Mycophenolate Mofetil - Uses, Dosage, Side Effects, and Drug Warnings

Overview:

Mycophenolate mofetil is an immunosuppressant drug that decreases the strength of the body’s immune system. It is used to prevent rejection of the transplanted organ and treat autoimmune diseases. Mycophenolate mofetil was initially used to manage patients with organ transplants and is now known for treating many autoimmune diseases. It is also used to manage patients suffering from rheumatoid arthritis (RA) and lupus, particularly with symptoms of kidney disease, inflammatory bowel diseases such as Crohn's disease, kidney and skin disorders, and inflammatory eye disease (such as uveitis and scleritis).

Mycophenolate is used in combination with other drugs, such as steroids and Cyclosporine, in patients with organ transplants (kidney, heart, or liver) to decrease the body's natural immunity. The body's white blood cells try to reject the transplanted organ in patients with an organ transplant. Mycophenolate hence prevents the white blood cells from attacking the transplantation organ. This drug is available in various dosage forms like capsules, tablets, and powders for suspension.

How Does Mycophenolate Mofetil Work?

Mycophenolate mofetil, an inhibitor of inosine-5'-monophosphate dehydrogenase, is a prodrug of mycophenolic acid (MPA). MPA depletes guanosine nucleotides, especially in T and B lymphocytes, and inhibits their proliferation, hence suppressing cell-mediated immune responses and antibody formation. It also inhibits glycosylation, the appearance of adhesion molecules, and the enrollment of lymphocytes and monocytes into areas of inflammation.

MPA depletes tetrahydrobiopterin and reduces nitric oxide (NO) production by inducible NO synthase without influencing the action of constitutive NO synthases. Activated macrophages produce NO and superoxide that combine to yield tissue-damaging peroxynitrite. With the help of these two mechanisms, MMF exerts anti-inflammatory action. Dissimilar to calcineurin inhibitors, MMF is a non-neurotoxic drug and does not cause the production of TGF-beta, which is fibrogenic. MMF does not stimulate recipients' cholesterol or triglyceride levels and blood pressure. MMF decreases acute and chronic rejection in allograft recipients and is effective in some nephropathies.

Uses

1. Organ Transplant - With the evolution of new immunosuppressive agents, the focus of anti-rejection treatment has changed from preventing acute allograft rejection to emphasizing sufficient immunosuppression with minimal toxicity. Mycophenolate mofetil (MMF) is a newly formulated immunosuppressive drug that works to inhibit T and B cell proliferation by obstructing the production of guanosine nucleotides needed for DNA synthesis.

2. Off-label Uses - MMF is also used in the treatment of atopic dermatitis, psoriasis, bullous dermatoses including bullous, linear IgA, pemphigoid, pemphigus, and epidermolysis bullosa, autoimmune connective tissue diseases enclosing systemic and subacute cutaneous lupus erythematosus, systemic sclerosis, and dermatomyositis, and vasculitis.

Dosages:

Mycophenolate mofetil is available as 500 mg tablets, 250 mg capsules, and a powder for 200 mg/mol oral suspension. It is also available as a powder in a vial, equal to 500 mg of Mycophenolate mofetil as the hydrochloride salt for intravenous administration. The normal dosage for adults can range between 1.25 to 2 grams per day. The dose can be tapered to 1 g daily in divided doses with improvement in conditions. Pediatric patients' dosage should range between 600 mg per square meter every 12 hours to a maximum daily dose of two grams. Dose reduction should be evaluated in patients with severe renal impairment. Enteric-coated tablets are used as an alternative in patients with adverse MMF-induced gastrointestinal effects.

Indications:

The only FDA (food and drug administration) approved indication of MMF is for the prevention of organ transplant rejection in combination with Cyclosporine and Corticosteroids. This drug was initially used in psoriasis in 1975, and since then, clinical trials have reported its use in different dermatological situations as off-label indications. Mycophenolate mofetil is used either as a single drug or in combination with systemic steroids, or as a steroid-sparing agent. MMF works best in patients in whom other systemic immunotherapies are contraindicated due to hypertension, impaired renal function, or liver disease. Even though early reports have shown good effectiveness and tolerability towards MMF, randomized clinical trials with long supervision duration are required to document the effectiveness and long-term safety of the drug in different skin diseases.

Warning:

1) Serious Infection Risk - Mycophenolate being an immunosuppressive drug, weakens the body's immune system and the ability to fight against infections. It increases the risk of getting serious infections, such as severe bacterial, fungal, or viral infections that spread through the body. Prior information should be given to the physician if the patient has or ever had acquired immunodeficiency syndrome (AIDS), hepatitis B, hepatitis C virus infection, or herpes zoster infection.

2) Risk of Birth Defects - Mycophenolate mofetil should not be taken by pregnant women or who are trying to conceive. There is a high risk of miscarriage or loss of the pregnancy with the intake of Mycophenolate during the first three months of pregnancy or its consumption during pregnancy results in a birth defect. So, it is necessary to be tested negative for pregnancy before starting the treatment with Mycophenolate. Acceptable birth control pills should be taken during and after stopping Mycophenolate for six weeks. For a male with a female partner who may become pregnant, the use of permissible birth control should be taken during treatment and for at least three months after the last dose.

3) Cancer - Mycophenolate increases the risk of developing progressive multifocal leukoencephalopathy, a rare brain infection. It cannot be treated, prevented, or cured, and it generally results in death or severe disability. Mycophenolate can increase the risk of developing several types of cancer, such as lymphoma and skin cancer. Avoid long exposure to sunlight, sunlamps, tanning beds, and light therapy, and wear protective clothing, sunglasses, and sunscreen.

For Patients:

Learn About Organ Transplant Rejection:

Organ transplant rejection occurs when the recipient's immune system attacks the newly transplanted organ or tissue. The immune system protects against harmful organisms, such as germs and substances like poison, and also against cancer cells. Organs that are not matched closely or mismatched organs can trigger transplant rejection. To help prevent this reaction, the matching of both the donor and the person who is receiving the organ is a must. Drugs are used to suppress the recipient's immune system when the organ is not closely matched. If these medicines are not used, then the immune system will destroy the transplanted organ.

There are three types of rejection-

• Hyperacute Rejection - A transplant rejection that occurs a few minutes after the organ transplant is hyperacute rejection. This occurs when the antigens are completely unmatched.

• Acute Rejection - It can occur any time from the first week to three months after the transplant. All recipients go through this type of acute rejection.

• Chronic Rejection - It can occur many years after a transplant. The constant immune response of the body against the new organ slowly damages the transplanted organs.

Learn More About Mycophenolate Mofetil

Before Starting Mycophenolate Mofetil:

Why and When to Start Mycophenolate Mofetil?

Mycophenolate is a class of drugs that belongs to immunosuppressive agents. These drugs weaken the immune system of the body to prevent its attack and reject the transplanted organ. Mycophenolate mofetil is combined with other drugs to prevent organ transplant rejection. It is prescribed by the doctor in adults and children three months of age and older who are at risk of an attack on the transplanted organ by their immune system receiving the organ heart, kidney, or liver transplants. Mycophenolate is combined with other drugs to prevent the body from the immune system from rejecting kidney transplants in adults and children five years of age and older.

Things to Tell Physicians Before They Prescribe Mycophenolate Mofetil:

Inform the physician if an allergy is present to Mycophenolate, Mycophenolic acid, or any other medications or ingredients in the Mycophenolate or Mycophenolic acid before taking it. Inform the physician prior if allergic to aspartame or sorbitol as the liquid form of Mycophenolate contains Aspartame and Sorbitol. Also, it is mandatory to inform the doctor about all the ongoing prescription and nonprescription medications, nutritional supplements, vitamins, and herbal products. Be sure to inform the doctor before stopping any medications. They may need to change the doses of the medications or monitor for side effects. Follow the instructions provided by the physician before taking antacids containing magnesium or aluminum. Inform the doctor if there is a presence of inherited diseases such as Lesch-Nyhan syndrome. Ulcers or any disease that affects the stomach, intestines, digestive system, kidney, or liver disease should be treated on priority. Do not drive a car or use machinery, as this drug causes drowsiness, confusion, dizziness, lightheadedness, or uncontrollable shaking of a part of the body.

Starting Mycophenolate Mofetil:

How to Take Mycophenolate Mofetil?

Mycophenolate is available in capsules, a tablet, delayed-release tablets, and a suspension (liquid) form to be taken via the oral route. It is usually prescribed twice a day and to be taken on an empty stomach an hour or two before eating or drinking). The Mycophenolate tablet should be taken at about the same time every day and should be taken with a 12 hours gap in between. Follow the directions written on the prescription label carefully, and ask the pharmacist to explain any part that one does not understand. Take Mycophenolate strictly as directed. Stick to the dose and avoid consuming lesser or more amounts than prescribed.

Swallow the capsule, tablets, or delayed-release tablets completely. Avoid chewing, spitting, or crushing the tablet. If a tablet is accidentally opened, avoid its contact with the skin and eyes and avoid breathing in the powder. If contact happens, wash the affected area with soap and water; rinse the eyes with water. Avoid mixing Mycophenolate suspension with any other drugs. In case of suspension, be careful not to spill it or splash it onto the skin. If the suspension comes in contact with the skin, wash the area with soap and water. If the suspension comes in contact with the eyes, rinse with plain water or use wet paper towels to wipe up the spilled liquids. Mycophenolate helps prevent organ transplant rejection only if taken. Therefore continue to take Mycophenolate even if one feels well. Be sure to consult the doctor before taking Mycophenolate.

Look Out for the Side Effects:

• Nausea.

• Vomiting.

• Constipation.

• Pain in the back, muscles, or joints.

• Gas.

• Swelling of the extremities.

• Difficulty in falling asleep.

• Headache.

• Tingling or burning sensations on the skin.

• Diarrhea.

• Pain in the chest.

• A rash.

• Itching.

• Tremors.

• Sudden and severe stomach ache.

• Difficulty breathing.

• Unusual bleeding, vomiting, spitting up blood, or bruising.

• Tarry stools.

• Fever, joint stiffness, or pain.

• Fainting, lack of energy, pale skin, shortness of breath, or fast heartbeat.

For Doctors

Pharmacology and Mechanism of Action:

Mycophenolate mofetil is a prodrug, and it depletes guanosine nucleotides targeting the T and B lymphocytes and inhibits their expansion, resulting in suppressing cell-mediated immune responses and antibody formation. MPA also inhibits the expression of adhesion molecules and glycosylation and the recruitment of lymphocytes and monocytes into areas of inflammation. It also depletes tetrahydrobiopterin and reduces nitric oxide production without influencing the activity of constitutive NO synthases. These two mechanisms of MMF exert anti-inflammatory activity. MMF is not nephrotoxic as it does not produce TGFbeta (tissue growth factor), which is fibrogenic, unlike calcineurin inhibitors. However, it reduces acute and chronic rejection and is effective in some nephropathies.

Pharmacodynamics:

Mycophenolic acid is the active ingredient of the drug. Nowadays, two Mycophenolate compounds are available, Mycophenolate mofetil and enteric-coated (EC) Mycophenolate sodium. MPA is a powerful and reversible inhibitor of (IMPDH) inosine monophosphate dehydrogenase that causes the eventual arrest of T- and B-lymphocyte proliferation. Mycophenolate mofetil and EC-Mycophenolate sodium are completely hydrolyzed to MPA by esterases in the gut wall, liver, blood, and tissues. The overall bioavailability of MPA, subsequent to Mycophenolate mofetil administration, ranges from 80.7 to 94 %, whereas EC-Mycophenolate sodium has an absolute bioavailability of MPA of 72 %. MPA binds to serum albumin 97 to 99 % in patients with normal liver and renal function. It is metabolized in the gastrointestinal tract, liver, and kidney by uridine diphosphate glucuronosyltransferases (UGTs). 7-O-MPA-glucuronide (MPAG) is the main metabolite of MPA. MPAG is normally present in the plasma at 20 to 100 times higher concentrations than MPA, but it is not pharmacologically active. Three minor metabolites are also formed, of which an acyl-glucuronide has pharmacological potency comparable to MPA. MPAG is eliminated into the urine via active tubular secretion and bile by multidrug resistance protein 2 (MRP-2). It is de-conjugated back to MPA by gut bacteria and then reabsorbed in the colon. Mycophenolate mofetil and EC-Mycophenolate sodium both exhibit linear pharmacokinetics.

Absorption:

Mycophenolate mofetil is absorbed in the small intestine and attains its maximum concentration in 60 to 90 minutes after an oral dose. The average bioavailability of orally administered Mycophenolate mofetil is 94 %.

Metabolism:

Mycophenolate mofetil is metabolized in the liver by carboxylesterases 1 and 2 to mycophenolic acid (MPA), the active drug, after both intravenous and oral administration. MPA is then metabolized by the enzyme glucuronyl transferase, creating the inactive phenolic glucuronide of MPA. The glucuronide metabolite is crucial, as it is then converted to MPA by enterohepatic recirculation. Mycophenolate mofetil, which exits metabolism in the intestine, comes into the liver via the portal vein and is converted to pharmacologically active MPA in the liver cells.

Elimination:

MPA is excreted in small amounts in the urine (less than 1 %). Mycophenolate Mofetil, when administered orally in a pharmacokinetic study, it was established that 93 % is excreted in urine and 6 % is excreted in feces. About 87 % is MPAG of the total administered dose excreted in the urine as an inactive metabolite. The average half-life of Mycophenolate Mofetil is 17.9 hours post-oral administration. Its half-life after intravenous administration is 16.6 hours.

Contraindications:

• Mycophenolate mofetil is contraindicated in patients allergic to it. Hypersensitivity or allergy to any of its components.

• Patients suffering from shingles, cytomegalovirus infection, and opportunistic fungal infection.

• Cancer.

• Liver problems.

• Pregnancy.

• Breastfeeding mothers.

• Progressive multifocal leukoencephalopathy.

• Skin cancer.

• Malignant lymphoma.

Drug Interactions:

• Mycophenolate mofetil should not be taken with antacids containing aluminum or magnesium, or calcium-free phosphate binders.

• Mycophenolate is found to decrease the excretion rate of Abacavir, which results in an increased serum level of the drug.

• Acetaminophen can decrease the excretion rate of Mycophenolate, resulting in its higher serum level.