Docetaxel

Docetaxel is a cytotoxic taxane. It acts on microtubules, the protein tubes that make up the cell’s internal skeleton and the spindle that separates chromosomes when a cell divides. By stabilising them, docetaxel stops cancer cells from completing division and leads to their death.

Mechanism of Action

• Microtubule stabilisation: docetaxel binds to tubulin (to its β-subunit) in microtubules, promotes the assembly of tubulin into stable microtubules and inhibits their disassembly. Free tubulin therefore falls markedly. The binding does not change the number of protofilaments.
• Loss of dynamic instability: microtubules normally lengthen and shorten as cells divide. Stabilised microtubules cannot do so, which disrupts the microtubule network needed for mitotic and interphase functions and produces abnormal microtubule bundles and asters.
• Cell death: laboratory work indicates that docetaxel triggers apoptosis, and it has also been reported to bind and block the anti-apoptotic protein Bcl-2.
• Anti-tumour activity: in vitro, docetaxel is cytotoxic against many murine and human tumour cell lines and against freshly excised human tumour cells. It reaches high intracellular concentrations and stays in the cell for a long time. It is active in some, but not all, cell lines that overexpress P-glycoprotein, the product of the multidrug resistance gene.
• Schedule independence: in vivo, its activity does not depend on the dosing schedule, and it has a broad spectrum of experimental activity against advanced murine and human grafted tumours.

Pharmacokinetics

• Kinetic profile: docetaxel kinetics are dose-independent and follow a three-compartment model. With sampling up to 24 hours, the half-lives of the α, β and γ (terminal) phases are about 4 minutes, 36 minutes and 11.1 to 17.5 hours. With sampling over 22 days, the mean terminal elimination half-life was 91 to 120 hours, reflecting slow efflux from the peripheral compartment.
• Exposure and distribution: after a 100 mg/m² one-hour infusion, the mean peak plasma concentration was 3.7 µg/mL with an AUC of 4.6 h·µg/mL. Mean total body clearance was 21 L/h/m² (inter-individual variation about 50%) and the steady-state volume of distribution 113 L. More than 95% is bound to plasma proteins.
• Metabolism: docetaxel is oxidised by cytochrome P450 enzymes (CYP3A4 and CYP3A5) at the tert-butyl ester group, giving one major and three minor inactive metabolites.
• Elimination: in a study with radiolabelled docetaxel in three patients, about 6% of the radioactivity appeared in urine and about 75% in faeces within seven days. About 80% of the faecal radioactivity was excreted in the first 48 hours, as the metabolites with very little unchanged drug.
• Special populations: age and sex did not alter the pharmacokinetics in a population analysis of 577 patients. In 23 patients whose blood tests suggested mild to moderate liver impairment (ALT or AST at least 1.5 times and alkaline phosphatase at least 2.5 times the upper limit of normal), total clearance was lowered by 27% on average.

Both Taxotere presentations (the 80 mg/4 mL concentrate and the 20 mg/0.5 mL concentrate with solvent) have the same indications.

• Breast cancer, adjuvant: in combination with doxorubicin and cyclophosphamide, for operable node-positive and for operable node-negative breast cancer. In node-negative disease, adjuvant treatment is restricted to patients eligible for chemotherapy under internationally established criteria for the primary therapy of early breast cancer.
• Breast cancer, first line for advanced disease: in combination with doxorubicin, for locally advanced or metastatic breast cancer in patients who have not previously received cytotoxic therapy for this condition.
• Breast cancer after failure of cytotoxic therapy: as monotherapy for locally advanced or metastatic breast cancer. Previous chemotherapy should have included an anthracycline or an alkylating agent.
• HER2-overexpressing breast cancer: in combination with trastuzumab, for metastatic breast cancer whose tumours overexpress HER2, in patients who have not previously received chemotherapy for metastatic disease.
• Breast cancer with capecitabine: in combination with capecitabine, for locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.
• Non-small cell lung cancer: as monotherapy for locally advanced or metastatic disease after failure of prior chemotherapy; and in combination with cisplatin for unresectable, locally advanced or metastatic disease in patients who have not previously received chemotherapy for this condition.
• Prostate cancer: in combination with prednisone or prednisolone for metastatic castration-resistant prostate cancer; and in combination with androgen-deprivation therapy (ADT), with or without prednisone or prednisolone, for metastatic hormone-sensitive prostate cancer.
• Gastric adenocarcinoma: in combination with cisplatin and 5-fluorouracil, for metastatic gastric adenocarcinoma, including adenocarcinoma of the gastro-oesophageal junction, in patients who have not received prior chemotherapy for metastatic disease.
• Head and neck cancer: in combination with cisplatin and 5-fluorouracil, for induction treatment of locally advanced squamous cell carcinoma of the head and neck.

• Hypersensitivity to docetaxel or to any of the excipients (polysorbate 80, ethanol, citric acid).
• A baseline neutrophil count below 1,500 cells/mm³.
• Severe liver impairment.
• The contraindications of other medicines also apply when they are combined with docetaxel.

The reactions below follow the SmPC table for docetaxel 100 mg/m² as a single agent in breast cancer, with post-marketing reports added. The SmPC gives separate tables for 75 mg/m² and for each combination regimen, so frequencies and severity differ by indication, and the severity of docetaxel’s adverse events may be greater when it is combined with other chemotherapy. The most commonly reported reactions of docetaxel alone are neutropenia (reversible and not cumulative; the median time to the lowest count was 7 days, and severe neutropenia, below 500 cells/mm³, lasted a median of 7 days), anaemia, alopecia, nausea, vomiting, stomatitis, diarrhoea and asthenia. At 100 mg/m², neutropenia occurs in 97% of patients and reaches grade 4 in 76%.

Very common (≥1/10): infections (including sepsis and pneumonia, fatal in 1.7% of patients), neutropenia, anaemia, febrile neutropenia, hypersensitivity, anorexia, peripheral sensory neuropathy, peripheral motor neuropathy, dysgeusia, dyspnoea, stomatitis, diarrhoea, nausea, vomiting, alopecia, skin reactions, nail disorders, myalgia, fluid retention, asthenia, pain.

Common (≥1/100 to <1/10): infection associated with grade 4 neutropenia, thrombocytopenia, arrhythmia, hypotension, hypertension, haemorrhage, constipation, abdominal pain, gastrointestinal haemorrhage, arthralgia, infusion site reaction, non-cardiac chest pain, increased bilirubin, alkaline phosphatase, AST and ALT.

Uncommon (≥1/1,000 to <1/100): cardiac failure, oesophagitis, acute myeloid leukaemia and myelodysplastic syndrome (seen in pivotal breast cancer studies with the doxorubicin, cyclophosphamide and docetaxel regimen).

Rare (≥1/10,000 to <1/1,000): bleeding associated with grade 3 or 4 thrombocytopenia, convulsions or transient loss of consciousness (sometimes during the infusion), lacrimal duct obstruction with excessive tearing, ototoxicity (hearing disorders or loss), myocardial infarction, venous thromboembolic events, acute respiratory distress syndrome, interstitial pneumonia or pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure (sometimes fatal), radiation pneumonitis, dehydration after gastrointestinal events, gastrointestinal perforation, ileus and intestinal obstruction, radiation recall, pulmonary oedema.

Very rare (<1/10,000): transient visual disturbances (flashes, scotoma), hepatitis (sometimes fatal, mainly in patients with pre-existing liver disorders), non-reversible alopecia.

Not known: second primary malignancies (including non-Hodgkin lymphoma) when docetaxel is combined with other anticancer treatments known to cause them, hypersensitivity in patients who previously reacted to paclitaxel, ventricular arrhythmia including ventricular tachycardia (sometimes fatal) in combination regimens with doxorubicin, 5-fluorouracil or cyclophosphamide, enterocolitis (including colitis, ischaemic colitis and neutropenic enterocolitis), cutaneous lupus erythematosus, bullous eruptions such as erythema multiforme, severe cutaneous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis), scleroderma-like skin changes, permanent alopecia, injection site recall reaction, tumour lysis syndrome (potentially fatal), myositis.

Also reported after marketing, without a stated frequency: bone marrow suppression, disseminated intravascular coagulation, anaphylactic shock (sometimes fatal), cystoid macular oedema, renal insufficiency and renal failure, and electrolyte disturbances (low sodium, potassium, magnesium or calcium).

Combination regimens add their own reactions. With trastuzumab, serious adverse events (40% against 31%) and grade 4 events (34% against 23%) were more frequent than with docetaxel alone, grade 3 or 4 neutropenia was more frequent (32% against 22%), and symptomatic cardiac failure occurred in 2.2% against 0%. With capecitabine, hand-foot syndrome (grade 3 or 4 in 24%), stomatitis (18%) and diarrhoea (14%) were prominent. In the adjuvant regimen with doxorubicin and cyclophosphamide, congestive heart failure occurred in 3.5% of patients, and persistent alopecia, amenorrhoea, peripheral oedema, lymphoedema and asthenia were reported during follow-up.

Docetaxel is metabolised by CYP3A4/5, so inhibitors, inducers and competing substrates of CYP3A can change its exposure.

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole): docetaxel side effects may increase because of reduced metabolism. If the combination cannot be avoided, close clinical surveillance is needed and a docetaxel dose adjustment may be suitable while the inhibitor is taken. In a study of 7 patients, ketoconazole reduced docetaxel clearance by 49%.
• Other CYP3A modulators: in vitro studies show that substances that induce, inhibit or are metabolised by CYP3A, such as ciclosporin, ketoconazole and erythromycin, may modify docetaxel metabolism. Caution is advised because a significant interaction is possible.
• Prednisone: prednisone, a CYP3A4 inducer, had no statistically significant effect on docetaxel pharmacokinetics in patients with metastatic prostate cancer.
• Protein binding: docetaxel is highly bound to plasma proteins (more than 95%); dexamethasone does not affect this binding.
• Alcohol content: the ethanol in the product may alter the effects of other medicines.
• Grapefruit and St John’s wort: grapefruit products inhibit CYP3A4 and may raise docetaxel levels, so they should be avoided. St John’s wort induces CYP3A4 and may lower docetaxel levels, so use caution.

Docetaxel must be used only in units specialised in giving cytotoxic chemotherapy and under the supervision of a physician qualified in anticancer chemotherapy. It is given as a one-hour intravenous infusion every three weeks, prepared and diluted as described in the SmPC. Doses are given in mg/m² of body surface area.

Premedication and Supportive Treatment

• Breast, non-small cell lung, gastric, and head and neck cancers: premedication with an oral corticosteroid such as dexamethasone 16 mg per day (for example 8 mg twice daily) for 3 days, starting 1 day before docetaxel, can be used unless contraindicated.
• Metastatic castration-resistant prostate cancer: because prednisone or prednisolone is given at the same time, the recommended premedication is oral dexamethasone 8 mg at 12 hours, 3 hours and 1 hour before the infusion.
• Metastatic hormone-sensitive prostate cancer: the same dexamethasone regimen is recommended whether or not prednisone or prednisolone is given.
• G-CSF: prophylactic G-CSF may be used to lower the risk of haematological toxicity. It should be used in the gastric cancer regimen.

Recommended Doses

Breast cancer

• Adjuvant treatment: docetaxel 75 mg/m² given 1 hour after doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m², every 3 weeks for 6 cycles (TAC regimen).
• Locally advanced or metastatic disease: 100 mg/m² as monotherapy. In first-line treatment, 75 mg/m² is given together with doxorubicin 50 mg/m².
• With trastuzumab: 100 mg/m² every 3 weeks, with trastuzumab given weekly. In the pivotal study the first docetaxel infusion was started the day after the first trastuzumab dose, and later docetaxel doses were given straight after the trastuzumab infusion if the previous trastuzumab dose was well tolerated. For trastuzumab dosing see its SmPC.
• With capecitabine: 75 mg/m² every 3 weeks, combined with capecitabine 1,250 mg/m² twice daily (within 30 minutes after a meal) for 2 weeks followed by a 1-week rest period. For capecitabine dosing see its SmPC.

Non-small cell lung cancer

• Chemotherapy-naive patients: 75 mg/m² immediately followed by cisplatin 75 mg/m² over 30 to 60 minutes.
• After failure of prior platinum-based chemotherapy: 75 mg/m² as a single agent.

Prostate cancer

• Metastatic castration-resistant disease: 75 mg/m², with prednisone or prednisolone 5 mg orally twice daily given continuously.
• Metastatic hormone-sensitive disease: 75 mg/m² every 3 weeks for 6 cycles. Prednisone or prednisolone 5 mg orally twice daily may be given continuously.

Gastric adenocarcinoma

• Docetaxel 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 as a 24-hour continuous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every 3 weeks.
• Antiemetic premedication and appropriate hydration for cisplatin are required, and prophylactic G-CSF should be used.

Head and neck cancer

• Antiemetic premedication and appropriate hydration (before and after cisplatin) are required. Prophylactic G-CSF may be used. All patients on the docetaxel arm of the TAX 323 and TAX 324 studies received prophylactic antibiotics.
• Induction followed by radiotherapy (TAX 323): docetaxel 75 mg/m² as a 1-hour infusion, then cisplatin 75 mg/m² over 1 hour on day 1, then 5-fluorouracil 750 mg/m² per day as a continuous infusion for 5 days, every 3 weeks for 4 cycles. Radiotherapy follows chemotherapy.
• Induction followed by chemoradiotherapy (TAX 324): docetaxel 75 mg/m² as a 1-hour infusion on day 1, then cisplatin 100 mg/m² as a 30-minute to 3-hour infusion, then 5-fluorouracil 1,000 mg/m² per day as a continuous infusion from day 1 to day 4, every 3 weeks for 3 cycles. Chemoradiotherapy follows chemotherapy.
• For cisplatin and 5-fluorouracil dose modifications see their SmPCs.

Dose Adjustments During Treatment

• General: docetaxel should be given when the neutrophil count is at least 1,500 cells/mm³. After febrile neutropenia, neutrophils below 500 cells/mm³ for more than one week, severe or cumulative skin reactions, or severe peripheral neuropathy, the dose is reduced from 100 to 75 mg/m² and/or from 75 to 60 mg/m². If these reactions continue at 60 mg/m², treatment is stopped.
• Adjuvant breast cancer (TAC): primary G-CSF prophylaxis should be considered. After febrile neutropenia or neutropenic infection, the dose is reduced to 60 mg/m² in all later cycles. After grade 3 or 4 stomatitis, it is also reduced to 60 mg/m².
• With cisplatin: for patients started on 75 mg/m² whose platelet nadir in the previous course was below 25,000 cells/mm³, or who had febrile neutropenia or serious non-haematological toxicity, the dose in later cycles is reduced to 65 mg/m².
• With capecitabine: for a first grade 2 toxicity that persists at the next cycle, delay treatment until grade 0 to 1 and resume at 100% of the original dose. For a second grade 2 toxicity, or a first grade 3 toxicity at any time in the cycle, delay until grade 0 to 1 and resume with docetaxel 55 mg/m². For any further toxicity, or any grade 4 toxicity, stop docetaxel.
• With cisplatin and 5-fluorouracil: if febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF, reduce docetaxel from 75 to 60 mg/m²; if it happens again, from 60 to 45 mg/m². After grade 4 thrombocytopenia, reduce from 75 to 60 mg/m². Do not retreat until neutrophils are above 1,500 cells/mm³ and platelets above 100,000 cells/mm³, and stop treatment if these toxicities persist.
• Diarrhoea and stomatitis with cisplatin and 5-fluorouracil: grade 3 diarrhoea, first episode, reduce 5-fluorouracil by 20%, second episode, reduce docetaxel by 20%. Grade 4 diarrhoea, first episode, reduce docetaxel and 5-fluorouracil by 20%, second episode, stop treatment. Grade 3 stomatitis or mucositis, first episode, reduce 5-fluorouracil by 20%, second episode, stop 5-fluorouracil only in all later cycles, third episode, reduce docetaxel by 20%. Grade 4, first episode, stop 5-fluorouracil only in all later cycles, second episode, reduce docetaxel by 20%.
• In the pivotal head and neck studies, patients with complicated neutropenia were advised to use G-CSF as prophylaxis (for example on days 6 to 15) in all later cycles.

Special Populations

• Hepatic impairment: when ALT and/or AST are above 1.5 times the upper limit of normal (ULN) together with alkaline phosphatase above 2.5 times the ULN, the recommended dose is 75 mg/m². When bilirubin is above the ULN and/or ALT and AST are above 3.5 times the ULN with alkaline phosphatase above 6 times the ULN, no dose reduction can be recommended and docetaxel should not be used unless strictly indicated. In the gastric cancer regimen, the pivotal study excluded patients with ALT or AST above 1.5 times the ULN with alkaline phosphatase above 2.5 times the ULN and bilirubin above the ULN; for them no dose reduction can be recommended. No data exist in hepatic impairment for the other combination indications. Severe liver impairment is a contraindication.
• Elderly: no special instructions, based on a population pharmacokinetic analysis. With capecitabine, a starting dose reduction of capecitabine to 75% is recommended for patients aged 60 years or more.
• Renal impairment: the dosing section of the SmPC gives no separate recommendation. About 6% of a dose is excreted in the urine and most in the faeces.
• Children and adolescents: safety and efficacy in nasopharyngeal carcinoma in children from 1 month to under 18 years have not been established. There is no relevant paediatric use in breast cancer, non-small cell lung cancer, prostate cancer, gastric carcinoma or head and neck cancer (other than type II and III less differentiated nasopharyngeal carcinoma).

Missed or Delayed Dose

Docetaxel is given in hospital on a fixed three-week schedule, so there is no patient-managed missed dose. The SmPC gives no separate rule for a delayed infusion; each cycle is given when the neutrophil count is at least 1,500 cells/mm³.

Premedication with a Corticosteroid

For breast and non-small cell lung cancer, an oral corticosteroid such as dexamethasone 16 mg per day (for example 8 mg twice daily) for 3 days, starting 1 day before docetaxel and unless contraindicated, can reduce the incidence and severity of fluid retention and the severity of hypersensitivity reactions. For prostate cancer, the premedication is oral dexamethasone 8 mg at 12 hours, 3 hours and 1 hour before the infusion.

Haematology and Neutropenia

• Neutropenia is the most frequent adverse reaction. The lowest neutrophil counts occurred at a median of 7 days, possibly sooner in heavily pre-treated patients.
• Complete blood counts should be checked frequently in all patients. Patients should be retreated when neutrophils have recovered to at least 1,500 cells/mm³.
• If severe neutropenia (below 500 cells/mm³ for seven days or more) occurs during a course, the dose in later courses should be reduced or appropriate symptomatic measures used.
• With cisplatin and 5-fluorouracil (TCF), febrile neutropenia and neutropenic infection were less frequent when patients received prophylactic G-CSF. All patients on TCF should receive it and be monitored closely.
• With doxorubicin and cyclophosphamide (TAC), rates were also lower with primary G-CSF prophylaxis, which should be considered for adjuvant breast cancer treatment. In the GEICAM 9805 study, febrile neutropenia occurred in 25.2% of TAC-treated patients without and 5.5% with primary G-CSF prophylaxis.

Gastrointestinal Reactions

Caution is needed in neutropenic patients, who are especially at risk of gastrointestinal complications. Enterocolitis can develop at any time, although most cases occurred in the first or second cycle, and it can be fatal from the first day of onset. Patients should be watched closely for early signs of serious gastrointestinal toxicity.

Hypersensitivity Reactions

Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. They may begin within a few minutes of the start of the infusion, so facilities to treat hypotension and bronchospasm must be available. Mild symptoms such as flushing or localised skin reactions do not require the infusion to be stopped. Severe reactions, such as severe hypotension, bronchospasm or a generalised rash or erythema, require immediate discontinuation and appropriate treatment. Patients who have had a severe hypersensitivity reaction should not be given docetaxel again. Patients who have previously had a hypersensitivity reaction to paclitaxel may be at risk of one with docetaxel, including a more severe reaction, and should be closely monitored when docetaxel is started.

Fluid Retention

Fluid retention is cumulative in incidence and severity. It includes peripheral oedema, which usually starts in the lower limbs and can become generalised with a weight gain of 3 kg or more, and less often pleural effusion, pericardial effusion, ascites and weight gain. With corticosteroid premedication, moderate or severe retention started later (median cumulative dose 818.9 mg/m²) than without it (489.7 mg/m²), although some patients had it in the first cycles. Fluid retention did not come with acute oliguria or hypotension; dehydration and pulmonary oedema were rarely reported. Patients with severe fluid retention, such as pleural effusion, pericardial effusion or ascites, should be monitored closely.

Skin and Nail Reactions

Reversible skin reactions, usually mild to moderate, were seen: rash, mainly on the feet and hands (including severe hand-foot syndrome) but also on the arms, face or chest, often with itching, generally within a week of the infusion. Severe or cumulative skin reactions call for a dose reduction. Severe nail disorders can involve pigment change, pain and nail loosening. Severe cutaneous adverse reactions have been reported after marketing.

Severe Cutaneous Adverse Reactions

Severe eruptions followed by desquamation have led to docetaxel being interrupted or stopped. Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported. Patients should be told about the signs and symptoms of serious skin reactions and be closely monitored, and stopping docetaxel should be considered if signs suggest one of these reactions.

Neurotoxicity

Mild to moderate neurosensory signs include tingling, abnormal sensation and burning pain; neuromotor signs are mainly weakness. Severe peripheral neurotoxicity requires a dose reduction.

Respiratory Disorders

Acute respiratory distress syndrome, interstitial pneumonia or pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure have been reported and may be fatal; radiation pneumonitis has been reported in patients having radiotherapy at the same time. If new or worsening lung symptoms develop, patients should be closely monitored, promptly investigated and appropriately treated. Interrupting docetaxel is recommended until a diagnosis is available, early supportive care may help, and the benefit of resuming docetaxel must be carefully weighed.

Liver and Kidney Function

• Liver: in patients given docetaxel 100 mg/m² as a single agent, ALT and/or AST above 1.5 times the upper limit of normal together with alkaline phosphatase above 2.5 times the upper limit carries a higher risk of severe reactions, such as toxic deaths (including sepsis and gastrointestinal haemorrhage, which can be fatal), febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. Liver function tests should be measured at baseline and before each cycle; the dose limits are under Administration and Dosage.
• Kidney: no data are available in patients with severely impaired renal function.

Cardiac Toxicity

• With trastuzumab: heart failure has been seen, particularly after anthracycline (doxorubicin or epirubicin) chemotherapy; it can be moderate to severe and has been linked to death. Candidates for the combination should have a baseline cardiac assessment, and cardiac function should be monitored during treatment (for example every three months). The trastuzumab SmPC gives more detail.
• With doxorubicin, 5-fluorouracil and/or cyclophosphamide: ventricular arrhythmia, including ventricular tachycardia (sometimes fatal), has been reported. A baseline cardiac assessment is recommended.

Eye Disorders

Cystoid macular oedema has been reported with docetaxel. Patients with impaired vision should have a prompt and complete ophthalmological examination. If cystoid macular oedema is diagnosed, docetaxel should be stopped and appropriate treatment started.

Second Primary Malignancies

Second primary malignancies have been reported when docetaxel was given with anticancer treatments known to be associated with them. They (including acute myeloid leukaemia, myelodysplastic syndrome and non-Hodgkin lymphoma) may appear several months or years after docetaxel-containing therapy, so patients should be monitored for them.

Tumour Lysis Syndrome

Tumour lysis syndrome has been reported with docetaxel after the first or second cycle. Patients at risk (for example with renal impairment, hyperuricaemia, a bulky tumour or rapid progression) should be closely monitored. Correcting dehydration and treating high uric acid levels before treatment starts is recommended.

Strong CYP3A4 Inhibitors

Strong CYP3A4 inhibitors (for example ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) should be avoided with docetaxel (see Drug Interactions).

Additional Cautions in Adjuvant Breast Cancer

• Complicated neutropenia: after prolonged neutropenia, febrile neutropenia or infection, G-CSF and a dose reduction should be considered.
• Gastrointestinal symptoms: early abdominal pain and tenderness, fever or diarrhoea, with or without neutropenia, may be early signs of serious gastrointestinal toxicity and need prompt evaluation and treatment.
• Congestive heart failure: patients should be monitored for symptoms during treatment and follow-up. After the TAC regimen for node-positive breast cancer, the risk was higher during the first year after treatment.
• Four or more positive nodes: the benefit on disease-free and overall survival was not statistically significant in this group, so a positive benefit/risk ratio for TAC was not fully shown at the final analysis.

Older Patients

• Adjuvant breast cancer: data are limited in patients over 70 years of age given docetaxel with doxorubicin and cyclophosphamide.
• Castration-resistant prostate cancer (TAX 327): nail changes were at least 10% more frequent in patients aged 65 or over than in younger patients, and fever, diarrhoea, anorexia and peripheral oedema at least 10% more frequent in those aged 75 or over than in those under 65.
• Hormone-sensitive prostate cancer (STAMPEDE): hypersensitivity, neutropenia, anaemia, fluid retention, dyspnoea and nail changes were reported more often in patients aged 65 or over, though none of the differences reached 10%. In those aged 75 or over, neutropenia, anaemia, diarrhoea, dyspnoea and upper respiratory tract infection were at least 10% more frequent than in younger patients.
• Gastric adenocarcinoma (with cisplatin and 5-fluorouracil): serious adverse events were more frequent in older patients, and lethargy, stomatitis and neutropenic infection were at least 10% more frequent in those aged 65 or over. Older patients on this regimen should be closely monitored.

Other Serious Reactions Reported

Reports after marketing include interstitial lung disease and acute respiratory distress syndrome, cardiac events (cardiac failure, arrhythmia, myocardial infarction), cystoid macular oedema and other visual disturbances, hepatitis, renal failure, second primary malignancies, acute leukaemia and myelodysplastic syndrome (3 of 744 and 2 of 744 patients on the adjuvant TAC regimen after 10 years of follow-up in one study), and tumour lysis syndrome. Patients should be advised to report new respiratory, cardiac, visual or skin symptoms promptly.

Alcohol Content

Each 80 mg/4 mL vial contains 2 mL of anhydrous ethanol (1.58 g), the 20 mg/1 mL vial 0.5 mL (395 mg) and the 160 mg/8 mL vial 4 mL (3.16 g). The solvent vial of the 20 mg/0.5 mL presentation contains 252 mg of ethanol 95% v/v, and that of the 80 mg/2 mL presentation 932 mg. This amount of alcohol may alter the effects of other medicines and, together with the side effects, may impair the ability to drive or use machines. For the 80 mg/4 mL vial, the SmPC adds that the medicinal product contains 50 vol % anhydrous ethanol, equivalent to about 40 mL of beer or 17 mL of wine per vial, and that this is harmful for people with alcoholism. It should be taken into account in pregnant or breastfeeding women, in children and in high-risk groups such as patients with liver disease or epilepsy, and possible effects on the central nervous system should be considered.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential and men should be advised to avoid becoming pregnant or fathering a child and to tell the treating physician at once if it happens. Because of the genotoxic risk, women of childbearing potential must use effective contraception during treatment and for 2 months after it ends. Men must use effective contraception during treatment and for 4 months after it ends.
• Pregnancy: there is no information in pregnant women. Docetaxel was embryotoxic and foetotoxic in rabbits and rats and, like other cytotoxic medicines, may cause foetal harm. It must not be used in pregnancy unless clearly indicated.
• Breastfeeding: docetaxel is lipophilic, but it is not known whether it passes into human milk. Because of the potential for adverse reactions in nursing infants, breastfeeding must be stopped for the duration of treatment.
• Fertility: animal studies show that docetaxel may alter male fertility. Men being treated should seek advice on sperm conservation before treatment.

Effect on Driving

No studies on the ability to drive and use machines have been done. The alcohol in this medicine and its side effects may impair that ability, so patients should be warned of this and advised not to drive or use machines if they experience such effects during treatment.

The 80 mg/4 mL concentrate must not be stored above 25 °C. The 20 mg/0.5 mL concentrate and solvent must not be stored above 25 °C or below 2 °C. Both are kept in the original package to protect them from light. No cold chain is needed. Storage conditions after dilution are given under Shelf Life. The 80 mg/4 mL concentrate comes in a 7 mL clear glass vial with a magenta seal, one vial per box; not all pack sizes may be marketed. Keep out of the sight and reach of children.

Taxotere 80 mg/4 mL concentrate

• Unopened vial: 3 years.
• After opening: each vial is for single use and should be used immediately after opening. If it is not, in-use times and conditions are the responsibility of the user.
• Infusion solution: preparation and dilution must take place under controlled and aseptic conditions, and the solution should be used immediately. Once added to the infusion bag as recommended and stored below 25 °C, the infusion solution is stable for 6 hours and should be used within 6 hours, including the one-hour infusion.

Taxotere 20 mg/0.5 mL concentrate and solvent

• Unopened pack: 2 years.
• Premix solution (10 mg/mL docetaxel): use immediately after preparation. Chemical and physical stability has been shown for 8 hours at 2–8 °C or at room temperature (below 25 °C).
• Infusion solution: use within 4 hours at room temperature (below 25 °C).

Prescription only (Rx), on restricted medical prescription (Annex II B of the EU marketing authorisation). Use is confined to units specialised in giving cytotoxic chemotherapy, under the supervision of a physician qualified in anticancer chemotherapy. Docetaxel is prepared, diluted and infused in hospital, so it is supplied to the hospital or clinic that administers it. It is stored below 25 °C and protected from light, so no cold-chain delivery is needed.