Health and Prostate

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Adverse Effects, Treatment, and Precautions

As for Paclitaxel. Neutropenia, anaemia and skin reactions are common with docetaxel and may be severe. Fluid retention, resulting in oedema, ascites, pleural and pericardial effusion, and weight gain, is also common, and may be cumulative; premedication with a corticosteroid can reduce fluid retention as well as the severity of hypersensitivity reactions. Asthenia and fatigue have also been reported. Rare cases of ototoxicity, hearing impairment or loss have occurred. Very rare cases of acute myeloid leukaemia and myelodysplastic syndrome have been reported with combination chemotherapy regimens containing docetaxel; haematological follow-up may be required. Docetaxel should not be used in patients hypersensitive to polysorbate 80, which is contained in the formulation. Patients with hepatic impairment show increased sensitivity to toxic effects of docetaxel, and should be given the drug with great care and in reduced doses, if at all.

Effects on the eyes. Excessive tear formation (epiphora) severe enough to interfere with reading and driving has been reported in patients given docetaxel. Canalicular stenosis has been described as the mechanism for this effect, and docetaxel has been measured in tear fluid suggesting that irritation of the ocular surface and fibrosis of the tear drainage ducts may be caused by direct contact with docetaxel. Epiphora and canalicular stenosis are more severe and occur more frequently in patients who receive weekly docetaxel than in those who receive the drug every 3 weeks. The mean cumulative dose of docetaxel was found to be higher in those patients who developed stenosis. Management of this adverse effect includes probing and irrigation of the lachrymal ducts and canalicular silicone tubing placement, or surgery followed by tube placement. The condition is generally reversible and tubing can be removed 4 to 6 weeks after stopping docetaxel therapy. The use of topical tobramycin and dexamethasone on a tapering regimen can eliminate the need for silicone intubation or surgery in some patients.

Very rare cases of transient visual disturbances such as flashing lights and scotomata have occurred during docetaxel infusion, and in association with hypersensitivity reactions. These were reversible upon stopping the infusion. For reference to a report of glaucoma possibly related to docetaxel, see Paclitaxel.

Effects on the gastrointestinal tract. Ischaemic colitis has occurred in patients treated with docetaxel. Some patients also received vinorelbine, which may have exacerbated this complication.

Effects on the heart. For comment on the increased risk of heart failure when docetaxel is given with trastuzumab and after anthracyclines, see under Interactions, below.

Effects on the musculoskeletal system. For reference to cases of taxane-induced arthralgia and myalgia successfully treated with gabapentin, see Paclitaxel.

Effects on the skin and nails. Palmar-plantar erythrodysesthesia syndrome has been reported with the use of docetaxel. For reference to the use of vitamin E to alleviate palmar-plantar erythrodysesthesia syndrome caused by docetaxel and capecitabine, see Chemotherapy-induced Toxicity, under Uses of Vitamin E. Cases of radiation recall dermatitis associated with docetaxel have also been reported. There is a further report of recall dermatitis at sites previously treated with a laser. A hyperpigmented eruption developed in a patient at the site of docetaxel injection after insufficient venous flushing; no eruption occurred after a second infusion with abundant venous flushing. Licensed drug information states that very rare cases of bullous eruption such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported with docetaxel, but that other factors may have contributed to the development of these reactions.

For further reference to reports of scleroderma and adverse effects on the nails after the use of docetaxel, see Paclitaxel.

In a multicentre study, patients given docetaxel wore a frozen glove on the right hand, leaving the left hand unprotected to serve as a control. The use of the glove significantly reduced skin and nail toxicity.

Hypersensitivity. For a discussion of taxane-induced hypersensitivity, including references to desensitisation protocols, see under Paclitaxel.

Tumour lysis syndrome. Fatal cases of tumour lysis syndrome have been reported after the second-line use of docetaxel.

Interactions

For a general outline of antineoplastic drug interactions.

Docetaxel is metabolised by cytochrome P450 isoenzyme CYP3A, and theoretically has the potential to interact with other drugs that are inhibitors or inducers of this enzyme.

Antifungals. In a pharmacokinetic study, no consistent effects on docetaxel concentrations were seen with the addition of ketoconazole. Significant inter- and intrapatient variability was observed and a potential interaction could not be excluded. In another study in 7 patients, however, the clearance of docetaxel was significantly reduced by 49% when given with ketoconazole.

Antineoplastics. The clearance of a dose of docetaxel was markedly reduced when it was given after 4 days of treatment with topotecan, rather than on day 1; this resulted in worsened neutropenia.

Sorafenib may increase systemic exposure to docetaxel. An increased incidence of febrile neutropenia and gastrointestinal disorders, including 2 fatalities, was reported in patients given docetaxel with doxorubicin} although others considered this high incidence unrepresentative of usual toxicity rates with this combination.

Heart failure has been reported in patients given docetaxel with other cytotoxic drugs, especially trastuzumab, and particularly after anthracycline-containing therapy. UK licensed drug information therefore recommends that patients given docetaxel with trastuzumab should undergo baseline cardiac assessment and cardiac function should be monitored during treatment.

Pharmacokinetics

On intravenous dosage docetaxel is rapidly distributed to body tissues. Docetaxel is more than 95% bound to plasma proteins. It is extensively metabolised via hepatic cytochrome P450 isoenzyme CYP3A4 and excreted chiefly in the faeces as metabolites. Only about 6% of a dose is excreted in urine. The terminal elimination half-life is about 11 hours. Clearance is reduced in hepatic impairment.

Uses and Administration

Docetaxel is a semisynthetic taxane similar to paclitaxel. It is manufactured from a taxane precursor derived from the needles of the European yew tree Taxus baccata. Docetaxel is used for locally advanced or metastatic breast cancer. It may be used as first-line treatment with doxorubicin; in the treatment of refractory disease, it is used alone or with capecitabine. In the treatment of metastatic breast cancer that overexpresses HER2 (human epidermal growth receptor 2), docetaxel may be used with trastuzumab as initial therapy. For adjuvant treatment of operable, nodepositive breast cancer, docetaxel is given with doxorubicin and cyclophosphamide. Docetaxel is also indicated for the treatment of locally advanced or metastatic non-small cell lung cancer, either with cisplatin for initial treatment of unresectable disease, or after failure of previous platinum-based chemotherapy. It is used with prednisone or prednisolone in hormone-refractory metastatic prostate cancer. Docetaxel is given with cisplatin and fluorouracil in the first-line treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastro-oesophageal junction; it is also used in this combination for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck.

Docetaxel is given by intravenous infusion in glucose 5% or sodium chloride 0.9% at a concentration not exceeding 0.74 mg/mL. Infusion is normally over 1 hour. Premedication with an oral corticosteroid, such as dex-amethasone 16 mg daily, for 3 days starting 1 day before docetaxel is recommended with many regimens. The licensed dose for docetaxel as a single agent in the treatment of breast cancer after failure of previous chemotherapy is 60 to 100 mg/m once every 3 weeks. A dose of 75 mg/m once every 3 weeks is given in combination therapy with doxorubicin, or capecitabine, or when used as adjuvant therapy with doxorubicin and cyclophosphamide. When used with trastuzumab, docetaxel is given at a dose of 100 mg/m once every 3 weeks.

The dose for non-small cell lung cancer is 75 mg/m once every 3 weeks, for both first-line combination therapy and monotherapy after failure of previous chemotherapy.

For gastric adenocarcinoma docetaxel 75 mg/m is given before cisplatin and fluorouracil; treatment is repeated every 3 weeks.

In the induction treatment of head and neck cancer, the recommended dose of docetaxel is 75 mg/m, given before cisplatin and fluorouracil; treatment is given every 3 weeks for 3 cycles, followed by chemoradiotherapy, or for 4 cycles when followed by radiotherapy alone.

For prostate cancer, the dose of docetaxel is 75 mg/m once every 3 weeks, with prednisone or prednisolone 5 mg orally twice daily given continuously. The use of prednisone or prednisolone reduces the need for a premedication corticosteroid; dexamethasone 8 mg may be given at 12 hours, 3 hours, and 1 hour before docetaxel.

Regular blood counts are required, and dosage in subsequent courses should be reduced in patients who experience severe or febrile neutropenia (see also Bone-marrow Depression), or severe cutaneous reactions or peripheral neuropathy. The dose of docetaxel should be reduced in hepatic impairment, see below.

Administration. Docetaxel has been investigated as a low-dose weekly infusion, in patient groups such as the elderly, those with poor performance status, or refractory disease. Weekly doses of 30 to 40 mg/m are considered to be of similar efficacy to the standard three-weekly dosage regimen. A pharmacokinetic study in 20 elderly patients suggested that a suitable starting dose might be 26 mg/m, increased provided there was no toxicity.

Administration in hepatic impairment. UK licensed product information recommends that doses of docetaxel monotherapy should be reduced from 100 mg/m to 75 mg/m in mild to moderate hepatic impairment, defined as alanine aminotransferase (ALT/SGPT) and/or aspartate aminotransferase (AST/SGOT) more than 1.5 times the upper limit of normal (ULN), and alkaline phosphatase more than 2.5 times the ULN. Hepatic function should be monitored; use should be avoided if possible in severe hepatic impairment. US licensed information advises against the use of docetaxel in patients with bilirubin above ULN, or in those with mild to moderate hepatic impairment (defined as for the UK, above).

Proprietary Preparations

Argentina: Asodocel; Docekebir; Dolectran; Donataxel; Doxetal; Doxmil †; Eriox; Neocel †; Plustaxano; Taxotere; Texot; Trazoteva; Trixotene †;

Australia: Taxotere;

Austria: Taxotere;

Belgium: Taxotere;

Brazil: Taxotere;

Canada: Taxotere;

Chile: Taxotere;

Czech Republic: Taxotere;

Denmark: Taxotere;

Finland: Taxotere;

France: Taxotere;

Germany; Taxotere;

Greece: Taxotere;

Hong Kong; Taxotere;

Hungary: Taxotere;

India: Daxotel; Docetax;

Indonesia: Taxotere;

Israel: Taxotere;

Italy: Taxotere;

Japan: Taxotere;

Malaysia: Taxotere;

Mexico: Taxotere;

Netherlands: Taxotere;

Norway: Taxotere;

New Zealand: Taxotere;

Philippines: Taxotere;

Poland: Taxotere;

Portugal: Taxotere;

Russia: Tautax; Taxotere;

South Africa: Taxotere;

Singapore: Taxotere;

Spain: Taxotere;

Sweden: Taxotere;

Switzerland: Taxotere;

Thailand: Daxotel †; Taxotere;

Turkey: Taxotere;

United Kingdom (UK): Taxotere;

United States of America (USA): Taxotere;

Venezuela: Daxotel; Taxotere.