Summary Of Exposure |
A) USES: Gemcitabine is used alone or in combination with other agents (eg; paclitaxel, cisplatin, carboplatin) to treat patients with metastatic breast cancer, inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer, advanced ovarian cancer, and locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas.
B) PHARMACOLOGY: Gemcitabine is a nucleoside analogue that has antitumor activity. It has cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase), and also blocks the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Its cytotoxic effect is attributed to a combination of two actions of the diphosphate and the triphosphate nucleosides, leading to inhibition of DNA synthesis.
C) TOXICOLOGY: After overdose, the effects of decreased DNA synthesis and cell death are noticed primarily in organ systems with rapidly dividing cells (bone marrow, gastrointestinal tract).
D) EPIDEMIOLOGY: Overdose is rare.
E) WITH THERAPEUTIC USE
1) COMMON: Nausea, vomiting, diarrhea, fever, mild dyspnea, mild peripheral edema, elevated liver enzymes, mild proteinuria and hematuria, macular or finely granular maculopapular pruritic rash may occur with therapy. The primary dose-limiting toxicity has been myelosuppression, but less than 1% of patients required discontinuation of therapy due to thrombocytopenia, anemia, or leukopenia. INFREQUENT: Acute lung injury, pulmonary edema, mild paresthesias, mucositis and stomatitis may develop. RARE: Hemolytic uremic syndrome has been reported. Several cases of fatal pulmonary toxicity, hypersensitivity pneumonitis, and pulmonary hemorrhage have also occurred. In most cases, symptoms developed after several doses/cycles of gemcitabine. Cardiovascular events (myocardial infarction, congestive heart failure, atrial fibrillation, cerebrovascular accident, dysrhythmia, hypotension, and hypertension) have been reported; however, most patients had a prior history of cardiac disease.
F) WITH POISONING/EXPOSURE
1) Clinical events in overdose are anticipated to be an extension of adverse effects. A single dose of 5700 mg/m(2) of gemcitabine given intravenously over 30 minutes every 2 weeks resulted in myelosuppression, paresthesias, and severe rash (primary toxicities) in several patients during a Phase I clinical trial. Severe toxicity was reported during a phase III clinical trial in which several patients received 6400 mg/m(2) of gemcitabine. One patient developed bullous skin ulceration and another severe mucositis with hemorrhagic ulceration and necrosis.
|
Vital Signs |
3.3.1) SUMMARY
A) WITH THERAPEUTIC USE 1) Fever has been reported frequently with therapeutic use, and generally not associated with clinical infection.
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) During clinical trials, the overall incidence of fever was 41% and was often not associated with clinical infection (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011; Gupta et al, 2002).
2) Flu-like symptoms have been reported in up to 20% of patients, and were frequently associated with fever (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011; Gupta et al, 2002).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) CARDIOVASCULAR FINDING 1) WITH THERAPEUTIC USE a) Approximately 2% of patients discontinued gemcitabine therapy due to cardiovascular events (myocardial infarction, cerebrovascular accident, dysrhythmia, and hypertension); however, most patients had a prior history of cardiac disease (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
b) In a meta-analysis (n=979 patients), infrequent reports of myocardial infarction (0.5%), congestive heart failure (0.4%), and dysrhythmias (0.2%) occurred following gemcitabine therapy. Several cases of hypotension were also reported (Aapro et al, 1998).
B) ATRIAL FIBRILLATION 1) WITH THERAPEUTIC USE a) CASE REPORT: A 78-year-old man with pancreatic adenocarcinoma developed atrial fibrillation after the first cycle of gemcitabine therapy, which occurred approximately 18 hours after administration. Symptoms resolved with intravenous propafenone. Subsequent doses of gemcitabine resulted in episodes of atrial fibrillation 18 to 22 hours after administration. Despite prophylactic oral propafenone therapy and a lack of precipitating causes, the dysrhythmias continued to occur. No further episodes developed after gemcitabine was discontinued (Santini et al, 2000).
b) CASE REPORTS: Two women with lung cancer developed paroxysmal atrial fibrillation (AF) with rapid ventricular response 12 to 24 hours after receiving gemcitabine (1200 milligrams/meter(2) days 1-8 every 21 days). After the first episode of AF, the first patient spontaneously converted to sinus rhythm; however, she required therapy with amiodarone for the second episode. The second patient was treated with digitalis to control the ventricular response; however, a stable sinus rhythm could not be attained. Following the discontinuation of chemotherapy, she was discharged 5 days later in good hemodynamic control with compensated AF. The authors suggested that 2',2'-difluorodeoxyuridine, an active metabolite of gemcitabine, could be the cause of the toxic effect (Ferrari et al, 2006).
C) PERIPHERAL EDEMA 1) WITH THERAPEUTIC USE a) Mild cases of peripheral edema have occurred in up to 20% of patients receiving gemcitabine therapy; most cases did not require a disruption in therapy (Anon, 1993; Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
b) INCIDENCE: In a review of the literature, peripheral edema has been reported to range from 9% to 40% of patients (Gupta et al, 2002).
D) LACK OF EFFECT 1) WITH THERAPEUTIC USE a) Cortes-Funes et al (1997) reported no cardiac toxicity in patients (n=360) receiving therapeutic gemcitabine (Cortes-Funes et al, 1997).
|
Respiratory |
3.6.2) CLINICAL EFFECTS
A) DYSPNEA 1) WITH THERAPEUTIC USE a) Dyspnea is a relatively common side effect of gemcitabine therapy (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011; Cortes-Funes et al, 1997); however, many patients appeared to have underlying pulmonary dysfunction prior to starting therapy (primary or metastatic lung cancer) (Aapro et al, 1998; Vander Els & Miller, 1998). In one study, 6% of patients discontinued therapy due to gemcitabine-induced pulmonary toxicity (Gupta et al, 2002). b) INCIDENCE: Overall, dyspnea has been reported in up to 23% of patients with up to 3% reporting severe dyspnea (Prod Info Gemzar(R), gemcitabine HCL, 1998; Aapro et al, 1998). As expected, the incidence of dyspnea was higher in lung cancer studies (35.4%) as compared with non-lung cancer studies (15.8%) (Cortes-Funes et al, 1997). 1) CLINICAL FINDINGS ASSOCIATED WITH DYSPNEA: Rosado et al (2002) described three distinct patterns that have been associated with gemcitabine-induced dyspnea (Rosado et al, 2002): a) an acute hypersensitivity reaction with associated self-limiting bronchospasm;
b) nonspecific dyspnea of uncertain origin occurring within days of treatment and resolving spontaneously;
c) a rare idiosyncratic reaction associated with pulmonary infiltrates on chest radiograph.
2) Infrequent reports (less than 2% of patients) of dyspnea with bronchospasm have been described (Prod Info Gemzar(R), gemcitabine HCL, 1998; Aapro et al, 1998). Most cases of dyspnea were mild and developed several hours after beginning therapy and often resolved within 3 to 12 hours with no specific therapy (Cortes-Funes et al, 1997; Aapro et al, 1998). 3) CASE REPORT: A dry cough, progressive dyspnea, and interstitial infiltrates were reported in a 60-year-old female with non-small cell lung cancer after 5 weekly doses of gemcitabine (1600 mg/dose). Symptoms resolved within a week of beginning prednisone 60 milligrams (tapered over several weeks) (Vander Els & Miller, 1998). c) PATIENT CHARACTERISTICS: Although it is difficult to predict which patients may be more susceptible to gemcitabine-induced pulmonary toxicity, increasing reports in the literature have identified a subset of individuals that may be more likely to develop symptoms. The following patient characteristics have been observed: over 65 years of age, male, previous radiation therapy to the mediastinum, lung neoplasm, and the total number of doses of gemcitabine received (Gupta et al, 2002). d) MECHANISM: It has been suggested that gemcitabine produces pulmonary toxicity by a cytokine-mediated inflammatory reaction of the alveolar capillary wall. This creates abnormal membrane permeability, resulting in accumulation of fluid, inflammatory cells in the interstitial space, myofibroblast proliferation, and collagen deposit (Rosado et al, 2002). B) ACUTE LUNG INJURY 1) WITH THERAPEUTIC USE a) SUMMARY: Several reports of fatal pulmonary toxicity have occurred following therapeutic use of gemcitabine (Maniwa et al, 2003; Tempero & Brand, 1998; Marruchella et al, 1998; Pavlakis et al, 1997).
b) CASE REPORT: A 68-year-old male developed pulmonary infiltrates and hypoxemia consistent with adult respiratory distress syndrome (ARDS) following a second cycle of gemcitabine (10 mg/m(2)/min) for pancreatic adenocarcinoma (Tempero & Brand, 1998). Treatment included mechanical ventilation and steroids.
c) CASE REPORT: A 68-year-old male with squamous-cell lung cancer developed ARDS following his sixth dose (1250 milligrams/meter(2)) of gemcitabine while on concomitant prednisone (12.5 milligrams/day) therapy (Marruchella et al, 1998). His worsening hypoxia became refractory to oxygen therapy (the patient declined mechanical ventilation) despite continuous-positive-airway pressure. Postmortem exam was consistent with ARDS.
d) CASE SERIES: Pavlakis et al (1997) reported that 3 patients treated with gemcitabine developed tachypnea, marked hypoxemia, and interstitial infiltrates consistent with pulmonary edema. Postmortem exam confirmed ARDS in two patients (Pavlakis et al, 1997).
e) CASE REPORT: A 75-year-old man with non-small cell lung cancer developed ARDS following the ingestion of gemcitabine (1,500 milligram total dose). He died of respiratory failure on the fourteenth post-chemotherapeutic day. Post-mortem exam of the lungs showed mixed hyaline membrane formation, compatible with diffuse alveolar damage. Additionally, multiple microscopic fibroid thromboses were noted in arterioles and capillaries of the lungs, liver, and kidney. These findings were consistent with disseminated intravascular coagulation (DIC) (Maniwa et al, 2003).
C) PNEUMONITIS 1) WITH THERAPEUTIC USE a) SUMMARY 1) Rare cases of drug-induced pneumonitis have been reported with gemcitabine use (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011). Hypersensitivity pneumonitis has been described in the literature (Rosado et al, 2002). A case of pneumonitis developed after one dose of gemcitabine (Linskens et al, 2000).
D) PULMONARY HEMORRHAGE 1) WITH THERAPEUTIC USE a) CASE REPORT: Grunewald et al (1992) reported that one patient with thrombocytopenia (platelet count less than 30,000/microliter) developed pulmonary hemorrhage at 240 milligrams/square meter during a Phase I clinical trial of patients with acute leukemia or blast crisis of chronic myelogenous leukemia (CML)(Grunewald et al, 1992a).
E) PULMONARY VENO-OCCLUSIVE DISEASE 1) WITH THERAPEUTIC USE a) CASE REPORT: A 57-year-old male with adenocarcinoma of the lung and malignant pericardial effusion was treated with gemcitabine and developed symptoms of dyspnea with each course of therapy. The patient was treated symptomatically with diuretics and digoxin (for a presumptive diagnosis of heart failure). During the fifth cycle, the patient developed progressive dyspnea along with peripheral edema. Chest x-ray showed increased interstitial markings and a prominent left-sided pleural effusion. Corticosteroids were added to the therapy and given before each cycle of gemcitabine. However, the patient died of rapid cardiopulmonary deterioration during cycle 7; autopsy was consistent with the diagnosis of pulmonary veno-occlusive disease (Vansteenkiste et al, 2001).
F) PNEUMONIA 1) WITH THERAPEUTIC USE a) CASE REPORT: Pneumocystis carinii pneumonia was associated with gemcitabine use in a 56-year-old male with carcinoma of the pancreas with liver metastases and a negative HIV serological test. The patient developed symptoms of weakness, dyspnea and dry cough during the third dose of gemcitabine (a palliative monotherapy of weekly intravenous infusions of 1800 mg {100 milligrams/meter(2) body surface}). Signs and symptoms improved following antibiotic therapy; rechallenge was not considered (Weber et al, 2000).
G) CASE REPORT 1) An 85-year-old male with stage IV non-small-cell lung cancer was treated with gemcitabine and developed severe dyspnea during his second cycle of therapy. Computed tomography revealed bilateral extensive ground-glass opacity in the entire left lung and portions of the right lung, which was consistent with hypersensitivity pneumonitis. Despite medical intervention, the patient's clinical status worsened and sepsis developed. The patient died 17 days after admission; a postmortem examination was refused by the family (Rosado et al, 2002). A similar case report was described in a 71-year-old male (Gupta et al, 2002).
2) Linskens et al (2000) reported that a 58-year-old female with metastatic pancreatic carcinoma developed dyspnea and hypoxemia along with pulmonary infiltrates, consistent with non-cardiogenic pulmonary edema, 4 days after receiving a single dose of gemcitabine. Acute respiratory failure was successfully treated with diuretic and corticosteroid therapies; no permanent sequelae occurred. Rechallenge was not considered (Linskens et al, 2000).
3) A 55-year-old female with ovarian cancer received 3 cycles of gemcitabine (1250 milligrams/meter(2)) and developed rapid, progressive dyspnea (Pavlakis et al, 1997). Lung biopsy showed nonspecific interstitial pneumonitis. Treatment consisted of dexamethasone 16 milligrams daily with clinical improvement of respiratory symptoms.
4) A 52-year-old male with stage IV non-small-cell lung cancer developed acute interstitial pneumonitis after receiving a total of 6 doses of gemcitabine. The patient was diagnosed with non-specific interstitial pneumonitis and treated with corticosteroid therapy. Complete resolution of signs and symptoms occurred 2 months after exposure (Attar et al, 2000).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) PARESTHESIA 1) WITH THERAPEUTIC USE a) Mild paresthesias were reported in 10% of patients receiving gemcitabine during clinical trials; less than 1% developed severe paresthesias (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
2) WITH POISONING/EXPOSURE a) During Phase I clinical trials, several patients received a single dose, as high as 5700 mg/m(2), of gemcitabine given intravenously over 30 minutes every 2 weeks and developed myelosuppression, paresthesias, and severe rash (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
B) DROWSY 1) WITH THERAPEUTIC USE a) Somnolence has been reported in approximately 9.1% of patients; symptoms were generally mild to moderate and required NO adjustment in therapy (Aapro et al, 1998).
C) DISORDER OF AUTONOMIC NERVOUS SYSTEM 1) WITH THERAPEUTIC USE a) CASE REPORT: A 55-year-old female with non-small cell lung cancer described symptoms of acid reflux and difficulty swallowing after 2 doses of gemcitabine (800 mg/m(2)). Evaluation revealed autonomic dysfunction of the esophagus and heart. Symptoms had disappeared 4 weeks after stopping therapy (Dormann et al, 1998).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) SUMMARY: In clinical trials, nausea and vomiting were frequently reported (65% to 69%), but symptoms were generally mild to moderate (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011; Gupta et al, 2002). b) INCIDENCE: Moderate to severe nausea and vomiting was reported in <15% of patients (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011; Aapro et al, 1998). 1) Cortes-Funes et al (1997) reported moderate (vomiting requiring therapy) and severe (intractable) vomiting after receiving gemcitabine in 19.4% and 0.8% of patients, respectively. Treatment for nausea and vomiting was required in approximately 20% of patients receiving this agent; however, most cases were treatable with standard antiemetics (Cortes-Funes et al, 1997).
c) In a phase 1 trial, the maximum tolerated dose of gemcitabine in children with refractory leukemia was 10 mg/m(2)/min for 360 minutes 3 times weekly followed by a 1-week rest period. In a phase 2 trial, gemcitabine 10 mg/m(2)/min for 360 minutes 3 times weekly followed by a 1-week rest period was used in patients with relapsed acute lymphoblastic leukemia (n=22). Bone marrow suppression, febrile neutropenia, elevation of liver enzymes, nausea, and rash/desquamation were reported (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011). B) DIARRHEA 1) WITH THERAPEUTIC USE a) INCIDENCE: Diarrhea was reported in 19% of patients during clinical trials (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011). Moderate diarrhea (requiring therapy) was reported in only 0.4% of patients treated with therapeutic doses of gemcitabine (Cortes-Funes et al, 1997).
C) ACUTE MUCOSITIS 1) WITH THERAPEUTIC USE a) Mucositis and stomatitis have occurred with therapy and appear dose-dependent (Grunewald et al, 1992; Anon, 1993).
2) WITH POISONING/EXPOSURE a) Severe toxicity was reported during a phase III clinical trial in which several patients received 6400 mg/m(2) of gemcitabine. One patient developed bullous skin ulceration and another severe mucositis with hemorrhagic ulceration and necrosis (Anon, 1993).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) Transient elevations of serum transaminases have occurred frequently in patients, but patients remained asymptomatic (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011; Cortes-Funes et al, 1997).
b) In a phase 1 trial, the maximum tolerated dose of gemcitabine in children with refractory leukemia was 10 mg/m(2)/min for 360 minutes 3 times weekly followed by a 1-week rest period. In a phase 2 trial, gemcitabine 10 mg/m(2)/min for 360 minutes 3 times weekly followed by a 1-week rest period was used in patients with relapsed acute lymphoblastic leukemia (n=22). Bone marrow suppression, febrile neutropenia, elevation of liver enzymes, nausea, and rash/desquamation were reported (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) UREMIA 1) WITH THERAPEUTIC USE a) SUMMARY: Mild proteinuria and hematuria have been commonly reported (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011; Aapro et al, 1998); hemolytic uremic syndrome was reported in 6 of 2429 patients (0.25%) (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
b) INCIDENCE: Aapro et al (1998) found a 0.6% incidence of hemolytic uremic syndrome in a meta-analysis of gemcitabine's safety. The authors suggested that this condition may be anticipated in a number of patients with a diagnosis of advanced cancer. (Aapro et al, 1998).
c) CASE REPORT: A 45-year-old maN with non-small cell lung cancer was diagnosed with hemolytic uremic syndrome after his sixth cycle of gemcitabine (cumulative dose 21250 mg/m(2)) . Despite immediate steroid therapy and plasmapheresis, the patient became dialysis-dependent secondary to chronic renal failure. Hemolysis resolved within 3 weeks of diagnosis (Browdowicz et al, 1997).
B) CHRONIC DRUG-INDUCED TUBULOINTERSTITIAL NEPHRITIS 1) WITH THERAPEUTIC USE a) CASE REPORTS: Two patients with advance pancreatic cancer in stage IV-A developed acute tubulointerstitial nephritis after receiving several cycles of gemcitabine (cumulative doses of 30,000 milligrams/meter(2) and 17,000 milligrams/meter(2) in case 1 and 2, respectively). The first patient had a sudden rise in serum urea nitrogen (87 mg/dL) and serum creatinine (4.4 mg/dL) after being well for 23 months. The second patient was well for 11 months until a sudden rise in serum urea nitrogen and serum creatinine. Both patients died from acute renal failure. The autopsy of both cases showed a tumor confined around the pancreas. Histology of kidneys revealed acute tubulointerstitial nephritis. The following signs were also observed: interstitial edema and lymphocytic infiltration of plasma cells, with a few granulocytes; tubular dilatation and attenuation of the epithelium; inflammatory cells infiltrated the tubules with partial destruction of the epithelium; and crystal deposits within the lumen. Glomeruli and blood vessels were normal (Yamamoto et al, 2007).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) MYELOSUPPRESSION 1) WITH THERAPEUTIC USE a) SUMMARY: In clinical trials myelosuppression was the dose-limiting effect of gemcitabine, with less than 1% of patients requiring discontinuation of therapy (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011). 1) INCIDENCE: Approximately 16% of patients experienced petechiae or mild blood loss; fewer than 1% required platelet transfusions (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
b) In a phase 1 trial, the maximum tolerated dose of gemcitabine in children with refractory leukemia was 10 mg/m(2)/min for 360 minutes 3 times weekly followed by a 1-week rest period. In a phase 2 trial, gemcitabine 10 mg/m(2)/min for 360 minutes 3 times weekly followed by a 1-week rest period was used in patients with relapsed acute lymphoblastic leukemia (n=22). Bone marrow suppression, febrile neutropenia, elevation of liver enzymes, nausea, and rash/desquamation were reported (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011). 2) WITH POISONING/EXPOSURE a) During Phase I clinical trials, several patients received a single dose, as high as 5700 mg/m(2), of gemcitabine given intravenously over 30 minutes every 2 weeks and developed myelosuppression, paresthesias, and severe rash (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
B) THROMBOCYTOPENIC DISORDER 1) WITH THERAPEUTIC USE a) SUMMARY: In general, thrombocytopenia has been a mild effect of gemcitabine therapy (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011; Cortes-Funes et al, 1997; Aapro et al, 1998).
b) INCIDENCE: The incidence of thrombocytopenia has been low (1.2% of patients or less), with mild symptoms which have not been clinically significant (Cortes-Funes et al, 1997; Aapro et al, 1998). In addition, no signs or symptoms of cumulative toxicity have been observed (Aapro et al, 1998).
c) CASE REPORT: Delayed, irreversible, severe thrombocytopenia (7000/microliter), with occasional petechial bleeding, occurred 8 months following gemcitabine therapy (cumulative dose 22345 milligrams/meter(2)) in a 62-year-old female with squamous-cell lung cancer. Bone marrow biopsy showed an absence of erythropoiesis and thrombopoiesis. Treatment consisted of weekly platelet and red blood cell transfusions (Malayeri et al, 1997).
C) ANEMIA 1) WITH THERAPEUTIC USE a) INCIDENCE: Fewer than 1% of patients have required discontinuation of gemcitabine therapy secondary to anemia (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011). Other studies have reported moderate (grade 3) to severe (grade 4) toxicity in 5.0% and up to 0.8% of patients, respectively (Cortes-Funes et al, 1997; Aapro et al, 1998).
b) CASE REPORT: Delayed, irreversible anemia was reported 6 months after completion of gemcitabine therapy in a 62-year-old female with a history of squamous-cell lung cancer. Red blood cell transfusions were required on a regular basis to treat ongoing anemia while erythropoietin therapy provided NO clinical improvement (Malayeri et al, 1997).
D) LEUKOPENIA 1) WITH THERAPEUTIC USE a) In a meta-analysis, leukopenia was reported as a serious event in 0.6% (6 of 979) of patients receiving gemcitabine; only one patient needed to have therapy withdrawn. Leukocyte levels of grade 3 and 4 (moderate to severe) were reported in 8.6% and 0.7% of patients, respectively, with corresponding neutrophil toxicity of 19.3% and 6.0%, respectively (Aapro et al, 1998).
E) DISSEMINATED INTRAVASCULAR COAGULATION 1) WITH THERAPEUTIC USE a) CASE REPORT: A 75-year-old man with non-small cell lung cancer developed ARDS following the ingestion of gemcitabine (1,500 milligrams total dose). He died of respiratory failure on the fourteenth post-chemotherapeutic day. Post-mortem exam of the lungs showed mixed hyaline membrane formation, compatible with diffuse alveolar damage. Additionally, multiple microscopic fibroid thromboses were noted in arterioles and capillaries of the lungs, liver, and kidney. These findings were consistent with disseminated intravascular coagulation (DIC) (Maniwa et al, 2003).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) ERUPTION 1) WITH THERAPEUTIC USE a) INCIDENCE: Macular or finely granular maculopapular pruritic rash has been reported in 30% of patients during clinical trials (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
b) TREATMENT: Cortes-Funes et al (1997) reported that most cases of rash required only localized treatment without cessation of gemcitabine therapy (Cortes-Funes et al, 1997).
c) In a phase 1 trial, the maximum tolerated dose of gemcitabine in children with refractory leukemia was 10 mg/m(2)/min for 360 minutes 3 times weekly followed by a 1-week rest period. In a phase 2 trial, gemcitabine 10 mg/m(2)/min for 360 minutes 3 times weekly followed by a 1-week rest period was used in patients with relapsed acute lymphoblastic leukemia (n=22). Bone marrow suppression, febrile neutropenia, elevation of liver enzymes, nausea, and rash/desquamation were reported (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
2) WITH POISONING/EXPOSURE a) During Phase I clinical trials, several patients received a single dose, as high as 5700 mg/m(2), of gemcitabine given intravenously over 30 minutes every 2 weeks and developed myelosuppression, paresthesias, and severe rash (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
B) SKIN ULCER 1) WITH POISONING/EXPOSURE a) Severe toxicity was reported during a phase III clinical trial in which several patients received 6400 mg/m(2) of gemcitabine. One patient developed bullous skin ulceration and another severe mucositis with hemorrhagic ulceration and necrosis (Anon, 1993).
C) RADIATION DERMATITIS 1) WITH THERAPEUTIC USE a) SUMMARY: Two reports of radiation recall dermatitis have been reported in patients receiving gemcitabine therapy (Burstein, 2000; Castellano et al, 2000). Although the pathophysiology is unknown, this event has occurred with other antineoplastic agents (e.g. bleomycin, doxorubicin, paclitaxel, tamoxifen), and may be related to prior tissue injury (Burstein, 2000).
b) CASE REPORT: A 41-year-old woman with metastatic breast cancer developed radiation recall dermatitis (maculopapular confluent erythematous, pruritic rash) after 2 weeks of therapy with gemcitabine. History of breast irradiation had occurred 6 months prior to therapy. Symptoms resolved with drug cessation (Burstein, 2000).
c) CASE REPORT: A 61-year-old male with stage IV non-small-cell lung cancer began chemotherapy 4 weeks after completion of radiation, and developed a painful erythremic pruritic rash (confined only to the area of irradiation) after 2 doses of gemcitabine. The rash resolved with steroid therapy and diphenhydramine (Castellano et al, 2000).
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Reproductive |
3.20.1) SUMMARY
A) Gemcitabine is classified as FDA pregnancy category D. There are no adequate or well-controlled studies of gemcitabine use in pregnant women. However, in animal studies, gemcitabine was embryotoxic causing fetal malformations in mice and rabbits. Embryolethality was observed in mice at a dose of about 1/1300th the recommended human dose (RHD) on a mg/m(2) basis. It is not known whether gemcitabine and its metabolites are excreted in human milk. Decreased fertility has been seen in male mice.
3.20.2) TERATOGENICITY
A) ANIMAL STUDIES 1) MICE, RABBITS: IV administration of gemcitabine was embryotoxic in mice, causing fetal malformations of cleft palate and incomplete ossification at doses of 1.5 mg/kg/day (approximately 1/200th the recommended human dose (RHD) on a mg/m(2) basis). Fetal malformations of fused pulmonary artery and absence of gall bladder were also noted in rabbits administered gemcitabine at doses of 0.1 mg/kg/day in rabbits (about 1/600th the RHD on a mg/m(2) basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays (Prod Info GEMZAR(R) intravenous injection, powder, lyophilized, 2014).
3.20.3) EFFECTS IN PREGNANCY
A) LACK OF INFORMATION 1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info GEMZAR(R) intravenous injection, powder, lyophilized, 2014).
B) PREGNANCY CATEGORY 1) Gemcitabine is classified as FDA pregnancy category D (Prod Info GEMZAR(R) intravenous injection, powder, lyophilized, 2014).
2) There are no adequate or well-controlled studies of gemcitabine use in pregnant women. However, adverse reproductive effects are expected to result from the administration of gemcitabine based on its mechanism of action (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011). In general, antineoplastic agents when given during the first trimester are believed to cause increases in the risk of congenital malformations, but when given during the second or third trimesters are believed to only increase the risk of growth retardation (Glantz, 1994; Doll et al, 1988). Fetal malformations and embryotoxicity were observed in animal studies of mice and rabbits administered gemcitabine. Therefore, if gemcitabine is used during pregnancy or if a patient becomes pregnant while undergoing gemcitabine therapy, she should be advised of the potential hazard to the fetus (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
C) ANIMAL STUDIES 1) MICE, RABBITS: Embryolethality was observed in mice following IV gemcitabine at doses of 0.25 mg/kg/day (approximately 1/1300th the recommended human dose (RHD) on a mg/m(2) basis). Decreased fetal viability and reduced live litter sizes were observed in rabbits at gemcitabine doses of 0.1 mg/kg/day in rabbits (about 1/600th the RHD on a mg/m(2) basis) (Prod Info GEMZAR(R) intravenous injection, powder, lyophilized, 2014; Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) It is not known whether gemcitabine and its metabolites are excreted in human milk (Prod Info GEMZAR(R) intravenous injection, powder, lyophilized, 2014).
2) No reports describing the use of gemcitabine during human lactation are available and the effects on the nursing infant from exposure to the drug in milk are unknown. It is not known whether gemcitabine and its metabolites are excreted in human milk. Because potential harm to a nursing infant exists and because many drugs are excreted in human milk, either breastfeeding or gemcitabine should be discontinued considering the need for treatment of the mother (Prod Info GEMZAR(R) IV injection, powder, lyophilized, for solution, 2011).
3.20.5) FERTILITY
A) LACK OF EFFECT 1) FEMALE MICE: Fertility was NOT affected, but maternal toxicities were observed at 1.5 mg/kg/day IV (about 1/200th the human dose on a mg/m(2) basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day IV (about 1/1300th the human dose on a mg/m(2) basis) (Prod Info GEMZAR(R) intravenous injection, powder, lyophilized, 2014).
B) ANIMAL STUDIES 1) MALE MICE: In males, doses of 0.5 mg/kg/day (about 1/700th the human dose on a mg/m(2) basis) caused moderate to severe hypospermatogenesis, decreased fertility, and decreased implantation (Prod Info GEMZAR(R) intravenous injection, powder, lyophilized, 2014).
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Carcinogenicity |
3.21.4) ANIMAL STUDIES
A) LACK OF INFORMATION 1) Long-term animal studies have not been conducted (Prod Info Gemzar(R), gemcitabine HCL, 1998).
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