Mycophenolic Acid

Mycophenolic acid, given as the enteric-coated sodium salt, is the active moiety of mycophenolate mofetil formulated to delay release to the small intestine and reduce upper gastrointestinal effects. It has the same pharmacology and the same pregnancy hazards, but doses differ and the two are not interchangeable milligram for milligram.

Class. Antimetabolite immunosuppressant, inosine monophosphate dehydrogenase inhibitor.

Mechanism. Reversible, non-competitive inhibition of inosine monophosphate dehydrogenase type 2, limiting guanosine nucleotide synthesis in activated lymphocytes.

Pharmacokinetics. Absorption is delayed by the enteric coating, with a peak at 1.5 to 2 hours (up to 3 to 5 hours with food) and absolute bioavailability about 72 percent. Glucuronidation and enterohepatic recirculation mirror the parent drug. Half-life about 12 to 16 hours.

Kidney transplantation (adults).

• 720 mg twice daily orally (1440 mg daily), equivalent to 1 g twice daily of mycophenolate mofetil.

• Maximum dose: 1440 mg daily in routine use; higher doses are not routinely given.

• Loading dose: none; start within 48 hours of transplant.

• Maintenance: 720 mg twice daily, adjusted to counts and tolerance.

Paediatric kidney transplant (5 years and over, stable). 400 mg/m2 twice daily, maximum 720 mg twice daily.

Lupus nephritis (off label, when mofetil is not tolerated). 720 to 1080 mg twice daily for induction, 540 to 720 mg twice daily for maintenance.

Conversion from mycophenolate mofetil. 500 mg mofetil equals 360 mg mycophenolic acid; 1 g mofetil twice daily equals 720 mg twice daily.

Contraindications. Pregnancy, hypersensitivity, and Lesch-Nyhan syndrome.

Boxed-warning-level risks. Embryofoetal toxicity, malignancy and serious infection.

Adverse effects. Common: diarrhoea, leucopenia, anaemia, vomiting, hypertension. Serious: neutropenia, pure red cell aplasia, cytomegalovirus and BK virus infection, progressive multifocal leukoencephalopathy, gastrointestinal haemorrhage.

Major interactions. Antacids containing magnesium or aluminium, proton pump inhibitors (reduced absorption of the enteric-coated form), colestyramine, azathioprine (avoid), rifampicin, ciclosporin, aciclovir and ganciclovir (raised levels), and live vaccines (avoid).

Common prescribing errors. Prescribing mycophenolic acid and mycophenolate mofetil interchangeably at equal milligram doses; crushing or splitting enteric-coated tablets; omitting contraception counselling.

Special groups.

• Pregnancy: contraindicated, with the same contraception periods as mycophenolate mofetil (women during treatment and 6 weeks after; men with condoms during treatment and 90 days after).

• Breastfeeding: avoid.

• Children: body surface area dosing, 400 mg/m2 twice daily to a maximum of 720 mg twice daily.

• Older adults: monitor for infection and cytopenia.

• Kidney impairment: eGFR under 25 mL/min, no doses over 1440 mg daily and close monitoring.

• Liver impairment: limited data; monitor.

• Region: screen for hepatitis B, HIV and latent tuberculosis; exclude infective diarrhoea before attributing to the drug.

Formulations. 180 mg and 360 mg enteric-coated tablets, swallowed whole on an empty stomach (1 hour before or 2 hours after food), at the same times each day.

Baseline. Full blood count, liver enzymes, creatinine, pregnancy test (repeat 8 to 10 days later), and hepatitis B, C and HIV serology.

Monitoring. Full blood count weekly for 4 weeks, twice monthly for 2 months, then monthly during the first year. Therapeutic monitoring of the area under the curve (about 30 to 60 mg.h/L) in selected recipients.

Stop or reduce thresholds. Neutrophils under 1.3 x 10^9/L: hold and repeat; severe or persistent diarrhoea; pregnancy; serious infection.

Referral and escalation. Refer to a transplant physician for persistent cytopenia, graft dysfunction or severe gastrointestinal symptoms.