#  VEENAT 400mg (Imatinib Mesylate)

 

Veenat (Imatinib) by Natco is generic version of  Gleevec.

Generic Name : Imatinib 

Brand Names : Imatinib , Gleevec

It comes in Pack of 120 tablets 100mg and 30 tablets 400 Mg (Imatinib Tablets)

DRUG DESCRIPTION

Imatinib is a small molecule kinase inhibitor. Imatinib film-coated tablets contain imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base. Imatinib mesylate is designated chemically as 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate and its structural formula is

Imatinib mesylate is a white to off-white to brownish or yellowish tinged crystalline powder. Its molecular formula is C29H31N7O CH4SO3 and its molecular weight is 589.7. Imatinib mesylate is soluble in aqueous buffers ≤ pH 5.5 but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers. In non-aqueous solvents, the drug substance is freely soluble to very slightly soluble in dimethyl sulfoxide, methanol and ethanol, but is insoluble in n-octanol,acetone and acetonitrile.

Inactive Ingredients: colloidal silicon dioxide (NF); crospovidone (NF); hydroxypropyl methylcellulose (USP); magnesium stearate (NF); and microcrystalline cellulose (NF). Tablet coating: ferric oxide, red (NF); ferric oxide, yellow (NF); hydroxypropyl methylcellulose (USP); polyethylene glycol (NF) and talc (USP).

DOSAGE AND ADMINISTRATION

Therapy should be initiated by a physician experienced in the treatment of patients with hematological malignancies or malignant sarcomas, as appropriate. The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.

In children, Imatinib treatment can be given as a once-daily dose or alternatively the daily dose may be split into two - once in the morning and once in the evening. There is no experience with Imatinib treatment in children under 2 years of age.

For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s).

For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron.

Treatment may be continued as long as there is no evidence of progressivedisease or unacceptable toxicity.

Adult Patients with Ph+ CML CP, AP and BC

The recommended dose of Imatinib is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis.  

In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia orthrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response. 

Pediatric Patients with Ph+ CML

The recommended dose of Imatinib for children with newly diagnosed Ph+ CML is 340 mg/m/day (not to exceed 600 mg). The recommended Imatinib dose is 260 mg/m/day for children with Ph+ chronic phase CML recurrent after stem cell transplant or who are resistant to interferon-alpha therapy. 

Ph+ ALL

The recommended dose of Imatinib is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL. 

MDS/MPD

The recommended dose of Imatinib is 400 mg/day for adult patients with MDS/MPD. 

ASM

The recommended dose of Imatinib is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, treatment with Imatinib 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

HES/CEL

The recommended dose of Imatinib is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 

DFSP

The recommended dose of Imatinib is 800 mg/day for adult patients with DFSP.

GIST

The recommended dose of Imatinib is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions.

The recommended dose of Imatinib is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In the clinical study, Imatinib was administered for one year. The optimal treatment duration with Imatinib is not known.

Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse Reactions

If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, Imatinib should be withheld until bilirubin levels have returned to a < 1.5 x IULN and transaminase levels to < 2.5 x IULN. In adults, treatment with Imatinib may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg or 800 mg to 600 mg). In children, daily doses can be reduced under the same circumstances from 340 mg/m/day to 260 mg/m/day or from 260 mg/m/day to 200 mg/m/day, respectively.

If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Imatinib should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.

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HOW SUPPLIED

Dosage Forms And Strengths

100 mg film coated tablets 
400 mg film coated tablets

Each film-coated tablet contains 100 mg or 400 mg of imatinib free base. 

Storage and Handling

Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. Protect from moisture.

Dispense in a tight container, USP.

Imatinib tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly as outlined in the references. Personnel should avoid exposure to crushed tablets.

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.

Chronic Myeloid Leukemia

The majority of Imatinib-treated patients experienced adverse reactions at some time. Most reactions were of mild-to-moderate grade, but drug was discontinued for drug-related adverse reactions in 2.4% of newly diagnosed patients, 4% of patients in chronic phase after failure of interferon-alpha therapy, 4% in accelerated phase and 5% in blast crisis. 

The most frequently reported drug-related adverse reactions were edema, nauseaand vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 for newly diagnosed CML, Table 3 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of Imatinib.

A variety of adverse reactions represent local or general fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting Imatinib treatment and using diuretics or other appropriate supportive care measures. A few of these reactions may be serious or life threatening, and one patient with blast crisis died with pleural effusion,congestive heart failure, and renal failure. 

Hepatotoxicity

Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.

Adverse Reactions in Pediatric Population

The overall safety profile of pediatric patients treated with Imatinib in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Although most patients experienced adverse reactions at some time during the study, the incidence of Grade 3/4 adverse reactions was low. 

Adverse Reactions in Other Subpopulations

In older patients ( ≥ 65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade &fract12; superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.

Acute Lymphoblastic Leukemia

The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps and rash, which were easily manageable. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were rarely severe and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Imatinib. 

Aggressive Systemic Mastocytosis

All ASM patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash and lower respiratory tract infection. None of the 5 patients in the phase 2 study with ASM discontinued Imatinib due to drug-related adverse reactions or abnormal laboratory values.

Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia

The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of Imatinib observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being gastrointestinal, cutaneous and musculoskeletal disorders.

Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia and anemia.

Gastrointestinal Stromal Tumors

Unresectable and/or Malignant Metastatic GIST

In the Phase 3 trials the majority of Imatinib-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Imatinib Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%). 

Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group. 

Adjuvant Treatment of GIST

The majority of both Imatinib and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Imatinib and placebo treated patients respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention and diarrhea), fatigue, low hemoglobin and rash were the most frequently reported adverse reactions at the time of discontinuation.

Hepatotoxicity

Hepatotoxicity, occasionally severe, may occur with Imatinib. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with interruption and/or dose reduction of the treatment with Imatinib [see DOSAGE AND ADMINISTRATION].

When Imatinib is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.

Hemorrhage

In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. 

Gastrointestinal Disorders

Imatinib is sometimes associated with GI irritation. Imatinib should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation. 

Hypereosinophilic Cardiac Toxicity

In patients with hypereosinophilic syndrome and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of Imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Imatinib. Myelodysplastic/myeloproliferative disease andsystemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Imatinib should be considered at the initiation of therapy.

Dermatologic Toxicities

Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Imatinib.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ≥ 30 mg/kg/day. Target organs forneoplastic changes were the kidneys (renal tubule and renal pelvis), urinarybladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach. Neoplastic lesions were not seen at: 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland. The papilloma/carcinoma of the preputial/clitoral gland were noted at 30 and 60 mg/kg/day, representing approximately 0.5 to 4 or 0.3 to 2.4 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 to 3.0 times the daily exposure in children (based on AUC) at 340 mg/m. The renal tubule adenoma/carcinoma, renal pelvis transitional cell neoplasms, the urinary bladder and urethra transitional cell papillomas, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumors of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day. The relevance of these findings in the rat carcinogenicity study for humans is not known. 

Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cellassay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouselymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterialcell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay.

In a study of fertility, male rats were dosed for 70 days prior to mating and female rats were dosed 14 days prior to mating and through to gestational Day 6. Testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately three-fourths the maximum clinical dose of 800 mg/day based on body surface area. This was not seen at doses ≤ 20 mg/kg (one-fourth the maximum human dose of 800 mg). The fertility of male and female rats was not affected.

In a pre- and post-natal development study in female rats dosed with imatinib mesylate at 45 mg/kg (approximately one-half the maximum human dose of 800 mg/day, based on body surface area) from gestational Day 6 until the end oflactation, red vaginal discharge was noted on either gestational Day 14 or 15. In the first generation offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice. First generation offspring fertility was not affected but reproductive effects were noted at 45 mg/kg/day including an increased number of resorptions and a decreased number of viable fetuses. 

Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights as well as a reduced number of motile sperm were observed in the high dose males rats. In the preclinical pre- and postnatal study in rats, fertility in the first generation offspring was also not affected by Imatinib.

Human studies on male patients receiving Imatinib and its affect on male fertility and spermatogenesis have not been performed. Male patients concerned about their fertility on Imatinib treatment should consult with their physician.

Use In Specific Populations

Imatinib can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/kg (approximately equal to the maximum human dose of 800 mg/day based on body surface area). Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ≥ 45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by either early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ≤ 30 mg/kg (one-third the maximum human dose of 800 mg).

There are no adequate and well-controlled studies with Imatinib in pregnant women. Women should be advised not to become pregnant when taking Imatinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus

Nursing Mothers

Imatinib and its active metabolite are excreted into human milk. Based on data from three breastfeeding women taking Imatinib, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infantcould receive up to 10 % of the maternal therapeutic dose based on body weight. Because of the potential for serious adverse reactions in nursing infants from Imatinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Imatinib safety and efficacy have been demonstrated in children with newly diagnosed Ph+ chronic phase CML and in children with Ph+ chronic phase CML with recurrence after stem cell transplantation or resistance to interferon-alpha therapy. There are no data in children under 2 years of age. Follow-up in children with newly diagnosed Ph+ chronic phase CML is limited. 

As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a Cmax of 2-4 hours. Apparent oral clearance was similar to adult values (11.0 L/hr/m in children vs. 10.0 L/hr/m in adults), as was the half-life (14.8 hours in children vs. 17.1 hours in adults). Dosing in children at both 260 mg/m and 340 mg/m achieved an AUC similar to the 400 mg dose in adults. The comparison of AUC on Day 8 vs. Day 1 at 260 mg/m and 340 mg/m dose levels revealed a 1.5- and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC did not increase proportionally with increasing dose.

Geriatric Use

In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of Imatinib was similar in older and younger patients.

In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.

In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of Imatinib was similar in patients older than 65 years and younger patients.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 cancer patients with varying degrees of hepatic impairment at imatinib doses ranging from 100-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group. Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic

Renal Impairment

The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment. The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment. Two patients with severe renal impairment were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day. Dose reductions are necessary for patients with moderate and severe renal impairment

Experience with doses greater than 800 mg is limited. Isolated cases of Imatinib overdose have been reported. In the event of overdosage, the patient should be observed and appropriate supportive treatment given. 

Adult Overdose

1,200 to 1,600 mg (duration varying between 1 to 10 days)

Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, musclespasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 

1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days)

Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain

6,400 mg (single dose)

One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases.

8 to 10 g (single dose)

Vomiting and gastrointestinal pain have been reported.

A patient with myeloid blast crisis experienced Grade 1 elevations of serumcreatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of Imatinib daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of Imatinib daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of Imatinib on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy.

Pediatric Overdose

One 3 year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhea and anorexia and another 3 year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhea.

CLINICAL PHARMACOLOGY

Mechanism of Action

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the bcr-abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by thePhiladelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in bcr-abl positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients. 

In vivo, imatinib inhibits tumor growth of bcr-abl transfected murine myeloid cells as well as bcr-abl positive leukemia lines derived from CML patients in blast crisis. 

Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-kit mutation.

Pharmacokinetics

The pharmacokinetics of Imatinib have been evaluated in studies in healthy subjects and in population pharmacokinetic studies in over 900 patients. The pharmacokinetics of Imatinib are similar in CML and GIST patients. Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose.

Mean absolute bioavailability is 98%. Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 mg-1,000 mg. There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at steady state when Imatinib is dosed once daily. At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and α1-acid glycoprotein.

CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. The plasma AUC for this metabolite is about 15% of the AUC for imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound. Human liver microsome studies demonstrated that Imatinib is a potent competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5 with Ki values of 27, 7.5 and 8 μM, respectively.

Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites.

Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicity.

Late Chronic Phase CML and Advanced Stage CML: Three international, open-label, single-arm phase 2 studies were conducted to determine the safety and efficacy of Imatinib in patients with Ph+ CML: 1) in the chronic phase after failure of IFN therapy, 2) in accelerated phase disease, or 3) in myeloid blast crisis. About 45% of patients were women and 6% were Black. In clinical studies 38%-40% of patients were ≥ 60 years of age and 10%-12% of patients were ≥ 70 years of age. 

Chronic Phase, Prior Interferon-Alpha Treatment: 532 patients were treated at a starting dose of 400 mg; dose escalation to 600 mg was allowed. The patients were distributed in three main categories according to their response to prior interferon: failure to achieve (within 6 months), or loss of a complete hematologic response (29%), failure to achieve (within 1 year) or loss of a major cytogenetic response (35%), or intolerance to interferon (36%). Patients had received a median of 14 months of prior IFN therapy at doses ≥ 25 x 106 IU/week and were all in late chronic phase, with a median time from diagnosis of 32 months. Effectiveness was evaluated on the basis of the rate of hematologic response and by bone marrow exams to assess the rate of major cytogenetic response (up to 35% Ph+ metaphases) or complete cytogenetic response (0% Ph+ metaphases). Median duration of treatment was 29 months with 81% of patients treated for ≥ 24 months (maximum = 31.5 months). Efficacy results are reported in Table 15. Confirmed major cytogenetic response rates were higher in patients with IFN intolerance (66%) and cytogenetic failure (64%), than in patients with hematologic failure (47%). Hematologic response was achieved in 98% of patients with cytogenetic failure, 94% of patients with hematologic failure, and 92% of IFN-intolerant patients.

Accelerated Phase: 235 patients with accelerated phase disease were enrolled. These patients met one or more of the following criteria: ≥ 15%- < 30% blasts in PB or BM; ≥ 30% blasts + promyelocytes in PB or BM; ≥ 20% basophils in PB; and < 100 x 109/L platelets. The first 77 patients were started at 400 mg, with the remaining 158 patients starting at 600 mg. 

Effectiveness was evaluated primarily on the basis of the rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia (i.e., clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML. Cytogenetic responses were also evaluated. Median duration of treatment was 18 months with 45% of patients treated for ≥ 24 months (maximum=35 months). Efficacy results are reported in Table 15. Response rates in accelerated phase CML were higher for the 600 mg dose group than for the 400 mg group: hematologic response (75% vs. 64%), confirmed and unconfirmed major cytogenetic response (31% vs. 19%).

Pediatric CML

A total of 51 pediatric patients with newly diagnosed and untreated CML in chronic phase were enrolled in an open-label, multicenter, single arm phase 2 trial. Patients were treated with Imatinib 340 mg/m/day, with no interruptions in the absence of dose limiting toxicity. Complete hematologic response (CHR) was observed in 78% of patients after 8 weeks of therapy. The complete cytogenetic response rate (CCyR) was 65%, comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16%. The majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 6.74 months.

One open-label, single-arm study enrolled 14 pediatric patients with Ph+ chronic phase CML recurrent after stem cell transplant or resistant to interferon-alpha therapy. Patients ranged in age from 3-20 years old; 3 were 3-11 years old, 9 were 12-18 years old, and 2 were > 18 years old. Patients were treated at doses of 260 mg/m/day (n=3), 340 mg/m/day (n=4), 440 mg/m/day (n=5) and 570 mg/m/day (n=2). In the 13 patients for whom cytogenetic data are available, 4 achieved a major cytogenetic response, 7 achieved a complete cytogenetic response, and 2 had a minimal cytogenetic response. 

In a second study, 2 of 3 patients with Ph+ chronic phase CML resistant to interferon-alpha therapy achieved a complete cytogenetic response at doses of 242 and 257 mg/m/day.

 

PATIENT INFORMATION

Dosing and Administration

Patients should be informed to take Imatinib exactly as prescribed, not to change their dose or to stop taking Imatinib unless they are told to do so by their doctor. If patients miss a dose they should be advised to take their dose as soon as possible unless it is almost time for their next dose in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose. Patients should be advised to take Imatinib with a meal and a large glass of water. 

Pregnancy and Breast-Feeding

Patients should be advised to inform their doctor if they are or think they may be pregnant. Patients should also be advised not to breast feed while taking Imatinib. 

Adverse Reactions

Patients should be advised to tell their doctor if they experience side effects during Imatinib therapy including fever, shortness of breath, blood in their stools, jaundice, sudden weight gain, symptoms of cardiac failure, or if they have a history of cardiac disease or risk factors for cardiac failure.

Drug Interactions

Patients should be advised not to take any other medications, including over-the-counter medications such as acetaminophen or herbal products without talking to their doctor or pharmacist first. Examples of other medications that should not be taken with Imatinib are warfarin, erythromycin, and phenytoin. Patients should also be advised to tell their doctor if they are taking or plan to take iron supplements. Patients should also avoid grapefruit juice and other foods known to inhibit CYP3A4 while taking Imatinib. 

CONSUMER

IMPORTANT NOTE:This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

IMATINIB - ORAL

USES:This medication is used to treat certain types of cancer (e.g., chronic myeloid leukemia, gastrointestinal stromal tumors, and myelodysplastic/myeloproliferative diseases). Imatinib works by stopping or slowing the growth of cancer cells (tumors). It also works by causing cancer cells to die.

HOW TO USE:Take this medication by mouth with a meal and a full glass of water (8 ounces or 240 milliliters), usually once or twice daily or as directed by your doctor. The US manufacturer recommends that if you have trouble swallowing the tablets whole, you may dissolve your dose in a glass of water or apple juice. The amount of liquid will vary depending on your dose. Consult your doctor or pharmacist for more detailed instructions. Stir the mixture well until the tablet(s) dissolve, and drink immediately.

The dosage is based on your medical condition and response to therapy. Do not increase your dose or take this medication more often than prescribed. Your condition will not improve any faster, and the risk of serious side effects may be increased.

Since this drug can be absorbed through the skin and lungs, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the tablets.

SIDE EFFECTS:Upset stomach, nausea, vomiting, diarrhea, headache, joint pain, or muscle cramps/pain may occur. If any of these effects persist or worsen, notify your doctor.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: easy bruising/bleeding, fast/pounding heartbeat, extreme tiredness, sudden/unexplained weight gain, swelling (especially of lower legs/the area around eyes), increasing trouble breathing (shortness of breath).

Tell your doctor immediately if any of these rare but very serious side effects occur: black/bloody stools, dark urine, stomach/abdominal pain, vomit that looks like coffee grounds, yellowing eyes/skin.

This medication can lower the body's ability to fight an infection. Notify your doctor promptly if you develop any signs of an infection such as fever, chills, or persistent sore throat.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching, swelling, dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice any other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects.

PRECAUTIONS:Before taking imatinib, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: bleeding problems, heart problems (e.g., heart failure), kidney problems, liver problems.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose. Wash your hands well to prevent the spread of infections.

To lower your risk of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

Before having surgery, tell your doctor or dentist that you are using this medication.

The elderly may be more sensitive to the side effects of this drug (e.g., swelling). Also, the manufacturer recommends a routine heart test (LV ejection fraction) in the elderly before treatment.

This medication is not recommended for use during pregnancy. It may harm the unborn baby. If you become pregnant or think you may be pregnant, inform your doctor immediately. To avoid pregnancy, both males and females using this drug must use reliable form(s) of birth control (e.g., condoms, birth control pills) during treatment with this drug. Talk with your doctor about effective forms of birth control.

It is not known whether this drug passes into breast milk. Because of the potential risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.