Myfortic180 mg

Myfortic is an immunosuppressant approved, in combination with cyclosporine and corticosteroids, for the following use:

• Prophylaxis of organ rejection in kidney (renal) transplantation - established, FDA-approved indication in adult and pediatric patients (5 years of age and older, at least 6 months post-transplant). Myfortic must always be used as part of a combination immunosuppressive regimen; it is not used as monotherapy.

Off-label/guideline-supported uses (not FDA-approved, used based on transplant center protocols and specialist judgement): maintenance immunosuppression in liver, heart, lung, and pancreas transplantation, and in select autoimmune conditions (e.g., lupus nephritis) as a mycophenolate mofetil alternative in patients with intolerance to that formulation. These uses should only be undertaken under the supervision of a specialist experienced in transplantation or immunosuppressive therapy.

Each delayed-release (enteric-coated) tablet contains Mycophenolic acid (as mycophenolate sodium) 180 mg or 360 mg. Mycophenolic acid is the active moiety; it is formulated as an enteric-coated, delayed-release tablet designed to release the drug in the small intestine, which may reduce upper gastrointestinal side effects compared with immediate-release mycophenolate mofetil.

Myfortic is a potent, selective, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme required for the de novo synthesis of guanosine nucleotides. Because lymphocytes depend heavily on this de novo pathway (unlike most other cell types, which can use a salvage pathway), Myfortic selectively suppresses T- and B-lymphocyte proliferation, thereby reducing the immune response responsible for transplant rejection.

Myfortic is marketed as an enteric-coated, delayed-release tablet (the active moiety of mycophenolate mofetil) and is used only under specialist supervision as part of combination immunosuppressive therapy after kidney transplantation.

Mechanism of action: Mycophenolic acid reversibly and non-competitively inhibits IMPDH, blocking de novo purine (guanosine nucleotide) synthesis. T- and B-lymphocytes are particularly dependent on this pathway, so Mycophenolic acid preferentially inhibits their proliferation, reducing antibody formation and cytotoxic T-cell generation involved in graft rejection.

Pharmacokinetics: The delayed-release (enteric-coated) formulation of Mycophenolic acid delays absorption until the tablet reaches the small intestine, with peak plasma concentration reached in about 1.5-2.75 hours. Mycophenolic acid is highly protein-bound (mainly albumin), is metabolized in the liver (mainly by glucuronidation to an inactive glucuronide, MPAG, and undergoes enterohepatic recirculation), and is eliminated predominantly via the kidneys as MPAG.

Myfortic has several clinically significant drug interactions:

• Antacids containing magnesium and aluminum hydroxide: reduce absorption of Myfortic; avoid simultaneous administration.
• Cholestyramine and other bile-acid-binding agents: reduce exposure to Myfortic by interrupting enterohepatic recirculation; avoid concurrent use.
• Live attenuated vaccines: immune response may be reduced and vaccine-strain infection may occur; live vaccines should generally be avoided during treatment with Myfortic.
• Azathioprine and other bone-marrow-suppressing agents: concurrent use increases the risk of additive hematologic toxicity; avoid combining with Myfortic.
• Rifampin: can substantially reduce Myfortic exposure; monitor for reduced efficacy if co-administration is unavoidable.
• Cyclosporine: reduces enterohepatic recirculation of Myfortic, lowering its exposure compared to use with other immunosuppressants (e.g., tacrolimus).
• Acyclovir/valacyclovir and ganciclovir/valganciclovir: may compete for renal tubular secretion, increasing concentrations of both Myfortic metabolite and the antiviral; monitor for toxicity, particularly in renal impairment.
• Oral contraceptives: Myfortic is not expected to reduce contraceptive efficacy based on available data, but reliable contraception remains essential given teratogenic risk (see Pregnancy and Lactation).

The most common adverse reactions (occurring in ≥20% of patients) associated with Myfortic include:

• Gastrointestinal: diarrhea, constipation, nausea, vomiting, dyspepsia, abdominal pain
• Hematologic: anemia, leukopenia (low white blood cell count)
• Infections: urinary tract infection, cytomegalovirus (CMV) infection (reflecting immunosuppression)
• Other: insomnia, headache, tremor, peripheral edema, hypertension, postoperative pain, and elevated liver enzymes

Serious/less common effects: severe neutropenia or pancytopenia (requiring regular blood count monitoring), progressive multifocal leukoencephalopathy (PML) and other opportunistic infections, increased risk of lymphoma and skin malignancies (see Precautions and Warnings), and pure red cell aplasia (rare).

Pregnancy: Myfortic carries a well-established, serious risk of pregnancy loss (first-trimester miscarriage) and congenital malformations (including external ear and other craniofacial defects, and malformations of the limbs, heart, esophagus, and kidneys) when used during pregnancy. Myfortic should not be used during pregnancy unless there is no suitable alternative to prevent organ transplant rejection, and only after a detailed discussion of risks with the treating specialist. Women of reproductive potential must use effective contraception before starting, throughout treatment, and for 6 weeks after stopping Myfortic (two reliable methods are generally recommended unless abstinence is the chosen method).

Lactation: Myfortic is excreted in human breast milk; because of the potential for serious adverse effects in a breastfed infant (including immunosuppression and unknown long-term effects), breastfeeding is not recommended during treatment with Myfortic. Discuss feeding options with the treating physician.

Boxed warnings:

• Pregnancy loss and congenital malformations: see Pregnancy and Lactation for full detail; effective contraception is mandatory.
• Increased risk of infections and malignancy: immunosuppression with Myfortic increases susceptibility to bacterial, viral (including CMV and BK virus/polyomavirus-associated nephropathy), fungal, and opportunistic infections, and increases the risk of lymphoma and other malignancies, particularly of the skin. Patients should limit sun exposure and use protective clothing/sunscreen.
• Specialist supervision required: Myfortic should only be prescribed by physicians experienced in immunosuppressive therapy and management of transplant recipients, with facilities for adequate monitoring.

Other precautions:

• Hematologic monitoring: complete blood counts should be performed weekly during the first month, twice monthly for the second and third months, then monthly through the first year, to detect neutropenia or other cytopenias; dose reduction or interruption may be needed.
• Gastrointestinal toxicity: Myfortic can cause GI bleeding, ulceration, and perforation; use with caution in patients with active serious digestive disease.
• Live vaccines: avoid administration of live attenuated vaccines during treatment with Myfortic; vaccination response overall may be diminished.
• Rare enzyme deficiency: avoid use in patients with hereditary hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) deficiency (e.g., Lesch-Nyhan or Kelley-Seegmiller syndrome).
• Do not switch formulations (e.g., between Myfortic delayed-release tablets and mycophenolate mofetil) without physician guidance, as they are not bioequivalent on a milligram-for-milligram basis.

Reported experience with Myfortic overdose is limited but is expected to cause exaggerated immunosuppression, increasing the risk of infection and bone marrow suppression (low white blood cells, anemia, or low platelets). There is no specific antidote.

In case of suspected overdose, seek immediate medical attention or contact a poison control center/emergency services right away. Management is supportive and symptomatic, with monitoring of blood counts and signs of infection; hemodialysis is not expected to remove clinically significant amounts of active drug, though the inactive glucuronide metabolite may be removed. Do not attempt home treatment.

Store at room temperature (below 30°C), protected from light and moisture, in the original container. Keep out of reach of children.

Renal impairment: In patients with severe chronic renal impairment outside the immediate post-transplant period, avoid doses of Myfortic exceeding 720 mg twice daily and monitor closely.

Hepatic impairment: No formal dose adjustment established; monitor patients with significant hepatic parenchymal disease.

Elderly: Elderly transplant recipients may be at greater risk of adverse effects (e.g., certain infections and gastrointestinal bleeding) due to greater overall immunosuppression; use with appropriate monitoring.

Pediatrics: Safety and efficacy of Myfortic delayed-release tablets are established in kidney transplant patients 5 years of age and older, at least 6 months post-transplant, dosed by body surface area. Safety and efficacy in kidney transplant patients under 5 years of age, and in heart or liver transplant patients of any age, have not been established.

Hereditary enzyme deficiency: Avoid in patients with HGPRT deficiency (see Precautions and Warnings).

Immunosuppressants; inosine monophosphate dehydrogenase (IMPDH) inhibitors; antiproliferative/anti-rejection agents.

D