Phenocept

A. Approved Indications

• Prophylaxis of Organ Rejection
  Mycophenolate mofetil is indicated for the prevention of acute rejection in renal, cardiac, and hepatic transplant recipients, used in combination with a calcineurin inhibitor (e.g., cyclosporine or tacrolimus) and corticosteroids.

B. Off-label or Clinically Accepted Uses

• Lupus Nephritis: Used as induction and maintenance therapy in patients with systemic lupus erythematosus (SLE).
• Autoimmune Hepatitis: Second-line immunosuppressive therapy when first-line agents are not tolerated.
• Myasthenia Gravis: As an adjunctive immunosuppressive treatment.
• Autoimmune Uveitis: For steroid-sparing immunomodulation.
• ANCA-associated Vasculitis: Alternative or maintenance therapy.
• Pemphigus Vulgaris and Other Autoimmune Dermatologic Conditions: In severe, refractory cases.

Route of Administration: Oral (tablet/suspension) and Intravenous

Available Formulations in Bangladesh (per Medex.com.bd):

• Tablets: 500 mg
• Capsules: 250 mg
• Powder for oral suspension: 200 mg/mL
• IV infusion: 500 mg/vial

Adults:

• Renal Transplant (Approved):
  1 g twice daily (total 2 g/day)
• Cardiac Transplant (Approved):
  1.5 g twice daily (total 3 g/day)
• Hepatic Transplant (Approved):
  1 g twice daily (total 2 g/day)
• Lupus Nephritis (Off-label):
• Induction: 1–1.5 g twice daily
• Maintenance: 0.5–1 g twice daily
• Other Autoimmune Diseases:
  1–2 g/day in divided doses, adjusted to disease severity and tolerance

Pediatric Patients (≥3 months):

• Transplant Prophylaxis:
  600 mg/m² twice daily, up to 1 g twice daily

Geriatrics:

• No specific dose adjustments, but close monitoring for adverse effects is necessary.

Renal Impairment:

• Severe renal impairment (GFR <25 mL/min):
  Dose should be reduced to 1 g/day in renal transplant patients.

Hepatic Impairment:

• Liver transplant recipients:
  Start with IV formulation until oral absorption is adequate.

Administration Tips:

• Oral formulations should be taken on an empty stomach (1 hour before or 2 hours after food).
• Do not crush or open capsules or tablets.
• IV infusion: Administer over 2 hours, avoid rapid bolus.

Mycophenolate mofetil is a prodrug that is rapidly converted to mycophenolic acid (MPA), the active immunosuppressive agent. MPA selectively and reversibly inhibits inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in de novo guanosine nucleotide synthesis. T and B lymphocytes rely almost exclusively on this pathway for proliferation. Inhibiting IMPDH results in suppression of lymphocyte proliferation, reduced antibody formation, and inhibition of cytotoxic T-cell function, thereby preventing graft rejection and modulating autoimmunity.

• Absorption:
  Rapidly absorbed and hydrolyzed to mycophenolic acid. Peak plasma levels occur within 1 hour (MMF) and 1.5–2.5 hours (MPA).
• Bioavailability:
  ~94% (oral formulations)
• Distribution:
  Extensively protein-bound (97% to albumin)
• Metabolism:
  Metabolized in the liver via glucuronidation (UGT enzymes) to inactive metabolite MPAG
• Active Metabolites:
  Mycophenolic acid (active); MPAG (inactive)
• Half-life:
  MPA: 16–18 hours
  MPAG: 12–17 hours
• Elimination:
  Primarily renal as MPAG (~87%)
  Also undergoes enterohepatic recirculation, prolonging drug effect

• Pregnancy:
• FDA Pregnancy Category D (no longer used)
• Strongly associated with increased risk of spontaneous abortion and congenital malformations (e.g., facial defects, heart defects, ear abnormalities)
• Contraindicated in pregnancy unless no suitable alternatives are available
• Lactation:
• Excreted into human milk
• Breastfeeding is contraindicated due to potential for serious adverse effects in the infant
• Contraception Guidance:
• Two reliable contraceptive methods should be used during treatment and for 6 weeks after discontinuation
• Negative pregnancy test required before starting therapy

• Primary Therapeutic Class: Immunosuppressant
• Subclass: Prodrug of mycophenolic acid / Selective IMPDH inhibitor

• Known hypersensitivity to mycophenolate mofetil, mycophenolic acid, or formulation components
• Pregnancy (unless no alternatives exist)
• Breastfeeding
• Severe untreated active infection
• Known hypersensitivity to polysorbate 80 (in IV formulation)

• Pregnancy Risk:
  Major teratogenic risk; strict contraception and monitoring required
• Infection Risk:
  Increased susceptibility to opportunistic infections (e.g., CMV, BK virus, PML)
• Hematologic Toxicity:
  May cause anemia, leukopenia, thrombocytopenia—monitor CBC regularly
• Malignancy Risk:
  Long-term use increases the risk of lymphomas and skin cancers
• Gastrointestinal Effects:
  Risk of ulcers, GI bleeding, colitis; use caution in patients with GI disorders
• Vaccination:
  Avoid live vaccines during treatment; reduced efficacy of inactivated vaccines is possible
• Monitoring Parameters:
  CBC with differential, liver and renal function, signs of infection, and drug levels if needed

Common:

• Gastrointestinal:
  Nausea, vomiting, diarrhea, abdominal cramps
• Hematologic:
  Leukopenia, anemia, thrombocytopenia
• Infectious:
  Opportunistic infections (CMV, BK virus, HSV)
• Neurological:
  Headache, dizziness, insomnia
• Dermatologic:
  Rash, acne, skin thinning

Less Common:

• Hypercholesterolemia, tremor, edema, back pain

Serious:

• Progressive multifocal leukoencephalopathy (PML)
• Sepsis, pneumonia
• Severe neutropenia (ANC <500/mm³)
• GI bleeding or perforation
• Malignancies (lymphoma, skin cancer)

Timing:

• Gastrointestinal symptoms often occur early
• Hematologic and infectious complications may develop during prolonged therapy

• Cyclosporine:
  May reduce enterohepatic recirculation of MPA, lowering efficacy
• Cholestyramine:
  Decreases mycophenolate absorption; avoid co-administration
• Acyclovir/Ganciclovir:
  Compete for renal excretion; increases risk of nephrotoxicity and hematologic suppression
• Antacids (magnesium/aluminum):
  Reduce absorption; separate dosing by ≥2 hours
• Rifampin:
  May decrease MPA levels via induction of glucuronidation
• Live Vaccines:
  Contraindicated due to immunosuppressive effects
• Enzyme Pathways:
  Not metabolized by CYP450
  Metabolized by UGT enzymes

• FDA REMS Program (Reinforced 2023):
  Ongoing requirement for risk mitigation related to teratogenicity; includes educational materials and contraception enforcement
• KDIGO Guidelines (2023):
  Recommend mycophenolate as a preferred maintenance therapy in renal transplant and as induction/maintenance in lupus nephritis
• EULAR Recommendations (2023):
  Support mycophenolate use in autoimmune diseases including lupus nephritis, vasculitis, and others
• Emerging Evidence:
  Increased data support its use in long-term maintenance therapy with better tolerability than older agents like azathioprine

• Oral Formulations:
• Store at 20°C to 25°C (68°F to 77°F)
• Protect from moisture and light
• Do not crush or chew tablets/capsules
• Oral Suspension:
• Store powder at room temperature
• Reconstituted suspension: Refrigerate (2°C to 8°C); use within 60 days
• Shake well before each use
• IV Formulation:
• Store below 25°C
• Reconstituted solution must be used within 4 hours
• Do not freeze
• General Handling:
• Use gloves when handling crushed or broken tablets
• Dispose of unused product properly
• Keep out of reach of children