CELLMUNE S Tablets (Mycophenolic Acid Delayed Release Tablets USP 360 mg)

Table of Content

To be sold by retail on the prescription of a Specialist only.

 Black Box 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 counselled regarding pregnancy prevention and planning .
  • Increased risk of development of lymphoma and other malignancies, particularly of the skin, due to immunosuppression .
  • Increased susceptibility to bacterial, viral, fungal, and protozoal infections, including opportunistic infections .

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe CELLMUNE S Tablets. Patients receiving CELLMUNE S 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 .

Qualitative and Quantitative Composition

Each Delayed-Release tablet contains:

Mycophenolate Sodium USP equivalent to Mycophenolic Acid……….360 mg

Colour: Titanium Dioxide IP

Dosage Form(S) And Strength(S)

Tablet containing 360 mg of mycophenolic acid

Clinical Particulars

Therapeutic Indications

For the prophylaxis of acute organ rejection and for the treatment of refractory organ rejection in adult’s patients receiving allogeneic renal transplant in combination with cyclosporine and corticosteroids.

Limitations of Use

CELLMUNE S Tablets and mycophenolate mofetil (MMF) oral dosage forms should not be used interchangeably without physician supervision because the rate of absorption following the administration of these two products is not equivalent.

Posology and Method of Administration

Dosage in Adult Kidney Transplant Patients

Treatment with CELLMUNE S Tablets must be initiated and maintained by transplant specialists. 

The recommended dose of CELLMUNE S Tablets is 720 mg administered twice daily (1440 mg total daily dose).

CELLMUNE S Tablets should be taken on an empty stomach one hour before or two hours after food intake. The tablet should be swallowed whole. Do not crush or chew the tablet.

Contraindications

Hypersensitivity Reactions

CELLMUNE S Tablets is 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 .

Special Warnings and Precautions for Use

Embryo-Fetal Toxicity

Use of CELLMUNE S 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 CELLMUNE S Tablets during pregnancy if safer treatment options are available .

Management of Immunosuppression

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe CELLMUNE S 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 .

Lymphoma and Other Malignancies

Patients receiving immunosuppressants, including CELLMUNE S Tablets, 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 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.

Serious Infections

Patients receiving immunosuppressants, including CELLMUNE S Tablets, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, and new or reactivated viral infections, including opportunistic infections . These infections may lead to serious, including fatal outcomes. Because of the danger of over suppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.

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 of mycophenolate sodium 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 .

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.

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 CELLMUNE S Tablets therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimize the risk of graft rejection.

Patients receiving CELLMUNE S Tablets should be monitored for blood dyscrasias (e.g., neutropenia or anemia). The development of neutropenia may be related to CELLMUNE S 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 , dosing with CELLMUNE S Tablets should be interrupted or the dose reduced, appropriate tests performed, and the patient managed accordingly.

Serious GI Tract Complications

Gastrointestinal bleeding (requiring hospitalization), intestinal perforations, gastric ulcers, and duodenal ulcers have been reported in patients treated with CELLMUNE S Tablets. CELLMUNE S Tablets should be administered with caution in patients with active serious digestive system disease.

Immunizations

During treatment with CELLMUNE S 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.

Rare Hereditary Deficiencies

MPA is an inosine monophosphate dehydrogenase inhibitor (IMPDH Inhibitor). CELLMUNE S 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.

Blood Donation

Patients should not donate blood during therapy and for at least 6 weeks following discontinuation of CELLMUNE S Tablets 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 CELLMUNE S Tablets .

Drugs Interactions

Antacids with Magnesium and Aluminium Hydroxides

Concomitant use of CELLMUNE S Tablets and antacids decreased plasma concentrations of MPA. It is recommended that CELLMUNE S Tablets and antacids not be administered simultaneously.

Azathioprine

Given that azathioprine and MMF inhibit purine metabolism, it is recommended that CELLMUNE S Tablets not be administered concomitantly with azathioprine or MMF.

Cholestyramine, Bile Acid Sequestrates, Oral Activated Charcoal and Other Drugs that Interfere with Enterohepatic Recirculation

Drugs that interrupt enterohepatic recirculation may decrease MPA plasma concentrations when co-administered with MMF. Therefore, do not administer CELLMUNE S Tablets with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, e.g., bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of CELLMUNE S Tablets.

Sevelamer

Concomitant administration of sevelamer and MMF may decrease MPA plasma concentrations. Sevelamer and other calcium free phosphate binders should not be administered simultaneously with CELLMUNE S Tablets

Cyclosporine

Cyclosporine inhibits the enterohepatic recirculation of MPA, and therefore, MPA plasma concentrations may be decreased when CELLMUNE S Tablets is co-administered with cyclosporine. Clinicians should be aware that there is also a potential change of MPA plasma concentrations after switching from cyclosporine to other immunosuppressive drugs or from other immunosuppressive drugs to cyclosporine in patients concomitantly receiving CELLMUNE S Tablets.

Norfloxacin and Metronidazole

MPA plasma concentrations may be decreased when MMF is administrated with norfloxacin and metronidazole. Therefore, CELLMUNE S Tablets is not recommended to be given with the combination of norfloxacin and metronidazole. Although there will be no effect on MPA plasma concentrations when CELLMUNE S Tablets is concomitantly administered with norfloxacin or metronidazole when given separately.

Rifampin

The concomitant administration of MMF and rifampin may decrease MPA plasma concentrations. Therefore, CELLMUNE S Tablets is not recommended to be given with rifampin concomitantly unless the benefit outweighs the risk.

Hormonal Contraceptives

In a drug interaction study, mean levonorgestrel AUC was decreased by 15% when co-administered with MMF. Although mycophenolate sodium may not have any influence on the ovulation-suppressing action of oral contraceptives, additional barrier contraceptive methods must be used when CELLMUNE S Tablets is co-administered with hormonal contraceptives (e.g., birth control pill, transdermal patch, vaginal ring, injection, and implant) .

Acyclovir (Valacyclovir), Ganciclovir (Valganciclovir), and Other Drugs that Undergo Renal Tubular Secretion

The coadministration of MMF and acyclovir or ganciclovir may increase plasma concentrations of mycophenolate sodium glucuronide (MPAG) and acyclovir/valacyclovir/ganciclovir/valganciclovir as their coexistence competes for tubular secretion. Both acyclovir/valacyclovir/ganciclovir/valganciclovir and MPAG concentrations will be also increased in the presence of renal impairment.

Acyclovir/valacyclovir/ganciclovir/ valganciclovir may be taken with CELLMUNE S Tablets; however, during the period of treatment, physicians should monitor blood cell counts.

Ciprofloxacin, Amoxicillin plus Clavulanic Acid and Other Drugs that Alter the Gastrointestinal Flora

Drugs that alter the gastrointestinal flora, such as ciprofloxacin or amoxicillin plus clavulanic acid may interact with MMF by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption when CELLMUNE S Tablets is concomitantly administered with ciprofloxacin or amoxicillin plus clavulanic acid. The clinical relevance of this interaction is unclear; however, no dose adjustment of CELLMUNE S Tablets is needed when co-administered with these drugs.

Pantoprazole

Administration of a pantoprazole at a dose of 40 mg twice daily for 4 days to healthy volunteers did not alter the pharmacokinetics of a single dose of CELLMUNE S Tablets.

Use in Special Populations

Pregnant Women

Risk Summary

Following oral or intravenous (IV) administration, MMF is metabolized to mycophenolic acid (MPA), the active ingredient in CELLMUNE S Tablets and the active form of the drug. Use of MMF 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 (0.05 and 1.1 times exposure at the recommended clinical doses in kidney transplant patients for rats and rabbits, respectively) .

Risks and benefits of CELLMUNE S Tablets should be discussed with the patient. When appropriate, consider alternative immunosuppressants with less potential for embryo-fetal toxicity.

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% to 20%, respectively.

Data

Human Data

A spectrum of congenital malformations (including multiple malformations in individual new-borns) has been reported in 23% to 27% of live births in MMF 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, kidney, and nervous system. Based on published data from pregnancy registries, the risk of first trimester pregnancy loss has been reported at 45% to 49% following MMF exposure.

Animal Data

In animal reproductive toxicology studies, congenital malformations and pregnancy loss occurred when pregnant rats and rabbits received mycophenolate at dose multiples equivalent to and less than the recommended human dose. Oral administration of mycophenolate sodium to pregnant rats from Gestational Day 7 to Day 16 at a dose as low as 1 mg per kg resulted in malformations including anophthalmia, exencephaly, and umbilical hernia. The systemic exposure at this dose represents 0.05 times the clinical exposure at the human dose of 1440 mg per day CELLMUNE S Tablets. Oral administration of mycophenolate to pregnant rabbits from Gestational Day 7 to Day 19 resulted in embryofetal lethality and malformations including ectopia cordis, ectopic kidneys, diaphragmatic hernia, and umbilical hernia at doses equal to or greater than 80mg per kg per day, in the absence of maternal toxicity. This corresponds to about 1.1 times the recommended clinical dose based on 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 on the effects of mycophenolate on a breastfed child. Studies in rats treated with MMF have shown MPA to be present in milk. Because available data are limited, it is not possible to exclude potential risks to a breastfeeding infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CELLMUNE S Tablets and any potential adverse effects on the breastfed infant from CELLMUNE S Tablets or from the underlying maternal condition. Because available data are limited, it is not possible to exclude potential risks to a breastfeeding infant.

Data

Limited information is available from the global Transplantation Pregnancy Registry. Of seven infants reported by this Registry to have been breastfed while the mother was taking mycophenolate, all were born at 34 to 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 female patients taking CELLMUNE S Tablets who are considering pregnancy, consider alternative immunosuppressants with less potential for embryo-fetal toxicity. Risks and benefits of CELLMUNE S Tablets should be discussed with the patient.

Pregnancy Testing

To prevent unplanned exposure during pregnancy, females of reproductive potential should have a serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL immediately before starting CELLMUNE S Tablets. Another pregnancy test with the same sensitivity should be done 8 to 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 CELLMUNE S Tablets must receive contraceptive counseling and use acceptable contraception (see Table 1). Patients must use acceptable birth control during entire CELLMUNE S Tablets therapy, and for 6 weeks after stopping CELLMUNE S Tablets, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely).

Patients should be aware that CELLMUNE S Tablets reduces blood levels of the hormones in the oral contraceptive pill and could theoretically reduce its effectiveness .

Table 1: 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 had a vasectomy

OR

Option 2

Hormone Methods

choose 1

 

Barrier Methods

choose 1

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 1

 

Barrier Methods

choose 1

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 S Tablets and for at least 90 days after cessation of treatment

Pediatric Patients

The safety and efficacy of mycophenolate sodium have not been investigated in children and adolescents. Its use in such patients therefore cannot be recommended.

Geriatric Patients

Pharmacokinetics in elderly patients has not been specifically studied . No dose adjustment is required in this patient population. Patients experiencing delayed renal graft function post-operatively. Patients with severe chronic renal failure (creatinine clearance <10 mL/min) should be closely monitored.

Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. The mechanism of action and pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.

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 .
  • New or Reactivated Viral Infections .
  • Blood Dyscrasias, Including Pure Red Cell Aplasia .
  • Serious GI Tract Complications .
  • Rare Hereditary Deficiencies .

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 mycophenolate sodium 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 mycophenolate sodium 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 mycophenolate sodium and MMF arms, respectively. The most common adverse reactions leading to discontinuation in the Mycophenolate sodium 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 mycophenolate sodium and MMF arms, respectively. The most frequent reasons for dose reduction in the mycophenolate sodium 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 mycophenolate sodium 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

Mycophenolate sodium

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 mycophenolate sodium 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

 

Mycophenolate sodium

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 mycophenolate sodium 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 .

The adverse reactions reported in <10% of de novo or conversion patients treated with mycophenolate sodium in combination with cyclosporine and corticosteroids are listed in Table 4.

Table 4: Adverse Reactions Reported in <10% of Patients Treated with Mycophenolate sodium 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 mycophenolic acid (MPA) when administered as a sodium salt or as mofetil ester:

Gastrointestinal: Intestinal perforation, gastrointestinal hemorrhage, gastric ulcers, duodenal ulcers , colitis (including CMV colitis), pancreatitis, esophagitis, and ileus.

Infections: Serious life-threatening infections, such as meningitis and infectious endocarditis, tuberculosis, and atypical mycobacterial infection .

Respiratory: Interstitial lung disorders, including fatal pulmonary fibrosis.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of mycophenolate sodium or other MPA derivatives. 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:

  • Congenital malformations, including ear, facial, cardiac and nervous system malformations and an increased incidence of first trimester pregnancy loss have been reported following exposure to MMF during pregnancy .
  • Infections .
    • Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal.
    • Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection, associated with serious outcomes, including deteriorating renal function and renal graft loss.
    • Viral reactivation in patients infected with HBV or HCV.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives in combination with other immunosuppressive agents .

The following additional adverse reactions have been identified during post-approval use of mycophenolate sodium: agranulocytosis, asthenia, osteomyelitis, lymphadenopathy, lymphopenia, wheezing, dry mouth, gastritis, peritonitis, anorexia, alopecia, pulmonary edema, Kaposi’s sarcoma.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorisation 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 (PvPI) 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

Signs and Symptoms

There have been anecdotal reports of deliberate or accidental overdoses with mycophenolate sodium, whereas not all patients experienced related adverse reactions.

In those overdose cases in which adverse reactions were reported, the reactions fall within the known safety profile of the class. Accordingly, an overdose of mycophenolate sodium could possibly result in oversuppression of the immune system and may increase the susceptibility to infection, including opportunistic infections, fatal infections and sepsis. If blood dyscrasias occur (e.g., neutropenia with absolute neutrophil count <1.5 x 103/mcL or anemia), it may be appropriate to interrupt or discontinue mycophenolate sodium.

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

Treatment and Management

General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Although dialysis may be used to remove the inactive metabolite mycophenolate sodium glucuronide (MPAG), it would not be expected to remove clinically significant amounts of the active moiety, mycophenolic acid (MPA), due to the 98% plasma protein binding of MPA. By interfering with enterohepatic circulation of MPA, activated charcoal or bile sequestrates, such as cholestyramine, may reduce the systemic MPA exposure.

Pharmacological Properties

Mechanism of Action

Mycophenolic acid (MPA), an immunosuppressant, is an uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation to DNA. 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 cytostatic effects on lymphocytes.

Mycophenolate sodium has been shown to prevent the occurrence of acute rejection in rat models of kidney and heart allotransplantation. Mycophenolate sodium also decreases antibody production in mice.

Pharmacokinetic Properties

The pharmacokinetics of mycophenolate sodium is dose proportional and linear over the dose range 180 to 2160 mg.

Absorption

Following oral administration, mycophenolate sodium is extensively absorbed. The absolute bioavailability to MPA is 71%. There is a limited first-pass effect. The peak plasma concentration of MPA is attained after about 1.5-2 hours. Compared to the fasting state, administration of mycophenolate sodium 720 mg with a high fat meal (55 g fat, 1000 calories) had no effect on the AUC of MPA. However, a 33% decrease in the peak concentration of MPA (Cmax) was observed. A second MPA peak is detectable approx. 6-8 hours after administration of mycophenolate sodium; this is due to enterohepatic circulation.

Distribution

The steady-state volume of distribution of MPA is 50 litters. Both MPA and Mycophenolic Acid Glucuronides (MPAG) are highly protein bound (98% and 82%, respectively). The concentration of free MPA may increase under conditions of decreased plasma protein (uremia, liver failure, hypoalbuminemia), as well as with concomitant use of other drugs with high protein binding. This is associated with an increased risk of MPA-related adverse effects.

Metabolism

MPA is metabolized principally by glucuronyl transferase to form the inactive MPAG.

Elimination

The majority of MPA is excreted in the urine as MPAG. MPAG secreted in the bile is subject to enterohepatic circulation. The half-life of MPA is 11.7 hours and its clearance is 8.6 litres/hour. The half-life of MPAG is linger than that of MPA, amounting to approx. 15.7 hours. Its clearance is 0.45 litres/hour.

Pharmacokinetics in Renal Transplant Patients

The mean pharmacokinetic parameters for MPA following the administration of mycophenolate sodium in renal transplant patients on cyclosporine, USP MODIFIED based immunosuppression are shown in Table 5. Single-dose Mycophenolate sodium pharmacokinetics predicts multiple-dose pharmacokinetics. However, in the early post -transplant period, mean MPA AUC and Cmax were approximately one-half of those measured 6 months post-transplant.

After near equimolar dosing of mycophenolate sodium 720 mg twice daily and MMF 1000 mg twice daily (739 mg as MPA) in both the single- and multiple-dose cross-over trials, mean systemic MPA exposure (AUC) was similar.

Table 5: Mean ± SD Pharmacokinetic Parameters for MPA Following the Oral Administration of Mycophenolate sodium to Renal Transplant Patients on Cyclosporine, USP MODIFIED Based Immunosuppression

Patient

Mycophenolate sodium Dosing

N

Dose

(mg)

Tmax*(h)

Cmax

(mcg/mL)

AUC(0-12h)

(mcg*h/mL)

Adult

Single

24

720

2 (0.8–8)

26.1± 12.0

66.5± 22.6**

Adult

Multiple x6 days, twice daily

10

720

2 (1.5–3.0)

37.0± 13.3

67.9± 20.3

Adult

Multiple x28 days, twice daily

36

720

2.5 (1.5–8)

31.2± 18.1

71.2± 26.3

Adult

Chronic, multiple dose, twice daily

 

2 weeks post-transplant

12

720

  1.8 (1.0–5.3)

15.0± 10.7

28.6± 11.5

3 months post-transplant

12

720

2 (0.5–2.5)

26.2± 12.7

52.3± 17.4

6 months post-transplant

12

720

2 (0–3)

24.1± 9.6

57.2± 15.3

Adult

Chronic, multiple dose, twice daily

18

720

1.5 (0–6)

18.9± 7.9

57.4± 15.0
Special Populations

Renal Insufficiency: The plasma level of MPA has been found to be comparable over the range of normal to absent renal function (glomerular filtration rate <5 mL/min). MPAG exposure has been found to increase with decreased renal function; in conditions of anuria, it has been reported to be approx. 8 times higher than normal. Clearance of both MPA and MPAG is unaffected by haemodialysis. Free MPA may increase significantly in the presence of renal failure. This is probably due to decreased plasma protein binding of MPA.

Hepatic Insufficiency: In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. However, in patients with hepatic disease, with predominantly biliary damage, such as primary biliary cirrhosis, an effect on the enterohepatic circulation cannot be ruled out.

Gender: There are no significant gender differences in mycophenolate sodium pharmacokinetics.

Paediatrics: Data on the use of mycophenolate sodium in children and adolescents is extremely limited.

Elderly: Pharmacokinetics in elderly patients has not been specifically studied. Increasing age does not appear to be associated with a clinically significant change in the bioavailability of MPA.

Ethnicity: Following a single dose administration of 720 mg of mycophenolate sodium to 18 Japanese and 18 Caucasian healthy subjects, the exposure (AUCinf) for MPA and MPAG were 15% and 22% lower in Japanese subjects compared to Caucasians. The peak concentrations (Cmax) for MPAG were similar between the two populations, however, Japanese subjects had 9.6% higher Cmax for MPA. These results do not suggest any clinically relevant differences.

Non-Clinical Properties

Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week oral carcinogenicity study in rats, mycophenolate sodium was not tumorigenic at daily doses up to 9 mg per kg, the highest dose tested. This dose resulted in approximately 0.6 to 1.2 times the systemic exposure (based on plasma AUC) observed in renal transplant patients at the recommended dose of 1440 mg per day. Similar results were observed in a parallel study in rats performed with MMF. In a 104-week oral carcinogenicity study in mice, MMF was not tumorigenic at a daily dose level as high as 180 mg per kg (which corresponds to 0.6 times the recommended mycophenolate sodium therapeutic dose, based on body surface area).

The genotoxic potential of mycophenolate sodium was determined in five assays. Mycophenolate sodium was genotoxic in the mouse lymphoma/thymidine kinase assay, the micronucleus test in V79 Chinese hamster cells, and the in vivo mouse micronucleus assay. Mycophenolate sodium was not genotoxic in the bacterial mutation assay (Salmonella typhimurium TA 1535, 97a, 98, 100, and 102) or the chromosomal aberration assay in human lymphocytes.

Mycophenolate mofetil generated similar genotoxic activity. The genotoxic activity of MPA is probably due to the depletion of the nucleotide pool required for DNA synthesis as a result of the pharmacodynamic mode of action of MPA (inhibition of nucleotide synthesis).

Mycophenolate sodium had no effect on male rat fertility at daily oral doses as high as 18 mg per kg and exhibited no testicular or spermatogenic effects at daily oral doses of 20 mg per kg for 13 weeks (approximately 2 times the systemic exposure of MPA at the recommended therapeutic dose). No effects on female fertility were seen up to a daily dose of 20 mg per kg (approximately 3 times the systemic exposure of MPA at the recommended therapeutic dose).

Description

Mycophenolate sodium is the sodium salt of mycophenolic acid (MPA). Mycophenolate sodium is an immunosuppressive agent. As the sodium salt, MPA is chemically designated as (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4­ enoic acid sodium salt.

Its empirical formula is C17H19O6Na. The molecular weight is 342.32 g/mol and the structural formula is:

Pharmaceutical Particulars

Incompatibilities

NA

Shelf life    

As on Pack

Packaging Information

CELLMUNE S Tablets: Alu-Alu blister pack of 10 tablets.

Storage and Handling Instruction

Store protected from light & moisture at a temperature not exceeding 25°C.

Keep out of reach of children.

Patient Counselling Information

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

CELLMUNE S Tablets can cause serious side effects, including:

  • Increased risk of loss of pregnancy (miscarriage) and higher risk of birth defects. Females who take CELLMUNE S Tablets 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) while taking CELLMUNE S Tablets.
    • you should have a pregnancy test immediately before starting CELLMUNE S Tablets and another pregnancy test 8 to 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 S Tablets therapy and for 6 weeks after stopping CELLMUNE S Tablets, unless at any time you choose to avoid sexual intercourse (abstinence) with a man completely. CELLMUNE S 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 S Tablets, and you could become pregnant. If you decide to take birth control pills while using CELLMUNE S Tablets, you must also use another form of birth control. Talk to your doctor about other birth control methods that can be used while taking CELLMUNE S Tablets.
  • If you are a sexually active male whose female partner can become pregnant while you are taking CELLMUNE S Tablets, use effective contraception during treatment and for at least 90 days after stopping CELLMUNE S 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 S Tablets, do not stop taking CELLMUNE S Tablets. Call your doctor right away. You and your doctor may decide that other medicines to prevent rejection may be right for you.
  • Increased risk of getting serious infections. CELLMUNE S Tablets weakens the body’s immune system and affects your ability to fight infections. Serious infections can happen with CELLMUNE S Tablets and can lead to 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 S Tablets include:
  • Shingles, other herpes infections, and cytomegalovirus (CMV). CMV can cause serious tissue and blood infections.
  • BK virus. BK virus can affect how your kidney works and 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 S 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. You should tell your healthcare provider right away if you have any of the following symptoms:
    • Weakness on one side of the body
    • You do not care about things that you usually care about (apathy)
    • You are confused or have problems thinking.
    • You cannot control your muscles.
  • Fungal infections. Yeast and other types of fungal infections can happen with CELLMUNE S Tablets and cause serious tissue and blood infections. See “What are the possible side effects of CELLMUNE S Tablets?”

Call your doctor right away if you have any of these 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 or you need to urinate often.
    • White patches in the mouth or throat
    • Unexpected bruising or bleeding
    • Cuts, scrapes, or incisions that are red, warm, and oozing pus.
  • Increased risk of getting certain cancers. People who take CELLMUNE S Tablets have a higher risk of getting lymphoma, and other cancers, especially skin cancer. Tell your doctor if you have:
  • unexplained fever, tiredness that does not go away, 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 other parts.
  • a change in the size or color of a mole
  • a new skin lesion or bump
  • any other changes to your health

CELLMUNE S Tablets is a prescription medicine given to prevent rejection (antirejection medicine) in people who have received a kidney transplant. Rejection is when the body’s immune system senses the new organ as “foreign” and attacks it.

CELLMUNE S Tablets is used with other medicines containing cyclosporine and corticosteroids.

Who should not take CELLMUNE S Tablets?

Do not take CELLMUNE S Tablets if you are allergic to mycophenolic acid (MPA), mycophenolate sodium, mycophenolate mofetil, or any of the ingredients in CELLMUNE S Tablets.

What should I tell my doctor before I start taking CELLMUNE S Tablets?

Tell your healthcare provider about all of your medical conditions, including if you:

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

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Some medicines may affect the way CELLMUNE S Tablets works and CELLMUNE S Tablets may affect how some medicines work.

Especially tell your doctor if you take:

  • birth control pills (oral contraceptives). See “What is the most important information I should know about CELLMUNE S Tablets?”
  • antacids that contain aluminium or magnesium. CELLMUNE S Tablets and antacids should not be taken at the same time.
  • acyclovir, ganciclovir
  • azathioprine
  • cholestyramine

Know the medicines you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist when you get a new medicine. Do not take any new medicine without talking to your doctor.

How should I take CELLMUNE S Tablets?

  • Take CELLMUNE S Tablets exactly as prescribed. Your healthcare provider will tell you how much CELLMUNE S Tablets to take.
  • Do not stop taking or change your dose of CELLMUNE S Tablets without talking to your healthcare provider.
  • CELLMUNE S Tablets should be taken with or without food as advised by concerned doctor.
  • Swallow CELLMUNE S Tablets whole. Do not crush, chew, or cut CELLMUNE S Tablets. The CELLMUNE S Tablets have a coating so that the medicine will pass through your stomach and dissolve in your intestine.
  • If you forget to take CELLMUNE S Tablets, take it as soon as you remember and then take your next dose at its regular time. If it is almost time for your next dose, skip the missed dose. Do not take two doses at the same time. Call your doctor or pharmacist if you are not sure what to do.
  • If you take more than the prescribed dose of CELLMUNE S Tablets, call your doctor right away.
  • Do not change (substitute) between using CELLMUNE S Tablets and mycophenolate mofetil oral dosage forms for one another unless your healthcare provider tells you to. These medicines are absorbed differently. This may affect the amount of medicine in your blood.
  • Be sure to keep all appointments at your transplant clinic. During these visits, your doctor may perform regular blood tests.

What should I avoid while taking CELLMUNE S Tablets?

  • Avoid pregnancy. See “What is the most important information I should know about CELLMUNE S Tablets?”
  • Limit the amount of time you spend in sunlight. Avoid using tanning beds and sunlamps. People who take CELLMUNE S Tablets have a higher risk of getting skin cancer. See “What is the most important information I should know about CELLMUNE S Tablets?” Wear protective clothing when you are in the sun and use a broad-spectrum sunscreen with a high sun protection factor (SPF 30 and above). This is especially important if your skin is fair (light colored), or you have a family history of skin cancer.
  • You should not donate blood while taking CELLMUNE S Tablets and for at least 6 weeks after stopping CELLMUNE S Tablets.
  • You should not donate sperm while taking CELLMUNE S Tablets and for 90 days after stopping CELLMUNE S Tablets.
  • Elderly patients 65 years of age or older may have more side effects with CELLMUNE S Tablets because of a weaker immune system.

What are the possible side effects of CELLMUNE S Tablets?

CELLMUNE S Tablets can cause serious side effects.

See "What is the most important information I should know about CELLMUNE S Tablets?"

Stomach and intestinal bleeding can happen in people who take CELLMUNE S Tablets. Bleeding can be severe, and you may have to be hospitalized for treatment.

The most common side effects of taking CELLMUNE S Tablets include:

In people with a new transplant:

  • low blood cell counts
  • red blood cells
  • white blood cells
  • platelets
  • constipation
  • nausea
  • diarrhea
  • vomiting
  • urinary tract infections
  • stomach upset.

In people who take CELLMUNE S Tablets for a long time (long-term) after transplant:

  • low blood cell counts
  • red blood cells
  • white blood cells
  • nausea
  • diarrhea
  • sore throat

Your healthcare provider will do blood tests before you start taking CELLMUNE S Tablets and during treatment with CELLMUNE S Tablets to check your blood cell counts. Tell your healthcare provider right away if you have any signs of infection (see “What is the most important information I should know about CELLMUNE S Tablets?”), or any unexpected bruising or bleeding. Also, tell your healthcare provider if you have unusual tiredness, dizziness, or fainting.

These are not all the possible side effects of CELLMUNE S Tablets. Your healthcare provider may be able to help you manage these side effects.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorisation 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 (PvPI) 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 S Tablets?

Store below 30°C. Protect from light and moisture. Keep out of reach of children.

General information about CELLMUNE S Tablets

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

Details of The Manufacturer

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

LIC. NO. 110. dated 29.09.2020

Date of Revision

19/04/2021

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