Usage
Gemcitabine, often administered with Mannitol as a part of the infusion solution, is prescribed for various cancers, including:
- Bladder cancer: Locally advanced or metastatic bladder cancer.
- Breast cancer: Metastatic breast cancer (often in combination with other chemotherapy drugs).
- Non-small cell lung cancer (NSCLC): In combination with cisplatin for locally advanced or metastatic NSCLC.
- Ovarian cancer: In combination with carboplatin.
- Pancreatic cancer: Metastatic pancreatic cancer (sometimes combined with other therapies).
Pharmacological classification: Gemcitabine is an antineoplastic antimetabolite, specifically a pyrimidine analog. Mannitol is an osmotic diuretic.
Mechanism of Action: Gemcitabine interferes with DNA synthesis, inhibiting cell growth and division, primarily affecting cells in the S phase (DNA synthesis phase) of the cell cycle. It gets incorporated into DNA and inhibits further DNA elongation and repair, leading to cell death. Mannitol is used to increase the excretion of certain toxic substances and reduce intracranial and intraocular pressure. When used with Gemcitabine, mannitol primarily acts as a vehicle for administration.
Alternate Names
Gemcitabine hydrochloride is the chemical name. Mannitol is also known as D-mannitol.
Brand names: Gemzar, Gemcitabine Kabi, Gemtero.
How It Works
Pharmacodynamics (Gemcitabine): Gemcitabine is a prodrug that needs to be converted into active metabolites (gemcitabine diphosphate and triphosphate) inside the cell. These metabolites exert their cytotoxic effects by inhibiting ribonucleotide reductase (decreasing deoxynucleotide pools, including dCTP) and competing with dCTP for incorporation into DNA. Gemcitabine triphosphate incorporation into DNA causes masked chain termination, inhibiting DNA synthesis and repair mechanisms, ultimately leading to apoptosis (programmed cell death) of rapidly dividing cancer cells.
Pharmacokinetics (Gemcitabine): It is administered intravenously and rapidly metabolized, primarily by cytidine deaminase in the liver, kidney, blood, and other tissues. Elimination occurs mainly through renal excretion, with less than 10% excreted unchanged. The half-life is short, ranging from 32-94 minutes after a 30-minute infusion.
Pharmacodynamics (Mannitol): Mannitol exerts its osmotic effects by remaining primarily within the extracellular compartment, increasing osmotic pressure. This pulls fluid from intracellular and interstitial spaces into the vascular system, increasing diuresis. In the brain, it reduces edema and intracranial pressure by decreasing interstitial fluid volume.
Pharmacokinetics (Mannitol): Mannitol is administered intravenously and is not metabolized. It is excreted unchanged through the kidneys, with its serum half-life being about 100 minutes in individuals with normal renal function. Impaired renal function will prolong half-life.
Dosage
Gemcitabine dosing is based on body surface area (BSA, calculated from height and weight). Mannitol is used as an excipient in Gemcitabine formulations and its quantity doesn’t directly affect the dosage of Gemcitabine.
Standard Dosage
Adults:
Gemcitabine dosage varies depending on the cancer being treated and concurrent chemotherapy:
- Ovarian Cancer: 1000 mg/m² IV over 30 minutes on days 1 and 8 of each 21-day cycle in combination with carboplatin.
- Non-Small Cell Lung Cancer: 1000 mg/m² IV over 30 minutes on days 1, 8, and 15 of each 28-day cycle, often combined with cisplatin.
- Breast Cancer: 1250 mg/m² IV over 30 minutes on days 1 and 8 of each 21-day cycle, often combined with paclitaxel.
- Bladder Cancer: 1000 mg/m² IV over 30 minutes on days 1 and 8 of each 21-day cycle, often combined with cisplatin.
Children:
The safety and efficacy of gemcitabine in pediatric patients have not been established.
Special Cases:
- Elderly patients: Dose reduction may be necessary due to decreased renal function. Close monitoring is crucial.
- Patients with renal impairment: Dose reduction is required. Dosage should be based on creatinine clearance.
- Patients with hepatic dysfunction: Caution is advised, and close monitoring of liver function tests is necessary. Dose modifications might be necessary.
Clinical Use Cases
The use of Gemcitabine + Mannitol is primarily for chemotherapy regimens as outlined above. Mannitol’s specific use in intubation, surgical procedures, mechanical ventilation, ICU care, and emergency situations are independent of gemcitabine administration.
Dosage Adjustments
Dose adjustments are required for patients with renal or hepatic impairment, myelosuppression, or other significant toxicities.
Side Effects
Common Side Effects:
- Myelosuppression (neutropenia, thrombocytopenia, anemia)
- Nausea and vomiting
- Fatigue
- Flu-like symptoms (fever, chills, myalgia)
- Alopecia (hair loss)
- Skin rash
- Elevated liver enzymes
Rare but Serious Side Effects:
- Pulmonary toxicity (dyspnea, interstitial pneumonitis)
- Hemolytic uremic syndrome
- Severe allergic reactions
- Renal toxicity
Long-Term Effects:
- Chronic pulmonary dysfunction
Adverse Drug Reactions (ADR):
- Anaphylaxis, capillary leak syndrome, severe myelosuppression, pulmonary toxicity
Contraindications
- Hypersensitivity to gemcitabine
- Pregnancy (except in life-threatening situations)
- Breastfeeding
Drug Interactions
- Radiation therapy: Concurrent radiation can enhance gemcitabine toxicity.
- Other myelosuppressive drugs: Increased risk of myelosuppression.
Pregnancy and Breastfeeding
Gemcitabine is contraindicated during pregnancy due to teratogenic effects. It is also contraindicated during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Antimetabolite, inhibits DNA synthesis.
- Side Effects: Myelosuppression, nausea/vomiting, fatigue, flu-like symptoms, alopecia, skin rash.
- Contraindications: Hypersensitivity, pregnancy, breastfeeding.
- Drug Interactions: Radiation therapy, other myelosuppressive drugs.
- Pregnancy & Breastfeeding: Contraindicated.
Popular Combinations
- Carboplatin for ovarian cancer.
- Cisplatin for lung and bladder cancers.
- Paclitaxel for breast cancer.
Precautions
- Monitor blood counts regularly.
- Administer intravenously over 30 minutes.
- Use cautiously in patients with renal or hepatic impairment.
- Monitor for pulmonary toxicity.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Gemcitabine?
A: The dosage varies depending on the cancer type, BSA, and other chemotherapy given concurrently but typically ranges between 1000-1250 mg/m² administered intravenously over 30 minutes.
Q2: What are the most common side effects of Gemcitabine?
A: Myelosuppression, nausea, vomiting, fatigue, flu-like symptoms, and hair loss are common side effects.
Q3: Can Gemcitabine be given during pregnancy?
A: No, Gemcitabine is contraindicated during pregnancy due to its potential to harm the fetus.
Q4: How is Gemcitabine administered?
A: Gemcitabine is administered intravenously over 30 minutes.
Q5: What are the dose adjustments for renal impairment?
A: Dose adjustments are necessary based on creatinine clearance. Consult specific guidelines or a pharmacist for appropriate dose modifications.
Q6: How does mannitol interact with Gemcitabine?
A: Mannitol is primarily used as a vehicle during Gemcitabine administration and is not expected to pharmacologically interact with Gemcitabine.
Q7: What should be monitored during Gemcitabine therapy?
A: Close monitoring of blood counts, renal function, and liver function tests, as well as monitoring for signs and symptoms of pulmonary toxicity is essential during Gemcitabine therapy.
Q8: Can patients on Gemcitabine receive vaccinations?
A: Live vaccines are contraindicated during Gemcitabine therapy due to the risk of systemic infection.
Q9: What are signs of Gemcitabine overdose?
A: Severe myelosuppression, potentially leading to infections and bleeding, pulmonary toxicity (dyspnea, pneumonitis), and renal toxicity are all potential signs of Gemcitabine overdose. Supportive care should be administered.
