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Gemcitabine Hydrochloride

Pronunciation

Pronunciation: jem-SYE-ta-been
Class: Pyrimidine analog

Trade Names

Gemcitabine
- Injection, lyophilized powder for solution 2 g

Gemcitabine
- Injection, solution, concentrate 38 mg/mL

Gemzar
- Injection, lyophilized powder for solution 200 mg
- Injection, lyophilized powder for solution 1 g

Pharmacology

Exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis in the S-phase. It also blocks the progression of cells through the G1/S-phase boundary.

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Pharmacokinetics

Distribution

Protein binding is negligible. Vd is 50 L/m 2 (short infusion) and 370 L/m 2 (long infusion).

Metabolism

To inactive uracil metabolite (dFdU).

Elimination

Cl is 40.7 to 92.2 L/h/m 2 (men); 30.7 to 69.4 L/h/m 2 (women). Primary route is renal. Short infusion half-life is 42 to 94 min. Long infusion half-life is 245 to 638 min.

Special Populations

Elderly

The lower Cl in elderly patients results in higher concentrations of gemcitabine for any given dose.

Gender

The lower Cl in women results in higher concentrations of gemcitabine for any given dose.

Indications and Usage

First-line treatment of locally advanced or metastatic pancreatic adenocarcinoma in patients previously treated with 5-fluorouracil; in combination with cisplatin as first-line treatment of inoperable locally advanced or metastatic non–small cell lung cancer; in combination with carboplatin for treatment of advanced ovarian cancer that has relapsed at least 6 mo after completion of platinum-based therapy; in combination with paclitaxel as first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines are clinically contraindicated.

Unlabeled Uses

Treatment of biliary cancer, bladder cancer, relapsed or refractory testicular cancer, squamous cell carcinoma of the head and neck.

Contraindications

Hypersensitivity to the drug.

Dosage and Administration

Pancreatic Cancer
Adults

IV 1,000 mg/m 2 over 30 min once weekly for up to 7 wk followed by 1 wk of rest.

Dosage adjustment

Based on degree of hematologic toxicity. If marrow suppression is detected, modify gemcitabine dosage as follows: absolute granulocyte count (AGC) is 500 to 999 × 10 6 /L or platelet count is 50,000 to 99,999 × 10 6 /L, give 75% of full dose; AGC is less than 500 × 10 6 /L or platelet count is less than 50,000 × 10 6 /L, hold dose.

Subsequent cycles

Give the same dose once weekly for 3 consecutive wk followed by 1 wk of rest. After at least 7 doses (1 cycle), the dose may be increased to 1,250 mg/m 2 once weekly for 3 wk, followed by 1 wk of rest, if the following criteria are met: nonhematologic toxicity is no greater than WHO grade 1, platelet nadirs are greater than 100,000 × 10 6 /L, and AGC nadir is more than 1,500 × 10 6 /L.

If patient still meets the above criteria after receiving 3 doses of the higher regimen, the gemcitabine dose may be increased to 1,500 mg/m 2 IV once weekly for 3 wk, followed by 1 wk of rest.

Non–small Cell Lung Cancer
Adults

IV In combination with cisplatin, gemcitabine 1,000 mg/m 2 over 30 min on days 1, 8, and 15 of each 28-day cycle. Alternatively, gemcitabine 1,250 mg/m 2 may be given IV on days 1 and 8 of a 21-day cycle.

Dosage adjustment

Reduce or delay the gemcitabine dose in patients with neutropenia or thrombocytopenia on the day of treatment. On the day of the scheduled dose, if AGC is 500 to 999 × 10 6 /L or platelet count is 50,000 to 99,999 × 10 6 /L, give 75% of the prior dose. If AGC is less than 500 × 10 6 /L or platelet count is less than 50,000 × 10 6 /L, hold dose. For severe (grade 3 or 4) nonhematologic toxicity, hold gemcitabine or reduce the dose by 50% in patients with non–small cell lung cancer. Dosage reduction is not required for alopecia or nausea and vomiting.

Ovarian Cancer
Adults

IV 1,000 mg/m 2 over 30 min on days 1 and 8 of each 21-day cycle in combination with carboplatin. Monitor prior to each dose with a CBC, including differential counts. Prior to each cycle, the AGC should be at least 1,500 × 10 6 /L and the platelet count should be at least 100,000 × 10 6 /L.

If any of the below recur after the initial dose reduction, for the subsequent cycle, give gemcitabine 800 mg/m 2 on day 1 only.

Dosage adjustment

Based on granulocyte and platelet counts on day 8 of therapy. If marrow suppression is detected, modify gemcitabine dosage as follows: AGC is 1,000 to 1,499 × 10 6 /L and/or platelet count is 75,000 to 99,999 × 10 6 /L, give 50% of full dose; AGC is less than 1,000 × 10 6 /L and/or platelet count is less than 75,000 × 10 6 /L, hold dose. For severe (grade 3 or 4) nonhematologic toxicity, except nausea/vomiting, hold gemcitabine therapy or decrease 50%.

Subsequent cycles

Dose adjustments for gemcitabine in combination with carboplatin are based on observed toxicity. Reduce the gemcitabine dose to 800 mg/m 2 on days 1 and 8 if any of the following hematologic toxicities are present: AGC less than 500 × 10 6 /L for more than 5 days, AGC less than 100 × 10 6 /L for more than 3 days, febrile neutropenia, platelet count less than 25,000 × 10 6 /L, and cycle delay of more than 1 wk because of toxicity.

Breast Cancer
Adults

IV 1,250 mg/m 2 over 30 min on days 1 and 8 of each 21-day cycle in combination with paclitaxel. Monitor prior to each dose with a CBC, including differential. Prior to each cycle, AGC should be at least 1,500 × 10 6 /L and the platelet count should be at least 100,000 × 10 6 /L.

Dosage adjustment

Based on granulocyte and platelet counts on day 8 of therapy. If marrow suppression is detected, modify gemcitabine dosage as follows: AGC is 1,000 to 1,199 × 10 6 /L or platelet count is 50,000 to 75,000 × 10 6 /L, give 75% of full dose; AGC is 700 to 999 × 10 6 /L and platelet count is at least 50,000 × 10 6 /L, give 50% of full dose; AGC is less than 700 × 10 6 /L or platelet count is less than 50,000 × 10 6 /L, hold gemcitabine. For severe (grade 3 or 4) nonhematologic toxicity, except alopecia and nausea/vomiting, hold gemcitabine therapy or decrease by 50%.

Renal/Hepatic function impairment

Dosage reduction may be necessary in renal or hepatic function impairment. Use additional caution in these patients.

General Advice

  • Administer by IV infusion over 30 min.
  • Prolonging infusion past 60 min and more frequently than weekly increases risk of toxicity.
  • Discard any unused product.
  • Powder for solution
  • Reconstitute with preservative-free sodium chloride 0.9%.
  • Reconstituted solution may be administered as prepared or further diluted with sodium chloride 0.9% to a final gemcitabine concentration as low as 0.1 mg/mL.
  • Reconstituted gemcitabine is a clear, colorless to light straw–colored solution. Do not administer if particulate matter or discoloration is found.
  • Injection solution
  • Each vial contains gemcitabine at a concentration of 38 mg/mL; withdrawing 5.26, 26.3, or 52.6 mL of the vial contents will provide gemcitabine 200 mg, 1 g, or 2 g, respectively.
  • The drug should be further diluted with sodium chloride 0.9% injection to concentrations as low as 0.1 mg/mL.

Storage/Stability

Powder for solution

Store vials at 68° to 77°F. Reconstituted solutions are stable for up to 24 h at 68° to 77°F. Do not refrigerate reconstituted product; crystals may form in the bag or bottle.

Injection solution

Store unopened vials at 36° to 46°F. Do not freeze. When prepared as directed, diluted gemcitabine solutions are stable for 24 h when stored at 68° to 77°F.

Drug Interactions

Doxorubicin

Risk of hemolytic uremic syndrome may be increased. Close clinical monitoring is warranted.

Hydantoins (eg, phenytoin)

GI absorption of hydantoins may be decreased because of intestinal mucosal damage from gemcitabine. Monitor hydantoin concentrations and adjust the dose as needed.

Palifermin

Palifermin may increase rapid cycling of oral epithelial cells, increasing gemcitabine cytotoxic effects. Palifermin should not be administered within 24 h before, during, or 24 h after gemcitabine administration.

Radiation

A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and nonconcurrent use of gemcitabine.

Virus vaccines, live

The risk of live vaccine–induced adverse reactions may be increased. Defer use of live vaccines in patients receiving gemcitabine.

Warfarin

The anticoagulant effect of warfarin may be increased, necessitating a decrease in warfarin dosage.

Adverse Reactions

The following adverse reactions are for weekly administration of single-agent gemcitabine as a 30-min infusion for treatment of a wide variety of malignancies.

Cardiovascular

Arrhythmias, CHF, MI, peripheral vasculitis (postmarketing).

CNS

Somnolence (11%); paresthesia (10%).

Dermatologic

Rash (30%); alopecia (15%); pruritus (13%); bullous skin eruptions, cellulitis, desquamation, gangrene (postmarketing).

GI

Nausea and vomiting (71%); diarrhea (30%); stomatitis (11%).

Genitourinary

Proteinuria (45%); hematuria (35%); increased BUN (16%); elevated creatinine (8%); hemolytic uremic syndrome (0.25%); renal failure (postmarketing).

Hematologic-Lymphatic

Anemia (73%); leukopenia (64%); neutropenia (63%); thrombocytopenia (36%); hemorrhage (17%); petechiae (16%).

Hepatic

Elevated AST (78%); increased alkaline phosphatase (77%); elevated ALT (72%); elevated bilirubin (26%); elevated gamma-glutamyl transferase, hepatic veno–occlusive disease, hepatotoxicity, liver failure (postmarketing).

Respiratory

Dyspnea (23%); bronchospasm (2%); parenchymal toxicity including adult respiratory distress syndrome, interstitial pneumonitis, pulmonary edema, and pulmonary fibrosis, respiratory failure (postmarketing).

Miscellaneous

Fever (41%); peripheral edema (20%); flu-like syndrome (19%); infection (16%); edema (13%); injection-site reaction (4%); radiation recall reactions (postmarketing).

Precautions

Monitor

Prior to each dose, monitor with a CBC, including differential and platelet count; perform laboratory evaluation of renal and hepatic function (including serum creatinine, potassium, calcium, and magnesium) prior to starting therapy and periodically thereafter.


Pregnancy

Category D .

Lactation

Undetermined. Avoid breast-feeding.

Children

Safety and efficacy not established.

Renal Function

Use with caution in patients with preexisting renal function impairment.

Hepatic Function

Use with caution in patients with preexisting hepatic function impairment.

Renal Effects

Hemolytic uremic syndrome and renal failure have been reported. Renal failure leading to death or requiring dialysis, despite discontinuing therapy, has been reported.

Hepatic Effects

Serious hepatotoxicity, including liver failure and death, has been reported.

Extravasation

May occur.

Hematology

May suppress bone marrow function manifested by anemia, leukopenia, or thrombocytopenia; myelosuppression is usually the dose-limiting adverse reaction.

Pulmonary

Pulmonary toxicity has been reported. In cases of severe toxicity, discontinue therapy immediately and institute supportive measures.

Overdosage

Symptoms

Myelosuppression, paresthesia, severe rash.

Patient Information

  • Inform patients of the risk of low blood cell counts and instruct them to immediately contact their health care provider if any sign of infection develops, including fever.
  • Advise patients to contact their health care provider if bleeding or symptoms of anemia, such as tiredness, occur.
  • Advise women of childbearing potential to avoid becoming pregnant. Inform patients if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the risks to the fetus need to be discussed with their health care provider.
  • Advise women to avoid breast-feeding during gemcitabine treatment.

Copyright © 2009 Wolters Kluwer Health.

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