Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use
For breast and non-small cell lung cancers, premedication consisting of an oral corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to docetaxel administration, unless contraindicated, can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions. For prostate cancer, the premedication is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.2).

Haematology

Neutropenia is the most frequent adverse reaction of docetaxel. Neutrophil nadirs occurred at a median of 7 days but this interval may be shorter in heavily pre-treated patients. Frequent monitoring of complete blood counts should be conducted on all patients receiving docetaxel. Patients should be retreated with docetaxel when neutrophils recover to a level of ≥ 1500 cells/mm3 (see section 4.2).

In the case of severe neutropenia (< 500 cells/mm3 for 7 days or more) during a course of docetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate symptomatic measures are recommended (see section 4.2).

In patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (TCF), febrile neutropenia and neutropenic infection occurred at lower rates when patients received prophylactic G-CSF. Patients treated with TCF should receive prophylactic G-CSF to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TCF should be closely monitored (see sections 4.2 and 4.8).

In patients treated with docetaxel in combination with doxorubicin and cyclophosphamide (TAC), febrile neutropenia and/or neutropenic infection occurred at lower rates when patients received primary G-CSF prophylaxis. Primary G-CSF prophylaxis should be considered in patients who receive adjuvant therapy with TAC for breast cancer to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TAC should be closely monitored (see sections 4.2 and 4.8).


Gastrointestinal reactions

Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. Although majority of cases occurred during the first or second cycle of docetaxel containing regimen, enterocolitis could develop at any time, and could lead to death as early as on the first day of onset. Patients should be closely monitored for early manifestations of serious gastrointestinal toxicity (see sections 4.2, 4.4 Haematology, and 4.8).

Hypersensitivity reactions

Patients should be observed closely for hypersensitivity reactions especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of docetaxel, thus facilities for the treatment of hypotension and bronchospasm should be available. If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not require interruption of therapy. However, severe reactions, such as severe hypotension, bronchospasm or generalised rash/erythema require immediate discontinuation of docetaxel and appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with docetaxel. Patients who have previously experienced a hypersensitivity reaction to paclitaxel may be at risk to develop hypersensitivity reaction to docetaxel, including more severe hypersensitivity reaction. These patients should be closely monitored during initiation of docetaxel therapy.

Cutaneous reactions

Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedema followed by desquamation has been observed. Severe symptoms such as eruptions followed by desquamation which lead to interruption or discontinuation of docetaxel treatment were reported (see section 4.2).

Severe Cutaneous Adverse Reactions (SCARs) such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP) have been reported with docetaxel treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and closely monitored. If signs and symptoms suggestive of these reactions appear discontinuation of docetaxel should be considered.

Fluid retention

Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be monitored closely.

Respiratory disorders

Acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure have been reported and may be associated with fatal outcome. Cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.

If new or worsening pulmonary symptoms develop, patients should be closely monitored, promptly investigated, and appropriately treated. Interruption of docetaxel therapy is recommended until diagnosis is available. Early use of supportive care measures may help improve the condition. The benefit of resuming docetaxel treatment must be carefully evaluated.

Patients with liver impairment

In patients treated with docetaxel at 100 mg/m2 as single agent who have serum transaminase levels (ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as  toxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel in those patients with elevated liver function test (LFTs) is 75 mg/m2 and LFTs should be measured at baseline and before each cycle (see section 4.2).

For patients with serum bilirubin levels > ULN and/or ALT and AST > 3.5 times the ULN concurrent with serum alkaline phosphatase levels > 6 times the ULN, no dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.

In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma, the pivotal clinical study excluded patients with ALT and/or AST > 1.5 times ULN associated with alkaline phosphatase > 2.5 times ULN and bilirubin > 1 times ULN; for these patients, no dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by docetaxel in combination in the other indications.

Patients with renal impairment

There are no data available in patients with severely impaired renal function treated with docetaxel.
This medicinal product contains Macrogol 300 which may increase the risk of nephrotoxicity in patients with renal impairment.

Nervous system

The development of severe peripheral neurotoxicity requires a reduction of dose (see section 4.2).
Cardiac toxicity

Heart failure has been observed in patients receiving docetaxel in combination with trastuzumab, particularly following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. This may be moderate to severe and has been associated with death (see section 4.8).

When patients are candidates for treatment with docetaxel in combination with trastuzumab, they should undergo baseline cardiac assessment. Cardiac function should be further monitored during treatment (e.g. every three months) to help identify patients who may develop cardiac dysfunction. For more details see summary of product characteristics of trastuzumab.

Ventricular arrhythmia including ventricular tachycardia (sometimes fatal) has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide (see section 4.8).

Baseline cardiac assessment is recommended.

Eye disorders
Cystoid macular oedema (CMO) has been reported in patients treated with docetaxel. Patients with impaired vision should undergo a prompt and complete ophthalmologic examination. In case CMO is diagnosed, docetaxel treatment should be discontinued and appropriate treatment initiated (see section 4.8).

Second primary malignancies

Second primary malignancies have been reported when docetaxel was given in combination with anticancer treatments known to be associated with second primary malignancies. Second primary malignancies (including acute myeloid leukaemia, myelodysplastic syndrome and non-Hodgkin lymphoma) may occur several months or years after docetaxel-containing therapy. Patients should be monitored for second primary malignancies (see section 4.8).


Tumour lysis syndrome

Tumour lysis syndrome has been reported with docetaxel after the first or the second cycle (see section 4.8). Patients at risk of tumour lysis syndrome (e.g. with renal impairment, hyperuricemia, bulky tumour, rapid progression) should be closely monitored. Correction of dehydration and treatment of high uric acid levels are recommended prior to initiation of treatment.

Others

Women of childbearing potential must use contraceptive measures during treatment and for 2 months after cessation of treatment with docetaxel. Men must use contraceptive measures during treatment and for 4 months after cessation of treatment with docetaxel (see section 4.6).

The concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) should be avoided (see section 4.5).

Additional cautions for use in adjuvant treatment of breast cancer

Complicated neutropenia
For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia or infection), G-CSF and dose reduction should be considered (see section 4.2).

Gastrointestinal reactions

Symptoms such as early abdominal pain and tenderness, fever, diarrhoea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly.

Congestive heart failure (CHF)

Patients should be monitored for symptoms of congestive heart failure during therapy and during the follow-up period. In patients treated with the TAC regimen for node positive breast cancer, the risk of CHF has been shown to be higher during the first year after treatment (see sections 4.8 and 5.1).

Patients with 4+ nodes

As the benefit observed in patient with 4+ nodes was not statistically significant on disease-free survival (DFS) and overall survival (OS), the positive benefit/risk ratio for TAC in patients with 4+ nodes was not fully demonstrated at the final analysis (see section 5.1).

Elderly

Cautions for use in adjuvant treatment of breast cancer
There are limited data available in patients > 70 years of age on docetaxel use in combination with doxorubicin and cyclophosphamide.

The proportion of older people was 5.5% and 6.6% in the AC-TH and TCH regimens, respectively, and is too limited to allow for conclusions regarding the adverse events occurring by age (<65 years vs.
≥65 years).

Cautions for use in prostate cancer


Of the 333 patients treated with docetaxel every three weeks in a prostate cancer study (TAX 327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with docetaxel every three weeks, the incidence of related nail changes occurred at a rate ≥ 10% higher in patients who were 65 years of age or greater compared to younger patients. The incidence of related fever, diarrhoea, anorexia and peripheral oedema occurred at rates ≥ 10% higher in patients who were 75 years of age or greater versus less than 65 years.

Cautions for use in gastric adenocarcinoma cancer

Among the 300 (221 patients in the phase III part of the study and 79 patients in the phase II part) patients treated with docetaxel in combination with cisplatin and 5-fluorouracil in the gastric cancer study, 74 were 65 years of age or older and 4 patients were 75 years of age or older. The incidence of serious adverse events was higher in older people compared to younger patients. The incidence of the following adverse events (all grades): lethargy, stomatitis, neutropenic infection occurred at rates ≥ 10% higher in patients who were 65 years of age or older compared to younger patients.

Older people treated with TCF should be closely monitored.
Excipient information

Ethanol content
20mg/2 mL vial
Each 2 mL vial of concentrate contains 364 mg anhydrous ethanol (see section 2), which is equivalent to less than 10 mL beer or 4 mL wine.

80 mg/8 mL vial
Each 8 mL vial of concentrate contains 1455 mg anhydrous ethanol (see section 2), which is equivalent to less than 37 mL beer or 15 mL wine.

160 mg/16 mL vial
Each 16 mL vial of concentrate contains 2911 mg anhydrous ethanol (see section 2), which is equivalent to less than 73 mL beer or 30 mL wine.

An example of ethanol exposure based on maximum single daily dose (see section 4.2) is as follows: • Administration of 18 mL of this medicinal product to an adult weighing 70 kg would result in exposure to 46.8 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of 7.8 mg/100 mL.

For comparison, for an adult drinking a glass of wine or 500 mL of beer, the BAC is likely to be about 50 mg/100 mL.

Co-administration with medicines containing e.g. propylene glycol or ethanol may lead to accumulation of ethanol and induce adverse effects, particularly in young children with low or immature metabolic capacity.

The amount of ethanol in this medicine is not likely to have an effect in adults and adolescents, and its effects in children are not likely to be noticeable. It may have some effects, such as somnolence, in neonates and young children.

The ethanol content in this medicinal product should be carefully considered in the following patient groups who may be at higher risk of ethanol-related adverse effects:
• Pregnant or breast-feeding women
• Patients with liver disease
• Patients with epilepsy
• Patients suffering from alcoholism.

Consideration should be given to possible effects on the central nervous system.



Effects on Driving

4.7         Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. The side effects of the product may impair the ability to drive or use machines (see sections 4.4 and 4.8).
Therefore, patients should be warned of the potential impact of the side effects of this medicinal product on the ability to drive or use machines, and be advised not to drive or use machines if they experience these side effects during treatment.