Fonkogem

Uses

Ovarian Cancer: Gemcitabine in combination with carboplatin is used for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

Breast Cancer: Gemcitabine in combination with paclitaxel is used for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraused.

Non-Small Cell Lung Cancer: Gemcitabine is used for combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer.

Pancreatic Cancer: Gemcitabine is used for first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemcitabine is used for patients previously treated with 5-FU.

Fonkogem is also used to associated treatment for these conditions: Advanced Ovarian Cancer, Bladder Transitional Cell Carcinoma Stage IV, Cervical Cancers, Cutaneous T-Cell Lymphoma (CTCL), Head and Neck Carcinoma, Hodgkins Disease (HD), Locally Advanced Pancreatic Adenocarcinoma, Mesothelioma, Metastatic Breast Cancer, Non-Small Cell Lung Cancer Stage IIIB, Non-small Cell Lung Cancer (NSCLC), Stage IV, Non-small Cell Lung Cancer Stage IIIA, Small Cell Lung Cancer (SCLC), Stage 4 Pancreatic adenocarcinoma

How Fonkogem works

Gemcitabine is a potent and specific deoxycytidine analog. After uptake into malignant cells, gemcitabine is phosphorylated by deoxycytidine kinase to form gemcitabine monophosphate, which is then converted to the active compounds, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). These active metabolites are nucleosides that mediate antitumour effects. dFdCTP competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA, thereby competitively inhibiting DNA chain elongation. The non-terminal position of dFdCTP in the DNA chain prevents detection of dFdCTP in the chain and repair by proof-reading 3′5′-exonuclease: this process is referred to as "masked DNA chain termination." Incorporation of dFdCTP into the DNA chain ultimately leads to chain termination, DNA fragmentation, and apoptotic cell death of malignant cells.

Gemcitabine has self-potentiating pharmacological actions that can increase the probability of successful incorporation of gemcitabine triphosphate into the DNA chain: dFdCDP inhibits ribonucleotide reductase, an enzyme responsible for catalyzing the reactions that generate dCTP for DNA synthesis. Since dFdCDP reduces the levels of dCTP, there is less competition for gemcitabine triphosphate for incorporation into DNA. Gemcitabine can also reduce metabolism and elimination of active metabolites from the target ce1l, prolonging high intracellular concentrations of the active metabolites. Such self-potentiating effects are not present with cytarabine.

Dosage

Fonkogem dosage

Intravenous (Adult)-

• Advanced non-small cell lung cancer: 1000 mg/m2 on days 1, 8 and 15 of each 28-day cycle; or 1250 mg/m2 on days 1 and 8 of each 21-day cycle.
• Pancreatic carcinoma: 1000 mg/m2 once wkly for up to 7 wk followed by 1 wk of rest. Continue thereafter with once wkly infusions for 3 consecutive wk out of 4.
• Ovarian carcinoma: To be given before carboplatin: 1000 mg/m2 on days 1 and 8 of each 21-day cycle.
• Breast cancer: Usually in combination with a taxane such as paclitaxel: 1250 mg/m2 on days 1 and 8 of each 21-day cycle.
• Bladder cancer: To be given before cisplatin. 1000 mg/m2 on days 1, 8 and 15 of each 28-day cycle.

Side Effects

Bone marrow suppression as manifested by leukopenia, thrombocytopenia, anaemia and myelosuppression. Mild GI effects; rashes; renal impairment, pulmonary toxicity, influenza-like symptoms; interstitial pneumonia, pulmonary oedema. Proteinuria, haematuria and haemolytic uraemic syndrome. Elevation of serum transaminase.

Toxicity

The oral LD₅₀ is 333 mg/kg in mice and >500 mg/kg in rats. The dermal LD₅₀ in rabbits is >1000 mg/kg.

There is no known antidote for gemcitabine overdose. In a dose-escalation study, patients were administered a single dose of gemcitabine as high as 5700 mg/m²

Precaution

Children, hepatic and renal impairment. May impair ability to drive or operate machinery. Discontinue on 1st sign of microangiopathic haemolytic anaemia. Prolonged infusion time (>60 minutes) and more frequent than wkly dosing may increase toxicity. Monitor CBC before every dose. Increased risk of haemolytic uraemic syndrome and/or thrombocytcpenic purpura which may lead to irreversible renal failure.

Interaction

May increase the anticoagulant effect of warfarin when used together.

Volume of Distribution

In patients with various solid tumours, the volume of distribution increased with infusion length. The volume of distribution of gemcitabine was 50 L/m² following infusions lasting less than 70 minutes. For long infusions, the volume of distribution rose to 370 L/m².

Gemcitabine triphosphate, the active metabolite of gemcitabine, accumulates and retains in solid tumour cells in vitro and in vivo. It is not extensively distributed to tissues after short infusions that last less than 70 minutes. It is not known whether gemcitabine crosses the blood-brain barrier, but gemcitabine is widely distributed into tissues, including ascitic fluid. In rats, placental and lacteal transfer occurred rapidly at five to 15 minutes following drug administration.

Elimination Route

Peak plasma concentrations of gemcitabine range from 10 to 40 mg/L following a 30-minute intravenous infusion, and are reached at 15 to 30 minutes. One study showed that steady-state concentrations of gemcitabine showed a linear relationship to dose over the dose range 53 to 1000 mg/m². Gemcitabine triphosphate, the active metabolite of gemcitabine, can accumulate in circulating peripheral blood mononuclear cells. In one study, the C_max of gemcitabine triphosphate in peripheral blood mononuclear cells occurred within 30 minutes of the end of the infusion period and increased increased proportionally with gemcitabine doses of up to 350 mg/m².

Half Life

Following intravenous infusions lasting less than 70 minutes, the terminal half-life ranged from 0.7 to 1.6 hours. Following infusions ranging from 70 to 285 minutes, the terminal half-life ranged from 4.1 to 10.6 hours. Females tend to have longer half-lives than male patients. Gemcitabine triphosphate, the active metabolite of gemcitabine, can accumulate in circulating peripheral blood mononuclear cells. The terminal half-life of gemcitabine triphosphate, the active metabolite, from mononuclear cells ranges from 1.7 to 19.4 hours.

Clearance

Following intravenous infusions lasting less than 70 minutes, clearance ranged from 41 to 92 L/h/m² in males and ranged from 31 to 69 L/h/m² in females. Clearance decreases with age. Females have about 30% lower clearance than male patients.

Elimination Route

Gemcitabine mainly undergoes renal excretion. Within a week following administration of a single dose of 1000 mg/m infused over 30 minutes, about 92-98% of the dose was recovered in urine where 89% of the recovered dose was excreted as difluorodeoxyuridine (dFdU) and less than 10% as gemcitabine. Monophosphate, diphosphate, or triphosphate metabolites of gemcitabine are not detectable in urine. In a single-dose study, about 1% of the administered dose was recovered in the feces.

Pregnancy & Breastfeeding use

Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Concurrent radical radiotherapy; pregnancy, lactation; hypersensitivity

Storage Condition

Store at 25° C.

Innovators Monograph

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