Mycophenolic acid (Tablets) Instructions for Use

ATC Code

L04AA06 (Mycophenolic acid)

Active Substance

Mycophenolic acid (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressants, selective immunosuppressants

Pharmacological Action

Immunosuppressive agent. The mechanism of action is associated with the inhibition of guanosine nucleotide synthesis through selective suppression of inosine monophosphate dehydrogenase.

As a result, the proliferation of T- and B-lymphocytes is suppressed, and to a much greater extent than that of other cells, since lymphocyte proliferation depends mainly on de novo synthesis.

Pharmacokinetics

After oral administration, mycophenolate sodium is intensively absorbed.

In patients with a stably functioning renal transplant receiving basic immunosuppressive therapy with cyclosporine in microemulsion form, the extent of MPA absorption from the gastrointestinal tract is 93%, and bioavailability is 72%.

In the dose range from 180 to 2160 mg, the pharmacokinetics of mycophenolic acid is linear and dose-dependent.

The AUC when taking mycophenolic acid on an empty stomach did not differ from that when taken with a high-fat meal (55 g of fat, 1000 calories). However, the C_max of MPA decreases by 33%.

MPA is predominantly metabolized with the participation of glucuronyltransferase to form the main pharmacologically inactive metabolite, mycophenolic acid phenolic glucuronide (MPAG).

In patients with a stably functioning renal transplant receiving basic immunosuppressive therapy with cyclosporine, about 28% of the oral dose of mycophenolic acid is metabolized to MPAG during first-pass metabolism through the liver.

The V_d of MPA at steady state is 50 L. Both MPA and MPAG are highly bound to plasma proteins – 97% and 82%, respectively.

With a decrease in protein binding sites (in uremia, hepatic insufficiency, simultaneous use of drugs with high plasma protein binding, hypoalbuminemia), an increase in the concentration of free MPA in plasma is possible.

The T_1/2 of MPA is 11.7 h, clearance is 8.6 L/h. MPA is excreted mainly in the urine as MPAG, and very small amounts (<1.0%) are excreted unchanged.

The T_1/2 of MPAG is 15.7 h, clearance is 0.45 L/h. MPAG is also secreted with bile into the intestine, where it is broken down (by deconjugation) by the intestinal flora.

The MPA resulting from this breakdown can then be reabsorbed. A second peak in MPA concentration is observed 6-8 hours after taking mycophenolic acid, which corresponds to the reabsorption of deconjugated MPA.

Indications

Prevention of transplant rejection in patients with allogeneic kidney transplants receiving basic immunosuppressive therapy with cyclosporine and corticosteroids.

ICD codes

Dosage Regimen

Administer orally.

The recommended dose for adult patients is 720 mg taken twice daily.

Take the total daily dose of 1440 mg.

Swallow tablets whole; do not crush, split, or chew.

Take on an empty stomach, at least 1 hour before or 2 hours after a meal.

Maintain a consistent dosing schedule approximately every 12 hours.

Do not adjust the dosage or discontinue therapy without consulting your physician.

In case of a missed dose, take it as soon as you remember unless it is nearly time for the next dose.

Do not take a double dose to make up for a missed one.

Adhere strictly to the prescribed regimen to maintain stable drug levels and ensure therapeutic efficacy.

Concurrent administration with antacids containing magnesium and aluminum hydroxide is not recommended due to significantly reduced absorption.

If co-administration is unavoidable, separate the timing of mycophenolic acid and antacid intake by several hours.

Dosage adjustments may be necessary based on clinical response, tolerability, and laboratory parameters, including complete blood counts.

Close therapeutic drug monitoring is essential, particularly during the initial post-transplant period.

Adverse Reactions

Infections: very common – viral, bacterial and fungal infections: urinary tract infections, Herpes zoster, oral candidiasis, sinusitis, gastroenteritis, Herpes simplex, nasopharyngitis; common – upper respiratory tract infections, pneumonia; uncommon – wound infections, sepsis, osteomyelitis.

Blood and lymphatic system disorders: very common – leukopenia; common – anemia, thrombocytopenia; uncommon – lymphocele, lymphopenia, neutropenia, lymphadenopathy.

Psychiatric disorders: common – irritability; uncommon – delusional perception.

Nervous system disorders: common – dizziness, headache; uncommon – tremor, insomnia.

Respiratory, thoracic and mediastinal disorders: common – cough, dyspnea, exertional dyspnea; uncommon – interstitial lung disease, including pulmonary fibrosis with fatal outcome, “congested” lung, stridor.

Gastrointestinal disorders: very common – diarrhea; common – abdominal distension, abdominal pain, constipation, dyspepsia, flatulence, gastritis, loose stools, nausea, vomiting; uncommon – abdominal wall tension, pancreatitis, belching, halitosis, intestinal obstruction, esophagitis, peptic ulcer, subileus, gastrointestinal bleeding, dry mouth, lip ulceration, parotid salivary gland duct obstruction, gastroesophageal reflux disease, gingival hyperplasia, peritonitis.

Metabolism and nutrition disorders: very common – hypocalcemia, hypokalemia, hyperuricemia; common – hyperkalemia, hypomagnesemia; uncommon – anorexia, hyperlipidemia, diabetes mellitus, hypercholesterolemia, hypophosphatemia.

Skin and subcutaneous tissue disorders: uncommon – alopecia, acne.

Hepatobiliary disorders: common – abnormal liver function tests.

Cardiac disorders: very common – increased blood pressure, decreased blood pressure; common – increased severity of arterial hypertension; uncommon – tachycardia, pulmonary edema.

Eye disorders: uncommon – conjunctivitis, “blurred” vision.

Musculoskeletal and connective tissue disorders: common – arthralgia, asthenia, myalgia; uncommon – back pain, muscle cramps.

Benign, malignant and unspecified neoplasms: uncommon – skin papilloma, basal cell carcinoma, Kaposi’s sarcoma, lymphoproliferative disorders, squamous cell carcinoma.

Renal and urinary disorders: common – increased blood creatinine; uncommon – hematuria, renal tubular necrosis, urethral stricture.

General disorders and administration site conditions: common – fatigue, peripheral edema, pyrexia; uncommon – influenza-like illness, lower limb edema, thirst, weakness, contusion.

Contraindications

Hypersensitivity to mycophenolic acid, mycophenolate sodium, mycophenolate mofetil; pediatric age; pregnancy, breastfeeding period.

With caution congenital deficiency of hypoxanthine-guanine phosphoribosyltransferase (including in Lesch-Nyhan and Kelley-Seegmiller syndromes). Gastrointestinal diseases in the acute phase.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

When mycophenolic acid was used during pregnancy, an increased risk of pregnancy loss, including spontaneous abortions, as well as the development of congenital anomalies was observed.

It is not recommended to start therapy until a negative pregnancy test result is obtained. If pregnancy occurs, the patient should immediately consult a doctor.

It is not known whether Mycophenolic acid is excreted in breast milk. Since there is a potential risk of serious adverse reactions in the breastfed infant, a decision should be made either to discontinue mycophenolic acid or, considering the importance of therapy for the mother, to discontinue breastfeeding throughout therapy and for 6 weeks after its discontinuation.

Use in Hepatic Impairment

In patients with severe liver disease associated with predominant parenchymal damage, no dose adjustment is required.

Use in Renal Impairment

In patients with delayed recovery of renal transplant function, no change in the dose of mycophenolic acid is required. Close monitoring of patients with chronic severe renal impairment is necessary.

Pediatric Use

Contraindicated in children. The efficacy and safety of mycophenolic acid in children have not been studied.

Geriatric Use

Should be used with caution in elderly patients. In this category of patients, the risk of adverse reactions is generally higher due to immunosuppression.

Special Precautions

Treatment should be carried out by qualified physicians with experience in managing patients in a transplant department.

Patients receiving combined immunosuppressive therapy, including mycophenolic acid preparations, have an increased risk of developing lymphomas and other malignancies, especially skin cancer.

There is evidence of a genotoxic effect of mycophenolic acid. This risk is most likely not associated with the use of the drug, but with the intensity and duration of immunosuppressive therapy. To reduce exposure to sunlight and ultraviolet radiation in order to reduce the risk of skin cancer, it is recommended to protect the skin with clothing and use sunscreens with a high protection factor.

Patients receiving mycophenolic acid therapy should be instructed to immediately report to the doctor all cases of infection, unexpected bruising, bleeding, and any other manifestations of bone marrow suppression.

Excessive immunosuppression increases the likelihood of developing infections, including opportunistic ones, as well as sepsis and fatal infections.

In patients receiving mycophenolic acid therapy, the development of neutropenia cannot be ruled out, due to the effect of mycophenolic acid itself, concomitant drugs, viral infections, or a combination of these factors.

In patients receiving this drug, a complete blood count should be performed regularly (to detect neutropenia or anemia): during the first month of therapy – weekly, during the second and third months – 2 times/month, then, during the first year – 1 time/month. If neutropenia or anemia develops, it is advisable to interrupt or discontinue mycophenolic acid therapy.

Cases of partial red cell aplasia of the bone marrow have been reported with the use of mycophenolic acid derivatives (mycophenolate mofetil and mycophenolate sodium) in combination with other immunosuppressants.

The mechanism of development of partial red cell aplasia of the bone marrow during therapy with mycophenolic acid derivatives, as well as the role of other immunosuppressants and their combinations, is currently unknown.

However, it should be taken into account that mycophenolic acid derivatives can cause neutropenia and anemia. In a number of cases, when the dose was reduced or therapy with mycophenolic acid derivatives was discontinued, the patients’ condition normalized.

Changing the dosage regimen of this drug should be carried out only under proper monitoring of the patient’s condition to reduce the risk of transplant rejection.

Patients should be warned that during therapy with mycophenolic acid derivatives, vaccination may be less effective and that the use of live attenuated vaccines should be avoided.

Influenza vaccination should be carried out in accordance with the recommendations of local health authorities regarding influenza vaccination.

Since taking mycophenolic acid may be accompanied by gastrointestinal adverse reactions (ulceration of the gastrointestinal mucosa, gastrointestinal bleeding, gastrointestinal perforations), caution should be exercised when using it in patients with active digestive tract diseases.

Mycophenolic acid has been used in combination with the following drugs: antithymocyte globulin, basiliximab, cyclosporine (in microemulsion form) and glucocorticoids. The efficacy and safety of mycophenolic acid when used with other immunosuppressive drugs have not been studied.

Effect on ability to drive vehicles and operate machinery

During the treatment period, patients should exercise caution when driving vehicles and engaging in other activities that require high concentration and speed of psychomotor reactions.

Drug Interactions

Mycophenolic acid and azathioprine should not be administered simultaneously.

Live vaccines should not be used in patients with impaired immune response. When using other vaccines, antibody production may be reduced.

With simultaneous use of MPAG and acyclovir in patients with impaired renal function, the concentrations of both MPAG and acyclovir in the blood may increase. They may compete during excretion from the body (similar excretion pathway – tubular secretion). Such patients require careful monitoring.

When co-administered with antacid drugs, the absorption of mycophenolate sodium is reduced, resulting in a 37% decrease in MPA AUC and a 25% decrease in C_max. Caution should be exercised when co-administering mycophenolic acid with antacid preparations containing magnesium and aluminum hydroxide.

Due to its ability to bind bile acids in the intestine, cholestyramine may reduce the blood concentration and AUC of MPA. Due to the possible decrease in the effectiveness of mycophenolic acid, caution should be exercised when co-administering it with cholestyramine and drugs that affect enterohepatic circulation.

Concomitant use of ganciclovir does not affect the pharmacokinetics of MPA and MPAG. When therapeutic concentration of MPA is reached, the clearance of ganciclovir does not change. However, when mycophenolic acid and ganciclovir are co-administered to patients with impaired renal function, adjustment of the ganciclovir dosage regimen may be required; such patients should be closely monitored.

In patients with a stable kidney transplant, a crossover study examined the steady-state pharmacokinetics of mycophenolic acid when used concomitantly with cyclosporine and tacrolimus.

The mean MPA AUC values when mycophenolic acid was taken concomitantly with tacrolimus were 19% higher than when mycophenolic acid was taken concomitantly with cyclosporine, and the MPA C_max values were 20% lower. For MPAG, AUC and C_max values were 30% lower when mycophenolic acid was taken with tacrolimus than when mycophenolic acid was taken with cyclosporine.

Studies in patients with a stable renal transplant have shown that against the background of steady-state concentrations of mycophenolic acid, the pharmacokinetics of cyclosporine did not change.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.