Mycophenolate Mofetil

L04A - Immunosuppressants ATC L04AA06 Small molecule approved 1995 Oral Parenteral Prodrug Natural product Black-box warning

Active form: Mycophenolic Acid.

JFDA label: MyOra 500mg Tab

⚠ Black-Box Warning

Experienced physician:
Serious infections:
Malignancies and serious infections:
Embryo-fetal toxicity:

Mechanism of Action

Inhibitor of Inosine-5'-monophosphate dehydrogenase (IMPDH) — Inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor

Target	Action	Gene / class
Inosine-5'-monophosphate dehydrogenase (IMPDH) efficacy	INHIBITOR

Indications

Approved

Organ transplantation

Off-label

Acute graft-versus-host disease, refractory (treatment)
Chronic graft-versus-host disease, refractory (treatment)
Graft-versus-host disease (prevention)
Hepatitis (autoimmune, refractory)
Lupus nephritis
Myasthenia gravis
Psoriasis (moderate-to-severe)
Rejection in heart transplant patients (recurrent or persistent)
Rejection in liver transplant patients unable to tolerate tacrolimus or cyclosporine due to toxicity
Systemic sclerosis (scleroderma)

Contraindications

Source: Lexicomp · Curated

Additional contraindications (not in the US labeling): Pregnancy Absolute
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 Absolute
Pregnancy — teratogenic (category D); contraceptive measures mandatory Absolute
breast-feeding Absolute
women of childbearing potential and not using highly effective contraceptive methods Absolute
women of childbearing potential not providing a pregnancy test result Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (6)

Very Common chest pain · edema · Hypertension · hypotension · peripheral edema · tachycardia

Nervous system disorders (24)

Very Common anxiety · dizziness · headache · insomnia · Pain · paresthesia

Common Abnormality in thinking · agitation · confusion · delirium · depression · drowsiness · emotional lability · hallucination · hypertonia · hypoesthesia · malaise · myasthenia · nervousness · neuropathy · psychosis · seizure · vertigo · voice disorder

Hepatobiliary disorders (9)

Very Common Abnormal hepatic function tests · ascites

Common Cholestatic jaundice · hepatic insuffiency · hepatitis · hyperbilirubinemia · increased serum alkaline phosphatase · increased serum transaminases · jaundice

Renal and urinary disorders (20)

Very Common increased blood urea nitrogen · Increased serum creatinine · renal function abnormality · Urinary tract infection

Common Dysuria · hematuria · Hydronephrosis · impotence · nocturia · oliguria · pelvic pain · prostatic disease · pyelonephritis · renal failure · renal tubular necrosis · scrotal edema · urinary frequency · urinary incontinence · urinary retention · urinary tract abnormality

Blood and lymphatic system disorders (17)

Very Common anemia · hypochromic anemia · leukocytosis · Leukopenia · thrombocytopenia

Common Blood coagulation disorder · bruise · hemophthalmos · hemorrhage · neoplasm · neutropenia · pancytopenia · petechia · polycythemia · prolonged partial thromboplastin time · prolonged prothrombin time · skin carcinoma

Metabolism and nutrition disorders (31)

Very Common hypercholesterolemia · Hyperglycemia · hyperkalemia · hypocalcemia · hypokalemia · hypomagnesemia · increased lactate dehydrogenase

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

Gastrointestinal disorders (30)

Very Common Abdominal pain · anorexia · constipation · diarrhea · dyspepsia · nausea · vomiting

Common 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 · Mucocutaneous candidiasis · oral candidiasis · oral mucosa ulcer · peritonitis · stomatitis · xerostomia

Skin and subcutaneous tissue disorders (11)

Very Common Skin rash

Common Acne vulgaris · alopecia · cellulitis · dermal ulcer · diaphoresis · fungal dermatitis · pallor · pruritus · skin hypertrophy · vesiculobullous dermatitis

Musculoskeletal and connective tissue disorders (9)

Very Common Back pain · tremor · weakness

Common Arthralgia · arthropathy · leg cramps · myalgia · neck pain · osteoporosis

Eye disorders (5)

Common Abnormal lacrimation · amblyopia · cataract · conjunctivitis · visual disturbance

Ear and labyrinth disorders (4)

Common Deafness · ear disease · otalgia · tinnitus

Infections and infestations (8)

Very Common candidiasis · herpes simplex infection · infection · Sepsis

Common abscess (local) · Cytomegalovirus disease · herpes zoster · infection (of ileus)

General disorders and administration site conditions (4)

Very Common Fever

Common Abnormal healing · cyst · fever and chills

Respiratory, thoracic and mediastinal disorders (24)

Very Common cough · Dyspnea · pleural effusion · pulmonary disease · respiratory tract infection · sinusitis

Common 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

Other (22)

Common 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

Dosing

Source: Lexicomp

Note: May be used IV for up to 14 days; transition to oral therapy as soon as tolerated. Autoimmune hepatitis, refractory (off-label use): CellCept: Oral: 2 g daily (Manns 2010) 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 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): CellCept: Oral: 1 g twice daily (range: 1 to 3 g daily) (Cahoon 2006; Ciafaloni 2001; Merriggioli 2003) Psoriasis, moderate-to-severe (off-label use): CellCept: Oral: 2 to 3 g daily (Menter 2009) 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: 1,440 mg) 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)

(For additional information see "Mycophenolate mofetil (Cellcept) and enteric-coated mycophenolate sodium (Myfortic): Pediatric drug information") 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 2: 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)

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.

Renal transplant: GFR 2 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.

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.

Warnings & Precautions

Source: Lexicomp

Infections

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 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

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. 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 (1,000 mg) 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 (1,000 mg twice daily) or delayed release mycophenolic acid (720 mg twice daily) (Budde, 2004; 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

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. Other warnings/precautions:

Experienced physician

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.

Pregnancy & Lactation

Pregnancy

FDA category D Teratogenic

Avoid

Switch to azathioprine ≥6 weeks before planned conception. EMA/FDA RMP requires contraception and pregnancy testing

Lactation

It is not known if mycophenolate is present in human milk. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug (during therapy or within 6 weeks after treatment is complete), taking into account the importance of treatment to the mother.

Monitoring

Clinical pearl	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

Clinical pearl

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

Chemistry & Properties

Formula	C23H31NO7
Molecular weight	433.5 g/mol
IUPAC name	2-morpholin-4-ylethyl (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate
CAS	128794-94-5
PubChem CID	5281078
InChIKey	`RTGDFNSFWBGLEC-SYZQJQIISA-N`
logP	2.52 (XLogP 3.2)
Polar surface area	94.53 Å²
H-bond acceptors / donors	8 / 1
Drug-likeness (QED)	0.47
Lipinski violations	0

SMILES

COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)MRP2 (Substrate)OATP1B3 (Substrate)P-gp (Substrate)

Drug–drug interactions (90, DDInter)

Interacting drug	Severity	Management
Activated charcoal	major
Adalimumab	major
Baricitinib	major
Certolizumab pegol	major
Cladribine	major
Deferiprone	major
Etanercept	major
Ethinylestradiol	major
Fingolimod	major
Golimumab	major
Infliximab	major
Leflunomide	major
Medroxyprogesterone acetate	major
Natalizumab	major
Ozanimod	major
Siponimod	major
Talimogene laherparepvec	major
Teriflunomide	major
Tofacitinib	major
Upadacitinib	major
Alefacept	moderate
Alemtuzumab	moderate
Aluminum hydroxide	moderate
Amikacin	moderate
Amoxicillin	moderate
Anakinra	moderate
Azathioprine	moderate
Bacitracin	moderate
Calcium carbonate	moderate
Canakinumab	moderate
Chloramphenicol	moderate
Clarithromycin	moderate
Clindamycin	moderate
Cyclosporine	moderate
Demeclocycline	moderate
Dexlansoprazole	moderate
Dimethyl fumarate	moderate
Doxycycline	moderate
Efalizumab	moderate
Erythromycin	moderate

Showing 40 of 90.

Registered Products (8)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Mycokem	Tablet 250 mg	10 tab	Sahar Drug Store	6.140
Mycofit 500	Tablet 500 mg	10 tab	AL Razi Drug Store	8.450
IMUPHEN 500	Tablet 500.00 mg	50 tab	Omicron Pharma	28.450
Lamucon	Tablet 500 mg	50 tab	Nabulsi Drug Store	39.290
Cellcept F.C.Tablet	Film-Coated Tablet 500 mg	50 tab	Shawi & Rushedat Drug Store	49.650
MyOra	Tablet 500 mg	50 tab pack varies	The Arab Pharmaceutical Manufacturing PSC/Salt	50.290
Mofetab	Tablet 500 mg	150 tab	Sukhtian Group	111.420
MyOra	Tablet 500 mg	150 tab pack varies	The Arab Pharmaceutical Manufacturing PSC/Salt	141.820