Gleevec

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

1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite, increased bilirubin and liver transaminase level. 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain. 6400 mg (single dose): A case report in the literature about one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increased transaminases. 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Each scored tablet contains: imatinib 100 mg (as mesylate). Nonmedicinal ingredients: cellulose (microcrystalline), colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose and magnesium stearate; coating: ferric oxide (red), ferric oxide (yellow), hydroxypropyl methylcellulose, polyethylene glycol and talc. Blister strips of 10, cartons of 6, 12 and 18.

Each scored or unscored tablet contains: imatinib 400 mg (as mesylate). Nonmedicinal ingredients: cellulose (microcrystalline), colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose and magnesium stearate; coating: ferric oxide (red), ferric oxide (yellow), hydroxypropyl methylcellulose, polyethylene glycol and talc. Blister strips of 10, cartons of 1, 3 and 9.

Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals.

GLEEVEC and its metabolites are not excreted via the kidney to a significant extent. Creatinine clearance (CrCL) is known to decrease with age, and age did not significantly affect imatinib kinetics.

In patients with impaired renal function, GLEEVEC plasma exposure is higher (1.5- to 2-fold increase) than in patients with normal renal function, probably due to an elevated plasma level of alpha-acid glycoprotein (AGP), a GLEEVEC-binding protein, in patients with renal dysfunction. As well, there is a significant correlation in the incidence of serious adverse events with decreased renal function (p=0.0096). Patients with mild or moderate renal impairment should be treated with caution (see Dosage and Administration). Since the effect of GLEEVEC treatment on patients with severe renal dysfunction or on dialysis has not been sufficiently assessed, recommendations on the treatment of these patients with GLEEVEC cannot be made.

GLEEVEC is sometimes associated with GI irritation. GLEEVEC should be taken with food and a large glass of water to minimize this problem.

A 2-year preclinical carcinogenicity study conducted in rats demonstrated renal adenomas/carcinomas, urinary bladder and urethra papillomas, papillomas/carcinomas of the preputial and clitoral gland, adenocarcinomas of the small intestine, adenomas of the parathyroid glands, benign and malignant tumors of the adrenal medulla and papillomas/carcinomas of the nonglandular stomach.

Long-term, non-neoplastic histological changes identified in the preclinical carcinogenicity study in rats include cardiomyopathy.

The relevance of these findings in the rat carcinogenicity study for humans is not known. An analysis of the clinical safety data from clinical trials and spontaneous adverse event reports did not provide evidence of an increased overall incidence of malignancies in patients treated with imatinib mesylate compared to that of the general population.

However, adverse events in cancer patients are significantly under reported and a large proportion of patients treated with GLEEVEC have had limited follow-up thus not permitting a final analysis of the potential for an increased incidence of a secondary malignancy in patients treated with GLEEVEC.

Treatment with GLEEVEC is often associated with neutropenia or thrombocytopenia (see Adverse Reactions, Table 7, Table 8, Table 9 and Table 10). Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example every 2-3 months). The occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias involving neutropenia (31%), thrombocytopenia (16%) and anemia (14%). These generally occur within the first several months of therapy (see Dosage and Administration).

An increased rate of opportunistic infections was observed in a monkey study with chronic imatinib treatment. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans, where all grades of lymphopenia were observed in 0.3% patients).

GLEEVEC (imatinib mesylate) is often associated with edema and occasionally serious fluid retention (see Adverse Reactions Table 1 and Table 2). All Grades of fluid retention/edema were reported in up to 61.7% for newly diagnosed CML patients, up to 76.2% for other CML patients across all clinical trials, and up to 80.3% for GIST patients. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention as fluid retention can occur after months of treatment. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher imatinib dose and age >65 years. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking GLEEVEC and in 2.1% to 5.8% of other adult CML patients taking GLEEVEC. In addition, other severe fluid retention events (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) were reported in 1.3% of newly diagnosed CML patients taking GLEEVEC and in 1.7% to 6.2% of other adult CML patients taking GLEEVEC.

There is no experience with the use of GLEEVEC in pediatric patients with CML under 2 years of age. There is very limited experience with the use of GLEEVEC in children under 3 years of age in other indications.

There are no adequate and well-controlled studies in pregnant women. The potential risk for the fetus is unknown. There have been post-market reports of spontaneous abortions and infant congenital anomalies from women who have taken GLEEVEC. Imatinib is teratogenic in animals, therefore, GLEEVEC should not be administered to pregnant women unless clearly necessary. If used during pregnancy the patient should be apprised of the potential risk to the fetus. Women of childbearing potential must be advised to use effective birth control during treatment.

There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some cases the outcome was fatal.

Erythema multiforme and Stevens Johnson syndrome have been reported in patients who have received GLEEVEC.

In the phase II studies, approximately 40% of patients were older than 60 years and 10% older than 70 years. There was a higher frequency of mild to moderate superficial edema in patients older than 65 years of age as compared to younger patients. No other age associated differences in safety profile were observed. The efficacy of GLEEVEC was similar in all age groups studied.

All Grades of hemorrhage were reported in up to 28.9% for newly diagnosed CML patients, up to 53% for other CML patients across all clinical trials, and up to 29.9% for GIST patients.

In the newly diagnosed CML trial, 1.8% of patients had Grades 3/4 hemorrhage. In the GIST clinical trial eight patients (5.4%, five patients in the 600 mg dose group and three patients in the 400 mg dose group) were reported to have had gastrointestinal (GI) bleeds or intra-tumoral bleeds. Four patients with intra-tumoral bleeds had either intra-abdominal or intra-hepatic, depending on the anatomical location of the tumor lesions. One patient, who had a history of GI bleeding prior to the study, died due to gastrointestinal bleeding. Caution should be exercised with the concomitant use of antiplatelet agents or warfarin.

Because follow-up of most patients treated with imatinib is relatively short (<6 months), there are no long-term safety data on GLEEVEC treatment. It is important to consider potential toxicities suggested by animal studies, specifically, liver and kidney toxicity and immunosuppression. Liver toxicity was observed in rats, dogs and cynomolgus monkeys in repeated dose studies. Most severe toxicity was noted in dogs and included elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia.

Hepatotoxicity, occasionally severe, may occur with GLEEVEC (see Adverse Reactions, Table 1, Table 2 and Table 5). 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 GLEEVEC. (See Dosage and Administration.) Patients with hepatic impairment should be closely monitored. Although pharmacokinetic analysis results showed there is considerable inter-subject variation, the mean exposure to imatinib did not differ significantly between patients with mild and moderate liver dysfunction (as measured by dose normalized AUC) and patients with normal liver function. Patients with severe liver dysfunction demonstrated increased exposure to imatinib and its active metabolite CGP 74588. Liver function monitoring remains crucial as no long term toxicity and tolerability have been established (see Action and Clinical Pharmacology).

In GIST patients with liver metastases, exposure to GLEEVEC may be higher than in CML patients, due to impaired liver function (see Adverse Reactions).

Patients with known cardiac disease or risk factors for cardiac failure should be monitored carefully and those with symptoms or signs consistent with CHF should be evaluated and treated. In patients with history of cardiac disease or in elderly patients, a baseline evaluation of LVEF is recommended prior to initiation of GLEEVEC therapy (see Warnings and Precautions).

For patients receiving GLEEVEC, complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example every 2-3 months) (see Warnings and Precautions and Dosage and Administration).

Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly or as clinically indicated (see Warnings and Precautions and Dosage and Administration).

Patients should be weighed and monitored regularly for signs and symptoms of fluid retention as fluid retention can occur after months of treatment with GLEEVEC (see Warnings and Precautions).

Thyroid-Stimulating Hormone (TSH) levels should be closely monitored in thyroidectomy patients undergoing levothyroxine replacement during treatment with GLEEVEC (see Warnings and Precautions).

During treatment with GLEEVEC serum electrolytes should be regularly monitored for possible hypophosphatemia, hyperkalemia, and hyponatremia in all CML patients; in addition in pediatric patients blood sugar, serum calcium and albumin should also be regularly monitored. Grades 3/4 hypophosphatemia have been observed in 16.5% (15% Grade 3 and 1.5% Grade 4) of patients in a phase I dose finding study 03001 (N=143) and a phase II study 0102 (N=260) of chronic myeloid leukemia in blast crisis.

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with GLEEVEC. Thyroid-Stimulating Hormone (TSH) levels should be closely monitored in such patients.

Rare cases of pulmonary fibrosis and interstitial pneumonitis have been reported in patients who have received GLEEVEC. However, no definitive relationship has been established between the occurrence of these pulmonary events and treatment with GLEEVEC.

In animals, imatinib and/or its metabolites were extensively excreted in milk. Both imatinib and its active metabolite can be distributed into human milk. There are two known cases of imatinib exposure during lactation. Their analysis shows the following results: the milk: plasma ratio was determined to be 0.5 for imatinib and 0.9 for the metabolite. Since the effects of exposure of the infant to imatinib are potentially serious, women taking GLEEVEC should not breast feed.

Severe congestive heart failure (CHF) and reduction of left ventricular ejection fraction (LVEF) have been reported in patients taking GLEEVEC. Although several of these patients had pre-existing conditions including hypertension, diabetes and prior coronary artery disease, they were subsequently diagnosed with CHF. Patients with known cardiac disease or risk factors for cardiac failure should be monitored carefully and those with symptoms or signs consistent with CHF should be evaluated and treated. In patients with history of cardiac disease or in elderly patients, a baseline evaluation of LVEF is recommended prior to initiation of GLEEVEC therapy.

In patients with hypereosinophilic syndrome (HES) and cardiac involvement, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of GLEEVEC therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding GLEEVEC. Myelodysplastic/myeloproliferative diseases (MDS/MPD) and systemic mastocytosis (SM) might 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 and SM-AHNMD associated with high eosinophil levels. These patients with HES/CEL or ASM, SM-AHNMD and MDS/MPD must be also on 1- to 2 mg/kg of prednisone equivalent oral steroids for one to two weeks, initiated at least 2 days prior to beginning GLEEVEC therapy.

At clinically relevant concentrations of imatinib, binding to plasma proteins is approximately 95% on the basis of in vitro experiments, mostly to albumin and α₁-acid glycoprotein, with little binding to lipoproteins.

In in vitro experiments, the active metabolite, CGP74588, exhibited similar protein binding behaviour to imatinib at clinically relevant concentrations

The pharmacokinetics (PK) of GLEEVEC have been evaluated in 591 patients and 33 healthy subjects over a dosage range of 25 to 1000 mg.

Administration of rifampin 600 mg daily for eight days to 14 healthy adult volunteers, followed by a single 400 mg dose of GLEEVEC increased imatinib oral dose clearance by 3.8-fold (90% CI 3.5- to 4.3-fold). Mean C_max, AUC_0-24 and AUC_0-∞ decreased by 54%, 68% and 74%, respectively compared to treatment without rifampin. In patients in whom rifampin or other CYP3A4 inducers are indicated, alternate therapeutic agents with less enzyme induction potential should be considered. (See Drug Interactions.)

Mean absolute bioavailability for the capsule formulation is 98%. The coefficient of variation for plasma imatinib AUC is in the range of 40-60% after an oral dose. When given with a high fat meal the rate of absorption of imatinib was reduced (11% decrease in C_max and prolongation of t_max by 1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions.

Human liver microsome studies demonstrated that imatinib is a potent competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5 with K_i values of 27, 7.5, and 8 µM, respectively. Imatinib is likely to increase the blood level of drugs that are substrates of CYP2C9, CYP2D6 and CYP3A4/5. (See Drug Interactions.)

Based on the recovery of compound(s) after an oral ¹⁴C-labelled 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.

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 and the terminal half-life is approximately 40 h at steady state. The plasma protein binding of the N-demethylated metabolite CGP74588 was shown to be similar to that of the parent compound in both healthy volunteers and Acute Myeloid Leukemia (AML) patients although there were variabilities in blood distribution and protein binding between AML patients. Some of the AML patients showed a significantly higher unbound fraction of both compounds which led to a higher blood cell uptake.

A phase I study has shown a 4- to 7-fold accumulation of the metabolite CGP74588 at steady state following once daily dosing, which was greater than the parent drug (see Plasma Pharmacokinetics). This might be due to the fact that CGP74588 is metabolized at a 53% lower metabolic conversion rate compared to GLEEVEC in human hepatocytes. The reduced metabolic clearance of CGP74588 is further implied by in vitro experiments which showed a lower infinity of CGP74588 to CYP3A4 in comparison to STI571.

There was a significant increase in exposure to imatinib (mean C_max and AUC increased by 26% and 40%, respectively) in healthy subjects when GLEEVEC was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). (See Drug Interactions.)

Following oral administration in healthy volunteers, the t_½ was approximately 18 hours suggesting that once daily dosing is appropriate. Plasma pharmacokinetic profiles were analyzed in CML patients on Day 1 and on either Day 7 or 28, by which time plasma concentrations had reached steady state. The increase in mean imatinib AUC with increasing dose was linear and dose proportional in the range 25-1000 mg after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation is 1.5-2.5 fold at steady state when GLEEVEC is dosed once daily.

The effect of body weight on the clearance of imatinib is such that for a patient weighing 50 kg the mean clearance is expected to be 8.5 L/h, while for a patient weighing 100 kg the clearance will rise to 11.8 L/h. These changes are not considered sufficient to warrant dose adjustment based on body weight. There is no effect of gender on the kinetics of imatinib.

A total of 31 pediatric patients with either chronic phase CML (n=15), CML in blast crisis (n=4) or acute leukemias (n=12) have been enrolled in a dose-escalation phase I trial. In this trial the effective dose in pediatric patients was not identified. This was a population of heavily pretreated patients; 45% had received prior BMT and 68% prior multi-agent chemotherapy. Newly diagnosed patients or those eligible for bone marrow transplantation were not studied. The median age was 14 years (range 3 to 20 years). Of the 31 patients, n=12 were three to 11 years old at the start of the study, n=17 were between 12 and 18 years, and only two were more than 18 years old. Patients were treated with doses of GLEEVEC of 260 mg/m²/day (n=6), 340 mg/m²/day (n=11), 440 mg/m²/day (n= 8) and 570 mg/m²/day (n=6). Dosing based upon body surface area resulted in some patients receiving higher than the adult therapeutic dose, and the effect of this on pediatric patient safety is limited.

As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients in both phase I and phase II studies. Dosing in children at 260 and 340 mg/m²/day achieved similar exposure, respectively, as doses of 400 mg and 600 mg in adult patients, although this was based upon a small sample size. The comparison of AUC_0-24 on Day 8 versus Day 1 at the 340 mg/m²/day dose level revealed a 1.7- fold drug accumulation after repeated once daily dosing. As in adults, there was considerable inter-patient variability in the pharmacokinetics, and the coefficient of variation for AUC_0-24 ranged from 21% (260 mg/m²/day) to 68% (570 mg/m²/day). The AUC did not increase proportionally with dose within the range of doses examined. The active metabolite, GCP 74588, contributed about 20% of the AUC for imatinib. Total plasma clearance is about 8-10 L/h at steady state. The plasma AUC of imatinib is significantly lower (p=0.02) in children at ages between 2 and <12 years old (29.3 µg*hr/mL) than those at ages between 12 and <20 years old (34.6 µg*hr/mL). However, the difference between the two age groups does not seem to be clinically significant, only 15% of difference (geometric mean of 29.3 in children compared to 34.6 in adolescents). The AUC exposure in both age groups falls within the adult AUC(_{0-24 h}) range, between 24.8 and 39.7 μg*h/mL, achieved at 400 mg and 600 mg daily doses, respectively.

The clinical utility of detecting mutations remains to be demonstrated, since mutations have been described among GLEEVEC treated patients without evidence of disease progression. In addition, the approach to managing resistance will differ by CML disease stage, irrespective of treatment. Clinical and molecular resistance is much more prevalent among patients with blast crisis and accelerated phase CML, than among patients with chronic phase CML.

Based on population PK analysis, there was an effect of age on the volume of distribution (12% increase in patients >65 years old). This change is not thought to be clinically significant.

Imatinib increased the mean C_max and AUC of simvastatin (CYP3A4 substrate) by 2- and 3.5- fold, respectively, indicating an inhibition of CYP3A4 by imatinib. (See Drug Interactions.)