Mycophenolic Acid: Package Insert and Label Information

MYCOPHENOLIC ACID- mycophenolate sodium tablet, delayed release
Lupin Pharmaceuticals, Inc.

WARNING:EMBRYO-FETAL TOXICITY, MALIGNANCIES, AND SERIOUS INFECTIONS

  • Use during pregnancy is associated with increased risks of pregnancy loss and congenital malformations. Avoid if safer treatment options are available. Females of reproductive potential must be counseled regarding pregnancy prevention and planning [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3) ].
  • Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression [see Warnings and Precautions (5.3) ].
  • Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections [see Warnings and Precautions (5.4 , 5.5 ) ].
  • Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe mycophenolic acid delayed-release tablets. Patients receiving mycophenolic acid delayed-release tablets 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 [see Warnings and Precautions (5.2) ].

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Organ Rejection in Kidney Transplant

Mycophenolic acid delayed-release tablets are indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant.

Mycophenolic acid delayed-release tablets are indicated for the prophylaxis of organ rejection in pediatric patients 5 years of age and older who are at least 6 months post kidney transplant.

Mycophenolic acid delayed-release tablets are to be used in combination with cyclosporine and corticosteroids.

1.2 Limitations of Use

Mycophenolic acid delayed-release tablets and mycophenolate mofetil (MMF) tablets and capsules should not be used interchangeably without physician supervision because the rate of absorption following the administration of these two products is not equivalent.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Adult Kidney Transplant Patients

The recommended dose of mycophenolic acid delayed-release tablets is 720 mg administered twice daily (1440 mg total daily dose).

2.2 Dosage in Pediatric Kidney Transplant Patients

The recommended dose of mycophenolic acid delayed-release tablets in conversion (at least 6 months post-transplant) pediatric patients age 5 years and older is 400 mg/m2 body surface area (BSA) administered twice daily (up to a maximum dose of 720 mg administered twice daily).

2.3 Administration

Mycophenolic acid delayed-release tablets should be taken on an empty stomach, 1 hour before or 2 hours after food intake [see Clinical Pharmacology (12.3)].

Mycophenolic acid delayed-release tablets should not be crushed, chewed, or cut prior to ingesting. The tablets should be swallowed whole in order to maintain the integrity of the enteric coating.

Pediatric patients with a BSA of 1.19 m2 to 1.58 m2 may be dosed either with three mycophenolic acid delayed-release 180 mg tablets, or one 180 mg tablet plus one 360 mg tablet twice daily (1080 mg daily dose). Patients with a BSA of >1.58 m2 may be dosed either with four mycophenolic acid delayed-release 180 mg tablets, or two mycophenolic acid delayed-release 360 mg tablets twice daily (1440 mg daily dose). Pediatric doses for patients with BSA <1.19 m2 cannot be accurately administered using currently available formulations of mycophenolic acid delayed-release tablets.

3 DOSAGE FORMS AND STRENGTHS

Mycophenolic acid delayed-release tablets are available as 360 mg and 180 mg tablets.

Table 1: Description of Mycophenolic acid Delayed-Release Tablets
Dosage Strength 360 mg tablet 180 mg tablet
Active ingredient mycophenolic acid as mycophenolate sodium mycophenolic acid as mycophenolate sodium
Appearance Pink to light pink colored, enteric coated, ovaloid biconvex tablet Lime green colored, enteric coated, round biconvex tablet
Imprint “C2″on one side and plain on other side “C1″on one side and plain on other side

4 CONTRAINDICATIONS

4.1 Hypersensitivity Reactions

Mycophenolic acid delayed-release tablets are contraindicated in patients with a hypersensitivity to mycophenolate sodium, mycophenolic acid (MPA), mycophenolate mofetil, or to any of its excipients. Reactions like rash, pruritus, hypotension, and chest pain have been observed in clinical trials and post marketing reports [see Adverse Reactions (6) ].

5 WARNINGS AND PRECAUTIONS

5.1 Embryo-Fetal Toxicity

Use of mycophenolic acid delayed-release tablets 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. Females of reproductive potential must be aware of these risks and must be counseled regarding pregnancy prevention and planning. Avoid use of Mycophenolic acid delayed-release tablets during pregnancy if safer treatment options are available [see Use in Specific Populations (8.1, 8.3)].

5.2 Management of Immunosuppression

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe mycophenolic acid delayed-release tablets. 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 ].

5.3 Lymphoma and Other Malignancies

Patients receiving immunosuppressants, including mycophenolic acid delayed-release tablets, are at increased risk of developing lymphomas and other malignancies, particularly of the skin [see Adverse Reactions (6) ]. 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 broad-spectrum 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.

5.4 Serious Infections

Patients receiving immunosuppressants, including mycophenolic acid delayed-release tablets, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, and new or reactivated viral infections, including opportunistic infections [see Warnings and Precautions (5.5) ]. 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.

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) have been reported in patients treated with immunosuppressants, including the mycophenolic acid (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 tablet 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 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.

5.9 Rare Hereditary Deficiencies

Mycophenolic acid delayed-release tablets are an 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.

5.10 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.

5.11 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.

  • Embryo-Fetal 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) ]
  • Rare Hereditary Deficiencies [see Warnings and Precautions (5.9) ]

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 tables 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.

Table 2: Adverse Reactions (%) Reported in ≥10% of de novo Kidney Transplant Patients in Either Treatment Group
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 (5.3) ].

The adverse reactions reported in <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
*
USP MODIFIED.
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

The following additional adverse reactions have been associated with the exposure to mycophenolic acid (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.

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