Profile of side effects associated with the immunosuppressive agents is often difficult to establish because of the underlying disease and simultaneous use of many other drugs.
The main side reactions associated with the use of MMF in combination with cyclosporine and glucocorticosteroids to prevent rejection of the renal, cardiac or hepatic graft are diarrhea, leukopenia, sepsis and vomiting; there are also data on the increase in the incidence of certain types of infections, for example, opportunistic infections (see section "Special instructions").
As against the combined immunosuppression in general, and with the use of MMF as a component of the immunosuppressive regimen, there is an increased risk of developing lymphomas and other malignant tumors, especially the skin (see section "Side effect"). In controlled clinical trials in patients who underwent kidney transplantation,heart or liver and observed for at least 1 year, lymphoproliferative diseases or lymphomas developed in 0.4-1% of patients receiving MMF (in doses of 2 or 3 g / day) in combination with other immunosuppressants. Skin cancer (excluding melanoma) was noted in 1.6-3.2% of patients, malignant neoplasms of other types - in 0.7-2.1% of patients. Three-year data on safety in patients after kidney or heart transplant did not reveal any unexpected changes in the incidence rate of malignant tumors, compared with annual indicators. After liver transplant patients were observed for at least 1 year, but less than 3 years.
The risk of opportunistic infections is increased in all posttransplant patients and increases with an increase in the degree of immunosuppression (see section "Special instructions"). In controlled clinical trials using MMF (2 or 3 g / day) in combination with other immunosuppressants in patients who were observed for 1 year after kidney transplantation (at a dose of 2 g per day), heart and liver, the most frequent infections were candidiasis of the skin and mucous membranes, cytomegalovirus (CMV) infection: CMV viremia / CMV syndrome (13.5%) and infection caused by the herpes simplex virus.After kidney transplantation, sepsis (usually associated with CMV) was more likely to occur in patients receiving MMF than in the control group. In patients receiving MMF at a dose of 3 g, the incidence of sepsis was higher than in patients receiving MMF at a dose of 2 g.
The type of adverse reactions and the frequency of their occurrence in a clinical trial with oral administration of 600 mg / m2 MMF 2 times a day in children aged 3 months to 18 years (N = 100) did not differ from those in adult patients who received the drug at a dose of 1 g 2 times a day. However, such adverse reactions as diarrhea, leukopenia, sepsis, infections, anemia were more common (≥10%) in children, especially under the age of 6 years.
Adverse events noted in ≥10% and in 3-10% of patients receiving MMF in combination with cyclosporine and glucocorticosteroids in controlled prevention studiesrejection of renal transplant (3 studies, data on a daily dose of 2 and 3 mg), in a controlled heart transplantation study and in a controlled liver transplantation study.
| Adverse events after kidney transplantation (n = 991) * | Adverse events after cardiac transplantation (n = 289) ** | Adverse events after liver transplantation (n = 277) *** |
Infectious and parasitic diseases | 3-<10% | infection, sepsis | infection, sepsis | infection, sepsis |
Violations of the blood and lymphatic system | ≥10% | anemia (including hypochromic), leukocytosis, leukopenia, thrombocytopenia | anemia (including hypochromic), leukocytosis, leukopenia, thrombocytopenia, ecchymosis | anemia (including hypochromic), leukocytosis, leukopenia, thrombocytopenia |
3-<10% | ecchymosis, polycythemia, bleeding | petechiae, increased prothrombin and thromboplastin time, bleeding | ecchymosis, increased prothrombin time, pancytopenia, bleeding |
Disorders from the endocrine system | 3-<10% | diabetes mellitus, parathyroid gland disease (increased parathyroid hormone level) | diabetes, Cushing's syndrome, hypothyroidism | diabetes |
Disorders from the metabolism and nutrition | ≥10% | | acidosis (metabolic or respiratory), hypervolemia, weight gain | |
3-<10% | acidosis (metabolic or respiratory), dehydration, hypervolemia, weight gain | alkalosis, dehydration, gout, hypovolemia, hypoxia, respiratory acidosis, thirst, weight loss, hypervolemia | acidosis (metabolic or respiratory), dehydration, hypervolemia, hypoxia, hypovolemia, weight gain, weight loss |
Disturbances from the nervous system | ≥10% | dizziness, insomnia, tremor, headache | agitation, anxiety, confusion, depression, dizziness, hypertonia, insomnia, paresthesia, drowsiness, tremor, agitation, headache | anxiety, confusion, depression, dizziness, insomnia, paresthesia, tremor, headache |
3-<10% | anxiety, depression, hypertonia, paresthesia, drowsiness | convulsions, emotional lability, hallucinations, neuropathy, thinking disorders, vertigo, dizziness | agitation, convulsions, delirium, dry mouth, hypertonus, hypoesthesia, neuropathy, psychosis, drowsiness, thinking disorders, delirium, agitation |
Disturbances on the part of the organ of sight | ≥10% | | amblyopia | |
3-<10% | amblyopia, cataract, conjunctivitis | visual disturbances, conjunctivitis, hemorrhages in the eye | visual impairment, amblyopia, conjunctivitis |
Hearing disorders and labyrinthine disorders | 3-<10% | | deafness, earache, tinnitus | deafness |
Heart Disease | ≥10% | | arrhythmia, bradycardia, heart failure, pericardial effusion | tachycardia |
3-<10% | Angina pectoris, atrial fibrillation, tachycardia, palpitations | angina, arrhythmias (supraventricular and ventricular extrasystoles, flutter and atrial fibrillation, supraventricular and ventricular tachycardias), cardiac arrest, congestive heart failure, syncope | Atrial fibrillation, arrhythmias, bradycardia, syncope |
Vascular disorders | ≥10% | increase in blood pressure | decrease and increase of arterial pressure | decrease and increase of arterial pressure |
3-<10% | lowering of arterial pressure, orthostatic hypotension, thrombosis, vasodilation | orthostatic hypotension, pulmonary hypertension, vasospasm, increased venous pressure | arterial thrombosis, vasodilation |
Disturbances from the respiratory system, chest and mediastinal organs | ≥10% | cough, dyspnea, pharyngitis, pneumonia, bronchitis | asthma, coughing, dyspnea, pharyngitis, pleural effusion, pneumonia, rhinitis, sinusitis | cough, dyspnea, pharyngitis, pneumonia, pleural effusions, sinusitis, atelectasis |
3-<10% | asthma, pleural effusion, pulmonary edema, rhinitis, sinusitis | apnea, atelectasis, bronchitis, epistaxis, hemoptysis, hiccough, neoplasm, pneumothorax, pulmonary edema, increased sputum separation, voice change | asthma, bronchitis, epistaxis, hyperventilation, pneumothorax, pulmonary edema, candidiasis of the respiratory tract, rhinitis |
Disorders from the gastrointestinal tract | ≥10% | constipation, diarrhea, indigestion, nausea and vomiting, candidiasis of the oral mucosa, abdominal pain | constipation, diarrhea, indigestion, flatulence, nausea and vomiting, candidiasis of the oral mucosa, abdominal pain | anorexia, constipation, diarrhea, dyspepsia, flatulence, nausea and vomiting, candidiasis of the oral mucosa, hernia, peritonitis, ascites, abdominal pain, bloating |
3-<10% | anorexia, flatulence, gastroenteritis, gastrointestinal bleeding, candidiasis of the gastrointestinal tract, gingivitis, gingival hyperplasia, intestinal obstruction, stomatitis, esophagitis, loss of appetite, gastritis, hernia, bloating | anorexia, dysphagia, gastroenteritis, gingivitis, gingival hyperplasia, melena, stomatitis, esophagitis, loss of appetite, hernia, bloating | dysphagia, gastritis, gastrointestinal bleeding, intestinal obstruction, melena, ulceration of the oral mucosa, esophagitis, rectal damage, gastric ulcer |
Disturbances from the liver and bile ducts | ≥10% | | increased activity of lactate dehydrogenase (LDH), aspartate aminotransferase (ACT), alanine aminotransferase (ALT), bilirubinemia | bilirubinemia, cholangitis, cholestatic jaundice, hepatitis, increased activity of hepatic enzymes (including aspartate aminotransferase (ACT), alanine aminotransferase (ALT)) |
3-<10% | impaired liver function, increased concentrations of alkaline phosphatase, hepatitis, increased activity of hepatic enzymes (including aspartate aminotransferase (ACT), alanine aminotransferase (ALT)) | impaired liver function, increased concentrations of alkaline phosphatase, jaundice, increased activity of hepatic enzymes (including aspartate aminotransferase (ACT), alanine aminotransferase (ALT)) | jaundice |
Disturbances from the skin and subcutaneous tissues | ≥10% | acne, herpes simplex | acne, herpes simplex, shingles, rash | rash, itching, excessive sweating, hard-healing wounds |
3- <10% | hair loss, benign neoplasms of the skin, fungal dermatitis, shingles, hirsutism, itching, skin cancer, skin hypertrophy (including actinic keratosis), excessive sweating, skin ulcers, rash | benign skin tumors, fungal dermatitis, hemorrhages, itching, skin cancer, skin hypertrophy, excessive sweating, skin ulcers, hard-healing wounds, cellulite | acne, fungal dermatitis, hemorrhages, herpes simplex, shingles, hirsutism, benign skin lesions, skin ulcers, vesicle-bullous rash, cellulitis, scrotal edema, abscesses |
Disturbances from musculoskeletal and connective tissue | ≥10% | back pain | cramps in the legs, muscle aches, muscle weakness, back pain | back pain |
3-<10% | pain in the joints, leg cramps, muscle pain, muscle weakness | pain in the joints, pain in the neck | pain in the joints, leg cramps, muscle pain, muscle weakness, osteoporosis |
Disorders from the kidneys and urinary tract | ≥10% | hematuria, renal tubular necrosis, urinary tract infection | impaired renal function (decreased kidney function, increased serum creatinine concentration), oliguria, urinary tract infection | impaired renal function (decreased kidney function, increased serum creatinine concentration), oliguria, urinary tract infection |
3- <10% | albuminuria, dysuria, hydronephrosis, pyelonephritis, frequent urination | dysuria, hematuria, nocturia, renal failure, frequent urination, incontinence and urinary retention | acute renal failure, dysuria, hematuria, renal failure, frequent urination, incontinence |
Violations of the genitals, mammary glands | 3-<10% | impotence | impotence | |
General disorders and disorders at the site of administration | ≥10% | asthenia, fever, infection, pain in the chest, swelling, sepsis | asthenia, fever, chills, infections, pain in the chest, swelling, sepsis | asthenia, fever, chills, infections, pain in the chest, swelling, sepsis |
3- <10% | cysts (including lymphocele and hydrocele), facial swelling, flu-like syndrome, malaise, pelvic pain | cysts (including lymphocele and hydrocele), facial swelling, flu-like syndrome, malaise, pelvic pain, pallor of the skin | cysts (including lymphocele and hydrocele), flu-like syndrome, malaise, pain in the neck |
Laboratory and instrumental data | ≥10% | hypercholesterolemia, hyperglycemia, hyperkalemia, hypokalemia, hypophosphataemia | hyperbilirubinemia, increased residual nitrogen, increased creatinine concentration, increased activity of enzymes (lactate dehydrogenase (LDH), aspartate aminotransferase (ACT), alanine aminotransferase (ALT)) in the blood serum, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipidemia, hyperuricemia, hypokalemia, hyponatremia | hyperbilirubinemia, increased residual nitrogen, increased creatinine concentration, hyperglycemia, hyperkalemia, hypokalemia, hypocalcemia, hypoglycemia, hypomagnesemia, hypophosphatemia, hypoproteinemia |
| 3-<10% | increased activity of alkaline phosphatase, increased activity of enzymes (gamma glutamyltranspeptidase, lactate dehydrogenase (LDH), aspartate aminotransferase (ACT), alanine aminotransferase (ALT)) in serum, increased serum creatinine concentration, hypercalcemia, hyperlipidemia, hypocalcemia, hypoglycemia, hypoproteinemia, hyperuricemia | increased activity of alkaline phosphatase, hypocalcemia, hypochloraemia, hypoglycemia, hypoproteinemia, hypophosphataemia | increased activity of alkaline phosphatase, increased activity of enzymes (aspartate aminotransferase (ACT), alanine aminotransferase (ALT)) in the blood serum, hypercholesterolemia, hyperlipidemia, hyperphosphatemia, hyponatremia |
In three controlled studies on the prevention of kidney transplant rejection, the safety profile of MMF in a daily dose of 2 g was slightly better than in a daily dose of 3 g.
Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, were observed in patients taking MMF. In reports on these cases, there is information about the presence of additional risk factors for the development of PML in patients, including immunosuppressive therapy and impairment of immunity.
In patients taking MMF, there were cases of development of nephropathy associated with VC virus (VC virus-associated nephropathy).This infection can lead to serious consequences, sometimes to the death of a kidney transplant.
Other undesirable reactions observed during the post-marketing use of the drug do not differ from the undesirable reactions recorded in controlled clinical trials.