Docetere 20 mg/1 mL/80 mg/4 mL Solution

DOCETERE RTU is indicated for the following:

• 1. Breast cancer DOCETERE RTU, in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer. DOCETERE RTU, in combination with doxorubicin, is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition. DOCETERE RTU monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer, after failure of cytotoxic therapy. DOCETERE RTU, in combination with capecitabine, is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.
• 2. Non-small cell lung cancer (NSCLC) DOCETERE RTU, in combination with cisplatin, is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer, who have not previously received chemotherapy for this condition. DOCETERE RTU is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer, even after failure of platinum-based chemotherapy.
• 3. Ovarian cancer DOCETERE RTU is indicated, after failure of first-line or subsequent chemotherapy, for treatment of metastatic carcinoma of the ovary.
• 4. Prostate cancer DOCETERE RTU in combination with prednisone or prednisolone is indicated for the treatment of patients with androgen-independent (hormone refractory) metastatic prostate cancer.
• 5. Head and neck cancer DOCETERE RTU in combination with cisplatin and 5-fluorouracil is indicated for the induction treatment of patients with inoperable locally advanced squamous cell carcinoma of the head and neck.
• 6. Gastric adenocarcinoma DOCETERE RTU in combination with cisplatin and 5-fluorouracil is indicated for the palliative treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastro-oesophageal junction, who have not received prior chemotherapy for advanced disease.

DOCETERE RTU should be administered by intravenous infusion only. Patients should be observed closely, especially during the first and second infusion of DOCETERE RTU, because of the risk of hypersensitivity reactions.

Posology

A premedication consisting of a corticosteroid (see below for prostate cancer), such as oral dexamethasone 16 mg per day (e.g. 8 mg twice daily) for 3 days, starting one day prior to DOCETERE RTU administration, unless contraindicated, can be used. For prostate cancer, given the concurrent use of prednisone or prednisolone, the recommended premedication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the DOCETERE RTU infusion. Prophylactic G-CSF may be used to mitigate the risk of haematological toxicities. DOCETERE RTU is administered as a one-hour infusion every three weeks.

• 1. Breast cancer In the adjuvant treatment of operable node-positive breast cancer, the recommended DOCETERE RTU dose is 75 mg/m2 administered one hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 cycles (see also Dosage adjustments during treatment). In first-line treatment, DOCETERE RTU 75 mg/m2 is administered in combination therapy with doxorubicin (50 mg/m2). For the second-line treatment of breast cancer the recommended dosage of DOCETERE RTU therapy is 100 mg/m2 in monotherapy. In combination with capecitabine, the recommended dose of DOCETERE RTU is 75 mg/m2 every three weeks, combined with capecitabine at 1 250 mg/m2 orally twice daily (within 30 minutes after a meal) for 2 weeks followed by a 1-week rest period. For capecitabine dose calculation according to body surface area, see capecitabine manufacturersu2019 prescribing information.
• 2. Non-small cell lung cancer In combination therapy (chemotherapy nau00efve patients) The recommended dosage regimen is DOCETERE RTU 75 mg/m2 immediately followed by cisplatin 75 mg/m2 over 30 u2013 60 minutes. In monotherapy (for previously treated patients) The recommended dosage of DOCETERE RTU therapy is 100 mg/m2 as a single agent.
• 3. Ovarian cancer The recommended dosage of DOCETERE RTU therapy is 100 mg/m2.
• 4. Prostate cancer The recommended dose of DOCETERE RTU is 75 mg/m2. Prednisone or prednisolone 5 mg orally twice daily is administered continuously.
• 5. Head and neck cancer For the induction treatment of locally advanced inoperable squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of DOCETERE RTU is 75 mg/m2 as a 1-hour infusion followed by cisplatin 75 mg/m2 over 1 hour, on day one, followed by 5-fluorouracil as a continuous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy. Patients must receive premedication with anti-emetics and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. For cisplatin and 5-fluorouracil dose modifications, see local professional information leaflet.
• 6. Gastric adenocarcinoma For gastric adenocarcinoma, the recommended dose of DOCETERE RTU is 75 mg/m2 as a 1-hour infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour infusion (both on day 1 only), followed by 5-fluorouracil 750 mg/m2 per day given as a 24-hour continuous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with anti-emetics and appropriate hydration for cisplatin administration. Prophylactic G-CSF should be used to mitigate the risk of haematological toxicities (see Dosage adjustments during treatment).

Dosage adjustments during treatment

ONLY the doctor can modify the schedule of administration. DOCETERE RTU should be administered when the neutrophil count is u2265 1 500 cells/mm3. Patients who experienced either febrile neutropenia, neutrophil count < 500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or severe neurosensory signs and/or symptoms during DOCETERE RTU therapy, should have the dosage of DOCETERE RTU reduced, during the subsequent cycle, from 100 mg/m2 to 75 mg/m2 and/or from 75 mg/m2 to 60 mg/m2. If the patient continues to experience these reactions at 60 mg/m2, the treatment should be discontinued.

DOCETERE RTU is contraindicated in patients who have a history of severe hypersensitivity reactions to docetaxel, polysorbate 80 or any of the ingredients listed in section 6.1. DOCETERE RTU should not be used in patients with baseline neutrophil count of < 1 500 cells/mm3. Pregnancy and lactation, as DOCETERE RTU is teratogenic in animals (see section 4.6). The safe use of DOCETERE RTU in children has not been established. DOCETERE RTU should not be used in patients with severe liver impairment since there is no data available (see section 4.4 and section 4.2). Contraindications for other medicines also apply when combined with DOCETERE RTU.

DOCETERE RTU (docetaxel) concentrate for solution for infusion should be administered under the supervision of a qualified doctor experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. The incidence of treatment-related mortality associated with DOCETERE RTU therapy is increased in patients with abnormal liver function and in patients receiving higher doses. DOCETERE RTU should generally not be given to patients with serum bilirubin levels > upper limit of normal (ULN), or to patients with AST and/or ALT > 1,5 x ULN concomitant with alkaline phosphatase levels > 2,5 x ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity and toxic death. Bilirubin, AST or ALT and alkaline phosphatase values should be obtained prior to each cycle of DOCETERE RTU therapy and reviewed by the treating doctor. DOCETERE RTU therapy should not be given to patients with neutrophil counts of < 1 500 cells/mm3. In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood cell counts should be performed on all patients receiving DOCETERE RTU. Severe hypersensitivity reactions characterised by hypotension and/or bronchospasm, or generalised rash/erythema occurred in 2,2 % (2/92) of patients who received the recommended 3-day dexamethasone premedication. Hypersensitivity reactions requiring discontinuation of the DOCETERE RTU infusion were reported in five patients who did not receive premedication. These reactions resolved after discontinuation of the infusion and the administration of appropriate therapy. DOCETERE RTU must not be given to patients who have a history of severe hypersensitivity reactions to DOCETERE RTU or to other medicines formulated with polysorbate 80. Severe fluid retention occurred in 6,5 % (6/92) of patients despite the use of a recommended dexamethasone premedication regimen. It was characterised by one or more of the following events: poorly tolerated peripheral oedema, generalised oedema, pleural effusion requiring urgent drainage, dyspnoea at rest, cardiac tamponade or pronounced abdominal distension (due to ascites). The use of DOCETERE RTU should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a qualified oncologist. Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available. During the infusion, it is recommended that vital functions should be closely monitored.

Premedication with a corticosteroid

Premedication consisting of an oral corticosteroid (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g. 8 mg twice daily) for 3 days, starting one day prior to DOCETERE RTU administration, unless contraindicated, may reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions. The pre-treatment regimen for prostate cancer is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the DOCETERE RTU regimen.

Neutropenia

Neutropenia is the most frequent adverse reaction of DOCETERE RTU and occurs in almost all patients. Severe neutropenia (grade 3 u2013 4) occurred in 99 % of patients on combination therapy with doxorubicin. 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 DOCETERE RTU. Patients should be re-treated with DOCETERE RTU only after neutrophils recover to a level u2265 1 500 cells/mm3 (see section 4.2). In the case of severe neutropenia (< 500 cells/mm3 for seven days or more) during a course of DOCETERE RTU therapy, a reduction in dose for subsequent courses of therapy and the use of appropriate symptomatic measures are recommended.

In patients treated with DOCETERE RTU in combination with cisplatin and 5-fluorouracil (TCF), febrile neutropenia and/or 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.

Gastrointestinal reactions

Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. 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 Neutropenia, above and section 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 DOCETERE RTU, 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, more severe reactions, such as hypotension with a reduction of more than 20 mm Hg, bronchospasm or generalised rash/erythema require immediate discontinuation of the infusion and appropriate symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with DOCETERE RTU. Patients who have previously experienced a hypersensitivity reaction to paclitaxel may develop a potentially fatal hypersensitivity reaction to DOCETERE RTU.

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. This type of toxicity can lead to the interruption or discontinuation of treatment. Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalised exanthematous pustulosis (AGEP) have been reported in association with DOCETERE RTU treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and monitored closely. In case SCARs are observed, treatment discontinuation should be considered.

Fluid retention

Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be monitored closely. See Premedication with a corticosteroid, above.

Patients with liver impairment

In patients treated with DOCETERE RTU at 100 mg/m2 who have serum transaminase levels (ALT and/or AST) greater than 1,5 times the upper limit of the normal range (ULN) concurrent with serum alkaline phosphatase levels greater than 2,5 times the upper limit of the normal range (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 DOCETERE RTU in patients with elevated liver function tests (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 DOCETERE RTU should not be used unless strictly indicated. The amount of ethanol in DOCETERE RTU should be taken into account when given to patients with hepatic impairment (see Excipients, below).

Nervous system

The development of severe peripheral neurotoxicity including paraesthesia, dysaesthesia and pain has been observed in patients and requires a reduction of the dose. When symptoms persist, treatment should be stopped.

Cardiac toxicity

Ventricular dysrhythmia including ventricular tachycardia (sometimes fatal) has been reported in patients treated with DOCETERE RTU 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, DOCETERE RTU treatment should be discontinued and appropriate treatment initiated (see section 4.8, Post-marketing experiences).

Second primary malignancies

Second primary malignancies have been reported when DOCETERE RTU was given in combination with anticancer treatments known to be associated with second primary malignancies. Second primary malignancies (including acute myeloid leukaemia, myelodysplastic syndrome, non-Hodgkin lymphoma and renal cancer) 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 DOCETERE RTU (see section 4.8 u2013 Post-marketing experiences). Patients at risk of tumour lysis syndrome (i.e. with renal impairment, hyperuricaemia, bulky tumour) should be closely monitored in order to properly manage this syndrome. Correction of dehydration and treatment of high uric acid levels are recommended prior to initiation of treatment.

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

Pregnancy and lactation are contraindicated as DOCETERE RTU is teratogenic in animals (see section 4.3).

No studies on the effects on the ability to drive and use machines have been performed. The amount of ethanol in DOCETERE RTU may impair the patientu2019s ability to drive or use machines (see section 4.4 - Excipients). Therefore, patients should be warned of the potential impact of the side effects of the 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.

Blood and lymphatic system disorders The most frequent adverse reaction to DOCETERE RTU was neutropenia (in patients who did not receive G-CSF), which was reversible and not cumulative. The median day to nadir was 7 days and the median duration of severe neutropenia (< 500 cells/mm3) was 7 days. Fever in absence of infection, in patients with non-small cell lung cancer, was reported in 17,2 % (1,2 % severe) of patients treated in combination with cisplatin.

Bleeding episodes have occurred and were infrequently associated with severe thrombocytopenia (< 50 000 cells/mm3). Bone marrow suppression and other haematological adverse reactions to DOCETERE RTU include:

% Patients with haematological events

Single agent Combination with doxorubicin Combination with cisplatin

Number of patients n = 1 312 n = 121 n = 258 n = 406

100 mg/m2 75 mg/m2 75 mg/m2 75 mg/m2

Neutropenia: All 96,6 89,8 99,2 91,1

Severe ** 74,8 Severe * 76,4 54,2 91,7 51,5

Febrile neutropenia: All 11,8 4,6 8,3 34,1 4,9

Thrombocytopenia: All 7,8 10 28,1 14,9

Severe ** 2,7 Severe * 0,2 1,7 0,8 0,5

Anaemia: All 90,4 93,3 96,1 88,6

Severe ** 8,9 10,8 9,4 6,9

Infections: All 20 10,7 35,3 14,3

Severe ** 5,7 5 7,8 5,7

* NCI grade 4 ** NCI grade 3 u2013 4

Immune system disorders Hypersensitivity reactions may occur, usually within a few minutes following the start of the infusion of DOCETERE RTU. The most frequently reported symptoms are flushing, rash with or without pruritus, chest tightness, back pain, dyspnoea and medicine fever or chills. Severe anaphylactic reactions characterised by hypotension and/or bronchospasm or generalised rash/erythema, requiring therapeutic intervention may occur. These may resolve after discontinuing the infusion and appropriate therapy.

% Patients with anaphylactic reactions

Single agent Combination with doxorubicin Combination with cisplatin

100 mg/m2 75 mg/m2 75 mg/m2 75 mg/m2

All 25,9 2,5 4,7 10,6

Severe * 5,3 0 1,2 2,5

* NCI grade 3 u2013 4

Nervous system disorders Neurosensory signs characterised by paraesthesia, dysaesthesia or pain including burning, may occur. Neuromotor events, mainly characterised by weakness, may occur. These events were spontaneously reversible within 3 months in 35,3 % of patients with neurotoxicity following DOCETERE RTU treatment at 100 mg/m2 as a single agent.

Cardiac disorders Hypertension has been reported.

% Patients with cardiovascular events

Single agent Combination with doxorubicin

100 mg/m2 75 mg/m2 75 mg/m2

Hypotension 3,8 1,7 0,4

Cardiac dysrhythmia: All 4,1 2,5 1,2

Severe * 0,7 0 0

Heart failure 0,5 0 2,3

* NCI grade 3 u2013 4

% Patients with neurological events

Single agent Combination with doxorubicin Combination with cisplatin

100 mg/m2 75 mg/m2 75 mg/m2 75 mg/m2

Neurosensory: All 50 24 30,2 40,4

Severe * 4,1 0,8 0,4 3,7

Neuromotor: All 13,8 9,9 2,3 12,8

Severe ** 4 2,5 0,4 2,0

* NCI grade 3 ** NCI grade 3 u2013 4

Vascular disorders Fluid retention: Events such as peripheral oedema and less frequently, pleural effusion, pericardial effusion, ascites, increased capillary permeability and weight gain have been reported. The peripheral oedema usually starts at the lower extremities and may become generalised with a weight gain of 3 kg or more after 4 cycles or a cumulative dose u2265 400 mg/m2. Fluid retention is cumulative in incidence and severity. The onset of moderate and severe retention is delayed in patients with premedication compared with patients without premedication, however, it has been reported in some patients during the early courses of therapy. The median time to fluid retention reversibility was 16,4 weeks (range 0 to 42 weeks) in patients receiving the recommended premedication. Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Fluid retention has been less frequently reported in patients receiving the recommended premedication compared with patients without premedication.

Gastrointestinal disorders Gastrointestinal effects such as nausea, vomiting, diarrhoea, abdominal pain and constipation may occur. Stomatitis, oesophagitis and taste perversion may occur.

% Patients with fluid retention

Single agent Combination with doxorubicin Combination with cisplatin

100 mg/m2 75 mg/m2 75 mg/m2 75 mg/m2

All 64,1 24,8 35,7 25,9

Severe 6,5 0,8 1,2 0,7

Gastrointestinal bleeding may occur. Anorexia may occur and may be severe.

Hepato-biliary disorders In patients treated at 100 mg/m2 as a single agent, increases in serum levels of AST, ALT, bilirubin and alkaline phosphatase greater than 2,5 times the ULN were observed. In patients treated at 75 mg/m2 as a single agent, no NCI grade 3 u2013 4 increases in serum levels of AST, ALT and alkaline phosphatase were observed and less than 2 % of the patients experienced grade 3 u2013 4 increase in bilirubin.

% Patients with gastrointestinal events

Single agent Combination with doxorubicin Combination with cisplatin

100 mg/m2 75 mg/m2 75 mg/m2 75 mg/m2

Nausea: All 40,5 28,9 64 69,0

Severe * 4 3,3 5 9,6

Vomiting: All 24,5 16,5 45 53,4

Severe* 3 0,8 5 7,6

Diarrhoea: All 40,6 11,6 45,7 41,1

Severe * 4 1,7 6,2 6,4

Anorexia 16,8 19,0 8,5 28,8

Constipation 9,8 6,6 14,3 9,4

Stomatitis: All Severe * 41,8 5,3 24,8 1,7 58,1 7,8 23,4 2,0

* NCI grade 3 u2013 4

In patients treated in combination with doxorubicin at 75 mg/m2, less than 1 % of patients experienced grade 3 u2013 4 increases in AST and ALT. Grade 3 u2013 4 increase in bilirubin and alkaline phosphatase were observed in less than 2,5 % of the patients.

% Patients with hepatic events

Single agent Combination with doxorubicin

100 mg/m2 75 mg/m2 75 mg/m2

AST increase: Severe * < 3,0 0 < 1,0

ALT increase: Severe * < 2,0 0 < 1,0

Bilirubin increase: Severe * < 5,0 < 2,0 < 2,5

Alkaline phosphatase increase: Severe * < 4,0 0 < 2,5

* NCI grade 3 u2013 4

Skin and subcutaneous tissue disorders Reversible cutaneous reactions may occur. The majority of these events were reversible within 21 days. The cutaneous reactions were characterised by a rash including localised eruptions mainly on the feet and hands (including severe hand-foot syndrome), but also on the arms, face or thorax and frequently associated with pruritus. Eruptions generally occurred within one week after the DOCETERE RTU infusion. Nail disorders may occur. These were characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis. Less frequently, severe symptoms such as eruptions followed by desquamation which may rarely lead to interruption or discontinuation of DOCETERE RTU treatment, may occur.

% Patients with cutaneous events

Single agent Combination with doxorubicin Combination with cisplatin

100 mg/m2 75 mg/m2 75 mg/m2 75 mg/m2

Cutaneous: All 56,6 15,7 13,6 11,1

Severe * 5,9 0,8 0 0,2

Nail changes: All 27,9 9,9 20,2 13,3

Severe 2,6 0,8 0,4 0,7

* NCI grade 3 u2013 4

Other Infusion site reactions may consist of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein. In patients treated with 100 mg/m2 as single agent, alopecia has been observed in 79 % of patients. Alopecia was considered severe in about 0,5 % of the patients. Asthenia has been observed in 62,6 % of patients. Asthenia was severe in 11,2 % of the patients. Arthralgias and myalgia may occur. Dyspnoea may occur and is frequently associated with acute hypersensitivity reactions, respiratory infections and cancerous lung involvement. Generalised or localised pain may occur, including chest pain without any cardiac or respiratory involvement.

% Patients with other events

Single agent Combination with doxorubicin Combination with cisplatin

100 mg/m2 75 mg/m2 75 mg/m2 75 mg/m2

Alopecia: All Severe* 79 0,5 38 94,6 73,6

Asthenia: All Severe 62,6 11,2 48,8 12,4 54,7 8,1 51,5 9,9

Myalgia: All 20 5,8 8,5 13,8 Severe 1,4 0 0 0,5

Infusion site reactions 5,6 0 3,1 6,2 Pain 16,5 10,7 17,1 5,4

* NCI grade 3 u2013 4

In case of overdose, the patient should be kept in a specialised unit and vital functions closely monitored. There is no known antidote for DOCETERE RTU overdosage. The primary anticipated complications of overdosage would consist of neutropenia, mucositis, cutaneous reactions and paraesthesia. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.