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Mycophenolate

Pronunciation

Pronunciation

(mye koe FEN oh late)

Index Terms

  • MMF
  • MPA
  • Mycophenolate Mofetil
  • Mycophenolate Sodium
  • Mycophenolic Acid

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as mofetil:

CellCept: 250 mg [contains fd&c blue #2 (indigotine)]

Generic: 250 mg

Solution Reconstituted, Intravenous, as mofetil hydrochloride:

CellCept Intravenous: 500 mg (1 ea)

Suspension Reconstituted, Oral, as mofetil:

CellCept: 200 mg/mL (160 mL) [contains aspartame, methylparaben, soybean lecithin; mixed fruit flavor]

Generic: 200 mg/mL (160 mL)

Tablet, Oral, as mofetil:

CellCept: 500 mg [contains fd&c blue #2 aluminum lake]

Generic: 500 mg

Tablet Delayed Release, Oral, as mycophenolic acid:

Myfortic: 180 mg [contains fd&c blue #2 (indigotine)]

Myfortic: 360 mg

Generic: 180 mg, 360 mg

Brand Names: U.S.

  • CellCept
  • CellCept Intravenous
  • Myfortic

Pharmacologic Category

  • Immunosuppressant Agent

Pharmacology

MPA exhibits a cytostatic effect on T and B lymphocytes. It is an inhibitor of inosine monophosphate dehydrogenase (IMPDH) which inhibits de novo guanosine nucleotide synthesis. T and B lymphocytes are dependent on this pathway for proliferation.

Absorption

Rapid and extensive; early post-transplant period mycophenolic acid (MPA) AUC values are lower (~45% to 53%) than later post-transplant period (>3 months) MPA AUC values in both pediatric patients and adults

Oral: Myfortic: 93%

Distribution

CellCept: MPA: Oral: 4 L/kg; IV: 3.6 L/kg

Myfortic: MPA: Oral: 54 L (at steady state); 112 L (elimination phase)

Metabolism

Hepatic and via GI tract; CellCept is completely hydrolyzed in the liver to mycophenolic acid (MPA; active metabolite); enterohepatic recirculation of MPA may occur; MPA is glucuronidated to MPAG (inactive metabolite)

Excretion

CellCept: MPA: Urine (<1%), feces (6%); MPAG: Urine (87%)

Myfortic: MPA: Urine (3%), feces; MPAG: Urine (>60%)

Onset of Action

Peak effect: Correlation of toxicity or efficacy is still being developed, however, one study indicated that 12-hour AUCs >40 mcg/mL/hour were correlated with efficacy and decreased episodes of rejection

Time to Peak

Plasma: Oral: MPA:

CellCept: 1 to 1.5 hours

Myfortic: 1.5 to 2.75 hours

Half-Life Elimination

CellCept: MPA: Oral: 18 hours; IV: 17 hours

Myfortic: MPA: Oral: 8 to16 hours; MPAG: 13 to 17 hours

Protein Binding

MPA: >97%, MPAG 82%

Special Populations: Renal Function Impairment

Cellcept

Mycophenolic acid AUC increased 75%, and mycophenolic acid glucuronide AUC increased 3- to 6-fold in patients with severe renal impairment (glomerular filtration rate [GFR] <25 mL/minute/1.73 m2). Hemodialysis usually does not remove mycophenolic acid or mycophenolic acid glucuronide.

Use: Labeled Indications

Organ transplantation: Prophylaxis of organ rejection concomitantly with cyclosporine and corticosteroids in patients receiving allogeneic renal (CellCept, Myfortic), cardiac (CellCept), or hepatic (CellCept) transplants

Use: Unlabeled

Treatment of rejection in liver transplant patients unable to tolerate tacrolimus or cyclosporine due to toxicity; treatment of recurrent or persistent rejection in heart transplant patients; treatment of moderate-severe psoriasis; treatment of lupus nephritis; treatment of myasthenia gravis; prevention of graft-versus-host disease (GVHD); treatment of refractory acute GVHD and chronic GVHD; treatment of refractory autoimmune hepatitis

Contraindications

Hypersensitivity to mycophenolate mofetil, mycophenolic acid, mycophenolate sodium, or any component of the formulation

Cellcept: Intravenous formulation is also contraindicated in patients who are allergic to polysorbate 80

Canadian labeling: Additional contraindications (not in US labeling): Cellcept: Pregnancy; women of childbearing potential and not using highly effective contraceptive methods; women of childbearing potential not providing a pregnancy test result; breast-feeding

Dosing: Adult

Note: May be used IV for up to 14 days; transition to oral therapy as soon as tolerated.

Renal transplant:

CellCept:

Oral: 1 g twice daily. Doses >2 g daily are not recommended.

IV: 1 g twice daily

Myfortic: Oral: 720 mg twice daily (total daily dose: 1440 mg)

Cardiac transplantation: CellCept:

Oral: 1.5 g twice daily

IV: 1.5 g twice daily

Hepatic transplantation: CellCept:

Oral: 1.5 g twice daily

IV: 1 g twice daily

Autoimmune hepatitis, refractory (off-label use): CellCept: Oral: 2 g daily (Manns, 2010)

Lupus nephritis (off-label use): CellCept: Oral:

Induction: 1 g twice daily for 6 months in combination with a glucocorticoid (Ong, 2005) or 2-3 g daily for 6 months in combination with glucocorticoids (Hahn, 2012)

Maintenance: 0.5-3 g daily (Contreras, 2004) or 1 g twice daily (Dooley, 2011) or 1-2 g daily (Hahn, 2012)

Myasthenia gravis (off-label use): CellCept: Oral: 1 g twice daily (range: 1-3 g daily) (Cahoon, 2006; Ciafaloni, 2001; Merriggioli, 2003)

Psoriasis, moderate-to-severe (off-label use): CellCept: Oral: 2-3 g daily (Menter, 2009)

Dosing: Geriatric

Dosage is the same as younger patients, however, dosing should be cautious due to possibility of increased hepatic, renal, or cardiac dysfunction. Elderly patients may be at an increased risk of certain infections, gastrointestinal hemorrhage, and pulmonary edema, as compared to younger patients.

Dosing: Pediatric

Renal transplant: Oral:

CellCept: Infants ≥3 months, Children, and Adolescents: Cellcept suspension: 600 mg/m2/dose twice daily; maximum dose: 1 g twice daily

Alternatively, may use Cellcept solid dosage forms according to BSA as follows:

BSA 1.25 to 1.5 m2: 750 mg capsule twice daily

BSA >1.5 m2: 1 g capsule or tablet twice daily

Myfortic: Children ≥5 years and Adolescents: Usual dosage: 400 mg/m2/dose twice daily; maximum dose: 720 mg twice daily

BSA <1.19 m2: Use of this formulation is not recommended

BSA 1.19 to 1.58 m2: 540 mg twice daily (maximum: 1080 mg daily)

BSA >1.58 m2: 720 mg twice daily (maximum: 1440 mg daily)

Dosing: Renal Impairment

Renal transplant: GFR <25 mL/minute/1.73 m2 in patients outside the immediate post-transplant period:

CellCept: Doses of >1 g administered twice daily should be avoided; patients should also be carefully observed; no dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively

Myfortic: No dose adjustments are needed in renal transplant patients experiencing delayed graft function postoperatively; however, monitor carefully for potential concentration dependent adverse events

Cardiac or liver transplant: No data available; mycophenolate may be used in cardiac or hepatic transplant patients with severe chronic renal impairment if the potential benefit outweighs the potential risk.

Autoimmune disease (off-label use): There have been no specific dosage adjustments identified, although use of lower doses may be required. MPA exposure appears to be inversely related to renal function (Abd Rahman, 2013); monitor closely for efficacy and adverse effects, especially in patients with end-stage renal disease (Haubitz, 2002; MacPhee, 2000).

Hemodialysis: Not removed; supplemental dose is not necessary.

Peritoneal dialysis: Supplemental dose is not necessary.

Dosing: Hepatic Impairment

No dosage adjustment is recommended for renal patients with severe hepatic parenchymal disease; however, it is not currently known whether dosage adjustments are necessary for hepatic disease with other etiologies.

Dosing: Adjustment for Toxicity

Neutropenia (ANC <1.3 x 103/μL): Dosing should be interrupted or the dose reduced, appropriate diagnostic tests performed and patients managed appropriately

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Oral suspension: Should be constituted prior to dispensing to the patient and not mixed with any other medication. Add 47 mL of water to the bottle and shake well for ~1 minute. Add another 47 mL of water to the bottle and shake well for an additional minute. Final concentration is 200 mg/mL of mycophenolate mofetil.

IV: Reconstitute the contents of each vial with 14 mL of 5% dextrose injection; dilute the contents of a vial with 5% dextrose in water to a final concentration of 6 mg mycophenolate mofetil per mL. Note: Vial is vacuum-sealed; if a lack of vacuum is noted during preparation, the vial should not be used.

Extemporaneously Prepared

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]). When manipulating capsules, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH 2014).

A 50 mg/mL oral suspension may be made with mycophenolate mofetil capsules, Ora-Plus, and cherry syrup. In a vertical flow hood, empty six 250 mg capsules into a mortar; add 7.5 mL Ora-Plus and mix to a uniform paste. Mix while adding 15 mL of cherry syrup in incremental proportions; transfer to a calibrated bottle, rinse mortar with cherry syrup, and add sufficient quantity of cherry syrup to make 30 mL. Label "shake well". Stable for 210 days at 5°C, for 28 days at 25°C to 37°C, and for 11 days at 45°C.

Venkataramanan R, McCombs JR, Zuckerman S, et al, "Stability of Mycophenolate Mofetil as an Extemporaneous Suspension," Ann Pharmacother, 1998, 32(7-8):755-7.9681090

Administration

Oral dosage formulations (tablet, capsule, suspension) should be administered on an empty stomach (1 hour before or 2 hours after meals) to avoid variability in MPA absorption. The oral solution may be administered via a nasogastric tube (minimum 8 French, 1.7 mm interior diameter); oral suspension should not be mixed with other medications. Delayed release tablets should not be crushed, cut, or chewed. Cellcept may be administered with food in stable renal transplant patients when necessary. If a dose is missed, administer as soon as it is remembered. If it is close to the next scheduled dose, skip the missed dose and resume at next regularly scheduled time; do not double a dose to make up for a missed dose.

Intravenous solutions should be administered over at least 2 hours (either peripheral or central vein); do not administer intravenous solution by rapid or bolus injection.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]). NIOSH recommends single gloving for administration of intact capsules or tablets. Double gloving and a protective gown are recommended for administration of oral liquids. When preparing the oral suspension, or if it is necessary to manipulate the capsules or tablets (eg, to prepare an oral suspension), it is recommended to double glove, wear a protective gown, and prepare in a controlled device (NIOSH 2014).

Dietary Considerations

Some products may contain phenylalanine.

Compatibility

Stable in D5W.

Y-site administration: Incompatible with micafungin.

Storage

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

Tablets: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture and light.

Oral suspension: Store powder for oral suspension at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Once reconstituted, the oral solution may be stored at room temperature or under refrigeration. Do not freeze. The mixed suspension is stable for 60 days.

Injection: Store intact vials and solutions diluted in D5W at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Begin infusion within 4 hours of reconstitution.

Drug Interactions

Acyclovir-Valacyclovir: May increase the serum concentration of Mycophenolate. Mycophenolate may increase the serum concentration of Acyclovir-Valacyclovir. Monitor therapy

Antacids: May decrease the absorption of Mycophenolate. Management: Separate doses of mycophenolate and antacids by at least 2 hours. Monitor for reduced effects of mycophenolate if taken concomitant with antacids. Exceptions: Sodium Bicarbonate. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bile Acid Sequestrants: May decrease the serum concentration of Mycophenolate. Avoid combination

Cholestyramine Resin: May decrease the serum concentration of Mycophenolate. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Contraceptives (Estrogens): Mycophenolate may decrease the serum concentration of Contraceptives (Estrogens). Average AUC values were unchanged, but there was evidence of substantial patient-to-patient variability in response to this combination. Management: Women of childbearing potential who are receiving mycophenolate mofetil should consider using an alternative and/or additional form of contraception. Consider therapy modification

Contraceptives (Progestins): Mycophenolate may decrease the serum concentration of Contraceptives (Progestins). Management: Use of an additional or alternative (nonhormonal) method of contraception should be considered. Consider therapy modification

CycloSPORINE (Systemic): May decrease the serum concentration of Mycophenolate. Specifically, cyclosporine may decrease concentrations of the active metabolite mycophenolic acid. Management: Mycophenolate requirements may be greater in patients receiving cyclosporine. Monitor mycophenolate dosing and response to therapy particularly closely when adjusting concurrent cyclosporine (starting, stopping, or changing dose). Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Ganciclovir-Valganciclovir: Mycophenolate may increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Mycophenolate. Monitor therapy

Isavuconazonium Sulfate: May increase the serum concentration of Mycophenolate. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Magnesium Salts: May decrease the serum concentration of Mycophenolate. Management: Separate doses of mycophenolate and oral magnesium salts. Monitor for reduced effects of mycophenolate if taken concomitant with oral magnesium salts. Consider therapy modification

MetroNIDAZOLE (Systemic): May decrease the serum concentration of Mycophenolate. Specifically, metronidazole may decrease concentrations of the active metabolite of mycophenolate. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Penicillins: May decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Probenecid: May increase the serum concentration of Mycophenolate. Monitor therapy

Proton Pump Inhibitors: May decrease the serum concentration of Mycophenolate. Specifically, concentrations of the active mycophenolic acid may be reduced. Monitor therapy

Quinolone Antibiotics: May decrease the serum concentration of Mycophenolate. Specifically, quinolones may decrease concentrations of the active metabolite of mycophenolate. Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Mycophenolate. Specifically, rifamycin derivatives may decrease the concentration of the active metabolite mycophenolic acid. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sevelamer: May decrease the serum concentration of Mycophenolate. Management: Administer mycophenolate at least 2 hours prior to sevelamer administration. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Teriflunomide: May increase the serum concentration of OAT3 Substrates. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Data for incidence >20% as reported in adults following oral dosing of CellCept alone in renal, cardiac, and hepatic allograft rejection studies. Profile in 3% to <20% range reflects use in combination with cyclosporine and corticosteroids. In general, lower doses used in renal rejection patients had less adverse effects than higher doses. Rates of adverse effects were similar for each indication, except for those unique to the specific organ involved. The type of adverse effects observed in pediatric patients was similar to those seen in adults, with the exception of abdominal pain, anemia, diarrhea, fever, hypertension, infection, pharyngitis, respiratory tract infection, sepsis, and vomiting; lymphoproliferative disorder was the only type of malignancy observed. Percentages of adverse reactions were similar in studies comparing CellCept to Myfortic in patients following renal transplant.

>20%:

Cardiovascular: Hypertension (28% to 78%), hypotension (33%), peripheral edema (27% to 64%), edema (27% to 28%), chest pain (26%), tachycardia (20% to 22%)

Central nervous system: Pain (31% to 76%), headache (16% to 54%), insomnia (41% to 52%), fever (21% to 52%), dizziness (29%), anxiety (28%)

Dermatologic: Rash (22%)

Endocrine & metabolic: Hyperglycemia (44% to 47%), hypercholesterolemia (41%), hypomagnesemia (39%), hypokalemia (32% to 37%), hypocalcemia (30%), hyperkalemia (22%)

Gastrointestinal: Abdominal pain (25% to 63%), nausea (20% to 55%), diarrhea (31% to 51%), constipation (19% to 41%), vomiting (33% to 34%), anorexia (25%), dyspepsia (22%)

Genitourinary: Urinary tract infection (37%)

Hematologic: Leukopenia (23% to 46%), anemia (26% to 43%; hypochromic 25%), leukocytosis (22% to 41%), thrombocytopenia (24% to 38%)

Hepatic: Liver function tests abnormal (25%), ascites (24%)

Neuromuscular & skeletal: Back pain (35% to 47%), weakness (35% to 43%), tremor (24% to 34%), paresthesia (21%)

Renal: Creatinine increased (39%), BUN increased (35%), kidney function abnormal (22% to 26%)

Respiratory: Dyspnea (31% to 37%), respiratory tract infection (22% to 37%), pleural effusion (34%), cough (31%), lung disorder (22% to 30%), sinusitis (26%)

Miscellaneous: Infection (18% to 27%), sepsis (27%), lactate dehydrogenase increased (23%), Candida (17% to 22%), herpes simplex (10% to 21%)

3% to <20%:

Cardiovascular: Angina, arrhythmia, arterial thrombosis, atrial fibrillation, atrial flutter, bradycardia, cardiac arrest, cardiac failure, CHF, extrasystole, facial edema, hyper-/hypovolemia, orthostatic hypotension, pallor, palpitation, pericardial effusion, peripheral vascular disorder, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombosis, vasodilation, vasospasm, venous pressure increased, ventricular extrasystole, ventricular tachycardia

Central nervous system: Agitation, chills with fever, confusion, delirium, depression, emotional lability, hallucinations, hypoesthesia, malaise, nervousness, psychosis, seizure, somnolence, thinking abnormal, vertigo

Dermatologic: Acne, alopecia, bruising, cellulitis, fungal dermatitis, hirsutism, petechia, pruritus, skin carcinoma, skin hypertrophy, skin ulcer, vesiculobullous rash

Endocrine & metabolic: Acidosis, alkalosis, Cushing's syndrome, dehydration, diabetes mellitus, gout, hypercalcemia, hyper-hypophosphatemia, hyperlipemia, hyperuricemia, hypochloremia, hypoglycemia, hyponatremia, hypoproteinemia, hypothyroidism, parathyroid disorder

Gastrointestinal: Abdomen enlarged, dysphagia, esophagitis, flatulence, gastritis, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, gum hyperplasia, ileus, melena, mouth ulceration, oral moniliasis, stomach disorder, stomach ulcer, stomatitis, xerostomia, weight gain/loss

Genitourinary: Impotence, nocturia, pelvic pain, prostatic disorder, scrotal edema, urinary frequency, urinary incontinence, urinary retention, urinary tract disorder

Hematologic: Coagulation disorder, hemorrhage, neutropenia, pancytopenia, polycythemia, prothrombin time increased, thromboplastin time increased

Hepatic: Alkaline phosphatase increased, bilirubinemia, cholangitis, cholestatic jaundice, GGT increased, hepatitis, jaundice, liver damage, transaminases increased

Local: Abscess

Neuromuscular & skeletal: Arthralgia, hypertonia, joint disorder, leg cramps, myalgia, myasthenia, neck pain, neuropathy, osteoporosis

Ocular: Amblyopia, cataract, conjunctivitis, eye hemorrhage, lacrimation disorder, vision abnormal

Otic: Deafness, ear disorder, ear pain, tinnitus

Renal: Albuminuria, creatinine increased, dysuria, hematuria, hydronephrosis, oliguria, pyelonephritis, renal failure, renal tubular necrosis

Respiratory: Apnea, asthma, atelectasis, bronchitis, epistaxis, hemoptysis, hiccup, hyperventilation, hypoxia, respiratory acidosis, pharyngitis, pneumonia, pneumothorax, pulmonary edema, pulmonary hypertension, respiratory moniliasis, rhinitis, sputum increased, voice alteration

Miscellaneous: Candida (mucocutaneous 16% to 18%), CMV viremia/syndrome (12% to 14%), CMV tissue invasive disease (6% to 12%), herpes zoster cutaneous disease (4% to 10%), cyst, diaphoresis, flu-like syndrome, healing abnormal, hernia, ileus infection, neoplasm, peritonitis, thirst

<1% (Limited to important or life-threatening): Atypical mycobacterial infection, BK virus-associated nephropathy, bronchiectasis (Boddana 2011, Rook 2006), colitis, gastrointestinal perforation, hypogammaglobulinemia (Boddana 2011; Keven 2003; Robertson 2009), infectious endocarditis, interstitial lung disorder, intestinal villous atrophy, lymphoma, lymphoproliferative disease, malignancy, meningitis, pancreatitis, progressive multifocal leukoencephalopathy (sometimes fatal), pulmonary fibrosis (fatal), pure red cell aplasia, tuberculosis

ALERT: U.S. Boxed Warning

Experienced physician:

Only health care providers experienced in immunosuppressive therapy and management of organ transplant patients should prescribe mycophenolate. Manage patients receiving the drug in facilities equipped and staffed with adequate laboratory and supportive medical resources. The health care provider responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Serious infections:

Immunosuppression may lead to increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections.

Malignancies and serious infections:

Immunosuppression may lead to increased risk of development of lymphoma and other malignancies, particularly of the skin.

Embryo-fetal toxicity:

Use during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations. Women of reproductive potential must be counseled regarding pregnancy prevention and planning.

Warnings/Precautions

Concerns related to adverse effects:

• Infections: [US Boxed Warning]: Risk for bacterial, viral, fungal, and protozoal infections, including opportunistic infections, is increased with immunosuppressant therapy; infections may be serious and potentially fatal. Due to the risk of oversuppression of the immune system, which may increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.

• New or reactivated viral infections: Polyomavirus associated nephropathy (PVAN), JC virus-associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, and reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported with use. A reduction in immunosuppression should be considered for patients with new or reactivated viral infections; however, in transplant recipients, the risk that reduced immunosuppression presents to the functioning graft should also be considered. PVAN, primarily from activation of BK virus, may lead to the deterioration of renal function and/or renal graft loss. PML, a potentially fatal condition, commonly presents with hemiparesis, apathy, ataxia, cognitive deficiencies, confusion, and hemiparesis. Risk factors for development of PML include treatment with immunosuppressants and immune function impairment; consultation with a neurologist should be considered in any patient with neurological symptoms receiving immunosuppressants. Risk of CMV viremia or disease is increased in transplant recipients CMV seronegative at the time of transplant who receive a graft from a CMV seropositive donor; however, routine approaches to limiting CMV exist and should be utilized. In patients infected with HBV or HCV, viral reactivation may occur; these patients should be monitored for signs of active HBV or HCV.

• Lymphoproliferative disorders: [US Boxed Warning]: Risk of development of lymphoma and skin malignancy is increased. The risk for malignancies is related to intensity/duration of therapy. Patients should be monitored appropriately, instructed to limit exposure to sunlight/UV light to decrease the risk of skin cancer, and given supportive treatment should these conditions occur. Post-transplant lymphoproliferative disorder related to EBV infection has been reported in immunosuppressed organ transplant patients; risk is highest in EBV seronegative patients (including many young children).

• Neutropenia: Neutropenia (including severe neutropenia) may occur, requiring dose reduction or interruption of treatment (risk greater from day 31-180 post-transplant).

• Pure red cell aplasia (PRCA): PRCA, a type of anemia which can range from subclinical to severe, has been reported in patients receiving mycophenolate concomitantly with other immunosuppressive agents (eg, tacrolimus, cyclosporine, corticosteroids). Symptoms may include fatigue, lethargy, or pallor. Although not precisely known, risk factors for the development of PRCA may include immunosuppression and treatment with immunosuppressant therapy. Dose reduction or discontinuation of immunosuppressive therapy may reverse PRCA; however, in transplant recipients, the risk of reduced immunosuppression and graft rejection should be considered.

Disease-related concerns:

• Gastrointestinal disorders: Use may rarely be associated with gastric or duodenal ulcers, GI bleeding and/or perforation. Use caution in patients with active serious digestive system disease; patients with active peptic ulcers were not included in clinical studies.

• Hypoxanthine-guanine phosphoribosyltransferase deficiency: Theoretically, use should be avoided in patients with the rare hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase (such as Lesch-Nyhan or Kelley-Seegmiller syndrome).

• Renal impairment: Use with caution in patients with renal impairment as toxicity may be increased; may require dosage adjustment in severe impairment.

Dosage form specific issues:

• Non-interchangeability of forms: Note: CellCept and Myfortic dosage forms should not be used interchangeably due to differences in absorption.

• Phenylalanine: Some dosage forms may contain phenylalanine.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

Special populations:

• Pregnancy: [US Boxed Warning]: Mycophenolate is associated with an increased risk of congenital malformations and first trimester pregnancy loss when used by pregnant women. Females of reproductive potential must be counseled about pregnancy prevention and planning. Alternative agents should be considered for women planning a pregnancy. Females of reproductive potential should have a negative pregnancy test with a sensitivity of ≥25 milliunits/mL immediately before therapy and the test should be repeated 8-10 days later. Pregnancy tests should be repeated during routine follow-up visits. Acceptable forms of contraception should be used during treatment and for 6 weeks after therapy is discontinued.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

• Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, tablets should not be crushed or cut, and capsules should not be opened or crushed. Avoid inhalation or direct contact with skin or mucous membranes of the powder contained in the capsules and the powder for oral suspension. Caution should be exercised in the handling and preparation of solutions of intravenous mycophenolate. Avoid skin contact with the intravenous solution and reconstituted suspension. If such contact occurs, wash thoroughly with soap and water, rinse eyes with plain water.

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of a physician experienced in immunosuppressive therapy.

• Immunizations: Live attenuated vaccines should be avoided during use; vaccinations may be less effective during therapy.

• IV administration: Intravenous solutions should be given over at least 2 hours; never administer intravenous solution by rapid or bolus injection.

Monitoring Parameters

Complete blood count (weekly for first month, twice monthly during months 2 and 3, then monthly thereafter through the first year); renal and liver function; signs and symptoms of organ rejection; signs and symptoms of bacterial, fungal, protozoal, new or reactivated viral, or opportunistic infections; neurological symptoms (eg, hemiparesis, confusion, cognitive deficiencies, ataxia) suggestive of PML, pregnancy test (immediately prior to initiation and 8-10 days later in females of childbearing potential, followed by repeat tests during therapy); monitor skin (for lesions suspicious of skin cancer); monitor for signs of lymphoma

Pregnancy Risk Factor

D

Pregnancy Considerations

[US Boxed Warning]: Mycophenolate is associated with an increased risk of congenital malformations and first trimester pregnancy loss when used by pregnant women. Females of reproductive potential must be counseled about pregnancy prevention and planning. Alternative agents should be considered for women planning a pregnancy. The following congenital malformations have been reported following exposure during pregnancy: external ear abnormalities, cleft lip and palate, anomalies of the distal limbs, heart, esophagus, kidney, and nervous system. Spontaneous abortions have also been noted. Females of reproductive potential (girls who have entered puberty, women with a uterus who have not passed through clinically confirmed menopause) should have a negative pregnancy test with a sensitivity of ≥25 milliunits/mL immediately before therapy and the test should be repeated 8 to 10 days later. Pregnancy tests should be repeated during routine follow-up visits. Acceptable forms of contraception should be used during treatment and for 6 weeks after therapy is discontinued. The effectiveness of hormonal contraceptive agents may be affected by mycophenolate. The Canadian labeling recommends that males (including those who have undergone vasectomy) receiving treatment and their female partners use highly effective contraception during treatment and for at least 90 days after the last dose. Use for organ transplantation is contraindicated in pregnant women, in women of childbearing potential not using highly effective contraceptive methods, and in women of childbearing potential not providing a pregnancy test result by some manufacturers. Mycophenolate is not recommended for the treatment of psoriasis in pregnant women (Menter 2009). For women with lupus nephritis taking mycophenolate and who are planning a pregnancy, mycophenolate should be discontinued at least 6 weeks prior to trying to conceive (Hahn 2012).

Healthcare providers should report female exposures to mycophenolate during pregnancy or within 6 weeks of discontinuing therapy to the Mycophenolate Pregnancy Registry (800-617-8191). The National Transplantation Pregnancy Registry (NTPR, Temple University) is a registry for pregnant women taking immunosuppressants following any solid organ transplant. The NTPR encourages reporting of all immunosuppressant exposures during pregnancy in transplant recipients at 877-955-6877.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience injection site irritation, back pain, constipation, lack of appetite, flatulence, tremors, or insomnia. Have patient report immediately to prescriber signs of infection, signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of progressive multifocal leukoencephalopathy (confusion, depression, trouble with memory, behavioral changes, change in strength on one side, trouble speaking, change in balance, vision changes), signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), angina, tachycardia, bradycardia, arrhythmia, severe headache, excessive weight loss, loss of strength and energy, burning or numbness feeling, mole changes, skin growths, severe dizziness, passing out, night sweats, severe diarrhea, severe nausea, vomiting, severe abdominal pain, swelling of arms or legs, enlarged lymph nodes, pale skin, white patches in mouth, vaginitis, or jaundice (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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