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, kidney, and nervous system [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 [see New Or Reactivated Viral 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 x 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, kidney and nervous system. 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.