Gemcitabine

Registered South African indications:

• Locally advanced non-small cell lung cancer
• Metastatic non-small cell lung cancer
• Locally advanced (non-resectable Stage II or Stage III) adenocarcinoma of the pancreas
• Metastatic (Stage IV) adenocarcinoma of the pancreas
• Adenocarcinoma of the pancreas and previously treated with 5-FU
• Transitional cell bladder carcinoma
• Unresectable, locally recurrent or metastatic breast carcinoma, with relapse following adjuvant/neoadjuvant chemotherapy
• Recurrent epithelial ovarian carcinoma, with relapse following platinum-based chemotherapy

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Breastfeeding

Cautions

• Pregnancy
• Renal impairment
• Hepatic impairment
• Male patients of reproductive potential
• Prolongation of the infusion time
• Increased dosing frequency
• Concurrent liver metastases
• Pre-existing medical history of hepatitis
• Alcoholism
• Cirrhosis of the liver
• Concomitant radiotherapy
• History of cardiovascular events
• Sodium controlled diet
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Used for the treatment of

• Unresectable, locally recurrent or metastatic breast carcinoma, with relapse following adjuvant/neoadjuvant chemotherapy

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Gemcitabine is given in combination with paclitaxel. Prior chemotherapy should have included an anthracycline, unless clinically contraindicated

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• Recurrent epithelial ovarian carcinoma, with relapse following platinum-based chemotherapy

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Gemcitabine should be given alone or in combination

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• Locally advanced non-small cell lung cancer
• Metastatic non-small cell lung cancer
• Locally advanced (non-resectable Stage II or Stage lll) adenocarcinoma of the pancreas
• Metastatic (Stage IV) adenocarcinoma of the pancreas as first-line treatment
• Adenocarcinoma of the pancreas and previously treated with 5-FU
• Transitional cell bladder carcinoma

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Consult specialist for dosages and regimens

Not established for use in children

Pregnancy

• Caution; positive evidence of risk
• There are no adequate data from the use of gemcitabine in pregnant women. Studies in animals have shown reproductive toxicity. Based on results from animal studies and the mechanism of action of gemcitabine, this medicine should not be used during pregnancy unless clearly necessary. Women should be advised not to become pregnant during treatment with gemcitabine and to warn their attending doctor immediately, should this occur after all

Breastfeeding

• Contraindicated
• It is not known whether gemcitabine is excreted in human milk and adverse effects on the suckling child cannot be excluded. Breastfeeding must be discontinued during gemcitabine therapy

Fertility

• In fertility studies, gemcitabine caused hypospermatogenesis in male mice. Therefore, men being treated with gemcitabine are advised not to father a child during and up to 6 months after treatment and to seek further advice regarding cryoconservation of sperm prior to treatment because of the possibility of infertility due to therapy with gemcitabine

Renal Impairment

• Caution; no dose adjustment recommended
  For ESRD on haemodialysis; Start haemodialysis 6-12 hrs after gemcitabine infusion

Hepatic Impairment

• Caution; no dose adjustment recommended
  Stop gemcitabine treatment if hepatotoxicity occurs

Specific recommendations

• Elevated transaminases with normal bilirubin: No dose adjustment recommended
• Serum bilirubin >1.6mg/dL: Caution; dose adjustment recommended

Elderly

• No dose adjustment recommended

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Insomnia
• Somnolence
• Cerebrovascular accidents
• Asthenia
• Irritation
• Paraesthesia
• Posterior reversible encephalopathy syndrome
  - acute hypertension
  - seizure
  - headache
  - lethargy
  - confusion
  - blindness

Cardiovascular Disorders

• Arrhythmias, predominantly supraventricular in nature
• Heart failures
• Myocardial infarction
• Peripheral vasculitis
• Gangrene
• Hypotension
• Capillary leak syndrome
  - generalised oedema
  - weight gain
  - hypoalbuminaemia
  - severe hypotension
  - acute renal impairment
  - pulmonary oedema
• Peripheral oedema
• Hypertension

Respiratory Disorders

• Dyspnoea
• Cough
• Rhinitis
• Interstitial pneumonitis
• Bronchospasm
• Pulmonary oedema
• Lung toxicity, parenchymal or interstitial pneumonitis (with associated pulmonary infiltrates)
• Adult respiratory distress syndrome (ARDS)

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Stomatitis
• Ulceration of the mouth
• Constipation
• Ischaemic colitis

Hepatobiliary Disorders

• Increased hepatic transaminases (AST/ALT)
• Increased alkaline phosphatase
• Increased bilirubin
• Serious hepatotoxicity, including hepatic failure and death
• Increased gamma-glutamyl transferase (GGT)

Genitourinary Disorders

• Haematuria
• Mild proteinuria
• Renal failure
• Haemolytic uraemic syndrome (HUS)
  - microangiopathic haemolytic anaemia
  - thrombocytopaenia
  - elevation of serum bilirubin
  - serum creatinine
  - blood urea nitrogen, or LDH

Endocrine and Metabolic Disorders

• Anorexia
• Chills

Musculoskeletal Disorders

• Myalgia
• Back pain

Skin and Subcutaneous Tissue Disorders

• Allergic skin rash, frequently associated with pruritus
• Alopecia
• Itching
• Sweating
• Severe skin reactions
• Desquamation
• Bullous skin eruptions
• Ulceration
• Vesicle and sore formation
• Scaling
• Pseudocellulitis
• Stevens-Johnson syndrome
• Lyell's Syndrome

Immune, Blood and Lymphatic System Disorders

• Leucopenia
• Thrombocytopaenia
• Anaemia
• Bone marrow suppression
• Febrile neutropenia
• Thrombocytosis
• Thrombotic microangiopathy
• Anaphylactoid reaction
• Infections
• Sepsis
• Neutropenia
• Myelosuppression
• Haemorrhage
• Fever

Others

• Influenza-like symptoms
  - fever
  - headache
  - chills
  - myalgia
  - asthenia
  - anorexia
  - cough
  - rhinitis
  - malaise
  - perspiration
  - sleeping difficulties
• Injection site reactions
• Radiation toxicity
• Radiation recall

• Live vaccines
• Radiotherapy
• Blood dyscrasia-causing medicines
• Immunosuppressants
• Azathioprine
• Chlorambucil
• Corticosteroids
• Cyclophosphamide
• Ciclosporin
• Mercaptopurine
• Tacrolimus

• Full blood count
• Renal function
• Hepatic function

None routine. Specific cases may require

• Serum electrolytes (when in combination therapy with cisplatin)
• Pregnancy test

Recommendations for safe handling:

Follow these handling precautions for cytostatic agents:

• The agent should be reconstituted in a designated area by trained staff only
• Since gemcitabine is an antineoplastic agent, caution should be exercised when handling and preparing gemcitabine solutions
• Cover the work surface with disposable plastic-backed absorbent paper. Adequate protective gloves and apparel should be worn
• If gemcitabine powder or infusion solution should come into contact with the skin, wash immediately and thoroughly with soap and water. If gemcitabine concentrate or infusion solution should come into contact with the eyes or mucous membranes wash immediately and thoroughly with water
• Pregnant personnel must not handle the cytotoxic preparation
• Ensure that adequate care and precautions are taken in the disposal of items used to reconstitute gemcitabine

General:

• Patients should be closely monitored when receiving therapy with gemcitabine
• To monitor patient status laboratory facilities should be available for the evaluation of kidney and liver function
• Treatment may be required for a patient compromised by medicine toxicity

Laboratory tests:

• In patients with compromised bone marrow function therapy should be started cautiously
• Consider the possibility of cumulative bone marrow suppression when using a combination or sequential chemotherapy
• Even after gemcitabine has been stopped, peripheral blood counts may continue to fall

Renal toxicity:

• There have been reports of haemolytic uraemic syndrome (HUS) and renal failure
• Caution is required when gemcitabine is administered to patients with impaired renal function
• Discontinue gemcitabine at the first signs of microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concurrent thrombocytopenia, the elevation of serum bilirubin, serum creatinine, blood urea, or LDH
• Renal failure may be irreversible even with cessation of therapy and dialysis may be required

Pulmonary toxicity:

• Interstitial pneumonitis together with pulmonary infiltrates have been reported
• In such cases, treatment with gemcitabine must be discontinued. Steroids may alleviate symptoms in such situations
• There have been reports of severe rarely fatal pulmonary effects, such as pulmonary oedema, interstitial pneumonitis and ARDS. In such cases, it is necessary to discontinue gemcitabine treatment
• Initiating supportive therapy at an early stage may improve the situation

Patients with renal or hepatic Impairment:

• Caution is required when gemcitabine is given to patients with impaired renal function or hepatic insufficiency
• Mild to moderate renal insufficiency (GFR from 30 mt/min to 80 ml /min) has no consistent, significant effect on the pharmacokinetic properties of gemcitabine

Gemcitabine (dFdC), which is a pyrimidine antimetabolite, is metabolised intracellularly by nucleoside kinase to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is due to inhibition of DNA synthesis by two mechanisms of action by dFdCDP and dFdCTP. First, dFdCDP inhibits ribonucleotide reductase, which is uniquely responsible for catalysing the reactions that produce deoxynucleoside triphosphates (dCTP) for DNA synthesis. Inhibition of this enzyme by dFdCDP reduces the concentration of deoxynucleosides in general and, in particular, dCTP. Second, dFdCTP competes with dCTP for incorporation into DNA (self-potentiation).

Likewise, a small amount of gemcitabine may also be incorporated into RNA. Thus, the reduced intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA. DNA polymerase epsilon lacks the ability to eliminate gemcitabine and to repair the growing DNA strands. After gemcitabine is incorporated into DNA, one additional nucleotide is added to the growing DNA strands. After this addition there is essentially a complete inhibition in further DNA synthesis (masked chain termination). After incorporation into DNA, gemcitabine appears to induce the programmed cell death process known as apoptosis.

Injection (per vial) 200mg

• Gemtaz (Ranbaxy)
• Gemzar (Eli Lilly)
• Mylan gemcitabine (Xixia)
• Oncogem (Cipla)

Injection (per 5ml) 200mg

• Gemcitabine Sandoz 200mg/5ml (Sandoz SA)

Injection (per 10ml) 200mg

• Accord gemcitabine (Accord)
• Cerbigem (Hetero drug South Africa)
• Cytigem (Eurolab)
• Gemcitabine 200mg RTU Fresenius (Fresenius Kabi SA)
• Rogem 200 (Zydus Healthcare SA)

Injection (per vial) 1000mg

• Gemtaz (Ranbaxy)
• Gemzar (Eli Lilly)
• Mylan gemcitabine (Xixia)
• Oncogem (Cipla)

Injection (per 25ml) 1000mg

• Gemcitabine 1g RTU Fresenius (Fresenius Kabi SA)
• Gemcitabine Sandoz 1000mg/25ml (Sandoz SA)

Injection (per 50ml) 1000mg

• Accord gemcitabine (Accord)
• Cerbigem (Hetero drug South Africa)
• Cytigem (Eurolab)
• Rogem 1 (Zydus Healthcare SA)