Phenolate

Uses

Phenolate or Mycophenolic acid is used for the prophylaxis of organ rejection in patients receiving allogeneicrenal, cardiac or hepatic transplants. This should be used concomitantly with cyclosporine and corticosteroids.

Phenolate is also used to associated treatment for these conditions: Heart Transplant Rejection, Kidney Transplant Rejection, Liver Transplant Rejection

How Phenolate works

The active metabolite of mycophenolate, mycophenolic acid, prevents T-cell and B-cell proliferation and the production of cytotoxic T-cells and antibodies. Lymphocyte and monocyte adhesion to endothelial cells of blood vessels that normally part of inflammation is prevented via the glycosylation of cell adhesion molecules by MPA. MPA inhibits de novo purine biosynthesis (that promotes immune cell proliferation) by inhibiting inosine 5’-monophosphate dehydrogenase enzyme (IMPDH), with a preferential inhibition of IMPDH II. IMPDH normally transforms inosine monophosphate (IMP) to xanthine monophosphate (XMP), a metabolite contributing to the production of guanosine triphosphate (GTP). GTP is an important molecule for the synthesis of ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and protein. As a result of the above cascade of effects, mycophenolate mofetil reduces de-novo production of guanosine nucleotides, interfering with the synthesis of DNA, RNA, and protein required for immune cell production. Further contributing to the above anti-inflammatory effects, MMF depletes tetrahydrobiopterin, causing the decreased function of inducible nitric oxide synthase enzyme, in turn decreasing the production of peroxynitrite, a molecule that promotes inflammation.

Dosage

Phenolate dosage

Renal Transplantation:

• Adults: A dose of 1 gm administered orally or intravenously (over NO LESS THAN 2 HOURS) twice a day (daily dose of 2 gm) is recommended for use inrenal transplantpatients. Although a dose of 1.5 g administered twice daily (daily dose of 3 gm) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving 2 gm/day of Mycophenolate demonstrated an overall better safety profile than did patients receiving 3 gm/day of Mycophenolate .
• Pediatrics (3 Months To 18 Years Of Age): The recommended dose of Mycophenolate oral suspension is 600 mg/m2administered twice daily (up to a maximum daily dose of 2 gm/10 ml oral suspension). Patients with a body surface area of 1.25 m2to 1.5 m2may be dosed with Mycophenolate capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area >1.5 m2may be dosed with Mycophenolate capsules or tablets at a dose of 1 gm twice daily (2 gm daily dose).

Cardiac Transplantation: A dose of 1.5 gbidadministered intravenously (over NO LESS THAN 2 HOURS) or 1.5 g bid oral (daily dose of 3 gm) is recommended for use in adultcardiac transplantpatients.

Hepatic Transplantation: A dose of 1 gm bid administered intravenously (over NO LESS THAN 2 HOURS) or 1.5 g bid oral (daily dose of 3 gm) is recommended for use in adulthepatic transplantpatients.

Side Effects

Diarrhoea, vomiting, GI haemorrhage and perforation; leucopenia; asthenia, pain, headache, anaemia, thrombocytopenia, renal tubular necrosis, haematuria, BP changes, hyperglycaemia, disturbances of electrolytes and blood lipids, peripheral oedema, dyspnoea, cough, acne, rash, alopecia, dizziness, insomnia, paraesthesia, tremor, hypersensitivity reactions, pancreatitis, hepatitis.

Toxicity

LD50

The LD50 of oral mycophenolate mofetil in rats is 250 mg/kg and >4000 mg/kg in mice.

Overdose information

Possible signs and symptoms of acute overdose may consist of hematological abnormalities including leukopenia and neutropenia, and gastrointestinal symptoms.

Precaution

Teratogenic in animals; avoid inhalation or direct skin contact. Monitor patients for lymphoproliferative disorders; advise patient to limit exposure to sunlight/UV light. Active peptic ulcer disease. Severe renal impairment. Mycophenolate mofetil and mycophenolate sodium are not interchangeable. Perform CBCs; monitor for neutropenia.

Interaction

Increased plasma levels of both drugs when combined with aciclovir, valaciclovir, ganciclovir and valganciclovir. Reduced absorption with colestyramine, magnesium- and aluminium hydroxide-containing products, sevelamer and other calcium-free phosphate binders. Reduced plasma levels with ciclosporin, metronidazole, quinolones, rifamycins. May reduce plasma levels of progestins; may reduce efficacy of oral contraceptives. Increased plasma levels with probenecid. May reduce efficacy of live vaccines.

Food Interaction

• Avoid multivalent ions. Take multivalent ions such as calcium, iron, or magnesium at least 2 hours after taking this medication.
• Take on an empty stomach. Take at least 1 hour before or 2 hours after meals.

Volume of Distribution

The volume of distribution of mycophenolate mofetil is 3.6 (±1.5) to 4.0 (±1.2) L/kg.

Elimination Route

Mycophenolate mofetil is rapidly absorbed in the small intestine. The maximum concentration of its active metabolite, MPA, is attained 60 to 90 minutes following an oral dose. The average bioavailability of orally administered mycophenolate mofetil in a pharmacokinetic study of 12 healthy patients was 94%. In healthy volunteers, the Cmax of mycophenolate mofetil was 24.5 (±9.5)μg/mL. In renal transplant patients 5 days post-transplant, Cmax was 12.0 (±3.82) μg/mL, increasing to 24.1 (±12.1)μg/mL 3 months after transplantation. AUC values were 63.9 (±16.2) μg•h/mL in healthy volunteers after one dose, and 40.8 (±11.4) μg•h/mL, and 65.3 (±35.4)μg•h/mL 5 days and 3 months after a renal transplant, respectively. The absorption of mycophenolate mofetil is not affected by food.

Half Life

The average apparent half-life of mycophenolate mofetil is 17.9 (±6.5) hours after oral administration and 16.6 (±5.8) hours after intravenous administration.

Clearance

Plasma clearance of mycophenolate mofetil is 193 mL/min after an oral dose and 177 (±31) mL/min after an intravenous dose.

Elimination Route

A small amount of drug is excreted as MPA in the urine (less than 1%). When mycophenolate mofetil was given orally in a pharmacokinetic study, it was found to be 93% excreted in urine and 6% excreted in feces. Approximately 87% of the entire administered dose is found to be excreted in the urine as MPAG, an inactive metabolite.

Pregnancy & Breastfeeding use

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Pregnancy, lactation. Rare hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), including Kelley-Seegmiller or Lesch-Nyhan syndrome.

Special Warning

Prophylaxis of acute renal graft rejection: Severe chronic renal impairment (GFR<25 ml/min/1.73 m2): Avoid >1 g bid of mycophenolate mofetil.

Acute Overdose

No reported cases. At plasma levels >100 mcg/ml, small amounts of the inactive metabolite may be removed by haemodialysis. Excretion of MPA may be enhanced by bile acid sequestrants (e.g. colestyramine).

Storage Condition

Store at 15-30° C. Protect tablet from light. Do not freeze oral suspension.

Innovators Monograph

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