Philachromin^® (Capsules) Instructions for Use

Marketing Authorization Holder

Pharmental Group, LLC (Russia)

Manufactured By

Nativa, LLC (Russia)

Or

Pharmstandard-UfaVITA OJSC (Russia)

ATC Code

L01EA01 (Imatinib)

Active Substance

Imatinib (Rec.INN registered by WHO)

Dosage Forms

	Philachromin®	Capsules 50 mg: 30 pcs.
		Capsules 100 mg: 24, 36, 48, 96, 120 or 180 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size 3, white body, dark green cap; capsule contents – powder or powder with granules from white to yellow with a brownish tint.

Excipients: microcrystalline cellulose – 46 mg, crospovidone – 7.5 mg, colloidal silicon dioxide – 0.75 mg, magnesium stearate – 1 mg.

Capsule body composition titanium dioxide – 2%, gelatin – up to 100%.
Capsule cap composition indigo carmine – 0.3%, titanium dioxide – 1%, yellow iron oxide – 1.7143%, gelatin – up to 100%..

10 pcs. – blister packs (3) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.

Capsules hard gelatin, size 1, white body, dark green cap; capsule contents – powder or powder with granules from white to yellow with a brownish tint.

Excipients: microcrystalline cellulose – 92 mg, crospovidone – 15 mg, colloidal silicon dioxide – 1.5 mg, magnesium stearate – 2 mg.

Capsule body composition titanium dioxide – 2%, gelatin – up to 100%.
Capsule cap composition indigo carmine – 0.3%, titanium dioxide – 1%, yellow iron oxide – 1.7143%, gelatin – up to 100%.

6 pcs. – blister packs (4) – cardboard packs.
6 pcs. – blister packs (6) – cardboard packs.
6 pcs. – blister packs (8) – cardboard packs.
6 pcs. – blister packs (16) – cardboard packs.
6 pcs. – blister packs (20) – cardboard packs.
6 pcs. – blister packs (30) – cardboard packs.
12 pcs. – blister packs (2) – cardboard packs.
12 pcs. – blister packs (3) – cardboard packs.
12 pcs. – blister packs (4) – cardboard packs.
12 pcs. – blister packs (8) – cardboard packs.
12 pcs. – blister packs (10) – cardboard packs.
12 pcs. – blister packs (15) – cardboard packs.
24 pcs. – polymer bottles (1) – cardboard packs.
36 pcs. – polymer bottles (1) – cardboard packs.
48 pcs. – polymer bottles (1) – cardboard packs.
96 pcs. – polymer bottles (1) – cardboard packs.
120 pcs. – polymer bottles (1) – cardboard packs.
180 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; BCR-ABL tyrosine kinase inhibitors

Pharmacological Action

Imatinib selectively inhibits the enzyme Ber-Abl tyrosine kinase, which is formed by the fusion of the Ber (breakpoint cluster region) gene region and the Abl (Abelson) proto-oncogene at the cellular level.

Imatinib selectively suppresses proliferation and induces apoptosis of cell lines expressing Ber-Abl tyrosine kinase, as well as immature leukemic cells in chronic myeloid leukemia with positive Philadelphia chromosome and in acute lymphoblastic leukemia.

In patients with chronic myeloid leukemia, Imatinib selectively inhibits Ber-Abl-positive colonies and has antitumor activity in monotherapy.

Imatinib selectively inhibits Ber-Abl-positive colonies obtained from blood cells of patients with chronic myeloid leukemia.

Activation of platelet-derived growth factor receptors or the Abl fragment of tyrosine kinase can be the cause of both myelodysplastic/myeloproliferative diseases and hypereosinophilic syndrome and chronic eosinophilic leukemia and dermatofibrosarcoma protuberans.

Activation of the c-Kit receptor tyrosine kinase and platelet-derived growth factor receptors may underlie the pathogenesis of systemic mastocytosis.

Imatinib inhibits signal transduction in cells and cell proliferation resulting from dysregulation of platelet-derived growth factor and stem cell factor, c-Kit receptor, and Abl fragment tyrosine kinase activity.

Imatinib inhibits proliferation and induces apoptosis of gastrointestinal stromal tumor cells expressing tyrosine kinase with a mutated c-Kit receptor.

Pharmacokinetics

Absorption

After oral administration, the bioavailability of imatinib averages 98%. When the drug is taken with a high-fat meal, compared to taking it on an empty stomach, a slight decrease in the extent of absorption and a slowdown in the rate of absorption are noted. The coefficient of variation for the AUC indicator is 40-60%.

Distribution

Binding to plasma proteins is about 95% (mainly to albumin and acidic alpha-glycoproteins, to a lesser extent to lipoproteins).

Metabolism

Imatinib is metabolized mainly in the liver. The main metabolite of imatinib circulating in the bloodstream is the N-demethylated piperazine derivative, which in vitro has pharmacological activity similar to that of the parent drug.

Excretion

Imatinib is excreted mainly as metabolites within 7 days after a single dose (via the intestine – 68%, via the kidneys – 13%). About 25% of the dose is excreted unchanged (20% via the intestine and 5% via the kidneys). T_1/2 of imatinib is about 18 hours. With repeated doses administered once daily, the pharmacokinetics of imatinib do not change. The steady-state concentration value exceeds the initial value by 1.5-2.5 times.

Pharmacokinetics in special clinical cases

In patients over 65 years of age, V_d slightly increases (by 12%). The clearance value of imatinib increases with increasing patient body weight. However, these changes do not require dose adjustment of the drug depending on the patient’s body weight and age.

The pharmacokinetics of imatinib does not depend on gender.

As in adults, in children and adolescents under 18 years of age, the drug is rapidly absorbed after oral administration. Accumulation of the drug after repeated administration has been established.

In case of impaired liver function, serum concentrations of imatinib may increase. When using imatinib in patients with mild or moderate renal impairment (creatinine clearance > 30 ml/min), an increase in drug exposure in plasma by 1.5-2 times is noted, corresponding to an increase in the concentration of acidic alpha-glycoproteins (the main plasma proteins that bind to imatinib). No correlation was found between drug exposure and the severity of renal impairment.

Indications

• Newly diagnosed Philadelphia chromosome-positive (Ph+), chronic myeloid leukemia in children and adults;
• Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in the chronic phase after failure of prior interferon alpha therapy or in the accelerated phase, or blast crisis in children and adults;
• Newly diagnosed Philadelphia chromosome-positive (Ph+);
• Acute lymphoblastic leukemia in adult patients in combination with chemotherapy;
• Relapsed or refractory Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia in adult patients as monotherapy;
• Myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements in adult patients;
• Systemic mastocytosis in adult patients lacking the D816V c-Kit mutation or with unknown c-Kit mutation status;
• Hypereosinophilic syndrome and/or chronic eosinophilic leukemia in adult patients with positive or negative abnormal FIP1L1-PDGRF alpha tyrosine kinase;
• Adjuvant therapy of gastrointestinal stromal tumors (GIST) positive for c-Kit (CD 117) in adult patients;
• Inoperable and/or metastatic malignant gastrointestinal stromal tumors (GIST) positive for c-Kit (CD 117) in adult patients;
• Inoperable, recurrent and/or metastatic dermatofibrosarcoma protuberans in adult patients.

ICD codes

Dosage Regimen

Philachromin^® should be taken orally, with a meal, with a full glass of water.

Doses of 400 and 600 mg per day should be taken in one dose, the daily dose of 800 mg should be divided into two doses – 400 mg in the morning and 400 mg in the evening. For patients (including children) who cannot swallow the capsule whole, the capsule contents are diluted with water or apple juice. The resulting “suspension” should be taken orally immediately after preparation.

For chronic myeloid leukemia (CML) the recommended dose of Philachromin^® depends on the phase of the disease. In the chronic phase of CML the dose for adults is 400 mg/day; in the accelerated phase and blast crisis – 600 mg/day. The drug should be taken once a day. Treatment with the drug is continued as long as the clinical effect persists.

In the absence of severe adverse effects and neutropenia or thrombocytopenia not associated with leukemia, it is possible to increase the dose from 400 mg to 600 mg or to 800 mg in patients in the chronic phase of the disease and from 600 mg to 800 mg per day in patients in the accelerated phase and blast crisis. Such a dose increase may be necessary in case of CML progression (at any stage), in the absence of a satisfactory hematological response after 3 months of treatment, a cytogenetic response after 12 months of therapy, or loss of a previously achieved hematological and/or cytogenetic response.

The calculation of the dosage regimen in children over 2 years of age is based on body surface area (mg/m²).

For children with chronic phase and accelerated phase CML the recommended dose is 340 mg/m²/day. The total daily dose in children should not exceed 600 mg. The daily dose of the drug can be taken at one time or divided into two equal doses – in the morning and in the evening.

There are no data on the use of the drug in children under 2 years of age.

For acute lymphoblastic leukemia with (Ph+) the recommended dose of Philachromin^® is 600 mg/day.

For myelodysplastic/myeloproliferative diseases (MDS/MPD) the recommended dose of Philachromin^® is 400 mg/day.

For inoperable and/or metastatic GIST the recommended dose of Philachromin^® is 400 mg/day. In the absence of adverse effects of the drug and an insufficient response, it is possible to increase the daily dose of Philachromin^® from 400 mg to 600 mg or to 800 mg.

Treatment with Philachromin^® is continued until the first signs of disease progression.

When using the drug as adjuvant therapy in patients with GIST, the recommended dose is 400 mg/day. The optimal duration of adjuvant therapy has not been established.

For inoperable, recurrent and/or metastatic dermatofibrosarcoma protuberans the recommended dose of Philachromin^® is 800 mg/day.

For hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CEL) in adult patients the recommended dose of Philachromin^® is 400 mg/day. In patients with HES/CEL caused by abnormal FIP1L1-PDGFR alpha tyrosine kinase, the recommended initial dose is 100 mg/day. If the effectiveness is insufficient and there are no severe adverse effects, it is possible to increase the daily dose to 400 mg. Treatment with the drug is continued as long as the clinical effect persists.

For systemic mastocytosis in the absence of the D816V c-Kit mutation the recommended dose of Philachromin^® is 400 mg/day. With an unknown mutation status and insufficient effectiveness of previous therapy, the recommended dose is 400 mg/day.

For systemic mastocytosis caused by abnormal FIP1L1-PDGFR alpha tyrosine kinase, formed as a result of the fusion of the Fip 1L1 and PDGFR genes, the recommended initial dose is 100 mg/day. Increasing the dose from 100 mg to 400 mg may be considered if the effectiveness is insufficient and there are no adverse effects.

Patients with impaired liver function

Since Imatinib is metabolized mainly in the liver, patients with mild, moderate or severe liver dysfunction should be prescribed the drug at the minimum daily dose – 400 mg. If undesirable toxic effects develop, the dose of the drug should be reduced. Patients with severe hepatic insufficiency should be prescribed the drug with caution.

Patients with impaired renal function

The kidneys do not play a significant role in the excretion of imatinib and its metabolites. In patients with mild or moderate renal impairment, treatment should be started with the minimum effective dose – 400 mg once a day. Although experience with imatinib in patients with severe renal impairment or undergoing regular hemodialysis is limited, therapy with the drug in this category of patients can also be started at a dose of 400 mg once a day. If therapy with imatinib is poorly tolerated, the initial dose of the drug may be reduced; if the effectiveness is insufficient, it may be increased.

Elderly patients

In elderly patients, no adjustment of the drug dosage regimen is required.

Adjustment of the dosage regimen for the development of non-hematological adverse effects of the drug

Treatment should be suspended if any serious non-hematological adverse effect associated with taking the drug develops until the situation resolves. Then treatment can be resumed depending on the severity of the observed serious adverse effect.

If the concentration of bilirubin and the activity of liver transaminases in the blood serum increase to 3 and 5 times the upper limit of normal (ULN), respectively, treatment with the drug should be temporarily suspended until the bilirubin concentration decreases to less than 1.5 x ULN and the activity of liver transaminases to less than 2.5 x ULN. Therapy with Philachromin^® should be resumed at a reduced daily dose: in adults, the dose is reduced from 400 mg to 300 mg per day or from 600 mg to 400 mg per day, or from 800 mg to 600 mg per day; in children – from 340 to 260 mg/m² per day.

Adjustment of the dosage regimen for the development of serious adverse effects from the hematopoietic system (severe thrombocytopenia, neutropenia)

If neutropenia and thrombocytopenia occur, temporary withdrawal of the drug or a reduction in its dose is required, depending on the severity of these adverse effects.

Recommendations for dose reduction in accordance with the development of neutropenia and thrombocytopenia are presented in the table

Adverse Reactions

In the advanced stage of CML or GIST, patients may have multiple concomitant disorders that complicate the assessment of imatinib adverse reactions due to a range of symptoms associated with comorbidities, their progression, and the use of various medications.

It is known that daily long-term oral administration of imatinib in adults and children with CML is generally well tolerated. In most patients, adverse effects that are mild or moderate in severity are possible at a certain stage of treatment.

Adverse effects are similar in patients receiving Imatinib for various indications.

In patients with malignant GIST, myelosuppression is less common, and intratumoral bleeding is characteristic only of this group.

The incidence of adverse effects and the overall frequency of adverse effects of varying severity are similar in patients receiving imatinib therapy at a dose of 400 mg per day and 800 mg per day.

The most frequent adverse effects associated with the drug intake are transient mild nausea, vomiting, diarrhea, abdominal pain, increased fatigue, myalgia and muscle cramps, rash, peripheral edema predominantly in the periorbital area and lower limbs. All these phenomena are easily controlled.

Combined adverse reactions, such as pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without peripheral edema, can be generally classified as “fluid retention”. To eliminate the aforementioned adverse effects, it is necessary to temporarily discontinue imatinib therapy and prescribe diuretics. In some cases, these phenomena can reach a serious and even life-threatening degree.

Adverse reactions reported more frequently than isolated observations are listed below by organs and systems with an indication of their frequency of occurrence. Frequency definition: very common (> 10%), common (from > 1% to < 10%), uncommon (>0.1% to < 1%), rare (>0.01% to < 0.1%), very rare (< 0.01%), including isolated reports.

Infections and infestations uncommon – herpes simplex, herpes zoster, pneumonia¹, upper respiratory tract infections, nasopharyngitis, sinusitis, cellulitis, influenza, urinary tract infections, gastroenteritis, sepsis; rare – fungal infections.

Benign, malignant and unspecified neoplasms (including cysts and polyps): rare – tumor lysis syndrome.

Blood and lymphatic system disorders: very common – neutropenia, thrombocytopenia, anemia; common – pancytopenia, febrile neutropenia; uncommon – thrombocytopenia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy; rare – hemolytic anemia.

Metabolism and nutrition disorders common – anorexia; uncommon – hypokalemia, increased appetite or decreased appetite, gout, hypophosphatemia, dehydration, hyperuricemia, hyponatremia, hypercalcemia, hyperglycemia; rare – hyperkalemia, hypomagnesemia.

Psychiatric disorders common – insomnia; uncommon – depression, anxiety, decreased libido; rare – confusion.

Nervous system disorders very common – headache²; common – dizziness, taste disturbance, paresthesia, hypoesthesia; uncommon – migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome (Wittmaack-Ekbom syndrome), tremor, hemorrhagic stroke, cerebral edema; rare – increased intracranial pressure, convulsions, optic neuritis.

Eye disorders common – eyelid edema, conjunctivitis, increased lacrimation, blurred vision, conjunctival hemorrhage, conjunctival xerosis; uncommon – eye irritation, eye pain, orbital edema, macular edema, papilledema, retinal hemorrhages, blepharitis; rare – cataract, glaucoma, optic disc edema, vitreous hemorrhage.

Ear and labyrinth disorders uncommon – vertigo, tinnitus, hearing loss, vertigo.

Cardiac disorders: uncommon – palpitations, congestive heart failure³, pulmonary edema, tachycardia, increased capillary permeability; increased blood pressure, decreased blood pressure, flushing⁴, thromboses/embolisms; rare – arrhythmias, atrial fibrillation, atrial fibrillation, sudden cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion, pericarditis, cardiac tamponade.

Vascular disorders uncommon – hemorrhages⁴; rare – hematomas, cold extremities, Raynaud’s syndrome.

Respiratory, thoracic and mediastinal disorders: common – epistaxis, dyspnea, cough; uncommon – pleural effusion⁵, pharyngeal pain, or, laryngeal pain, pharyngitis, acute respiratory failure, interstitial pneumonia; rare – pleural pain, pulmonary fibrosis, pleurisy, pulmonary hypertension, pulmonary hemorrhage.

Gastrointestinal disorders: very common – nausea, vomiting, diarrhea, dyspepsia, reflux esophagitis, abdominal pain⁶; common – abdominal distension, flatulence, constipation, mouth ulceration, stomatitis, dry mouth, gastritis, pancreatitis; uncommon – eructation, gastrointestinal hemorrhages⁷, tumor necrosis, cheilitis, ascites, gastric ulcer, dysphagia, melena, pancreatitis, diverticulitis; rare – colitis, paralytic/obstructive ileus, enterocolitis, diverticulitis.

Hepatobiliary disorders common – increased hepatic enzymes; uncommon – jaundice, hepatitis, hyperbilirubinemia; rare – hepatic failure⁹, hepatic necrosis⁹.

Skin and subcutaneous tissue disorders very common – periorbital edema, dermatitis, eczema, skin rash; common – face edema, eyelid edema, pruritus, erythema, dry skin, alopecia, night sweats, photosensitivity reactions; uncommon – petechiae, ecchymosis, hyperhidrosis, urticaria, ecchymoses, easy bruising, urticaria, nail disorder, purpura, hypotrichosis, skin hyperpigmentation/hypopigmentation, folliculitis, psoriasis, exfoliative dermatitis, bullous rash; rare – acute febrile neutrophilic dermatosis (Sweet’s syndrome), angioedema, nail discoloration, erythema multiforme, leukocytoclastic vasculitis, vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, lichenoid keratosis, lichen planus; very rare – toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders very common – muscle spasms and cramps, musculoskeletal pain including myalgia, arthralgia, bone pain⁸; common – joint swelling; uncommon – sciatica, muscle and joint stiffness; rare – muscle weakness, arthritis, acute necrosis of skeletal muscles (rhabdomyolysis), myopathy, avascular necrosis of femoral head.

Renal and urinary disorders uncommon – renal failure, renal pain, pollakiuria, hematuria, acute renal failure.

Reproductive system and breast disorders uncommon – gynecomastia, breast enlargement, nipple pain, scrotal edema, decreased potency, erectile dysfunction, sexual dysfunction, menorrhagia, menstrual disorder; very rare – ovarian cyst hemorrhage in women.

General disorders and administration site conditions: very common – fluid retention and edema, increased fatigue; common – asthenia, pyrexia, chills, tremor, anasarca; uncommon – malaise, chest pain.

Investigations: very common – weight increased; common – weight decreased; uncommon – increased alkaline phosphatase, creatine phosphokinase, lactate dehydrogenase and serum creatinine concentrations; rare – increased plasma amylase; very rare – anaphylactic shock.

¹Pneumonia is most frequently reported in patients with CML in accelerated phase, blast crisis and with inoperable and/or metastatic malignant GIST.
² Headache is most frequently reported in patients with inoperable and/or metastatic GIST.

³Cardiac adverse events, including congestive heart failure, are more frequently reported in patients with CML in accelerated phase and blast crisis compared to patients with CML in chronic phase.

⁴ Flushing is most frequently reported in patients with inoperable and/or metastatic malignant GIST; hemorrhages (hematomas, hemorrhages) are most frequently reported in patients with CML in accelerated phase, blast crisis and with inoperable and/or metastatic malignant GIST.

⁵Pleural effusion is more frequently reported in patients with CML in accelerated phase and blast crisis compared to patients with CML in chronic phase.

^6/7Abdominal pain and gastrointestinal hemorrhages are most frequently reported in patients with inoperable and/or metastatic malignant GIST.

⁸Musculoskeletal pain, including myalgia, arthralgia, bone pain, are more frequently reported in patients with inoperable and/or metastatic malignant GIST.

⁹ Isolated cases of hepatic failure and hepatic necrosis have been reported.

Contraindications

• Children under 2 years of age (efficacy and safety have not been established);
• Pregnancy;
• Breastfeeding period;
• Hypersensitivity to the active substance or any other component of the drug.

Should be used with caution in patients with severe hepatic impairment, severe renal impairment, cardiovascular diseases or in the presence of risk factors for heart failure, as well as during regular hemodialysis procedure.

Use in Pregnancy and Lactation

Currently, there are no data on the use of imatinib in pregnant women. Imatinib has toxic effects on reproductive function, but the potential risk to the fetus is currently unknown.

Imatinib should not be prescribed during pregnancy, except in cases where it is vitally necessary, and the patient should be warned about the potential risk to the fetus. Women of childbearing potential should use effective contraceptive methods during imatinib therapy.

It is known that unchanged Imatinib and/or its metabolites are excreted in significant amounts in milk. Women taking Philachromin^® should discontinue breastfeeding.

Use in Hepatic Impairment

Since Imatinib is metabolized mainly in the liver, patients with mild, moderate or severe hepatic impairment should receive the drug at the minimum daily dose of 400 mg. If undesirable toxic effects develop, the drug dose should be reduced. Patients with severe hepatic impairment should be treated with caution.

Use in Renal Impairment

The kidneys do not play a significant role in the excretion of imatinib and its metabolites. In patients with mild or moderate renal impairment, treatment should be started with the minimum effective dose of 400 mg once daily. Although experience with imatinib in patients with severe renal impairment or undergoing regular hemodialysis procedure is limited, therapy in this category of patients can also be started at a dose of 400 mg once daily. If imatinib therapy is poorly tolerated, the initial dose of the drug may be reduced; if the efficacy is insufficient, it may be increased.

Pediatric Use

Contraindicated in children under 2 years.

Geriatric Use

In elderly patients, no dose adjustment of the drug is required.

Special Precautions

Treatment with Philachromin^® should be carried out only under the supervision of a physician experienced in the use of anticancer drugs.

Caution is recommended when handling the capsule contents to avoid contact with the skin, mucous membranes of the eyes, or accidental inhalation of the drug powder. After opening the capsules, hands should be washed immediately.

Regular clinical blood tests and monitoring of liver function (transaminases, bilirubin, alkaline phosphatase) are recommended.

When prescribing the drug to patients with liver diseases, regular clinical peripheral blood tests and liver enzyme tests should be performed.

Close monitoring of patients with heart disease is recommended.

In elderly patients with cardiovascular diseases, body weight should be regularly determined, as pronounced fluid retention is often observed with the use of imatinib.

In case of rapid unexpected weight gain, the patient should be examined and, if necessary, Philachromin^® therapy should be temporarily discontinued and/or diuretics should be prescribed. In isolated cases, pronounced fluid retention can have a severe course with a fatal outcome.

In patients with malignant GIST, gastrointestinal bleeding and tumor bleeding are possible. Both intra-abdominal and intrahepatic bleeding are observed, depending on the anatomical location of the tumor.

In patients with MDS/MPN and a high level of eosinophils, ECG examination and determination of serum troponin concentration should be performed. If abnormalities are detected at the beginning of therapy, the possibility of prophylactic use of systemic corticosteroids (1-2 mg/kg) for 1-2 weeks simultaneously with imatinib should be considered.

Marked increases in transaminase levels or bilirubin are observed in less than 3% of patients with CML and are usually controlled by dose reduction or temporary interruption of treatment (the average duration of such episodes is about 1 week).

The efficacy and safety of Philachromin^® in children under 2 years of age have not yet been established.

Patients who have undergone thyroidectomy and are receiving replacement therapy with levothyroxine sodium require regular determination of thyroid-stimulating hormone concentration, as hypothyroidism may develop.

In patients with hypereosinophilic syndrome and heart disease at the beginning of imatinib therapy, isolated cases of cardiogenic shock/left ventricular failure have been observed, which were controlled by the administration of systemic corticosteroids, measures aimed at maintaining circulation, and temporary withdrawal of imatinib.

The kidneys do not play a significant role in the excretion of imatinib and its metabolites. There are no specific recommendations for the dosing regimen of Philachromin^® in patients with renal impairment.

Effects on ability to drive and use machines

Currently, there are no data on the possible effect of Philachromin^® on the ability to drive vehicles and operate machinery. Nevertheless, considering that the use of the drug may lead to the development of such adverse effects as dizziness, fainting, and blurred vision, it is recommended to exercise caution when driving a car or working with machinery.

Overdose

Cases of imatinib overdose have been observed in clinical practice. In general, the outcome of overdose was favorable (patients’ condition improved). An antidote to imatinib is not known. In case of overdose, medical observation and symptomatic therapy are recommended.

Overdose in adults

When taking imatinib at a dose of 1200-1600 mg for 1-10 days, a patient with CML in blast crisis experienced nausea, vomiting, diarrhea; skin rash, erythema, edema, joint swelling, increased fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

When taking imatinib at a dose of 1800-3200 mg (the highest dose was 3200 mg/day for 6 days), weakness, myalgia, gastrointestinal pain, increased blood concentrations of creatine phosphokinase and bilirubin were observed. When imatinib was used at a single dose of 6400 mg, the patient developed nausea, vomiting, abdominal pain, hyperthermia, facial edema, decreased neutrophil count, and increased liver transaminase activity.

When taking imatinib at a single dose of 8-10 g, vomiting and gastrointestinal pain were observed.

Overdose in children and adolescents

When taking imatinib at a single dose of 400 mg, a 3-year-old child experienced vomiting, diarrhea, and anorexia. In another case, when taking imatinib at a single dose of 980 mg, a 3-year-old child experienced diarrhea and decreased white blood cell count.

Drug Interactions

An increase in imatinib plasma concentration is possible with simultaneous use of imatinib with drugs that inhibit the cytochrome P450 isoenzyme CYP3A4 (ketoconazole, itraconazole, erythromycin, clarithromycin) due to slowing of imatinib metabolism. Caution is necessary when using Philachromin^® concomitantly with drugs that are inhibitors of CYP3A4 isoenzymes.

Concomitant use with drugs that are inducers of CYP3A4 (e.g., dexamethasone, rifampicin, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, phenobarbital, fosphenytoin, primidone, or preparations containing St. John’s wort) may lead to accelerated metabolism of imatinib and, consequently, a decrease in its plasma concentration.

With simultaneous use of imatinib and simvastatin, an increase in the blood concentration of simvastatin is observed, which is a consequence of inhibition of CYP3A4 by imatinib.

Caution is recommended with simultaneous use of imatinib and drugs that are substrates of CYP3A4 and have a narrow therapeutic range (e.g., cyclosporine and pimozide).

Imatinib may increase serum concentrations of other drugs metabolized by the CYP3A4 isoenzyme (triazolobenzodiazepines, dihydropyridines, slow calcium channel blockers, most HMG-CoA reductase inhibitors, including statins).

Imatinib in vitro also inhibits CYP2C9 and CYP2C19.

With simultaneous use with warfarin, an increase in prothrombin time is possible. With concomitant use with coumarin derivatives, short-term monitoring of prothrombin time is necessary at the beginning and end of imatinib therapy, as well as when changing the imatinib dosing regimen. Alternatively, the use of low molecular weight heparin derivatives should be considered.

When imatinib is combined with high-dose chemotherapeutic drugs, transient hepatotoxicity in the form of increased liver transaminase activity and hyperbilirubinemia may develop.

When combining imatinib and chemotherapy regimens that may potentially have a hepatotoxic effect, liver function monitoring should be provided. In vitro, Imatinib inhibits the CYP2D6 isoenzyme at the same concentrations at which it inhibits CYP3A4. In this regard, the possibility of enhanced effects of drugs that are substrates of the CYP2D6 isoenzyme when used concomitantly with imatinib should be taken into account.

When using imatinib at a dose of 400 mg twice daily concomitantly with metoprolol, a substrate of the CYP2D6 enzyme, a moderate decrease in metoprolol metabolism was observed, accompanied by an increase in C_max and AUC by approximately 21%. Given the moderate enhancement of the effects of drugs that are substrates of the CYP2D6 isoenzyme (e.g., metoprolol) when used concomitantly with imatinib, no dose adjustment is required.

In vitro, Imatinib inhibits the O-glucuronidation of paracetamol. A case of acute liver failure with a fatal outcome has been described in a patient with the simultaneous use of imatinib and paracetamol. Caution should be exercised when using imatinib concomitantly with paracetamol.

Storage Conditions

In a dry place, protected from light, at a temperature between 15°C (59°F) and 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.