Mycophenolate Mofetil Hydrochloride

FDA Drug Information • Also known as: Cellcept, Mycophenolate Mofetil

Brand Names: Cellcept, Mycophenolate Mofetil
Route: INTRAVENOUS
Dosage Form: INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: EMBRYOFETAL TOXICITY, MALIGNANCIES and SERIOUS INFECTIONS Use during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations. Avoid if safer treatment options are available. Females of reproductive potential must be counseled regarding pregnancy prevention and planning [see Warnings and Precautions (5.1) , Use in Special Populations (8.1 , 8.3) ] . Increased risk of development of lymphoma and other malignancies, particularly of the skin [see Warnings and Precautions (5.2) ] . Increased susceptibility to bacterial, viral, fungal and protozoal infections, including opportunistic infections and viral reactivation of hepatitis B and C, which may lead to hospitalizations and fatal outcomes [see Warnings and Precautions (5.3) ] . WARNING: EMBRYOFETAL TOXICITY, MALIGNANCIES and SERIOUS INFECTIONS See full prescribing information for complete boxed warning Use during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations. Avoid if safer treatment options are available. Females of reproductive potential must be counseled regarding pregnancy prevention and planning [see Warnings and Precautions (5.1) ]. Increased risk of development of lymphoma and other malignancies, particularly of the skin [see Warnings and Precautions (5.2) ] . Increased susceptibility to infections, including opportunistic infections and severe infections with fatal outcomes [see Warnings and Precautions (5.3) ].

Description

11 DESCRIPTION Mycophenolate Mofetil (mycophenolate mofetil) is an antimetabolite immunosuppressant. It is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor. The chemical name for mycophenolate mofetil (MMF) is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has an empirical formula of C 23 H 31 NO 7 , a molecular weight of 433.50, and the following structural formula: MMF is a white to off-white crystalline powder. It is slightly soluble in water (43 μg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol. The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for MMF are 5.6 for the morpholino group and 8.5 for the phenolic group. MMF hydrochloride has a solubility of 65.8 mg/mL in 5% Dextrose Injection USP (D5W). The pH of the reconstituted solution is 2.4 to 4.1. Mycophenolate Mofetil for Injection USP is the hydrochloride salt of MMF. The chemical name for the hydrochloride salt of MMF is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate hydrochloride. It has an empirical formula of C 23 H 31 NO 7 HCl and a molecular weight of 469.96. Mycophenolate Mofetil for Injection USP is available as a sterile white to off-white lyophilized powder in single-dose vials containing MMF hydrochloride for administration by intravenous infusion only. Each vial contains 500 mg of mycophenolate mofetil equivalent to 542 mg of mycophenolate mofetil hydrochloride. The inactive ingredients are polysorbate 80, 25 mg, and citric acid, 5 mg. Sodium hydroxide and/or hydrochloric acid may have been used in the manufacture of Mycophenolate Mofetil for Injection USP to adjust the pH. Reconstitution and dilution with...

What Is Mycophenolate Mofetil Hydrochloride Used For?

1 INDICATIONS AND USAGE Mycophenolate Mofetil [mycophenolate mofetil (MMF)] is indicated for the prophylaxis of organ rejection, in adult and pediatric recipients 3 months of age and older of allogeneic kidney [see Clinical Studies (14.1) ], heart [see Clinical Studies (14.2) ] or liver transplants [see Clinical Studies (14.3) ] , in combination with other immunosuppressants. Mycophenolate Mofetil is an antimetabolite immunosuppressant indicated for the prophylaxis of organ rejection in adult and pediatric recipients 3 months of age and older of allogeneic kidney, heart or liver transplants, in combination with other immunosuppressants. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION ADULTS DOSAGE Kidney Transplant 1 g twice daily, orally or intravenously (IV) over no less than 2 h ( 2.2 ) Heart Transplant 1.5 g twice daily orally or IV, over no less than 2 h ( 2.3 ) Liver Transplant 1.5 g twice daily orally or 1g twice daily IV over no less than 2 h ( 2.4 ) PEDIATRICS Kidney Transplant 600 mg/m 2 orally twice daily, up to maximum of 2 g daily ( 2.2 ) Heart Transplant 600 mg/m 2 orally twice daily (starting dose) up to a maximum of 900 mg/m 2 twice daily (3 g or 15 mL of oral suspension) ( 2.3 ) Liver Transplant 600 mg/m 2 orally twice daily (starting dose) up to a maximum of 900 mg/m 2 twice daily (3 g or 15 mL of oral suspension) ( 2.4 ) Mycophenolate Mofetil for Injection is an alternative when patients cannot tolerate oral medication. Administer within 24 hours following transplantation, until patients can tolerate oral medication, up to 14 days. ( 2.1 ) Reduce or interrupt dosing in the event of neutropenia. ( 2.5 ) See full prescribing information (FPI) for: adjustments for renal impairment and neutropenia ( 2.5 ), preparation of oral suspension and IV solution. ( 2.6 ) 2.1 Important Administration Instructions Mycophenolate Mofetil should not be used without the supervision of a physician with experience in immunosuppressive therapy Mycophenolate Mofetil for Injection Mycophenolate Mofetil for Injection is recommended for patients unable to take oral Mycophenolate Mofetil. Mycophenolate Mofetil for Injection should be administered within 24 hours following transplant. Mycophenolate Mofetil for Injection can be administered for up to 14 days; however, patients should be switched to oral Mycophenolate Mofetil as soon as they can tolerate oral medication. Mycophenolate Mofetil for Injection must be reconstituted before use [see Dosage and Administration (2.6) ] . Mycophenolate Mofetil for Injection is incompatible with other intravenous infusion solutions and should not be mixed or administered concurrently via the same infusion catheter with other intravenous drugs or infusion admixtures. Mycophenolate Mofetil for Injection must not be administered as a bolus. Following reconstitution, Mycophenolate Mofetil for Injection must be administered by slow intravenous infusion over a period of no less than 2 hours by either peripheral or central vein, as rapid infusion increases the risk of local adverse reactions such as phlebitis and thrombosis [see Adverse Reactions (6.1) ] . 2.2 Dosage Recommendations for Kidney Transplant Patients Adults The recommended dosage for adult kidney transplant patients is 1 g orally or intravenously infused over no less than 2 hours, twice daily (total daily dose of 2 g). Pediatrics (3 months and older) Pediatric dosing is based on body surface area (BSA). The recommended dosage of CELLCEPT oral suspension for pediatric kidney transplant patients 3 months and older is 600 mg/m 2 , administered twice daily (maximum total daily dose of 2 g or 10 mL of the oral...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS 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) ] 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 BPI Labs LLC at 1-727-471-0850 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.com 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) ] . Mycophenolate Mofetil Oral 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 g twice daily intravenously for up to 14 days followed by Mycophenolate Mofetil 1.5 g twice daily orally or azathioprine 1 to 2 mg/kg/day intravenously followed by 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 5 Adverse Reactions in Controlled Studies of De Novo Kidney, Heart or Liver Transplantation Reported in ≥20% of Patients in the Mycophenolate Mofetil Group Adverse drug reaction Kidney Studies Heart Study Liver Study...

Drug Interactions

7 DRUG INTERACTIONS See FPI for drugs that may interfere with systemic exposure and reduce Mycophenolate Mofetil efficacy: antacids with magnesium or aluminum hydroxide, proton pump inhibitors, drugs that interfere with enterohepatic recirculation, telmisartan, calcium-free phosphate binders. ( 7.1 ) Mycophenolate Mofetil may reduce effectiveness of oral contraceptives. Use of additional barrier contraceptive methods is recommended. ( 7.2 ) See FPI for other important drug interactions. ( 7 ) 7.1 Effect of Other Drugs on Mycophenolate Mofetil Table 7 Drug Interactions with Mycophenolate Mofetil that Affect Mycophenolic Acid (MPA) Exposure Antacids with Magnesium or Aluminum Hydroxide Clinical Impact Concomitant use with an antacid containing magnesium or aluminum hydroxide decreases MPA systemic exposure [see Clinical Pharmacology (12.3) ] , which may reduce Mycophenolate Mofetil efficacy. Prevention or Management Administer magnesium or aluminum hydroxide containing antacids at least 2h after Mycophenolate Mofetil administration. Proton Pump Inhibitors (PPIs) Clinical Impact Concomitant use with PPIs decreases MPA systemic exposure [see Clinical Pharmacology (12.3) ] , which may reduce Mycophenolate Mofetil efficacy. Prevention or Management Monitor patients for alterations in efficacy when PPIs are co-administered with Mycophenolate Mofetil. Examples Lansoprazole, pantoprazole Drugs that Interfere with Enterohepatic Recirculation Clinical Impact Concomitant use with drugs that directly interfere with enterohepatic recirculation, or indirectly interfere with enterohepatic recirculation by altering the gastrointestinal flora, can decrease MPA systemic exposure [see Clinical Pharmacology (12.3) ] , which may reduce Mycophenolate Mofetil efficacy. Prevention or Management Monitor patients for alterations in efficacy or Mycophenolate Mofetil related adverse reactions when these drugs are co-administered with Mycophenolate Mofetil. Examples Cyclosporine A, trimethoprim/sulfamethoxazole, bile acid sequestrants (cholestyramine), rifampin as well as aminoglycoside, cephalosporin, fluoroquinolone and penicillin classes of antimicrobials Drugs Modulating Glucuronidation Clinical Impact Concomitant use with drugs inducing glucuronidation decreases MPA systemic exposure, potentially reducing Mycophenolate Mofetil efficacy, while use with drugs inhibiting glucuronidation increases MPA systemic exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of Mycophenolate Mofetil related adverse reactions. Prevention or Management Monitor patients for alterations in efficacy or Mycophenolate Mofetil related adverse reactions when these drugs are co-administered with Mycophenolate Mofetil. Examples Telmisartan (induces glucuronidation); isavuconazole (inhibits glucuronidation). Calcium Free Phosphate Binders Clinical Impact Concomitant use with calcium free phosphate binders decrease MPA systemic exposure [see Clinical Pharmacology (12.3) ] ,...

Contraindications

4 CONTRAINDICATIONS Allergic reactions to Mycophenolate Mofetil have been observed; therefore, Mycophenolate Mofetil is contraindicated in patients with a hypersensitivity to mycophenolate mofetil (MMF), mycophenolic acid (MPA) or any component of the drug product. Mycophenolate Mofetil for Injection is contraindicated in patients who are allergic to Polysorbate 80 (TWEEN).

Hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product ( 4 )

Patients allergic to Polysorbate 80 (present in Mycophenolate Mofetil IV) ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to mycophenolate during pregnancy and those becoming pregnant within 6 weeks of discontinuing Mycophenolate Mofetil treatment. To report a pregnancy or obtain information about the registry, visit www.psmycophenolaterems.com or call 1-877-310-4015. 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 Error! Hyperlink reference not valid. ]. Consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of Mycophenolate Mofetil should be discussed with the pregnant woman. The estimated background risk of pregnancy loss and congenital malformations in organ transplant populations is not clear . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data A spectrum of congenital malformations (including multiple malformations in individual newborns) has been reported in 23 to 27% of live births in MMF exposed pregnancies, based on published data from pregnancy registries. Malformations that have been documented include external ear, eye, and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidney, and nervous system. Based on published data from pregnancy registries, the risk of first trimester pregnancy loss has been reported at 45 to...

Overdosage

10 OVERDOSAGE Possible signs and symptoms of acute overdose include hematological abnormalities such as leukopenia and neutropenia, and gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, vomiting, and dyspepsia. The experience with overdose of Mycophenolate Mofetil in humans is limited. The reported effects associated with overdose fall within the known safety profile of the drug. The highest dose administered to kidney transplant patients in clinical trials has been 4 g/day. In limited experience with heart and liver transplant patients in clinical trials, the highest doses used were 4 g/day or 5 g/day. At doses of 4 g/day or 5 g/day, there appears to be a higher rate, compared to the use of 3 g/day or less, of gastrointestinal intolerance (nausea, vomiting, and/or diarrhea), and occasional hematologic abnormalities, particularly neutropenia [see Warnings and Precautions (5.4) ] . Treatment and Management MPA and the phenolic glucuronide metabolite of MPA (MPAG) are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 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 [see Clinical Pharmacology (12.3) ].

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Handling and Disposal Mycophenolate mofetil (MMF) has demonstrated teratogenic effects in humans [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in Mycophenolate Mofetil for Injection USP (during or after preparation) [see Dosage and Administration (2.6) ]. Follow applicable special handling and disposal procedure 1 . 16.5 Mycophenolate Mofetil for Injection, USP For injection: 500 mg mycophenolate mofetil as the hydrochloride salt in a 20 mL sterile single-dose vial cartons of 4 vials Cartons of 4 single-dose vials NDC 54288-141-04 Storage Store powder and reconstituted infusion solution at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Discard unused portion.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.