Gemcitabine

Usage

Gemcitabine is a nucleoside analog antimetabolite used to treat various types of cancer. It is prescribed for:

• Bladder cancer: As a single agent or in combination with cisplatin.
• Breast cancer: In combination with paclitaxel.
• Non-small cell lung cancer (NSCLC): As a single agent or in combination with cisplatin.
• Ovarian cancer: In combination with carboplatin.
• Pancreatic cancer: As a single agent.

Pharmacological Classification: Antineoplastic antimetabolite.

Mechanism of Action: Gemcitabine inhibits DNA synthesis, leading to cell death. It is a prodrug that needs to be intracellularly metabolized to its active diphosphate and triphosphate nucleotide forms. Gemcitabine diphosphate inhibits ribonucleotide reductase, thus decreasing deoxynucleotide triphosphates (dCTP) available for DNA synthesis. Gemcitabine triphosphate competes with dCTP for incorporation into DNA, triggering apoptosis (programmed cell death).

Alternate Names

• Generic name: Gemcitabine hydrochloride
• Brand names: Gemzar, Infugem

How It Works

Pharmacodynamics: Gemcitabine’s primary effect is to inhibit DNA synthesis, leading to cell cycle arrest and apoptosis in rapidly dividing cancer cells.

Pharmacokinetics:

• Absorption: Administered intravenously.
• Metabolism: Gemcitabine is a prodrug that is metabolized intracellularly by deoxycytidine kinase to its active diphosphate and triphosphate nucleotides.
• Elimination: Primarily via renal excretion, with less than 10% excreted as unchanged drug. The half-life is relatively short, ranging from 42 to 94 minutes, depending on age and gender. Clearance is affected by age and gender, being lower in women and the elderly.

Mode of Action: Gemcitabine incorporates into DNA, causing “masked chain termination,” halting further DNA synthesis and triggering apoptosis.

Receptor binding, Enzyme Inhibition, or Neurotransmitter Modulation: Gemcitabine diphosphate inhibits ribonucleotide reductase.

Elimination pathways: Renal excretion is the main route. Hepatic metabolism also plays a role.

Dosage

Standard Dosage

Adults: Dosage varies depending on the type of cancer and combination therapy. Generally, 1000 mg/m² to 1250 mg/m² is administered intravenously over 30 minutes. Specific dosing schedules are outlined below in Clinical Use Cases.

Children: Gemcitabine’s safety and efficacy in children have not been fully established. Limited studies exist but do not provide sufficient data for standardized dosing.

Special Cases:

• Elderly Patients: Gemcitabine’s clearance decreases, and half-life increases with age. Dose adjustments are generally not necessary, but close monitoring is recommended.
• Patients with Renal Impairment: Gemcitabine should be used with caution. No clear dosage guidelines exist for this population. Close monitoring is crucial.
• Patients with Hepatic Dysfunction: Gemcitabine should be used with caution. Dose reduction may be necessary, particularly in patients with hyperbilirubinemia.
• Patients with Comorbid Conditions: Consider patient-specific factors and adjust dosage accordingly.

Clinical Use Cases

• Bladder Cancer (single agent): 1250 mg/m² IV over 30 minutes on Days 1, 8, and 15 of each 28-day cycle.
• Bladder Cancer (combination with cisplatin): 1000 mg/m² IV over 30 minutes on Days 1, 8, and 15 of each 28-day cycle, along with cisplatin (70 mg/m² on Day 1 or 2).
• Breast Cancer (combination with paclitaxel): 1250 mg/m² IV over 30 minutes on Days 1 and 8 of each 21-day cycle with paclitaxel (175 mg/m² on Day 1).
• NSCLC (single agent): 1000 mg/m² IV over 30 minutes once weekly for three weeks followed by a one-week rest.
• NSCLC (combination with cisplatin, 28-day schedule): 1000 mg/m² IV over 30 minutes on Days 1, 8, and 15 of each 28-day cycle, with cisplatin (100 mg/m² on Day 1).
• NSCLC (combination with cisplatin, 21-day schedule): 1250 mg/m² IV over 30 minutes on Days 1 and 8 of each 21-day cycle with cisplatin (100 mg/m² on Day 1).
• Ovarian Cancer (combination with carboplatin): 1000 mg/m² IV over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin (AUC 4 on Day 1).
• Pancreatic Cancer: 1000 mg/m² IV over 30 minutes once weekly for up to 7 weeks followed by a one-week rest; subsequent cycles: once weekly for 3 weeks out of every 4 weeks.
• Intubation/Surgical Procedures/Mechanical Ventilation/ICU Use/Emergency Situations: Gemcitabine does not have specific dosage recommendations for these scenarios. It’s typically not used in these contexts.

Dosage Adjustments

Dose adjustments are based primarily on myelosuppression (bone marrow suppression). Monitor blood counts (neutrophils, platelets) before each dose. Dosage may need to be reduced or omitted if counts are low. Also, consider dose modifications for patients with hepatic or renal impairment.

Side Effects

Common Side Effects

• Myelosuppression (neutropenia, thrombocytopenia, anemia)
• Nausea and vomiting
• Flu-like symptoms (fever, chills, fatigue, headache, myalgia)
• Proteinuria
• Skin rash
• Edema
• Musculoskeletal pain
• Alopecia (hair loss)
• Diarrhea
• Elevated liver enzymes

Rare but Serious Side Effects

• Pulmonary toxicity (dyspnea, pulmonary edema, acute respiratory distress syndrome)
• Hemolytic uremic syndrome
• Anaphylaxis
• Thrombotic microangiopathy
• Ischemic digital changes
• Severe hepatic toxicity

Long-Term Effects

Chronic pulmonary toxicity can occur.

Adverse Drug Reactions (ADR)

• Anaphylaxis
• Hemolytic uremic syndrome
• Severe myelosuppression requiring intervention

Contraindications

• Known hypersensitivity to gemcitabine.
• Pregnancy.

Drug Interactions

Gemcitabine may interact with other drugs, including:

• Warfarin: Increased risk of bleeding. Close monitoring of INR is required.
• Radiation therapy: Increased risk of esophagitis and pneumonitis.
• Other myelosuppressive drugs: Increased risk of myelosuppression.
• Vaccines (live attenuated): Not recommended due to risk of infection, especially in immunocompromised patients.

Many other potential drug interactions exist (see sources). Check for potential interactions before co-prescribing medications.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D. Gemcitabine is contraindicated in pregnancy due to its potential to cause fetal harm. Effective contraception should be used during treatment and for 6 months after the final dose in females and 3 months after the final dose in males.
• Breastfeeding: Gemcitabine is excreted in breast milk and is contraindicated during breastfeeding. Breastfeeding should be discontinued during treatment and for one week after the final dose.

Drug Profile Summary

• Mechanism of Action: Nucleoside analog antimetabolite that inhibits DNA synthesis.
• Side Effects: Myelosuppression, nausea, vomiting, flu-like symptoms, rash, edema, pulmonary toxicity.
• Contraindications: Hypersensitivity to gemcitabine, pregnancy.
• Drug Interactions: Warfarin, radiation therapy, other myelosuppressive drugs.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: Varies depending on cancer type and combination therapy; typically 1000-1250 mg/m² IV over 30 minutes.
• Monitoring Parameters: Complete blood counts (CBC) with differential, renal function, liver function.

Popular Combinations

• Cisplatin: For bladder and non-small cell lung cancers.
• Paclitaxel: For breast cancer.
• Carboplatin: For ovarian cancer.

Precautions

• Monitor blood counts before each dose.
• Use with caution in patients with hepatic or renal impairment.
• Monitor for signs of pulmonary toxicity.
• Avoid extravasation during intravenous administration.
• Patients receiving radiation therapy should be closely monitored.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Gemcitabine?

A: The dosage varies depending on the cancer type. Commonly, it’s 1000-1250 mg/m² intravenously over 30 minutes on a specific schedule (see Clinical Use Cases).

Q2: What are the most common side effects?

A: Myelosuppression, nausea, vomiting, flu-like symptoms, and rash are the most common side effects.

Q3: What are the contraindications for Gemcitabine?

A: Known hypersensitivity to gemcitabine and pregnancy.

Q4: How should Gemcitabine be administered?

A: Intravenously over 30 minutes.

Q5: Can Gemcitabine be given to pregnant or breastfeeding women?

A: No, Gemcitabine is contraindicated in both pregnancy and breastfeeding.

Q6: What should be monitored during Gemcitabine treatment?

A: Complete blood counts (CBC) with differential, renal function, and liver function should be monitored regularly.

Q7: What are the signs of pulmonary toxicity?

A: Shortness of breath, cough, and fever. Severe cases may present with pulmonary edema or acute respiratory distress syndrome.

Q8: How should Gemcitabine be dosed in elderly patients?

A: Dose adjustments are usually not necessary, but close monitoring is recommended due to decreased clearance in elderly patients.

Q9: Are there any significant drug interactions with Gemcitabine?

A: Yes, significant interactions exist with warfarin, radiation therapy, and other myelosuppressive agents. Consult resources for a complete list.

Q10: How does renal impairment affect Gemcitabine dosage?

A: Gemcitabine should be used cautiously in patients with renal impairment. There are no definitive dosage guidelines, so close monitoring and possible dose reduction may be necessary.