Mycophenolate Mofetil

Mycophenolate mofetil is an inosine monophosphate dehydrogenase inhibitor prodrug of mycophenolic acid. It is a cornerstone of transplant maintenance therapy and of induction and maintenance in lupus nephritis, and is used off label in vasculitis and other autoimmune diseases.

Class. Antimetabolite immunosuppressant, selective lymphocyte proliferation inhibitor.

Mechanism. Mycophenolic acid reversibly inhibits inosine monophosphate dehydrogenase type 2, blocking de novo guanosine nucleotide synthesis, on which T and B lymphocytes depend.

Pharmacokinetics. Rapid esterase conversion to mycophenolic acid with bioavailability about 94 percent. Glucuronidation produces an inactive metabolite that undergoes enterohepatic recirculation, giving a second plasma peak at 6 to 12 hours. Half-life about 17 hours. Excretion is renal as the glucuronide.

Kidney transplantation.

• 1 g twice daily orally, started within 72 hours of transplant. Intravenous dose 1 g twice daily over 2 hours.

• Maximum dose: 3 g daily in adults.

• Loading dose: none.

• Maintenance dose: 1 g twice daily or lower with calcineurin inhibitor exposure and tolerability; some centres reduce to 500 to 750 mg twice daily in the long term.

Heart or liver transplantation. 1.5 g twice daily (heart); 1 g twice daily intravenous or 1.5 g twice daily oral (liver).

Lupus nephritis, induction (class III, IV or V). 1 to 1.5 g twice daily (2 to 3 g daily), combined with a glucocorticoid taper, for at least 6 months.

Lupus nephritis, maintenance. 500 mg to 1 g twice daily (1 to 2 g daily) usually for 3 years or more, reduced gradually after sustained remission.

ANCA vasculitis, myasthenia gravis, autoimmune hepatitis, refractory nephrotic syndrome (off label). 1 to 1.5 g twice daily, specialist initiated.

Children (transplantation). 600 mg/m2 twice daily, maximum 1 g twice daily.

Contraindications. Pregnancy (unless no alternative), hypersensitivity to mycophenolate or polysorbate (intravenous form), and severe active infection. Rare hereditary hypoxanthine-guanine phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome).

Boxed-warning-level risks. Embryofoetal toxicity (miscarriage and congenital malformations), increased risk of serious infection and malignancy (lymphoma and skin cancer).

Adverse effects. Common: diarrhoea, nausea, vomiting, leucopenia, anaemia, urinary tract infection. Serious: neutropenia and pure red cell aplasia, progressive multifocal leukoencephalopathy, cytomegalovirus and BK virus infection, colitis, gastrointestinal bleeding, hypogammaglobulinaemia.

Major interactions. Antacids with magnesium or aluminium, colestyramine and iron (reduced absorption), proton pump inhibitors (lower mycophenolic acid exposure), aciclovir and ganciclovir (raised levels of both), azathioprine (avoid), rifampicin (lower exposure), live vaccines (avoid), ciclosporin (lowers mycophenolic acid level by interrupting recirculation; tacrolimus does not).

Common prescribing errors. Substituting mycophenolic acid at the same milligram dose; prescribing to women without reliable contraception; combining with azathioprine.

Special groups.

• Pregnancy: contraindicated. Women: negative pregnancy test before starting and 8 to 10 days later, effective contraception during treatment and for 6 weeks after stopping. Men: condoms during treatment and for 90 days afterwards.

• Breastfeeding: avoid.

• Children: body surface area dosing.

• Older adults: monitor for infection and cytopenia; the usual dose is tolerated.

• Kidney impairment: avoid doses over 1 g twice daily when eGFR is under 25 mL/min outside the immediate post-transplant period; monitor for neutropenia.

• Liver impairment: no adjustment in severe parenchymal disease for renal transplant; limited data otherwise.

• Region: screen for hepatitis B, HIV and latent tuberculosis; diarrhoea may mimic or hide infectious gastroenteritis, so test stool for infection first.

Formulations. 250 mg capsules, 500 mg tablets, oral suspension, and intravenous infusion (reconstitute in 5 percent glucose and infuse over at least 2 hours; do not give as a bolus).

Baseline. Full blood count, liver enzymes, creatinine, pregnancy test, and hepatitis B, C and HIV serology.

Monitoring. Full blood count weekly for 4 weeks, twice monthly for the next 2 months, then monthly through the first year, then every 3 months. Therapeutic drug monitoring of mycophenolic acid area under the curve (target about 30 to 60 mg.h/L) is optional in higher-risk transplant recipients.

Stop or reduce thresholds. Neutrophils under 1.3 x 10^9/L: hold and repeat; severe diarrhoea unresponsive to dose splitting; confirmed infection such as progressive multifocal leukoencephalopathy; pregnancy.

Referral and escalation. Refer for persistent cytopenia, severe diarrhoea, or rising creatinine in a transplant recipient.