Gemcitabine Hydrochloride; Indications, Contraindications

Gemcitabine Hydrochloride is the hydrochloride salt of an analog of the antimetabolite nucleoside deoxycytidine with antineoplastic activity. Gemcitabine is converted intracellularly to the active metabolites difluorodeoxycytidine di- and triphosphate (dFdCDP, dFdCTP). dFdCDP inhibits ribonucleotide reductase, thereby decreasing the deoxynucleotide pool available for DNA synthesis; dFdCTP is incorporated into DNA, resulting in DNA strand termination and apoptosis.

Gemcitabine hydrochloride is a 2′-deoxycytidine hydrochloride having geminal fluoro substituents in the 2′-position. An inhibitor of ribonucleotide reductase, gemcitabine hydrochloride is used in the treatment of various carcinomas, including non-small cell lung cancer, pancreatic cancer, bladder cancer, and breast cancer. It has a role as an immunosuppressive agent, an antiviral drug, an antimetabolite, an antineoplastic agent, an EC 1.17.4.1 (ribonucleoside-diphosphate reductase) inhibitor and a radiosensitizing agent. It is an organofluorine compound and hydrochloride. It contains gemcitabine.

Mechanism of Action of Gemcitabine Hydrochloride

Gemcitabine hydrochloride, a synthetic pyrimidine nucleoside, is an antineoplastic agent. The nucleoside analog consists of the pyrimidine base difluoro cytidines, 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′-difluoro cytidines) depends on intracellular conversion to its 5′-diphosphate and -triphosphate metabolites; thus, deoxydifluorocytidine-5?-diphosphate (dFdCDP, gemcitabine diphosphate) and –triphosphate (dFdCTPgemcitabine 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.
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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 cytarabine and is thought to contribute to gemcitabine’s expanded spectrum of antineoplastic activity relative to such agents. In CEM T lymphoblastoid cells, gemcitabine induces internucleosomal DNA fragmentation, which is characteristic of programmed cell death.

Indications of Gemcitabine Hydrochloride

  • Gemcitabine is indicated for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy; metastatic ovarian cancer; inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer; and locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas.
  • Pancreatic Cancer
  • Non-Small Cell Lung Cancer
  • Breast Cancer
  • Ovarian Cancer
  • Advanced Ovarian Cancer
  • Breast Cancer Metastatic
  • Locally Advanced Biliary Tract Cancer
  • Locally Advanced Non-Small Cell Lung Cancer
  • Locally Advanced Pancreatic Adenocarcinoma
  • Metastatic Biliary Tract Cancer
  • Metastatic Bladder Cancer
  • Non-small Cell Lung Cancer (NSCLC), Stage IV
  • Advanced Bladder cancer
  • Stage 4 Pancreatic adenocarcinoma
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Therapeutic Uses

  •  Antineoplastic
  • Gemcitabine in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after the failure of prior anthracycline-containing adjuvant chemotherapy unless anthracyclines are clinically contraindicated.
  • Gemcitabine is indicated as first-line therapy for locally advanced (nonresectable stage II or III) or metastatic (stage IV) adenocarcinoma of the pancreas. It is also indicated as second-line therapy for patients who have previously been treated with fluorouracil. Treatment with gemcitabine is primarily palliative.
  • Gemcitabine is indicated in combination with cisplatin as first-line therapy for inoperable, locally advanced (Stage IIIA or IIIB) or metastatic (Stage IV) non-small cell lung carcinoma.
  • Gemcitabine is indicated for the treatment of locally advanced, unresectable, or metastatic biliary tract (ie, cholangiocarcinoma, biliary tree carcinoma, bile duct carcinoma) and gall bladder carcinomas.
  • Gemcitabine is indicated for the treatment of metastatic bladder (urothelial) carcinoma, based on response rates (both complete and partial responses) achieved in clinical trials.
  • Gemcitabine is indicated, alone or in combination with other chemotherapeutic agents, as reasonable medical therapy at some point in the management of patients with advanced or relapsed epithelial ovarian carcinoma (evidence rating: IIID).
  • Gemcitabine is indicated, alone or in combination with other agents, for the treatment of relapsed Hodgkin’s and non-Hodgkin’s lymphomas (T-cell and B-cell). /Not included in US product label/
  • Gemcitabine is indicated for the treatment of relapsed/refractory, progressive, metastatic, or non-seminomatous gonadal (i.e., testicular, ovarian) and extragonadal germ cell tumors.

Contraindications of Gemcitabine Hydrochloride

  • Infection
  • Syndrome characterized by Anemia and Renal Failure
  • Decreased function of bone marrow
  • Anemia
  • Decreased blood platelets
  • Decreased Neutrophils a Type of White Blood Cell
  • Plasma Fluid & Proteins Leaking Outside of Capillaries
  • Interstitial Pneumonitis
  • Acute Respiratory Distress Syndrome
  • Hardening of the Liver caused by Alcohol
  • Hardening of the Liver
  • Hepatitis
  • Hepatitis caused by Drugs
  • Kidney disease with a reduction in kidney function
  • Pregnancy
  • A mother who is producing milk and breastfeeding
  • Brain-Capillary Leak Syndrome
  • Cancer That Has Spread To The Liver
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Dosage of Gemcitabine Hydrochloride

Strengths: 200 mg; 1 g; 2 g; 38 mg/mL; 100 mg/mL

Breast Cancer

  • 1250 mg/m2 IV over 30 minutes on days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m2 IV on day 1 as a 3 hour IV infusion before gemcitabine administration
  • Dose reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient. Patients should have an absolute granulocyte count of at least 1,500,000,000/L prior to initiation of gemcitabine plus paclitaxel combination.

Ovarian Cancer

  • 1000 mg/m2 IV over 30 minutes on days 1 and 8 of each 21-day cycle. Carboplatin should be administered IV on day 1 of each 21-day cycle after gemcitabine administration.

Pancreatic Cancer

  • 1000 mg/m2 IV one time over 30 minutes.
  • Weeks 1 through 8: Weekly dosing for the first 7 weeks, followed by one week of rest. If toxicity occurs, a dose should be held.
  • After week 8: Weekly dosing on Days 1, 8, and 15 of 28-day cycles

Non-Small Cell Lung Cancer

  • Four-week schedule: 1000 mg/m2 IV over 30 minutes on days 1, 8, and 15 in combination with cisplatin therapy
  • Three-week schedule: 1250 mg/m2 IV over 30 minutes on days 1 and 8 in combination with cisplatin therapy.

Side Effects of Gemcitabine Hydrochloride

More Common

  • Black, tarry stools
  • bleeding gums
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • blood in the urine or stools
  • blurred vision
  • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
  • chest pain
  • cloudy urine
  • confusion
  • cough
  • coughing up blood
  • diarrhea
  • difficult or labored breathing
  • difficulty in moving
  • difficulty in swallowing
  • dizziness
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position

Common

  • severe constipation for 3 days that has not been relieved by laxatives
  • severe diarrhea (3 or more watery bowel movements per day lasting more than 24 hours)
  • signs of clotting problems (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood,  bleeding gums, cuts that don’t stop bleeding)
  • signs of kidney problems (e.g., increased urination at night, decreased urine production, blood in the urine, change of urine color)
  • signs of  liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
  • skin rash
  • sores on mouth or lips
  • swelling of fingers, feet, or lower legs
  • symptoms of anemia (i.e., shortness of breath, paleness, tiredness, fast heart rate, yellowing of the skin or eyes, dark urine)
  • symptoms of infection (i.e., fever, cough, chills, difficult or painful urination, pain in the side or lower back)
  • vision changes
  • vomiting lasting more than 24 hours after treatment
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Rare

  • Difficulty having a bowel movement
  • hair loss
  • sleepiness or unusual drowsiness
  • thinning of hair
  • Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site.

Drug Interactions of Gemcitabine Hydrochloride

Gemcitabine may interact with following drugs, supplements & may change the efficacy of the drug

  • other cancer medications
  • clozapine
  • deferiprone
  • denosumab
  • digoxin
  • dipyrone
  • echinacea
  • fingolimod
  • fluorouracil
  • leflunomide
  • natalizumab
  • nivolumab
  • pimecrolimus
  • roflumilast
  • tacrolimus
  • tofacitinib
  • trastuzumab
  • vaccines
  • warfarin

Pregnancy Category

AU TGA Pregnancy Category: D
US FDA Pregnancy Category: D

Pregnancy

Gemcitabine should not be used during pregnancy. Effective birth control should be used while receiving this medication. Gemcitabine may harm the baby if used during pregnancy. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

It is not known if gemcitabine passes into breast milk. Women receiving gemcitabine should not breast-feed. The safety and effectiveness of using this medication have not been established for children.

References

Gemcitabine Hydrochloride

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