Medicine > All about Imarech (Imatinib Mesylate) tablet

All about Imarech (Imatinib Mesylate) tablet

Name of Medicine: Imarech

Composition: Imatinib Mesylate 400mg

Chemical Formula: C30H35N7O4S

Description: Imarech is a formulation of Imatinib Mesylate, available as tablets in the strength of 400mg for oral use.

What is Imarech?

Imarech is a prescription drug that belongs to a class of medications known as anti-cancer agents. It is an effective formulation of a kinase inhibitor namely Imatinib Mesylate. Imarech (Imatinib Mesylate) tablet inhibits the proliferation and induces apoptosis (planned cell death) in BCR-ABL positive cells (cancer cells). 

Clinical Relevance 

Imarech, comprising Imatinib Mesylate, is a kinase inhibitor prescribed for the treatment of:

  • Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

  • Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP); provided- after the failure of interferon-alpha therapy. 

  • Ph+ CML in chronic phase (newly diagnosed or recurred).

  • Relapsed Philadelphia chromosome-positive agents acute lymphoblastic leukemia (Ph+ ALL).

  • Myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene rearrangements. 

  • Aggressive systemic mastocytosis (ASM). 

  • Hypereosinophilic syndrome (HES).

  • Chronic eosinophilic leukemia (CEL). 

  • Metastatic dermatofibrosarcoma protuberans (DFSP)

  • Positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). 

Clinical Pharmacology 

Pharmacodynamics 

Imatinib Mesylate belongs to the group of antineoplastic agents. It is a 2-phenylaminopyrimidine derivative that is used in the treatment of a type of Blood Cancer namely chronic myelogenous leukemia. It tends to work as a specific inhibitor of a number of tyrosine kinase enzymes. Chronic myelogenous leukemia is associated with the Philadelphia chromosome that is responsible for the promotion of generation of BCR-ABL mutation, which results from the combination of two genes, known as BCR and ABL. BCR-ABL generates a fusion protein that acts as a constitutively active tyrosine kinase and this compound tends to inhibit this constitutive enzymatic activity.

Mechanism of Action

Imatinib Mesylate is a protein-tyrosine kinase inhibitor that is responsible for the inhibition of the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase made by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). the compound works to inhibit proliferation and works to induces apoptosis in Bcr-Abl positive cell lines with fresh leukemic cells from Philadelphia chromosome-positive chronic myeloid leukemia. It tends to inhibit the receptor tyrosine kinases for a platelet-derived growth factor and stem cell factor which is known as c-kit. The compound was found and identified in the late 1990s by Dr. Brian J. Druker and its development is an appropriate example of rational drug design. After the identification of the bcr-abl target, the hunt for an inhibitor was started. Chemists then used a high-throughput screen of chemical libraries in order to identify the molecule 2-phenylaminopyrimidine. The lead compound was studied and then modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in Imatinib.

Metabolism 

Primarily hepatic via CYP3A4. Other cytochrome P450 enzymes including the following play an important role in its metabolism: 

  • CYP1A2 

  • CYP2D6

  • CYP2C9 

  • CYP2C19

In humans, the main circulating active metabolite in humans is the N-demethylated piperazine derivative that is formed predominantly by CYP3A4. It is similar in potency to the parent compound.

Route of Elimination

The elimination of Imatinib Mesylate is done via the feces, mostly as metabolites. 81% of the dose is excreted within a period of 7 days, in feces and urine. The unchanged compound was about 25% of the dose (5% urine, 20% faces), and the remainder were metabolites.

Clinical Trials 

Targeted cancer therapy has long been sought by oncology researchers as a potentially better approach than currently available therapies. One targeted therapy that has demonstrated huge success is the tyrosine kinase inhibitor imatinib mesylate which was recently approved for use in the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML). Basic scientific research into the molecular causes and pathogenesis of CML and increasingly encouraging preclinical investigations on the mechanism of action of the compound led to the initiation of phase I clinical trials. The majority (88%) of interferon-alpha-resistant or intolerant patients in chronic-phase CML achieved a complete hematologic response to imatinib mesylate. More importantly, approximately half of patients achieved a major cytogenetic response, a result historically associated with improved survival. Furthermore, 21% of patients in accelerated-phase CML and 13.5% of patients in blastic-phase CML (patient populations with typically poor prognosis before the advent of imatinib mesylate) achieved major cytogenetic responses. Results from ongoing studies will prove the durability of these responses and will investigate methods to customize therapy in advanced-stage patients using the compound with other therapies. Additional trials are planned to study the efficacy and safety of imatinib mesylate to treat certain types of solid tumors whose pathogenesis is driven by the other tyrosine kinase targets, c-Kit, and platelet-derived growth factor receptor.

Interactions

Drug Interactions 

  • CYP3A4 inducers: Coadministration of an agent inducing CYP3A4 metabolism with Imarech may lead to a decrease in the total exposure of Imatinib Mesylate.

  • CYP3A4 inhibitors: Coadministration of an agent inhibiting CYP3A4 metabolism with Imarech may lead to an increase in the total exposure of Imatinib Mesylate.

  • CYP3A4 metabolized drugs: Imarech may lead to an increase in CYP3A4 metabolized drugs. Use these medications with utmost caution. 

Food Interactions

  • Grapefruit is an agent that is responsible for the inhibition of CYP3A4 metabolism. It may increase the serum levels of Imatinib Mesylate. 

Disease Interactions

  • Hepatic Impairment: Mild and moderate hepatic impairment may not influence the working and concentration of Imatinib Mesylate. However, in patients with severe hepatic impairment, Imatinib Mesylate should be administered cautiously. Regular monitoring should be done in such cases to avoid adverse events. 

  • Renal Impairment: When Imatinib Mesylate was administered to a patient suffering from renal impairment, AUC of Imatinib Mesylate was increased in the cases of mild and moderate renal impairment by approximately 1.5- to 2-fold. There is no confirmed or studied data for severe renal impairment. 

Drug Category 

  • Myelosuppressive Agents: The agents that work by stopping or slowing the growth of blood-forming cells in the bone marrow are known as Myelosuppressive agents. Myelosuppressive agents are responsible for the destruction of some normal cells and cancer cells in the body. 

  • Kinase Inhibitors: These agents work by blocking the action of one or more protein kinases. Kinase Inhibitors belong to the class of enzyme inhibitors. Kinase inhibitors affect the functioning of certain proteins in the body. 

  • Immunosuppressive Agents: These drugs are used in the treatment of autoimmune diseases. Immunosuppressive agents are used to hinder organ rejection that may lead to immunodeficiency including malignancy and infections.

Dosage and Administration 

Administration 

The recommended dosage of Imarech (Imatinib Mesylate) should be administered orally with food and a glass full of water. The tablet should be administered once a day. In the case of patients who are unable to swallow the tablet as a whole, the tablet should be dispersed in water or apple juice. The suspension should be administered immediately once the tablet dissolves.

Overdosage 

Overdose may occur when a dose of 800mg or more is administered to a patient. In such a case, the patient should be monitored for adverse effects and thereby provided with supportive care. 

Dose Adjustments

  • Hepatic Impairment: Mild and moderate hepatic impairment may not influence the working and concentration of Imatinib Mesylate. However, in patients with severe hepatic impairment, Imatinib Mesylate should be administered cautiously. Regular monitoring should be done in such cases to avoid adverse events. Dose adjustment may be needed in severe hepatic impairment. 

  • Renal Impairment: When Imatinib Mesylate was administered to a patient suffering from renal impairment, AUC of Imatinib Mesylate was increased in the cases of mild and moderate renal impairment by approximately 1.5- to 2-fold. There is no confirmed or studied data for severe renal impairment. Dose adjustment may be needed in severe renal impairment. 

  • CYP3A4 inducers/inhibitors: Coadministration of an agent inducing CYP3A4 metabolism with Imarech may lead to a decrease in the total exposure of Imatinib Mesylate whereas coadministration of an agent inhibiting CYP3A4 metabolism with Imarech may lead to an increase in the total exposure of Imatinib Mesylate. Dose adjustments may be needed in both cases. 

Adverse Reactions 

Common Adverse Events

  • Several gastrointestinal effects such as peptic ulcers, gastritis (inflammation of the stomach lining), gastroenteritis (including diarrhea, cramps, vomiting, and fever), stomach ache, and bloating may occur. Imarech should be taken with food to minimize or treat these effects. 

  • Dermatologic Toxicities in some patients may occur during the course of Imarech. These reactions include photosensitivity reaction, dermatitis, pigmentation disorder (a severe condition in which skin loses its pigment cells), dry skin, acne, nail disorder, urticaria (itchy welts due to a skin reaction), and hyperhidrosis.

Serious Adverse Events

  • Fluid retention and edema: Imarech is associated with edema and severe fluid retention. It refers to an accumulation of fluid in the tissues of the body. Regular monitoring should be done in patients for related signs and symptoms. 

  • Hematologic toxicity: Imatinib Mesylate is associated with anemia (low red blood cell count), neutropenia (low level of neutrophils), and thrombocytopenia (low platelet count). 

  • Heart failure: In some patients, the administration of Imarech may lead to congestive heart failure and left ventricular dysfunction. This adverse event may be common in patients with patients already suffering from cardiac disease. The patients should be monitored for such symptoms. 

  • Hepatotoxicity: This condition (liver damage) occurs due to exposure to certain drugs. It is an uncommon but serious adverse reaction. The most common effects associated with Hepatotoxicity are rash, nausea, vomiting, fatigue, loss of appetite, and jaundice. 

  • Hemorrhage: It can occur either inside or outside the body. Hemorrhage may occur in some patients administering Imarech. This may show some symptoms like weakness, tingling, seizures, difficulty in speaking, changes in vision, difficulty using fine motor skills, and vomiting. 

Packaging and Storage

Imarech (Imatinib Mesylate) is available in the form of tablets for oral use in strips packed in a box containing 30 tablets. Store the tablets at 59°F to 86°F (15°C to 30°C). Keep Imarech tablets away from the reach of your pets and children. Do not keep it under direct light and heat. Protect from direct moisture. Know the ways to dispose of the used and expired packs of Imarech from a pharmacist. Women who are pregnant should not handle Imarech tablets without protection (gloves).

Warnings and Precautions 

  • Pregnancy: Imarech (Imatinib Mesylate) tablets may lead to fetal harm when administered to a woman who is pregnant. This drug is not indicated to patients who are pregnant or planning to become pregnant. Women having child-bearing potential are recommended to start using proper contraceptive measures 28 days before the course of Imarech (Imatinib Mesylate).

  • Breastfeeding: It is unknown whether Imarech (Imatinib Mesylate) is excreted in human milk or not. Since most other medicines are excreted in human milk, it is important to take precautions to avoid adverse effects. Therefore, breastfeeding should be discontinued while receiving treatment with Imarech.

  • Hepatic Impairment: Mild and moderate hepatic impairment may not influence the working and concentration of Imatinib Mesylate. However, in patients with severe hepatic impairment, Imatinib Mesylate should be administered cautiously. Regular monitoring should be done in such cases to avoid adverse events. 

  • Renal Impairment: When Imatinib Mesylate was administered to a patient suffering from renal impairment, AUC of Imatinib Mesylate was increased in the cases of mild and moderate renal impairment by approximately 1.5- to 2-fold. There is no confirmed or studied data for severe renal impairment. 

  • Hepatotoxicity: This condition (liver damage) occurs due to exposure to certain drugs. It is an uncommon but serious adverse reaction. The most common effects associated with Hepatotoxicity are rash, nausea, vomiting, fatigue, loss of appetite, and jaundice. 

Fluid retention and edema: Imarech is associated with edema and severe fluid retention. It refers to an accumulation of fluid in the tissues of the body. Regular monitoring should be done in patients for related signs and symptoms.