MYFORTIC® (mycophenolic acid)

MYFORTIC® (mycophenolic acid) delayed-release tablets

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MYFORTIC® (mycophenolic acid)

Myfortic® (mycophenolic acid) delayed-release tablets are an enteric formulation of mycophenolate sodium that delivers the active moiety mycophenolic acid (MPA). Myfortic is an immunosuppressive agent. As the sodium salt, MPA is chemically designated as (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid sodium salt.

Its empirical formula is C17H19O6Na. The molecular weight is 342.32 g/mol

Myfortic, as the sodium salt, is a white to off-white, crystalline powder and is highly soluble in aqueous media at physiological pH and practically insoluble in 0.1N hydrochloric acid.

Myfortic is available for oral use as delayed-release tablets containing either 180 mg or 360 mg of mycophenolic acid.

Inactive ingredients include colloidal silicon dioxide, crospovidone, lactose anhydrous, magnesium stearate, povidone (K30), and starch. The enteric coating of the tablet consists of hypromellose phthalate, titanium dioxide, iron oxide yellow, and indigotine (180 mg) or iron oxide red (360 mg).

Indications and usage

  • Myfortic is an antimetabolite immunosuppressant indicated for prophylaxis of organ rejection in adult patients receiving kidney transplants and in pediatric patients at least 5 years of age and older who are at least 6 months post kidney transplant.
  • Use in combination with cyclosporine and corticosteroids.

Limitations of Use:

  • Myfortic delayed release tablets and mycophenolate mofetil tablets and capsules should not be used interchangeably

Mechanism of Action

Mycophenolic acid (MPA), an immunosuppressant, is an uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation to DNA. T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways. MPA has cytostatic effects on lymphocytes.

Dosage and administration

In adults: 720 mg by mouth, twice daily (1440 mg total daily dose) on an empty stomach, 1 hour before or 2 hours after food intake.

In children: 5 years of age and older (who are at least 6 months post kidney transplant), 400 mg/m2 by mouth, twice daily (up to a maximum of 720 mg twice daily).

Do not crush, chew, or cut tablet prior to ingestion.

Warnings and precautions

  • New or Reactivated Viral Infections: Consider reducing immunosuppression.
  • Blood Dyscrasias, including Pure Red Cell Aplasia (PRCA): Monitor for neutropenia or anemia; consider treatment interruption or dose reduction.
  • Serious GI Tract Complications (gastrointestinal bleeding, perforations and ulcers): Administer with caution to patients with active digestive system disease.
  • Immunizations: Avoid live attenuated vaccines.
  • Patients with Hereditary Deficiency of Hypoxanthine-guanine Phosphoribosyl-transferase (HGPRT): May cause exacerbation of disease symptoms; avoid use.
  • Blood Donation: Avoid during therapy and for 6 weeks thereafter.
  • Semen Donation: Avoid during therapy and for 90 days thereafter

Adverse reactions

Most common adverse reactions (≥20%): anemia, leukopenia, constipation, nausea, diarrhea, vomiting, dyspepsia, urinary tract infection, CMV infection, insomnia, and postoperative pain.

Drug interactions

  • Antacids with Magnesium and Aluminum Hydroxides: Decreases concentrations of MPA; concomitant use is not recommended.
  • Azathioprine: Competition for purine metabolism; concomitant administration is not recommended.
  • Cholestyramine, Bile Acid Sequestrates, Oral Activated Charcoal, and Other Drugs that Interfere with Enterohepatic Recirculation: May decrease MPA concentrations; concomitant use is not recommended.
  • Sevelamer: May decrease MPA concentrations; concomitant use is not recommended.
  • Cyclosporine: May decrease MPA concentrations; exercise caution when switching from cyclosporine to other drugs or from other drugs to cyclosporine.
  • Norfloxacin and Metronidazole: May decrease MPA concentrations; concomitant use with both drugs is not recommended.
  • Rifampin: May decrease MPA concentrations; concomitant use is not recommended unless the benefit outweighs the risk.
  • Hormonal Contraceptives: May reduce the effectiveness of oral contraceptives. Additional barrier contraceptive methods must be used.
  • Acyclovir, Valacyclovir, Ganciclovir, Valganciclovir, and Other Drugs that Undergo Renal Tubular Secretion: May increase concentrations of mycophenolic acid glucuronide (MPAG) and co-administered drug; monitor blood cell counts.

Contraindications

Hypersensitivity Reactions: Myfortic is contraindicated in patients with a hypersensitivity to mycophenolate sodium, mycophenolic acid (MPA), mycophenolate mofetil, or to any of its excipients. Reactions like rash, pruritus, hypotension, and chest pain have been observed in clinical trials and post marketing reports

Use in specific populations

Pregnancy: Following oral or intravenous (IV) administration, MMF is metabolized to mycophenolic acid (MPA), the active ingredient in Myfortic and the active form of the drug. Use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of multiple congenital malformations in multiple organ systems. Oral administration of mycophenolate to rats and rabbits during the period of organogenesis produced congenital malformations and pregnancy loss at doses less than the recommended clinical dose (0.05 and 1.1 times exposure at the recommended clinical doses in kidney transplant patients for rats and rabbits, respectively).

Risks and benefits of Myfortic should be discussed with the patient. When appropriate, consider alternative immunosuppressants with less potential for embryo-fetal toxicity.

Lactation: There are no data on the presence of mycophenolate in human milk, or the effects on milk production. There are limited data in the National Transplantation Pregnancy Registry on the effects of mycophenolate on a breastfed child. Studies in rats treated with MMF have shown mycophenolic acid to be present in milk. Because available data are limited, it is not possible to exclude potential risks to a breastfeeding infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Myfortic and any potential adverse effects on the breastfed infant from Myfortic or from the underlying maternal condition. Because available data are limited, it is not possible to exclude potential risks to a breastfeeding infant.

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Females and Males of Reproductive Potential

Females of reproductive potential must be made aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning.

Pregnancy Planning: For female patients taking Myfortic who are considering pregnancy, consider alternative immunosuppressants with less potential for embryo-fetal toxicity. Risks and benefits of Myfortic should be discussed with the patient.

Pregnancy Testing: To prevent unplanned exposure during pregnancy, females of reproductive potential should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL immediately before starting Myfortic. Another pregnancy test with the same sensitivity should be done 8 to 10 days later. Repeat pregnancy tests should be performed during routine followup visits. Results of all pregnancy tests should be discussed with the patient. In the event of a positive pregnancy test, consider alternative immunosuppressants with less potential for embryo-fetal toxicity whenever possible.

Contraceptive: Females of reproductive potential taking Myfortic must receive contraceptive counseling and use acceptable contraception. Patients must use acceptable birth control during entire Myfortic therapy, and for 6 weeks after stopping Myfortic, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely).

Patients should be aware that Myfortic reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness.

Male Patients: Genotoxic effects have been observed in animal studies at exposures exceeding the human therapeutic exposures by approximately 2.5 times. Thus, the risk of genotoxic effects on sperm cells cannot be excluded. Based on this potential risk, sexually active male patients and/or their female partners are recommended to use effective contraception during treatment of the male patient and for at least 90 days after cessation of treatment. Also, based on the potential risk of genotoxic effects, male patients should not donate sperm during treatment with Myfortic and for at least 90 days after cessation of treatment.

Pediatric Use: The safety and effectiveness of Myfortic have been established in pediatric kidney transplant patients 5 to 16 years of age who were initiated on Myfortic at least 6 months post-transplant. Use of Myfortic in this age group is supported by evidence from adequate and well-controlled studies of Myfortic in a similar population of adult kidney transplant patients with additional pharmacokinetic data in pediatric kidney transplant patients. Pediatric doses for patients with BSA <1.19 m2 cannot be accurately administered using currently available formulations of Myfortic tablets.

Geriatric Use: Clinical studies of Myfortic did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 372 patients treated with Myfortic in the clinical trials, 6% (N=21) were 65 years of age and older and 0.3% (N=1) were 75 years of age and older. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Overdosage

There have been anecdotal reports of deliberate or accidental overdoses with Myfortic, whereas not all patients experienced related adverse reactions.

In those overdose cases in which adverse reactions were reported, the reactions fall within the known safety profile of the class. Accordingly, an overdose of Myfortic could possibly result in oversuppression of the immune system and may increase the susceptibility to infection, including opportunistic infections, fatal infections and sepsis. If blood dyscrasias occur (e.g., neutropenia with absolute neutrophil count <1.5 x 103 /mcL or anemia), it may be appropriate to interrupt or discontinue Myfortic.

Possible signs and symptoms of acute overdose could include the following: hematological abnormalities, such as leukopenia and neutropenia, and gastrointestinal symptoms, such as abdominal pain, diarrhea, nausea and vomiting, and dyspepsia

Treatment and Management

General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Although dialysis may be used to remove the inactive metabolite mycophenolic acid glucuronide (MPAG), it would not be expected to remove clinically significant amounts of the active moiety, mycophenolic acid, due to the 98% plasma protein binding of mycophenolic acid. By interfering with enterohepatic circulation of mycophenolic acid, activated charcoal or bile sequestrates, such as cholestyramine, may reduce the systemic mycophenolic acid exposure.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container (USP).

Handling

Keep out of reach and sight of children. Myfortic tablets should not be crushed or cut in order to maintain the integrity of the enteric coating.

Teratogenic effects have been observed with mycophenolate sodium. If for any reason, the Myfortic tablets must be crushed, avoid inhalation of the powder, or direct contact of the powder, with skin or mucous membranes.

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