Key-Docetaxel 20 mg, 80 mg Concentrate for solution for infusion

1. Breast Cancer

• KEY-DOCETAXEL, in combination with doxorubicin and cyclophosphamide, is indicated for the adjuvant treatment of patients with operable node-positive breast cancer.
• KEY-DOCETAXEL, 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.
• KEY-DOCETAXEL monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer, after failure of cytotoxic therapy.
• KEY-DOCETAXEL, 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)

• KEY-DOCETAXEL, 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.
• KEY-DOCETAXEL 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

• KEY-DOCETAXEL is indicated, after failure of first-line or subsequent chemotherapy, for treatment of metastatic carcinoma of the ovary.

4. Prostate Cancer

• KEY-DOCETAXEL, 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

• KEY-DOCETAXEL, 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.

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 KEY-DOCETAXEL 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 KEY-DOCETAXEL infusion.
• Prophylactic G-CSF may be used to mitigate the risk of haematological toxicities.
• KEY-DOCETAXEL 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 KEY-DOCETAXEL 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 therapy).
• In first-line treatment, KEY-DOCETAXEL 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 KEY-DOCETAXEL therapy is 100 mg/m2 in monotherapy.
• In combination with capecitabine, the recommended dose of KEY-DOCETAXEL is 75 mg/m2 every three weeks, combined with capecitabine at 1250 mg/m2 orally twice daily (within 30 minutes after a meal) for 2 weeks followed by a 1-week rest period.

2. Non-Small Cell Lung Cancer

• In combination therapy (chemotherapy-nau00efve patients): The recommended dosage regimen is KEY-DOCETAXEL 75 mg/m2 immediately followed by cisplatin 75 mg/m2 over 30-60 minutes.
• In monotherapy (for previously treated patients): The recommended dosage of KEY-DOCETAXEL therapy is 100 mg/m2 as a single medicine.

3. Ovarian cancer

• The recommended dosage of KEY-DOCETAXEL therapy is 100 mg/m2.

4. Prostate cancer

• The recommended dose of KEY-DOCETAXEL is 75 mg/m2.
• Prednisone or prednisolone 5 mg orally twice daily is administered continuously. Patients should be observed closely, especially during the first and second infusion of KEY-DOCETAXEL, because of the risk of hypersensitivity reactions.

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 KEY-DOCETAXEL is 75 mg/m2 as a 1-hour intravenous infusion, followed by cisplatin 75 mg/m2 over 1 hour, on day one, followed by 5-fluorouracil at 750 mg/m2 per day for 5 days. This regimen is administered every 3 weeks for 4 cycles.
• Following chemotherapy, patients should receive radiotherapy.
• Patients must receive premedication with antiemetics 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 package insert.

Dosage adjustments during treatment

• General
• ONLY the medical practitioner can modify the schedule of administration.
• KEY-DOCETAXEL should be administered when the neutrophil count is > 1 500 cells/mm3.
• Patients who experienced 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 KEY-DOCETAXEL therapy, should have their dosage of KEY-DOCETAXEL reduced, during the subsequent cycle, from 100 to 75 mg/m2 and/or from 75 to 60 mg/m2.
• If the patient continues to experience these reactions at 60 mg/m2, treatment should be discontinued.
• Combination therapy with KEY-DOCETAXEL for NSCLC
• For patients who are dosed initially at docetaxel 75 mg/m2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is < 25 000 cells/mm3, or in patients who experience febrile neutropenia, or in patients with serious non-haematologic toxicities, the KEY-DOCETAXEL dosage in subsequent cycles should be reduced to 65 mg/m2.
• For cisplatin dosage adjustments, see cisplatin package insert.
• Combination therapy with KEY-DOCETAXEL for Breast Cancer
• Patients who receive adjuvant therapy for breast cancer and who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their KEY-DOCETAXEL dose reduced to 60 mg/m2. If G-CSF is not used, the KEY-DOCETAXEL dose should be reduced from 75 to 60 mg/m2.
• For capecitabine dose modifications when combined with KEY-DOCETAXEL, see capecitabine package insert.
• For patients developing the first appearance of a Grade 2 toxicity which persists at the time of the next KEY-DOCETAXEL/capecitabine treatment, delay treatment until resolved to Grade 0-1, and resume at 100 % of the original dose.
• For patients developing the second appearance of a Grade 2 toxicity, or the first appearance of a Grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to Grade 0-1, then resume treatment with KEY-DOCETAXEL 55 mg/m2.
• For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the KEY-DOCETAXEL dose.
• For KEY-DOCETAXEL dose modifications due to hepatic impairment (see section 4.4).
• Special populations
• Elderly population: Based on a population pharmacokinetic analysis, there are no special instructions for the use in the elderly.
• For capecitabine dosage reduction when combined with KEY-DOCETAXEL, see capecitabine package insert.
• Patients with hepatic impairment: Patients with bilirubin > ULN should generally not receive KEY-DOCETAXEL.
• Also, patients with AST and/or ALT > 1,5 x ULN concomitant with alkaline phosphatase > 2,5 x ULN, should generally not receive KEY-DOCETAXEL.
• Paediatric population: The safety and efficacy of KEY-DOCETAXEL in children under 18 years of age, have not been established.

Method of administration

KEY-DOCETAXEL should be administered by intravenous infusion only.

Recommendation for safe handling: Handling precautions for cytostatic medicines should be followed:

• Only trained personnel should reconstitute the medicine in a designated area.
• KEY-DOCETAXEL is an antineoplastic medicine and caution should be exercised when handling it and preparing KEY-DOCETAXEL solutions.
• The work surface should be covered with disposable plastic-backed absorbent paper.
• Adequate protective gloves and clothing should be worn.
• If KEY-DOCETAXEL concentrate, premix solution or infusion solution should come into contact with the skin, wash immediately and thoroughly with soap and water.
• If KEY-DOCETAXEL concentrate, premix solution or infusion solution should come into contact with the eyes or mucous membranes, wash immediately and thoroughly with water.
• KEY-DOCETAXEL must not be handled by pregnant staff.
• Adequate care and precautions should be taken in the disposal of items used to reconstitute the medicine.

• KEY-DOCETAXEL is contraindicated in patients who have a history of severe hypersensitivity reactions to docetaxel, ethanol (anhydrous), polysorbate 80, or to any of the other excipients.
• KEY-DOCETAXEL should not be used in patients with baseline neutrophil count of < 1500 cells/mm3.
• KEY-DOCETAXEL should not be used in pregnancy and lactation as docetaxel is teratogenic in animals.
• The safe use of KEY-DOCETAXEL in children has not been established.
• KEY-DOCETAXEL should not be used in patients with severe liver impairment since there is no data available (see section 4.4 and section 4.2).

KEY-DOCETAXEL (DOCETAXEL) Concentrate for Solution for Infusion should be administered under the supervision of a qualified medical practitioner experienced in the use of antineoplastic medicines.

• Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
• The incidence of treatment-related mortality associated with KEY-DOCETAXEL therapy is increased in patients with abnormal liver function, and in patients receiving higher doses.
• KEY-DOCETAXEL should generally not be given to patients with bilirubin > 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. Patients with isolated elevations of transaminase > 1,5 x ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death.
• Bilirubin, AST or ALT, and alkaline phosphatase values should be obtained prior to each cycle of KEY-DOCETAXEL therapy and reviewed by the treating medical practitioner.
• KEY-DOCETAXEL therapy should not be given to patients with neutrophil counts of < 1500 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 KEY-DOCETAXEL.
• Severe hypersensitivity reactions characterised by hypotension and/or bronchospasm, or by generalised rash/erythema occurred in patients who received the recommended 3-day dexamethasone premedication. Hypersensitivity reactions requiring discontinuation of the KEY-DOCETAXEL infusion have also been reported in patients who did not receive pre-medication. These reactions resolved after discontinuation of the infusion and the administration of appropriate therapy.
• KEY-DOCETAXEL must not be given to patients who have a history of severe hypersensitivity reactions to KEY-DOCETAXEL or to other medicines formulated with polysorbate 80.
• Severe fluid retention occurred in patients despite use of a 3-day 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 distention (due to ascites).
• The use of KEY-DOCETAXEL should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a qualified medical practitioner. 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 consisting of an oral corticosteroid (see below for prostate) such as dexamethasone 16 mg per day (e.g. 8 mg twice daily) for 3 days, starting one day prior to docetaxel administration, unless contraindicated, may reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions. The pretreatment regimen for prostate cancer is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the KEY-DOCETAXEL regimen (see sub-header Fluid Retention).

• There have been no formal clinical studies to evaluate the interactions of KEY-DOCETAXEL. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolised by (and thus may inhibit the enzyme competitively) cytochrome P450 3A, such as ciclosporin, ketoconazole, erythromycin, and troleandomycin. As a result, caution should be exercised when treating patients with these medicines as concomitant therapy, since there is a potential for a significant interaction.
• Docetaxel is highly protein bound (> 95 %). Although the possible in vivo interaction of KEY-DOCETAXEL with concomitantly administered medicines have not been investigated formally, in vitro interactions with tightly protein-bound medicines such as erythromycin, diphenhydramine, propranalol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of docetaxel.
• In addition, dexamethasone did not affect protein binding of docetaxel.
• Docetaxel did not influence the binding of digoxin.
• In the doxorubicin/docetaxel combination, the clearance of docetaxel was increased.
• When used in combination, KEY-DOCETAXEL does not influence the clearance of doxorubicin and the plasma levels of doxorubicinol (a doxorubicin metabolite). However, the clearance of KEY-DOCETAXEL was increased.
• Clearance of KEY-DOCETAXEL in combination therapy with cisplatin was similar to that observed following monotherapy. The pharmacokinetic profile of cisplatin administered shortly after KEY-DOCETAXEL infusion is similar to that observed with cisplatin alone.
• Phase I studies evaluating the effect of capecitabine on the pharmacokinetics of KEY-DOCETAXEL and vice versa showed no effect by capecitabine on the pharmacokinetics of KEY-DOCETAXEL (Cmax and AUC) and no effect by KEY-DOCETAXEL on the pharmacokinetics of the main capecitabine metabolite 5u2019-DFUR.
• The effect of prednisone on the pharmacokinetics of KEY-DOCETAXEL administered with standard dexamethasone premedication has been studied in 42 patients. No effect of prednisone on the pharmacokinetics of KEY-DOCETAXEL was observed.

Women of childbearing potential/Contraception in males and females

Pregnancy

Use during pregnancy and lactation is contraindicated as KEY-DOCETAXEL is teratogenic. Contraceptive measures must be taken during and for at least three months after cessation of therapy.

The amount of alcohol in this medicine may impair the patientu2019s ability to perform or execute tasks or activities requiring mental alertness, judgment, sound coordination or vision to drive or use machines. No studies on the effects on the ability to drive and use machines have been performed.

a. Summary of the safety profile

Not Applicable

b. Tabulated summary of adverse reactions

DOCETAXEL 100 mg/m2 single medicine:

DOCETAXEL 75 mg/m2 single medicine:

DOCETAXEL 75 mg/m2 in combination with doxorubicin:

DOCETAXEL 75 mg/m2 in combination with cisplatin:

DOCETAXEL 75 mg/m2 in combination with capecitabine:

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8). In case of overdosage, the patient should be kept in a specialised unit where vital functions can be closely monitored. There is no known antidote for KEY-DOCETAXEL 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. Treatment should be symptomatic and supportive.