Gemcitabine

Gemcitabine is an antineoplastic agent belonging to the pharmacological class of antimetabolites.

Gemcitabine has been approved by the FDA for the treatment of various types of cancers such as non-small cell lung cancer, pancreatic cancer, breast cancer, and ovarian cancer.

Gemcitabine is rapidly and extensively absorbed after intravenous administration, distributing widely into tissues, including ascitic fluid. It undergoes rapid metabolism in the liver, kidney, blood, and other tissues, primarily by cytidine deaminase. The drug is mainly eliminated through urine,

The most common side effects of Gemcitabine include nausea,loss of appetite, vomiting, hair loss and low blood platelets.

Gemcitabine is available as a powder for injection and injectable solutions.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Gemcitabine is an antineoplastic agent belonging to the pharmacological class of antimetabolites.

The pyrimidine analogue gemcitabine shares structural features with cytarabine, but because of its distinct cellular pharmacology and mode of action, it exhibits a broader range of antitumor activity. Two active metabolites, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP), are produced during the intracellular metabolism of Gemcitabine. Through the incorporation of dFdCTP into DNA with the help of dFdCDP, Gemcitabine's cytotoxic effects are mediated, causing apoptosis induction and inhibition of DNA synthesis. A radiation-sensitizing drug is Gemcitabine.3 It is phase-specific to the cell cycle (S and G1/S phases).

After a 30-minute intravenous infusion, peak gemcitabine plasma concentrations are reached in 15–30 minutes and range from 10 to 40 mg/L.

• Non-small cell lung cancer
• Breast cancer
• Pancreatic cancer
• Urinary bladder cancer
• Ovarian cancer

• In Non-small cell lung cancer: Gemcitabine is an effective treatment for non-small cell lung cancer (NSCLC), which affects both smokers and non-smokers. It can be used alone or in combination with other medications. Gemcitabine relieves the symptoms of advanced non-small cell lung cancer (NSCLC) and improves patients' quality of life by blocking DNA synthesis and upsetting the cell cycle.
• In Breast Cancer: Gemcitabine is used to treat breast cancer. It can be used alone or in conjunction with other treatments like chemotherapy to treat symptoms like breast lumps, bloody discharge, and breast shape changes. It functions by either eliminating cancer cells or stopping their growth and division. It is not, however, typically the first line of treatment for breast cancer.
• In Pancreatic cancer: By interfering with the DNA synthesis process in cancer cells, Gemcitabine inhibits the growth of cancer cells, which is a vital component in managing pancreatic cancer. It relieves the symptoms of pancreatic cancer, including appetite loss and unexplained weight loss. Gemcitabine works by inhibiting the actions of substances that promote the development and metastasis of pancreatic cancer.
• In Urinary bladder cancer: Gemcitabine is an effective treatment for advanced or metastasized bladder cancer when combined with medications such as cisplatin. It reduces symptoms and enhances the quality of life for patients by inhibiting DNA synthesis, disrupting the cell cycle, and also stopping the growth of cancer cells.
• Ovarian cancer: Ovarian cancer is a cancer that originates in the female organs that produce eggs (ovaries). It can also be fatal, and this form of cancer tends to be identified much later. The pelvis and stomach are typically affected as well. Gemcitabine interferes with the growth and multiplication of cancer cells in the ovaries by blocking DNA synthesis and disrupting the cell cycle. Gemcitabine can kill or stop cancer cell growth and prevent cancer cell multiplication.

Gemcitabine is indicated for the following conditions:

• First-line therapy for individuals with pancreatic adenocarcinomas that are either metastatic (stage IV) or locally advanced (nonresectable, stages II or III). For patients previously treated with 5-FU.
• For non-small cell lung cancer in conjunction with cisplatin.
• As first-line treatment in combination with paclitaxel for metastatic breast cancer when previous adjuvant chemotherapy containing anthracyclines failed, unless anthracyclines were clinically contraindicated.
• When combined with carboplatin for the management of advanced ovarian cancer that has returned at least half a year after platinum-based treatment.

Gemcitabine is available as a powder for injection and injectable solutions.

Dose Adjustment in Adult Patients:

Pancreas Cancer

IV infusion of 1000 mg/m² once every seven days for thirty minutes; one week off after that

Every 28-day cycle, 1000 mg/m² IV is administered once every three weeks.

There are several regimens available, such as monotherapy and combination therapy with other chemotherapy agents (such as capecitabine, erlotinib, and paclitaxel protein bound).

Non-small Cell Lung Cancer

On days 1, 8, and 15 of every 28-day cycle, an IV infusion of 1000 mg/m² administered over 30 minutes.

IV infusion of 1250 mg/m² for 30 minutes on days 1 and 8 of every 21-day cycle

Cancer of the breast

On Days 1 and 8 of every 21-day cycle, an IV infusion of 1250 mg/m² is administered over 30 minutes.

With a three-hour infusion of paclitaxel 175 mg/m² on Day 1 before Gemcitabine

Cancer of Ovaries

On Days 1 and 8 of every 21-day cycle, an IV infusion of 1000 mg/m² is administered over 30 minutes.

With carboplatin, AUC 4 following Gemcitabine on Day 1.

Follow the dietary guidelines while taking Gemcitabine: Consume lean meats, healthy fats, fruits, vegetables, and whole grains for increased energy. Avoid alcohol due to potential interactions. Ensure hydration with adequate water intake, which is vital in cancer management. Refrain from tobacco use.

The dietary restriction should be individualized as per patient requirements.

• Longer than 60-minute infusion periods or dosages more frequently than once per week may result in increased toxicity.
• Every cycle, check for myelosuppression and, in the event of severe myelosuppression, consider reducing or stopping the dose.
• If there is evidence of severe pulmonary toxicity or if dyspnea is developing or becoming unexplained, stop using gemcitabine injection promptly.
• Before and during treatment, maintain a close watch on renal function. In cases of Hemolytic-Uremic Syndrome (HUS) or severe renal impairment, stop injecting Gemcitabine.
• Before starting treatment and throughout it, maintain a close watch on liver function. In the event of severe hepatic toxicity, stop the gemcitabine injection.
• Gemcitabine may harm pregnancy. Men and women who are capable of having children should be advised to use reliable contraception.
• When given during or during the first seven days of radiation treatment, it may cause severe and potentially fatal toxicity.
• If capillary leak syndrome is suspected, stop injecting Gemcitabine.
• If symptoms of posterior reversible encephalopathy syndrome develop, stop the gemcitabine injection.

The adverse reactions related to Gemcitabine can be categorized as:

• Common Adverse Effects: Melosuppression, leading to anemia, neutropenia, and thrombocytopenia.
• Less Common Adverse Effects: Pulmonary toxicity and respiratory failure
• Rare Adverse Effects: Hemolytic-uremic syndrome (HUS), hepatotoxicity, and embryo-fetal toxicity

Postmarketing Reports:

Recaps of Postmarketing

Cardiovascular conditions include supraventricular arrhythmias, CHF, and MI.

Vascular conditions include gangrene, capillary leak syndrome, and peripheral vasculitis.

Skin: Desquamation, bullous skin eruptions, cellulitis, pseudo cellulitis, and severe skin reactions

Hepatic: Veno-occlusive disease of the liver, failure of the liver

The cardiovascular system: Interstitial pneumonia, heart failure, pulmonary oedema, acute respiratory distress syndrome

Pulmonary: Pulmonary eosinophilia

Thrombotic microangiopathy: a blood and lymphatic system

The clinically relevant drug interactions of Gemcitabine are briefly summarized here.

• Drug-Drug Interactions: Acetaminophen, aceclofenac, diuretics, antiviral/anti-HIV medications (abacavir), anti-rheumatoid medications (abatacept), and any anticoagulants (acenocoumarol) may interact with Gemcitabine.
• Drug-Disease Interactions: Patients with a history of hypersensitivity reaction, epilepsy, kidney or liver disease, lung or breathing problems, or insomnia should use Gemcitabine with caution.

• Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

Treatment can harm a fetus if it is given to a pregnant woman, according to data from animals and its mode of action; therapy is anticipated to have adverse effects on reproduction; drug was found to be teratogenic, embryotoxic, and fetotoxic in mice and rabbits; expectant mothers should be warned of the possible risk to the fetus.

Contraception

Advise women who are capable of having children to use reliable contraception both during and for six months following the last dose of treatment.

Male patients who have female partners who are capable of having children should be advised to use effective contraception during the final dose and for three months after.

Infertility

According to research on animals, gemcitabine injection may reduce fertility in males of reproductive potential.

Pregnancy Testing

Before starting therapy, determine if a female patient is pregnant.

When given to a pregnant woman, contraception therapy can harm the fetus.

Females

Recommend effective contraception to females who may become pregnant during treatment and for six months following the last dose due to the possibility of genotoxicity.

Males

It is recommended that males who have female partners who are capable of reproduction use effective contraception during their treatment and for three months after the last dose due to the possibility of genotoxicity.

• Nursing Mothers

Due to its potential of severe side effects in nursing infants from therapy, it is advised that a lactating woman not breastfeed during treatment and for one week following the last dose. There is no data on the presence of the drug in human milk or the effects of Gemcitabine on milk production.

• Pediatric Use

As per the FDA, the safety and efficacy of Gemcitabine have not been specifically studied in pediatric patients.

• Geriatric Use

In clinical trials, older patients experienced a higher rate of Grade 3–4 thrombocytopenia than younger patients who received Gemcitabine as a single agent for a variety of cancers.

Women 65 years of age or older experienced significantly higher Grade 3/4 neutropenia in a randomized trial involving women with ovarian cancer.

Dose Adjustment in Kidney Impairment Patients:

Limited information is available on the use of Gemcitabine in patients with Kidney Impairment.

Dose Adjustment in Hepatic Impairment Patients:

Limited information is available on the use of Gemcitabine in patients with Hepatic Impairment.

Pharmacodynamic

In vitro, Gemcitabine showed dose-dependent synergistic activity with cisplatin. Cisplatin was found not to affect the accumulation of gemcitabine triphosphate or DNA double-strand breaks. Gemcitabine and cisplatin demonstrated some in vivo activity against human lung xenografts, specifically the LX-1 and CALU-6 xenografts; however, minimal activity was observed with the NCI-H460 or NCI-H520 xenografts. In the Lewis lung murine xenograft, Gemcitabine and cisplatin worked in concert.

The maximum interaction was produced by sequential gemcitabine exposure four hours before cisplatin.

Pharmacokinetics

• Absorption: After intravenous injection, Gemcitabine is rapidly and extensively absorbed by the body, where it quickly becomes its active metabolite.
• Distribution: With a volume of distribution ranging from 50 L/m² (less than 70 minutes) to 370 L/m² (between 70 and 285 minutes), it extensively distributes into various tissues, including ascitic fluid.
• Metabolism: Cytidine deaminase is the main enzyme that promotes rapid metabolism, which occurs in the liver, kidney, blood, and other tissues. By this process, 2'-deoxy-2',2'-difluorouridine (dFdU), an inactive metabolite, is formed. The active metabolites, gemcitabine diphosphate and triphosphate nucleosides, are produced by nucleoside kinases during intracellular metabolism.
• Excretion: Most excretion occurs through urine (92–98%, mainly as dFdU; <10% as unchanged drug), with faeces accounting for less than 1% of the total. Approximately 42-94 minutes (≤70 minutes for infusion) and 4-10.5 hours (3-5 hours for infusion). The half-life of gemcitabine triphosphate ranges from 1.7 to 19.4 hours.

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• https://www.ncbi.nlm.nih.gov/books/NBK548575/
• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Gemzar® (Gemcitabine HCl)
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209604s003lbl.pdf