Mycophenolic Acid (Page 2 of 10)

5.5 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), SARS-CoV-2 infection, have been reported in patients treated with immunosuppressants, including MPA derivatives mycophenolic acid delayed-release tablets 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 ( 6.1) ].

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.

5.6 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 mycophenolic acid delayed-release tablets therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimize the risk of graft rejection.

Patients receiving mycophenolic acid delayed-release tablets should be monitored for blood dyscrasias (e.g., neutropenia or anemia). The development of neutropenia may be related to mycophenolic acid delayed-release tablets 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 mycophenolic acid delayed-release tablets should be interrupted or the dose reduced, appropriate tests performed, and the patient managed accordingly.

5.7 Serious GI Tract Complications

Gastrointestinal bleeding (requiring hospitalization), intestinal perforations, gastric ulcers, and duodenal ulcers have been reported in patients treated with mycophenolic acid delayed-release tablets. Mycophenolic acid delayed-release tablets should be administered with caution in patients with active serious digestive system disease.

5.8 Acute Inflammatory Syndrome Associated with Mycophenolate Products

Acute inflammatory syndrome (AIS) has been reported with the use of mycophenolate products, and some cases have resulted in hospitalization. AIS is a paradoxical pro-inflammatory reaction characterized by fever, arthralgias, arthritis, muscle pain and elevated inflammatory markers including, C-reactive protein and erythrocyte sedimentation rate, without evidence of infection or underlying disease recurrence. Symptoms occur within weeks to months of initiation of treatment or a dose increase. After discontinuation, improvement of symptoms and inflammatory markers are usually observed within 24 to 48 hours.

Monitor patients for symptoms and laboratory parameters of AIS when starting treatment with mycophenolate products or when increasing the dosage. Discontinue treatment and consider other treatment alternatives based on the risk and benefit for the patient.

5.9 Immunizations

During treatment with mycophenolic acid delayed-release tablets, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Advise patients to discuss with the physician before seeking any immunizations.

5.10 Rare Hereditary Deficiencies

Mycophenolic acid delayed-release are inosine monophosphate dehydrogenase inhibitor (IMPDH inhibitor). Mycophenolic acid delayed-release tablets 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.

5.11 Blood Donation

Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of mycophenolic acid delayed-release tablets because their blood or blood products might be administered to a female of reproductive potential or a pregnant woman.

5.12 Semen Donation

Based on animal data, men should not donate semen during therapy and for 90 days following discontinuation of mycophenolic acid delayed-release tablets [see Use in Specific Populations (8.3)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label.

• Embryofetal Toxicity [see Boxed Warning, Warnings and Precautions (5.1)]
• Lymphomas and Other Malignancies [see Boxed Warning, Warnings and Precautions (5.3) ]
• Serious Infections [see Boxed Warning, Warnings and Precautions (5.4) ]
• New or Reactivated Viral Infections [see Warnings and Precautions (5.5)]
• Blood Dyscrasias Including Pure Red Cell Aplasia [ see Warnings and Precautions 5.6 ]
• Serious GI Tract Complications [see Warnings and Precautions (5.7)]
• Acute Inflammatory Syndrome Associated with Mycophenolate Products [see Warnings and Precautions (5.8) ]
• Rare Hereditary Deficiencies [see Warnings and Precautions (5.10)]

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below derive from two randomized, comparative, active-controlled, double-blind, double-dummy trials in prevention of acute rejection in de novo and converted stable kidney transplant patients.

In the de novo trial, patients were administered either mycophenolic acid delayed-release tablets 1.44 grams per day (N = 213) or MMF 2 grams per day (N=210) within 48 hours post-transplant for 12 months in combination with cyclosporine, USP MODIFIED and corticosteroids. Forty-one percent of patients also received antibody therapy as induction treatment. In the conversion trial, renal transplant patients who were at least 6 months post-transplant and receiving 2 grams per day MMF in combination with cyclosporine USP MODIFIED, with or without corticosteroids for at least two weeks prior to entry in the trial were randomized to mycophenolic acid delayed-release tablets 1.44 grams per day (N = 159) or MMF 2 grams per day (N = 163) for 12 months.

The average age of patients in both studies was 47 years and 48 years (de novo study and conversion study, respectively), ranging from 22 to 75 years. Approximately 66% of patients were male; 82% were white, 12 % were black, and 6% other races. About 40% of patients were from the United States and 60% from other countries.

In the de novo trial, the overall incidence of discontinuation due to adverse reactions was 18% (39/213) and 17% (35/210) in the mycophenolic acid delayed-release tablets and MMF arms, respectively. The most common adverse reactions leading to discontinuation in the mycophenolic acid delayed-release tablets arm were graft loss (2%), diarrhea (2%), vomiting (1%), renal impairment (1%), CMV infection (1%), and leukopenia (1%). The overall incidence of patients reporting dose reduction at least once during the 0-to 12-month study period was 59% and 60% in the mycophenolic acid delayed-release tablets and MMF arms, respectively. The most frequent reasons for dose reduction in the mycophenolic acid delayed-release tablets arm were adverse reactions (44%), dose reductions according to protocol guidelines (17%), dosing errors (11%) and missing data (2%).

The most common adverse reactions (≥20%) associated with the administration of mycophenolic acid delayed-release tablets were anemia, leukopenia, constipation, nausea, diarrhea, vomiting, dyspepsia, urinary tract infection, CMV infection, insomnia and postoperative pain.

The adverse reactions reported in ≥10% of patients in the de novo trial are presented in Table 2 below.

	de novo Renal Trial **
System organ class Adverse drug reactions	Mycophenolic Acid Delayed-Release Tablets 1.44 grams per day (n=213) (%)	Mycophenolate mofetil (MMF) 2 grams per day (n=210) (%)
Blood and Lymphatic System Disorders
Anemia	22	22
Leukopenia	19	21
Gastrointestinal System Disorders
Constipation	38	40
Nausea	29	27
Diarrhea	24	25
Vomiting	23	20
Dyspepsia	23	19
Abdominal pain upper	14	14
Flatulence	10	13
General and Administrative Site Disorders
Edema	17	18
Edema lower limb	16	17
Pyrexia	13	19
Investigations
Increased blood creatinine	15	10
Infections and Infestations
Urinary tract infection	29	33
CMV infection	20	18
Metabolism and Nutrition Disorders
Hypocalcemia	11	15
Hyperuricemia	13	13
Hyperlipidemia	12	10
Hypokalemia	13	9
Hypophosphatemia	11	9
Musculoskeletal, Connective Tissue and Bone Disorders
Back pain	12	6
Arthralgia	7	11
Nervous System Disorder
Insomnia	24	24
Tremor	12	14
Headache	13	11
Vascular Disorders
Hypertension	18	18

**The trial was not designed to support comparative claims for mycophenolic acid delayed-release tablets for the adverse reactions reported in this table

Table 3 summarizes the incidence of opportunistic infections in de novo transplant patients.

Table 3: Viral and Fungal Infections (%) Reported Over 0 to 12 Months

de novo Renal Trial
	Mycophenolic Acid Delayed-Release Tablets 1.44 grams per day (n=213) (%)	Mycophenolate mofetil (MMF) 2 grams per day (n=210) (%)
Any Cytomegalovirus	22	21
– Cytomegalovirus Disease	5	4
Herpes Simplex	8	6
Herpes Zoster	5	4
Any Fungal Infection	11	12
– Candida NOS	6	6
– Candida albicans	2	4

Lymphoma developed in 2 de novo patients (1%), (1 diagnosed 9 days after treatment initiation) and in 2 conversion patients (1%) receiving mycophenolic acid delayed-release tablets with other immunosuppressive agents in the 12-month controlled clinical trials.

Nonmelanoma skin carcinoma occurred in 1% de novo and 12% conversion patients. Other types of malignancy occurred in 1% de novo and 1% conversion patients [see Warnings and Precautions ( 5.4) ].

The adverse reactions reported in less than 10% of de novo or conversion patients treated with mycophenolic acid delayed-release tablets in combination with cyclosporine and corticosteroids are listed in Table 4.

Table 4: Adverse Reactions Reported in <10% of Patients Treated With Mycophenolic Acid Delayed-Release Tablets in Combination With Cyclosporine* and Corticosteroids

Blood and Lymphatic Disorders	Lymphocele, thrombocytopenia
Cardiac Disorder	Tachycardia
Eye Disorder	Vision blurred
Gastrointestinal Disorders	Abdominal pain, abdominal distension, gastroesophageal reflux disease, gingival hyperplasia
General Disorders and Administration-Site Conditions	Fatigue, peripheral edema
Infections and Infestations	Nasopharyngitis, herpes simplex, upper respiratory infection, oral candidiasis, herpes zoster, sinusitis, influenza, wound infection, implant infection, pneumonia, sepsis
Investigations	Hemoglobin decrease, liver function tests abnormal
Metabolism and Nutrition Disorders	Hypercholesterolemia, hyperkalemia, hypomagnesemia, diabetes mellitus, hyperglycemia
Musculoskeletal and Connective Tissue Disorders	Arthralgia, pain in limb, peripheral swelling, muscle cramps, myalgia
Nervous System Disorders	Dizziness (excluding vertigo)
Psychiatric Disorders	Anxiety
Renal and Urinary Disorders	Renal tubular necrosis, renal impairment, hematuria, urinary retention
Respiratory, Thoracic and Mediastinal Disorders	Cough, dyspnea, dyspnea exertional
Skin and Subcutaneous Tissue Disorders	Acne, pruritus, rash
Vascular Disorders	Hypertension aggravated, hypotension

*USP MODIFIED.

The following additional adverse reactions have been associated with the exposure to MPA when administered as a sodium salt or as mofetil ester:

Gastrointestinal: Intestinal perforation, gastrointestinal hemorrhage, gastric ulcers, duodenal ulcers [see Warnings and Precautions ( 5.7) ], colitis (including CMV colitis), pancreatitis, esophagitis, and ileus.

Infections: Serious life-threatening infections, such as meningitis and infectious endocarditis, tuberculosis, and atypical mycobacterial infection [see Warnings and Precautions ( 5.4) ].

Respiratory: Interstitial lung disorders, including fatal pulmonary fibrosis.