Glemyhib^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

L01EA01 (Imatinib)

Active Substance

Imatinib (Rec.INN registered by WHO)

Dosage Forms

	Glemyhib®	Film-coated tablets, 100 mg: 100 or 120 pcs.
		Film-coated tablets, 400 mg: 100 or 120 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from dark yellow to brownish-orange in color, round, biconvex, with a score and engravings “I” and “1” on either side of the score on one side of the tablet and smooth on the other; the cross-section shows two layers: a coating from dark yellow to brownish-orange in color and an almost white core.

Excipients: magnesium stearate – 0.5 mg.

Film coating composition Opadry 03F565018 brown – 2.25 mg (hypromellose (E464) – 62.5%, talc (E553b) – 6%, macrogol 6000 – 6.5%, iron oxide yellow (E172) – 24%, iron oxide red (E172) – 1%).

10 pcs. – blisters (12) – cardboard packs.
100 pcs. – bottles (1) – cardboard packs.

Film-coated tablets from dark yellow to brownish-orange in color, oval, biconvex, with a score and engravings “I” and “2” on either side of the score on one side of the tablet and smooth on the other; the cross-section shows two layers: a coating from dark yellow to brownish-orange in color and an almost white core.

Excipients: magnesium stearate – 2 mg.

Film coating composition Opadry 03F565018 brown – 9 mg (hypromellose (E464) – 62.5%, talc (E553b) – 6%, macrogol 6000 – 6.5%, iron oxide yellow (E172) – 24%, iron oxide red (E172) – 1%).

10 pcs. – blisters (12) – cardboard packs.
100 pcs. – bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Protein kinase inhibitor

Pharmacotherapeutic Group

Antineoplastic agent, protein tyrosine kinase inhibitor

Pharmacological Action

Protein tyrosine kinase inhibitor. It inhibits the Bcr-Abl tyrosine kinase enzyme at the cellular level, in vitro and in vivo. It selectively suppresses the proliferation and induces apoptosis of Bcr-Abl-positive cell lines, as well as young leukemic cells in chronic myeloid leukemia with a positive Philadelphia chromosome and in acute lymphoblastic leukemia.

In colony transformation studies conducted on samples of peripheral blood and bone marrow, it was shown that Imatinib selectively inhibits Bcr-Abl-positive colonies obtained from patients with chronic myeloid leukemia.

In in vivo studies on animal models using Bcr-Abl-positive tumor cells, it was shown that Imatinib has antitumor activity in monotherapy.

In addition, Imatinib is an inhibitor of tyrosine kinase receptors for platelet-derived growth factor and stem cell factor, and also suppresses cellular responses mediated by the aforementioned factors.

In vitro, Imatinib inhibits the proliferation and induces apoptosis of gastrointestinal stromal tumor cells expressing kit mutations.

Pharmacokinetics

After oral administration, the bioavailability averages 98%. The coefficient of variation for AUC is 40-60%. When taken with a high-fat meal compared to fasting, a slight decrease in the extent of absorption (decrease in C_max by 11%, AUC by 7.4%) and a slowdown in the rate of absorption (prolongation of T_max by 1.5 hours) are noted.

At clinically significant concentrations of imatinib, its binding to plasma proteins is about 95% (mainly to albumin and acid alpha-1-glycoprotein, to a lesser extent to lipoprotein).

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 unchanged active substance. The AUC value for the metabolite is 16% of the imatinib AUC.

After oral administration of ¹⁴C-labeled imatinib, 68% of the administered dose was excreted in feces and 13% of the dose in urine over 7 days. About 25% of the dose is excreted unchanged (20% in feces and 5% in urine). The remaining amount of imatinib is excreted as metabolites.

The T_1/2 of imatinib in healthy volunteers was about 18 hours.

In case of impaired liver function, an increase in the plasma concentration of imatinib is possible.

Indications

Newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in children and adults; Ph+ CML 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 acute lymphoblastic leukemia (Ph+ ALL) in children and adult patients in combination with chemotherapy; recurrent or refractory Ph+ ALL 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 without the D816V c-Kit mutation or with an unknown c-Kit mutation status; hypereosinophilic syndrome and/or chronic eosinophilic leukemia in adult patients with positive or negative abnormal FIP1L1-PDGFR alpha tyrosine kinase; inoperable and/or metastatic malignant gastrointestinal stromal tumors (GIST), positive for c-Kit (CD117) in adult patients; adjuvant therapy in adult patients with GIST, positive for c-Kit (CD117); inoperable, recurrent and/or metastatic dermatofibrosarcoma protuberans in adult patients.

ICD codes

Dosage Regimen

Take orally, with a meal and a large glass of water to minimize gastrointestinal irritation.

The recommended daily dose for adults with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase is 400 mg once daily.

The recommended daily dose for adults with Ph+ CML in the accelerated phase or blast crisis is 600 mg once daily.

For adult patients with recurrent or refractory Ph+ ALL, the recommended dose as monotherapy is 600 mg once daily.

For adult patients with unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST), the recommended dose is 400 mg once daily.

Dose escalation from 400 mg to 600 mg or 800 mg, given as 400 mg twice daily, may be considered in CML and GIST patients with disease progression, inadequate response, or loss of previous response.

For pediatric patients with newly diagnosed Ph+ CML in the chronic phase, the recommended daily dose is 340 mg/m² (not to exceed 600 mg).

For pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis, and for pediatric patients with newly diagnosed Ph+ ALL, the recommended daily dose is 340 mg/m² (not to exceed 600 mg).

Calculate the dose for children using body surface area (BSA). Administer the daily dose as a single dose or divided into two doses (once or twice daily).

Treatment continues as long as the patient derives clinical benefit. Dosing may be temporarily interrupted and/or reduced for severe adverse reactions such as severe neutropenia, thrombocytopenia, or severe non-hematological adverse reactions.

For patients with severe hepatic impairment, reduce the recommended dose by 25%.

For patients with severe renal impairment (CrCl < 30 mL/min), consider reducing the recommended starting dose by 50%.

Monitor response and adjust dose based on individual tolerance and efficacy. Regularly perform complete blood counts and liver function tests.

Adverse Reactions

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

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

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

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

Nervous system disorders: very common – headache; common – dizziness, paresthesia, taste disturbance, hypoesthesia; uncommon – migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, hemorrhagic stroke; rare – increased intracranial pressure, convulsions, optic neuritis.

Eye disorders: common – eyelid edema, lacrimation increased, conjunctival hemorrhage, conjunctivitis, dry eye syndrome, vision blurred; uncommon – eye irritation, eye pain, periorbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema; rare – cataract, papilledema, glaucoma.

Ear and labyrinth disorders: uncommon – vertigo, tinnitus, hearing impaired.

Cardiac disorders: common – flushing, hemorrhage; uncommon – palpitations, tachycardia, chronic heart failure, pulmonary edema, increased or decreased blood pressure, hematoma, subdural hematoma, cold extremities, Raynaud’s syndrome; rare – arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion.

Respiratory, thoracic and mediastinal disorders: common – epistaxis, dyspnea, cough; uncommon – pleural effusion, pharyngolaryngeal pain, pharyngitis; rare – pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage.

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

Hepatobiliary disorders: common – increased hepatic transaminases; uncommon – jaundice, hepatitis, hyperbilirubinemia; rare – hepatic failure, hepatic necrosis.

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

Musculoskeletal and connective tissue disorders: very common – muscle cramps and spasms, musculoskeletal pain including myalgia and arthralgia, bone pain; common – joint swelling; uncommon – muscle and joint stiffness; rare – muscle weakness, arthritis.

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

Reproductive system and breast disorders: uncommon – gynecomastia, erectile dysfunction, menorrhagia, menstrual cycle disorders, sexual dysfunction, nipple pain, breast enlargement, scrotal edema.

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

Investigations: uncommon – increased blood creatinine, increased blood creatine phosphokinase, increased alkaline phosphatase, increased lactate dehydrogenase; rare – increased plasma amylase.

Contraindications

Hypersensitivity to imatinib; pregnancy, breastfeeding period; children under 1 year of age in patients with Ph+ acute lymphoblastic leukemia, under 2 years of age in patients with Ph+ chronic myeloid leukemia, under 18 years of age for other indications (efficacy and safety not established).

With caution in patients with severe hepatic impairment; patients with severe renal impairment; patients with cardiovascular diseases or with risk factors for heart failure; during regular hemodialysis procedure; with simultaneous use of drugs that inhibit the CYP3A4 isoenzyme, strong inducers of the CYP3A4 isoenzyme, drugs that are substrates of the CYP3A4 isoenzyme; with simultaneous use of paracetamol, warfarin.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Use with caution in patients with severe hepatic impairment.

Use in Renal Impairment

Use with caution in patients with severe renal impairment.

Pediatric Use

Imatinib is contraindicated for use in patients under 1 year of age with Ph+ acute lymphoblastic leukemia; under 2 years of age with Ph+ chronic myeloid leukemia; under 18 years of age for other indications.

Geriatric Use

Should be used with caution in elderly patients.

The highest frequency of fluid retention is observed in elderly patients with concomitant cardiovascular diseases.

Special Precautions

Treatment with imatinib should be carried out only under the supervision of a physician experienced in working with antitumor drugs.

Cases of severe fluid retention have been observed with the use of imatinib; it is recommended to regularly monitor body weight. In case of unexpected rapid weight gain, an examination should be performed and, if necessary, imatinib therapy should be temporarily discontinued, and/or diuretics should be initiated.

The development of neutropenia or thrombocytopenia has been observed with the use of imatinib; these phenomena were clearly related to the stage of the disease, their frequency was higher in patients with CML in blast crisis or accelerated phase compared to patients with CML in the chronic phase. It may be necessary to temporarily suspend therapy or reduce the dose of imatinib.

When using imatinib, it is recommended to regularly perform clinical blood tests and monitor liver function (transaminases, bilirubin, alkaline phosphatase). When used in patients with liver diseases, clinical blood tests and determination of liver enzyme activity should be performed regularly.

Imatinib and its metabolites are excreted by the kidneys to a small extent. Creatinine clearance decreases with age, while age does not have a significant effect on the pharmacokinetic parameters of imatinib. No correlation was found between imatinib exposure and the degree of renal impairment in patients with renal impairment from mild (creatinine clearance 40-59 ml/min) to severe (creatinine clearance <20 ml/min). Nevertheless, in case of intolerance in patients of this category, the initial dose of imatinib should be reduced.

There are reports of the development of hypothyroidism during the use of imatinib in patients who have undergone thyroidectomy and are receiving replacement therapy with levothyroxine sodium. Regular determination of thyroid-stimulating hormone concentration should be carried out in this category of patients.

Close monitoring should be provided for patients with cardiovascular diseases, risk factors for heart failure, as well as patients with a history of renal failure. If signs or symptoms indicating these conditions are detected, the patient’s condition should be assessed and appropriate treatment initiated.

In patients with myelodysplastic/myeloproliferative diseases and a high eosinophil count, an ECG and determination of serum cardiospecific troponin concentration should be performed. If abnormalities are detected at the beginning of therapy, the possibility of prophylactic use of systemic corticosteroids for 1-2 weeks simultaneously with imatinib should be considered.

There are isolated reports of cases of gastric antral vascular ectasia (GAVE syndrome), a rare cause of gastrointestinal bleeding, registered in patients with CML and ALL and other diseases.

It is necessary to monitor the condition of the gastrointestinal tract in patients with metastatic malignant GIST ( abdominal pain, gastrointestinal bleeding, constipation, and others) at the beginning and throughout imatinib therapy. If necessary, the possibility of discontinuing imatinib therapy should be considered.

Due to the risk of tumor lysis syndrome, clinically significant dehydration and elevated uric acid concentrations should be corrected prior to imatinib use, if necessary.

In patients who are carriers of the hepatitis B virus, reactivation of this virus is possible following therapy with BCR-ABL tyrosine kinase inhibitor drugs, such as Imatinib. In some cases, the use of drugs in this class has been associated with the development of acute liver failure or fulminant hepatitis, leading to liver transplantation or a fatal outcome.

All patients should be tested for the hepatitis B virus before starting imatinib therapy. The condition of a patient who is a carrier of the hepatitis B virus and requires treatment with imatinib should be carefully monitored for the development of signs and symptoms of an active infectious process, both during imatinib therapy and for several months after its completion.

Influence on the Ability to Drive Vehicles and Operate Machinery

Some side effects, such as dizziness and blurred vision, may negatively affect the ability to drive vehicles and perform other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. Therefore, patients experiencing the described adverse events should refrain from performing these activities.

Drug Interactions

With the simultaneous use of imatinib with drugs that inhibit the cytochrome P450 isoenzyme CYP3A4, for example, viral protease inhibitors (indinavir, lopinavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir), antifungal drugs of the azole group (including ketoconazole, itraconazole, posaconazole, voriconazole), some macrolide antibiotics (erythromycin, clarithromycin, telithromycin), a slowdown in the metabolism of imatinib and an increase in its plasma concentration are possible. Caution is required when using imatinib concomitantly with drugs that are inhibitors of the CYP3A4 isoenzymes.

Concomitant use of drugs that are inducers of the CYP3A4 isoenzyme (for example, rifampicin, dexamethasone, preparations of St. John’s wort, antiepileptic drugs: carbamazepine, oxcarbazepine, phenytoin, primidone) may lead to increased metabolism of imatinib and, as a result, a decrease in its plasma concentration and ineffectiveness of therapy. The simultaneous use of imatinib and strong inducers of the CYP3A4 isoenzyme should be avoided.

With the simultaneous use of imatinib and simvastatin, an increase in the C_max and AUC of simvastatin by 2 and 3.5 times, respectively, was noted, which is a consequence of the inhibition of CYP3A4 by imatinib. Caution is recommended when using imatinib concomitantly with drugs that are substrates of CYP3A4 and have a narrow therapeutic range (for example, cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, fentanyl, terfenadine, bortezomib, docetaxel, quinidine). Imatinib may increase serum concentrations of other drugs metabolized by the CYP3A4 isoenzyme (triazolobenzodiazepines, dihydropyridine, “slow” calcium channel blockers, most HMG-CoA reductase inhibitors, including statins).

Imatinib also inhibits the CYP2C9 isoenzyme and the CYP2C19 isoenzyme in vitro. With simultaneous use with warfarin, an increase in prothrombin time was observed. When used concomitantly with coumarin derivatives, short-term monitoring of prothrombin time is necessary at the beginning and end of therapy, as well as when changing the dosage regimen. The use of low molecular weight heparins should be considered as an alternative to warfarin.

The issue of drug interaction between imatinib and chemotherapy drugs in patients with Ph+ ALL has not been sufficiently studied. Caution should be exercised when using imatinib and chemotherapeutic drugs concomitantly due to a possible increased risk of drug complications, such as hepatotoxicity, myelosuppression, and others.

When imatinib is combined with chemotherapeutic drugs in high doses, transient hepatic toxicity in the form of increased activity of liver transaminases and hyperbilirubinemia may develop. When combining imatinib with chemotherapy regimens that may potentially cause liver dysfunction, monitoring of liver function should be provided.

In vitro, Imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 at the same concentrations at which it inhibits the CYP3A4 isoenzyme.

In patients after thyroidectomy receiving replacement hormone therapy with levothyroxine sodium, a decrease in its concentration is possible with simultaneous use with imatinib.

There have been reports of liver damage with the simultaneous use of imatinib and asparaginase.

Cases of fatal liver failure have been reported when imatinib was taken simultaneously with paracetamol.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.