Citagem

Gemcitabine hydrochloride.

Each vial contains: Gemcitabine (as hydrochloride) 200 mg or 1 g.

Ovarian cancer: In combination with carboplatin, for the treatment of patients with recurrent epithelial ovarian carcinoma who have relapsed at least 6 months following platinum-based therapy.
Breast cancer: In combination with paclitaxel, for the first-line treatment of patients with unresectable, locally recurrent or metastatic breast cancer who have relapsed following adjuvant/neoadjuvant chemotherapy. Prior therapy should have included an anthracycline, unless clinically contraindicated.
Non-small cell lung cancer (NSCLC): Alone or in combination with cisplatin, for the first-line treatment of patients with inoperable, locally advanced (inoperable stage IIIA or IIIB) or metastatic (stage IV) NSCLC. Monotherapy may be considered in elderly patients or those with performance status 2.
Pancreatic cancer: For the first-line treatment of adult patients with locally advanced (nonresectable stage II or III) or metastatic (stage IV) adenocarcinoma of the pancreas. It can be used as first-line therapy or second-line therapy in patients with 5-fluorouracil-refractory pancreatic cancer.
Bladder cancer: In combination with cisplatin, for the treatment of advanced transitional cell bladder cancer (muscle invasive stage IV tumors with or without metastases).

Gemcitabine is for intravenous (IV) use only. Reconstituted and diluted solutions of gemcitabine are generally infused over a period of 30 minutes; any unused portion after preparation of the appropriate dose should be discarded.
Infusion time should not exceed 60 minutes and not more frequent than once a week (see Precautions). (See Table 1.)

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Dosage Adjustments: Patients receiving gemcitabine should be monitored prior to each dose for platelet, leukocyte and granulocyte counts and, if necessary, the dose of gemcitabine may be either reduced or withheld in the presence of hematological toxicity.
For the detection of nonhematologic toxicity, periodic physical examination and checks of renal and hepatic function should be made.
Ovarian Cancer: The dose of gemcitabine within a cycle of treatment should be adjusted according to the granulocyte and platelet counts obtained on day 8 of therapy: See Table 2.

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Generally, for severe (grade 3/4) nonhematologic toxicity other than nausea and vomiting, gemcitabine should be withheld or reduced to 50% depending on the judgment of the treating physician. For carboplatin dosage adjustment, see respective product label for complete prescribing information.
Dose adjustment for gemcitabine in combination with carboplatin in subsequent cycles should be adjusted according to observed toxicity. The dose should be reduced to 800 mg/m² on days 1 and 8 if any of the following hematologic toxicities occur: Absolute granulocyte counts <500 x 10⁶/L for more than 5 days.
Absolute granulocyte counts <100 x 10⁶/L for more than 3 days.
Febrile neutropenia.
Platelet counts <25,000 x 10⁶/L.
Cycle delay of more than 1 week due to toxicity.
If any of these toxicities recur after the initial dosage reduction, gemcitabine should be administered on day 1 only at a dose of 800 mg/m² for the subsequent cycle.
Breast Cancer: The dose of gemcitabine should be adjusted according to the granulocyte and platelet counts obtained on day 8 of therapy: See Table 3.

Click on icon to see table/diagram/image

Generally, for severe (grade 3/4) nonhematologic toxicity other than alopecia and nausea/vomiting, gemcitabine should be withheld or reduced to 50% depending on the judgment of the treating physician. For paclitaxel dosage adjustment, see respective product label for complete prescribing information.
NSCLC/Pancreatic Cancer/Bladder Cancer: The dose of gemcitabine should be adjusted according to the granulocyte and platelet counts obtained on the day of therapy: See Table 4.

Click on icon to see table/diagram/image

Generally, in patients receiving gemcitabine in combination with cisplatin who develop grade 3/4 nonhematologic toxicity other than alopecia or nausea and vomiting, gemcitabine and cisplatin doses should be withheld or reduced by 50%.

Patients with hypersensitivity to gemcitabine or any ingredient of the product.
Breastfeeding.

General: Gemcitabine should only be administered under the supervision of a qualified physician experienced in cancer chemotherapeutic drugs. Most adverse effects are reversible and do not need discontinuation, although doses may need to be withheld or reduced.
IV infusion of gemcitabine over periods exceeding 60 minutes and administration more frequent than once a week may be associated with increased toxicity (e.g., myelosuppression).
Gemcitabine should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose bone marrow function is recovering from previous chemotherapy.
Hematologic Effects: Myelosuppression is the dose-limiting toxicity of gemcitabine, including leukopenia, thrombocytopenia and anemia. Patients receiving the drug may require red blood cell transfusions or, less frequently, platelet transfusions. Patients should be monitored for myelosuppression during therapy and doses should be modified accordingly (see Laboratory Tests as follows and Dosage & Administration).
Respiratory Effects: Acute shortness of breath with a temporal relationship to gemcitabine administration may occur. Pulmonary toxicity has also been reported with the use of gemcitabine. In cases of severe lung toxicity, gemcitabine therapy should be discontinued immediately and appropriate supportive care measures instituted (see Adverse Reactions).
Renal Effects: Hemolytic-uremic syndrome (HUS) and/or renal failure have been reported in patients receiving one or more doses of gemcitabine. In rare cases, renal failure leading to death or requiring dialysis have occurred despite discontinuance of gemcitabine therapy. Cases of renal failure leading to death were typically caused by HUS (see Laboratory Tests as follows).
Hepatic Effects: Serious hepatotoxicity, including hepatic failure and death, has been reported in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic agents.
Laboratory Tests: Patients receiving gemcitabine should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. Suspension or modification of therapy should be considered when myelosuppression is detected (see Dosage & Administration).
Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter. The diagnosis of HUS should be considered and gemcitabine should be discontinued immediately in patients who develop anemia with evidence of microangiopathic hemolysis, elevation of serum bilirubin or LDH, reticulocytosis, and/or severe thrombocytopenia with or without evidence of renal failure [e.g., elevation of serum creatinine or blood urea nitrogen (BUN)].
Effects on the Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. However, gemcitabine has been reported to cause mild to moderate somnolence, especially in combination with alcohol consumption. Patients should be cautioned against driving or operating machinery until it is established that they do not become somnolent.
Patients with Renal or Hepatic Impairment: Gemcitabine should be used with caution in patients with pre-existing renal impairment or hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendations for these populations. Gemcitabine has not been studied in patients with significant renal or hepatic impairment. Use of gemcitabine in patients with current liver metastases or a history of hepatitis, alcoholism or cirrhosis may lead to exacerbation of the underlying hepatic insufficiency.
Women: Gemcitabine clearance is reduced and half-life is increased in women. Dose reductions, including withholding of doses in some cases, may be more likely in this population. However, there are currently no recommended dose adjustments specifically for women.
There was a greater tendency in women, especially older women, not to proceed to the next cycle.
Carcinogenicity, Mutagenicity and Impairment of Fertility: Long-term animal studies to evaluate carcinogenic potential of gemcitabine have not been conducted. Gemcitabine induced forward mutations in vitro in a mouse lymphoma assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine was negative when tested using the Ames, in vivo sister chromatid exchange, and in vitro chromosomal aberration assays, and did not cause unscheduled DNA synthesis in vitro. Intraperitoneal gemcitabine doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m² basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day IV (about 1/200 the human dose on a mg/m² basis) and fetotoxicity or embryolethality was observed at 0.025 mg/kg/day (about 1/300 the human dose on a mg/m² basis).
Use in Children (<17 years old): The safety and efficacy of gemcitabine have not been established in pediatric patients <17 years old.
Use in Elderly (>65 years old): Since gemcitabine clearance is reduced and half-life is increased in geriatric patients, dose reductions, including withholding of doses in some cases, may be more likely. However, there is no evidence that dose adjustments based on age are necessary in patients over 65 years old. In general, adverse reaction rates in the single-agent safety database of 979 patients were similar in patients above and below 65 years old. Grade 3/4 thrombocytopenia was more common in the elderly.

Use in Pregnancy: Pregnancy Category D: Gemcitabine can cause fetal harm when administered to a pregnant woman. In pre-clinical studies in mice and rabbits, gemcitabine was teratogenic, embryotoxic and fetotoxic. There are no adequate and well-controlled studies of gemcitabine in pregnant women. Women of childbearing age receiving gemcitabine should be advised to avoid becoming pregnant. If gemcitabine is used during pregnancy, or if the patient becomes pregnant while receiving the drug, evaluate potential hazard to the fetus.
Use in Lactation: It is not known whether gemcitabine or its metabolites are excreted in human milk. However, studies in lactating rats have shown gemcitabine and/or its metabolites in the milk 10 minutes after an IV dose. Breastfeeding must be discontinued during gemcitabine therapy.

Hematological Effects: Gemcitabine is a myelosuppressant: anemia, leukopenia and thrombocytopenia may occur. Myelosuppression is usually mild to moderate, of short duration, reversible, not cumulative over time, and is more pronounced for the granulocyte count. Anemia is manageable with the use of conventional transfusions. Dose reduction or omission may be necessary for severe leukopenia or thrombocytopenia (see Dosage & Administration). Febrile neutropenia is also commonly reported. Rare cases of petechiae or mild blood loss (hemorrhage) have been reported. Thrombocytosis was reported very rarely.
Gastrointestinal (GI) Effects: Nausea and vomiting were commonly reported but were usually mild to moderate in severity, rarely dose-limiting and easily manageable with standard antiemetics. Diarrhea and stomatitis are commonly reported, but no patient discontinued treatment because of diarrhea. Oral toxicity (soreness or erythema) and mild constipation have been reported rarely.
Hepatic Effects: In clinical studies, gemcitabine was associated with transient elevations in serum transaminases; however, there was no evidence of increasing hepatotoxicity with either longer duration of exposure to gemcitabine or with greater cumulative doses. Elevated liver function test results, including increased concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP), alkaline phosphatase, and bilirubin, have been reported rarely. These effects are usually mild, non-progressive, and rarely necessitate stopping treatment. ALT effects decline over time despite continued treatment. Serious hepatotoxicity, including hepatic failure and death, has been reported very rarely in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic agents.
Genitourinary Effects: Mild proteinuria and hematuria were reported, but are rarely clinically significant and are not usually associated with any change in serum creatinine or BUN. However, a few cases of renal failure of uncertain etiology have been reported and gemcitabine should be used with caution in patients with impaired renal function. Renal failure may be irreversible even with discontinuation of therapy and dialysis may be required. Rare cases of possible HUS have been reported (see Precautions). Cumulative renal toxicity has not been observed.
Fever and Flu-like Symptoms: Gemcitabine may cause fever even in the absence of infections. Fever was frequently associated with other flu-like symptoms and was usually mild and clinically manageable. Reported flu-like symptoms were usually mild, short-lived, and rarely dose-limiting. Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly reported. Fever and asthenia were also reported as isolated symptoms. Insomnia, rhinitis, sweating, and malaise were reported infrequently.
Dermatological Effects: Rash and pruritus were reported in some patients. The rash was usually mild, not dose-limiting, responded to local therapy, and typically a macular or finely granular maculopapular pruritic eruption of mild to moderate severity involving the trunk and extremities. Minimal to moderate hair loss was reported in a few patients. Complete but reversible alopecia was reported rarely. Severe skin reactions, including desquamation and bullous skin eruptions such as toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS), have been reported very rarely.
Respiratory Effects: Severe and sometimes fatal adverse pulmonary effects, including pulmonary edema, interstitial pneumonitis, pulmonary fibrosis, and adult respiratory distress syndrome (ARDS), have been reported in patients receiving one or more doses of gemcitabine; the drug should be discontinued immediately and appropriate supportive care (e.g., diuretics, bronchodilators, corticosteroids, and/or oxygen) should be promptly provided in patients developing such effects. Onset of pulmonary symptoms has occurred up to 2 weeks following administration of the last dose of gemcitabine, and in rare instances, respiratory failure and death have occurred despite discontinuance of gemcitabine therapy. Dyspnea occurring within hours following gemcitabine injection has been reported in a few patients. This is usually mild and short-lived, rarely dose-limiting and usually abates spontaneously without any specific therapy. Dose-limiting pulmonary toxicity, including pulmonary fibrosis and pneumonitis, occurred in patients receiving gemcitabine and concurrent thoracic radiation therapy for NSCLC. Fatal pulmonary veno-occlusive disease has been reported in a patient who developed progressive dyspnea during gemcitabine therapy.
Edema: Edema, peripheral edema, generalized edema, and some cases of facial edema have been reported. Pulmonary edema was reported rarely. Edema or peripheral edema is usually mild to moderate, rarely dose-limiting, sometimes reported as painful and usually reversible after stopping gemcitabine treatment.
Infection: Infections were reported in a few patients. Sepsis was reported rarely.
Neurological Effects: Mild to moderate somnolence, asthenia and paresthesias were reported.
Extravasation: Gemcitabine is well tolerated during infusion, with only a few cases of injection site reaction reported. There have been no reports of injection site necrosis. Gemcitabine is not a vesicant.
Hypersensitivity: Rash and pruritus have been reported. The rash is usually mild, not dose-limiting, and responds to local therapy. Desquamation, vesiculation and ulceration have been reported rarely. Bronchospasm is usually mild and transient, but parenteral therapy may be required.
Cardiovascular Effects: Cardiovascular toxicity, including chest pain, congestive heart failure, myocardial infarction, arrhythmias (predominantly supraventricular), cerebrovascular accident, hypotension, and hypertension have been reported rarely.
Many of these patients had a prior history of cardiovascular disease. Clinical signs of peripheral vasculitis and gangrene have been reported very rarely.
Injury, Poisoning and Procedural Complications: Radiation toxicity and radiation recall reactions have been reported.

No confirmed interactions have been reported with the use of gemcitabine. No specific drug interaction studies have been conducted.
Radiation Therapy: A pattern of tissue injury usually associated with radiation toxicity has been reported in association with concurrent and non-concurrent use of gemcitabine and radiation therapy. Radiosensitizing activity of gemcitabine was observed in preclinical and clinical studies when the drug was administered with or within 7 days of radiation therapy (i.e., concurrent therapy). Gemcitabine has been associated with radiation recall reactions, but administration more than 7 days before or after radiation therapy (i.e., non-concurrent therapy) does not otherwise appear to enhance toxicity. Available data suggest that gemcitabine therapy may be initiated once the acute effects of radiation therapy have resolved, or at least one week following radiation therapy.
Vaccine Use: Yellow fever and other live attenuated vaccines are not recommended in patients treated with gemcitabine due to the risk of systemic, possibly fatal disease, particularly in immunosuppressed patients.

Cytotoxic Chemotherapy

L01BC05 - gemcitabine ; Belongs to the class of antimetabolites, pyrimidine analogues. Used in the treatment of cancer.

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