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Myfortic

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Myfortic

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Embryofetal Toxicity

Use of Myfortic during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney [see Use in Specific Populations].

Pregnancy Exposure Prevention and Planning

Females of reproductive potential must be aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning. For recommended pregnancy testing and contraception methods see Use In Specific Populations.

Management of Immunosuppression

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Myfortic. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physicians responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see BOXED WARNING].

Lymphoma and Other Malignancies

Patients receiving immunosuppressants, including Myfortic, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see ADVERSE REACTIONS]. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.

As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Post-transplant lymphoproliferative disorder (PTLD) has been reported in immunosuppressed organ transplant recipients. The majority of PTLD events appear related to Epstein Barr Virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV seronegative, a population which includes many young children.

Serious Infections

Patients receiving immunosuppressants, including Myfortic, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, and new or reactivated viral infections including opportunistic infections. These infections may lead to serious, including fatal outcomes. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.

New or Reactivated Viral Infections

Polyomavirus associated nephropathy (PVAN), JC virus associated progressive multifocal leukoencephalopathy (PML), cytomegalovirus (CMV) infections, reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including the mycophenolic acid (MPA) derivatives Myfortic and MMF. Reduction in immunosuppression should be considered for patients who develop evidence of new or reactivated viral infections. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.

PVAN, especially due to BK virus infection, is associated with serious outcomes, including deteriorating renal function and renal graft loss. Patient monitoring may help detect patients at risk for PVAN.

PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.

The risk of CMV viremia and CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease. [see ADVERSE REACTIONS].

Viral reactivation has been reported in patients infected with HBV or HCV. Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended.

Blood Dyscrasias Including Pure Red Cell Aplasia

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressive agents. The mechanism for MPA derivatives induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppressive regimen is also unknown. In some cases PRCA was found to be reversible with dose reduction or cessation of therapy with MPA derivatives. In transplant patients, however, reduced immunosuppression may place the graft at risk. Changes to Myfortic therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimize the risk of graft rejection.

Patients receiving Myfortic should be monitored for blood dyscrasias (e.g., neutropenia or anemia). The development of neutropenia may be related to Myfortic itself, concomitant medications, viral infections, or some combination of these reactions. Complete blood count should be performed weekly during the first month, twice monthly for the second and the third month of treatment, then monthly through the first year. If blood dyscrasias occur [neutropenia develops (ANC < 1.3 103/mcL) or anemia], dosing with Myfortic should be interrupted or the dose reduced, appropriate tests performed, and the patient managed accordingly.

Serious GI Tract Complications

Gastrointestinal bleeding (requiring hospitalization), intestinal perforations, gastric ulcers, and duodenal ulcers have been reported in patients treated with Myfortic. Myfortic should be administered with caution in patients with active serious digestive system disease.

Immunizations

The use of live attenuated vaccines should be avoided during treatment with Myfortic; examples include (but not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Rare Hereditary Deficiencies

Myfortic is an inosine monophosphate dehydrogenase inhibitor (IMPDH Inhibitor). Myfortic should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndromes because it may cause an exacerbation of disease symptoms characterized by the overproduction and accumulation of uric acid leading to symptoms associated with gout such as acute arthritis, tophi, nephrolithiasis or urolithiasis and renal disease including renal failure.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide)

Embryofetal Toxicity
  • Inform pregnant women and females of reproductive potential that use of Myfortic in pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations [see Use In Specific Populations].
  • In the event of a positive pregnancy test, discuss the risks and benefits of Myfortic with the patient. Encourage her to enroll in the pregnancy registry. (1-800-617-8191). [see Use In Specific Populations].
Pregnancy Exposure Prevention and Planning
  • Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential [see Females of Reproductive Potential].
  • Inform females of reproductive potential must use acceptable birth control during entire Myfortic therapy and for 6 weeks after stopping Myfortic, unless the patient chooses to avoid heterosexual sexual intercourse completely (abstinence) [see WARNINGS AND PRECAUTIONS and Females of Reproductive Potential].
  • For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of Myfortic should be discussed with the patient [see Females of Reproductive Potential].
Nursing Mothers

Advise patients that they should not breastfeed during Myfortic therapy [see Nursing Mothers].

Development of Lymphoma and Other Malignancies
  • Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression.
  • Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor.
Increased Risk of Infection

Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection [see WARNINGS AND PRECAUTIONS].

Blood Dyscrasias

Inform patients they are at increased risk for developing blood dyscrasias (e.g., neutropenia or anemia) and to immediately contact their healthcare provider if they experience any evidence of infection, unexpected bruising, bleeding, or any other manifestation of bone marrow suppression [see WARNINGS AND PRECAUTIONS].

Gastrointestinal Tract Complications

Inform patients that Myfortic can cause gastrointestinal tract complications including bleeding, intestinal perforations, and gastric or duodenal ulcers. Advise the patient to contact their healthcare provider if they have symptoms of gastrointestinal bleeding or sudden onset or persistent abdominal pain [see WARNINGS AND PRECAUTIONS].

Immunizations

Inform patients that Myfortic can interfere with the usual response to immunizations and that they should avoid live vaccines [see WARNINGS AND PRECAUTIONS].

Administration Instructions

Advise patients to swallow Myfortic tablets whole, and not crush, chew, or cut the tablets. Inform patients to take Myfortic on an empty stomach, 1 hour before or 2 hours after food intake.

Drug Interactions

Patients should be advised to report to their doctor the use of any other medications while taking Myfortic. The simultaneous administration of any of the following drugs with Myfortic may result in clinically significant adverse reactions:

Antacids with magnesium and aluminum hydroxides
Azathioprine
Cholestyramine
Hormonal Contraceptives (e.g., birth control pill, transdermal patch, vaginal ring, injection, and implant)

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week oral carcinogenicity study in rats, mycophenolate sodium was not tumorigenic at daily doses up to 9 mg per kg, the highest dose tested. This dose resulted in approximately 0.6 to 1.2 times the systemic exposure (based on plasma AUC) observed in renal transplant patients at the recommended dose of 1440 mg per day. Similar results were observed in a parallel study in rats performed with MMF. In a 104-week oral carcinogenicity study in mice, MMF was not tumorigenic at a daily dose level as high as 180 mg per kg (which corresponds to 0.6 times the recommended mycophenolate sodium therapeutic dose, based on body surface area).

The genotoxic potential of mycophenolate sodium was determined in five assays. Mycophenolate sodium was genotoxic in the mouse lymphoma/thymidine kinase assay, the micronucleus test in V79 Chinese hamster cells, and the in vivo mouse micronucleus assay. Mycophenolate sodium was not genotoxic in the bacterial mutation assay (Salmonella typhimurium TA 1535, 97a, 98, 100, and 102) or the chromosomal aberration assay in human lymphocytes.

Mycophenolate mofetil generated similar genotoxic activity. The genotoxic activity of mycophenolic acid (MPA) is probably due to the depletion of the nucleotide pool required for DNA synthesis as a result of the pharmacodynamic mode of action of MPA (inhibition of nucleotide synthesis).

Mycophenolate sodium had no effect on male rat fertility at daily oral doses as high as 18 mg per kg and exhibited no testicular or spermatogenic effects at daily oral doses of 20 mg per kg for 13 weeks (approximately 2 times the systemic exposure of MPA at the recommended therapeutic dose). No effects on female fertility were seen up to a daily dose of 20 mg per kg (approximately 3 times the systemic exposure of MPA at the recommended therapeutic dose).

Use In Specific Populations

Pregnancy

Pregnancy Category D

[See WARNINGS AND PRECAUTIONS]

For those females using Myfortic at any time during pregnancy and those becoming pregnant within 6 weeks of discontinuing therapy, the healthcare practitioner should report the pregnancy to the Mycophenolate Pregnancy Registry (1-800-617-8191). The healthcare practitioner should strongly encourage the patient to enroll in the pregnancy registry. The information provided to the registry will help the Health Care Community to better understand the effects of mycophenolate in pregnancy.

Risk Summary

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 congenital malformations, especially external ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney. In animal studies, congenital malformations and pregnancy loss occurred when pregnant rats and rabbits received mycophenolic acid at dose multiples similar to and less than clinical doses.

Risks and benefits of Myfortic should be discussed with the patient. When appropriate, consider alternative immunosuppressants with less potential for embryofetal toxicity. In certain situations, the patient and her healthcare practitioner may decide that the maternal benefits outweigh the risks to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Data

Human Data

In the National Transplantation Pregnancy Registry (NTPR), there were data on 33 MMF-exposed pregnancies in 24 transplant patients; there were 15 spontaneous abortions (45%) and 18 live-born infants. Four of these 18 infants had structural malformations (22%). In postmarketing data (collected from 1995 to 2007) on 77 women exposed to systemic MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or fetus. Six of 14 malformed offspring had ear abnormalities. Because these postmarketing data are reported voluntarily, it is not always possible to reliably estimate the frequency of particular adverse outcomes. These malformations are similar to findings in animal reproductive toxicology studies. For comparison, the background rate for congenital anomalies in the United States is about 3%, and NTPR data show a rate of 4%–5% among babies born to organ transplant patients using other immunosuppressive drugs. There are no relevant qualitative or quantitative differences in the teratogenic potential of mycophenolate sodium and MMF.

Animal Data

In a teratology study performed with mycophenolate sodium in rats, at a dose as low as 1 mg per kg, malformations in the offspring were observed, including anophthalmia, exencephaly, and umbilical hernia. The systemic exposure at this dose represents 0.05 times the clinical exposure at the dose of 1440 mg per day Myfortic. In teratology studies in rabbits, fetal resorptions and malformations occurred at doses equal to or greater than 80 mg per kg per day, in the absence of maternal toxicity (which corresponds to about 1.1 times the recommended clinical dose, based on body surface area).

Nursing Mothers

It is not known whether MPA is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Myfortic, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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 [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY]. Pediatric doses for patients with BSA < 1.19 m² cannot be accurately administered using currently available formulations of Myfortic tablets.

The safety and effectiveness of Myfortic in de novo pediatric kidney transplant patients and in pediatric kidney transplant patients below the age of 5 years have not been established.

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.

Females of Reproductive Potential

Pregnancy Exposure Prevention and Planning

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.

Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not passed through menopause. Menopause is the permanent end of menstruation and fertility. Menopause should be clinically confirmed by a patient's healthcare practitioner. Some commonly used diagnostic criteria include 1) 12 months of spontaneous amenorrhea (not amenorrhea induced by a medical condition or medical therapy), or 2) postsurgical from a bilateral oophorectomy.

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 follow-up visits. Results of all pregnancy tests should be discussed with the patient.

In the event of a positive pregnancy test, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations.

Contraception

Females of reproductive potential taking Myfortic must receive contraceptive counseling and use acceptable contraception (see Table 5 for Acceptable Contraception Methods). 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 [see PATIENT INFORMATION, DRUG INTERACTIONS].

Table 5: Acceptable Contraception Methods for Females of Reproductive Potential
Pick from the following birth control options:

Option 1      
Methods to Use Alone Intrauterine devices (IUDs) Tubal sterilization Patient's partner had a vasectomy    
OR      
Option 2 Hormone Methods choose 1   Barrier Methods choose 1
Choose One Hormone Method AND One Barrier Method Estrogen and Progesterone Oral Contraceptive Pill Transdermal patch Vaginal ring Progesterone-only Injection AND Diaphragm with spermicide Cervical cap with spermicide Contraceptive sponge Male condom Female condom
OR      
Option 3 Barrier Methods choose 1   Barrier Methods choose 1
Choose One Barrier Method from each column (must choose two methods) Diaphragm with spermicide Cervical cap with spermicide Contraceptive sponge AND Male condom Female condom

Pregnancy Planning

For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of Myfortic should be discussed with the patient.

Last reviewed on RxList: 10/14/2013
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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