Summary Of Exposure |
A) USES: Mycophenolate is used in combination with cyclosporine and corticosteroids for the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac, or hepatic transplants.
B) PHARMACOLOGY: Mycophenolate mofetil undergoes rapid and complete metabolism to mycophenolic acid, which is the active metabolite. Mycophenolic acid is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase thereby inhibiting the de novo synthesis pathway of guanosine nucleotides without being incorporated into DNA. Mycophenolic acid exerts a potent cytostatic effect on B and T lymphocytes by inhibiting de novo synthesis because it is a crucial pathway for proliferation.
C) TOXICOLOGY: Because mycophenolate is an immunosuppressant, it can also increase risk of infection, lymphoma, and lymphoproliferative disorders.
D) EPIDEMIOLOGY: Overdose is rare.
E) WITH THERAPEUTIC USE
1) COMMON: Nausea, vomiting, diarrhea, leukopenia, hypertension, and sepsis. An increase in certain types of infections (eg, cytomegalovirus) have also been reported with mycophenolate mofetil. OTHER EFFECTS: Hypotension, fever, peripheral edema, rash, anemia, thrombocytopenia, hypokalemia, hyperkalemia, hypomagnesemia, hypocalcemia, renal dysfunction, urinary tract infection, elevated liver enzymes, dyspnea, respiratory infection, pleural effusion, cough, tremor, anxiety and paraesthesia, heart failure, dysrhythmias, gastrointestinal bleeding, colitis, meningitis, and thrombophlebitis. In postmarketing reports, progressive multifocal leukoencephalopathy (PML), including fatalities has been observed with mycophenolate mofetil (CellCept(R)) use in transplant patients and in patients with systemic lupus erythematosus.
F) WITH POISONING/EXPOSURE
1) There are limited reports of overdose with mycophenolate mofetil. Since many adverse effects are dose-dependent, it is anticipated that overdose effects may be an extension of events reported with therapeutic use. Nausea and mild abdominal cramping were observed 4 hours after a woman with lupus nephritis ingested 10 gram of mycophenolate mofetil (5 times her therapeutic dose). A kidney recipient developed anorexia, lethargy, headache, and moderate leukopenia after ingesting 25 grams of mycophenolate mofetil.
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Vital Signs |
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) FEVER: Fever was reported in 23.3% of renal transplant patients, 47.4% of cardiac transplant patients, and 52.3% of hepatic transplant patients receiving oral mycophenolate mofetil 3 grams/day and 21.4% of renal transplant patients receiving 2 grams/day in randomized, comparative, double-blind trials (n=330, n=289 and n=277, n=336, respectively) (Prod Info CELLCEPT(R) oral capsules, tablets, suspension, powder for IV injection, 2007).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) HYPERTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) Hypertension has been reported in heart, renal and liver transplant recipients during therapy (Sollinger, 1995) .
b) INCIDENCE: Hypertension occurred in 77.5% of cardiac transplant recipients, 62.1% of liver transplant recipients, and 28% to 32% of renal transplant patients during clinical trials with mycophenolate mofetil (Prod Info CellCept(R) oral tablets, capsules, suspension and intravenous injection, 2009).
B) HYPOTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) Hypotension was reported in 32% of cardiac transplant recipients receiving mycophenolate mofetil (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
C) PERIPHERAL EDEMA 1) WITH THERAPEUTIC USE a) Peripheral edema has been reported in renal and cardiac transplant recipients, and has ranged from 28% to 64% of patients, respectively (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
D) ENDOCARDITIS 1) WITH THERAPEUTIC USE a) In postmarketing experience, endocarditis has been reported with therapeutic use of mycophenolate mofetil (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
E) THROMBOPHLEBITIS 1) WITH THERAPEUTIC USE a) After peripheral intravenous administration of mycophenolate mofetil, phlebitis and thrombosis were reported in 4% of patients (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
F) CARDIOVASCULAR FINDING 1) WITH THERAPEUTIC USE a) Other adverse cardiac events have included: dysrhythmias, pericardial effusion, and heart failure. Hypercholesterolemia is also relatively common in cardiac transplant patients following mycophenolate mofetil therapy. Effects appeared similar following oral or intravenous administration (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) DYSPNEA 1) WITH THERAPEUTIC USE a) In clinical trials, dyspnea has been reported in various transplant recipients receiving mycophenolate mofetil. The incidence ranged from 15% to 17% (renal), up to 36.7% (cardiac) in some transplant patients. Effects appeared similar following oral or intravenous administration (Prod Info CellCept(R), mycophenolate mofetil, 2000; Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
B) RESPIRATORY TRACT INFECTION 1) WITH THERAPEUTIC USE a) In clinical trials involving renal and cardiac transplant patients, respiratory infection occurred in 22% to 24%, and 37%, respectively. Pharyngitis and sinusitis are also relatively common adverse events occurring in solid organ transplant recipients. Effects appeared similar following oral or intravenous administration (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
C) COUGH 1) WITH THERAPEUTIC USE a) Increased cough has been reported in various transplant recipients. The following rates were reported: 13% to 15% (renal), 15.9% (liver) and 31.1% (cardiac). Effects appeared similar following oral or intravenous administration (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
D) PLEURAL EFFUSION 1) WITH THERAPEUTIC USE a) Pleural effusion was reported in 34.3% of hepatic transplant patients receiving oral mycophenolate mofetil 3 grams/day in a randomized, comparative, double-blind trial (n=277). Intravenous and oral mycophenolate mofetil have a similar adverse effect profile. Interstitial lung disorders, including pulmonary fibrosis, have been reported in rare instances and should be considered in the differential diagnosis of pulmonary symptoms ranging from dyspnea to respiratory failure in transplant patients receiving mycophenolate mofetil (Prod Info CELLCEPT(R) oral capsules, tablets, suspension, powder for IV injection, 2007).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) HEADACHE 1) WITH THERAPEUTIC USE a) Headache has been reported in solid organ transplant recipients following mycophenolate mofetil therapy (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012). It has been reported infrequently in patients with rheumatoid arthritis (Goldblum, 1993).
b) Following relatively high doses of oral mycophenolic acid for the treatment of psoriasis, headache was reported during the first year of therapy and diminished significantly during subsequent years of treatment (Epinette et al, 1987).
c) INCIDENCE: The occurrence of headache ranged from 16% to 21% (renal) and 53.8% (liver) to 54.3% (cardiac) in solid organ transplant recipients (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
2) WITH POISONING/EXPOSURE a) Headache was reported in a female kidney recipient after ingesting 25 grams of mycophenolate mofetil (Wu et al, 2008).
B) LETHARGY 1) WITH POISONING/EXPOSURE a) Lethargy was reported in a female kidney recipient after ingesting 25 grams of mycophenolate mofetil (Wu et al, 2008).
C) INSOMNIA 1) WITH THERAPEUTIC USE a) Insomnia is a relatively common adverse event of therapy (Lynch & Roenigk, 1977; Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
b) Following relatively high doses of oral mycophenolic acid for the treatment of psoriasis, insomnia was reported during the first year of therapy and diminished significantly during subsequent years of treatment (Epinette et al, 1987).
D) DIZZINESS 1) WITH THERAPEUTIC USE a) In patients with rheumatoid arthritis, dizziness and weakness have been described occasionally (Goldblum, 1993).
b) After heart transplantation, dizziness occurred in 28.7% of patients treated with oral mycophenolate mofetil 3 grams/day (n=289) versus 27.7% of patients treated with azathioprine (AZA) 1.5 to 3 mg/kg/day (n=289) (Prod Info CellCept(R) oral capsules, tablets, suspension, IV injection, 2009).
E) ASTHENIA 1) WITH THERAPEUTIC USE a) In patients with rheumatoid arthritis, dizziness and weakness have been described occasionally (Goldblum, 1993). Following relatively high doses of oral mycophenolic acid for the treatment of psoriasis, weakness was described during the first year of therapy and symptoms diminished significantly during subsequent years of treatment (Epinette et al, 1987).
b) Asthenia was reported in 43.3% of cardiac transplant patients and 35.4% of hepatic transplant patients receiving oral mycophenolate mofetil 3 grams/day in randomized, comparative, double-blind trials (n=289 and n=277, respectively). Intravenous and oral mycophenolate mofetil have a similar adverse effect profile (Prod Info CellCept oral capsules, tablets, suspension, IV injection, 2008).
F) ANXIETY 1) WITH THERAPEUTIC USE a) After heart transplantation, anxiety occurred in 28.4% of patients treated with oral mycophenolate mofetil 3 grams/day (n=289) versus 23.9% of patients treated with azathioprine (AZA) 1.5 to 3 mg/kg/day (n=289) (Prod Info CellCept(R) oral capsules, tablets, suspension, IV injection, 2009).
G) PARESTHESIA 1) WITH THERAPEUTIC USE a) After heart transplantation, paresthesia occurred in 20.8% of patients treated with oral mycophenolate mofetil 3 grams/day (n=289) versus 18% of patients treated with azathioprine (AZA) 1.5 to 3 mg/kg/day (n=289) (Prod Info CellCept(R) oral capsules, tablets, suspension, IV injection, 2009).
H) TREMOR 1) WITH THERAPEUTIC USE a) Tremor was reported in 24.2% of cardiac transplant patients, and 33.9% of hepatic transplant patients receiving oral mycophenolate mofetil 3 grams/day in randomized, comparative, double-blind trials (n=289 and n=277, respectively). Intravenous and oral mycophenolate mofetil have a similar adverse effect profile (Prod Info CellCept oral capsules, tablets, suspension, IV injection, 2008).
I) MENINGITIS 1) WITH THERAPEUTIC USE a) In postmarketing experience, meningitis has been reported during therapeutic use (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
J) PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY 1) WITH THERAPEUTIC USE a) In postmarketing reports, progressive multifocal leukoencephalopathy (PML), including fatalities has been observed with mycophenolate mofetil (CellCept(R)) use in transplant patients and in patients with systemic lupus erythematosus (unapproved use). PML, a serious condition which usually results in death or irreversible nerve damage, has been known to occur in patients with suppressed immune systems and involves a reactivation of the JC virus. A diagnosis of PML should be considered in patients receiving mycophenolate mofetil who exhibit localized neurologic signs and symptoms such as vision changes, loss of coordination, clumsiness, memory loss, difficulty speaking to or understanding others, and leg weakness (US Food and Drug Administration, 2008; Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) GASTROINTESTINAL TRACT FINDING 1) WITH THERAPEUTIC USE a) SUMMARY: Diarrhea, nausea and abdominal cramps are the most common adverse events associated with mycophenolate mofetil therapy (Lynch & Roenigk, 1977; Prod Info CellCept(R) oral capsules, tablets, suspension, 2012; Fischer et al, 2000; Virji et al, 2001). Constipation is also relatively common, and vomiting is reported less frequently (Prod Info CellCept(R) capsules, tablets, oral suspension, injection, 2005). b) Nausea and diarrhea, usually occur early in therapy and respond to dose reduction or switching from two to three divided daily doses. The adverse effect profile was similar after oral or intravenous administration of mycophenolate mofetil (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012; Deierhoi et al, 1993; Sollinger et al, 1992a; Goldblum, 1993). c) Anorexia and dyspepsia have also been reported (Goldblum, 1993; Deierhoi et al, 1993; Ensley et al, 1993; Virji et al, 2001). d) Pancreatitis is a rare adverse effect of mycophenolate mofetil therapy (Deierhoi et al, 1993; Sollinger et al, 1992a). e) INCIDENCE: Diarrhea has been reported in up to 45.3% of patients receiving a solid organ transplant in clinical studies. Constipation has occurred in up to 41.2% of patients. Nausea occurred in up to 54% of transplant recipients (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012). 1) OVERALL INCIDENCE of adverse gastrointestinal complications requiring dose reduction (or more rarely discontinuance of therapy) has ranged from 5% to 20% in renal and heart transplant patients (Ensley et al, 1993; Sollinger et al, 1992a; Deierhoi et al, 1993). In heart transplant patients, doses greater than 4000 milligrams/day are likely to cause gastrointestinal intolerance (Renlund et al, 1996).
2) WITH POISONING/EXPOSURE a) Anorexia was reported in a female kidney recipient after ingesting 25 grams of mycophenolate mofetil (Wu et al, 2008).
b) CASE REPORT: Nausea and mild abdominal cramping were observed four hours after a 10 gram overdose of mycophenolate mofetil. A 24-year-old female with lupus nephritis presented to the emergency department four hours after ingesting five times her therapeutic dose, a total of 10 grams, of mycophenolate mofetil (ingestion confirmed with serum levels). She developed only mild gastrointestinal symptoms, which resolved within 24 hours(Bebarta et al, 2004).
B) GASTROINTESTINAL HEMORRHAGE 1) WITH THERAPEUTIC USE a) Gastrointestinal bleeding has been reported (Sollinger et al, 1992a; Sollinger et al, 1992; Sollinger, 1995; Prod Info CellCept(R) oral capsules, tablets, suspension, 2012). After kidney, heart, and liver transplantation, the incidence of gastrointestinal bleeding was 3%, 1.7%, and 5.4%, respectively, during therapy with mycophenolate mofetil 3 g per day. All patients required hospitalization to treat this adverse event (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
b) Although rare, gastrointestinal perforation has also been reported. In the majority of cases, the patients were receiving other drugs that could cause bleeding or perforation (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
C) COLITIS 1) WITH THERAPEUTIC USE a) CASE REPORT: A 49-year-old woman post-renal transplant recipient developed ischemic colitis 12 days after starting treatment with mycophenolate mofetil. Presenting symptoms included: abdominal pain and watery diarrhea that continued up to postoperative day 21, after which the diarrhea turned bloody. Colonoscopy revealed mucosal hyperemia, edema, and multiple ulcerations throughout the length of the colon. Therapy was discontinued, leading to rapid resolution of pain and bloody stools. Complete healing was confirmed one month later by follow-up colonoscopy (Kim & Park, 2000).
b) CASE REPORTS: Twelve patients with Crohn's disease were treated with oral mycophenolate mofetil (500 milligrams bid) for a mean of 12.5 weeks, and three developed atypical colitis, which included severe bloody diarrhea. Of those three patients, two required blood transfusions (Skelly et al, 2002).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) Liver enzymes were elevated in 24.9% of liver transplant patients receiving 3 grams/day of mycophenolate mofetil in a randomized, comparative, double-blind trial (n=277) (Prod Info CELLCEPT(R) oral capsules, tablets, suspension, powder for IV injection, 2007).
b) Elevation of liver enzymes has been reported occasionally in some studies (Sollinger et al, 1992a; Deierhoi et al, 1993).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) URINARY TRACT INFECTIOUS DISEASE 1) WITH THERAPEUTIC USE a) Urinary tract symptoms, including infections, have been reported during therapeutic use (Lynch & Roenigk, 1977; Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
b) INCIDENCE: Urinary tract infection occurred in 37% of renal transplant patients during clinical trials (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
c) Burning on urination and urinary frequency (urgency) were reported in 16% of psoriasis patients during the first year of mycophenolic acid treatment in one study (Epinette et al, 1987). Other studies have also reported urinary frequency symptoms (Goldblum, 1993).
B) BLOOD IN URINE 1) WITH THERAPEUTIC USE a) Hematuria has been reported following therapy with mycophenolate mofetil (Epinette et al, 1987; Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
C) CRUSH SYNDROME 1) WITH THERAPEUTIC USE a) Renal tubular necrosis has been reported with therapeutic use (Sollinger et al, 1992; Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
b) INCIDENCE: Renal tubular necrosis was reported in 6% to 10% of patients. Effects appeared similar following oral or intravenous administration (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
D) ABNORMAL RENAL FUNCTION 1) WITH THERAPEUTIC USE a) Elevations in serum creatinine have also been observed in cardiac and liver transplant recipients following therapy with mycophenolate mofetil (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
b) Kidney stones have been reported infrequently. The risk of kidney stone development did not decrease in severity during subsequent years of mycophenolate mofetil therapy (Epinette et al, 1987).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) LEUKOPENIA 1) WITH THERAPEUTIC USE a) Leukopenia is a common complication resulting from mycophenolate mofetil (Fischer et al, 2000; Prod Info CellCept(R) oral capsules, tablets, suspension, 2012). In one study, it was reported to be one of the most frequent events leading to discontinuation of therapy (Sollinger, 1995). 1) Although leukopenia has been reported with mycophenolate mofetil, no evidence of bone marrow suppression has been reported in several studies (Sollinger et al, 1992; Sollinger et al, 1992a).
b) In one study, patients receiving any dose of mycophenolate mofetil had a higher incidence of leukopenia than those treated with cyclosporine and prednisone alone. Most cases of leukopenia in the mycophenolate mofetil 3 g daily group were related to the development of cytomegalovirus (CMV) (Moreso et al, 1998). c) INCIDENCE: In controlled clinical studies, leukopenia has occurred in 23% to 43% of transplant patients receiving mycophenolate mofetil (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012). d) CASE REPORTS: Mild leukopenia and anemia have been reported rarely in rheumatoid arthritis patients treated with oral mycophenolate mofetil (Goldblum, 1993). 1) During long-term therapy of psoriasis with oral mycophenolic acid, leukopenia has also occurred, and has occasionally been dose-limiting. Mild anemia and thrombocytopenia have generally been less frequently reported (Epinette et al, 1987; Lynch & Roenigk, 1977).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 40-year-old woman kidney recipient developed moderate leukopenia after ingesting 25 grams of mycophenolate mofetil. On admission, laboratory results showed white blood cell (WBC) counts of 2990/mm(3). Despite treatment with 8 grams of cholestyramine (3 times per day) and rapid decline in serum mycophenolic acid concentrations (37.2, 1.1, 0.4, and 0.1 mcg/mL at 20, 24, 48, and 72 hours after ingestion, respectively), she experienced persistent leukopenia with nadir of 2040/mm(3) 5 days post-ingestion. Her WBC counts returned to 3580/mm(3) 3 weeks after presentation (Wu et al, 2008).
B) ANEMIA 1) WITH THERAPEUTIC USE a) Anemia has occurred after receiving mycophenolate mofetil therapy (Sollinger, 1995; Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
b) INCIDENCE: Anemia has developed in 25% to 43% of patients treated, and appears to vary with the dose, study and type of transplant. In addition, hypochromic anemia and leukocytosis occurred in approximately 7% to 25%, and 7% to 40% of patients, respectively. Effects appeared similar following oral or intravenous administration (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
C) THROMBOCYTOPENIC DISORDER 1) WITH THERAPEUTIC USE a) Thrombocytopenia has been reported in patients receiving mycophenolate mofetil therapy (Lynch & Roenigk, 1977).
b) INCIDENCE: Thrombocytopenia has occurred in 5% to 38% of patients (Lynch & Roenigk, 1977; Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) ERUPTION 1) WITH THERAPEUTIC USE a) After heart transplantation, rash occurred in 22.1% of patients treated with mycophenolate mofetil versus 18% of patients treated with azathioprine. This adverse effect occurred at a lower incidence with mycophenolate mofetil than azathioprine after liver transplant; it was not reported after kidney transplant (Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) PAIN 1) WITH THERAPEUTIC USE a) Leg cramps or pain, bone pain, myalgias, and hand cramps have been reported occasionally during mycophenolate mofetil administration (Sollinger et al, 1992a).
b) Back pain was reported in 34.6% of cardiac transplant patients and 46.6% of hepatic transplant patients receiving oral mycophenolate mofetil 3 grams/day in randomized, comparative, double-blind trials (n=289 and n=277, respectively). Intravenous and oral mycophenolate mofetil have a similar adverse effect profile (Prod Info CELLCEPT(R) oral capsules, tablets, suspension, powder for IV injection, 2007).
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Endocrine |
3.16.2) CLINICAL EFFECTS
A) HYPERGLYCEMIA 1) WITH THERAPEUTIC USE a) Hyperglycemia has been reported in 8% to 12% of renal transplant patients and up to 46.7% of cardiac transplant recipients (Prod Info CellCept(R), mycophenolate mofetil, 2000; Prod Info CellCept(R) oral capsules, tablets, suspension, 2012).
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Reproductive |
3.20.1) SUMMARY
A) Mycophenolate mofetil and mycophenolate sodium are classified as FDA pregnancy category D. Mycophenolate mofetil use during pregnancy is associated with an increased risk of first trimester pregnancy loss and congenital malformations, particularly external ear and other facial abnormalities, such as cleft lip and palate, and anomalies of distal limbs, heart, esophagus, and kidneys. Case reports with mycophenolate mofetil use during pregnancy have shown multiple malformations, some resulting in a decision to terminate pregnancy, particularly with use in the first trimester. Fetal resorptions and malformations have also occurred in rats and rabbits. Malformations, particularly of the head and eyes, were observed in the first generation offspring in the absence of maternal toxicity when pregnant rats were exposed to oral mycophenolate mofetil. Subsequent generations and the mothers were not affected.
3.20.2) TERATOGENICITY
A) CONGENITAL MALFORMATIONS 1) Mycophenolate mofetil (MMF) use during pregnancy was associated with esophageal atresia in 4 infants. In the first case, a 23-year-old woman with polycystic kidney disease was administered MMF throughout pregnancy. Polyhydramnios was detected by ultrasound. The infant was born at 35-weeks gestation and examination revealed mild facial asymmetry, dysplastic ears with absent antihelix, type I esophageal atresia, and patent foramen ovale. Gastrostomy was performed at birth. Definitive surgery was performed at 5 months of age. In the second case, a 34-year-old woman with systemic lupus erythematosus (SLE) was administered MMF until gestation week 8. A fetal ultrasound revealed a cleft lip/palate and cardiopathy. The infant was born at 36-weeks gestation and examination revealed microphthalmia, right upper eyelid coloboma, bilateral microtia, retrognathia, complete bilateral cleft lip and palate, dorsal hemivertebrae, type III esophageal atresia, atrioventricular canal, and patent ductus arteriosus. In the third case, a 32-year-old woman with SLE was administered MMF until gestation week 8. The infant was born at 37-weeks gestation and examination revealed complete unilateral cleft lip and palate, bilateral microtia, absent left external ear canal, ocular hypertelorism, bilateral coloboma of iris, choroid, and retina, esophageal atresia, lumbar vertebral anomalies, and patent ductus arteriosus. In the last case, a 29-year-old woman with a past history of kidney transplant was administered MMF until gestation week 6. A fetal ultrasound revealed polyhydramnios. The infant was born at 35-weeks gestation and examination revealed type III esophageal atresia and dorsal hemivertebrae. In cases 2, 3, and 4, the infants died within days of birth; no autopsies were performed (Martin et al, 2014).
2) Mycophenolate mofetil use during pregnancy is associated with an increased risk of first trimester pregnancy loss and congenital malformations, particularly external ear and other facial abnormalities, such as cleft lip and palate, and anomalies of distal limbs, heart, esophagus, and kidneys. The National Transplantation Pregnancy Registry (NTPR) reported 24 female kidney recipients with 33 pregnancies exposed to mycophenolate mofetil. There were 15 spontaneous abortions (45%) and 18 live births; of these, structural abnormalities were present in 4 of the 18 infants (22%). Postmarketing data collected by the NTPR from 1995 to 2007 from women with systemic exposure to mycophenolate mofetil during pregnancy (n=77) showed that spontaneous abortions occurred in 25 women and fetal/infant malformations were seen in 14 infants, including 6 infants with ear abnormalities (Prod Info MYFORTIC(R) oral delayed release tablets, 2015; Prod Info CellCept(R) oral capsules, oral tablets, oral suspension, 2013; Prod Info CellCept(R) intravenous injection, 2013).
3) A qualitative study of pregnancy outcomes where the father was exposed to mycophenolic acid products found that there was not a significant difference in outcomes, including incidences of premature births, birthweight, malformations, or fetal loss, compared with the general population. The study included 152 male participants who were treated with mycophenolic acid products at the time of conception, who participated in the National Transplantational Pregnancy Registry (NTPR), and who fathered 205 subsequent pregnancies (208 infants born, including 3 pairs of twins). Pregnancy outcomes included 194 live births and 14 spontaneous abortions, with no therapeutic abortions or stillbirths occurring. A comparison between the data entered into the NTPR and data from the general population included the following findings: prematurity, 10.8% vs 12.18%; low birth weight, 4.1% vs 8.16%; birth defect rate, 3.1% vs 3%; and fetal loss rate, 6.8% vs 17.1%, respectively. Although this study suggests that male exposure to mycophenolic acid products does not affect pregnancy outcomes, more research is needed and healthcare providers are encouraged to report pregnancy outcomes (Jones et al, 2013).
4) During a prospective study of pregnancies with maternal mycophenolate exposure (n=57) between January 1998 and June 2011, 16 spontaneous abortions (probability using survival analysis technique: 45%; 95% CI 29% to 66%), 12 elective terminations of pregnancy (including 2 late terminations for multiple malformations), and 29 liveborn infants were observed. Of these 29 live births, 18 infants (62%) were born premature and 31% had low birth weight. Of the 29 infants, one was classified as having a minor anomaly (small nevus) compared with 6 infants diagnosed with major malformations including 2 with external auditory canal atresia (with and without microtia), one with tracheoesophageal atresia, one with severe hydronephrosis, one with an atrial septal defect, and one with a myelomeningocele. Myelosuppression, a common side effect of mycophenolate treatment, was not observed in any of the infants. Overall, a high incidence of major malformations (26%) after first trimester exposure to mycophenolate was observed. However, the underlying maternal disease and concomitant medication may also have contributed to other poor pregnancy outcomes (Hoeltzenbein et al, 2012).
5) In a study of mycophenolate mofetil or sirolimus use during pregnancy, 26 pregnancies in 18 kidney recipients with mycophenolate mofetil exposure were reported. Fifteen were live births and 11 were spontaneous abortions which all occurred in the first trimester. In 4 of the 15 livebirths (26.7%), structural malformations were reported. In all 4 cases, posttransplant regimen also included tacrolimus, and prednisone. In the first case, the patient received a second kidney transplant at 3 weeks' gestation and was treated with mycophenolate mofetil 1000 mg twice daily. Pregnancy was diagnosed at 26 weeks and mycophenolate mofetil was reduced to 500 mg twice daily. At 33 weeks gestation, a preterm infant with hypoplastic nails and shortened fifth fingers was delivered. The child was healthy and developing normally at 6 years of age. In the second case, the patient was maintained on mycophenolate mofetil 500 mg twice daily when she conceived. Moderate acute rejection (Banff grade II A) was diagnosed at 24 weeks. Subsequently, she was switched from mycophenolate mofetil to sirolimus. At 31 weeks, she delivered a preterm infant with cleft lip and palate and microtia. At 4 years of age, the child, who wears bone conduction hearing aids, was healthy and developing well. In the third case, mycophenolate mofetil 250 mg twice daily was maintained throughout pregnancy. At 35 weeks, the patient delivered a premature infant who died 1 day later. There were multiple malformations including, cleft lip and palate, microtia, congenital diaphragmatic hernia and congenital heart defects, possibly associated with Fryn's syndrome. In the fourth case, mycophenolate mofetil 1000 mg twice daily was discontinued in the second trimester of the patient's pregnancy. At 39 weeks, a full-term normal weight infant with microtia was delivered (Sifontis et al, 2006).
6) A case report described facial, ocular, and auditory abnormalities in an infant born to a 25-year-old woman who was treated with mycophenolate mofetil for the first 10 weeks of gestation. The patient had received a renal transplant for severe renal insufficiency. After suffering organ rejection with the first transplant, she underwent a second one. Subsequently, immunosuppressive therapy with mycophenolate mofetil 500 mg/day and tacrolimus 12 mg/day was initiated. The patient became pregnant 2 years later while receiving this regimen. When pregnancy was diagnosed at 10 weeks' gestation, mycophenolate mofetil was discontinued and tacrolimus was continued for the remainder of her pregnancy. At 20 weeks, cleft lip and palate were detected using ultrasound. The patient decided to continue with the pregnancy. At 41 weeks, she delivered a female via caesarean with weight, length and head circumference of 3050 g, 52 cm, and 33.5 cm, respectively. The infant had bilateral upper cleft lip with complete cleft palate, bilateral microtia, hypertelorism, micrognathia and mild left ptosis. An ocular funduscopy was performed revealing a large chorioretinal coloboma in both eyes. A temporal bone CT-scan showed bilateral lack of external ear canals and small tympanic cavities with abnormal auditory ossicles. Semicircular ducts and other internal ear structures looked normal. Brain CT-scan, skeletal radiographs, and abdominal ultrasound results were all normal. At 8 months, cleft lip was corrected with a future surgery scheduled for the cleft palate. Bilateral conductive hearing loss was diagnosed requiring hearing aids. At 9 months, her physical and neurodevelopment examination was normal and age-appropriate (Perez-Aytes et al, 2008).
7) A case report described multiple fetal malformations resulting in pregnancy termination for a 27-year-old receiving treatment with mycophenolate mofetil at conception and during pregnancy. The patient had undergone renal transplantation at 2 years prior to her pregnancy. In the postoperative period after transplant rejection, her regimen being included mycophenolate mofetil 500 mg/day, tacrolimus, and prednisone. At 13 weeks gestation, pregnancy was diagnosed. Subsequently, mycophenolate mofetil was discontinued and azathioprine 50 mg/day was initiated. The first ultrasound at 14 weeks revealed no evidence of structural anomalies. However, at 22 weeks, multiple malformations were observed, including complete agenesis of the corpus callosum and cleft lip and palate resulting in a decision to terminate the pregnancy. A fetopathology exam reported a large left cleft lip and plate, micrognathia, ocular hypertelorism, microtia and external auditory duct atresia, and a left pelvic ectopic kidney. Complete agenesis of the corpus callosum was also documented. The patient became pregnant one year later while being treated with azathioprine, tacrolimus, and prednisone during pregnancy. At 34 weeks, the patient developed chorioamnionitis and delivered a 2640-g healthy boy with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. During the follow-up period, normal growth and development of the child was reported (LeRay et al, 2004).
8) A case report described multiple fetal malformations affecting the head, lower limbs, heart, and kidneys resulting in pregnancy termination for a 21-year-old woman who was treated with mycophenolate mofetil during the first 25 weeks of her pregnancy. She was treated with two 6-month courses of IV cyclophosphamide for flare ups of class IV lupus nephritis at 2 and 4 years prior to her pregnancy. Following the second course of cyclophosphamide, her lupus was in remission. She was initiated on mycophenolate mofetil 1000 mg twice daily 10 months prior to her pregnancy being discovered. Other medications included prednisone, hydroxychloroquine, and perindopril. A decision was made to terminate the pregnancy due to multiple malformations affecting the head (bilateral anotia, external auditory duct atresia), lower limb (polydactylia and nail hypoplasia), heart (anterior positioning of the aorta, interventricular communications) and kidneys (asymmetry) (ElSebaaly et al, 2007).
9) A case report described an infant who was delivered of a patient who received her second kidney transplant at 3 weeks gestation and was then treated with mycophenolate mofetil, tacrolimus and prednisone. The mycophenolate mofetil dosage was decreased from 1000 mg twice daily to 500 mg twice daily when the pregnancy was discovered at 26 weeks' gestation. The infant was born with hypoplastic nails and shortened fifth fingers, but was healthy and developing normally at 6 years of age. The second infant was conceived while the mother was treated with mycophenolate mofetil, tacrolimus and prednisone. Acute rejection of the kidney occurred approximately 24 weeks' gestation, and the mother was then treated with steroids, antithymocyte globulin, and sirolimus. The infant was born with cleft lip and palate, and an ear deformity (Armenti et al, 2003).
B) ANIMAL STUDIES 1) With doses below equivalent human clinical doses (0.02 to 0.9 times the recommended human dose for renal and cardiac transplant patients), fetal resorptions and malformations, including anophthalmia, agnathia, and hydrocephaly in rats and ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia in rabbits, have occurred in the absence of maternal toxicity (Prod Info CellCept(R) oral capsules, oral tablets, oral suspension, 2013; Prod Info CellCept(R) intravenous injection, 2013).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) The manufacturer has classified mycophenolate mofetil as FDA pregnancy category D (Prod Info CellCept(R) oral capsules, oral tablets, oral suspension, 2013; Prod Info CellCept(R) intravenous injection, 2013).
2) The manufacturer has classified mycophenolate sodium as FDA pregnancy category D (Prod Info MYFORTIC(R) oral delayed release tablets, 2015).
3) Mycophenolate mofetil use during pregnancy can result in fetal harm. In women of childbearing potential, pregnancy should be ruled out with a serum or urine pregnancy test with a sensitivity of at least 25 milli-International units/mL prior to initiating mycophenolate mofetil therapy. Repeat the pregnancy test 8 to 10 days after start of therapy, then during routine followup visits thereafter. Additionally, women should be counseled on the use of effective contraception, and advised to use acceptable contraception methods during therapy (ie, IUD or vasectomy in male partner, hormone plus barrier method, or 2 barrier methods) and for 6 weeks after therapy discontinuation. Advise patients that mycophenolate mofetil may reduce the effectiveness of hormonal contraceptives. Consider alternative immunosuppressants if pregnancy is planned or occurs up to 6 weeks after mycophenolate mofetil discontinuation. However, if the maternal benefit outweighs the potential risk to the fetus and mycophenolate mofetil is used during pregnancy, the patient should be informed of the potential hazard to the fetus. Encourage women exposed to mycophenolate mofetil at any time during pregnancy to call the Mycophenolate Pregnancy Registry at 1-800-617-8191 (Prod Info CellCept(R) oral capsules, oral tablets, oral suspension, 2013; Prod Info CellCept(R) intravenous injection, 2013).
B) PREGNANCY REGISTRY 1) MYCOPHENOLATE SODIUM a) Patients exposed to mycophenolate sodium during pregnancy may register with the Mycophenolate Pregnancy Registry by calling 1-800-617-8191 (Prod Info MYFORTIC(R) oral delayed release tablets, 2015).
C) PREGNANCY TESTING 1) MYCOPHENOLATE SODIUM a) Perform serum or urine pregnancy test with a sensitivity of at least 25 milli-international units/mL immediately before initiation of treatment. A pregnancy test with the same sensitivity should be performed within 8 to 10 days of treatment initiation and routinely thereafter (Prod Info MYFORTIC(R) oral delayed release tablets, 2015).
D) CONTRACEPTION 1) MYCOPHENOLATE SODIUM a) Use of adequate contraception is required during treatment with mycophenolate sodium and for at least 6 weeks after discontinuation (Prod Info MYFORTIC(R) oral delayed release tablets, 2015).
E) SPONTANEOUS ABORTIONS 1) Mycophenolate mofetil use during pregnancy is associated with an increased risk of first trimester pregnancy loss and congenital malformations, particularly external ear and other facial abnormalities, such as cleft lip and palate, and anomalies of distal limbs, heart, esophagus, and kidneys. The National Transplantation Pregnancy Registry (NTPR) reported 24 female kidney recipients with 33 pregnancies exposed to mycophenolate mofetil. There were 15 spontaneous abortions (45%) and 18 live births; of these, structural abnormalities were present in 4 of the 18 infants (22%). Postmarketing data collected by the NTPR from 1995 to 2007 from women with systemic exposure to mycophenolate mofetil during pregnancy (n=77) showed that spontaneous abortions occurred in 25 women and fetal/infant malformations were seen in 14 infants, including 6 infants with ear abnormalities (Prod Info CellCept(R) oral capsules, oral tablets, oral suspension, 2013; Prod Info CellCept(R) intravenous injection, 2013).
2) A qualitative study of pregnancy outcomes where the father was exposed to mycophenolic acid products found that there was not a significant difference in outcomes, including incidences of premature births, birthweight, malformations, or fetal loss, compared with the general population. The study included 152 male participants who were treated with mycophenolic acid products at the time of conception, who participated in the National Transplantational Pregnancy Registry (NTPR), and who fathered 205 subsequent pregnancies (208 infants born, including 3 pairs of twins). Pregnancy outcomes included 194 live births and 14 spontaneous abortions, with no therapeutic abortions or stillbirths occurring. A comparison between the data entered into the NTPR and data from the general population included the following findings: prematurity, 10.8% vs 12.18%; low birth weight, 4.1% vs 8.16%; birth defect rate, 3.1% vs 3%; and fetal loss rate, 6.8% vs 17.1%, respectively. Although this study suggests that male exposure to mycophenolic acid products does not affect pregnancy outcomes, more research is needed and healthcare providers are encouraged to report pregnancy outcomes (Jones et al, 2013).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) MYCOPHENOLATE MOFETIL a) No reports describing the use of mycophenolate mofetil during human lactation or measuring the amount, if any, of the drug excreted into milk have been found (Prod Info CellCept(R) oral capsules, oral tablets, oral suspension, 2013; Prod Info CellCept(R) intravenous injection, 2013).
2) MYCOPHENOLATE SODIUM a) Lactation studies with mycophenolate sodium have not been conducted in humans. It is not known whether mycophenolate sodium is excreted in human milk and the effects on the nursing infant from exposure to the drug in milk are unknown. Discontinue breastfeeding or discontinue treatment with mycophenolate sodium. The importance of the drug to the mother should be taken into consideration (Prod Info MYFORTIC(R) oral delayed release tablets, 2015).
B) ANIMAL STUDIES 1) Lactation studies in rats showed that mycophenolic acid was excreted in milk (Prod Info CellCept(R) oral capsules, oral tablets, oral suspension, 2013; Prod Info CellCept(R) intravenous injection, 2013).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) MALE RATS: There was no effect on fertility of male rats given oral mycophenolate mofetil doses up to 20 mg/kg/day (0.1 times and 0.07 times the recommended clinical dose in renal transplant patients and in cardiac transplant patients when corrected for body surface area, respectively) (Prod Info CellCept(R) oral capsules, oral tablets, oral suspension, 2013; Prod Info CellCept(R) intravenous injection, 2013). There was no effect on male rats fertility administered mycophenolate sodium doses up to 18 mg/kg and there were no testicular or spermatogenic effects at daily doses of 20 mg/kg for 13 weeks (about 2-fold the therapeutic systemic exposure of mycophenolic acid) (Prod Info Myfortic(R) oral delayed release tablets, 2012).
2) FEMALE RATS: Malformations, particularly of the head and eyes, were observed in first-generation offspring in the absence of maternal toxicity when oral mycophenolate mofetil was given to female rats at a dose that was 0.02 times and 0.01 times the recommended clinical dose in renal transplant patients and in cardiac transplant patients, respectively. However, no effects on fertility were observed in the mothers or in the subsequent generation (Prod Info CellCept(R) oral capsules, oral tablets, oral suspension, 2013; Prod Info CellCept(R) intravenous injection, 2013). No effects on female fertility were noted at mycophenolate sodium doses up to 20 mg/kg (3-fold higher than the recommended therapeutic dose based on systemic exposure) (Prod Info Myfortic(R) oral delayed release tablets, 2012).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) Patients who are receiving immunosuppressive therapy, including mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, particularly skin cancer.
3.21.3) HUMAN STUDIES
A) POTENTIAL CARCINOGENIC RISK 1) Patients who are receiving immunosuppressives including mycophenolate mofetil are at increased risk of developing lymphomas and other malignancies, particularly skin cancer. The risk is most likely related to the duration and intensity of immunosuppression rather than the drugs used. During clinical trials, lymphoproliferative disease or lymphoma developed in 0.4% and 1% of patients treated with mycophenolate mofetil 2 or 3 g/day in combination with other immunosuppressives (Prod Info CellCept(R), mycophenolate mofetil, 2000).
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