CELLMUNE Tablets (Mycophenolate mofetil 250 mg/500 mg)

Table of Content

To be sold by retail on prescription of Specialist only

Black Box Warning

Warning: Embryo-Fetal Toxicity, Malignancies and Serious Infections

  • Use during pregnancy is associated with increased risks of first trimester pregnancy loss and congenital malformations. Avoid if safer treatment options are available. Females of reproductive potential include all your suggested changes must be counseled regarding pregnancy prevention and planning .
  • Increased risk of development of lymphoma and other malignancies, particularly of the skin .
  • Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections and viral reactivation of hepatitis B and C, which may lead to hospitalizations and fatal outcomes .

Qualitative and Quantitative Composition

CELLMUNE 500 Tablets

Each film-coated tablet contains:

Mycophenolate Mofetil IP………500 mg

Excipients…………………………q.s.

Colors: Red oxide of Iron and Titanium Dioxide IP

Dosage Form(S) and Strength(S)

Oral, film-coated tablet containing mycophenolate mofetil 500 mg.

Clinical Particulars

Therapeutic Indications

Allogeneic Transplants:

For the prophylaxis of acute organ rejection and for the treatment of refractory organ rejection in patients receiving allogeneic renal and hepatic transplant, increased graft and patient’s survival receiving allogeneic cardiac transplants and use concomitantly with cyclosporine and corticosteroids.

Posology and Method of Administration

Important Administration Instructions

CELLMUNE 500 Tablets should not be used without the supervision of a physician with experience in immunosuppressive therapy.

Mycophenolate mofetil oral dosage forms should not be used interchangeably with mycophenolic acid (MPA) delayed-release tablets without the supervision of a physician with experience in immunosuppressive therapy because the rates of absorption following the administration of mycophenolate mofetil oral dosage forms and MPA delayed-release tablets are not equivalent.

CELLMUNE 500 Tablets should not be crushed.

Patients should be instructed to take a missed dose as soon as they remember, except if it is closer than 2 hours to the next scheduled dose; in this case, they should continue to take CELLMUNE 500 Tablets at the usual times.

General Dosing Guidance for Renal Transplant Patients

Adults

A dose of 1 g administered orally twice a day (daily dose of 2 g). Although a dose of 1.5 g twice daily (daily dose of 3 g) was used in clinical trials and was shown to be safe and effective, no efficacy advantage could be established for renal transplant patients. Patients receiving 2g/day demonstrate an overall better safety profile than patients receiving 3g/day.

General Dosing Guidance for Cardiac Transplant Patients

Adults

A dose of 1.5 g administered orally twice a day (daily dose of 3 g) is recommended.

General Dosing Guidance for Liver Transplant Patients

Adults

A dose of 1.5 g administered orally twice a day (daily dose of 3 g) is recommended.

The initial oral dose of CELLMUNE 500 Tablets should be given as soon as possible following kidney, heart, or liver transplant. It is recommended that CELLMUNE 500 Tablets be administered on an empty stomach. Food has been shown to decrease MPA Cmax by 40%.

Contraindications

Allergic reactions to mycophenolate mofetil have been observed; therefore, Mycophenolate mofetil is contraindicated in patients with a hypersensitivity to mycophenolate mofetil, mycophenolic acid or any component of the drug product.

Special Warnings and Precautions for Use

Embryo-Fetal Toxicity

Use of mycophenolate mofetil 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, kidneys and nervous system. Females of reproductive potential must be made aware of these risks and must be counseled regarding pregnancy prevention and planning. Avoid use of mycophenolate mofetil during pregnancy if safer treatment options are available .

Lymphoma and Other Malignancies

Patients receiving immunosuppressives, including mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, particularly of the skin .The risk appears to be related to the intensity and duration of immunosuppressant rather than to the use of any specific agent. 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) developed in 0.4–1% of patients receiving mycophenolate mofetil (2 g or 3 g) with other immunosuppressive agents in controlled clinical trials of kidney, heart and liver transplant patients.The majority of PTLD cases appear to be related to Epstein-Barr virus (EBV) infection. The risk of PTLD appears greatest in those individuals who are EBV-seronegative, a population that includes many young children. In pediatric patients, no other malignancies besides PTLD were observed in clinical trials .

Serious Infections

Patients receiving immunosuppressants, including mycophenolate mofetil, are at increased risk of developing bacterial, fungal, protozoal, and new or reactivated viral infections, including opportunistic infections. The risk increases with the total immunosuppressive load. These infections may lead to serious outcomes, including hospitalizations and death .

Serious viral infections reported include:

  • Polyomavirus-associated nephropathy (PVAN), especially due to BK virus infection
  • JC virus-associated progressive multifocal leukoencephalopathy (PML)
  • Cytomegalovirus (CMV) infections: CMV-seronegative transplant patients who receive an organ from a CMV-seropositive donor are at highest risk of CMV viremia and CMV disease.
  • Viral reactivation in patients infected with hepatitis B and C

Consider reducing immunosuppression in patients who develop new infections or reactivate viral infections, weighing 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 . In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms.

The risk of CMV viremia and CMV disease is highest among transplant recipients seronegative for CMV at the 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.

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.

Gastrointestinal Disorders

Gastrointestinal ulcerations, perforations and bleeding requiring hospitalization, ulceration and perforations were observed in clinical trials. Physicians should be aware of these serious adverse effects, particularly when administering mycophenolate mofetil to patients with a gastrointestinal disease.

Patients with Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency (HGPRT)Deficiency

Mycophenolate mofetil is an inosine monophosphate dehydrogenase(IMPDH) inhibitor; therefore, it 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.

Blood Dyscrasias: Neutropenia and Pure Red Cell Aplasia (PRCA)

Severe neutropenia developed in transplant patients receiving mycophenolate mofetil 3 g daily . Patients receiving mycophenolate mofetil should be monitored for neutropenia. Neutropenia has been observed most frequently in the period from 31–180 days post-transplant in patients treated for prevention of kidney, heart, and liver rejection. The development of neutropenia may be related to mycophenolate mofetil itself, concomitant medications, viral infections, or a combination of these causes. If neutropenia develops (ANC <1.3 x 103/µL), dosing with mycophenolate mofetil should be interrupted or the dose reduced, appropriate diagnostic tests performed, and the patient managed appropriately.

Patients receiving mycophenolate mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding, or any other manifestation of bone marrow depression.

Consider monitoring with complete blood counts weekly for the first month, twice monthly for the second and third months, and monthly for the remainder of the first year.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents. In some cases, PRCA was found to be reversible with dose reduction or cessation of mycophenolate mofetil therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk.

Immunizations

During treatment with mycophenolate mofetil, the use of live attenuated vaccines should be avoided (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines) and patients should be advised that vaccinations may be less effective. Advise patients to discuss with the physician before seeking any immunizations.

Blood Donation

Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of mycophenolate mofetil because their blood or blood products might be administered to a female of reproductive potential or a pregnant woman.

Semen Donation

Based on animal data, men should not donate semen during therapy and for 90 days following discontinuation of mycophenolate mofetil.

Effect of Concomitant Medications on Mycophenolic Acid Concentrations

A variety of drugs have potential to alter systemic MPA exposure when co-administered with mycophenolate mofetil. Therefore, determination of MPA concentrations in plasma before and after making any changes to immunosuppressive therapy, or when adding or discontinuing concomitant medications, may be appropriate to ensure MPA concentrations remain stable.

Drug Interactions

Effect of Other Drugs on Mycophenolate Mofetil

Table 1: Drug interactions with mycophenolate mofetil that affect mycophenolic acid (mpa) exposure

Antacids with Magnesium or Aluminum Hydroxide

Clinical Impact

Concomitant use with an antacid containing magnesium or aluminum hydroxide decreases MPA systemic exposure, which may reduce mycophenolate mofetil efficacy.

Prevention or Management

Administer magnesium or aluminum hydroxide containing antacids at least 2hours after mycophenolate mofetil administration.

Proton-Pump Inhibitors (PPIs)

Clinical Impact

Concomitant use with PPIs decreases MPA systemic exposure, which may reduce mycophenolate mofetil efficacy.

Prevention or Management

Monitor patients for alterations in efficacy when PPIs are co-administered with mycophenolate mofetil.

Examples

Lansoprazole, pantoprazole

Drugs that Interfere with Enterohepatic Recirculation

Clinical Impact

Concomitant use with drugs that directly interfere with enterohepatic recirculation, or indirectly interfere with enterohepatic recirculation by altering the gastrointestinal flora, can decrease MPA systemic exposure, which may reduce mycophenolate mofetil efficacy.

Prevention or Management

Monitor patients for alterations in efficacy or mycophenolate mofetil-related adverse reactions when these drugs are co-administered with mycophenolate mofetil.

Examples

Trimethoprim/sulfamethoxazole, bile acid sequestrants (cholestyramine), rifampin as well as aminoglycoside, cephalosporin, fluoroquinolone, and penicillin classes of antimicrobials.

Drugs Modulating Glucuronidation

Clinical Impact

Concomitant use with drugs inducing glucuronidation decreases MPA systemic exposure, potentially reducing mycophenolate mofetil efficacy, while use with drugs inhibiting glucuronidation increases MPA systemic exposure, which may increase the risk of mycophenolate mofetil- related adverse reactions.

Prevention or Management

Monitor patients for alterations in efficacy or mycophenolate mofetil-related adverse reactions when these drugs are co-administered with mycophenolate mofetil.

Examples

Telmisartan (induces glucuronidation); isavuconazole (inhibits glucuronidation).

Calcium-free Phosphate Binders

Clinical Impact

Concomitant use with calcium-free phosphate binders decrease MPA systemic exposure, which may reduce mycophenolate mofetil efficacy.

Prevention or Management

Administer calcium-free phosphate binders at least 2 hours after mycophenolate mofetil.

Examples

Sevelamer

Effect of Mycophenolate Mofetil on Other Drugs

Table 2:  Drug interactions with mycophenolate mofetil that affect other drugs

Drugs that Undergo Renal Tubular Secretion

Clinical Impact

When concomitantly used with mycophenolate mofetil, its metabolite MPAG, may compete with drugs eliminated by renal tubular secretion, which may increase plasma concentrations and/or adverse reactions associated with these drugs.

Prevention or Management

Monitor for drug-related adverse reactions in patients with renal impairment.

Examples

Acyclovir, ganciclovir, probenecid, valacyclovir, valganciclovir

Combination Oral Contraceptives

Clinical Impact

Concomitant use with mycophenolate mofetil decreased the systemic exposure to levonorgestrel, but did not affect the systemic exposure to ethinylestradiol, which may result in reduced combination oral contraceptive effectiveness.

Prevention or Management

Use additional barrier contraceptive methods.

Use in Special Populations

Patients with Renal Impairment

Patients with Kidney Transplant

No dose adjustments are needed in kidney transplant patients experiencing delayed graft function post-operatively, but patients should be carefully monitored. In kidney transplant patients with severe chronic impairment of the graft (GFR <25 mL/min/1.73 m2), no dose adjustments are necessary; however, doses greater than 1 g administered twice a day should be avoided.

Patients with Heart and Liver Transplant

No data are available for heart or liver transplant patients with severe chronic renal impairment. Mycophenolate mofetil may be used for heart or liver transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.

Patients with Hepatic Impairment

Patients with Kidney Transplant

No dose adjustments are recommended for kidney transplant patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies .

Patients with Heart Transplant

No data are available for heart transplant patients with severe hepatic parenchymal disease.

Pregnant Women

Risk Summary

Use of mycophenolate mofetil during pregnancy is associated with an increased risk of first-trimester pregnancy loss and an increased risk of multiple congenital malformations in multiple organ systems. Oral administration of mycophenolate to rats and rabbits during the period of organogenesis produced congenital malformations and pregnancy loss at doses less than the recommended clinical dose (0.02–0.1 times the recommended clinical doses in kidney and heart transplant patients).

Consider alternative immunosuppressants with less potential for embryo-fetal toxicity. Risks and benefits of mycophenolate mofetil should be discussed with the pregnant woman.

The estimated background risk of pregnancy loss and congenital malformations in organ transplant populations is not clear. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2– to 4% and 15–20%, respectively.

Data

Human Data

A spectrum of congenital malformations (including multiple malformations in individual newborns) has been reported in 23–27% of live births in mycophenolate mofetil-exposed pregnancies, based on published data from pregnancy registries. Malformations that have been documented include external ear, eye, and other facial abnormalities, including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, kidneys, and nervous system.

Based on published data from pregnancy registries, the risk of first-trimester pregnancy loss has been reported at 45–49% following mycophenolate mofetil exposure.

Animal Data

In animal reproductive toxicology studies, there were increased rates of fetal resorptions and malformations in the absence of maternal toxicity. Oral administration of mycophenolate mofetil  to pregnant rats from gestational day 7 to day 16 produced increased embryo-fetal lethality and fetal malformations, including anophthalmia, agnathia, and hydrocephaly at doses equivalent to 0.03 and 0.02 times the recommended human doses for renal and cardiac transplant patients, respectively, when corrected for BSA. Oral administration of mycophenolate mofetil  to pregnant rabbits from gestational day 7 to day 19 produced increased embryo-fetal lethality and fetal malformations included ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia at dose equivalents as low as 0.1 and 0.06 times the recommended human doses for renal and cardiac transplant patients, respectively, when corrected for BSA.

Lactating Women

Risk Summary

There are no data on the presence of mycophenolate in human milk, or the effects on milk production. There are limited data in the Transplantation Pregnancy Registry globally on the effects of mycophenolate on a breastfed child . Studies in rats treated with mycophenolate mofetil have shown MPA to be present in milk. Because available data are limited, it is not possible to exclude the potential risks to a breastfeeding infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mycophenolate mofetil and any potential adverse effects on the breastfed infant from mycophenolate mofetil or from the underlying maternal condition.

Data

Limited information is available from the Transplantation Pregnancy Registry globally. Of seven infants reported by this registry to have been breastfed while the mother was taking mycophenolate, all were born at 34–40 weeks’ gestation, and breastfed for up to 14 months. No adverse events were reported.

Females and Males of Reproductive Potential

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.

Pregnancy Planning

For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryo-fetal toxicity whenever possible. Risks and benefits of mycophenolate mofetil should be discussed with the patient.

Pregnancy Testing

To prevent unplanned exposure during pregnancy, all females of reproductive potential should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL immediately before starting mycophenolate mofetil. Another pregnancy test with the same sensitivity should be done 8–10 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, consider alternative immunosuppressants with less potential for embryo-fetal toxicity whenever possible.

Contraception

Female Patients

Females of reproductive potential taking mycophenolate mofetil must receive contraceptive counseling and use acceptable contraception. Patients must use acceptable birth control during the entire mycophenolate mofetil therapy, and for 6 weeks after stopping mycophenolate mofetil, unless the patient chooses abstinence.

Patients should be aware that mycophenolate mofetil reduces blood levels of the hormones from the oral contraceptive pill and could theoretically reduce its effectiveness .

Table 3: 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 vasectomy

OR

Option 2

Hormone Methods

(choose one)

Barrier Methods (choose one)

Choose One

Hormone Method AND One Barrier Method

Estrogen and Progesterone

  • Oral Contraceptive Pill
  • Transdermal patch
  • Vaginal ring

Progesterone only

  • Injection
  • Implant

AND

 

  • Diaphragm with spermicide
  • Cervical cap with spermicide
  • Contraceptive sponge
  • Male condom
  • Female condom

OR

Option 3

Barrier Methods (choose one)

Barrier Methods (choose one)

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

Male Patients

Genotoxic effects have been observed in animal studies at exposures exceeding the human therapeutic exposures by approximately 2.5 times. Thus, the risk of genotoxic effects on sperm cells cannot be excluded. Based on this potential risk, sexually active male patients and/or their female partners are recommended to use effective contraception during treatment of the male patient and for at least 90 days after cessation of treatment. Also, based on the potential risk of genotoxic effects, male patients should not donate sperm during treatment with CELLMUNE 500 Tablets and for at least 90 days after cessation of treatment .

Pediatric Patients

Safety and effectiveness of CELLMUNE 500 Tablets have not been established in pediatric patients.

Geriatric Patients

Clinical studies of mycophenolate mofetil did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. 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 take into consideration the presence of decreased hepatic, renal or cardiac function and of concomitant drug therapies. Male patients and/or their female partners are recommended to use effective contraception during treatment of the male patient and for at least 90 days after cessation of treatment. Also, based on the potential risk of genotoxic effects, male patients should not donate sperm during treatment with mycophenolate mofetil and for at least 90 days after cessation of treatment

Effects on Ability to Drive and Use Machines

CELLMUNE 500 Tablets may impact the ability to drive and use machines. Patients should avoid driving or using machines if they experience somnolence, confusion, dizziness, tremor, or hypotension during treatment with CELLMUNE 500 Tablets.

Undesirable Effects

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

  • Embryo-Fetal Toxicity
  • Lymphomas and Other Malignancies
  • Serious Infections
  • Blood Dyscrasias: Neutropenia, Pure Red Cell Aplasia
  • Gastrointestinal Complications

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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

An estimated total of 1,557 patients received mycophenolate mofetil during pivotal clinical trials in the prevention of acute organ rejection. Of these, 991 were included in the three renal studies, 277 were included in one hepatic study, and 289 were included in one cardiac study. Patients in all the study arms also received cyclosporine and corticosteroids.

The data described below primarily derive from five randomized, active-controlled double-blind 12-month trials of mycophenolate mofetil in de novo kidney (3) heart (1) and liver (1) transplant patients.

Mycophenolate Mofetil Oral

The incidence of adverse reactions for mycophenolate mofetil was determined in five randomized, comparative, double-blind trials in the prevention of rejection in kidney, heart and liver transplant patients (two active- and one placebo-controlled trials, one active-controlled trial, and one active-controlled trial, respectively).

The three de novo kidney studies with 12-month duration compared two dose levels of oral mycophenolate mofetil (1 g twice daily and 1.5 g twice daily) with azathioprine (2 studies) or placebo (1 study) when administered in combination with cyclosporine and corticosteroids to prevent acute rejection episodes. One study also included anti-thymocyte globulin induction therapy.

In the de novo heart transplantation study with 12-month duration, patients received mycophenolate mofetil 1.5 g twice daily (n=289) or azathioprine 1.5 to 3 mg/kg/day (n=289), in combination with cyclosporine and corticosteroids as maintenance immunosuppressive therapy.

In the de novo liver transplantation study with 12-month duration, patients received mycophenolate mofetil 1 g twice daily intravenously for up to 14 days followed by mycophenolate mofetil 1.5 g twice daily orally or azathioprine 1 to 2 mg/kg/day intravenously followed by azathioprine 1 to 2 mg/kg/day orally, in combination with cyclosporine and corticosteroids as maintenance immunosuppressive therapy. The total number of patients enrolled was 565.

Approximately 53% of the kidney transplant patients, 65% of the heart transplant patients, and 48% of the liver transplant patients were treated for more than 1 year. Adverse reactions reported in 20% of patients in the mycophenolate mofetil treatment groups are presented below. The safety data of three kidney transplantation studies are pooled together.

Table 4:         Adverse reactions in controlled studies of de novo kidney, heart or liver transplantation reported in ≥20% of patients in the mycophenolate mofetil group

Adverse Drug

Reaction (MedDRA)

System Organ Class

Kidney Studies

Heart Study

Liver Study

Mycophenolate Mofetil

(n=2g/day

(n=501)

or 3g/day 490)

AZA

1–2

mg/kg/day

or 100–

150

mg/day

Placebo

Mycophenolate Mofetil

3g/day

AZA

1.5–3

mg/kg/day

Mycophenolate Mofetil

3g/day

AZA

1–2

mg/kg/day

(n=991)

(n=326)

(n=166)

(n=289)

(n=289)

(n=277)

(n=287)

%

%

%

%

%

%

%

 

Infections and infestations

Bacterial infections

39.9

 

33.7

 

37.3

-

 

-

27.4

 

26.5

 

Viral infections

- a

 

-

 

-

31.1

 

24.9

-

 

-

 

Blood and lymphatic system disorders

Anemia

20.0

 

23.6

 

2.4

45.0

 

47.1

43.0

 

53.0

 

Ecchymosis

-

 

-

 

-

20.1

 

9.7

-

 

-

 

Leukocytosis

-

 

-

 

-

42.6

 

37.4

22.4

 

21.3

 

Leukopenia

28.6

 

24.8

 

4.2

34.3

 

43.3

45.8

 

39.0

 

Thrombocytopenia

-

 

-

 

-

24.2

 

28.0

38.3

 

42.2

 

Metabolism and nutrition disorders

Hyper-cholesterolemia

-

 

-

 

-

46.0

 

43.9

-

 

-

 

Hyperglycemia

-

 

-

 

-

48.4

 

53.3

43.7

 

48.8

 

Hyperkalemia

-

 

-

 

-

-

 

-

22.0

 

23.7

 

Hypocalcemia

-

 

-

 

-

-

 

-

30.0

 

30.0

 

Hypokalemia

-

 

-

 

-

32.5

 

26.3

37.2

 

41.1

 

Hypomagnesemia

-

 

-

 

-

20.1

 

14.2

39.0

 

37.6

 

Psychiatric disorders

Depression

-

 

-

 

-

20.1

 

15.2

-

 

-

 

Insomnia

-

 

-

 

-

43.3

 

39.8

52.3

 

47.0

 

Nervous system disorders

Dizziness

-

 

-

 

-

34.3

 

33.9

-

 

-

 

Headache

-

 

-

 

-

58.5

 

55.4

53.8

 

49.1

 

Tremor

-

 

-

 

-

26.3

 

25.6

33.9

 

35.5

 

Cardiac disorders

Tachycardia

-

 

-

 

-

22.8

 

21.8

22.0

 

15.7

 

Vascular disorders

Hypertension

27.5

 

32.2

 

19.3

78.9

 

74.0

62.1

 

59.6

 

Hypotension

-

 

-

 

-

34.3

 

40.1

-

 

-

 

Respiratory, thoracic and mediastinal disorders

Cough

-

 

-

 

-

40.5

 

32.2

-

 

-

 

Dyspnea

-

 

-

 

-

44.3

 

44.3

31.0

 

30.3

 

Pleural effusion

-

 

-

 

-

-

 

-

34.3

 

35.9

 

Gastrointestinal disorders

Abdominal pain

22.4

 

23.0

 

11.4

41.9

 

39.4

62.5

 

51.2

 

Constipation

-

 

-

 

-

43.6

 

38.8

37.9

 

38.3

 

Decreased appetite

-

 

-

 

-

-

 

-

25.3

 

17.1

 

Diarrhea

30.4

 

20.9

 

13.9

52.6

 

39.4

51.3

 

49.8

 

Dyspepsia

-

 

-

 

-

22.1

 

22.1

22.4

 

20.9

 

Nausea

-

-

-

56.1

60.2

54.5

51.2

Vomiting

-

-

-

39.1

34.6

32.9

33.4

Hepatobiliary disorders

Blood lactate

dehydrogenase

increased

-

-

-

23.5

18.3

-

-

Hepatic enzyme

Increased

-

-

-

-

-

24.9

19.2

Skin and subcutaneous tissues disorders

Rash

-

-

-

26.0

20.8

-

-

Renal and urinary disorders

Blood creatinine

Increased

-

-

-

42.2

39.8

-

-

Blood urea increased

-

-

-

36.7

34.3

-

-

General disorders and administration site conditions

Asthenia

-

-

-

49.1

41.2

35.4

33.8

Edema b

21.0

28.2

8.4

67.5

55.7

48.4

47.7

Pain c

24.8

32.2

9.6

79.2

77.5

74.0

77.5

Pyrexia

-

-

-

56.4

53.6

52.3

56.1

 

 

 

 

 

 

 

 

                                         
 

AZA=azathioprine

  1. : “-” Indicates that the incidence was below the cutoff value of 20% for inclusion in the table.
  2. : “Edema” includes peripheral edema, facial edema, scrotal edema.
  3. : “Pain” includes musculoskeletal pain (myalgia, neck pain, back pain).

In the three de novo kidney studies, patients receiving 2 g/day of mycophenolate mofetil had an overall better safety profile than did patients receiving 3 g/day of mycophenolate mofetil.

Post-transplant lymphoproliferative disease (PTLD, pseudolymphoma) developed in 0.4–1% of patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressive agents in controlled clinical trials of kidney, heart and liver transplant patients followed for at least 1 year. Non-melanoma skin carcinomas occurred in 1.6–4.2% of patients, other types of malignancy in 0.7–2.1% of patients. The 3-year safety data in kidney and heart transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. In pediatric patients, PTLD was observed in 1.35% (2/148) by 12 months’ post-transplant.

Cytopenias, including leukopenia, anemia, thrombocytopenia, and pancytopenia, are a known risk associated with mycophenolate and may lead or contribute to the occurrence of infections and hemorrhages. Severe neutropenia (ANC <0.5 x 103/µL) developed in up to 2% of kidney transplant patients, up to 2.8% of heart transplant patients and up to 3.6% of liver transplant patients receiving mycophenolate mofetil  3 g daily .

The most common opportunistic infections in patients receiving mycophenolate mofetil with other immunosuppressants were mucocutaneous candida, CMV viremia/syndrome, and herpes simplex. The proportion of patients with CMV viremia/syndrome was 13.5%. In patients receiving mycophenolate mofetil (2 g or 3 g) in controlled studies for prevention of kidney, heart or liver rejection, fatal infection/sepsis occurred in approximately 2% of kidney and heart patients and in 5% of liver patients .

The most serious gastrointestinal disorders reported were ulceration and hemorrhage, which are known risks associated with mycophenolate mofetil. Mouth, esophageal, gastric, duodenal, and intestinal ulcers often complicated by hemorrhage, as well as hematemesis, melena, and hemorrhagic forms of gastritis and colitis were commonly reported during the pivotal clinical trials, while the most common gastrointestinal disorders were diarrhea, nausea and vomiting. Endoscopic investigation of patients with mycophenolate mofetil-related diarrhea revealed isolated cases of intestinal villous atrophy .

The following adverse reactions were reported with 3% to <20% incidence in kidney, heart and liver transplant patients treated with mycophenolate mofetil in combination with cyclosporine and corticosteroids

Table 5:         Adverse reactions in controlled studies of de novo kidney, heart or liver transplantation reported in 3% to <20% of patients treated with mycophenolate mofetil in combination with cyclosporine and corticosteroids

System Organ

Class

Adverse Reactions

Body as a

Whole

cellulitis, chills, hernia, malaise

Infections and

Infestations

fungal infections

Hematologic

and Lymphatic

coagulation disorder, ecchymosis, pancytopenia

Urogenital

Hematuria

Cardiovascular

Hypotension

Metabolic and

Nutritional

acidosis, alkaline phosphatase increased, hyperlipemia,

hypophosphatemia, weight loss

Digestive

esophagitis, flatulence, gastritis, gastrointestinal hemorrhage,

hepatitis, ileus, nausea and vomiting, stomach ulcer, stomatitis

Neoplasm

benign,

malignant and

unspecified

Neoplasm

Skin and

Appendages

skin benign neoplasm, skin carcinoma

Psychiatric

confusional state

Nervous

hypertonia, paresthesia, somnolence

Musculoskeletal

arthralgia, myasthenia

Geriatric Patients

Elderly patients (≥65 years of age), particularly those who are receiving mycophenolate mofetil  as part of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal hemorrhage and pulmonary edema, compared with younger individuals.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of mycophenolate mofetil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

  • Embryo-Fetal Toxicity: Congenital malformations and spontaneous abortions, mainly in the first trimester, have been reported following exposure to mycophenolate mofetil in combination with other immunosuppressants during pregnancy.Congenital malformations include the following:
  • Facial malformations: cleft lip, cleft palate, micrognathia, hypertelorism of the orbits
  • Abnormalities of the ear and eye: abnormally formed or absent external/middle ear, coloboma, microphthalmos
  • Malformations of the fingers: polydactyly, syndactyly, brachydactyly
  • Cardiac abnormalities: atrial and ventricular septal defects
  • Esophageal malformations: esophageal atresia
  • Nervous system malformations: such as spina bifida.
  • Cardiovascular: Venous thrombosis has been reported in patients treated with mycophenolate mofetil administered intravenously.
  • Digestive: Colitis, pancreatitis
  • Hematologic and Lymphatic: Bone marrow failure, cases of PRCA and hypogammaglobulinemia have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressive agents .
  • Immune: Hypersensitivity, hypogammaglobinemia.
  • Infections: Meningitis, infectious endocarditis, tuberculosis, atypical mycobacterial infection, progressive multifocal leukoencephalopathy, BK virus infection, viral reactivation of hepatitis B and hepatitis C, protozoal infections .
  • Respiratory: Bronchiectasis, interstitial lung disease, fatal pulmonary fibrosis, have been reported rarely and should be considered in the differential diagnosis of pulmonary symptoms ranging from dyspnea to respiratory failure in post-transplant patients receiving mycophenolate mofetil.
  • Vascular: Lymphocele

Reporting of Side Effects

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side effects, write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

Possible signs and symptoms of acute overdose include hematological abnormalities such as leukopenia and neutropenia, and gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, vomiting and dyspepsia.

The experience with overdose of mycophenolate mofetil in humans is limited. The reported effects associated with overdose fall within the known safety profile of the drug. The highest dose administered to kidney transplant patients in clinical trials has been 4 g/day. In limited experience with heart and liver transplant patients in clinical trials, the highest doses used were 4 g/day or 5 g/day. At doses of 4 g/day or 5 g/day, there appears to be a higher rate, compared with the use of 3 g/day or less, of gastrointestinal intolerance (nausea, vomiting, and/or diarrhea), and occasional hematologic abnormalities, particularly neutropenia .

Treatment and Management

MPA and the phenolic glucuronide metabolite of MPA (MPAG) are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 µg/mL), small amounts of MPAG are removed. By increasing excretion of the drug, MPA can be removed by bile acid sequestrants, such as cholestyramine .

Pharmacological Properties

Mechanism of Action

Mycophenolate mofetil is absorbed following oral administration and hydrolyzed to MPA (mycophenolic acid), the active metabolite. MPA is a selective, uncompetitive, and reversible inhibitor of IMPDH (inosine monophosphate dehydrogenase) and, therefore, inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative responses of T- and B -lymphocytes to both mitogenic and allospecific stimulation. Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes. MPA also suppresses antibody formation by B-lymphocytes. MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection. MMF did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 (IL-1) and interleukin-2 (IL-2) but did block the coupling of these events to DNA synthesis and proliferation.

Pharmacodynamic Properties

There is a lack of information regarding the pharmacodynamic effects of mycophenolate mofetil.

Pharmacokinetic Properties

Absorption

Mycophenolate mofetil is rapidly absorbed following oral administration and converted to the active metabolite, MPA. The mean relative bioavailability of MPAis94% for oral administration. The maximum plasma concentration (Cmax) occurs approximately 2 hours after oral administration.

The mean (±SD) pharmacokinetic parameters estimates for MPA following the administration of mycophenolate mofetil given as single doses to healthy volunteers, and multiple doses to kidney, heart, and liver transplant patients, are shown in Table 6. The area under the plasma-concentration time curve (AUC) for MPA appears to increase in a dose-proportional fashion in kidney transplant patients receiving multiple oral doses of mycophenolate mofetil up to a daily dose of 3 g (1.5g twice daily)

Table 6:         Pharmacokinetic parameters for mpa following administration of mycophenolate mofetil to healthy volunteers (single dose), and kidney, heart and liver transplant patients (multiple doses)

Healthy Volunteers

Dose/Route

Tmax

Cmax

Total AUC

(h)

(mcg/mL)

(mcg•h/mL)

Single dose

1 g/oral

0.80

(±0.36)

(n=129)

24.5

(±9.5)

(n=129)

63.9

(±16.2)

(n=117)

Kidney Transplant Patients

(twice-daily dosing) Time After

Transplantation

Dose/Route

Tmax

(h)

Cmax

(mcg/mL)

Interdosing Interval

AUC(0-12h)

(mcg•h/mL)

5 days

1 g/iv

1.58

(±0.46)

(n=31)

12.0

(±3.82)

(n=31)

40.8

(±11.4)

(n=31)

6 days

1 g/oral

1.33

(±1.05)

(n=31)

10.7

(±4.83)

(n=31)

32.9

(±15.0)

(n=31)

Early (less than 40 days)

1 g/oral

1.31

(±0.76)

(n=25)

8.16

(±4.50)

(n=25)

27.3

(±10.9)

(n=25)

Early (less than 40 days)

1.5 g/oral

1.21

(±0.81)

(n=27)

13.5

(±8.18)

(n=27)

38.4

(±15.4)

(n=27)

Late (more than 3 months)

1.5 g/oral

0.90

(±0.24)

(n=23)

24.1

(±12.1)

(n=23)

65.3

(±35.4)

(n=23)

Heart transplant Patients

(twice-daily dosing) Time After

Transplantation

Dose/Route

Tmax

(h)

Cmax

(mcg/mL)

Interdosing Interval

AUC(0-12h)

(mcg•h/mL)

Early

(day before discharge)

1.5 g/oral

1.8

(±1.3)

(n=11)

11.5

(±6.8)

(n=11)

43.3

(±20.8)

(n=9)

Late (more than 6 months)

1.5 g/oral

1.1

(±0.7)

(n=52)

20.0

(±9.4)

(n=52)

54.1a

(±20.4)

(n=49)

Liver transplant Patients (twice-daily dosing)

Time After

Transplantation

Dose/Route

Tmax

(h)

Cmax

(mcg/mL)

Interdosing Interval

AUC(0-12h)

(mcg•h/mL)

4–9 days

1 g/iv

1.50

(±0.517)

(n=22)

17.0

(±12.7)

(n=22)

34.0

(±17.4)

(n=22)

Early (5–8 days)

1.5 g/oral

1.15

(±0.432)

(n=20)

13.1

(±6.76)

(n=20)

29.2

(±11.9)

(n=20)

Late (more than 6 months)

1.5 g/oral

1.54

(±0.51)

(n=6)

19.3

(±11.7)

(n=6)

49.3

(±14.8)

(n=6)

 

aAUC(0-12h) values quoted are extrapolated from data from samples collected over 4 hours.

In the early post-transplant period (less than 40 days post-transplant), kidney, heart and liver transplant patients had mean MPA AUCs approximately 20–41% lower and mean Cmax approximately 32–44% lower compared with the late transplant period (i.e., 3–6 months’ post-transplant) (non-stationarity in MPA pharmacokinetics).

Mean MPA AUC values following administration of 1 g twice-daily intravenous mycophenolate mofetil over 2 hours to kidney transplant patients for 5 days were about 24% higher than those observed after oral administration of a similar dose in the immediate post-transplant phase.

In liver transplant patients, administration of 1 g twice-daily intravenous mycophenolate mofetil followed by 1.5 g twice-daily oral mycophenolate mofetil resulted in mean MPA AUC estimates similar to those found in kidney transplant patients administered 1 g mycophenolate mofetil twice daily.

Effect of Food

Food (27 g fat, 650 calories) had no effect on the extent of absorption (MPA AUC) of MMF when administered at doses of 1.5 g twice daily to kidney transplant patients. However, MPA Cmax was decreased by 40% in the presence of food

Distribution

The mean (±SD) apparent volume of distribution of MPA in healthy volunteers was approximately 3.6 (±1.5) L/kg. At clinically relevant concentrations, MPA is 97% bound to plasma albumin. The phenolic glucuronide metabolite of MPA (MPAG) is 82% bound to plasma albumin at MPAG concentration ranges that are normally seen in stable kidney transplant patients; however, at higher MPAG concentrations (observed in patients with kidney impairment or delayed kidney graft function), the binding of MPA may be reduced as a result of competition between MPAG and MPA for protein-binding. Mean blood to plasma ratio of radioactivity concentrations was approximately 0.6 indicating that MPA and MPAG do not extensively distribute into the cellular fractions of blood.

In vitro studies to evaluate the effect of other agents on the binding of MPA to human serum albumin (HSA) or plasma proteins showed that salicylate (at 25 mg/dL with human serum albumin) and MPAG (at ≥460 mcg/mL with plasma proteins) increased the free fraction of MPA. MPA at concentrations as high as 100 mcg/mL had little effect on the binding of warfarin, digoxin, or propranolol, but decreased the binding of theophylline from 53% to 45% and phenytoin from 90% to 87%. MPA binding is not altered by the common immunosuppressive medications, including cyclosporine, prednisone and tacrolimus or other common medications, including warfarin, phenytoin and digoxin. MPA is minimally bound to plasma lipoproteins in a concentration-independent manner.

Elimination

Following oral administration, mean (±SD) apparent half-life and plasma clearance of MPA are 17.9 (±6.5) hours and 16.6 (±5.8) hours, respectively.

Metabolism

Metabolism to MPA occurs pre-systemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form MPAG, which is not pharmacologically active. In vivo, MPAG is converted to MPA during enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.

Due to the enterohepatic recirculation of MPAG/MPA, secondary peaks in the plasma MPA concentration-time profile are usually observed at 6–12 hours post-dose. Bile sequestrants, such as cholestyramine, reduce MPA AUC by interfering with this enterohepatic recirculation of the drug.

Excretion

A negligible amount of substance is excreted as MPA (<1% of dose) in the urine. Oral administration of radiolabeled mycophenolate mofetil results in complete recovery of the administered dose, with 93% of the administered dose recovered in the urine and 6% recovered in the feces. Most (about 87%) of the administered dose is excreted in the urine as MPAG. At clinically encountered concentrations, MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 mcg/mL), small amounts of MPAG are removed.

Increased plasma concentrations of mycophenolate mofetil metabolites (MPA: 50% increase; MPAG: approx.3-fold to 6-fold increase) are observed in patients with renal insufficiency.

Special Populations

Patients with Renal Impairment

In a single-dose study of MPA, plasma area under the curve increased almost twofold in patients with severe renal impairment. The mean (±SD) pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil given as single doses to non-transplant subjects with renal impairment are presented in Table 7.

In a single-dose study, mycophenolate mofetil was administered as a capsule or as an intravenous infusion over 40 minutes. Plasma MPA AUC observed after oral dosing to volunteers with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) was about 75% higher relative to that observed in healthy volunteers (GFR >80 mL/min/1.73 m2). In addition, the single-dose plasma MPAG AUC was 3-fold to 6-fold higher in volunteers with severe renal impairment than in volunteers with mild renal impairment or healthy volunteers, consistent with the known renal elimination of MPAG. No data are available on the safety of long-term exposure to this level of MPAG.

Plasma MPA AUC observed after single-dose (1 g) intravenous dosing to volunteers (n=4) with severe chronic renal impairment (GFR <25 mL/min/1.73 m2) was 62.4 mcg•h/mL (±19.3). Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied.

Patients with Delayed Graft Function or Nonfunction

In patients with delayed renal graft function post-transplant, mean MPA AUC(0-12h) was comparable with that seen in post-transplant patients without delayed renal graft function. There is a potential for a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. However, dose adjustment does not appear to be necessary in patients with delayed renal graft function. Mean plasma MPAG AUC(0-12h) was 2-fold to 3-fold higher than in post-transplant patients without delayed renal graft function.

In eight patients with primary graft non-function following kidney transplantation, plasma concentrations of MPAG accumulated about 6-fold to 8-fold after multiple dosing for 28 days. Accumulation of MPA was about 1-fold to 2-fold.

The pharmacokinetics of mycophenolate mofetil are not altered by hemodialysis. Hemodialysis usually does not remove MPA or MPAG. At high concentrations of MPAG (>100 mcg/mL), hemodialysis removes only small amounts of MPAG.

Patients with Hepatic Impairment

The mean (±SD) pharmacokinetic parameters for MPA following the administration of oral mycophenolate mofetil given as single doses to non-transplant subjects with hepatic impairment are presented in Table 7.

In a single-dose (1 g oral) study of 18 volunteers with alcoholic cirrhosis and 6 healthy volunteers, hepatic MPA glucuronidation processes appeared to be relatively unaffected by hepatic parenchymal disease when pharmacokinetic parameters of healthy volunteers and alcoholic cirrhosis patients within this study were compared. However, it should be noted that for unexplained reasons, the healthy volunteers in this study had about a 50% lower AUC as compared with healthy volunteers in other studies, thus making comparisons between volunteers with alcoholic cirrhosis and healthy volunteers difficult. In a single-dose (1 g intravenous) study of 6 volunteers with severe hepatic impairment (aminopyrine breath test less than 0.2% of dose) due to alcoholic cirrhosis, mycophenolate mofetil was rapidly converted to MPA. MPA AUC was 44.1 mcg•h/mL (±15.5).

Table 7: Pharmacokinetic parameters for mpa following single doses of mycophenolate mofetil capsules in chronic renal and hepatic impairment

Pharmacokinetic Parameters for Renal Impairment

 

 

Dose

Tmax

(h)

Cmax

(mcg/mL)

AUC(0-96h)

(mcg•h/mL)

Healthy Volunteers

GFR >80 mL/min/1.73 m2

(n=6)

1 g

0.75

(±0.27)

25.3

(±7.99)

45.0

(±22.6)

Mild Renal Impairment

GFR 50–80 mL/min/1.73 m2

(n=6)

1 g

0.75

(±0.27)

26.0

(±3.82)

59.9

(±12.9)

Moderate Renal Impairment

GFR 25–49 mL/min/1.73 m2

(n=6)

1 g

0.75

(±0.27)

19.0

(±13.2)

52.9

(±25.5)

Severe Renal Impairment

GFR <25 mL/min/1.73 m2

(n=7)

1 g

1.00

(±0.41)

16.3

(±10.8)

78.6

(±46.4)

Pharmacokinetic Parameters for Hepatic Impairment

 

Dose

Tmax

(h)

Cmax

(mcg/mL)

AUC(0-48h)

(mcg•h/mL)

Healthy Volunteers

(n=6)

1 g

0.63

(±0.14)

24.3

(±5.73)

29.0

(±5.78)

Alcoholic Cirrhosis

(n=18)

1 g

0.85

(±0.58)

22.4

(±10.1)

29.8

(±10.7)

Male and Female Patients

Data obtained from several studies were pooled to look at any gender-related differences in the pharmacokinetics of MPA (data were adjusted to 1 g oral dose). Mean (±SD) MPA AUC(0-12h) for males (n=79) was 32.0 (±14.5) and for females (n=41) was 36.5 (±18.8) mcg•h/mL while mean (±SD) MPA Cmax was 9.96 (±6.19) in the males and 10.6 (±5.64) mcg/mL in the females. These differences are not of clinical significance.

Geriatric Patients

The pharmacokinetics of mycophenolate mofetil and its metabolites have not been found to be altered in elderly transplant patients when compared with younger transplant patients.

Non-Clinical Properties

Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week oral carcinogenicity study in mice, mycophenolate mofetil in daily doses up to 180 mg/kg was not tumorigenic. The highest dose tested was 0.4 times the recommended clinical dose (2 g/day) in renal transplant patients and 0.3 times the recommended clinical dose (3 g/day) in cardiac transplant patients when corrected for differences in BSA. In a 104-week oral carcinogenicity study in rats, mycophenolate mofetil in daily doses up to 15 mg/kg was not tumorigenic. The highest dose was 0.07 times the recommended clinical dose in kidney transplant patients and 0.05 times the recommended clinical dose in heart transplant patients when corrected for BSA. While these animal doses were lower than those given to patients, they were maximal in those species and were considered adequate to evaluate the potential for human risk .

The genotoxic potential of mycophenolate mofetil was determined in five assays. Mycophenolate mofetil was genotoxic in the mouse lymphoma/thymidine kinase assay and the in vivo mouse micronucleus assay. Mycophenolate mofetil was not genotoxic in the bacterial mutation assay, the yeast mitotic gene conversion assay or the Chinese hamster ovary cell chromosomal aberration assay.

Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. This dose represents 0.1 times the recommended clinical dose in renal transplant patients and 0.06 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (principally of the head and eyes) in the first-generation offspring in the absence of maternal toxicity. This dose was 0.02 times the recommended clinical dose in renal transplant patients and 0.01 times the recommended clinical dose in cardiac transplant patients when corrected for BSA. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.

Description

Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor.  The chemical name for mycophenolate mofetil is 2-morpholinoethyl (E)-6-(1,3dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4hexenoate. It has an empirical formula of C23H31NO7, a molecular weight of 433.50, and the following structural formula:

 

Pharmaceutical Particulars

Incompatibility

None.

Shelf-Life

24 months

Packaging Information

CELLMUNE 500 Tablets: Blister strip of 10 tablets

Storage and Handling Instructions

Store protected from light and moisture at a temperature not exceeding 30C

Keep out of the reach of children.

Patient Counseling Information

What is the most important information I should know about CELLMUNE 500 Tablets?

  • CELLMUNE 500Tablets can cause serious side effects, including increased risk of loss of a pregnancy (miscarriage) and higher risk of birth defects. Females who take CELLMUNE 500Tablets during pregnancy have a higher risk of miscarriage during the first 3 months (first trimester), and a higher risk that their baby will be born with birth defects.
  • If you are a female who can become pregnant, your doctor must talk with you about acceptable birth control methods (contraceptive counseling) to use while taking CELLMUNE 500 Tablets. You should have one pregnancy test immediately before starting CELLMUNE 500 Tablets and another pregnancy test 8–10 days later. Pregnancy tests should be repeated during routine follow-up visits with your doctor. Talk to your doctor about the results of all of your pregnancy tests.

You must use acceptable birth control during your entire CELLMUNE 500 Tablets treatment and for 6 weeks after stopping CELLMUNE 500 Tablets, unless at any time you choose to avoid sexual intercourse (abstinence) with a man completely. CELLMUNE 500 Tablets decreases blood levels of the hormones in birth control pills that you take by mouth. Birth control pills may not work as well while you take CELLMUNE 500 Tablets, and you could become pregnant. If you take birth control pills while using CELLMUNE 500 Tablets you must also use another form of birth control. Talk to your doctor about other birth control methods that you can use while taking CELLMUNE 500Tablets.

  • If you are a sexually active male whose female partner can become pregnant while you are taking CELLMUNE 500 Tablets, use effective contraception during treatment and for at least 90 days after stopping CELLMUNE 500 Tablets.
  • If you plan to become pregnant, talk with your doctor. Your doctor will decide if other medicines to prevent rejection may be right for you.
  • If you become pregnant while taking CELLMUNE 500 Tablets, do not stop taking CELLMUNE 500 Tablets. Call your doctor right away. You and your doctor may decide that other medicines to prevent rejection may be right for you.
  • People who take CELLMUNE 500 Tablets have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Tell your doctor if you have:
  • unexplained fever, prolonged tiredness, weight loss or lymph node swelling
  • a brown or black skin lesion with uneven borders, or one part of the lesion does not look like the other
  • a change in the size and color of a mole
  • a new skin lesion or bump
  • any other changes to your health
  • Increased risk of getting serious infections. CELLMUNE 500 Tablets weakens the body’s immune system and affects your ability to fight infections. Serious infections can happen with CELLMUNE 500 Tablets and can lead to hospitalizations and death. These serious infections can include:
  • Viral infections. Certain viruses can live in your body and cause active infections when your immune system is weak. Viral infections that can happen with CELLMUNE 500 Tablets include the following:
    • Shingles, other herpes infections, and cytomegalovirus (CMV). CMV can cause serious tissue and blood infections.
    • BK virus: BK virus can affect how your kidneys work and can cause your transplanted kidney to fail.
    • Hepatitis B and C viruses: Hepatitis viruses can affect how your liver works. Talk to your doctor about how hepatitis viruses may affect you.
  • A brain infection called progressive multifocal leukoencephalopathy (PML). In some patients, CELLMUNE 500 Tablets may cause an infection of the brain that may cause death. You are at risk for this brain infection because you have a weakened immune system. Call your doctor right away if you have any of the following symptoms:
  • Weakness on one side of the body
  • You do not care about things you usually care about (apathy)
  • You are confused or have problems thinking
  • You cannot control your muscles
  • Fungal infections. Yeasts and other types of fungal infections can happen with CELLMUNE 500 Tablets and can cause serious tissue and blood infections (See “What are the possible side effects of CELLMUNE 500 Tablets?”).

Call your doctor right away if you have any of the following signs and symptoms of infection:

  • Temperature of 100.5°F or greater
  • Cold symptoms, such as a runny nose or sore throat
  • Flu symptoms, such as an upset stomach, stomach pain, vomiting or diarrhea
  • Earache or headache
  • Pain during urination
  • White patches in the mouth or throat
  • Unexpected bruising or bleeding
  • Cuts, scrapes or incisions that are red, warm and oozing pus

What is CELLMUNE 500Tablets?

  • CELLMUNE 500 Tablets is a prescription medicine to prevent rejection (antirejection medicine) in people who have received a kidney, heart or liver transplant. Rejection is when the body’s immune system perceives the new organ as a “foreign” threat and attacks it.
  • CELLMUNE 500 Tablets is used with other medicines containing cyclosporine and corticosteroids.

Who should not take CELLMUNE 500 Tablets?

Do not take CELLMUNE 500 Tablets if you are allergic to mycophenolate mofetil or any of the ingredients in CELLMUNE 500 Tablets.

What should I tell my doctor before taking CELLMUNE 500 Tablets?

Tell your doctor about all of your medical conditions, including If you:

  • have any digestive problems, such as ulcers.
  • have Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, or another rare inherited deficiency hypoxanthine-guanine phosphoribosyl-transferase (HGPRT). You should not take CELLMUNE 500 Tablets if you have one of these disorders.
  • plan to receive any vaccines. People taking CELLMUNE 500 Tablets should not receive live vaccines. Some vaccines may not work as well during treatment with CELLMUNE 500 Tablets.
  • are pregnant or plan to become pregnant. See “What is the most important information I should know about CELLMUNE 500 Tablets?”
  • are breastfeeding or plan to breastfeed. It is not known if CELLMUNE 500 Tablets passes into breast milk. You and your doctor will decide if you will take CELLMUNE 500 Tablets or breastfeed.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Some medicines may affect the way CELLMUNE 500 Tablets works, and CELLMUNE 500 Tablets may affect how some medicines work. Especially tell your doctor if you take the following:

  • Birth control pills (oral contraceptives).
  • Sevelamer (these products should be taken at least 2 hours after taking CELLMUNE 500 Tablets)
  • Acyclovir, valacyclovir, ganciclovir, valganciclovir
  • Rifampin
  • Antacids that contain magnesium and aluminum (mycophenolate mofetil and the antacid should not be taken at the same time)
  • Proton-pump inhibitors (PPIs)
  • Sulfamethoxazole/trimethoprim
  • Norfloxacin and ciprofloxacin and amoxicillin plus clavulanic acid
  • Azathioprine
  • Cholestyramine

How should I take CELLMUNE 500 Tablets?

  • Take CELLMUNE 500 Tablets exactly as prescribed.
  • Do not stop taking CELLMUNE 500 Tablets or change the dose unless your doctor tells you to.
  • If you miss a dose of CELLMUNE 500 Tablets, or you are not sure when you took your last dose, take your prescribed dose of CELLMUNE 500 Tablets as soon as you remember. If your next dose is less than 2 hours away, skip the missed dose and take your next dose at your normal scheduled time. Do not take two doses at the same time. Call your doctor if you are not sure what to do.
  • Take CELLMUNE 500 Tablets on an empty stomach, unless your doctor tells you otherwise. Do not crush CELLMUNE 500 Tablets.
  • If you take too much CELLMUNE 500 Tablets, call your doctor or the Poison Control Center right away.

What should I avoid while taking CELLMUNE 500 Tablets?

  • Avoid becoming pregnant. See “What is the most important information I should know about CELLMUNE 500 Tablets?”
  • Limit the amount of time you spend in sunlight. Avoid using tanning beds or sunlamps. People who take CELLMUNE 500 Tablets have a higher risk of getting skin cancer (See “What is the most important information I should know about CELLMUNE 500 Tablets?”). Wear protective clothing when you are in the sun and use a broad-spectrum sunscreen with a high protection factor. This is especially important if your skin is very fair or if you have a family history of skin cancer.
  • You should not donate blood while taking CELLMUNE 500 Tablets and for at least 6 weeks after stopping CELLMUNE 500 Tablets.
  • You should not donate sperm while taking CELLMUNE 500 Tablets and for 90 days after stopping CELLMUNE 500 Tablets.
  • CELLMUNE 500 Tablets may influence your ability to drive and use machines (See “What are the possible side effects of CELLMUNE 500 Tablets?”. If you experience drowsiness, confusion, dizziness, tremor, or low blood pressure during treatment with CELLMUNE 500 Tablets, you should be cautious about driving or using heavy machines.

What are the possible side effects of CELLMUNE 500 Tablets?

CELLMUNE 500 Tablets can cause serious side effects, including the following:

  • Low blood cell counts. People taking high doses of CELLMUNE 500 Tablets each day may have a decrease in blood counts, including:
    • White blood cells, especially neutrophils. Neutrophils fight against bacterial infections. You have a higher chance of getting an infection when your white blood cell count is low. This is most common from 1 month to 6 months after your transplant.
    • Red blood cells. Red blood cells carry oxygen to your body tissues. You have a higher chance of getting severe anemia when your red blood cell count is low.
    • Platelets. Platelets help with blood clotting.
  • Your doctor will do blood tests before you start taking CELLMUNE 500 Tablets and during treatment with CELLMUNE 500 Tablets to check your blood cell counts. Tell your doctor right away if you have any signs of infection (See “What is the most important information I should know about CELLMUNE 500 Tablets?”), including any unexpected bruising or bleeding. Also, tell your doctor if you have unusual tiredness, lack of energy, dizziness or fainting.
  • Stomach problems. Stomach problems including intestinal bleeding, a tear in your intestinal wall (perforation) or stomach ulcers can happen in people who take CELLMUNE 500 Tablets. Bleeding can be severe and you may have to be hospitalized for treatment. Call your doctor right away if you have sudden or severe stomach-area pain or stomach-area pain that does not go away, or if you have diarrhea.

The most common side effects of CELLMUNE 500 Tablets include the following:

  • Diarrhea
  • Blood problems, including low white and red blood cell counts
  • Infections
  • Blood pressure problems
  • Fast heartbeat
  • Swelling of the lower legs, ankles and feet
  • Changes in laboratory blood levels, including high levels of blood sugar (hyperglycemia)
  • Stomach problems including diarrhea, constipation, nausea and vomiting
  • Rash
  • Nervous system problems such as headache, dizziness, and tremor

These are not all of the possible side effects of CELLMUNE 500 Tablets. Tell your doctor about any side effect that bothers you or that does not go away.

Reporting of side effects

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side effects, write to drugsafety@cipla.com. You can also report side effects directly via the national Pharmacovigilance Program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

How should I store CELLMUNE 500 Tablets?

Store protected from light and moisture at a temperature not exceeding 300C.

Keep out of the reach of children.

General information about the safe and effective use of CELLMUNE 500 Tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CELLMUNE 500 Tablets for a condition for which it was not prescribed. Do not give CELLMUNE 500 Tablets to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Counseling Information section summarizes the most important information about CELLMUNE 500 Tablets. You can ask your pharmacist or healthcare provider for information about CELLMUNE 500 Tablets.

Details of the Manufacturer/Marketer

Manufactured by:

The Madras Pharmaceuticals

137-B, Old Mahabalipuram Road, Karapakkam, Chennai-600096

Marketed by:

Cipla Ltd.

Regd. Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai – 400 013, India

Details of Permission or Licence Number with Date

MGF. LIC. NO. 110.     Dated 03/02/2021

Date of Revision

17/02/2021