, gastric ulcers, and duodenal ulcers have been reported in patients treated with mycophenolic acid delayed-release tablets. Mycophenolic acid delayed-release tablets should be administered with caution in patients with active serious digestive system disease. 5.8 Acute Inflammatory Syndrome Associated with Mycophenolate Products Acute inflammatory syndrome (AIS) has been reported with the use of 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. 5.9 Im

CONTRAINDICATIONS Known hypersensitivity to mycophenolate sodium, mycophenolic acid ‎(MPA), mycophenolate mofetil, or to any of its excipients. ( 4.1 ) 4.1 Hypersensitivity Reactions Mycophenolic acid delayed-release tablets are contraindicated in patients with a hypersensitivity to mycophenolate sodium, mycophenolic acid (MPA), mycophenolate mofetil, or to any of its excipients. Reactions like rash, pruritus, hypotension, and chest pain have been observed in clinical trials and post marketing reports [see Adverse Reactions ( 6 ) ].

CLINICAL PHARMACOLOGY 12.1 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. 12.3 Pharmacokinetics Mycophenolic acid delayed-release tablets exhibits linear and dose-proportional pharmacokinetics over the dose-range (360 mg to 2,160 mg) evaluated. The absolute bioavailability of mycophenolic acid delayed-release tablets in stable renal transplant patients on cyclosporine was 72%. MPA is highly protein bound (> 98% bound to albumin). The predominant metabolite of MPA is the phenolic glucuronide (MPAG) which is pharmacologically inactive. A minor metabolite AcMPAG which is an acyl glucuronide of MPAG is also formed and has pharmacological activity comparable to MPA. MPAG undergoes renal elimination. A fraction of MPAG also undergoes biliary excretion, followed by deconjugation by gut flora and subsequent reabsorption as MPA. The mean elimination half-lives of MPA and MPAG ranged between 8 and 16 hours, and 13 and 17 hours, respectively. Absorption In vitro studies demonstrated that the enteric-coated mycophenolic acid delayed-release 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 mycophenolic acid delayed-release tablets oral administration without food in several pharmacokinetic studies conducted in renal transplant patients, consistent with its enteric-coated formulation, the median delay (T lag ) in the rise of MPA concentration ranged between 0.25 and 1.25 hours and the median time to maximum concentration (T max ) of MPA ranged between 1.5 and 2.75 hours. In comparison, following the administration of MMF, the median T max ranged between 0.5 and 1 hours. In stable renal transplant patients on cyclosporine, USP MODIFIED based immunosuppression, gastrointestinal absorption and absolute bioavailability of MPA following the administration of mycophenolic acid delayed-release tablet was 93% and 72%, respectively. Mycophenolic acid delayed-release tablets pharmacokinetics is dose proportional over the dose range of 360 mg to 2,160 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 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, MPAG, is the predominant metabolite of MPA and does not manifest pharmacological activity. The acyl glucuronide is a minor metabolite and has comparable pharmacological activity to MPA. In stable renal transplant patients on cyclosporine, USP MODIFIED based immunosuppression, approximately 28% of the oral mycophenolic acid delayed-release tablets dose was converted to MPAG by presystemic metabolism. The AUC ratio of MPA:MPAG:acyl glucuronide is approximately 1:24:0.28 at steady state. The mean clearance of MPA was 140 (± 30) mL/min. Elimination The majority of MPA dose administered is eliminated in the urine primarily as MPAG (> 60%) and approximately 3% as unchanged MPA following mycophenolic acid administration to stable renal transplant patients. The mean renal clearance of MPAG was 15.5 (± 5.9) mL/min. MPAG is also secreted in the bile and available for deconjugation by gut flora. MPA resulting from the deconjugation may then be reabsorbed and produce a second peak of MPA approximately 6 to 8 hours after mycophenolic acid 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 mycophenolic acid delayed-release tablets 720 mg with a high-fat meal (55 g fat, 1,000 calories) had no effect on the systemic exposure (AUC) of MPA. However, there was a 33% decrease in the maximal concentration (C max ), a 3.5-hour delay in the T lag (range, -6 to 18 hours), and 5-hour delay in the T max (range, -9 to 20 hours) of MPA. To avoid the variability in MPA absorption between doses, mycophenolic acid delayed-release tablets should be taken on an empty stomach [see Dosage and Administration (2.3) ]. Pharmacokinetics in Renal Transplant Patients The mean pharmacokinetic parameters for MPA following the administration of mycophenolic acid in renal transplant patients on cyclosporine, USP MODIFIED based immunosuppression are shown in Table 6. Single-dose mycophenolic acid pharmacokinetics predicts multiple-dose pharmacokinetics. However, in the early post-transplant period, mean MPA AUC and C max were approximately one-half of those measured 6 months post-transplant. After near equimolar dosing of mycophenolic acid 720 mg twice daily and MMF 1,000 mg twice daily (739 mg as MPA) in both the single- and multiple-dose crossover trials, mean systemic MPA exposure (AUC) was similar. Table 6: Mean ± SD Pharmacokinetic Parameters for MPA Following the Oral Administration of Mycophenolic Acid Delayed-Release Tablets to Renal Transplant Patients on Cyclosporine, USP MODIFIED Based Immunosuppression Patient Mycophenolic Acid Delayed-Release Tablets Dosing N Dose (mg) T max median (range). (hr) C max (mcg/mL) AUC 0 -12hr (mcg*hr/mL) Adult Single 24 720 2 (0.8 – 8) 26.1 ± 12 66.5 ± 22.6 AUCinf Pediatric age range of 5 to 16 years. Single 10 450/m 2 2.5 (1.5 – 24) 36.3 ± 20.9 74.3 ± 22.5 Adult Multiple x 6 days, twice daily 10 720 2 (1.5 – 3) 37 ± 13.3 67.9 ± 20.3 Adult Multiple x 28 days, twice daily 36 720 2.5 (1.5 – 8) 31.2 ± 18.1 71.2 ± 26.3 Adult Chronic, multiple-dose, twice daily 2 weeks post-transplant 12 720 1.8 (1 – 5.3) 15 ± 10.7 28.6 ± 11.5 3 months post-transplant 12 720 2 (0.5 – 2.5) 26.2 ± 12.7 52.3 ± 17.4 6 months post-transplant 12 720 2 (0 – 3) 24.1 ± 9.6 57.2 ± 15.3 Adult Chronic, multiple-dose, twice daily 18 720 1.5 (0 – 6) 18.9 ± 7.9 57.4 ± 15 Specific Populations Patients with Renal Insufficiency: No specific pharmacokinetic studies in individuals with renal impairment were conducted with mycophenolic acid delayed-release tablets. However, based on studies of renal impairment with MMF, MPA exposure is not expected to be appreciably increased over the range of normal to severely impaired renal function following mycophenolic acid delayed-release tablets administration. In contrast, MPAG exposure would be increased markedly with decreased renal function; MPAG exposure being approximately 8-fold higher in the setting of anuria. Although dialysis may be used to remove the inactive metabolite MPAG, it would not be expected to remove clinically significant amounts of the active moiety MPA. This is in large part due to the high plasma protein binding of MPA. Patients with Hepatic Insufficiency : No specific pharmacokinetic studies in individuals with hepatic impairment were conducted with mycophenolic acid delayed-release tablets. In a single dose (MMF 1,000 mg) trial of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when the pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this trial were compared. However, it should be noted that for unexplained re