Summary Of Exposure |
A) USES: Imatinib is used to treat patients with Philadelphia chromosome positive acute lymphoblastic leukemia (relapsed/refractory), chronic eosinophilic leukemia, chronic myeloid leukemia (CML), dermatofibrosarcoma protuberans, (unresectable, recurrent and/or metastatic), gastrointestinal stromal tumor, hypereosinophilic syndrome, myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements, and aggressive systemic mast cell disease.
B) PHARMACOLOGY: Imatinib mesylate, a protein-tyrosine kinase inhibitor, inhibits the abnormally functioning Bcr-Abl tyrosine kinase which is produced by the Philadelphia chromosome abnormality found in chronic myeloid leukemia (CML). Imatinib inhibits cell proliferation and promotes apoptosis in the Bcr-Abl cell lines and in the leukemic cells generated by CML. Imatinib also inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which express an activating c-kit mutation. In vitro studies demonstrate that imatinib is not entirely selective, as it also inhibits c-Kit and the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF) (including PDGF- and SCF-mediated cellular events).
C) EPIDEMIOLOGY: Overdose is rare.
D) WITH THERAPEUTIC USE
1) COMMON: Edema, nausea, vomiting, diarrhea, abdominal pain, muscle cramps, musculoskeletal pain, rash, and fatigue. OTHER EFFECTS: Dyspepsia, anorexia, stomatitis, headache, dizziness, asthenia, paresthesia, cough, dyspnea, nasopharyngitis, pneumonitis, elevated liver enzymes, elevated serum creatinine, increased lacrimation, conjunctivitis, blurred vision, periorbital edema, thrombocytopenia, neutropenia, leukopenia, anemia, febrile neutropenia, pancytopenia, hypokalemia, hypocalcemia, hypophosphatemia, pleural effusion, ascites, pulmonary edema, pericardial effusion, and Stevens-Johnson syndrome. DRUG INTERACTION: Drugs that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity, such as clarithromycin, erythromycin, itraconazole, ketoconazole, may decrease the metabolism and increase concentrations of imatinib.
E) WITH POISONING/EXPOSURE
1) Nausea, vomiting, abdominal pain, facial swelling, severe muscle pain, elevated serum CK levels, and elevated liver enzymes have been reported. Other expected effects include diarrhea and delayed myelosuppression (neutropenia, thrombocytopenia, anemia).
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Vital Signs |
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) In patients newly-diagnosed with chronic myeloid leukemia (CML), all-grade and CTC grade 3/4 pyrexia were reported in 17.8% and 0.9%, respectively, of patients treated with imatinib (n=551) compared with 42.6% and 3%, respectively, of patients treated with interferon alfa plus cytarabine (n=533) (Prod Info GLEEVEC oral tablets, 2012).
2) The incidence of pyrexia of all grades and grades 3/4 was 41% and 7% in myeloid blast (n=260), 41% and 8% in accelerated phase (n=235), and 21% and 2% in chronic phase (n=532), respectively, among CML patients treated with imatinib in clinical trials (Prod Info GLEEVEC oral tablets, 2012).
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) INCREASED LACRIMATION: The incidence of increased lacrimation was 25% (3/12) in an open-label, phase 2 study of patients with dermatofibrosarcoma protuberans (DFSP) (n=12) in adults who received imatinib 800 mg daily (Prod Info GLEEVEC oral tablets, 2012).
2) Conjunctivitis, blurred vision, periorbital edema were reported in 1% to 10% of patients during clinical trials of imatinib (Prod Info GLEEVEC oral tablets, 2012).
3) VISUAL DETERIORATION AND RETINAL EDEMA: A 38-year-old man with chronic-phase chronic myelogenous leukemia (CML) developed visual deterioration and retinal edema with imatinib therapy. The patient had a history of left eye amblyopia and acuity of 6/12 and 6/5 for his left and right eyes, respectively. After beginning imatinib 400 mg/day, he had mild visual deterioration and an ophthalmic examination approximately one month later revealed visual acuity deterioration (left eye, 6/9; right eye, 6/18) with bilateral, moderate-sized retinal hemorrhages and macular edema and localized swelling of the superior border of the right optic nerve head. Bilateral macular edema and right disc leakage with no retinal ischemia were seen on a fluorescein angiogram. A diagnosis of central nervous system leukemia was excluded by a negative MRI and cerebrospinal fluid cytology. The patient had improved vision and ophthalmic examination 2 weeks after imatinib therapy was discontinued; additionally, he had complete resolution of most symptoms (retinal hemorrhages were fading but not gone) and visual acuity returned to baseline by 6 weeks. Although the patient had well controlled CML on hydroxyurea therapy for 5 months, he began oral dasatinib 70 mg twice daily as part of a phase 2 study. After more than 24 months of dasatinib therapy, no visual symptoms or ophthalmic complications occurred (Bajel et al, 2008).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) CARDIOVASCULAR FINDING 1) WITH THERAPEUTIC USE a) Fluid retention with superficial edema appears to be dose-related and has been observed in 50% to 70% of patients (myeloid blast crisis n=260; accelerated phase n=235; chronic phase, IFN failure n=532) receiving 400 mg daily or higher. Edema has been more common in elderly patients (Kantarjian et al, 2002; Joensuu et al, 2001; Druker et al, 2001; Druker et al, 2001a; Prod Info GLEEVEC(R) oral tablets, 2008).
b) Complications, such as pleural effusion, ascites, pulmonary edema, pericardial effusion, and anasarca have occurred in up to 22% of patients (n=260) with CML in blast crisis; they are less common in those with accelerated phase or chronic phase CML (Prod Info GLEEVEC oral tablets, 2012).
c) Congestive heart failure has been reported rarely (Prod Info GLEEVEC oral tablets, 2012; Druker et al, 2001).
d) During postmarketing surveillance of imatinib, there have been reports of cardiac tamponade, including fatalities (Prod Info GLEEVEC oral tablets, 2012).
e) Cardiogenic shock/left ventricular dysfunction has been associated with imatinib therapy in patients with hypereosinophilic syndrome and cardiac involvement. The condition has been reported to be reversible (Prod Info GLEEVEC oral tablets, 2012).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) COUGH 1) WITH THERAPEUTIC USE a) In clinical trials, cough has occurred in up to 27% of CML patients (myeloid blast crisis n=260; accelerated phase n=235; chronic phase, IFN failure n=532) (Prod Info GLEEVEC oral tablets, 2012).
B) DYSPNEA 1) WITH THERAPEUTIC USE a) In clinical trials, dyspnea has occurred in up to 21% of CML patients (myeloid blast crisis n=260; accelerated phase n=235; chronic phase, IFN failure n=532) (Prod Info GLEEVEC oral tablets, 2012).
C) NASOPHARYNGITIS 1) WITH THERAPEUTIC USE a) In newly diagnosed patients with chronic myeloid leukemia (CML), treated with imatinib (n=551), all-grade and CTC grade 3/4 nasopharyngitis occurred in 30.5% and 0% of patients, compared with 8.8% and 0.4% in interferon alfa (IFN) plus cytarabine (Ara-C) treated patients (n=533) (Prod Info GLEEVEC oral tablets, 2012).
D) PNEUMONITIS 1) WITH THERAPEUTIC USE a) In clinical trials, pneumonia has occurred in up to 13% of CML patients (myeloid blast crisis n=260; accelerated phase n=235; chronic phase, IFN failure n=532) (Prod Info GLEEVEC oral tablets, 2012).
b) CASE REPORT: A 54-year-old man with primary myelofibrosis developed acute pneumonitis with imatinib therapy. The patient tolerated the initial imatinib dosage of 200 mg twice daily for 9 weeks; however, he developed rapidly worsening dyspnea when the dosage was increased to 600 mg daily. Testing revealed hypoxemia, impaired alveolar gas diffusion, and characteristics of interstitial lung disease. A high-resolution CT scan of the chest showed poorly defined, bilateral patchy infiltrates. Imatinib was discontinued and oral prednisolone 1 mg/kg/day was given for 10 weeks. The clinical signs and symptoms of pneumonitis were improved at 9 weeks after presentation, although mild patchy infiltrates and traction bronchiectasis were observed on a follow-up high-resolution CT scan (Robibaro et al, 2010).
E) DISORDER OF RESPIRATORY SYSTEM 1) WITH THERAPEUTIC USE a) Pleural effusion and pulmonary edema have occurred in up to 22% of patients (n=260) with CML in blast crisis; they are less common in those with accelerated phase or chronic phase CML (Prod Info GLEEVEC oral tablets, 2012).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) HEADACHE 1) WITH THERAPEUTIC USE a) Headache has occurred in up to 36% of CML patients (myeloid blast crisis n=260; accelerated phase n=235; chronic phase, IFN failure n=532) during therapy (Prod Info GLEEVEC oral tablets, 2012; Kantarjian et al, 2002; Druker et al, 2001; Druker et al, 2001a).
B) DIZZINESS 1) WITH THERAPEUTIC USE a) The incidence of dizziness of all grades and grades 3/4 were 12% and 0.4% in myeloid blast (n=260), 13% and 0% in accelerated phase (n=235), and 16% and 0.2% in chronic phase (n=532), respectively, of CML patients treated with imatinib in clinical trials (Prod Info GLEEVEC oral tablets, 2012).
C) ASTHENIA 1) WITH THERAPEUTIC USE a) The incidence of asthenia of all grades and grades 3/4 were 18% and 5% in myeloid blast (n=260), 21% and 5% in accelerated phase (n=235), and 15% and 0.2% in chronic phase (n=532), respectively, of CML patients treated with imatinib in clinical trials (Prod Info GLEEVEC oral tablets, 2012).
b) The incidence of all-grade fatigue/lethargy, malaise, and asthenia in gastrointestinal stromal tumors (GIST) patients treated with imatinib in clinical trials was 69.3% with 400 mg (n=818) and 74.9% with 800 mg (n=822) doses. Grade 3/4/5 fatigue/lethargy, malaise, and asthenia were reported in 11.7% and 12.2% of patients receiving a 400 mg or 800 mg daily dose, respectively (Prod Info GLEEVEC oral tablets, 2012).
D) PARESTHESIA 1) WITH THERAPEUTIC USE a) Paresthesia has been reported in 1% to 10% of patients receiving imatinib mesylate during clinical trials (Prod Info GLEEVEC oral tablets, 2012).
E) CEREBRAL EDEMA 1) WITH THERAPEUTIC USE a) During postmarketing surveillance of imatinib, there have been reports of cerebral edema, including fatalities (Prod Info GLEEVEC oral tablets, 2012).
F) FATIGUE 1) WITH THERAPEUTIC USE a) Fatigue has occurred in up to 48% of CML patients (myeloid blast crisis n=260; accelerated phase n=235; chronic phase, IFN failure n=532) during therapy (Prod Info GLEEVEC oral tablets, 2012; Kantarjian et al, 2002; Druker et al, 2001; Druker et al, 2001a).
b) The incidence of all-grade fatigue/lethargy, malaise, and asthenia in gastrointestinal stromal tumors (GIST) patients treated with imatinib in clinical trials was 69.3% with 400 mg (n=818) and 74.9% with 800 mg (n=822) doses. Grade 3/4/5 fatigue/lethargy, malaise, and asthenia were reported in 11.7% and 12.2% of patients receiving a 400 mg or 800 mg daily dose, respectively (Prod Info GLEEVEC oral tablets, 2012).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE 1) WITH THERAPEUTIC USE a) In CML patients (myeloid blast crisis n=260; accelerated phase n=235; chronic phase, IFN failure n=532) receiving 400 to 600 mg daily, nausea (up to 73% of patients), vomiting (up to 58%), diarrhea (up to 57%), abdominal pain (up to 33%), dyspepsia (up to 27%), and anorexia (up to 17%) have been reported; nausea and diarrhea were dose-related (Prod Info GLEEVEC oral tablets, 2012; Kantarjian et al, 2002; Druker et al, 2001).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 53-year-old woman with hypothyroidism and CML presented with severe abdominal pain and vomiting after ingesting 16,000 mg of imatinib (40 tablets of imatinib 400 mg). She recovered following supportive care. Serum imatinib concentrations were 5.45 mcg/mL 13 hours postingestion (normal, 1 mcg/mL at 24 hours), and 0.25 mcg/mL, 0.06 mcg/mL, 0.01 mcg/mL, and less than 0.01 mcg/mL on days 6, 9, 12, and 14, respectively (Dehours et al, 2010).
b) CASE REPORT: A 21-year-old woman with CML presented with nausea, vomiting, severe abdominal pain, and facial swelling after ingesting 16 imatinib 400 mg tablets (total, 6400 mg) in a suicide attempt. She developed a low white blood cell count (1.2 x 10(9)/L), fever, and a transient elevated liver enzymes 3 days postingestion. She recovered following supportive care (Bhargav et al, 2007).
B) STOMATITIS 1) WITH THERAPEUTIC USE a) In a double-blind, placebo-controlled, randomized trial in the adjuvant setting of patients with primary gastrointestinal stromal tumors who had previous gross resection of the tumor and received study treatment for 12 months, all-grade and grade 3/4 stomatitis was reported in 5% and 0.6%, respectively, of patients receiving imatinib 400 mg/day (n=337) and in 1.7% and 0%, respectively, of patients receiving placebo (n=345) (Prod Info GLEEVEC oral tablets, 2012).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) INJURY OF LIVER 1) WITH THERAPEUTIC USE a) Imatinib has hepatotoxic potential as evidenced by frequent elevation of transaminases or bilirubin (Druker et al, 2001; Druker et al, 2001a; Prod Info GLEEVEC oral tablets, 2012).(Ferrero et al, 2006) Transaminase rises were seen after a median of 16 days of treatment in one study, and were not dose-related (Druker et al, 2001a). Long term corticosteroid therapy has been used to help resolve imatinib-induced hepatotoxicity and allow for continuation of treatment with imatinib (Ferrero et al, 2006).
b) In clinical trials, severe elevation of transaminases or bilirubin were observed in 5% of CML patients; liver failure, resulting in fatality, occurred in one patient who was receiving concurrent acetaminophen (Prod Info GLEEVEC oral tablets, 2012).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 21-year-old woman with CML presented with nausea, vomiting, severe abdominal pain, and facial swelling after ingesting 16 imatinib 400 mg tablets (total, 6400 mg) in a suicide attempt. She developed a low white blood cell count (1.2 x 10(9)/L), fever, and a transient elevated liver enzymes 3 days postingestion. She recovered following supportive care (Bhargav et al, 2007).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) RENAL FAILURE SYNDROME 1) WITH THERAPEUTIC USE a) Severe elevation of serum creatinine has been observed rarely during treatment of CML (up to 1.5% of patients; myeloid blast crisis n=260; accelerated phase n=235; chronic phase, IFN failure n=532) (Prod Info GLEEVEC oral tablets, 2012).
b) The incidence of all-grade creatinine increase in 2 open-label, randomized, phase 3 clinical trials of patients with unresectable or metastatic malignant gastrointestinal stromal tumors (GIST) treated with imatinib in clinical trials was 10.8% with 400 mg (n=818) and 10.1% with 800 mg (n=822) doses. Grade 3/4/5 creatinine increase was reported in 0.4% and 0.6% of patients receiving a 400 mg or 800 mg daily dose, respectively. In a double-blind, placebo-controlled, randomized trial in the adjuvant setting of patients with primary GIST who had previous gross resection of the tumor and received study treatment for 12 months, all-grade and grade 3/4 increased blood creatinine was reported in 11.6% and 0%, respectively, of patients receiving imatinib 400 mg/day (n=337) and in 5.8% and 0.3%, respectively, of patients receiving placebo (n=345). In an open-label, randomized, phase 3 trial in the adjuvant setting of patients who had previous surgical resection of their GIST and treated with imatinib 400 mg/day, all-grade increased blood creatinine was reported in 30.4% of patients treated for 12 months (n=194) and in 44.4% of patients treated for 36 months (n=198); no (0%) increased blood creatinine reported in either group was of grade 3 or higher (Prod Info GLEEVEC oral tablets, 2012).
c) Acute renal failure has been reported (Druker et al, 2001a).
d) CASE REPORT: A 64-year-old man presented with nausea, vomiting, loss of appetite, and weakness the day after completing 14 days of imatinib mesylate therapy for treatment of prostate cancer. Laboratory data showed elevated BUN and serum creatinine levels (63 mg/dL and 11.6 mg/dL, respectively) and a serum uric acid level of 14.1 mg/dL (baseline of 7.4 mg/dL 5 days prior to admission/day 9 of imatinib therapy). A urinalysis showed proteinuria and hematuria. A renal biopsy, performed on hospital day 3, revealed extensive tubular vacuolization. The patient's renal failure resolved, with normalization of his BUN and serum creatinine levels, following 3 hemodialysis sessions (Foringer et al, 2005).
e) CASE REPORT: A 58-year-old woman with chronic myeloid leukemia developed acute renal failure with acute tubular necrosis after beginning imatinib therapy. The patient's renal function improved following 3 hemodialysis sessions and cessation of imatinib therapy; however, mild chronic renal insufficiency persisted one year later (Pou et al, 2003).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) MYELOSUPPRESSION 1) WITH THERAPEUTIC USE a) Thrombocytopenia, neutropenia, leukopenia, and anemia are relatively common during therapy of CML (Prod Info GLEEVEC oral tablets, 2012; Kantarjian et al, 2002; Druker et al, 2001; Druker et al, 2001a). A tendency toward a dose relationship has been observed for both complications (particularly grade 3 or 4) in chronic phase CML (Druker et al, 2001); only grade 4 thrombocytopenia appeared dose-related in acute leukemia patients (Druker et al, 2001a).
b) Pancytopenia and febrile neutropenia have been reported in 1% to 10% of patients receiving imatinib mesylate during clinical trials (Prod Info GLEEVEC oral tablets, 2012).
c) In clinical trials, thrombocytopenia, neutropenia, and anemia were reported in up to 48% of CML patients (myeloid blast crisis n=260; accelerated phase n=235; chronic phase, IFN failure n=532). Median durations of episodes of neutropenia and thrombocytopenia were 2 to 3 weeks and 3 to 4 weeks, respectively (Prod Info GLEEVEC oral tablets, 2012).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 21-year-old woman with CML presented with nausea, vomiting, severe abdominal pain, and facial swelling after ingesting 16 imatinib 400 mg tablets (total, 6400 mg) in a suicide attempt. She developed a low white blood cell count (1.2 x 10(9)/L), fever, and a transient elevated liver enzymes 3 days postingestion. She recovered following supportive care (Bhargav et al, 2007).
b) CASE REPORT: A 47-year-old woman with chronic-phase CML was found comatose after ingesting 2000 mg of imatinib, 12.5 mg of brotizolam, and 3.5 mg of triazolam. Laboratory results showed a white blood cell count of 11,600/mcL with 92.7% neutrophils, a serum hemoglobin value of 11.1 g/dL, and a platelet count of 19.8 x 10(4)/mcL. Following supportive care, she regained consciousness within 6 hours of admission. Her serum imatinib concentration was 3580 ng/mL at this time. The next day, she developed severe muscle cramps and laboratory results revealed serum CK concentration of 3880 International Units/L and serum imatinib concentration of 4700 ng/mL. Following supportive care, her serum CK concentration returned to normal 2 weeks after admission. The imatinib blood concentration decreased; however, a marked delay of the Tmax (30 hours; normal, 2 to 4 hours) was observed. It was suggested that imatinib inhibited the peristalsis of the small intestine, which caused a marked prolongation of absorption of the large dose imatinib (Iketani et al, 2012).
B) BLEEDING 1) WITH THERAPEUTIC USE a) In newly diagnosed patients with CML receiving imatinib (n=551), all-grade and grade 3/4 hemorrhage occurred in 28.9% and 1.8% of patients, respectively. All-grade and grade 3/4 gastrointestinal hemorrhage occurred in 1.6% and 0.5% of imatinib-treated patients, respectively (Prod Info GLEEVEC oral tablets, 2012).
b) In clinical trials, hemorrhage (including occasional central nervous system and gastrointestinal hemorrhage) was reported in up to 53% of CML patients treated with imatinib (Prod Info GLEEVEC oral tablets, 2012); causality in these cases is uncertain due to underlying hematologic pathology.
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) DISORDER OF SKIN 1) WITH THERAPEUTIC USE a) Skin rash, pruritus, and exfoliative dermatitis have been reported during imatinib therapy (Prod Info GLEEVEC oral tablets, 2012; Kantarjian et al, 2002; Druker et al, 2001; Druker et al, 2001a).
b) In clinical trials, skin rash occurred in 36% to 47% of CML patients (myeloid blast crisis n=260; accelerated phase n=235; chronic phase, IFN failure n=532) receiving 400 to 600 mg daily (Prod Info GLEEVEC oral tablets, 2012).
c) An acute generalized exanthematous pustulosis was observed in a patient with CML who was treated with imatinib (STI571). In this patient, the scarlatiniform erythema with nonfollicular pustules was confined to flexural areas (Brouard & Saurat, 2001).
B) SKIN HYPOPIGMENTED 1) WITH THERAPEUTIC USE a) Hypopigmentation of the skin has been reported in two patients following therapeutic administration of imatinib (Brazzelli et al, 2006; Hasan et al, 2003).
C) PSEUDOPORPHYRIA 1) WITH THERAPEUTIC USE a) CASE REPORT: A 63-year-old woman developed pseudoporphyria following treatment with imatinib for chronic myelogenous leukemia. The patient presented with a 19-month history of worsening blisters and skin fragility on her acral sites and extremities. A skin biopsy revealed a pauci-inflammatory subepidermal split consistent with porphyria cutanea tarda and a negative direct immunofluorescence. Both serum and urine porphyrin evaluations were normal. The patient chose to continue imatinib therapy (Berghoff & English, 2010).
D) LICHENOID DERMATITIS 1) WITH THERAPEUTIC USE a) CASE REPORT: A 75-year-old man treated with imatinib 400 mg/day for chronic myeloid leukemia experienced lichenoid eruption, which improved when imatinib was discontinued and recurred when rechallenged with imatinib. He presented with a 4-month history of asymptomatic lesions on his tongue. The patient had no prior exposure to dental restorative materials or other medications. Two months later, he developed whitish reticulate plaques on the dorsal and lateral areas of his tongue. A histopathological exam showed dense lichenoid inflammatory infiltrate with necrotic epithelial cells on the lower epithelium, along with parakeratosis. Imatinib was discontinued and treatment with prednisone 30 mg/day was initiated. Gradual improvement was seen; however, when rechallenged with imatinib 400 mg/day three weeks later, the lichenoid eruptions returned (Fernandez et al, 2010).
E) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE 1) WITH THERAPEUTIC USE a) During postmarketing evaluations, toxic epidermal necrolysis was reported in patients receiving imatinib. Incidence and causality could not be determined (Prod Info GLEEVEC oral tablets, 2012).
F) STEVENS-JOHNSON SYNDROME 1) WITH THERAPEUTIC USE a) There have been cases of bullous dermatologic reactions including Stevens-Johnson syndrome associated with the use of imatinib during postmarketing surveillance, which reoccurred upon rechallenge. In foreign postmarketing reports, imatinib was successfully resumed following resolution or improvement in the bullous reactions when lower doses of imatinib and concomitant corticosteroids or antihistamines were used (Prod Info GLEEVEC oral tablets, 2012).
b) CASE REPORT: A 60-year-old woman with chronic myeloid leukemia (CML) taking no other medications developed Stevens-Johnson syndrome (SJS) 12 days after taking imatinib mesylate 400 mg once daily. She developed a pruritic, maculopapular, erythematous rash and mild periorbital edema, which progressed into a disseminated rash with confluent areas over the neck, chest, and upper abdomen. Additionally, she had oral and vaginal mucosal erosions. A skin biopsy revealed parakeratosis and mild, irregular acanthosis of the epidermis with perivascular and peri-appendigeal lymphohistiocytic infiltration in the dermis. Imatinib mesylate was discontinued after the patient was diagnosed with SJS and 10 days later, she had complete resolution of her symptoms. The patient was restarted on imatinib mesylate 200 mg once daily 2 weeks later; however, she developed a perioral, pruritic, erythematous rash the next day and imatinib mesylate was stopped. She received fexofenadine and oral prednisolone (40 mg/day) and the rash resolved. After receiving hydroxyurea for one month, imatinib mesylate was restarted at 100 mg once daily with prednisolone 40 mg daily. Over 6 weeks, the prednisolone was gradually decreased and discontinued and the imatinib mesylate dose was titrated up to 300 mg/day. After 6 months on imatinib mesylate, the patient had no further recurrence of rash (Mahapatra et al, 2007).
G) DERMATITIS 1) WITH THERAPEUTIC USE a) In an open-label, randomized, phase 3 trial in the adjuvant setting of patients who had previous surgical resection of their gastrointestinal stromal tumors and treated with imatinib 400 mg/day, all-grade and grade 3/4 dermatitis was reported in 29.4% and 2.1%, respectively, of patients treated for 12 months (n=194) and in 38.9% and 1.5%, respectively, of patients treated for 36 months (n=198) (Prod Info GLEEVEC oral tablets, 2012).
H) EDEMA OF FACE 1) WITH THERAPEUTIC USE a) In an open-label, phase 2 study of patients with dermatofibrosarcoma protuberans (DFSP) (n=12), adults received imatinib 800 mg daily. Two patients (16.7%) experienced face edema, 33.3% (4/12) periorbital edema, 33% (4/12) peripheral edema, and 33% (4/12) eye edema. The incidences represent all-grade edema (Prod Info GLEEVEC oral tablets, 2012).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 21-year-old woman with CML presented with nausea, vomiting, severe abdominal pain, and facial swelling after ingesting 16 imatinib 400 mg tablets (total, 6400 mg) in a suicide attempt. She developed a low white blood cell count (1.2 x 10(9)/L), fever, and a transient elevated liver enzymes 3 days postingestion. She recovered following supportive care (Bhargav et al, 2007).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) MUSCLE PAIN 1) WITH THERAPEUTIC USE a) In clinical trials, muscle cramps and musculoskeletal pain were reported in 28% to 62% of patients (myeloid blast crisis n=260; accelerated phase n=235; chronic phase, IFN failure n=532) (Prod Info GLEEVEC oral tablets, 2012; Kantarjian et al, 2002; Druker et al, 2001).
b) In newly diagnosed patients with chronic myeloid leukemia (CML), treated with imatinib (n=551), all-grade and CTC grade 3/4 musculoskeletal pain occurred in 47% and 5.4% of patients, compared with 44.8% and 8.6% in interferon alfa (IFN) plus cytarabine (Ara-C) treated patients (n=533) (Prod Info GLEEVEC oral tablets, 2012).
B) INCREASED CREATINE KINASE LEVEL 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 47-year-old woman with chronic-phase CML was found comatose after ingesting 2000 mg of imatinib, 12.5 mg of brotizolam, and 3.5 mg of triazolam. Laboratory results showed a white blood cell count of 11,600/mcL with 92.7% neutrophils, a serum hemoglobin value of 11.1 g/dL, and a platelet count of 19.8 x 10(4)/mcL. Following supportive care, she regained consciousness within 6 hours of admission. Her serum imatinib concentration was 3580 ng/mL at this time. The next day, she developed severe muscle cramps and laboratory results revealed serum CK concentration of 3880 International Units/L and serum imatinib concentration of 4700 ng/mL. Following supportive care, her serum CK concentration returned to normal 2 weeks after admission. The imatinib blood concentration decreased; however, a marked delay of the Tmax (30 hours; normal, 2 to 4 hours) was observed. It was suggested that imatinib inhibited the peristalsis of the small intestine, which caused a marked prolongation of absorption of the large dose imatinib (Iketani et al, 2012).
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Endocrine |
3.16.2) CLINICAL EFFECTS
A) HYPOTHYROIDISM 1) WITH THERAPEUTIC USE a) Cases of hypothyroidism have been reported in thyroidectomy patients concurrently receiving imatinib and levothyroxine replacement (Prod Info GLEEVEC oral tablets, 2012).
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Reproductive |
3.20.1) SUMMARY
A) Imatinib is classified as FDA Pregnancy Category D. Three case reports of imatinib use during pregnancy demonstrated no adverse effects on the fetus; however, spontaneous abortions and infant congenital anomalies have been reported during postmarketing surveillance. Teratogenicity and fetal loss have been observed in animal studies. Imatinib and its active metabolite are excreted in human milk, with a milk:plasma ratio of about 0.5 and 0.9, respectively. Based on body weight, a breastfed infant could receive up to 10% of the maternal therapeutic dose if both components are combined; however, the risk to the nursing infant is not known. Adverse effects have been observed in animal fertility studies.
3.20.2) TERATOGENICITY
A) CONGENITAL MALFORMATIONS 1) Infant congenital anomalies have been reported during imatinib postmarketing surveillance (Prod Info GLEEVEC(R) oral tablets, 2015).
2) A case report describes a 27-year-old woman who was treated with imatinib mesylate (400 mg/day IM) for 4 years for chronic myelogenous leukemia during 3 pregnancies. The first pregnancy was ectopic, for which a laparotomy was performed, and her second pregnancy, approximately 1.5 years later, resulted in a normal vaginal delivery of a healthy infant. She later delivered twins at 35 weeks gestation; one healthy infant and another with congenital malformations and low birth weight (2.25 kg). Physical examination of the infant revealed malformed right external ear, preauricular tag on the left side, absence of right depressor angular oris muscle, and imperforate anus. Imaging results also showed dextrocardia, hemivertebrae in the thoracic region, cervical spina bifida occulta, absent right kidney, ectopic left kidney in the pelvic region, mild ventriculomegaly, and situs inversus in the neonate. The newborn underwent surgery for the imperforate anus and was discharged in good condition. The authors recommend that pregnant women should not be treated with imatinib mesylate, because such treatment can lead to teratogenicity (Jain et al, 2015).
B) LOW BIRTH WEIGHT 1) In a case report, birth weight, length, and head circumference measured below the 10th percentile (2613 g; 41 cm; and 33 cm, respectively) in a neonate delivered at 39 weeks' gestation with exposure from week 31 to interferon alpha 3 million units/day (4 total doses) and oral imatinib titrated to 200 mg twice daily due to maternal treatment for suspected blast crisis associated with chronic myelocytic leukemia (CML). No congenital abnormalities were detected. The 29-year-old mother presented with a WBC count of 659,000/mm(3) (normal range, 4000/mm(3) to 11,000/mm(3)) and a platelet count of 458,000/mm(3) (normal range, 130,000/mm(3) to 400,000/mm(3)). Baseline tests revealed a female fetus of 30 weeks' gestation with an estimated weight of 1527 g and normal anatomy, amniotic fluid index, and biophysical profile. The mother was treated with leukocytapheresis before initiation of interferon alpha in week 31. Imatinib was started 4 days later, and by delivery via cesarean section the mother's WBC count had normalized. The infant's WBC and platelet counts were also normal; 5 months later, the mother was in complete remission while the infant continued to grow and meet all neurodevelopmental milestones (Eskander et al, 2011).
C) ANIMAL STUDIES 1) RATS: In animal studies, systemic imatinib exposure in rats at approximately equal to the maximum human clinical dose of 800 mg/day showed evidence of teratogenicity. Adverse outcomes included exencephaly, encephalocele, absent/reduced frontal bones, and absent parietal bones (Prod Info GLEEVEC(R) oral tablets, 2015).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) The manufacturer has classified imatinib as FDA pregnancy category D. There are no adequate and well-controlled studies of imatinib use in pregnant women. Animal studies with imatinib have shown evidence of potential teratogenicity. Although there have been several case reports of successful outcomes in pregnant women exposed to imatinib, spontaneous abortions and congenital anomalies have been reported during postmarketing surveillance. Therefore, advise women of childbearing potential to avoid becoming pregnant while taking imatinib. If imatinib use is required during pregnancy, sexually active female patients should use adequate contraception. If a patient becomes pregnant while taking imatinib, counsel her regarding the potential hazard to the fetus (Prod Info GLEEVEC(R) oral tablets, 2015).
B) ABORTION 1) Spontaneous abortions have been reported during imatinib postmarketing surveillance (Prod Info GLEEVEC(R) oral tablets, 2015).
2) The outcomes or status of 26 pregnancies in women taking therapeutic doses of imatinib were anecdotally reported. Sixteen pregnancies resulted in either therapeutic or spontaneous abortions, and 4 others were still ongoing at the time of publication. Three pregnancies proceeded to term, producing two normal infants and one with hypospadias; no information was known about the remaining three pregnancies (Hensley & Ford, 2003).
C) LACK OF EFFECT 1) In two case reports, women with histories of Philadelphia chromosome-positive chronic myeloid leukemia (CML) who were treated with imatinib during middle to late gestation delivered healthy full-term female infants (3600 g and 2995 g) with little or no imatinib detected in umbilical cord blood. In the first case, a woman was initiated on imatinib during the third trimester. Although imatinib and its active metabolite, CGP74588, were present at concentrations of 886 nanograms (ng)/mL and 338 ng/mL, respectively, in maternal blood collected 11 hours after an imatinib dose, neither was detected in umbilical cord blood collected 38 hours after a maternal imatinib dose. In the second case, a woman was on imatinib maintenance therapy from conception through week 4 of gestation and was re-initiated at mid-gestation. Imatinib and CGP74588 were detected in placental homogenate at concentrations of 2452 ng/mL and 1462 ng/mL, respectively. Imatinib, at a concentration of 157 ng/mL, was detected in umbilical cord blood collected 12 hours after a maternal imatinib dose; CGP74588 was not detected. The umbilical cord blood to placenta ratio for imatinib concentration was 0.064 (Russell et al, 2007).
2) In another case report, a woman with chronic myeloid leukemia who was treated with imatinib from day 8 through day 33 of gestation delivered a healthy full-term infant. At 8 weeks of age, the infant developed pyloric stenosis which was operated upon successfully. At the time of the publication of this case report, the child was 25 months old, healthy, and developing normally (Heartin et al, 2004).
D) ANIMAL STUDIES 1) RATS: In animal studies, systemic imatinib exposure in rats at approximately half of the maximum human clinical dose of 800 mg/day led to fetal resorption early in gestation and stillbirths, nonviable pups and early postpartum pup deaths. All animals experienced fetal loss with exposure to doses higher than 100 mg/kg. Doses up to one-third of the maximum human dose showed no evidence of fetal loss (Prod Info GLEEVEC(R) oral tablets, 2015).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) Imatinib and its active metabolite are excreted in human milk, and data indicate a milk:plasma ratio of about 0.5 and 0.9, respectively. Based on body weight, a breastfed infant could receive up to 10% of the maternal therapeutic dose when the concentrations of both components are combined. Due to the lack of human safety information, a decision should be made whether to discontinue nursing or discontinue the drug, considering the importance of the drug to the mother (Prod Info GLEEVEC(R) oral tablets, 2015).
2) Imatinib and its active metabolite, CGP74588, were detected in the breast milk of a woman with a 1-year history of Philadelphia chromosome-positive chronic myeloid leukemia (CML) who had been treated with imatinib 400 mg/day from mid-gestation through postpartum. Originally maintained on imatinib therapy from conception through week 4 of gestation, the drug was discontinued when she became pregnant and restarted later during the pregnancy. At 7 days postpartum (15 hours after an imatinib dose), imatinib and CGP74588 were detected in the breast milk at concentrations of 596 nanograms (ng)/mL and 1513 ng/mL, respectively. Authors estimate that with a maternal imatinib dose of 400 mg/day, an infant consuming 600 to 1000 mL of breast milk would ingest 1.2 to 2 mg of imatinib and CGP74588. The risks to a nursing infant ingesting imatinib and CGP74588 at the levels detected in breast milk are not known (Russell et al, 2007).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) MALE RATS: In male rat fertility studies, doses of 20 mg/kg or less (one-fourth the maximum human dose of 800 mg/day) did not result in adverse effects. In preclinical fertility and early embryonic development studies, fertility was not affected. In male rats, testicular and epididymal weights and percent motile sperm were decreased following a dose of 60 mg/kg (approximately three-fourths the maximum human dose) given for 70 days prior to mating. In preclinical fertility and early embryonic development studies, male rats treated with high doses of imatinib resulted in lower testes and epididymal weights and a reduced number of motile sperm (Prod Info GLEEVEC(R) oral tablets, 2015).
2) FEMALE RATS:In female rats, a red vaginal discharge was noted on day 14 or 15 of gestation following doses of 45 mg/kg (approximately one-half the maximum human dose) given from day 6 of gestation until the end of lactation. At this dose, reduced mean body weights from birth until terminal sacrifice were observed in the first generation offspring. Although fertility of the first generation offspring was not affected, reproductive effects, including an increased number of resorptions and a decreased number of viable fetuses, were observed (Prod Info GLEEVEC(R) oral tablets, 2015).
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