Index of drugs

Treatment of advanced melanoma (inoperable or metastatic) in adults.

1 ml of concentrate contains 5 mg ipilimumab; the drug contains sodium - 0.1 mmol (2.30 mg) / ml.

An anti-cancer drug. Ipilimumab is a substance that strengthens the activity of T lymphocytes, which specifically blocks the CTLA-4 inhibitory signal, which causes activation of T lymphocytes, proliferation and increased T cell infiltration in tumors, leading to the death of tumor cells. The mechanism of action of ipilimumab is indirect, by strengthening the immune response mediated by T lymphocytes. After repeated administration of ipilimumab every 3 weeks, the clearance does not change over time and there is minimal systemic accumulation with a cumulative ratio of 1.5 or less. The steady state of ipilimumab is reached after the third dose. The average final T_0,5 is 15.4 days. The clearance of ipilimumab increases with increasing body weight and with the increase in the initial value of LDH activity; however, no dose adjustment is required for increased LDH activity or body weight if the medicine is administered in a dose expressed in mg / kg.

Hypersensitivity to ipilimumab or to any of the excipients.

Co-administration of ipilimumab and vemurafenib is not recommended, due to the risk of elevation of transaminases (ALT or AST> 5 x ULN - upper limit of normal) and bilirubin (total bilirubin> 3 x ULN). Treatment with ipilimumab is associated with the occurrence of inflammatory side effects caused by increased or excessive activity of the immune system (immune-related side effects) that may be serious or life-threatening, may affect the gastrointestinal tract, liver, skin, endocrine organs or other organs. If severe immune-related adverse reactions occur, it may be necessary to temporarily stop or discontinue ipilimumab treatment altogether and to use adjuvant therapy, including high-dose intravenous corticosteroids, with or without other immunosuppressants. Patients on ipilimumab should be monitored for signs and symptoms that may be indicative of an inflammatory bowel disease or gastrointestinal perforation (diarrhea, increased bowel movements, abdominal pain or blood in the stool, with or without fever). Diarrhea or colitis that occurred after administration of ipilimumab should be diagnosed as soon as possible to rule out infectious or other etiology. Loperamide, fluid replacement and oral corticosteroids were used to treat lighter gastrointestinal side effects. To treat severe symptoms - high doses of intravenous corticosteroids (methylprednisolone 2 mg / kg / day). Patients should be examined for gastrointestinal perforation or peritonitis. The clinical trial experience of managing steroid-resistant diarrhea and colitis is limited - infliximab at a dose of 5 mg / kg. Before each dose of ipilimumab, aminotransferases and bilirubin should be measured in the blood, as changes in laboratory tests may indicate that hepatitis is of an immune origin. In order to rule out other causes of liver damage, including infection, cancer progression or the effects of concomitant medication, and to monitor symptoms until their resolution resolves, AST, ALT and total bilirubin should be measured. Liver biopsies performed in patients with immunological hepatotoxicity showed signs of acute inflammation (neutrophils, lymphocytes and macrophages). High doses of intravenous corticosteroids and mycophenolate mofetil have been used to treat severe hepatotoxicity. The condition of the skin should be monitored due to the risk of serious side effects of immunological origin. The treatment of rash and pruritus induced by ipilimumab depends on their severity.Antihistamines and oral corticosteroids have been used to treat minor side effects. To treat severe symptoms - high doses of intravenous corticosteroids. Due to the risk of immune-related neurological effects, cases of indeterminable motor neuropathy, muscle weakness or sensory neuropathy lasting> 4 days should be investigated, and non-inflammatory causes such as disease progression, infections, metabolic syndromes and the effects of concomitant medications should be ruled out. Attention should be paid to the progressive symptoms of motor neuropathy and appropriate treatment. Patients should be treated in accordance with the guidelines for the management of sensory neuropathy and should immediately initiate intravenous corticosteroids. The thyroid function should be checked prior to initiating administration and prior to each dose of ipilimumab. Ipilimumab-induced endocrinopathy may be hypothalamic, pituitary hypotension, adrenal insufficiency and hypothyroidism, and patients may present with non-specific symptoms that may resemble other pathological conditions, for example brain metastases or other diseases. The most common clinical picture is headache and fatigue, also visual field disorders, changes in behavior, electrolyte imbalance and pressure reduction may occur. Adrenal crisis should be excluded as the cause of the patient's symptoms. Clinical experience of endocrinopathy associated with ipilimumab use is limited. If you experience symptoms of adrenal crisis, for example, severe dehydration, hypotension or shock, prompt administration of corticosteroids is recommended as soon as possible and the patient should be assessed for sepsis or infection. If symptoms of adrenal insufficiency are present, but the patient is not at the adrenal crisis, further tests, including laboratory and imaging, should be considered. Evaluation of laboratory tests determining the function of endocrine organs can be performed before corticosteroid treatment begins. In the case of abnormal results of pituitary imaging or laboratory tests to determine the function of endocrine organs, short-term treatment with high-dose corticosteroids (eg Dexamethasone at a dose of 4 mg every 6 hours) is recommended in order to treat the inflammation of a given organ. Appropriate hormone replacement therapy, which may be long-term, should also be included. In the case of uveitis, iritis or episcleritis associated with ipilimumab treatment, topical corticosteroids in the form of eye drops should be considered. Patients with ocular melanoma, primary central nervous system melanoma and active brain metastases were not included in the main clinical trial of ipilimumab. Clinical trials have not investigated patients who have a history of autoimmune disease (other than vitiligo and adequately controlled endocrine deficiencies such as hypothyroidism), including those requiring general immunosuppressive therapy due to previously diagnosed active autoimmune disease or maintenance treatment after organ transplantation. Ipilimumab may affect immunosuppressive therapy, resulting in a worsening of the underlying disease or an increased risk of transplant rejection. The use of ipilimumab should be avoided in patients with severe autoimmune disease in which further activation of the immune system could be life-threatening. In other patients with a history of autoimmune disease, ipilimumab should be used with caution, after careful consideration of the likely individual risk / benefit ratio. In the event of a severe infusion reaction, ipilimumab infusion should be discontinued and appropriate treatment instituted. Patients with mild and moderate infusion reactions may receive ipilimumab under careful supervision. Antipyretic and antihistamine medications may be considered as premedication. The safety and efficacy of ipilimumab in patients with renal or hepatic impairment has not been studied. In patients with transaminase ≥ 5 x ULN or bilirubin> 3 x ULN prior to initiating therapy, ipilimumab should be administered with caution. The safety and efficacy of the medicine in children <18 has not been established. y. - do not use.The sodium content of the preparation: 0.1 mmol (2.30 mg) sodium / ml should be taken into account when treating patients on a controlled sodium diet.

Human IgG1 penetrate the placental barrier. Ipilimumab is not recommended for use in pregnancy and in women of childbearing potential who do not use an effective method of contraception, unless the clinical benefit outweighs the potential risk. It is not known whether ipilimumab is excreted in human milk. The penetration of human G-type immunoglobulins into human milk is small and their oral bioavailability is low. It is not expected that the general exposure of the newborn would be large and no effects on the breast-fed newborn / infant are expected. However, due to the potential for side effects in a breastfed child, a decision should be made whether to discontinue breast-feeding or discontinue ipilimumab given the benefits of breast-feeding to the child and the benefits of treatment for the mother.

After a dose of 3 mg / kg. Very common: decreased appetite, diarrhea, vomiting, nausea, rash, pruritus, tiredness, reaction at the injection site, fever. Common: pain in the tumor, anemia, lymphopenia, hypopituitarism, hypothyroidism, dehydration, hypokalemia, confusion, peripheral sensory neuropathy, dizziness, headache, drowsiness, blurred vision, eye pain, reduced pressure, hot flush, shortness of breath , cough, gastrointestinal bleeding, enteritis (including death), constipation, gastro-oesophageal reflux, abdominal pain, abnormal liver function, dermatitis, erythema, albinism, urticaria, baldness, night sweats, dry skin, joint pain, muscle pain, musculoskeletal pain, muscle cramps, chills, asthenia, edema, pain, increase in ALT, AST, increase in bilirubin in the blood, weight loss. Uncommon: sepsis (including death), septic shock (including death), urinary tract infection, respiratory tract infection, paraneoplastic syndrome, haemolytic anemia (including death), thrombocytopenia, eosinophilia, neutropenia, hypersensitivity, adrenal insufficiency, hyperthyroidism , hypogonadism, hyponatremia, alkalosis, hypophosphatemia, tumor breakdown syndrome, mental state changes, depression, decreased libido, Guillain-Barre syndrome (including death), meningitis (aseptic), syncope, cranial nerve neuropathy, cerebral edema, peripheral neuropathy, ataxia, tremor, myoclonus, dysarthria, uveitis, vitreous hemorrhage, iritis, decreased visual acuity, feeling of a foreign body in the eyes, conjunctivitis, arrhythmia, atrial fibrillation, angiitis, angiopathy (including death), peripheral ischemia, orthostatic hypotension, respiratory failure wa, acute respiratory syndrome - ARDS (including death), infiltrates in the lungs, pulmonary edema, pneumonia, allergic rhinitis, gastrointestinal perforation (including death), perforation of the large intestine (including death), intestinal perforation (in including death), peritonitis (including death), gastroenteritis, diverticulitis, pancreatitis, colitis, gastric ulcer, colon ulcer, oesophagitis, obstruction, hepatic failure (including death), inflammation liver, enlarged liver, jaundice, toxic skin necrosis (including death), leukoclastic vasculitis, peeling skin, polymyalgia rheumatica, arthritis, renal failure (including death), glomerulonephritis, tubular acidosis, amenorrhea, multi-organ failure ( including death), an infusion reaction, an increase in blood creatinine, an increase in TSH, a decrease in ST blood cortisol, blood corticotropin, increased lipase, increased blood amylase, reduced testosterone in the blood.Additional side effects after other doses (both 3 mg / kg). With a frequency of 4%: flu-like symptoms, increased alkaline phosphatase in the blood.With a frequency of <1%: irritant syndrome (meningismus), myocarditis, pericardial effusion, cardiomyopathy, autoimmune hepatitis, erythema multiforme, erythema nodosum, changes in hair color, autoimmune nephritis, autoimmune pancreatitis, myasthenia gravis-like symptoms, weakness muscle, autoimmune thyroiditis, hyperthyroidism, secondary adrenal insufficiency, hypoparathyroidism, thyroiditis, systemic inflammatory syndrome, mucositis, infectious peritonitis, episcleritis, blepharitis, eye swelling, scleritis, temporal arteritis, symptom Raynaud, anal inflammation, palm-solitary erythrodysaesthesia, eczema, psoriasis, cytokine release syndrome, sarcoidosis, hematuria, proteinuria, increased GGT activity, decreased thyroid stimulating hormone (TSH) in the blood, decrease in blood gonadotropin concentration, decrease in thyroxine concentration, positive result of antinuclear antibodies, abnormal blood prolactin concentration, hypocalcaemia, leukopenia, polycythaemia, lymphocytosis, polymyositis, myelitis, myositis, neurosensory hearing loss and autoimmune central neuropathy (encephalitis).