The need to supplement the instructions for the use of medicines containing linezolid the following information:
In the section "Contraindications", the following information should be provided: "Hypersensitivity to linezolid and / or other components of the drug." Simultaneous reception of linezolid with preparations inhibiting monoamine oxidase A or B (eg, phenelzine, isocarboxazide), and within 2 weeks after discontinuation reception of these drugs.
In the absence of careful monitoring of patients and monitoring of blood pressure, linezolid should not be prescribed:
patients with uncontrolled arterial hypertension, pheochromocytoma, thyrotoxicosis, carcinoid syndrome, bipolar disorder, schizoaffective disorder and acute confusion;
patients receiving the following types of drugs: adrenomimetics (for example, pseudoephedrine, phenylpropanolamine, epinephrine, norepinephrine, dobutamine), dopaminomimetics (for example, dopamine), serotonin reuptake inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists (tryptanes), meperidine or buspirone. "Additionally, provide information depending on the dosage form (children's age) and the formulation of excipients.
The section "Side effect" is presented in the following edition: "The incidence of side effects listed below was determined according to the following (classification of the World Health Organization): very often (> 1/10), often (> 1/100 - <1/10), infrequently (> 1/1000 - <1/100), rarely (> 1/10000 - <1/1000), very rarely (<1/10000), the frequency is unknown (it is impossible to estimate the development rate according to available data).
The undesirable phenomena associated with the use of linezolid are usually of mild or moderate severity. More often than others the diarrhea, a headache, a nausea, vomiting are marked.
Adult patients
Infectious and parasitic diseases: often - candidiasis (including candidiasis of the oral cavity, vaginal candidiasis), fungal infections; infrequently - vaginitis; rarely - colitis, caused by the use of antibiotics (including pseudomembranous colitis).
Violations from the blood and lymphatic system: often - anemia; infrequently - leukopenia, neutropenia, thrombocytopenia, eosinophilia; rarely - pancytopenia; frequency unknown - myelosuppression, sideroblastic anemia.
Immune system disorders: frequency unknown - anaphylaxis.
Disorders from the metabolism and nutrition: infrequently - hyponatremia; frequency is unknown - lactic acidosis.
Disorders of the psyche: often - insomnia.
Impaired nervous system: often - headache, perversion of taste ("metallic" taste in the mouth), dizziness; infrequently - convulsions, hyposthenia, parasthesia; frequency is unknown - serotonin syndrome, peripheral neuropathy.
Disorders from the side of the organ of vision: infrequently - blurred vision; rarely the appearance of visual field defects; frequency unknown - neuropathy of the optic nerve, optic neuritis, loss of vision, changes in visual acuity, change in color vision.
Hearing disorders and labyrinthine disturbances: infrequent - ringing in the ears.
Disorders from the cardiovascular system: often - increased blood pressure; infrequently - arrhythmia (tachycardia), transient ischemic attack, phlebitis, thrombophlebitis.
Disorders from the gastrointestinal tract: often - diarrhea, nausea, vomiting, localized or diffuse pain in the abdomen, constipation, indigestion; infrequently - pancreatitis, gastritis, bloating, dry mouth, glossitis, loose stool, stomatitis, discoloration of the tongue mucosa and other abnormalities of the tongue; rarely - a superficial change in the color of the enamel of the teeth.
Disorders from the liver and bile ducts: often - changes in the results of functional liver tests, increased activity of "liver" enzymes (including alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (AFP)); infrequently, an increase in the concentration of total bilirubin.
Disorders from the rut and subcutaneous tissues: often - itching, rash; infrequently - hives, dermatitis, excessive sweating; frequency unknown - bullous skin lesions (such as Stevens-Johnson syndrome, toxic epidermal necrolysis), angioedema, alopecia.
Disorders from the kidneys and urinary tract: often - increased blood urea concentration; infrequently - renal insufficiency, increase in the concentration of creatinine in the blood plasma, polyuria.
Violations of the genitals and breast: infrequently - violations of the vagina and vulva.
General disorders and disorders at the site of administration: often - fever, localized pain; infrequently - chills, weakness, thirst; pain at the injection site (for solution for infusion).
Laboratory indicators: often - an increase in the number of neutrophils, eosinophils, a decrease in hemoglobin, hematocrit or the number of erythrocytes,increase or decrease in the number of platelets or leukocytes, increased activity of lactate dehydrogenase, creatine kinase, lipase, amylase, increased fasting glucose, reduced total protein, albumin, sodium or calcium, increased or decreased potassium or bicarbonate; infrequent - an increase in the content of sodium or calcium in the blood plasma, a decrease in glucose concentration not fasting, an increase or decrease in blood chlorides, an increase in the number of reticulocytes, a decrease in the number of neutrophils.
The following side effects with linezolid in rare cases were classified as serious: localized abdominal pain, transient ischemic attack, arterial hypertension.
In controlled clinical trials in which linezolid was used for a maximum of 28 days, only 2% of the patients developed anemia. In another study among patients with life-threatening infections, 2.5% (33/1326) of patients who received linezolid less than 28 days, anemia developed, while when linezolid was used for more than 28 days, anemia developed in 12.3% (53/430) patients.
The proportion of cases of development of anemia requiring a blood transfusion was 9% among patients receiving linezolid less than 28 days (3/33), and 15% (8/53) in those cases where linezolid used more than 28 days.
Side effects in children do not differ from those in adult patients. "
The section "Special instructions" should be presented in the following edition: "In an open study among severely ill patients with intravascular catheter-associated infections, there was an excess of mortality in patients who received linezolid, Compared with patients who received vancomycin / dicloxacillin / oxacillin [78/363 (21.5%) vs. 58/363 (16.0%)]. The main factor influencing mortality was the gram-positive pathogen of infection at the initial stage. The mortality rate was similar among patients who had infections caused by Gram-positive microorganisms only, but was significantly higher in the linezolid group when detected, and other microorganisms, or could not be detected at an early stage. The greatest imbalance was noted during treatment and within 7 days after the end of antibiotic therapy.In many patients linezolid groups were detected during the study of Gram-negative microorganisms, and they died from infection caused by Gram-negative microorganisms or polymicrobial infections. Thus, in the case of complicated infections of the skin and soft tissues linezolid should be used in patients with known or possible co-infection with gram-negative microorganisms, only if there are no alternative treatment options. In these cases, additional use of drugs acting on gram-negative microflora is shown simultaneously.
In some patients taking linezolid, reversible myelosuppression may develop (with anemia, thrombocytopenia, leukopenia and pancytopenia), depending on the duration of therapy. In elderly patients, the risk of developing this condition is also increased. Thrombocytopenia occurred more often in patients with severe renal failure, regardless of the patient's hemodialysis. In connection with this, during the treatment it is necessary to monitor blood levels in patients with an increased risk of bleeding, myelosuppression in history,as well as with the simultaneous use of drugs that reduce hemoglobin or the number of platelets and / or their functional properties, with severe renal failure, as well as in patients taking linezolid more than 2 weeks. Linezolid these patients are only used when it is possible to carefully monitor hemoglobin, the number of leukocytes and platelets. If during treatment with linezolid develops marked myelosuppression, treatment should be discontinued unless continuation of therapy is considered absolutely necessary. In this case, intensive monitoring of blood counts and appropriate treatment is necessary. In addition, it is recommended that a blood test (including determination of hemoglobin, platelet count and leukocyte counts (with the calculation of the leukocyte count)) be performed weekly in patients receiving linezolid regardless of the initial blood test. A higher incidence of severe anemia was observed in patients who received linezolid more than the maximum recommended duration of 28 days. These patients were more likely to require a blood transfusion.Cases of sideroblastic anemia were registered in the post-marketing period. In most cases, the duration of linezolid therapy exceeded 28 days. In most patients, the manifestations were completely or partially reversible after discontinuation of treatment with linezolid with / without specific treatment for anemia.
In patients taking antibacterial drugs, including linezolid, should take into account the risk of developing pseudomembranous colitis of varying severity. About cases of diarrhea associated with Clostridium difficile, was reported in connection with the use of almost all antibacterial drugs, including linezolid. The severity of diarrhea can range from mild to severe forms. Treatment with antibacterial drugs disrupts the normal intestinal microflora, which leads to excessive growth Clostridium difficile. Clostridium difficile produces toxins A and B, which lead to the development of diarrhea associated with Clostridium difficile. Excessive amount of toxins produced by strains Clostridium difficile, may cause an increase in mortality among patients, since such infections can be resistant to antimicrobial therapy, and may require a colonectomy. Do not use drugs that inhibit the intestinal motility.The possibility of developing diarrhea associated with Clostridium difficile, should be considered in all patients with diarrhea that followed the use of antibiotics. Careful medical supervision for 2 months patients who have had diarrhea associated with Clostridium difficile after the introduction of antibacterial drugs.
When symptoms of impaired visual function appear, such as changes in visual acuity, changes in color perception, blurred vision, visual field defects, it is recommended that you urgently consult an ophthalmologist for advice. Monitor visual function in all patients taking linezolid for a long time (more than 28 days), as well as for all patients with newly appeared symptoms of visual disturbances, regardless of the duration of therapy.
In the case of peripheral neuropathy and optic nerve neuropathy, the risk / benefit ratio of linezolid therapy in these patients should be assessed. The risk of developing neuropathy is higher if linezolid It is used in patients who are currently using or who have recently taken antimycobacterial drugs for the treatment of tuberculosis.
In connection with the use of linezolid, lactoacidosis was reported.Patients who experience repeated nausea or vomiting with linezolid, abdominal pain, unexplained acidosis, or a decrease in the concentration of bicarbonate anions, require close monitoring by the physician.
Linezolid inhibits the synthesis of the mitochondrial protein. Side effects, such as, lactic acidosis, anemia and neuropathy (peripheral or optic nerve), can result from this inhibition; these effects are more common when the drug is used more than 28 days.
Cramping was reported in patients taking linezolid, and in most cases in the history there was an indication of convulsions or the presence of risk factors for their development. Patients need to collect a detailed history of previous episodes of seizures.
If the drug is to be used in combination with selective serotonin reuptake inhibitors, patients should be constantly monitored to identify signs and symptoms of serotonin syndrome, such as cognitive impairment, hyperpyrexia, hyperreflexia and impaired coordination of movements.If these symptoms appear, you should cancel one or both of the drugs taken. When discontinuing the use of a serotonergic drug, symptoms of the withdrawal syndrome may be observed.
There have been reports of reversible surface changes in tooth enamel staining with linezolid. These changes in staining were removed by professional dental cleaning.
There were reported cases of symptomatic hypoglycemia in patients with diabetes mellitus who received linezolid simultaneously with insulin or hypoglycemic drugs. Although a causal relationship between the use of linezolid and the development of hypoglycemia has not been established, patients with diabetes should be warned about the possibility of developing hypoglycemia. In case of hypoglycaemia, correction of insulin dose / hypoglycemic drugs or cancellation of linezolid is necessary.
Patients should be advised not to take large amounts of food containing tyramine (such as red wine, old cheese, some alcoholic drinks, smoked meat).
Clinical studies examining the effect of linezolid on normal microflora of the human body, was not carried out.
The use of antibacterial drugs can sometimes lead to an increased growth of microorganisms that are not susceptible to it. In clinical studies, it was shown that approximately 3% of patients receiving recommended doses of linezolid developed candidiasis associated with taking antibiotics. If superinfections occur against the background of linezolid, appropriate medical measures should be taken.
Clinical researches.
The safety and efficacy of linezolid for more than 28 days have not been established.
In controlled clinical trials, patients with "diabetic foot" syndrome, bedsores or ischemic impairment, severe burns or gangrenous lesions did not participate. Thus, the experience of using linezolid in the therapy of these conditions is limited. "