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Mycophenolate

Medically reviewed on Nov 15, 2018

Pronunciation

See also: Entyvio

(mye koe FEN oh late)

Index Terms

  • ECMS
  • 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) [contains polysorbate 80]

Generic: 500 mg (1 ea)

Suspension Reconstituted, Oral, as mofetil:

CellCept: 200 mg/mL (160 mL) [contains aspartame, methylparaben, sorbitol, 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: ~3.6 ± 1.5 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: 17.9 ± 6.5 hours; IV: 16.6 ± 5.8 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).

Use: Labeled Indications

Organ transplantation: Prophylaxis of organ rejection in patients receiving allogeneic renal (CellCept [mycophenolate mofetil], Myfortic [enteric-coated mycophenolate sodium]), cardiac (CellCept), or liver (CellCept) transplants, in combination with other immunosuppressants

Note: While traditionally used in combination with cyclosporine, mycophenolate is now used primarily in combination with tacrolimus and, to a lesser extent, with a mammalian target of rapamycin inhibitor (everolimus or sirolimus) for prophylaxis of rejection in renal, cardiac, and hepatic transplants (AASLD [Lucey 2013]; Aliabadi 2012; Eisen 2013; Groetzner 2009; Guethoff 2013; ISHLT [Costanzo 2010]; KDIGO [Chapman 2010]).

Myfortic may also be used to prevent organ rejection in patients receiving cardiac and hepatic transplantations although not labeled for these transplantations (Lehmkuhl 2008; Wang 2015).

Off Label Uses

Acute graft-versus-host disease, refractory (treatment)

Data from a multicenter, randomized, 4-arm phase II trial in patients with acute graft-versus-host disease (GVHD) who had undergone an allogeneic hematopoietic stem cell transplantation (HSCT) support the use of mycophenolate (in combination with corticosteroids) in the treatment of this condition [Alousi 2009]. Additional trials may be necessary to further define the role of mycophenolate in this condition.

Autoimmune hepatitis (first-line agent)

Data from a prospective, open-label, observational study in Greece supports the use of mycophenolate mofetil in combination with corticosteroids as a first-line agent in treatment of autoimmune hepatitis [Zachou 2016]. Additional trials may be necessary to further define the role of mycophenolate mofetil for first line treatment of this condition.

Autoimmune hepatitis (refractory)

Based on the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines: Diagnosis and Management of Autoimmune Hepatitis, mycophenolate mofetil given for the treatment of refractory autoimmune hepatitis is effective and recommended in the management of this condition [Manns 2010].

Chronic graft-versus-host disease, refractory (treatment)

Based on the American Society for Blood and Marrow Transplant (ASBMT) Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease, mycophenolate is an effective and suitable second-line treatment for this condition.

Graft-versus-host disease (prevention)

Data from prospective cohort study in patients having undergone allogeneic HSCT treated with mycophenolate (in combination with tacrolimus) support the use of mycophenolate in the prevention of GVHD [Sabry 2009]. Additional trials may be necessary to further define the role of mycophenolate in this condition.

Lung transplant (prevention of bronchiolitis obliterans syndrome)

Data from a limited number of clinical trials suggests that mycophenolate in combination with other immunosuppressant medications may be beneficial for prevention of bronchiolitis obliterans syndrome [Glanville 2015], [McNeil 2006], [Speich 2010]. Additional data may be necessary to further define the role of mycophenolate in prevention of bronchiolitis obliterans syndrome.

Lung transplant (prevention of rejection)

Data from several studies and clinical experiences support the use of mycophenolate in combination with other immunosuppressant medications in the prevention of rejection after lung transplant [Lama 2003]. Additional trials may be necessary to further define the role of mycophenolate in prevention of rejection after lung transplant.

Lupus nephritis

Data from a multicenter, randomized study support the use of mycophenolate in combination with corticosteroids as induction therapy for the treatment of moderately severe proliferative lupus nephritis [Ong 2005]. Data from a randomized, double-blind, double-dummy, phase III study also support the use of mycophenolate in the treatment of lupus nephritis [Dooley 2011]. In patients with this condition mycophenolate was superior to azathioprine in maintaining a renal response and preventing relapse. Additionally, data from a single-center, randomized, open-label, controlled study support the use of mycophenolate as maintenance therapy in the treatment of lupus nephritis [Contreras 2004].

Based on the American College of Rheumatology Guidelines for Screening, Treatment, and Management of Lupus Nephritis, mycophenolate given for the treatment of lupus nephritis is effective and recommended in the management of this condition.

Myasthenia gravis

Based on the Myasthenia Gravis Foundation of America consensus-based guidance for the management of myasthenia gravis, mycophenolate is a recommended immunosuppressive agent in patients with myasthenia gravis who have not met treatment goals after an adequate trial of pyridostigmine. Mycophenolate may be added as monotherapy or in conjunction with glucocorticoids and/or pyridostigmine [Meriggioli 2003], [Sanders 2016].

Psoriasis (moderate to severe)

Based on the American Academy of Dermatology, Guidelines of Care for the Management of Psoriasis and Psoriatic Arthritis, mycophenolate given for the treatment of psoriasis is effective and recommended in the management of this condition [Menter 2009].

Systemic sclerosis (scleroderma)

Data from a limited number of observational clinical studies and case series suggest that mycophenolate may be beneficial for the treatment of systemic sclerosis, specifically for improving skin involvement and stabilizing pulmonary function and fibrosis [Derk 2009], [Gerbino 2008], [Henes 2013], [Herrick 2017], [Le 2011], [Mendoza 2012], [Nihtyanova 2007], [Simeon-Aznar 2011], [Yilmaz 2014]. One randomized controlled, double-blind trial in patients with scleroderma-related interstitial lung disease showed an improvement in lung function, measured by percent change in forced vital capacity from baseline, in patients receiving mycophenolate mofetil [Tashkin 2016]. Additional trials may be necessary to further define the role of mycophenolate in this condition.

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 (Tween)

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

Dosing: Adult

Note: Mycophenolate mofetil (CellCept) and enteric-coated mycophenolate sodium (Myfortic) are not equivalent. Conversion to equimolar doses is necessary. Myfortic 180 mg is considered equivalent to CellCept 250 mg (Budde 2004a; Salvadori 2004).

Autoimmune hepatitis, first-line (off-label use): CellCept: Oral: Initial: 500 mg twice daily for 3 weeks; gradually increase to 1.5 to 2 g/day (in combination initially with an oral corticosteroid [eg, prednisolone]); in the study, mycophenolate was continued for at least 2 years after a complete response (Zachou 2016).

Autoimmune hepatitis, refractory (off-label use): CellCept: Oral: 2 g/day given in divided doses (added to a combination of a corticosteroid and a calcineurin inhibitor) (AASLD [Manns 2010])

Cardiac transplantation:

Oral:

CellCept: Initial: 1.5 g twice daily in combination with cyclosporine and initially with corticosteroids (Eisen 2005; Kobashigawa 2006) or 1 g twice daily in combination with other immunosuppressants (tacrolimus, everolimus, or sirolimus) and initially with corticosteroids (Andreassen 2014; Kaczmarek 2013; Monchaud 2009)

Myfortic (off-label use): Initial: 1.08 g twice daily in combination with cyclosporine and initially with corticosteroids (Hummel 2007; Kobashigawa 2006; Lehmkuhl 2008). Although data do not exist for combination with tacrolimus, everolimus, or sirolimus, use of lower equimolar doses (eg, 720 mg twice daily) to mycophenolate mofetil may be appropriate when used with these other immunosuppressants; higher maintenance doses of 1.08 g twice daily may be required in some patients.

IV: CellCept: See oral dosing for CellCept; IV and oral doses (of mycophenolate mofetil) are equivalent. If converting from Myfortic to IV CellCept, convert Myfortic to equivalent CellCept oral dose first. Transition to oral therapy as soon as tolerated.

Liver transplantation:

Oral:

CellCept: Initial: 1.5 g twice daily when used in combination with cyclosporine or 1 g twice daily when used in combination with other immunosuppressants (eg, tacrolimus) (Eckhoff 1998; Nashan 2009). Maintenance doses vary based on concomitant immunosuppression.

Myfortic (off-label use): 360 mg to 720 mg twice daily in combination with other immunosuppressants (Cantisani 2006; Doria 2009; Lopez-Solis 2014; Toledo 2012; Wang 2015). Higher maintenance doses of 1.08 g twice daily may be required in some patients.

Note: At a minimum of 6 months post-liver transplant in order to avoid toxicities associated with calcineurin inhibitors, may convert gradually from calcineurin inhibitor based immunosuppression to mycophenolate monotherapy over a 2 to 3 month period (Schlitt 2001; Schmeding 2011). Mycophenolate may serve as a safe long-term immunosuppressant in a subgroup of patients (eg, patients with renal insufficiency).

IV: CellCept: See oral dosing for CellCept; IV and oral doses (of mycophenolate mofetil) are equivalent. After transplantation, the manufacturer recommends an initial IV dose of 1 g twice daily (based on clinical trial protocol) (Weisner 2001). Transition to oral therapy as soon as tolerated.

Lung transplantation (prevention of rejection and bronchiolitis obliterans syndrome) (off-label use):

Oral:

CellCept: Initial: 1.5 g twice daily when used in combination with cyclosporine and initially with corticosteroids (Speich 2010) or 1 g twice daily when used in combination with other immunosuppressants (eg, tacrolimus) and initially with corticosteroids (Treede 2001; Zuckermann 2003). Higher maintenance doses of 1.5 g twice daily may be required in some patients.

Myfortic: Initial: 1.08 g twice daily in combination with cyclosporine and initially with corticosteroids (Glanville 2015). Although data do not exist for combination with tacrolimus, everolimus, or sirolimus, use of lower equimolar doses (eg, 720 mg twice daily) to mycophenolate mofetil may be appropriate when used with these other immunosuppressants. Higher maintenance doses of 1.08 g twice daily may be required in some patients.

IV: See oral dosing for CellCept; IV and oral doses (of mycophenolate mofetil) are equivalent. If converting from Myfortic to IV CellCept, convert Myfortic to equivalent CellCept oral dose first. Transition to oral therapy as soon as tolerated.

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

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

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

Myasthenia gravis (off-label use): Patients who remain significantly symptomatic on pyridostigmine: CellCept: Oral: Initial: 500 mg twice daily; increase based on response and tolerability to a maintenance dose of 1 g to 1.5 g twice daily. May be added as monotherapy or in conjunction with glucocorticoids and/or pyridostigmine (Meriggioli 2003; Sanders 2016). Onset of clinical response to mycophenolate may take up to 6 to 12 months, with a maximum effect not apparent until 1 to 2 years (Sieb 2014).

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

Renal transplantation:

Oral:

CellCept: Initial: 1 g twice daily. Maintenance dose may vary based on concomitant immunosuppression. Doses >2 g/day have been associated with an increased incidence of adverse effects but may be necessary in some patients (EMMC study group 1999; TMMRT study group 1996).

Myfortic: Oral: Initial: 720 mg twice daily. Maintenance doses may vary based on concomitant immunosuppression.

IV: CellCept: See oral dosing for CellCept; IV and oral doses (of mycophenolate mofetil) are equivalent. If converting from Myfortic to IV CellCept, convert Myfortic to equivalent CellCept oral dose first. Transition to oral therapy as soon as tolerated.

Systemic sclerosis (scleroderma) (off-label use):

CellCept: Oral: Initial: 500 mg twice daily for 1 to 4 weeks; increase to a maintenance dose of 500 to 1,500 mg twice daily as tolerated (Derk 2009; Gerbino 2008; Herrick 2017; Le 2011; Mendoza 2012; Tashkin 2016; Yilmaz 2014)

Myfortic: Oral: Initial: 360 mg twice daily for 1 week, then 720 mg twice daily (Henes 2013; Simeon-Aznar 2011)

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: 1,080 mg daily)

BSA >1.58 m2: 720 mg twice daily (maximum: 1,440 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

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

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: May be administered with or without food as effects of food on bioavailability are minor (Abd Rahman 2013; Bullingham 1996; Bullingham 1998; Shipkova 2005). Oral suspension may be administered via a nasogastric tube (minimum 8 French, 1.7 mm interior diameter); do not mix oral suspension with other medications. Delayed-release tablets (Myfortic) should be swallowed whole and should not be crushed, cut, or chewed. 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.

IV: 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.

Dietary Considerations

Some products may contain phenylalanine.

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 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 2°C to 8°C (36°F to 46°F) or 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). 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

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. 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

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

Estrogen Derivatives (Contraceptive): Mycophenolate may decrease the serum concentration of Estrogen Derivatives (Contraceptive). 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

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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

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

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

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

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

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

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

Quinolones: 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

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

Tolvaptan: May increase the serum concentration of OAT3 Substrates. Consider therapy modification

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, which were more frequent in pediatric patients; 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%), dizziness (29%), anxiety (28%), paresthesia (21%)

Dermatologic: Skin rash (22%)

Endocrine & metabolic: Hyperglycemia (44% to 47%), hypercholesterolemia (41%), hypomagnesemia (39%), hypokalemia (32% to 37%), hypocalcemia (30%), increased lactate dehydrogenase (23%), 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 & oncologic: Leukopenia (23% to 46%), anemia (26% to 43%), leukocytosis (22% to 41%), thrombocytopenia (24% to 38%), hypochromic anemia (25%)

Hepatic: Abnormal hepatic function tests (25%), ascites (24%)

Infection: Sepsis (27%), infection (18% to 27%), candidiasis (17% to 22%), herpes simplex infection (10% to 21%)

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

Renal: Increased serum creatinine (39%), increased blood urea nitrogen (35%), renal function abnormality (22% to 26%)

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

Miscellaneous: Fever (21% to 52%)

3% to <20%:

Cardiovascular: Angina pectoris, arterial thrombosis, atrial fibrillation, atrial flutter, bradycardia, cardiac arrhythmia, cardiac failure, extrasystoles, facial edema, increased venous pressure, orthostatic hypotension, palpitations, pericardial effusion, peripheral vascular disorder, supraventricular extrasystole, supraventricular tachycardia, syncope, thrombosis, vasodilatation, vasospasm, ventricular premature contractions, ventricular tachycardia

Central nervous system: Abnormality in thinking, agitation, confusion, delirium, depression, drowsiness, emotional lability, hallucination, hypertonia, hypoesthesia, malaise, myasthenia, nervousness, neuropathy, psychosis, seizure, vertigo, voice disorder

Dermatologic: Acne vulgaris, alopecia, cellulitis, dermal ulcer, diaphoresis, fungal dermatitis, pallor, pruritus, skin hypertrophy, vesiculobullous dermatitis

Endocrine & metabolic: Acidosis, albuminuria, alkalosis, Cushing's syndrome, dehydration, diabetes mellitus, gout, hirsutism, hypercalcemia, hyperphosphatemia, hyperlipidemia, hypervolemia, hypochloremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, hypothyroidism, hypovolemia, increased gamma-glutamyl transferase, increased thirst, parathyroid disease, weight gain, weight loss

Gastrointestinal: Mucocutaneous candidiasis (16% to 18%), cholangitis, dysphagia, enlargement of abdomen, esophagitis, flatulence, gastric disease, gastric ulcer, gastritis, gastroenteritis, gastrointestinal hemorrhage, GI moniliasis, gingival hyperplasia, gingivitis, hernia, hiccups, intestinal obstruction, melena, oral candidiasis, oral mucosa ulcer, peritonitis, stomatitis, xerostomia

Genitourinary: Dysuria, hematuria, impotence, nocturia, oliguria, pelvic pain, prostatic disease, scrotal edema, urinary frequency, urinary incontinence, urinary retention, urinary tract abnormality

Hematologic & oncologic: Blood coagulation disorder, bruise, hemophthalmos, hemorrhage, neoplasm, neutropenia, pancytopenia, petechia, polycythemia, prolonged prothrombin time, prolonged partial thromboplastin time, skin carcinoma

Hepatic: Cholestatic jaundice, hepatic insufficiency, hepatitis, hyperbilirubinemia, increased serum alkaline phosphatase, increased serum transaminases, jaundice

Infection: Cytomegalovirus disease (viremia/syndrome: 12% to 14%; tissue invasive disease: 6% to 12%), herpes zoster (cutaneous disease: 4% to 10%), abscess (local), infection (of ileus)

Neuromuscular & skeletal: Arthralgia, arthropathy, leg cramps, myalgia, neck pain, osteoporosis

Ophthalmic: Abnormal lacrimation, amblyopia, cataract, conjunctivitis, visual disturbance

Otic: Deafness, ear disease, otalgia, tinnitus

Renal: Hydronephrosis, increased serum creatinine, pyelonephritis, renal failure, renal tubular necrosis

Respiratory: Apnea, asthma, atelectasis, bronchitis, epistaxis, flu-like symptoms, hemoptysis, hyperventilation, hypoxia, increased bronchial secretions, pharyngitis, pneumonia, pneumothorax, pulmonary edema, pulmonary hypertension, respiratory acidosis, respiratory tract infection (moniliasis), rhinitis

Miscellaneous: Abnormal healing, cyst, fever and chills

<1%, postmarketing and/or case reports: Atypical mycobacterial infection, bronchiectasis (Boddana 2011, Rook 2006), colitis, endocarditis (infectious), gastrointestinal perforation, hypogammaglobulinemia (Boddana 2011; Keven 2003; Robertson 2009), interstitial pulmonary disease, lymphoproliferative disorder, malabsorption (intestinal villous atrophy), malignant lymphoma, malignant neoplasm, meningitis, pancreatitis, progressive multifocal leukoencephalopathy, pulmonary fibrosis, pure red cell aplasia, renal disease (BK virus-associated), 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 and viral reactivation of hepatitis B and C, which may lead to hospitalizations and fatal outcomes.

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. Avoid if safer treatment options are available. 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 and viral reactivation of hepatitis B and C, 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 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 to 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. The purpose of the enteric-coated formulation (Myfortic) was to decrease GI side effects; however, studies have demonstrated similar rates of GI side effects between mycophenolate mofetil and the enteric-coated formulation (Budde 2004a; Budde 2010; Salvadori 2004).

• 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Non-interchangeability of dosage forms: Mycophenolate sodium and mycophenolate mofetil should not be used interchangeably without health care provider supervision because the rate of absorption following the administration of these two products is not equivalent. Single dose pharmacokinetic studies in adult renal transplant patients suggest that bioavailability is similar between oral mycophenolate mofetil (1 g) and delayed-release mycophenolic acid (720 mg) (Arns 2005). In clinical trials, comparative efficacy and safety profiles have been observed in adult renal transplant patients randomized to either oral mycophenolate mofetil (1 g twice daily) or delayed-release mycophenolic acid (720 mg twice daily) (Budde 2004b; Salvadori 2003).

• 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. Avoid use if safer treatment options are available. Women of reproductive potential must be counseled about pregnancy prevention and planning. Alternative agents should be considered for women planning a pregnancy. Women 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 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. Sexually active male patients and/or their female partners should use effective contraception during treatment of the male patient and for at least 3 months after last dose.

Other warnings/precautions:

• Blood donations: Patients should not donate blood or blood products during treatment and for at least 6 weeks after the last dose.

• Discontinuation of therapy: Myasthenia gravis: Abrupt cessation of this or any immunosuppressant, especially in clinically unstable individuals, may result in rapid deterioration of myasthenic symptoms and possibly myasthenic crisis (Melzer 2016).

• 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.

• Semen donations: Male patients should not donate semen during treatment and for 3 months after the last dose.

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 (sensitivity of ≥25 milliunits/mL; immediately prior to initiation and 8 to 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; monitor for signs of pure red cell aplasia or autoimmune hemolytic anemia (Elimelakh 2007; Hodo 2006; Schecter 2007).

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 with less potential for embryofetal toxicity 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. The combination of ear, eye, and lip/palate abnormalities has been identified as mycophenolate embryopathy (Perez-Aytes 2017). Spontaneous abortions have also been noted.

Females of reproductive potential (girls who have entered puberty and 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 mycophenolate therapy and the test should be repeated 8 to 10 days later. Pregnancy tests should then 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. Sexually active male patients and/or their female partners should use effective contraception during treatment of the male patient and for at least 3 months after last dose.

Current guidelines recommend that pregnancy be delayed following a kidney transplant until 1 year has passed without an acute rejection; this time period may be adjusted as clinically appropriate. Women planning a pregnancy and who are already taking mycophenolate following a kidney transplant should be switched to a different medication and mycophenolate should be discontinued for at least 6 weeks before pregnancy is attempted (KDIGO 2009). Mycophenolate is not recommended for the treatment of psoriasis in pregnant women (Menter 2009). Mycophenolate should not be used during pregnancy in women with lupus nephritis; women who become pregnant during mycophenolate therapy should be switched to a different medication (KDIGO 2012). 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).

Health care 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 Transplant Pregnancy Registry International (TPR) is a registry that follows pregnancies that occur in maternal transplant recipients or those fathered by male transplant recipients. The TPR encourages reporting of pregnancies following solid organ transplant by contacting them at 1-877-955-6877 or https://www.transplantpregnancyregistry.org.

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, nausea, vomiting, back pain, constipation, diarrhea, lack of appetite, joint pain, flatulence, tremors, or insomnia. Have patient report immediately to prescriber signs of infection, signs of skin infection, signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of progressive multifocal leukoencephalopathy (confusion, depression, memory impairment, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), angina, tachycardia, bradycardia, abnormal heartbeat, severe headache, edema, excessive weight loss, severe loss of strength and energy, burning or numbness feeling, muscle cramps, mole changes, skin growths, severe dizziness, passing out, vision changes, night sweats, severe abdominal pain, swollen glands, pale skin, thrush, 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 health care 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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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