Gemcitabine

Gemcitabine (dFdC) is a pyrimidine antimetabolite, a difluorinated analogue of the nucleoside deoxycytidine. It is cell-cycle specific: it kills mainly cells that are synthesising DNA (S phase) and, in some circumstances, blocks cells at the border between the G1 and S phases. Its cytotoxic effect in cell culture depends on both concentration and exposure time. In animal tumour models its activity depends on the dosing schedule: daily dosing caused high mortality with little antitumour effect, whereas dosing every three or four days allowed non-lethal doses with substantial activity against a wide range of tumours.

Mechanism of Action

• Activation in the cell: gemcitabine is taken up by tumour cells and phosphorylated, first by deoxycytidine kinase to the monophosphate and then by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP).
• Two ways of stopping DNA synthesis: dFdCDP inhibits ribonucleotide reductase, the enzyme that makes the deoxynucleoside triphosphates (including dCTP) needed for DNA synthesis, so the cell’s dCTP pool falls. dFdCTP then competes with the remaining dCTP for incorporation into DNA.
• Masked chain termination: after gemcitabine triphosphate is built into the DNA strand, one more nucleotide is added and the strand cannot be extended further. Because gemcitabine then sits at a non-terminal position, the cell’s proofreading enzymes do not detect and remove it. The result is DNA fragmentation and apoptosis (programmed cell death).
• Self-potentiation: the fall in dCTP reduces competition for incorporation, and gemcitabine can slow the removal of its own active metabolites from the cell, keeping intracellular levels high.
• Inactivation: deamination by cytidine deaminase to the inactive metabolite 2′-deoxy-2′,2′-difluorouridine (dFdU) accounts for most of the clearance of gemcitabine.

Pharmacokinetics

The SmPC pharmacokinetic data come from 353 patients in seven studies (121 women and 232 men aged 29 to 79 years; about 45% had non-small cell lung cancer and 35% pancreatic cancer), given 500 to 2,592 mg/m² as infusions of 0.4 to 1.2 hours.

• Absorption: given intravenously. Peak plasma concentrations of 3.2 to 45.5 µg/mL are reached within 5 minutes of the end of the infusion. After 1,000 mg/m² over 30 minutes, concentrations of the parent drug stay above 5 µg/mL for about 30 minutes after the infusion ends and above 0.4 µg/mL for about one hour more.
• Distribution: the volume of distribution of the central compartment is 12.4 L/m² in women and 17.5 L/m² in men (interindividual variability 91.9%); that of the peripheral compartment is 47.4 L/m² and does not depend on sex. Binding to plasma proteins is negligible.
• Metabolism: gemcitabine is rapidly metabolised by cytidine deaminase in the liver, kidney, blood and other tissues. Inside cells it forms the mono-, di- and triphosphates, of which the di- and triphosphate are active; these are not found in plasma or urine. The main metabolite, dFdU, is inactive and is found in plasma and urine.
• Elimination: systemic clearance ranges from 29.2 to 92.2 L/h/m² depending on sex and age (interindividual variability 52.2%). The half-life is 42 to 94 minutes, depending on age and sex. With the recommended schedule, elimination is virtually complete 5 to 11 hours after the start of the infusion, and there is no accumulation with once-weekly dosing. Most of a dose is excreted in the urine within a week, largely as dFdU and less than 10% as unchanged gemcitabine; about 1% is found in the faeces. With infusions longer than 70 minutes the half-life rises to roughly 4 to 11 hours.
• Special populations: clearance in women is about 25% lower than in men, and in both sexes it appears to fall with age. Despite this, the SmPC sees no need for age-specific dose adjustment.

Indications as listed in the SmPC of a nationally authorised gemcitabine concentrate (national product information can differ in detail, so the SmPC of the product supplied applies):

• Bladder cancer: locally advanced or metastatic bladder cancer, in combination with cisplatin.
• Pancreatic cancer: locally advanced or metastatic adenocarcinoma of the pancreas.
• Non-small cell lung cancer (NSCLC): in combination with cisplatin as first-line treatment of locally advanced or metastatic NSCLC. Gemcitabine alone can be considered in elderly patients or in those with performance status 2.
• Ovarian cancer: in combination with carboplatin for locally advanced or metastatic epithelial ovarian carcinoma in patients with relapsed disease, after a relapse-free interval of at least 6 months following first-line platinum-based therapy.
• Breast cancer: in combination with paclitaxel for unresectable, locally recurrent or metastatic breast cancer in patients who have relapsed after adjuvant or neoadjuvant chemotherapy. Prior chemotherapy should have included an anthracycline unless this was clinically contraindicated.

• Hypersensitivity to gemcitabine or to any of the excipients.
• Breast-feeding (lactation).

The most frequently reported side effects are nausea with or without vomiting, and raised liver transaminases (AST/ALT) and alkaline phosphatase, each in roughly 60% of patients; proteinuria and haematuria in roughly 50%; dyspnoea in 10–40% (most often in lung cancer); and an allergic-type skin rash in about 25%, with itching in about 10%. The dose, the speed of the infusion and the interval between doses all affect how often and how severe reactions are. The dose-limiting reactions are falls in platelet, white blood cell and granulocyte counts.

Very common (≥1/10): leukopenia (grade 3 neutropenia in 19.3% of patients, grade 4 in 6%), thrombocytopenia, anaemia, dyspnoea (usually mild and quickly passing without treatment), vomiting, nausea, raised AST, ALT and alkaline phosphatase, allergic skin rash (often with itching), alopecia, haematuria, mild proteinuria, flu-like syndrome (most often fever, headache, chills, myalgia, asthenia and anorexia; cough, rhinitis, malaise, sweating and sleep difficulties are also reported), oedema or peripheral oedema including facial oedema (usually reversible after treatment stops).

Common (≥1/100 to <1/10): infections, febrile neutropenia, anorexia, headache, insomnia, somnolence, cough, rhinitis, diarrhoea, stomatitis and mouth ulcers, constipation, raised bilirubin, itching, sweating, back pain, myalgia, fever, asthenia, chills.

Uncommon (≥1/1,000 to <1/100): stroke, arrhythmia (mainly supraventricular), heart failure, interstitial pneumonitis, bronchospasm (usually mild and transient but sometimes needing parenteral treatment), severe hepatotoxicity including liver failure and death, renal failure, haemolytic uraemic syndrome.

Rare (≥1/10,000 to <1/1,000): myocardial infarction, clinical signs of peripheral vasculitis and gangrene, hypotension, pulmonary oedema, acute respiratory distress syndrome, raised gamma-glutamyl transferase (GGT), severe skin reactions including scaling and blistering, skin ulceration, vesicle and blister formation, injection site reactions (usually mild), radiation-associated toxicity, late skin toxicity.

Very rare (<1/10,000): thrombocytosis, thrombotic microangiopathy, anaphylactoid reactions, posterior reversible encephalopathy syndrome, capillary leak syndrome, ischaemic colitis, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Not known: sepsis, pulmonary eosinophilia, pseudocellulitis, acute generalised exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS).

With paclitaxel in breast cancer, grade 3 and 4 haematological toxicity, particularly neutropenia, is more frequent, but this is not accompanied by more infections or bleeding. Fatigue and febrile neutropenia are also more frequent with the combination; fatigue not linked to anaemia usually settles after the first cycle.

The most important serious reactions are severe skin reactions, posterior reversible encephalopathy syndrome, capillary leak syndrome, haemolytic uraemic syndrome, severe hepatotoxicity, lung toxicity and serious cardiovascular events (see Special Instructions).

No specific interaction studies have been carried out.

• Concurrent radiotherapy (given together or no more than 7 days apart): gemcitabine has radiosensitising activity, and the resulting toxicity depends on the gemcitabine dose and frequency, the radiation dose, the radiotherapy planning technique and the tissue and volume irradiated. In one trial of gemcitabine 1,000 mg/m² given with thoracic radiotherapy for six consecutive weeks in non-small cell lung cancer, severe and potentially life-threatening mucositis, especially oesophagitis and pneumonitis, occurred, mainly with large radiotherapy volumes (median 4,795 cm³). Later studies suggest that low-dose gemcitabine can be given with radiotherapy with predictable toxicity, for example gemcitabine 600 mg/m² (4 doses) with cisplatin 80 mg/m² (2 doses) and 66 Gy of thoracic radiotherapy over 6 weeks. The best regimen for safe concurrent use with full therapeutic radiation doses has not been determined for all tumour types.
• Non-concurrent radiotherapy (more than 7 days apart): no increase in toxicity was found when gemcitabine was given at least 7 days before or after radiotherapy, apart from late skin toxicity.
• Other cytotoxic medicines: the risk of cumulative bone marrow suppression has to be considered when gemcitabine is combined with other chemotherapy. For doses of cisplatin, carboplatin and paclitaxel in combination regimens, see their own SmPCs.
• Live attenuated vaccines: yellow fever vaccine and other live attenuated vaccines are not recommended in patients treated with gemcitabine.
• Alcohol: mild to moderate somnolence has been reported with gemcitabine, especially in combination with alcohol.

Gemcitabine must be prescribed only by a specialist experienced in anti-cancer therapy. It is given by intravenous infusion, is well tolerated during the infusion and can be given on an outpatient basis. The 38 mg/mL concentrate is diluted further before use; instructions are in section 6.6 of the SmPC. If extravasation occurs, the infusion should generally be stopped at once and restarted in another vein, and the patient monitored carefully afterwards.

Recommended Doses by Indication

• Bladder cancer (with cisplatin): gemcitabine 1,000 mg/m² as a 30-minute infusion on days 1, 8 and 15 of each 28-day cycle, with cisplatin 70 mg/m² on day 1 after gemcitabine, or on day 2, of each 28-day cycle. The four-week cycle is then repeated.
• Pancreatic cancer: 1,000 mg/m² as a 30-minute intravenous infusion once a week for 7 weeks, followed by one week of rest. Later cycles are once a week for 3 consecutive weeks, followed by one week of rest.
• NSCLC, gemcitabine alone: 1,000 mg/m² as a 30-minute infusion once a week for 3 weeks, followed by one week of rest; the four-week cycle is then repeated.
• NSCLC, with cisplatin: 1,250 mg/m² as a 30-minute infusion on days 1 and 8 of each 21-day cycle. Cisplatin has been used at 75–100 mg/m² once every 3 weeks.
• Ovarian cancer (with carboplatin): 1,000 mg/m² as a 30-minute infusion on days 1 and 8 of each 21-day cycle. After gemcitabine, carboplatin is given on day 1 at a dose that gives a target AUC of 4.0 mg/mL × min.
• Breast cancer (with paclitaxel): paclitaxel 175 mg/m² on day 1 as an infusion of about 3 hours, followed by gemcitabine 1,250 mg/m² as a 30-minute infusion on days 1 and 8 of each 21-day cycle. Patients should have an absolute granulocyte count of at least 1,500 × 10⁶/L before the combination starts.

In every indication the dose can be reduced within a cycle or from cycle to cycle according to the toxicity the patient experiences.

Dose Adjustments for Toxicity

• Non-haematological toxicity: physical examination and checks of kidney and liver function are needed regularly. For severe (grade 3 or 4) non-haematological toxicity, except nausea and vomiting, gemcitabine should generally be delayed or reduced at the treating physician’s judgement, and doses withheld until the toxicity has resolved. For cisplatin, carboplatin and paclitaxel, follow their own SmPCs.
• Start of each cycle: platelet and granulocyte counts are checked before every dose. Patients should have a granulocyte count of at least 1,500 × 10⁶/L and a platelet count of at least 100,000 × 10⁶/L before each cycle begins (counts are in × 10⁶/L, equal to cells per µL).
• Bladder cancer, NSCLC and pancreatic cancer, within a cycle (alone or with cisplatin): granulocytes above 1,000 and platelets above 100,000, give 100% of the dose; granulocytes 500–1,000 or platelets 50,000–100,000, give 75%; granulocytes below 500 or platelets below 50,000, omit the dose. An omitted dose is not restarted within the cycle until granulocytes reach at least 500 and platelets at least 50,000.
• Breast cancer with paclitaxel, within a cycle: granulocytes at least 1,200 and platelets above 75,000, give 100%; granulocytes 1,000 to below 1,200 or platelets 50,000–75,000, give 75%; granulocytes 700 to below 1,000 and platelets at least 50,000, give 50%; granulocytes below 700 or platelets below 50,000, omit the dose. An omitted dose is not restarted within the cycle; treatment resumes on day 1 of the next cycle once granulocytes reach at least 1,500 and platelets at least 100,000.
• Ovarian cancer with carboplatin, within a cycle: granulocytes above 1,500 and platelets at least 100,000, give 100%; granulocytes 1,000–1,500 or platelets 75,000–100,000, give 50%; granulocytes below 1,000 or platelets below 75,000, omit the dose. An omitted dose is not restarted within the cycle; treatment resumes on day 1 of the next cycle once granulocytes reach at least 1,500 and platelets at least 100,000.
• Later cycles, all indications: reduce the starting dose to 75% of the original dose if there was any of the following: granulocytes below 500 × 10⁶/L for more than 5 days; granulocytes below 100 × 10⁶/L for more than 3 days; febrile neutropenia; platelets below 25,000 × 10⁶/L; a cycle delayed by more than a week because of toxicity.

Special Populations

• Hepatic or renal impairment: use with caution; there is not enough clinical-trial information to give clear dose recommendations.
• Elderly (over 65): gemcitabine is well tolerated, and nothing suggests that dose adjustments other than those recommended for all patients are needed.
• Children and adolescents (under 18): not recommended because of insufficient safety and efficacy data.

Infusion Time and Frequency

Lengthening the infusion time and increasing how often gemcitabine is given have both been shown to increase toxicity.

Bone Marrow Suppression

Gemcitabine can suppress bone marrow function, causing leukopenia, thrombocytopenia and anaemia. Platelet, white cell and granulocyte counts are checked before each dose, and suspending or changing treatment is considered if bone marrow suppression appears. The suppression is usually short-lived and seldom leads to dose reduction or stopping treatment, but blood counts can keep falling after the last dose. Start treatment with caution in patients with impaired bone marrow function, and remember that the risk of cumulative suppression rises when gemcitabine is combined with other chemotherapy.

Severe Skin Reactions

Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS and acute generalised exanthematous pustulosis can be life-threatening or fatal. Patients should be told about the signs and symptoms and to contact their doctor straight away if any appear. If such a reaction is suspected, stop gemcitabine at once and consider alternative treatment. A patient who has had a severe skin reaction with gemcitabine must never be treated with it again.

Liver and Kidney Function

Use gemcitabine with caution in kidney or liver impairment. In patients with liver metastases, or a history of hepatitis, alcoholism or cirrhosis, it can worsen existing liver failure. Kidney and liver function (including virological tests) should be checked regularly in the laboratory.

Haemolytic Uraemic Syndrome

Haemolytic uraemic syndrome has rarely been reported after marketing and is potentially life-threatening. Stop gemcitabine at the first sign of microangiopathic haemolytic anaemia, such as a rapid fall in haemoglobin with thrombocytopenia, or a rise in bilirubin, creatinine, blood urea nitrogen or LDH. Kidney failure may be irreversible even after treatment is stopped and may need dialysis.

Capillary Leak Syndrome

Capillary leak syndrome has been reported with gemcitabine alone or with other chemotherapy. It is usually treatable if recognised early and managed properly, but fatal cases have occurred. Fluid and protein leak from the blood vessels into the tissues, causing generalised oedema, weight gain, low albumin, severe hypotension, acute kidney failure and pulmonary oedema. Stop gemcitabine and give supportive care. It can occur in later cycles and has been linked in the literature to acute respiratory distress syndrome.

Lung Toxicity

Lung effects, sometimes severe (pulmonary oedema, interstitial pneumonitis or acute respiratory distress syndrome), have been reported. The cause is unknown. If they occur, stopping gemcitabine should be considered; prompt supportive treatment may help.

Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES) has been reported with gemcitabine alone or with other anticancer medicines and can have serious consequences. Most patients had acute hypertension and seizures; headache, lethargy, confusion and blindness can also occur. MRI is the best way to confirm it. PRES was reversible with proper supportive care. If it develops, stop gemcitabine permanently and give supportive measures, including blood pressure control and anticonvulsants.

Heart and Circulation

Because gemcitabine can cause heart and blood vessel disorders, take special care in patients with a history of cardiovascular events.

Radiotherapy and Live Vaccines

Toxicity has been reported with concurrent radiotherapy (see Drug Interactions). Yellow fever and other live attenuated vaccines are not recommended during treatment.

Pregnancy, Breastfeeding and Fertility

• Contraception: because gemcitabine may damage genetic material, women of childbearing potential must use effective contraception during treatment and for 6 months after it stops. Men are advised to use effective contraception and not to father a child during treatment and for 3 months afterwards.
• Pregnancy: there are not enough data in pregnant women, and animal studies show reproductive toxicity. Based on these results and the mechanism of action, gemcitabine should not be used in pregnancy unless clearly necessary. Women should be advised not to become pregnant and to tell their doctor immediately if they do.
• Breastfeeding: it is not known whether gemcitabine passes into human milk, and harm to the infant cannot be excluded. Breastfeeding must be stopped during treatment, and use during lactation is contraindicated.
• Fertility: gemcitabine caused reduced sperm production in male mice. Men are advised to seek information on sperm storage before treatment because it may cause infertility.

Sodium

The concentrate described here contains less than 1 mmol (23 mg) of sodium per vial, that is, it is essentially ‘sodium-free’.

Effect on Driving

No studies of the effect on the ability to drive or use machines have been done. Mild to moderate somnolence has been reported, especially together with alcohol. Patients should not drive or use machines until they are known not to be drowsy.

Store unopened vials in a refrigerator at 2–8 °C. Because it is a refrigerated product, gemcitabine must stay in a cold chain during transport and storage until it reaches the hospital or clinic. For storage after dilution, see Shelf Life.

The conditions on this page apply to the 38 mg/mL concentrate in single clear glass vials with a chlorobutyl stopper and a metal cap with a plastic disc (one vial per pack). Other presentations of gemcitabine, such as lyophilised powder, are authorised in some countries and have their own storage conditions in their SmPCs.

• Unopened vial: 18 months. Do not use after the expiry date on the pack.
• After dilution in 0.9% sodium chloride solution (final concentrations of 0.1 and 26 mg/mL), chemical and physical in-use stability was shown for 84 days at 2–8 °C protected from light in non-PVC (polyolefin) infusion bags; 24 hours at 2–8 °C protected from light in PVC bags; and 24 hours at 25 °C under normal light in PVC bags. The SmPC also gives data for 5% glucose solution and other conditions.

Prescription only (Rx), on the prescription of a specialist experienced in anti-cancer therapy; the SmPC states that gemcitabine must be prescribed only by such a specialist. It is infused in a hospital or oncology clinic (it can be given on an outpatient basis), so it is supplied to the hospital or clinic that administers it, as refrigerated vials in cold-chain delivery at 2–8 °C.