Gemcitabine

BRAND NAMES

Gemcitabine is primarily marketed under the brand name Gemzar. It is a chemotherapy medication used in the treatment of several cancers, such as pancreatic, lung, ovarian, and breast cancers. In addition to the original brand, it is also widely available as generic formulations and under other brand names, including Infugem, Inlexzo, and Avgemsi.

MECHANISM OF ACTION

Gemcitabine exerts its cytotoxic effects by targeting cells actively undergoing DNA synthesis and causing arrest at the G1/S phase boundary. Inside the cell, it is phosphorylated by nucleoside kinases to form active metabolites, gemcitabine diphosphate (dFdCDP) and triphosphate (dFdCTP). The diphosphate form inhibits ribonucleotide reductase, an enzyme essential for producing deoxynucleoside triphosphates required for DNA replication, thereby lowering intracellular deoxycytidine triphosphate (dCTP) levels. This depletion enhances the incorporation of the triphosphate form into DNA, where it competes with dCTP. Once incorporated, gemcitabine allows the addition of only one further nucleotide before DNA chain elongation is terminated, ultimately triggering apoptotic cell death.

PHARMACOKINETICS

Distribution

The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m² following infusions lasting <70 minutes. For long infusions, the volume of distribution rose to 370 L/m².

Metabolism

The active metabolite, gemcitabine triphosphate, can be extracted from peripheral blood mononuclear cells. The half-life of the terminal phase for gemcitabine triphosphate from mononuclear cells ranges from 1.7 to 19.4 hours.

Excretion

Gemcitabine disposition was studied in 5 patients who received a single 1000 mg/m² of radiolabeled drug as a 30-minute infusion. Within one (1) week, 92% to 98% of the dose was recovered, almost entirely in the urine. Gemcitabine (<10%) and the inactive uracil metabolite, 2´-deoxy-2´,2´-difluorouridine (dFdU), accounted for 99% of the excreted dose. The metabolite dFdU is also found in plasma.

PHARMACODYNAMICS

Gemcitabine is a nucleoside analogue and pyrimidine antimetabolite that functions as a cytotoxic drug by blocking DNA synthesis and promoting apoptosis. Once inside the cell, it is converted into its active forms, dFdCDP and dFdCTP. These metabolites interfere with DNA replication by incorporating into DNA and inhibiting ribonucleotide reductase, leading to arrest of the cell cycle in the S phase.

DOSAGE AND STRENGTH

Ovarian Cancer:

The usual dose of Gemcitabine Injection is 1000 mg/m² given intravenously over 30 minutes on Days 1 and 8 of a 21-day cycle. When used in combination therapy, carboplatin (AUC 4) is administered intravenously on Day 1 after the gemcitabine infusion. Refer to carboplatin prescribing information for additional information.

Breast Cancer:

The recommended dose of Gemcitabine Injection is 1250 mg/m², given intravenously over 30 minutes on Days 1 and 8 of a 21-day cycle. In combination therapy, paclitaxel 175 mg/m² is administered as a 3-hour intravenous infusion on Day 1 prior to the gemcitabine infusion. Refer to paclitaxel prescribing information for additional information

Non-Small Cell Lung Cancer:

The recommended dose of Gemcitabine Injection is 1000 mg/m², administered intravenously over 30 minutes on Days 1, 8, and 15 of a 28-day cycle. When used in combination therapy, cisplatin 100 mg/m² is given intravenously on Day 1 after the gemcitabine infusion.

Pancreatic Cancer:

• The recommended dose of Gemcitabine Injection is 1000 mg/m², administered intravenously over 30 minutes.

• The recommended treatment schedule is as follows:

• Weeks 1 to 8: weekly dosing for the first 7 weeks followed by one-week rest.

• After week 8, treatment is continued with a weekly schedule, with dosing on Days 1, 8, and 15 of each 28-day cycle.

Injection: 200 mg/5.26 mL (38 mg/mL), 1 g/26.3 mL (38 mg/mL), and 2 g/52.6 mL (38 mg/mL) as a clear and colorless to light straw-colored solution in a single-dose vial.

FOOD INTERACTIONS

Gemcitabine has no significant direct food interactions because it is given intravenously and not absorbed through the digestive system. However, patients are usually advised to maintain good hydration and a balanced diet during treatment. Alcohol should be limited, as it may worsen side effects like nausea and fatigue.

DRUG INTERACTIONS

Gemcitabine has important drug interactions, especially with other myelosuppressive treatments such as radiation therapy and additional chemotherapy agents, which can significantly increase the risk of bone marrow suppression and lead to low blood cell counts. It may also interact with anticoagulants like warfarin, requiring careful monitoring of INR due to an increased risk of bleeding. In addition, it can reduce the effectiveness of certain vaccines, such as the cholera vaccine, due to its immunosuppressive effects.

CONTRAINDICATIONS

Gemcitabine is contraindicated in individuals with a known severe hypersensitivity to the drug. It must not be used during pregnancy or breastfeeding because of the potential risk of harm to the fetus or nursing infant. It is also contraindicated in patients with severe pre-existing liver or kidney dysfunction, as well as in those with significant or acute bone marrow suppression.

SIDE EFFECTS

• Bone marrow suppression (low white blood cells, red blood cells, and platelets)

• Fatigue and weakness

• Nausea and vomiting

• Fever

• Loss of appetite

• Hair thinning or hair loss

• Flu-like symptoms (muscle aches, chills)

• Skin rash or itching

• Shortness of breath

• Elevated liver enzymes (liver function changes)

• Peripheral edema (swelling, especially in legs)

• Cough or respiratory symptoms

• Mild bleeding or easy bruising due to low platelets

Serious but less common effects:

• Severe infection due to immunosuppression

• Severe liver or kidney toxicity

• Lung inflammation (interstitial pneumonitis)

• Hemolytic uremic syndrome (rare but serious blood andkidneydisorder)

OVERDOSE

Gemcitabine overdose is rare but can cause severe bone marrow suppression, leading to dangerously low blood cell counts and an increased risk of infection, anemia, and bleeding. It may also result in significant gastrointestinal symptoms such as nausea and vomiting, along with possible liver or kidney dysfunction. There is no specific antidote, so treatment is supportive and includes close monitoring, management of infections, and blood transfusions or growth factor support if needed.

TOXICITY

Gemcitabine toxicity mainly involves dose-related bone marrow suppression, leading to low white blood cells, red blood cells, and platelets, which increases the risk of infections, anemia, and bleeding. Other toxic effects may include nausea, vomiting, fatigue, liver enzyme elevation, and flu-like symptoms. Less commonly, serious toxicities such as lung inflammation (interstitial pneumonitis), kidney injury, and hemolytic uremic syndrome can occur, requiring close monitoring and dose adjustment or discontinuation if severe.