Posology : מינונים

4.2   Posology and method of administration
Gemcitabine should only be prescribed by a physician qualified in the use of anti-cancer chemotherapy.

Recommended posology:

Non-Small Cell Lung Cancer:
Monotherapy: Adults: The recommended dose of gemcitabine is 1,000 mg/m2, given by 30- minute intravenous infusion. This should be repeated once weekly for three weeks, followed by a one week rest period. This four week cycle is then repeated. Dosage reduction is applied based upon the grade of toxicity experienced by the patient.

Combination use: Adults: Gemcitabine in combination with cisplatin: The recommended dose for gemcitabine is 1,250 mg/m2 body surface area given as a 30-minute intravenous infusion on Days 1 and 8 of the treatment cycle (21 days). Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.

Cisplatin has been used at doses between 75-100 mg/m2 once every 3 weeks.

Breast cancer: Combination use: Adults: Gemcitabine in combination with paclitaxel is recommended using paclitaxel (175 mg/m2) administered on Day 1 over approximately 3 hours as an intravenous infusion, followed by gemcitabine (1250 mg/m2) as a 30-minute intravenous infusion on Days 1 and 8 of each 21-day cycle. 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 (x106/L) prior to initiation of gemcitabine + paclitaxel combination.

Pancreatic Cancer:
Monotherapy :Adults: The recommended dose of gemcitabine is 1,000 mg/m2, given by 30- minute intravenous infusion. This should be repeated once weekly for up to 7 weeks, followed by a week of rest. Subsequent cycles should consist of injections once weekly for 3 consecutive weeks out of every 4 weeks. Dosage reduction is applied based upon the grade of toxicity experienced by the patient.

Bladder Cancer:
Combination use: Adults: The recommended dose for gemcitabine is 1000 mg/ m2, given by 30- minute infusion. The dose should be given on days 1, 8, and 15 of each 28 day cycle in combination with cisplatin. Cisplatin is given at a recommended dose of 70 mg/m2 on day 1 following gemcitabine or day 2 of each 28 day cycle. This four week cycle is then repeated.
Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.

Ovarian cancer.
Combination use: Adults: Gemcitabine in combination with carboplatin is recommended using gemcitabine 1000 mg/m2 administered on Days 1 and 8 of each 21-day cycle as a 30-minute intravenous infusion. After gemcitabine, carboplatin will be given on Day 1 consistent with a target Area under curve (AUC) of 4.0 mg/ml•min. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient.


Monitoring for toxicity and dose modification due to toxicity

Dose modification due to non- haematological toxicity
Periodic physical examination and checks of renal and hepatic function should be made to detect non-haematological toxicity. Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient. In general, for severe (Grade 3 or 4) non-haematological toxicity, except nausea/vomiting, therapy with gemcitabine should be withheld or decreased depending on the judgement of the treating physician.
Doses should be withheld until toxicity has resolved in the opinion of the physician.

For cisplatin, carboplatin, and paclitaxel dosage adjustment in combination therapy, please refer to the corresponding Summary of Product Characteristics.

Dose modification due to haematological toxicity

Initiation of a cycle
For all indications, the patient must be monitored before each dose for platelet and granulocyte counts. Patients should have an absolute granulocyte count of at least 1,500 (x 106/I) and platelet account of 100,000 (x 106/I) prior to the initiation of a cycle.

Within a cycle
Dose modifications of gemcitabine within a cycle should be performed according to the following tables:

Dose modification of gemcitabine within a cycle for bladder cancer, NSCLC and pancreatic cancer, given in monotherapy or in combination with cisplatin Absolute granulocyte count          Platelet count             Percentage of (x 106/l)                   (x 106/l)           standard dose of gemcitabine (%)
> 1,000                     and               > 100,000                     100 500-1,000                   or          50,000-100,000                      75 < 500                       or                 < 50,000                 Omit dose* *Treatment omitted will not be re-instated within a cycle before the absolute granulocyte count reaches at least 500 (x106/I) and the platelet count reaches 50,000 (x106/I).


Dose modification of gemcitabine within a cycle for breast cancer, given in combination with paclitaxel
Absolute granulocyte count                   Platelet count          Percentage of standard 6                                  (x10 6/l)          dose of gemcitabine (x10 /l)
(%)
≥1,200                        and               >75,000                         100 1,000- <1,200                   or            50,000-75,000                        75 700- <1,000                     and                 ≥ 50,000                       50 <700                            or                <50,000                     Omit dose* *Treatment omitted will not be re-instated within a cycle. Treatment will start on day 1 of the next cycle once the absolute granulocyte count reaches at least 1,500 (x106/l) and the platelet count reaches 100,000 (x106/l).


Dose modification of gemcitabine within a cycle for ovarian cancer, given in combination with carboplatin
Absolute granulocyte count                Platelet count                Percentage of (x106/l)                            (x106/l)              standard dose of gemcitabine (%)
> 1,500                      and                 ≥100,000                        100 1000-1,500                   or            75,000-100,000                         50 <1000                        or                < 75,000                     Omit dose* *Treatment omitted will not be re-instated within a cycle. Treatment will start on day 1 of the next cycle once the absolute granulocyte count reaches at least 1,500 (x106/l) and the platelet count reaches 100,000 (x106/l).

Dose modifications due to haematological toxicity in subsequent cycles, for all indications The gemcitabine dose should be reduced to 75% of the original cycle initiation dose, in the case of the following haematological toxicities:

•     Absolute granulocyte count < 500 x106/l for more than 5 days
•     Absolute granulocyte count < 100 x106/l for more than 3 days
•     Febrile neutropenia
•     Platelets < 25,000 x106/l
•     Cycle delay of more than 1 week due to toxicity 
Method of administration

Gemcitabine is tolerated well during infusion and may be administered ambulant. If extravasation occurs, generally the infusion must be stopped immediately and started again in another blood vessel. The patient should be monitored carefully after the administration.

Gemcitabine “Ebewe” 40 mg/ml concentrate for solution for infusion must be diluted before use (see section 4.4 and 6.6). It is recommended to use large veins for infusion to prevent damage to the vessel and extravasation.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Special populations
Patients with renal or hepatic impairment
Gemcitabine should be used with caution in patients with hepatic or renal impairment as there is insufficient information from clinical studies to allow for clear dose recommendations for these patient populations (see sections 4.4 and 5.2).

Elderly (> 65 years)
Gemcitabine has been well tolerated in patients over the age of 65. There is no evidence to suggest that dose adjustments, other than those already recommended for all patients, are necessary in the elderly (see section 5.2).


Paediatric population (<18 years)
Gemcitabine is not recommended for use in children under 18 years of age due to insufficient data on safety and efficacy.