CITAFINE INJECTION 1GM

Mechanism of action

Gemcitabine is phosphorylated by deoxycytidine kinase in malignant cells to form gemcitabine monophosphate, which is then converted into gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). These metabolites competitively inhibit DNA chain elongation by incorporating into DNA in place of deoxycytidine triphosphate (dCTP), leading to masked DNA chain termination. This results in DNA fragmentation and apoptotic cell death. Additionally, dFdCDP inhibits ribonucleotide reductase, reducing dCTP levels and enhancing the incorporation of dFdCTP into DNA. This self-potentiating action prolongs the intracellular concentration of active metabolites.

Pharmacodynamics

Gemcitabine promotes apoptosis in malignant cells during DNA synthesis, effectively blocking the G1/S-phase boundary of the cell cycle. It exhibits cytotoxic effects against a broad range of cancer cell lines in vitro and demonstrates schedule-dependent antitumor activity in various animal models. Clinical trials indicate that gemcitabine monotherapy produces objective response rates of 18-26% in advanced non-small cell lung cancer, with median survival times ranging from 6.2 to 12.3 months. The drug is more effective when administered as a prolonged infusion rather than at higher dosages.

Pharmacokinetics

Gemcitabine is administered intravenously, and its pharmacokinetics can vary based on the specific malignancy being treated and the combination with other agents. The drug is rapidly distributed in the body and metabolized primarily by deoxycytidine kinase into its active forms. Its elimination half-life is short, and active metabolites are cleared from the body relatively quickly. Caution is advised in patients with hepatic or renal impairment, and adjustment of dosage may be necessary.

Contra-indications

• Hypersensitivity to gemcitabine or any component of the formulation
• Pregnancy
• Severe hepatic impairment

Adverse effects

• Alopecia
• Anemia
• Nausea
• Vomiting
• Infection risk increase
• Fatigue
• Thrombocytopenia
• Neutropenia
• Diarrhea
• Stomatitis

Interactions

• Live vaccines may increase the risk of generalized infection, possibly life-threatening

Precautions

• Caution in handling due to irritant properties
• Monitor for signs of infection due to immunosuppression
• Adjust dosage in patients with renal or hepatic impairment
• Use with caution in elderly patients

Pregnancy

Avoid, teratogenic in animal studies.

Breast-feeding

Discontinue breastfeeding during treatment.

Storage

Store in a cool, dry place, protected from light. Refer to specific product labeling for storage conditions.

Formulations

• 100 mg/5 ml solution for injection
• 500 mg/20 ml solution for injection
• 1 g/20 ml solution for injection
• 2 g/200 ml infusion bags
• 5 g/100 ml solution for infusion vials

Mechanism of action

Gemcitabine is a potent and specific deoxycytidine analog. After uptake into malignant cells, gemcitabine is phosphorylated by deoxycytidine kinase to form gemcitabine monophosphate, which is then converted to the active compounds, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). These active metabolites are nucleosides that mediate antitumour effects. dFdCTP competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA, thereby competitively inhibiting DNA chain elongation. The non-terminal position of dFdCTP in the DNA chain prevents detection of dFdCTP in the chain and repair by proof-reading 3′5′-exonuclease: this process is referred to as "masked DNA chain termination." Incorporation of dFdCTP into the DNA chain ultimately leads to chain termination, DNA fragmentation, and apoptotic cell death of malignant cells. Gemcitabine has self-potentiating pharmacological actions that can increase the probability of successful incorporation of gemcitabine triphosphate into the DNA chain: dFdCDP inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate dCTP for DNA synthesis. Since dFdCDP reduces the levels of dCTP, there is less competition for gemcitabine triphosphate for incorporation into DNA. Gemcitabine can also reduce metabolism and elimination of active metabolites from the target ce1l, prolonging high intracellular concentrations of the active metabolites. Such self-potentiating effects are not present with [cytarabine]. Gemcitabine hydrochloride, a synthetic pyrimidine nucleoside, is an antineoplastic agent. The nucleoside analog consists of the pyrimidine base difluorocytidine, and the sugar moiety deoxyribose. Like most antimetabolite antineoplastic agents, gemcitabine is cell-cycle specific, acting principally in the S phase of the cell cycle; the drug also may cause cellular arrest at the G1-S border. The cytotoxic activity of gemcitabine (2'-deoxy-2',2'-difluorocytidine) depends on intracellular conversion to its 5'-diphosphate and -triphosphate metabolites; thus, deoxydifluorocytidine-5?-diphosphate (dFdCDP, gemcitabine diphosphate) and -triphosphate (dFdCTP, gemcitabine triphosphate) and not unchanged gemcitabine are the pharmacologically active forms of the drug. Gemcitabine is phosphorylated by deoxycytidine kinase to gemcitabine monophosphate, which subsequently is phosphorylated to the corresponding diphosphate and triphosphate nucleosides, presumably by deoxycytidylate kinase and nucleoside diphosphate kinase, respectively. The cytotoxic effect of gemcitabine is attributed to the combined actions of its diphosphate and triphosphate nucleosides, which lead to inhibition of DNA synthesis. Gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for catalyzing the formation of deoxynucleoside triphosphates needed in DNA synthesis. By inhibiting this reductase, gemcitabine diphosphate interferes with subsequent de novo nucleotide production. Gemcitabine triphosphate inhibits DNA synthesis by competing with the physiologic substrate, deoxycytidine triphosphate, for DNA polymerase and incorporation into DNA. The reduction in intracellular concentrations of deoxycytidine triphosphate induced by gemcitabine diphosphate actually enhances the incorporation of gemcitabine triphosphate into DNA, a mechanism referred to as ''self-potentiation.'' Following incorporation of gemcitabine triphosphate into the DNA chain, a single additional nucleotide, a normal base pair, is added and DNA synthesis is terminated, resulting in apoptosis (programmed cell death). DNA polymerase ? is unable to recognize the abnormal (gemcitabine) nucleotide and repair the DNA strand as a result of masking by the terminal normal base pair nucleotide (masked chain termination). This inability to recognize and excise the abnormal nucleotide results in a prolonged intracellular half-life of gemcitabine compared with other nucleoside analogs such as cyta

Pharmacodynamics

Gemcitabine is a nucleoside analog that mediates its antitumour effects by promoting apoptosis of malignant cells undergoing DNA synthesis. More specifically, it blocks the progression of cells through the G1/S-phase boundary. Gemcitabine demonstrated cytotoxic effects against a broad range of cancer cell lines _in vitro_. It displayed schedule-dependent antitumour activity in various animal models and xenografts from human non-small cell lung cancer (NSCLC) and pancreatic cancer. Therefore, the antineoplastic effects of gemcitabine are enhanced through prolonged infusion time rather than higher dosage. Gemcitabine inhibited the growth of human xenografts from carcinoma of the lung, pancreas, ovaries, head and neck, and breast. In mice, gemcitabine inhibited the growth of human tumour xenografts from the breast, colon, lung or pancreas by 69 to 99%. In clinical trials of advanced NSCLC, gemcitabine monotherapy produced objective response rates ranging from 18 to 26%, with a median duration of response ranging from 3.3 to 12.7 months. Overall median survival time was 6.2 to 12.3 months. The combined use of cisplatin and gemcitabine produced better objective response rates compared to monotherapy. In patients with advanced pancreatic cancer, objective response rates in patients ranged from 5.to 12%, with a median survival duration of 3.9 to 6.3 months. In Phase II trials involving patients with metastatic breast cancer, treatment with gemcitabine alone or with adjuvant chemotherapies resulted in response rate ranging from 13 to 42% and median survival duration ranging from 11.5 to 17.8 months. In metastatic bladder cancer, gemcitabine has a response rate 20 to 28%. In Phase II trials of advanced ovarian cancer, patients treated with gemcitabine had response rate of 57.1%, with progression free survival of 13.4 months and median survival of 24 months. Gemcitabine causes dose-limiting myelosuppression, such as anemia, leukopenia, neutropenia, and thrombocytopenia; however, events leading to discontinuation tend to occur less than 1% of the patients. Gemcitabine can elevate ALT, AST and alkaline phosphatase levels.