mycophenolic acid

Action and Spectrum

Actions and Spectrum: 

Actions: 

Mycophenolic acid, available as Myfortic, is a medication designed to influence the immune system, aiming to forestall rejection following a kidney transplant. The tablets are formulated with a unique coating, which may alleviate gastrointestinal side effects like upset stomach and diarrhea.  

Spectrum: 

Mycophenolic acid demonstrates a range of effects predominantly focused on immunosuppression. Its efficacy lies in preventing the rejection of transplanted organs, particularly kidneys, through the suppression of the immune response. This immunosuppressive function is linked to its inhibition of inosine monophosphate dehydrogenase (IMPDH), a crucial enzyme in DNA synthesis.

While its primary purpose is to prevent organ rejection, mycophenolic acid might also have potential applications in treating specific autoimmune disorders, expanding its range of activity beyond the realm of transplantation medicine. 

Drug Interaction

Adverse Reaction

Frequency not defined 

Headache 

Dizziness  

Anxiety 

Nausea  

Vomiting  

Stomach upset  

Gas  

Constipation  

Diarrhea  

Trouble sleeping (insomnia)  

Weight gain  

Joint or muscle pain  

Back pain  

Swelling in your hands or feet 

Black Box Warning

Black Box Warning: 

EMBRYOFETAL TOXICITY, MALIGNANCIES, AND SERIOUS INFECTIONS 

The use of this medication during pregnancy is linked to heightened risks of pregnancy loss and congenital malformations. Women of reproductive age must receive counseling regarding pregnancy prevention and planning. 

There is an elevated risk of developing lymphoma and other malignancies, particularly those affecting the skin, due to the drug’s immunosuppressive effects. Additionally, there is an increased vulnerability to bacterial, viral, fungal, and protozoal infections, including opportunistic infections. 

Prescribing Myfortic should be limited to senior physicians in the management of organ transplant patients and in immunosuppressive therapy. Patients using Myfortic should be under the care of facilities equipped with adequate laboratory and supportive medical resources. The physician overseeing maintenance therapy should possess comprehensive information necessary for the ongoing care of the patient. 

Contraindication / Caution

Contraindication/Caution: 

Contraindications 

• Hypersensitivity 

Cautions 

• Embryo-fetal toxicity 
• Immunosuppression management 
• Hepatic or renal impairment 
• Lymphomas and other malignancies 
• Drug interactions 
• Reactivated or new viral infections 
• Pregnancy  
• Breastfeeding 
• Blood dyscriasis 
• Pure red cell aplasia 
• GI isssues 
• Associated acute inflammatory syndrome 

Pregnancy / Lactation

Pregnancy consideration:  

No data is available regarding the administration of the drug during pregnancy. 

Breastfeeding warnings:  

No data is available regarding the excretion of drug in breast milk. 

Pregnancy category: D 

Category A: well-controlled and satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: No data is available for the drug under this category. 

Pharmacology

Pharmacology: 

Suppresses the proliferation of T- and B-cells, along with inhibiting antibody production. 

Functions as a non-competitive, reversible,  and selective inhibitor of inosine monophosphate dehydrogenase (IMPDH). 

Pharmacodynamics: 

By inhibiting inosine monophosphate dehydrogenase (IMPDH) in an uncompetitive and reversible manner, MPA prevents guanosine nucleotide synthesis from occurring de novo through incorporation into DNA.

Due to the fact that T- and B-lymphocytes rely significantly on de novo purine synthesis for their proliferation, while other cell types can resort to salvage pathways, MPA exerts potent cytostatic effects specifically on lymphocytes. 

In rat models of kidney and heart allotransplantation, Mycophenolate sodium has demonstrated efficacy in preventing acute rejection. Additionally, it has been observed to reduce antibody production in mice.

Pharmacokinetics: 

Absorption 

In laboratory experiments, it was observed that the enteric-coated Myfortic® (mycophenolic acid) tablet does not release MPA under acidic conditions (pH <5) in the stomach but exhibits high solubility in neutral pH conditions found in the intestine.

In various pharmacokinetic studies involving oral administration of Myfortic without food in renal transplant patients, the enteric-coated formulation consistently showed a median delay (Tlag) in the rise of MPA concentration ranging between 0.25 and 1.25 hours. The time to maximum concentration (Tmax) median of MPA ranged between 1.5 and 2.75 hours. For comparison, when mycophenolate mofetil was administered, the Tmax median ranged between 0.5 and 1.0 hours. 

In stable renal transplant patients receiving immunosuppression based on cyclosporine, USP (MODIFIED), the absolute bioavailability and gastrointestinal absorption of MPA following the administration of the Myfortic delayed-release tablet were determined to be 93% and 72%, respectively. Notably, Myfortic pharmacokinetics displayed dose proportionality within the dose range of 360 to 2160 mg.  

Distribution 

The average (± standard deviation) volume of distribution at steady state and during the elimination phase for MPA is 54 (± 25) L and 112 (± 48) L, respectively. MPA exhibits high protein binding, with over 98% binding to albumin. The mycophenolic acid glucuronide (MPAG) protein binding is 82%. Conditions such as hepatic failure, uremia, and hypoalbuminemia may lead to a potential increase in free MPA concentration due to decreased protein binding.  

Metabolism 

MPA undergoes primarily glucuronidation by glucuronyl transferase, resulting in the formation of glucuronidated metabolites. The primary metabolite, mycophenolic acid glucuronide (MPAG), is the predominant product and lacks pharmacological activity. The acyl glucuronide, a minor metabolite, exhibits comparable pharmacological activity to MPA. 

In stable renal transplant patients undergoing immunosuppression with cyclosporine, USP (MODIFIED), approximately 28% of the oral Myfortic dose is metabolized into MPAG through pre-systemic metabolism. The steady-state AUC ratio of MPA:MPAG: acyl glucuronide is approximately 1:24:0.28. The mean clearance of MPA is 140 (± 30) mL/min.  

Elimination and Excretion 

The predominant route of elimination for the administered MPA dose is through urine, primarily as mycophenolic acid glucuronide (MPAG) (>60%) and roughly 3% as unchanged MPA in stable renal transplant patients receiving Myfortic. The mean renal clearance of MPAG is 15.5 (± 5.9) mL/min.

MPAG is also excreted in the bile, where it can undergo deconjugation by gut flora. The resulting MPA can then be reabsorbed, leading to a second peak of MPA approximately 6 – 8 hours after administration of Myfortic. The mean elimination half-life of MPAG and MPA falls between the ranges of  13 to 17 hours and 8 to 16 hours, respectively. 

Adminstartion

Administration: 

Giving mycophenolic acid (Myfortic) on an empty stomach an hour before or two hours after meals is recommended. To preserve the enteric coating of the tablet, patients should be explicitly instructed not to crush, chew, or cut Myfortic tablets and should swallow them whole. 

Patients should receive comprehensive dosage instructions, along with information about the heightened risk of lymphoproliferative disease and certain other malignancies. Emphasize the necessity for regular laboratory tests during Myfortic treatment. 

Women of childbearing potential should be informed that the use of Myfortic during pregnancy is linked to an increased risk of first-trimester pregnancy loss and congenital disabilities. They must employ effective contraception. Discussion of pregnancy plans is crucial for female patients of childbearing potential. 

For female patients planning to start Myfortic therapy, highly effective contraception (two methods) should be initiated four weeks prior to treatment commencement and continued until six weeks after stopping Myfortic unless abstinence is chosen as the method. 

Patients contemplating pregnancy should not use Myfortic unless other immunosuppressant drugs are not viable. The risks and benefits of Myfortic and alternative immunosuppressants should be thoroughly discussed with the patient. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: mycophenolic acid 

Pronounced: my-ko-feh-NOL-ik acid 

Why do we use mycophenolic acid? 

Mycophenolic acid is commonly prescribed as an immunosuppressant medication, frequently utilized to thwart the rejection of transplanted organs, notably in procedures like kidney, heart, and liver transplants. 

It works by preventing the activity of an enzyme known as inosine monophosphate dehydrogenase (IMPDH), a key player in cellular DNA production. Through this inhibition of DNA synthesis, mycophenolic acid effectively manages the immune response, preventing the immune system from launching attacks on and rejecting the transplanted organ. 

While mycophenolic acid finds application in treating specific autoimmune disorders like lupus nephritis, characterized by the immune system targeting the kidneys, its predominant and more widespread usage remains in the prevention of organ rejection following transplantation.