Imulate

Imulate 1 g/5 ml powder for oral suspension is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.

Myfenax is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.

Prophylaxis Of Organ Rejection In Kidney Transplant

Imulate® (mycophenolic acid) is indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant.

Imulate is indicated for the prophylaxis of organ rejection in pediatric patients 5 years of age and older who are at least 6 months post kidney transplant.

Imulate is to be used in combination with cyclosporine and corticosteroids.

Limitations Of Use

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

Treatment with Imulate should be initiated and maintained by appropriately qualified transplant specialists.

Posology

Use in renal transplant

Adults

Oral Imulate 1 g/5 ml powder for oral suspension should be initiated within 72 hours following transplantation. The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose), i.e. 5 mL oral suspension twice daily.

Paediatric population aged 2 to 18 years

The recommended dose of Imulate 1 g/5 ml powder for oral suspension is 600 mg/m² administered twice daily (up to a maximum of 2 g/10 mL oral suspension daily). As some adverse reactions occur with greater frequency in this age group compared with adults, temporary dose reduction or interruption may be required; these will need to take into account relevant clinical factors including severity of reaction.

Paediatric population < 2 years

There are limited safety and efficacy data in children below the age of 2 years. These are insufficient to make dosage recommendations, and therefore use in this age group is not recommended.

Use in cardiac transplant

Adults

Oral Imulate should be initiated within 5 days following transplantation. The recommended dose in cardiac transplant patients is 1.5 g administered twice daily (3 g daily dose).

Paediatric population

No data are available for paediatric cardiac transplant patients.

Use in hepatic transplant

Adults

IV Imulate should be administered for the first 4 days following hepatic transplant, with oral Imulate initiated as soon after this as it can be tolerated. The recommended oral dose in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose).

Paediatric population

No data are available for paediatric hepatic transplant patients.

Use in special populations

Elderly

The recommended dose of 1 g administered twice a day for renal transplant patients and 1.5 g twice a day for cardiac or hepatic transplant patients is appropriate for the elderly.

Renal impairment

In renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25 mL/min/1.73 m²), outside the immediate post-transplant period, doses greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively.. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.

Severe hepatic impairment

No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease. No data are available for cardiac transplant patients with severe hepatic parenchymal disease.

Treatment during rejection episodes

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of Imulate is not required. There is no basis for Imulate dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.

Method of administration

Oral administration.

Note: If required, Imulate 1 g/5 ml powder for oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).

Precautions to be taken before handling or administering the medicinal product.

Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, avoid inhalation or direct contact with skin or mucous membranes of the dry powder as well as direct contact of the reconstituted suspension with the skin. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

Treatment with Myfenax should be initiated and maintained by appropriately qualified transplant specialists.

Posology

Use in renal transplant

Adults

Oral Myfenax should be initiated within 72°hours following transplantation. The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose).

Paediatric population aged 2 to 18 years

The recommended dose of Imulate is 600 mg/m² administered orally twice daily (up to a maximum of 2 g daily). Myfenax capsules should only be prescribed to patients with a body surface area of at least 1.25 m². Patients with a body surface area of 1.25 to 1.5 m² may be prescribed Myfenax capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area greater than 1.5 m² may be prescribed Myfenax capsules at a dose of 1 g twice daily (2 g daily dose). As some adverse reactions occur with greater frequency in this age group compared with adults, temporary dose reduction or interruption may be required; these will need to take into account relevant clinical factors including severity of reaction.

Paediatric population < 2 years

There are limited safety and efficacy data in children below the age of 2°years. These are insufficient to make dosage recommendations and therefore use in this age group is not recommended.

Use in cardiac transplant:

Adults

Oral Myfenax should be initiated within 5 days following transplantation. The recommended dose in cardiac transplant patients is 1.5°g administered twice daily (3°g daily dose).

Paediatric population

No data are available for paediatric cardiac transplant patients.

Use in hepatic transplant

Adults

Intravenous Imulate should be administered for the first 4°days following hepatic transplant, with oral Myfenax initiated as soon after this as it can be tolerated. The recommended oral dose in hepatic transplant patients is 1.5°g administered twice daily (3°g daily dose).

Paediatric population

No data are available for paediatric hepatic transplant patients.

Use in special populations

Elderly

The recommended dose of 1°g administered twice a day for renal transplant patients and 1.5°g twice a day for cardiac or hepatic transplant patients is appropriate for the elderly.

Renal impairment

In renal transplant patients with severe chronic renal impairment (glomerular filtration rate <°25 mL/min/1.73°m²), outside the immediate post-transplant period, doses greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.

Severe hepatic impairment

No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease. No data are available for cardiac transplant patients with severe hepatic parenchymal disease.

Treatment during rejection episodes

Mycophenolic acid (MPA) is the active metabolite of Imulate. Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of Myfenax is not required. There is no basis for Myfenax dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.

Method of administration

Oral administration

Precautions to be taken before handling or administering the medicinal product

Because Imulate has demonstrated teratogenic effects in rats and rabbits, Myfenax capsules should not be opened or crushed to avoid inhalation or direct contact with skin or mucous membranes of the powder contained in Myfenax capsules. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

Dosage In Adult Kidney Transplant Patients

The recommended dose of Imulate is 720 mg administered twice daily (1440 mg total daily dose).

Dosage In Pediatric Kidney Transplant Patients

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

Administration

Imulate tablets should be taken on an empty stomach, 1 hour before or 2 hours after food intake.

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

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

- Hypersensitivity reactions to Imulate have been observed.

- Imulate should not be given to women of childbearing potential who are not using highly effective contraception.

- Imulate treatment should not be initiated in women of child bearing potential without providing a pregnancy test result to rule out unintended use in pregnancy.

- Imulate should not be used in pregnancy unless there is no suitable alternative treatment to prevent transplant rejection.

- Imulate should not be given to women who are breastfeeding.

Myfenax should not be given to women of childbearing potential who are not using highly effective contraception.

Myfenax treatment should not be initiated in women of child bearing potential without providing a pregnancy test result to rule out unintended use in pregnancy.

Myfenax should not be used during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection.

Myfenax should not be given to women who are breastfeeding.

Hypersensitivity Reactions

Imulate is contraindicated in patients with a hypersensitivity to mycophenolate sodium, mycophenolic acid, 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.

Neoplasms

Patients receiving immunosuppressive regimens involving combinations of medicinal products, including Imulate, 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 general advice to minimise the 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.

Infections

Patients treated with immunosuppressants, including Imulate, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis. Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation and infections caused by polyomaviruses (BK virus associated nephropathy, JC virus associated progressive multifocal leukoencephalopathy PML). Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.

There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving Imulate in combination with other immunosuppressants. In some of these cases switching Imulate to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on Imulate who develop recurrent infections should have their serum immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobulinaemia, appropriate clinical action should be considered taking into account the potent cytostatic effects that mycophenolic acid has on T- and B-lymphocytes.

There have been published reports of bronchiectasis in adults and children who received Imulate in combination with other immunosuppressants. In some of these cases switching Imulate to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinaemia or to a direct effect on the lung. There have also been isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal. It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.

Blood and immune system

Patients receiving Imulate should be monitored for neutropenia, which may be related to Imulate itself, concomitant medications, viral infections, or some combination of these causes. Patients taking Imulate should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If neutropenia develops (absolute neutrophil count < 1.3 x 10³/µl), it may be appropriate to interrupt or discontinue Imulate.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Imulate in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of Imulate therapy. Changes to Imulate therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection.

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

Patients should be advised that during treatment with Imulate, vaccinations may be less effective, and the use of live attenuated vaccines should be avoided. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.

Gastro-intestinal

Imulate has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation. Imulate should be administered with caution in patients with active serious digestive system disease.

Imulate is an IMPDH (inosine monophosphate dehydrogenase) 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 syndrome.

Interactions

Caution should be exercised when switching combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation, e.g. ciclosporin, to others devoid of this effect, e.g. tacrolimus, sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure.). Therapeutic drug monitoring of MPA may be appropriate when switching combination therapy (e.g. from ciclosporin to tacrolimus or vice versa) or to ensure adequate immunosuppression in patients with high immunological risk (e.g. risk of rejection, treatment with antibiotics).

It is recommended that Imulate should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.

Imulate 1 g/5 ml powder for oral suspension contains aspartame. Therefore, care should be taken if Imulate 1 g/5 ml powder for oral suspension is administered to patients with phenylketonuria

This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Special populations

Elderly patients may be at an increased risk of adverse events such as certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared with younger individuals.

Teratogenic effects

Mycophenolate is a powerful human teratogen.(e.g. contraceptive methods, pregnancy testing) prior to, during, and after therapy with Imulate. Physicians should ensure that women taking mycophenolate understand the risk of harm to the baby, the need for effective contraception, and the need to immediately consult their physician if there is a possibility of pregnancy.

Contraception

Because of robust clinical evidence showing a high risk of abortion and congential malformations when mycophenolate mofetil is used in pregnancy every effort to avoid pregnancy during treatment should be taken. Therefore women with childbearing potential must use at least one form of reliable contraception before starting Imulate therapy, during therapy, and for six weeks after stopping the therapy, unless abstinence is the chosen method of contraception. Two complementary forms of contraception simultaneously are preferred to minimise the potential for contraceptive failure and unintended pregnancy.

Educational materials

In order to assist patients in avoiding foetal exposure to mycophenolate and to provide additional important safety information, the Marketing Authorisation holder will provide educational materials to healthcare professionals. The educational materials will reinforce the warnings about the teratogenicity of mycophenolate, provide advice on contraception before therapy is started and guidance on the need for pregnancy testing. Full patient information about the teratogenic risk and the pregnancy prevention measures should be given by the physician to women of childbearing potential and, as appropriate, to male patients.

Additional precautions

Patients should not donate blood during therapy or for at least 6 weeks following discontinuation of mycophenolate. Men should not donate semen during therapy or for 90 days following discontinuation of mycophenolate.

Neoplasms

Patients receiving immunosuppressive regimens involving combinations of medicinal products, including Myfenax, 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 general advice to minimise the risk for skin cancer, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Infections

Patients treated with immunosuppressants, including Myfenax, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis. Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation and infections caused by polyomaviruses (BK virus associated nephropathy, JC virus associated progressive multifocal leukoencephalopathy PML). Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.

There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving Imulate in combination with other immunosuppressants. In some of these cases switching Imulate to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on Imulate who develop recurrent infections should have their serum immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobulinaemia, appropriate clinical action should be considered taking into account the potent cytostatic effects that mycophenolic acid has on T- and B-lymphocytes.

There have been published reports of bronchiectasis in adults and children who received Imulate in combination with other immunosuppressants. In some of these cases switching Imulate to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinaemia or to a direct effect on the lung. There have also been isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal. It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.

Blood and immune system

Patients receiving Myfenax should be monitored for neutropenia, which may be related to Myfenax itself, concomitant medicinal products, viral infections, or some combination of these causes. Patients taking Myfenax should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment then monthly through the first year. If neutropenia develops (absolute neutrophil count <°1.3°x 10³/°Î¼l) it may be appropriate to interrupt or discontinue Myfenax.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Imulate in combination with other immunosuppressants. The mechanism for Imulate induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of Myfenax therapy. Changes to Myfenax therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection.

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

Patients should be advised that during treatment with Myfenax, vaccinations may be less effective and the use of live attenuated vaccines should be avoided. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.

Gastro-intestinal

Imulate has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation. Myfenax should be administered with caution in patients with active serious digestive system disease.

Myfenax 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 syndrome.

Interactions

Caution should be exercised when switching combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation e.g. ciclosporin to others devoid of this effect e.g. sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure.).

It is recommended that Imulate should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.

Special populations

Elderly patients may be at an increased risk of adverse events such as certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared with younger individuals.

Teratogenic effects

Mycophenolate is a powerful human teratogen.(e.g. contraceptive methods, pregnancy testing) prior to, during, and after therapy with mycophenolate. Physicians should ensure that women and men taking mycophenolate understand the risk of harm to the baby, the need for effective contraception, and the need to immediately consult their physician if there is a possibility of pregnancy.

Contraception

Because of the genotoxic and teratogenic potential of mycophenolate, women with childbearing potential should use two reliable forms of contraception simultaneously before starting Myfenax therapy, during therapy, and for six weeks after stopping the therapy; unless abstinence is the chosen method of contraception.

Sexually active men are recommended to use condoms during treatment and for at least 90 days after cessation of treatment. Condom use applies for both reproductively competent and vasectomized men, because the risks associated with the transfer of seminal fluid also apply to men who have had a vasectomy. In addition, female partners of male patients treated with mycophenolate are recommended to use highly effective contraception during treatment and for a total of 90 days after the last dose of mycophenolate.

Educational materials

In order to assist patients in avoiding foetal exposure to mycophenolate and to provide additional important safety information, the Marketing Authorisation holder will provide educational materials to healthcare professionals. The educational materials will reinforce the warnings about the teratogenicity of mycophenolate, provide advice on contraception before therapy is started and guidance on the need for pregnancy testing. Full patient information about the teratogenic risk and the pregnancy prevention measures should be given by the physician to women of childbearing potential and, as appropriate, to male patients.

Additional precautions

Patients should not donate blood during therapy or for at least 6 weeks following discontinuation of mycophenolate. Men should not donate semen during therapy or for 90 days following discontinuation of mycophenolate.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Embryofetal Toxicity

Use of Imulate 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.

Pregnancy Exposure Prevention And Planning

Females of reproductive potential must be aware of the increased risk of first trimester pregnancy loss and congenital malformations and must be counseled regarding pregnancy prevention and planning. For recommended pregnancy testing and contraception methods.

Management Of Immunosuppression

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Imulate. 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 Imulate, 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 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 Imulate, 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 oversuppression 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 Imulate 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 Imulate therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimize the risk of graft rejection.

Patients receiving Imulate should be monitored for blood dyscrasias (e.g., neutropenia or anemia). The development of neutropenia may be related to Imulate itself, concomitant medications, viral infections, or some combination of these reactions. Complete blood count should be performed weekly during the first month, twice monthly for the second and the third month of treatment, then monthly through the first year. If blood dyscrasias occur [neutropenia develops (ANC < 1.3 x 10³/mcL) or anemia], dosing with Imulate 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 Imulate. Imulate should be administered with caution in patients with active serious digestive system disease.

Immunizations

The use of live attenuated vaccines should be avoided during treatment with Imulate; examples include (but not limited to) the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

Rare Hereditary Deficiencies

Imulate is an inosine monophosphate dehydrogenase inhibitor (IMPDH Inhibitor). Imulate 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.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide)

Embryofetal Toxicity

• Inform pregnant women and females of reproductive potential that use of Imulate in pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations.
• In the event of a positive pregnancy test, discuss the risks and benefits of Imulate with the patient. Encourage her to enroll in the pregnancy registry. (1-800-617-8191)..

Pregnancy Exposure Prevention And Planning

• Discuss pregnancy testing, pregnancy prevention and planning with females of reproductive potential.
• Inform females of reproductive potential must use acceptable birth control during entire Imulate therapy and for 6 weeks after stopping Imulate, unless the patient chooses to avoid heterosexual sexual intercourse completely (abstinence).
• For patients who are considering pregnancy, discuss appropriate alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of Imulate should be discussed with the patient.

Nursing Mothers

Advise patients that they should not breastfeed during Imulate therapy.

Development Of Lymphoma And Other Malignancies

• Inform patients they are at increased risk of developing lymphomas and other malignancies, particularly of the skin, due to immunosuppression.
• Advise patients to limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and use a sunscreen with a high protection factor.

Increased Risk Of Infection

Inform patients they are at increased risk of developing a variety of infections, including opportunistic infections, due to immunosuppression and to contact their physician if they develop any symptoms of infection.

Blood Dyscrasias

Inform patients they are at increased risk for developing blood dyscrasias (e.g., neutropenia or anemia) and to immediately contact their healthcare provider if they experience any evidence of infection, unexpected bruising, bleeding, or any other manifestation of bone marrow suppression.

Gastrointestinal Tract Complications

Inform patients that Imulate can cause gastrointestinal tract complications including bleeding, intestinal perforations, and gastric or duodenal ulcers. Advise the patient to contact their healthcare provider if they have symptoms of gastrointestinal bleeding or sudden onset or persistent abdominal pain.

Immunizations

Inform patients that Imulate can interfere with the usual response to immunizations and that they should avoid live vaccines.

Administration Instructions

Advise patients to swallow Imulate tablets whole, and not crush, chew, or cut the tablets. Inform patients to take Imulate on an empty stomach, 1 hour before or 2 hours after food intake.

Drug Interactions

Patients should be advised to report to their doctor the use of any other medications while taking Imulate. The simultaneous administration of any of the following drugs with Imulate may result in clinically significant adverse reactions:

Antacids with magnesium and aluminum hydroxides
Azathioprine
Cholestyramine
Hormonal Contraceptives (e.g., birth control pill, transdermal patch, vaginal ring, injection, and implant)

Nonclinical Toxicology

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 mycophenolic acid (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).

Use In Specific Populations

Pregnancy

Pregnancy Category D

For those females using Imulate at any time during pregnancy and those becoming pregnant within 6 weeks of discontinuing therapy, the healthcare practitioner should report the pregnancy to the Mycophenolate Pregnancy Registry (1-800-617-8191). The healthcare practitioner should strongly encourage the patient to enroll in the pregnancy registry. The information provided to the registry will help the Health Care Community to better understand the effects of mycophenolate in pregnancy.

Risk Summary

Following oral or intravenous (IV) administration, MMF is metabolized to mycophenolic acid (MPA), the active ingredient in Imulate 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 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. In animal studies, congenital malformations and pregnancy loss occurred when pregnant rats and rabbits received mycophenolic acid at dose multiples similar to and less than clinical doses.

Risks and benefits of Imulate should be discussed with the patient. When appropriate, consider alternative immunosuppressants with less potential for embryofetal toxicity. In certain situations, the patient and her healthcare practitioner may decide that the maternal benefits outweigh the risks to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Data

Human Data

In the National Transplantation Pregnancy Registry (NTPR), there were data on 33 MMF-exposed pregnancies in 24 transplant patients; there were 15 spontaneous abortions (45%) and 18 live-born infants. Four of these 18 infants had structural malformations (22%). In postmarketing data (collected from 1995 to 2007) on 77 women exposed to systemic MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or fetus. Six of 14 malformed offspring had ear abnormalities. Because these postmarketing data are reported voluntarily, it is not always possible to reliably estimate the frequency of particular adverse outcomes. These malformations are similar to findings in animal reproductive toxicology studies. For comparison, the background rate for congenital anomalies in the United States is about 3%, and NTPR data show a rate of 4%-5% among babies born to organ transplant patients using other immunosuppressive drugs. There are no relevant qualitative or quantitative differences in the teratogenic potential of mycophenolate sodium and MMF.

Animal Data

In a teratology study performed with mycophenolate sodium in rats, at a dose as low as 1 mg per kg, malformations in the offspring were observed, including anophthalmia, exencephaly, and umbilical hernia. The systemic exposure at this dose represents 0.05 times the clinical exposure at the dose of 1440 mg per day Imulate. In teratology studies in rabbits, fetal resorptions and malformations occurred at doses equal to or greater than 80 mg per kg per day, in the absence of maternal toxicity (which corresponds to about 1.1 times the recommended clinical dose, based on body surface area).

Nursing Mothers

It is not known whether MPA is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Imulate, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Imulate have been established in pediatric kidney transplant patients 5 to 16 years of age who were initiated on Imulate at least 6 months post-transplant. Use of Imulate in this age group is supported by evidence from adequate and well-controlled studies of Imulate in a similar population of adult kidney transplant patients with additional pharmacokinetic data in pediatric kidney transplant patients. Pediatric doses for patients with BSA < 1.19 m² cannot be accurately administered using currently available formulations of Imulate tablets.

The safety and effectiveness of Imulate in de novo pediatric kidney transplant patients and in pediatric kidney transplant patients below the age of 5 years have not been established.

Geriatric Use

Clinical studies of Imulate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 372 patients treated with Imulate in the clinical trials, 6% (N=21) were 65 years of age and older and 0.3% (N=1) were 75 years of age and older. 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 be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Females Of Reproductive Potential

Pregnancy Exposure Prevention And Planning

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.

Females of reproductive potential include girls who have entered puberty and all women who have a uterus and have not passed through menopause. Menopause is the permanent end of menstruation and fertility. Menopause should be clinically confirmed by a patient's healthcare practitioner. Some commonly used diagnostic criteria include 1) 12 months of spontaneous amenorrhea (not amenorrhea induced by a medical condition or medical therapy), or 2) postsurgical from a bilateral oophorectomy.

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 Imulate. 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, females should be counseled with regard to whether the maternal benefits of mycophenolate treatment may outweigh the risks to the fetus in certain situations.

Contraception

Females of reproductive potential taking Imulate must receive contraceptive counseling and use acceptable contraception (see Table 5 for Acceptable Contraception Methods). Patients must use acceptable birth control during entire Imulate therapy, and for 6 weeks after stopping Imulate, unless the patient chooses abstinence (she chooses to avoid heterosexual intercourse completely).

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

Table 5: Acceptable Contraception Methods for Females of Reproductive Potential
Pick from the following birth control options:

Pregnancy Planning

For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of Imulate should be discussed with the patient.

The following undesirable effects cover adverse reactions from clinical trials:

The principal adverse reactions associated with the administration of Imulate in combination with ciclosporin and corticosteroids include diarrhoea, leucopenia, sepsis and vomiting, and there is evidence of a higher frequency of certain types of infections.

Malignancies

Patients receiving immunosuppressive regimens involving combinations of medicinal products, including Imulate, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. Lymphoproliferative disease or lymphoma developed in 0.6% of patients receiving Imulate (2 g or 3 g daily) in combination with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year. Non-melanoma skin carcinomas occurred in 3.6% of patients; other types of malignancy occurred in 1.1% of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1 year, but less than 3 years.

Opportunistic infections

All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load. The most common opportunistic infections in patients receiving Imulate (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials in renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5%.

Paediatric population

The type and frequency of adverse reactions in a clinical study, which recruited 92 paediatric patients aged 2 to 18 years who were given 600 mg/m² mycophenolate mofetil orally twice daily, were generally similar to those observed in adult patients given 1 g Imulate twice daily. However, the following treatment-related adverse events were more frequent in the paediatric population, particularly in children under 6 years of age, when compared to adults: diarrhoea, sepsis, leucopenia, anaemia and infection.

Elderly

Elderly patients (> 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving Imulate as part of a combination immunosuppressive regimen may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals.

Other adverse reactions

Adverse reactions, probably or possibly related to Imulate, reported in >1/10 and in >1/100 to <1/10 of patients treated with Imulate in the controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients are listed in the following table.

Adverse Reactions, Probably or Possibly Related to Imulate, Reported in Patients Treated with Imulate in Renal, Cardiac and Hepatic Clinical Trials when Used in Combination with Ciclosporin and Corticosteroids

Within the system organ classes, undesirable effects are listed under headings of frequency, using the following categories: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Note: 501 (2 g Imulate daily), 289 (3 g Imulate daily) and 277 (2 g IV / 3 g oral Imulate daily) patients were treated in Phase III studies for the prevention of rejection in renal, cardiac and hepatic transplantation, respectively.

The following undesirable effects cover adverse reactions from post-marketing experience

The types of adverse reactions reported during post-marketing with Imulate are similar to those seen in the controlled renal, cardiac and hepatic transplant studies. Additional adverse reactions reported during post-marketing are described below with the frequencies reported within brackets if known.

Gastrointestinal

Gingival hyperplasia (>1/100 to <1/10), colitis including cytomegaloviruscolitis, (>1/100 to <1/10), pancreatitis (>1/100 to <1/10) and intestinal villous atrophy.

Infections

Serious life-threatening infections including meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leucoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Imulate.

Agranulocytosis (>1/1000 to <1/100) and neutropenia have been reported; therefore regular monitoring of patients taking Imulate is advised. There have been reports of aplastic anaemia and bone marrow depression in patients treated with Imulate, some of which have been fatal.

Blood and lymphatic system disorder

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Imulate.

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with Imulate. These changes are not associated with impaired neutrophil function. These changes may suggest a 'left shift' in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive Imulate.

Hypersensitivity

Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction have been reported.

Pregnancy, puerperium and perinatal conditions

Congenital disorders

Respiratory, thoracic and mediastinal disorders

There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with Imulate in combination with other immunosuppressants, some of which have been fatal. There have also been reports of bronchiectasis in children and adults (frequency not known).

Immune system disorders

Hypogammaglobulinaemia has been reported in patients receiving Imulate in combination with other immunosuppressants (frequency not known).

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. Healthcare professionals are asked to report any suspected adverse reactions (see details below).

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

The following undesirable effects cover adverse reactions from clinical trials

The principal adverse reactions associated with the administration of Imulate in combination with ciclosporin and corticosteroids include diarrhoea, leucopenia, sepsis and vomiting and there is evidence of a higher frequency of certain types of infections.

Malignancies

Patients receiving immunosuppressive regimens involving combinations of medicinal products, including Imulate, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. Lymphoproliferative disease or lymphoma developed in 0.6% of patients receiving Imulate (2°g or 3°g daily) in combination with other immunosuppressants in controlled clinical trials of renal (2°g data), cardiac and hepatic transplant patients followed for at least 1°year. Non-melanoma skin carcinomas occurred in 3.6% of patients; other types of malignancy occurred in 1.1% of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1°year, but less than 3°years.

Opportunistic infections

All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load. The most common opportunistic infections in patients receiving Imulate (2°g or 3°g daily) with other immunosuppressants in controlled clinical trials of renal (2°g data), cardiac and hepatic transplant patients followed for at least 1°year were candida mucocutaneous, cytomegalovirus (CMV) viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5%.

Paediatric population

The type and frequency of adverse reactions in a clinical study, which recruited 92 paediatric patients aged 2 to 18°years who were given 600°mg/m² Imulate orally twice daily, were generally similar to those observed in adult patients given 1°g Imulate twice daily. However, the following treatment-related adverse events were more frequent in the paediatric population, particularly in children under 6°years of age, when compared to adults: diarrhoea, sepsis, leucopenia, anaemia and infection.

Elderly

Elderly patients (> 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving Myfenax as part of a combination immunosuppressive regimen may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals.

Other adverse reactions

Adverse reactions, probably or possibly related to Imulate, reported in >1/10 and in >1/100 to <1/10 of patients treated with Imulate in the controlled clinical trials of renal (2°g data), cardiac and hepatic transplant patients are listed in the following table.

Within the system organ classes, undesirable effects are listed under headings of frequency, using the following categories: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (≤1/10,000), not known (cannot be estimated from the available data).Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions, probably or possibly related to Imulate, reported in patients treated with Imulate in renal, cardiac and hepatic clinical trials when used in combination with ciclosporin and corticosteroids

Note: 501 (2°g Imulate daily), 289 (3°g Imulate daily) and 277 (2°g intravenous/3°g oral Imulate daily) patients were treated in Phase III studies for the prevention of rejection in renal, cardiac and hepatic transplantation, respectively.

The following undesirable effects cover adverse reactions from post-marketing experience

The types of adverse reactions reported during post-marketing with Imulate are similar to those seen in the controlled renal, cardiac and hepatic transplant studies. Additional adverse reactions reported during post-marketing are described below with the frequencies reported within brackets if known.

Gastrointestinal

Gingival hyperplasia (>1/100 to <1/10), colitis including cytomegalovirus colitis (>1/100 to <1/10), pancreatitis (>1/100 to <1/10) and intestinal villous atrophy.

Infections

Serious life-threatening infections including meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leucoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Myfenax. Agranulocytosis (>1/1000 to <1/100) and neutropenia have been reported; therefore regular monitoring of patients taking Myfenax is advised. There have been reports of aplastic anaemia and bone marrow depression in patients treated with Imulate, some of which have been fatal.

Blood and lymphatic system disorder

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Imulate.

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with Imulate. These changes are not associated with impaired neutrophil function. These changes may suggest a 'left shift' in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive Myfenax.

Hypersensitivity

Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction have been reported.

Pregnancy, puerperium and perinatal conditions

Congenital disorders

Respiratory, thoracic and mediastinal disorders

There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with Imulate in combination with other immunosuppressants, some of which have been fatal. There have also been reports of bronchiectasis in children and adults (frequency not known).

Immune system disorders

Hypogammaglobulinaemia has been reported in patients receiving Imulate in combination with other immunosuppressants (frequency not known).

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard, or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

• Embryofetal 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 Imulate 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 Imulate 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 Imulate and MMF arms, respectively. The most common adverse reactions leading to discontinuation in the Imulate 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 Imulate and MMF arms, respectively. The most frequent reasons for dose reduction in the Imulate 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 Imulate 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

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

Lymphoma developed in 2 de novo patients (1%), (1 diagnosed 9 days after treatment initiation) and in 2 conversion patients (1%) receiving Imulate 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 Imulate in combination with cyclosporine and corticosteroids are listed in Table 4.

Table 4: Adverse Reactions Reported in < 10% of Patients Treated with Imulate in Combination with Cyclosporine* and Corticosteroids

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 Imulate 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 postapproval use of Imulate: agranulocytosis, asthenia, osteomyelitis, lymphadenopathy, lymphopenia, wheezing, dry mouth, gastritis, peritonitis, anorexia, alopecia, pulmonary edema, Kaposi's sarcoma.

Reports of overdoses with mycophenolate mofetil have been received from clinical trials and during post-marketing experience. In many of these cases, no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicinal product.

It is expected that an overdose of mycophenolate mofetil could possibly result in oversuppression of the immune system and increase susceptibility to infections and bone marrow suppression. If neutropenia develops, dosing with Imulate should be interrupted or the dose reduced.

Haemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG. Bile acid sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepatic re-circulation of the drug.

Reports of overdoses with Imulate have been received from clinical trials and during post-marketing experience. In many of these cases, no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicinal product.

It is expected that an overdose of Imulate could possibly result in oversuppression of the immune system and increase susceptibility to infections and bone marrow suppression. If neutropenia develops, dosing with Myfenax should be interrupted or the dose reduced.

Haemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG. Bile acid sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepatic re-circulation of the drug.

Signs And Symptoms

There have been anecdotal reports of deliberate or accidental overdoses with Imulate, 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 Imulate 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 Imulate.

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 mycophenolic acid glucuronide (MPAG), it would not be expected to remove clinically significant amounts of the active moiety, mycophenolic acid, due to the 98% plasma protein binding of mycophenolic acid. By interfering with enterohepatic circulation of mycophenolic acid, activated charcoal or bile sequestrates, such as cholestyramine, may reduce the systemic mycophenolic acid exposure.

Pharmacotherapeutic group: immunosuppressive agents ATC code L04AA06

Mechanism of action

Mycophenolate mofetil is the 2-morpholinoethyl ester of MPA. MPA is a potent, selective, uncompetitive and reversible inhibitor of 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 utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.

Pharmacotherapeutic group: immunosuppressive agents ATC code: LO4A A06

Mechanism of action

Imulate is the 2-morpholinoethyl ester of mycophenolic acid (MPA). MPA is a potent, selective, uncompetitive and reversible inhibitor of 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 utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.

Absorption

Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression of acute rejection following renal transplantation, the immunosuppressant activity of Imulate is correlated with MPA concentration. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94% relative to IV mycophenolate mofetil. Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g BID to renal transplant patients. However, MPA C_max was decreased by 40% in the presence of food. Mycophenolate mofetil is not measurable systemically in plasma following oral administration.

Distribution

As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6 - 12 hours post-dose. A reduction in the AUC of MPA of approximately 40% is associated with the co-administration of cholestyramine (4 g TID), indicating that there is a significant amount of enterohepatic recirculation.

MPA at clinically relevant concentrations is 97% bound to plasma albumin.

Biotransformation

MPA is metabolised principally by glucuronyl transferase (isoform UGT1A9) to form the inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted back to free MPA via enterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some of MMF´s side effects (diarrhoea, leucopenia).

Elimination

A negligible amount of substance is excreted as MPA (< 1% of dose) in the urine. Oral administration of radiolabelled 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 faeces. Most (about 87%) of the administered dose is excreted in the urine as MPAG.

At clinically encountered concentrations, MPA and MPAG are not removed by haemodialysis. However, at high MPAG plasma concentrations (> 100µg/mL), small amounts of MPAG are removed. By interfering with enterohepatic circulation of the drug, bile acid sequestrants such as cholestyramine, reduce MPA AUC.

MPA's disposition depends on several transporters. Organic anion-transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are involved in MPA's disposition; OATP isoforms, MRP2 and breast cancer resistance protein (BCRP) are transporters associated with the glucuronides' biliary excretion. Multidrug resistance protein 1 (MDR1) is also able to transport MPA, but its contribution seems to be confined to the absorption process. In the kidney MPA and its metabolites potently interact with renal organic anion transporters.

In the early post-transplant period (< 40 days post-transplant), renal, cardiac and hepatic transplant patients had mean MPA AUCs approximately 30% lower and C_max approximately 40% lower compared to the late post-transplant period (3 - 6 months post-transplant).

Special populations

Renal impairment

In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severe chronic renal impairment (glomerular filtration rate < 25mL/min/1.73 m²) were 28 - 75% higher relative to the means observed in normal healthy subjects or subjects with lesser degrees of renal impairment. The mean single dose MPAG AUC was 3 - 6-fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects, consistent with the known renal elimination of MPAG. Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.

Delayed renal graft function

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

Hepatic impairment

In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.

Paediatric population

Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients (aged 2 to 18 years) given 600 mg/m² mycophenolate mofetil orally twice daily. This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving Imulate at a dose of 1 g bid in the early and late post-transplant period. MPA AUC values across age groups were similar in the early and late post-transplant period.

Elderly

Pharmacokinetic behaviour of Imulate in the elderly (> 65 years) has not been formally evaluated.

Patients taking oral contraceptives

A study of the co-administration of Imulate (1 g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.15 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) conducted in 18 non-transplant women (not taking other immunosupressants) over 3 consecutive menstrual cycles showed no clinically relevant influence of Imulate on the ovulation suppressing action of the oral contraceptives.).

Absorption

Following oral administration, Imulate undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression of acute rejection following renal transplantation, the immunosuppressant activity of Imulate is correlated with MPA concentration. The mean bioavailability of oral Imulate, based on MPA AUC, is 94% relative to intravenous Imulate. Food had no effect on the extent of absorption (MPA AUC) of Imulate when administered at doses of 1.5°g BID to renal transplant patients. However, MPA C_max was decreased by 40% in the presence of food. Imulate is not measurable systemically in plasma following oral administration.

Distribution

As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6-12°hours post-dose. A reduction in the AUC of MPA of approximately 40% is associated with the co-administration of cholestyramine (4°g TID), indicating that there is a significant amount of enterohepatic recirculation.

MPA at clinically relevant concentrations is 97% bound to plasma albumin.

Biotransformation

MPA is metabolised principally by glucuronyl transferase (isoform UGT1A9) to form the inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted back to free MPA via enterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some of MMF´s side effects (diarrhoea, leucopenia).

Elimination

A negligible amount of substance is excreted as MPA (<°1% of dose) in the urine. Oral administration of radiolabelled Imulate results in complete recovery of the administered dose; with 93% of the administered dose recovered in the urine and 6% recovered in the faeces. Most (about 87%) of the administered dose is excreted in the urine as MPAG.

At clinically encountered concentrations, MPA and MPAG are not removed by haemodialysis. However, at high MPAG plasma concentrations (>°100 μg/mL), small amounts of MPAG are removed. By interfering with enterohepatic circulation of the drug, bile acid sequestrants such as cholestyramine, reduce MPA AUC.

MPA's disposition depends on several transporters. Organic anion transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are involved in MPA's disposition; OATP isoforms, MRP2 and breast cancer resistance protein (BCRP) are transporters associated with the glucuronides' biliary excretion. Multidrug resistance protein 1 (MDR1) is also able to transport MPA, but its contribution seems to be confined to the absorption process. In the kidney MPA and its metabolites potently interact with renal organic anion transporters.

In the early post-transplant period (<°40 days post-transplant), renal, cardiac and hepatic transplant patients had mean MPA AUCs approximately 30% lower and C_max approximately 40% lower compared to the late post-transplant period (3 - 6°months post-transplant).

Special populations

Renal impairment

In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severe chronic renal impairment (glomerular filtration rate < 25°mL/min/1.73°m²) were 28-75% higher relative to the means observed in normal healthy subjects or subjects with lesser degrees of renal impairment. However, the mean single dose MPAG AUC was 3-6-fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects, consistent with the known renal elimination of MPAG. Multiple dosing of Imulate in patients with severe chronic renal impairment has not been studied. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.

Delayed renal graft function

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

Hepatic impairment

In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.

Paediatric population

Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients (aged 2 to 18°years) given 600°mg/m² Imulate orally twice daily. This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving Imulate at a dose of 1°g BID in the early and late post-transplant period. MPA AUC values across age groups were similar in the early and late post-transplant period.

Elderly

Pharmacokinetic behaviour of Imulate in the elderly (>°65 years) has not been formally evaluated.

Patients taking oral contraceptives

Imulate exhibits linear and dose-proportional pharmacokinetics over the dose-range (360 to 2160 mg) evaluated. The absolute bioavailability of Imulate in stable renal transplant patients on cyclosporine was 72%. MPA is highly protein bound ( > 98% bound to albumin). The predominant metabolite of MPA is the phenolic glucuronide (MPAG) which is pharmacologically inactive. A minor metabolite AcMPAG which is an acyl glucuronide of MPAG is also formed and has pharmacological activity comparable to MPA. MPAG undergoes renal elimination. A fraction of MPAG also undergoes biliary excretion, followed by deconjugation by gut flora and subsequent reabsorption as MPA. The mean elimination half-lives of MPA and MPAG ranged between 8 and 16 hours, and 13 and 17 hours, respectively.

Absorption

In vitro studies demonstrated that the enteric-coated Imulate tablet does not release MPA under acidic conditions (pH < 5) as in the stomach but is highly soluble in neutral pH conditions as in the intestine. Following Imulate oral administration without food in several pharmacokinetic studies conducted in renal transplant patients, consistent with its enteric-coated formulation, the median delay (Tlag) in the rise of MPA concentration ranged between 0.25 and 1.25 hours and the median time to maximum concentration (Tmax) of MPA ranged between 1.5 and 2.75 hours. In comparison, following the administration of MMF, the median Tmax ranged between 0.5 and 1.0 hours. In stable renal transplant patients on cyclosporine, USP MODIFIED based immunosuppression, gastrointestinal absorption and absolute bioavailability of MPA following the administration of Imulate delayed-release tablet was 93% and 72%, respectively. Imulate pharmacokinetics is dose proportional over the dose range of 360 to 2160 mg.

Distribution

The mean (± SD) volume of distribution at steady state and elimination phase for MPA is 54 (± 25) L and 112 (± 48) L, respectively. MPA is highly protein bound to albumin, > 98%. The protein binding of mycophenolic acid glucuronide (MPAG) is 82%. The free MPA concentration may increase under conditions of decreased protein binding (uremia, hepatic failure, and hypoalbuminemia).

Metabolism

MPA is metabolized principally by glucuronyl transferase to glucuronidated metabolites. The phenolic glucuronide of MPA, mycophenolic acid glucuronide (MPAG), is the predominant metabolite of MPA and does not manifest pharmacological activity. The acyl glucuronide is a minor metabolite and has comparable pharmacological activity to MPA. In stable renal transplant patients on cyclosporine, USP MODIFIED based immunosuppression, approximately 28% of the oral Imulate dose was converted to MPAG by presystemic metabolism. The AUC ratio of MPA:MPAG:acyl glucuronide is approximately 1:24:0.28 at steady state. The mean clearance of MPA was 140 (± 30) mL/min.

Elimination

The majority of MPA dose administered is eliminated in the urine primarily as MPAG ( > 60%) and approximately 3% as unchanged MPA following Imulate administration to stable renal transplant patients. The mean renal clearance of MPAG was 15.5 (± 5.9) mL/min. MPAG is also secreted in the bile and available for deconjugation by gut flora. MPA resulting from the deconjugation may then be reabsorbed and produce a second peak of MPA approximately 6 to 8 hours after Imulate dosing. The mean elimination half-life of MPA and MPAG ranged between 8 and 16 hours, and 13 and 17 hours, respectively.

Food Effect

Compared to the fasting state, administration of Imulate 720 mg with a high-fat meal (55 g fat, 1000 calories) had no effect on the systemic exposure (AUC) of MPA. However, there was a 33% decrease in the maximal concentration (Cmax), a 3.5-hour delay in the Tlag (range, -6 to 18 hours), and 5.0-hour delay in the Tmax (range, -9 to 20 hours) of MPA. To avoid the variability in MPA absorption between doses, Imulate should be taken on an empty stomach.

In experimental models, mycophenolate mofetil was not tumourigenic. The highest dose tested in the animal carcinogenicity studies resulted in approximately 2 - 3 times the systemic exposure (AUC or C_max) observed in renal transplant patients at the recommended clinical dose of 2 g/day and 1.3 - 2 times the systemic exposure (AUC or C_max) observed in cardiac transplant patients at the recommended clinical dose of 3 g/day.

Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolate mofetil to cause chromosomal aberrations. These effects can be related to the pharmacodynamic mode of action, i.e. inhibition of nucleotide synthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrate genotoxic activity.

Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. The systemic exposure at this dose represents 2 - 3 times the clinical exposure at the recommended clinical dose of 2 g/day in renal transplant patients and 1.3 - 2 times the clinical exposure at the recommended clinical dose of 3 g/day in cardiac transplant patients. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg^-/day caused malformations (including anophthalmia, agnathia, and hydrocephaly) in the first generation offspring in the absence of maternal toxicity. The systemic exposure at this dose was approximately 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.

In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at 6 mg/kg/day (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg/kg/day (including cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels is approximately equivalent to or less than 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients.

The haematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred at systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day for renal transplant recipients. Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended dose. Gastrointestinal and renal effects consistent with dehydration were also observed in the monkey at the highest dose (systemic exposure levels equivalent to or greater than clinical exposure). The nonclinical toxicity profile of mycophenolate mofetil appears to be consistent with adverse events observed in human clinical trials which now provide safety data of more relevance to the patient population.

In experimental models, Imulate was not tumourigenic. The highest dose tested in the animal carcinogenicity studies resulted in approximately 2-3 times the systemic exposure (AUC or C_max) observed in renal transplant patients at the recommended clinical dose of 2 g/day and 1.3-2 times the systemic exposure (AUC or C_max) observed in cardiac transplant patients at the recommended clinical dose of 3 g/day.

Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrow micronucleus test) showed a potential of Imulate to cause chromosomal aberrations. These effects can be related to the pharmacodynamic mode of action, i.e. inhibition of nucleotide synthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrate genotoxic activity.

Imulate had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. The systemic exposure at this dose represents 2-3°times the clinical exposure at the recommended clinical dose of 2 g/day in renal transplant patients and 1.3-2°times the clinical exposure at the recommended clinical dose of 3 g/day in cardiac transplant patients. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg/day caused malformations (including anophthalmia, agnathia and hydrocephaly) in the first generation offspring in the absence of maternal toxicity. The systemic exposure at this dose was approximately 0.5°times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3°times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.

In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at 6 mg/kg/day (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg/kg/day (including cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels is approximately equivalent to or less than 0.5°times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3°times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients.

The haematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with Imulate in the rat, mouse, dog and monkey. These effects occurred at systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day for renal transplant recipients. Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended doses. Gastrointestinal and renal effects consistent with dehydration were also observed in the monkey at the highest dose (systemic exposure levels equivalent to or greater than clinical exposure). The nonclinical toxicity profile of Imulate appears to be consistent with adverse events observed in human clinical trials which now provide safety data of more relevance to the patient population.

Not applicable.

It is recommended that Imulate 1 g/5 ml powder for oral suspension be reconstituted by the pharmacist prior to dispensing to the patient. Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution.

Preparation of suspension

1. Tap the closed bottle several times to loosen the powder.

2. Measure 94 mL of purified water in a graduated cylinder.

3. Add approximately half of the total amount of purified water to the bottle and shake the closed bottle well for about 1 minute.

4. Add the remainder of water and shake the closed bottle well for about 1 minute.

5. Remove child-resistant cap and push bottle adapter into neck of bottle.

6. Close bottle with child-resistant cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child-resistant status of the cap.

7. Write the date of expiration of the reconstituted suspension on the bottle label. (The shelf-life of the reconstituted suspension is two months.)

Any unused product or waste material should be disposed of in accordance with local requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.