Myfortic

A. Approved Indications

• Prevention of Organ Rejection in Transplant Recipients
  Mycophenolic acid is indicated for the prophylaxis of acute rejection in patients receiving renal, cardiac, or hepatic allografts, in combination with a calcineurin inhibitor (e.g., cyclosporine or tacrolimus) and corticosteroids.

B. Clinically Accepted Off-label Uses

• Lupus Nephritis (Systemic Lupus Erythematosus): Used as induction or maintenance therapy.
• Autoimmune Hepatitis (Refractory cases)
• Myasthenia Gravis (Adjunct therapy)
• Autoimmune Uveitis
• ANCA-associated Vasculitis (off-label immunosuppressive therapy)
• Psoriasis and Severe Atopic Dermatitis (Refractory cases)

Route of Administration: Oral
Available Formulations in Bangladesh (per Medex.com.bd): Delayed-release tablets: 180 mg and 360 mg

Adults:

• Renal Transplant (Approved):
  720 mg orally twice daily in combination with cyclosporine and corticosteroids.
• Lupus Nephritis (Off-label):
• Induction: 1200–1500 mg twice daily for 6 months
• Maintenance: 500–1000 mg twice daily for 12–24 months
• Autoimmune Diseases (e.g., uveitis, myasthenia gravis):
  720–1440 mg daily in divided doses based on disease severity and tolerability

Pediatric Patients (≥5 years, renal transplant):

• 400 mg/m² twice daily, not exceeding 720 mg twice daily

Geriatric Use:

• No specific dose adjustment required; monitor renal function and blood counts.

Renal Impairment:

• Mild to moderate: No dose adjustment necessary
• Severe impairment (eGFR <25 mL/min/1.73m²): Use with caution; increased monitoring of drug levels is advised

Hepatic Impairment:

• Mild to moderate: No dosage adjustment required
• Severe: Use with caution due to potential altered metabolism

Administration Tips:

• Administer on an empty stomach, at least 1 hour before or 2 hours after meals
• Swallow tablets whole; do not crush or chew
• Avoid taking with antacids or cholestyramine within 2 hours

Mycophenolic acid is a potent, selective, noncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), an essential enzyme in the de novo synthesis of guanosine nucleotides. T and B lymphocytes rely heavily on this pathway for proliferation due to their limited salvage pathway capacity. By inhibiting IMPDH, mycophenolic acid suppresses lymphocyte proliferation, reduces antibody production, and impairs cell-mediated immune responses—contributing to its immunosuppressive effects in transplantation and autoimmune diseases.

• Absorption:
  Delayed-release formulation is absorbed in the small intestine. Peak plasma concentrations occur within 1.5 to 2.5 hours.
• Bioavailability:
  Approximately 72% (delayed-release form)
• Distribution:
  Extensively protein-bound (~97%), primarily to albumin
• Metabolism:
  Metabolized in the liver by glucuronidation to inactive mycophenolic acid glucuronide (MPAG)
• Half-life:
  8–16 hours (can be prolonged in renal impairment)
• Elimination:
  Primarily excreted by the kidneys (87% as MPAG), with minor biliary excretion
  Undergoes enterohepatic recirculation, enhancing drug exposure

• Pregnancy:
• Classified as FDA Pregnancy Category D (system no longer in use)
• Associated with increased risk of miscarriage and congenital malformations (e.g., cleft palate, ear deformities, heart defects)
• Contraindicated during pregnancy unless no suitable alternatives exist
• Lactation:
• Excreted into breast milk
• Contraindicated during breastfeeding due to the risk of serious adverse effects in the infant
• Recommendations:
• Perform a pregnancy test before starting therapy
• Use two effective forms of contraception during treatment and for 6 weeks after stopping therapy

• Primary Therapeutic Class: Immunosuppressant
• Subclass: Selective Antiproliferative Agent / IMPDH Inhibitor

• Known hypersensitivity to Mycophenolic acid or any component of the formulation
• Pregnancy (unless no alternatives are available)
• Breastfeeding
• Active, untreated serious infections
• Known hypersensitivity to mycophenolate mofetil (prodrug of MPA)

• Teratogenicity:
  High risk of congenital malformations; avoid use during pregnancy unless essential
• Infection Risk:
  Increased susceptibility to serious bacterial, viral (e.g., CMV, BK virus), fungal, and opportunistic infections
• Hematologic Toxicity:
  Risk of neutropenia, anemia, and thrombocytopenia; monitor complete blood count regularly
• Malignancy Risk:
  Long-term use increases the risk of lymphomas and skin cancers; advise sun protection
• Gastrointestinal Toxicity:
  May cause GI bleeding, perforation, ulcers, or colitis
• Vaccination Precautions:
  Avoid live vaccines; effectiveness of inactivated vaccines may be reduced
• Monitoring Requirements:
  CBC, renal and liver function tests, signs of infection or malignancy, and drug levels if needed

Common Adverse Effects (≥1%):

• Gastrointestinal:
  Nausea, vomiting, diarrhea, abdominal pain
• Hematologic:
  Leukopenia, anemia, thrombocytopenia
• Infectious:
  Increased risk of infections (e.g., CMV, BK virus, HSV)
• Neurologic:
  Headache, insomnia, dizziness
• Dermatologic:
  Acne, rash

Less Common or Rare:

• Hyperlipidemia
• Peripheral edema
• Cough
• Back pain
• Elevated liver enzymes

Serious Adverse Effects:

• Progressive multifocal leukoencephalopathy (PML)
• Sepsis, pneumonia
• Lymphoma, skin malignancies
• Gastrointestinal perforation or bleeding
• Severe neutropenia (ANC <500/mm³)

Timing:

• GI symptoms typically appear early
• Hematologic and infectious risks increase with long-term use

• Cyclosporine:
  Reduces MPA levels by interfering with enterohepatic recirculation
• Cholestyramine:
  Decreases MPA absorption by binding in the gut
• Acyclovir, Ganciclovir:
  Compete for renal excretion, increasing the risk of toxicity
• Antacids (magnesium/aluminum):
  May reduce absorption; separate by at least 2 hours
• Live Vaccines:
  Avoid due to infection risk and reduced immunogenicity
• Enzyme Systems:
  Metabolized via UDP-glucuronosyltransferase (UGT) enzymes
  Not a CYP450 substrate or inhibitor

• FDA REMS (2022–2023):
  Reinforced requirement for REMS (Risk Evaluation and Mitigation Strategy) program due to teratogenicity
• KDIGO Guidelines (2023):
  Recommend mycophenolic acid as the preferred antiproliferative agent in renal transplant maintenance therapy
• EULAR (2023):
  Supports its use in lupus nephritis as an alternative to cyclophosphamide
• Recent Studies:
  Support increased therapeutic use in autoimmune diseases with improved tolerability vs. older immunosuppressants

• Temperature: Store below 25°C (77°F)
• Humidity: Store in a dry environment
• Light Protection: Keep in the original packaging, protected from light
• Handling Instructions:
• Do not crush, chew, or split delayed-release tablets
• Keep out of reach of children
• No reconstitution or refrigeration required