Mycophenolate Mofetil

CellCept (mycophenolate mofetil) 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-(1,3dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4hexenoate. It has an empirical formula of C23H31NO7, a molecular weight of 433.50, and the following structural formula:

Mycophenolate mofetil 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 mycophenolate mofetil are 5.6 for the morpholino group and 8.5 for the phenolic group.

Mycophenolate mofetil 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.

CellCept is available for oral administration as capsules containing 250 mg of mycophenolate mofetil, tablets containing 500 mg of mycophenolate mofetil, and as a powder for oral suspension, which when constituted contains 200 mg/mL mycophenolate mofetil.

Inactive ingredients in CellCept 250 mg capsules include croscarmellose sodium, magnesium stearate, povidone (K-90) and pregelatinized starch. The capsule shells contain black iron oxide, FD&C blue #2, gelatin, red iron oxide, silicon dioxide, sodium lauryl sulfate, titanium dioxide, and yellow iron oxide.

Inactive ingredients in CellCept 500 mg tablets include black iron oxide, croscarmellose sodium, FD&C blue #2 aluminum lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, povidone (K-90), red iron oxide, talc, and titanium dioxide; may also contain ammonium hydroxide, ethyl alcohol, methyl alcohol, n-butyl alcohol, propylene glycol, and shellac.

Inactive ingredients in CellCept Oral Suspension include aspartame, citric acid anhydrous, colloidal silicon dioxide, methylparaben, mixed fruit flavor, sodium citrate dihydrate, sorbitol, soybean lecithin, and xanthan gum.

CellCept Intravenous is the hydrochloride salt of mycophenolate mofetil. The chemical name for the hydrochloride salt of mycophenolate mofetil is 2-morpholinoethyl (E)-6(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4hexenoate hydrochloride. It has an empirical formula of C23H31NO7 HCl and a molecular weight of 469.96.

CellCept Intravenous is available as a sterile white to off-white lyophilized powder in vials containing mycophenolate mofetil hydrochloride for administration by intravenous infusion only. Each vial of CellCept Intravenous contains the equivalent of 500 mg mycophenolate mofetil as the hydrochloride salt. The inactive ingredients are polysorbate 80, 25 mg, and citric acid, 5 mg. Sodium hydroxide may have been used in the manufacture of CellCept Intravenous to adjust the pH. Reconstitution and dilution with 5% Dextrose Injection USP yields a slightly yellow solution of mycophenolate mofetil, 6 mg/mL. (For detailed method of preparation, see DOSAGE AND ADMINISTRATION).

CellCept (mycophenolate mofetil capsules) 250 mg

Blue-brown, two-piece hard gelatin capsules, printed in black with “CellCept 250” on the blue cap and “Roche” on the brown body. Supplied in the following presentations:

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

CellCept (mycophenolate mofetil tablets) 500 mg

Lavender-colored, caplet-shaped, film-coated tablets printed in black with “CellCept 500” on one side and “Roche” on the other. Supplied in the following presentations:

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Dispense in light-resistant containers, such as the manufacturer's original containers.

CellCept Oral Suspension (mycophenolate mofetil for oral suspension)

Supplied as a white to off-white powder blend for constitution to a white to off-white mixed-fruit flavor suspension. Supplied in the following presentation:

Store dry powder at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Store constituted suspension at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) for up to 60 days. Storage in a refrigerator at 2° to 8°C (36° to 46°F) is acceptable. Do not freeze.

CellCept Intravenous (mycophenolate mofetil hydrochloride for injection)

Supplied in a 20 mL, sterile vial containing the equivalent of 500 mg mycophenolate mofetil as the hydrochloride salt in cartons of 4 vials:

Store powder and reconstituted/infusion solutions at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Distributed by: Genentech USA, Inc. A Member of the Roche Group, 1 DNA Way, South San Francisco, CA 94080-4990. Revised: September 2013

• Lupus (Systemic Lupus Erythematosus or SLE)

Take mycophenolate mofetil exactly as your doctor prescribes it. Follow the directions on your prescription label carefully. Your doctor will determine the best dose for you.

The recommended adult dose with kidney transplant is 1 g taken by mouth twice a day.

The recommended adult dose with heart or liver transplant is 1.5 g taken by mouth twice daily.  

WARNING

Immunosuppression may lead to increased susceptibility to infection and possible development of lymphoma. Only physicians experienced in immunosuppressive therapy and management of renal, cardiac or hepatic transplant patients should use mycophenolate mofetil. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Female users of childbearing potential must use contraception. Use of mycophenolate mofetil during pregnancy is associated with increased risk of pregnancy loss and congenital malformations.

Usual Adult Dose for Organ Transplant -- Rejection Prophylaxis:

-RENAL TRANSPLANTATION: 1 g orally or IV 2 times a day (2 gm per day); [in clinical trials, 1.5 g orally or IV 2 times a day (3 gm per day) was used effectively, however, the safety profile for 3 gm a day was lower]
-CARDIAC TRANSPLANTATION: 1.5 g orally or IV 2 times a day (3 gm per day)
-HEPATIC TRANSPLANTATION: 1.5 gm orally or 1 gm IV 2 times a day (3 gm per day orally or 2 gm per day IV)

Comments:
-This drug should be used concomitantly with cyclosporine and corticosteroids.
-The IV formulation should be administered over no less than 2 hours.
-IV administration is recommended in patients unable to take oral medication; oral administration should be initiated as soon as possible.

Usual Geriatric Dose for Organ Transplant -- Rejection Prophylaxis:

-RENAL TRANSPLANTATION: 1 g orally or IV 2 times a day (2 gm per day)
-CARDIAC TRANSPLANTATION: 1.5 g orally or IV 2 times a day (3 gm per day)
-HEPATIC TRANSPLANTATION: 1.5 gm orally or 1 gm IV 2 times a day (3 gm per day orally or 2 gm per day IV)

Comments:
-This drug should be used concomitantly with cyclosporine and corticosteroids.
-The IV formulation should be administered over no less than 2 hours.
-IV administration is recommended in patients unable to take oral medication; oral administration should be initiated as soon as possible.

Usual Pediatric Dose for Organ Transplant -- Rejection Prophylaxis:

-RENAL TRANSPLANTATION:
3 months to 18 years of age:
Oral Suspension: 600 mg/m2 orally 2 times a day up to a maximum of 2 grams per day
-Pediatric patients with a body surface area of 1.25 to 1.5 m2 may be dosed with the oral capsules at 750 mg orally 2 times a day (1.5 g per day)
-Pediatric patients with a body surface area greater than 1.5 m2 may be dosed with the oral capsules at 1 g orally 2 times a day (2 g per day)

Comments:
-This drug should be used concomitantly with cyclosporine and corticosteroids.
-The IV formulation should be administered over no less than 2 hours.-IV administration is recommended in patients unable to take oral medication; oral administration should be initiated as soon as possible.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with mycophenolate mofetil, especially:

• azathioprine;

• cholestyramine;

• an antiviral medicine--acyclovir, ganciclovir, valacyclovir;

• an antibiotic--amoxicillin, ciprofloxacin, metronidazole, norfloxacin, rifampin;

• stomach acid reducers--lansoprazole (Prevacid), pantoprazole (Protonix), and others; or

• a sulfa drug (Bactrim, Septra, SMX-TMP or SMZ-TMP, and others).

This list is not complete. Other drugs may interact with mycophenolate mofetil, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

In the U.S.

• Cellcept

Available Dosage Forms:

• Powder for Suspension
• Capsule
• Tablet

Therapeutic Class: Immune Suppressant

(see boxed WARNING)

Embryofetal Toxicity

Mycophenolate Mofetil (MMF) can cause fetal harm when administered to a pregnant female. Use of MMF 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 over suppression 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 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.

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.

Neutropenia

Severe neutropenia [absolute neutrophil count (ANC) <0.5 x 103/mcL] developed in up to 2.0% of renal, up to 2.8% of cardiac, and up to 3.6% of hepatic transplant patients receiving Mycophenolate Mofetil 3 g daily (see ADVERSE REACTIONS). Patients receiving Mycophenolate Mofetil should be monitored for neutropenia (see PRECAUTIONS: Laboratory Tests). The development of neutropenia may be related to Mycophenolate Mofetil itself, concomitant medications, viral infections, or some combination of these causes. If neutropenia develops (ANC <1.3 x 103/mcL), dosing with Mycophenolate Mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see DOSAGE AND ADMINISTRATION). Neutropenia has been observed most frequently in the period from 31 to 180 days posttransplant in patients treated for prevention of renal, cardiac, and hepatic rejection.
Patients receiving Mycophenolate Mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.

Pure Red Cell Aplasia (PRCA)

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Mycophenolate Mofetil in combination with other immunosuppressive agents. The mechanism for Mycophenolate Mofetil induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppression regimen are also unknown. In some cases, PRCA was found to be reversible with dose reduction or cessation of Mycophenolate Mofetil therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk.

CAUTION: Mycophenolate Mofetil INTRAVENOUS SOLUTION MUST NOT BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION.

Renal Transplantation

Adults

A dose of 1 g administered orally or intravenously (over NO LESS THAN 2 HOURS) twice a day (daily dose of 2 g) is recommended for use in renal transplant patients. Although a dose of 1.5 g administered twice daily (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving 2 g/day of Mycophenolate Mofetil demonstrated an overall better safety profile than did patients receiving 3 g/day of Mycophenolate Mofetil.

Pediatrics (3 months to 18 years of age)

The recommended dose of Mycophenolate Mofetil oral suspension is 600 mg/m2 administered twice daily (up to maximum daily dose of 2g/10 mL oral suspension). Patients with a body surface area of 1.25 m2 to 1.5 m2 may be dosed with Mycophenolate Mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area >1.5 m2 may be dosed with Mycophenolate Mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose).

Cardiac Transplantation

Adults

A dose of 1.5 g bid administered intravenously (over NO LESS THAN 2 HOURS) or 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult cardiac transplant patients. 

Hepatic Transplantation

Adults

A dose of 1 g bid administered intravenously (over NO LESS THAN 2 HOURS) or 1.5 g bid oral (daily dose of 3 g) is recommended for use in adult hepatic transplant patients. 

Mycophenolate Mofetil Capsules, Tablets, and Oral Suspension

The initial oral dose of Mycophenolate Mofetil should be given as soon as possible following renal, cardiac or hepatic transplantation. Food had no effect on MPA AUC, but has been shown to decrease MPA Cmax by 40%. Therefore, it is recommended that Mycophenolate Mofetil be administered on an empty stomach. However, in stable renal transplant patients, Mycophenolate Mofetil may be administered with food if necessary.

Patients should be instructed to take a missed dose as soon as they remember, except if it is near the next scheduled dose, and then continue to take Mycophenolate Mofetil at the usual times.

Note:

If required, Mycophenolate Mofetil oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).

Patients With Hepatic Impairment

No dose adjustments are recommended for renal patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

No data are available for cardiac transplant patients with severe hepatic parenchymal disease.

Geriatrics 

The recommended oral dose of 1 g bid for renal transplant patients, 1.5 g bid for cardiac transplant patients, and 1 g bid administered intravenously or 1.5 g bid administered orally in hepatic transplant patients is appropriate for elderly patients (see PRECAUTIONS: Geriatric Use).

Oral Suspension

Dispense with patient instruction sheet and oral dispensers. It is recommended to write the date of expiration of the constituted suspension on the bottle label. (The shelf-life of the constituted suspension is 60 days.) After constitution the oral suspension contains 200 mg/mL Mycophenolate Mofetil. Store constituted suspension at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Storage in a refrigerator at 2° to 8°C (36° to 46°F) is acceptable. Do not freeze. Discard any unused portion 60 days after constitution.

Infusion Solution 

If the infusion solution is not prepared immediately prior to administration, the commencement of administration of the infusion solution should be within 4 hours from reconstitution and dilution of the drug product. Keep solutions at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Mycophenolate Mofetil Intravenous should not be mixed or administered concurrently via the same infusion catheter with other intravenous drugs or infusion admixtures. 

Dosage Adjustments 

In renal transplant patients with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) outside the immediate posttransplant period, doses of Mycophenolate Mofetil greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively (see CLINICAL PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: Patients with Renal Impairment).

No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment. Mycophenolate Mofetil may be used for cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.

If neutropenia develops (ANC <1.3 x 103/mcL), dosing with Mycophenolate Mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately (see WARNINGS: Neutropenia, ADVERSE REACTIONS, and PRECAUTIONS: Laboratory Tests).

HANDLING AND DISPOSAL

Mycophenolate Mofetil has demonstrated teratogenic effects in humans (see Pregnancy and WARNINGS: Embryofetal Toxicity). Mycophenolate Mofetil tablets should not be crushed and Mycophenolate Mofetil capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in Mycophenolate Mofetil capsules and Mycophenolate Mofetil oral suspension (before or after constitution). If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water. Should a spill occur, wipe up using paper towels wetted with water to remove spilled powder or suspension. Caution should be exercised in the handling and preparation of solutions of Mycophenolate Mofetil intravenous. Avoid direct contact of the prepared solution of Mycophenolate Mofetil intravenous with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.