Yervoy, 5 mg/ml 10.7 ml

Inoperable or metastatic melanoma in adult patients with ineffectiveness or intolerance of prior therapy.

Active ingredient

Composition

1 bottle of infusion solution contains*:

the active ingredient: ipilimumab 53.5 mg or 213.0 mg;

excipients: tromethamol hydrochloride 33.7 mg or 134.3 mg; sodium chloride 62.6 mg or 249.0 mg; mannitol 107.0 mg or 426.0 mg; pentetamic acid 0.42 mg or 1.67 mg; polysorbate 80 1.07 mg or 4.26 mg; sodium hydroxide and hydrochloric acid q.s. to pH 7.0; water for injection – q.s. to 10.7 ml or 42.6 ml.

How to take, the dosage

The drug should be administered under the direction of a physician experienced in the treatment of cancer.

The recommended dose of ERVOY® in adults is 3 mg/kg body weight in a 90-minute intravenous infusion given every 3 weeks. The course of treatment is 4 injections. If tolerated, the patient should receive the full course of treatment (4 doses) regardless of the appearance of new lesions or growth of existing lesions. Evaluation of the tumor is done after the completion of the full course of therapy.

Ahead of each drug administration and throughout the course of treatment with the drug, an evaluation should be performed to detect immune-mediated adverse reactions, including diarrhea and colitis. Liver and thyroid function should be evaluated before starting the course and also before each administration of the drug.

Calculating the dose of the drug

The calculation of the dose to be given is per kg of body weight; one patient may need more than one vial of the drug.

The total dose of ipilimumab in mg = the patient’s body weight (in kg) multiplied by the prescribed dose (in mg/kg).

The amount of medication (in ml) needed to give the dose = the total dose (in mg) divided by 5 (the ipilimumab concentration is 5 mg/ml).

Recommendations for adjusting the drug dose

In the use of the drug, immune-mediated adverse reactions may occur that may require skipping the dose or cancelling the drug and administering high doses of glucocorticosteroids. In some cases, additional therapy with other immunosuppressants may be required. Decreasing the dose of the drug is not recommended.

1.

If patients have mild immune-mediated adverse reactions or symptomatic endocrinopathy after drug administration, the scheduled next scheduled dose of the medication should be skipped.

For patients with complete or partial disappearance of adverse reactions (grade 0-1) when prescribed glucocorticosteroids (prednisolone or similar) at a dose of less than 7.5 mg daily, treatment with ERVOY® at a dose of 3 mg/kg every 3 weeks is resumed. The therapy is ended after the 4th planned dose or 16 weeks after the 1st dose.

Instructions for preparing and administering

Do not shake the bottle before use!

The diluted solution for infusion is prepared under aseptic conditions.

Please inspect the contents of the bottle before administering the drug.

The product should not be administered if there are foreign particles in it, or if the solution has become cloudy or has changed color.

Please allow the drug to stand at room temperature for 5 minutes before injecting. The drug may be used after dilution with sterile 0.9% sodium chloride solution for infusion or sterile 5% dextrose solution for infusion to a concentration of 1 to 4 mg/ml. The prepared solution is stirred by gently turning the infusion container.

Interaction

Pharmacokinetic interactions

The molecule of ipilimumab is a monoclonal antibody, so it is not metabolized with the participation of cytochrome P450 and other isoenzymes that metabolize drugs. Pharmacokinetic interactions of ipilimumab with other drugs are unlikely.

Other forms of interaction

Glucocorticosteroids

Due to the possibility of pharmacodynamic interaction the use of glucocorticosteroids should be avoided before therapy with ERVOY®. After initiation of ERVOY® therapy, glucocorticosteroids and other immunosuppressants can be used to correct immune-mediated adverse reactions caused by the effect of the drug on the immune system. The use of systemic glucocorticosteroids after initiation of treatment with the drug does not affect the effectiveness of the drug.

Anticoagulants

Anticoagulants are known to increase the risk of gastrointestinal bleeding. Because this is one of the adverse reactions of the drug, patients receiving EPBOY® and anticoagulants at the same time should be monitored closely.

Special Instructions

ERVOY® can cause severe, including fatal, adverse reactions due to immune system effects and its specific mechanism of action.

The immune system-related adverse reactions can affect the gastrointestinal tract, liver, skin, nervous system, endocrine system and other organ systems. They can be severe or life-threatening and usually develop during therapy, but there are also cases that occur months after the last dose.

If no other etiology is identified, the following adverse reactions should be considered inflammatory and are due to EPBOY® administration: diarrhea, increased frequency of defecation, blood in the stool, increased liver transaminase activity, skin rash, endocrinopathies. Their early diagnosis and appropriate treatment are essential to minimize life-threatening complications. To treat severe adverse reactions caused by the effects on the immune system, systemic administration of high doses of glucocorticosteroids with or without additional use of immunosuppressive therapy may be necessary. For the correction of adverse reactions of ERVOY®, treatment regimens specifically designed for this purpose should be used.

In the clinical trials of ERVOY® gastrointestinal immune-mediated serious adverse reactions (grade 3-5), sometimes with lethal outcome, were observed on average 8 weeks (median, range 5-13 weeks) after the initiation of therapy. There were also cases of lethal outcome due to gastrointestinal perforation. With targeted interventions, improvement (to at least grade 1 or baseline) was seen in 90% of patients after an average of 4 weeks (median, range 0.6-22 weeks). Patients should be closely monitored for symptoms that might indicate immune-mediated colitis or gastrointestinal perforation (diarrhea, increased number of defecations, abdominal pain, blood in the stool, with or without fever). Patients who develop diarrhea or colitis after drug administration should be monitored closely. An infectious or other etiology of these symptoms should be excluded. In clinical trials, immune-mediated colitis has manifested as mucosal inflammation with or without ulceration and infiltration of lymphocytes and neutrophils. Methods of correction of diarrhea and colitis are determined by the severity of these side effects. In patients with mild to moderate diarrhea (up to 6 defecations per day) and with suspected colitis (abdominal pain, bloody stools) of mild to moderate degree, treatment with EPBOY® should not be stopped. Symptomatic therapy (loperamide, fluid administration) and close monitoring of patients is recommended. If symptoms from mild to moderate recur or persist for 5-7 days, the planned dose of ERVOY® is not administered and oral glucocorticosteroids at a dose of 1 mg/kg/day (prednisolone or similar) are prescribed. When the patient’s condition improves (grade 0-1 or to baseline), therapy with EPBOY® may be resumed. ERVOY® is discontinued without restarting in patients with severe (grade 3 or 4) diarrhea or colitis who are immediately treated with high-dose intravenous glucocorticosteroids (methylprednisolone 2 mg/kg/day was used in clinical trials). When diarrhea and other symptoms are controlled, begin a slow reduction of the glucocorticosteroid dose over at least 1 month. In clinical trials, rapid dose reduction (in periods of less than 1 month) has led to recurrence of diarrhea or colitis in some patients. It is necessary to ensure that the patient does not have gastrointestinal perforation or peritonitis. If diarrhea or colitis persists despite the use of glucocorticosteroids, the prescription of an alternative immunosuppressant should be considered. In clinical trials, a single infliximab dose of 5 mg/kg has been administered in such cases, if there are no contraindications for its use. Infliximab should not be used if gastrointestinal perforation or sepsis is suspected.

Hepatotoxicity due to immune-mediated adverse reactions

In clinical trials of ERVOY® serious adverse liver reactions (grades 2-5), including fatal liver failure, have been reported 3-9 weeks after initiation of therapy. When specially designed methods of correction were used, the abnormalities disappeared or decreased after 0.7-2 weeks.

Hepatic transaminase activity and bilirubin concentration should be determined before each administration of ERVOY®. Impairment of liver function may be asymptomatic. If a patient showed increased alanine aminotransferase (ALT) and aspartate aminotransferase (ACT) activity or total bilirubin concentration, such causes of hepatotoxicity as the presence of infectious disease, cancer progression or concomitant therapy should be excluded, and liver function should be controlled until liver transaminases and bilirubin parameters improve. A liver biopsy in patients with immune-mediated hepatotoxicity showed signs of acute inflammation (neutrophils, lymphocytes and macrophages).

If ACT or ALT activity increases more than 5 but not more than 8 times the upper limit of normal, and total bilirubin concentration is more than 3 but not more than 5 times the upper limit of normal, the planned subsequent dose of EPBOY® is not administered, monitoring liver function until resolution. After improvement of liver function indexes (ACT and ALT indexes do not exceed the upper limit of normal by more than 5 times, concentration of total bilirubin does not exceed the upper limit of normal by more than 3 times) the treatment by EPOY® can be resumed.

. If the patient has ACT or ALT more than 8 times the upper limit of normal and bilirubin is more than 5 times the upper limit of normal, it is suspected that these changes are due to ERVOY® administration, therapy should be stopped without resumption and the patient should immediately receive high-dose treatment with glucocorticosteroids (for example, methylprednisolone 2 mg/kg/day or equivalent) intravenously. Liver function is monitored until it normalizes. Once symptoms have resolved and there is a steady improvement in liver function (or a return to baseline), the glucocorticosteroid dose is slowly reduced for at least 1 month. If liver function deteriorates during the dose reduction period, the dose of glucocorticosteroids is increased again, followed by a slow gradual decrease.

If significant impairment of liver function persists despite the use of glucocorticosteroids, additional prescribing of an alternative immunosuppressant should be considered. In clinical studies, mycophenolate mofetil has been prescribed in such cases.

Immune-mediated adverse skin reactions

In clinical studies of ERVOY® serious adverse skin reactions (grade 2-5) were noted on average 3 weeks (median, range 0.9-16 weeks) after initiation of therapy. Cases of fatal toxic epidermal necrosis have been reported in clinical trials. When using specially designed methods of correction in most cases (87%) an improvement was observed after 5 weeks (median, range 0.6-29 weeks) with the disappearance or return of symptoms to their original level

If during the treatment with EPBOY® the patient had immune-mediated adverse reactions in the form of skin rashes and itching, the measures of their correction depend on the severity of these adverse reactions. In patients with mild to moderate skin reactions (grade 1-2), treatment with ERVOY® is not withdrawn. Symptomatic therapy (antihistamines) is recommended. If skin rash or mild to moderate pruritus persists for 1-2 weeks and cannot be treated with topical glucocorticosteroids, therapy with oral glucocorticosteroids (e.g., prednisolone or similar in dose of 1 mg/kg orally, once daily) should be started.

Patients with severe (grade 3) skin reactions are not given a planned subsequent dose of ERVOY®. If the patient’s condition improves (grade 1 adverse reaction or complete resolution of symptoms) ERVOY® therapy may be resumed.

The treatment with EPBOY® is discontinued without restarting in patients with grade 4 skin rash or grade 3 pruritus who are treated immediately with high-dose glucocorticosteroids (e.g., methylprednisolone 2 mg/kg/day) intravenously. If the patient’s condition improves, slowly decrease the dose of glucocorticosteroids for at least 1 month. Immune-mediated adverse reactions in nervous system In clinical trials of ERVOY® serious neurological adverse reactions were observed: Guillain-Barré syndrome (including fatal), myasthenia gravis, muscle weakness, sensory neuropathy.

In case of motor neuropathy of unclear etiology, muscle weakness or sensory neuropathy lasting more than 4 days, non-inflammatory causes (progression of cancer, infections, metabolic syndrome, concomitant therapy with medications) should be excluded. In patients with moderate neuropathy (grade 2, motor and sensory or only motor), possibly associated with the use of ERVOY®, the drug administration should be suspended. When neurologic symptoms have resolved to baseline, ERVOY® may be resumed.

The ERVOY® treatment is discontinued without resumption in patients with severe sensory neuropathy (grade 3-4) when its association with ERVOY® is suspected. Patients are treated according to established treatments for sensory neuropathy, and intravenous glucocorticosteroids (e.g., methylprednisolone at a dose of 2 mg/kg/day) are started immediately. Progression of motor neuropathy should be considered as an immune-mediated adverse reaction and appropriate corrective measures should be taken. Treatment with ERVOY® should be discontinued without resumption in patients with severe (grade 3-4) motor neuropathy regardless of the causes of its development.

Immune-mediated adverse reactions in endocrine system

ERVOY® may cause inflammation of the endocrine organs, disorder of their function: hypophysitis, hypopituitarism, insufficiency of the adrenal cortex, hypothyroidism. Patients may have nonspecific symptoms that may resemble other diseases, such as brain metastases or manifestations of the underlying disease. The main symptoms are headache and fatigue. Visual field disturbances, behavioral changes, electrolyte imbalances, and decreased blood pressure may also be noted. Adrenal-adrenal crisis should be excluded as the cause of these symptoms. In clinical trials of ERVOY® preparation the cases of immune-mediated from moderate to severe endocrinopathy (degree 2-4) were observed 7-20 weeks after the treatment start. Usually in these cases the patient’s condition was corrected with immunosuppressants and hormone replacement therapy.

In case of any signs of adrenal-adrenal crisis (severe dehydration, decreased blood pressure or shock), immediate intravenous administration of glucocorticosteroids with mineralocorticoid activity is recommended. The presence or absence of sepsis or infections in the patient should be established. If there are signs of adrenal insufficiency, but the patient is not in an adrenal-adrenal crisis, the patient should be evaluated. If the results of the examination (pituitary scans or laboratory tests) reveal endocrine dysfunction, a short course of high-dose glucocorticosteroid treatment (e.g., dexamethasone 4 mg every 6 hours) should be prescribed to suppress inflammation in the gland concerned. In this case, the planned dose of ERVOY® should be cancelled. It is not known whether treatment with glucocorticosteroids promotes endocrine function recovery. Hormone replacement therapy should also be started, if necessary – long-term.

If the patient’s clinical symptoms or laboratory test results improve, treatment with EPOY® may be restarted, with glucocorticosteroid reductions slowly and gradually over at least 1 month.

Other adverse reactions caused by the effect of the drug on the immune system

In the clinical studies of ERVOY® the following adverse reactions which may be mediated by the effect of the drug on the immune system have been noted: uveitis, eosinophilia, increased lipase activity, glomerulonephritis. Additionally, iris inflammation, hemolytic anemia, increased amylase levels, and pneumonia have been noted. If these side effects are severe (grade 3-4), it may be necessary to use glucocorticosteroids in high doses immediately and cancel the drug EPBOY®. If a patient develops uveitis, iris inflammation or episcleritis during treatment with ERVOY®, the use of topical glucocorticosteroids in the form of eye drops is indicated.

Infusion reactions

The drug ERVOY® may cause severe infusion reactions. In case of severe infusion reactions, the drug infusion should be stopped and appropriate medication should be administered. Patients with mild to moderate infusion reactions may continue treatment with the drug with careful monitoring of the patient’s condition. Premedication with antihistamines and antipyretics may be considered.

Patients with ocular melanoma, primary central nervous system (CNS) melanoma and active brain metastases were not included in the main clinical trial of ERVOY®.

The clinical trials also did not include patients with a history of autoimmune disease (except vitiligo and compensated endocrine diseases with insufficient function, such as hypothyroidism), including patients who require systemic immunosuppressant therapy for an existing autoimmune disease or for an organ transplant. ERVOY® should be avoided in patients with severe autoimmune diseases in the active phase, since over-activation of the immune system may lead to a life-threatening condition. Caution should be exercised when prescribing ERVOY® to all patients with a history of autoimmune disease, carefully and on an individual basis weighing the risks and benefits of the drug in each patient.

The co-administration of vemurafenib

. In phase 1 clinical trials it was marked asymptomatic increase of transaminase activity of 3rd degree (ALT/AST 5 times higher than upper limit of norm) and concentration of bilirubin (total bilirubin 3 times higher than upper limit of norm) when using ERVOY® combination (3 mg/kg) and vemurafenib (960 mg or 720 mg 2 times per day) together. In view of this, co-administration of these drugs is not recommended.

Patients on a diet with controlled intake of sodium salts

1 ml of ERVOY® contains 0.1 mmol (2.30 mg) of sodium, which should be considered when prescribing to patients on a diet with controlled intake of sodium salts.

Contraindications

– Hypersensitivity to any component of the drug;

– children under 18 years of age due to lack of data on efficacy and safety;

– pregnancy and breast-feeding.

With caution:

– Severe autoimmune diseases in the active stage, in which further activation of the immune system may be potentially life-threatening;

– liver function disorders (liver transaminases activity 5 times or more exceeds the upper limit of normal; bilirubin concentration more than 3 times the upper limit of normal).

Side effects

Ervoi® has been used in more than 10,000 patients in clinical studies with different doses in patients with different types of tumors.

The most common adverse reactions to ERVOY® are due to increased immune system activity. Most of these adverse reactions, including serious ones, manage with appropriate therapy or withdrawal of the drug.

The most common adverse reactions seen in over 10% of patients in the clinical studies of ERVOY® were diarrhea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite and abdominal pain. Most adverse reactions were mild to moderate (grades 1 and 2). Therapy was discontinued because of adverse reactions in 10% of patients.

The adverse reactions reported in patients with advanced melanoma who were treated with ERVOY® at a dose of 3 mg/kg in clinical trials are listed below.

The adverse reactions with ERVOY® are presented according to their frequency of reporting: very frequent (≥1/10), frequent (≥1/100, < 1/10), infrequent (≥1/1,000, < 1/100), rare (≥1/10,000, < 1/1,000), very rare (< 1/10,000).

The incidence of immune-mediated adverse reactions in HLA-A2*0201-positive patients did not differ from that in the overall clinical program.

Infections and invasions:

infrequent: Sepsis1, septic shock1, meningitis (aseptic), gastroenteritis, diverticulitis, urinary tract infections, respiratory tract infections;

New growths of benign, malignant and unspecified nature:

frequent: tumor pain; infrequent: paraneoplastic syndrome;

Blood and lymphatic system disorders:

frequent: anemia, lymphopenia;

infrequent: neutropenia, thrombocytopenia, eosinophilia, hemolytic anemia;

Immune system disorders:

infrequent: hypersensitivity;

very rare: anaphylactic reactions (shock);

Endocrine system disorders:

frequent: hypopituitarism (including hypophysitis); hypothyroidism;

infrequent: adrenal insufficiency, hyperthyroidism, hypogonadism.

Disorders of the metabolic and nutritional system:

very frequent: decreased appetite;

frequent: hypokalemia, dehydration;

infrequent: hyponatremia, alkalosis, hypophosphatemia, tumor lysis syndrome.

Nervous system disorders:

frequent: confusion, peripheral sensory neuropathy, dizziness, headaches, lethargy;

infrequent: altered mental status, depression, decreased libido, Guillain-Barré syndrome1, syncope, cranial neuropathy, cerebral edema, peripheral neuropathy, ataxia, tremor, myoclonia, speech disorders;

Visual side:

frequent: blurred vision, eye pain;

infrequent: uveitis, vitreous hemorrhage, iris inflammation, decreased visual acuity, sensation of a foreign body in the eye, conjunctivitis;

Cardiovascular system:

frequent: decreased blood pressure, hyperemia, “flushes” with a sensation of heat;

infrequent: arrhythmia, atrial fibrillation, vasculitis, angiopathy1, peripheral ischemia, orthostatic hypotension;

Respiratory system:

frequent: shortness of breath, cough;

infrequent: respiratory failure, acute respiratory distress syndrome1, pulmonary infiltration, pulmonary edema, pneumonitis, allergic rhinitis;

gastrointestinal tract:

very frequent: diarrhea, vomiting, nausea;

frequent: gastrointestinal bleeding, colitis1, constipation, gastroesophageal reflux disease, abdominal pain;

infrequent: gastrointestinal perforation1, colonic perforation1, peritonitis (includingincluding infectious)1, pancreatitis (including autoimmune). autoimmune), enterocolitis, peptic ulcer, colonic ulcer, esophagitis, intestinal obstruction, mucosal inflammation;

Hepatic and biliary tract disorders:

frequent: impaired liver function;

infrequent: liver failure1, hepatitis, hepatomegaly, jaundice;

Skin and subcutaneous tissue:

very common: rash, itching;

frequent: dermatitis, erythema, vitiligo, urticaria, alopecia, night sweats, dry skin;

infrequent: toxic epidermal necrolysis1,2, leukocytoclastic vasculitis, skin exfoliation, eczema, hair color changes;

Motor system disorders:

frequent: myalgia, arthralgia, musculoskeletal pain, muscle spasms;

infrequent: rheumatic polymyalgia, arthritis;

Renal and urinary tract disorders:

infrequent: renal failure1, glomerulonephritis, renal tubular acidosis;

Reproductive system disorders:

infrequent: amenorrhea;

General disorders and reactions to the drug administration:

very frequent: fatigue, injection site reactions, pyrexia;

frequent: chills, asthenia, edema, pain, flu-like illness;

infrequent: multiple organ failure1, reactions to the drug administration rare: systemic inflammatory reaction syndrome1;

Laboratory findings:

frequent: increased alanine aminotransferase (ALT) activity, increased aspartate aminotransferase (ACT) activity, increased blood concentration of total bilirubin, increased alkaline phosphatase activity, weight loss;

infrequent: increased gamma-glutamyltransferase activity, increased blood creatinine concentration, increased blood thyrotropic hormone concentration, decreased blood cortisol concentration, decreased blood corticotropic hormone concentration, increased lipase activity, increased blood amylase activity, decreased blood testosterone concentration;

rare: abnormal blood prolactin concentration.

NOTE:

1Including fatal adverse reactions.

2 For more information on these adverse events, see “Special Precautions”.

The following adverse reactions (less than 3 mg/kg, more than 3 mg/kg) have been reported in clinical trials investigating the use of other doses of ERVOY® for the indication “melanoma” (less than 3 mg/kg, more than 3 mg/kg) (incidence less than 1%): Meningism, myocarditis, pericardial effusion (pericarditis), cardiomyopathy, autoimmune hepatitis, erythema multiforme, nodular erythema, autoimmune nephritis, myasthenia gravis-like symptoms, muscle weakness autoimmune thyroiditis, hyperpituitarism, secondary adrenal cortex insufficiency, parathyroid gland insufficiency, thyroiditis, episcleritis, blepharitis, ocular edema, scleritis, temporal artery inflammation, Raynaud syndrome, Raynaud’s disease, proctitis, palmar erythrodysesthesia syndrome, psoriasis, hematuria, proteinuria, decreased concentration of thyrotropic hormone in blood, decreased concentration of gonadotropin in blood, decreased concentration of thyroxine in blood, leukopenia, polycythemia, hypocalcemia, lymphocytosis, cytokine release syndrome, sarcoidosis, sensorineural hearing loss, autoimmune central neuropathy (encephalitis), myositis, polymyositis, myositis of the eye muscles.

Overdose

The maximum tolerated dose of ERVOY® has not been established. Doses up to and including 20 mg/kg have been used in clinical studies; no obvious toxic effects of the drug have been observed at this dose.

In case of overdose, treatment should be symptomatic drug therapy in accordance with the adverse reactions that occur while closely monitoring the patient.