November, 2007

IMPORTANT PRESCRIBING INFORMATION ABOUT MYFORTIC®
(mycophenolic acid) delayed-release tablet

Subject: Important Change in the Myfortic® (mycophenolic acid) Complete
Prescribing Information – Use of Myfortic® during pregnancy is
associated with increased risks of pregnancy loss and congenital
malformations / Change from Pregnancy Category C to Pregnancy
Category D
Dear Healthcare Professional:
Novartis Pharmaceuticals Corporation would like to inform you that use of Myfortic®
(mycophenolic acid, MPA) during pregnancy is associated with increased risks of
pregnancy loss and congenital malformations. This new important safety information in
the Myfortic Prescribing Information includes:
Boxed WARNING and WARNINGS:
• Increased risk of first trimester pregnancy loss and increased risk of congenital
malformations, especially external ear and facial abnormalities including cleft
lip and palate, and anomalies of the distal limbs, heart, esophagus, and
kidney.
PRECAUTIONS/Pregnancy:
• Changed to Pregnancy Category D based on positive evidence of fetal risk
associated with MPA observed in postmarketing data and from the United
States National Transplantation Pregnancy Registry (NTPR), similar to
malformations seen in animal reproductive toxicology studies.
PRECAUTIONS/Information for Patients subsection:
• Informing females of childbearing potential about risks (pregnancy loss /
malformations) associated with Myfortic use during pregnancy.
• Requiring that female patients of childbearing potential must receive
contraceptive counseling and must use effective contraception.
• Advising that a patient who is planning a pregnancy should not use Myfortic
unless she cannot be successfully treated with other immunosuppressant
drugs.
The pregnancy category for Myfortic has been changed from Category C (Risk of Fetal
Harm Cannot Be Ruled Out) to Category D (Positive Evidence of Fetal Risk). This change
is a result of postmarketing data from the United States National Transplantation
Pregnancy Registry (NTPR) and additional postmarketing data collected in women
exposed to systemic mycophenolate mofetil (MMF) during pregnancy. MMF is converted
to MPA, the active ingredient in Myfortic, following oral or IV administration. The
prescribing information revisions are in response to a Food and Drug Administration (FDA)
request sent to all marketed MMF and MPA products.
Based on the publication by Sifontis et al (Transplantation 2006;82:1698-1702,
Pregnancy Outcomes in Solid Organ Transplant Recipients with Exposure to
Mycophenolate or Sirolimus), postmarketing data from the NTPR, and MMF worldwide
adverse event reporting, 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 December 2006, the
NTPR published data from prospective cases where 24 female transplant patients
reported 33 pregnancies exposed to MMF-containing regimens. 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 post-marketing data are reported voluntarily, it is not
always possible to reliably estimate the frequency of particular adverse outcomes. Similar
structural malformations have been observed in preclinical animal reproductive toxicology
studies. Because MMF is converted to MPA, both drugs carry the same teratogenic risk in
humans.
During the development of Myfortic, animal reproductive toxicology studies were
performed to assess the potential for birth defects. In a teratology study performed with
mycophenolate sodium in rats, at a dose as low as 1 mg/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
1.44 g/day Myfortic. In teratology studies in rabbits fetal resorptions and malformations
occurred from 80 mg/kg/day, in the absence of maternal toxicity (dose levels are
equivalent to about 0.8 times the recommended clinical dose, corrected for BSA). There
are no relevant qualitative or quantitative differences in the teratogenic potential of
mycophenolate sodium and mycophenolate mofetil.
Women of childbearing potential should have a negative serum or urine pregnancy test
with a sensitivity of at least 25 mIU/mL within 1 week prior to beginning therapy. Myfortic
therapy should not be initiated until a negative pregnancy test is obtained. Women of
child-bearing potential (including pubertal girls and peri-menopausal women) taking
Myfortic must receive contraceptive counseling and use effective contraception. The
patient should begin using her two chosen methods of contraception 4 weeks prior to
starting Myfortic therapy, unless abstinence is the chosen method. She should continue
contraceptive use during therapy and for 6 weeks after stopping Myfortic. Patients
should be aware that Myfortic reduces blood levels of the hormones in the oral
contraceptive pill and could theoretically reduce its effectiveness. A patient who is
planning a pregnancy should not use Myfortic unless she cannot be successfully treated
with other immunosuppressant drugs. Risks and benefits of Myfortic and alternative
immunosuppressants should be discussed with the patient.
National Transplantation Pregnancy Registry: To monitor fetal outcomes of pregnant
women exposed to immunosuppressant drugs, including Myfortic, a National
Transplantation Pregnancy Registry has been established. Physicians are encouraged to
register patients by calling 1-877-955-6877.
At Novartis, patient safety is our highest priority and we are committed to ensuring that
healthcare professionals continue to have the information necessary to prescribe Myfortic
appropriately. Please carefully review this information and the revised labeling including
the information for patients section.
The complete revised prescribing information can be found on the Internet at
http://www.myfortic.com. Contact Novartis if you have any questions about this
information or the safe and effective use of Myfortic.
Healthcare professionals should report all serious adverse events suspected to be
associated with the use of Myfortic to Novartis Pharmaceuticals Corporation, One Health
Plaza, East Hanover, NJ 07936 or by phone 1-888-NOW-NOVA (1-888-669-6682),
Monday – Friday 8:30am -5:00pm EST.
Alternatively, this information may be reported to FDA’s MedWatch Reporting System by
phone at 1-800-FDA-1088, by facsimile at 1-800-FDA-0178, or by mail using the form
3500 at http://www.fda.gov/medwatch/index.html
Important Information About Myfortic® (mycophenolic acid)
Indications:
Myfortic® (mycophenolic acid) delayed-release tablets are indicated for the prophylaxis of
organ rejection in patients receiving allogeneic renal transplants, administered in
combination with cyclosporine and corticosteroids.
Contraindications:
Myfortic is contraindicated in patients with a hypersensitivity to mycophenolate sodium,
mycophenolic acid, mycophenolate mofetil, or to any of its excipients.
Important Safety Information:
WARNING
Immunosuppression may lead to increased susceptibility to infection and possible
development of lymphoma and other neoplasms. Only physicians experienced in
immunosuppressive therapy and management of organ transplant recipients should use
Myfortic® (mycophenolic acid). Patients receiving Myfortic should be managed in facilities
equipped and staffed with adequate laboratory and supportive medical resources. The
physician responsible for maintenance therapy should have complete information
requisite for the follow-up of the patient.
Female users of childbearing potential must use contraception. Use of Myfortic during
pregnancy is associated with increased risks of pregnancy loss and congenital
malformations.
• Patients receiving immunosuppressive regimens involving combinations of drugs,
including Myfortic, as part of an immunosuppressive regimen are at increased risk of
developing lymphomas and other malignancies, particularly of the skin.
• Oversuppression of the immune system can also increase susceptibility to infection,
including opportunistic infections, fatal infections, and sepsis.
• Mycophenolic acid can cause fetal harm when administered to a pregnant woman. A
patient who is planning a pregnancy should not use Myfortic unless she cannot be
successfully treated with other immunosuppressant drugs. Risks and benefits of
Myfortic and alternative immunosuppressants should be discussed with the patient.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking
this drug, the patients should be apprised of the potential hazard to the fetus.
• Women of childbearing potential (including pubertal girls and peri-menopausal
women) taking Myfortic must receive contraceptive counseling and use effective
contraception. The patient should begin using her two chosen contraceptive methods
4 weeks prior to starting Myfortic therapy, unless abstinence is the chosen method.
She should continue contraceptive use during therapy and for 6 weeks after stopping
Myfortic. Patients should be aware that Myfortic reduces blood levels of the
hormones in the oral contraceptive pill and could theoretically reduce its
effectiveness.
• Patients receiving Myfortic should be monitored for neutropenia. If neutropenia
develops (ANC < 1.3 x 103/μL), dosing with Myfortic should be interrupted or the dose
reduced, appropriate diagnostic tests performed, and the patient managed
appropriately (see DOSAGE AND ADMINISTRATION).
• Gastrointestinal bleeding (requiring hospitalization) has been reported in de novo
renal transplant patients (1.0%) and maintenance patients (1.3%) treated with
Myfortic (up to 12 months).
• Common adverse events reported in ≥20% of patients receiving Myfortic or
mycophenolate mofetil in the 12-months de novo renal study and maintenance renal
study, when used in combination with cyclosporine, USP (MODIFIED) and
corticosteroids, are listed in Table 4 of the ADVERSE REACTIONS section of the
Myfortic Prescribing Information.
Please see the enclosed Myfortic complete Prescribing Information, which includes
additional information for Warnings, Precautions, and Dosage and Administration.
If you have any questions about this information or the safe and effective use of Myfortic,
please contact Novartis Pharmaceuticals at 1-888-NOW-NOVA (1-888-669-6682),
Monday – Friday 8:30am – 5:00pm EST.
Sincerely,
􀀢 Stephen Cunningham
Dr. Stephen Cunningham
Chief Scientific Officer
US Clinical Development