DOCETAXEL injection

DOCETAXEL injection

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DOCETAXEL injection

Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate.

Docetaxel is a white to almost-white powder with an empirical formula of C43H53NO14•3H2O, and a molecular weight of 861.9. It is highly lipophilic and practically insoluble in water.

Indications and usage

Docetaxel Injection is a microtubule inhibitor indicated for:

  • Breast Cancer (BC): single agent for locally advanced or metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC
  • Non-small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC
  • Castration-Resistant Prostate Cancer (CRPC): with prednisone in metastatic castration-resistant prostate cancer
  • Gastric Adenocarcinoma (GC): with cisplatin and fluorouracil for untreated, advanced GC, including the gastroesophageal junction
  • Squamous Cell Carcinoma of the Head and Neck (SCCHN): with cisplatin and fluorouracil for induction treatment of locally advanced SCCHN

Dosage and administration

Administer in a facility equipped to manage possible complications (e.g., anaphylaxis). Administer intravenously (IV) over 1 hr every 3 weeks. PVC equipment is not recommended. Use a 20 gauge needle to withdraw Docetaxel Injection from the vial.

  • BC locally advanced or metastatic: 60 mg/m2 to 100 mg/m2 single agent
  • BC adjuvant: 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for 6 cycles
  • NSCLC: after platinum therapy failure: 75 mg/m2 single agent
  • NSCLC: chemotherapy-naive: 75 mg/m2 followed by cisplatin 75 mg/m2
  • HRPC: 75 mg/m2 with 5 mg prednisone twice a day continuously
  • GC: 75 mg/m2 followed by cisplatin 75 mg/m2 (both on day 1 only) followed by fluorouracil 750 mg/m2 per day as a 24-hr IV (days 1 – 5), starting at end of cisplatin infusion
  • SCCHN: 75 mg/m2 followed by cisplatin 75 mg/m2 IV (day 1), followed by fluorouracil 750 mg/m2 per day as a 24-hr IV (days 1 – 5), starting at end of cisplatin infusion; for 4 cycles
  • SCCHN: 75 mg/m2 followed by cisplatin 100 mg/m2 IV (day 1), followed by fluorouracil 1,000 mg/m2 per day as a 24-hr IV (days 1 – 4); for 3 cycles

For all patients

  • Premedicate with oral corticosteroids
  • Adjust dose as needed

Mechanism of Action

Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel’s binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use.

Warnings and precautions

  • Second primary malignancies: In patients treated with docetaxel-containing regimens, monitor for delayed AML, MDS, NHL, and renal cancer.
  • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe cutaneous adverse reactions have been reported. Severe skin toxicity may require dose adjustment or permanent treatment discontinuation.
  • Neurologic reactions: Reactions including paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent.
  • Eye disorders: Cystoid macular edema (CME) has been reported and requires treatment discontinuation.
  • Asthenia: Severe asthenia may occur and may require treatment discontinuation.
  • Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception.
  • Tumor lysis syndrome: Tumor lysis syndrome has been reported. Patients at risk should be well hydrated and closely monitored during treatment.

Adverse reactions

Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia.

Contraindications

Docetaxel Injection is contraindicated in patients with:

  • neutrophil counts of < 1,500 cells/mm3
  • a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80. Severe reactions, including anaphylaxis, have occurred
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Drug interaction

Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4.

In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of Docetaxel Injection and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients receiving treatment with Docetaxel Injection, close monitoring for toxicity and a Docetaxel Injection dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided.

Use in specific populations

Pregnancy: Based on findings in animal reproduction studies and its mechanism of action, Docetaxel Injection can cause fetal harm when administered to a pregnant woman. Available data from case reports in the literature and pharmacovigilance with docetaxel use in pregnant women are not sufficient to inform the drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproductive studies, administration of docetaxel to pregnant rats and rabbits during the period of organogenesis caused an increased incidence of embryo-fetal toxicities, including intrauterine mortality, at doses as low as 0.02 and 0.003 times the recommended human dose based on body surface area, respectively. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

Lactation: There is no information regarding the presence of docetaxel in human milk, or on its effects on milk production or the breastfed child. No lactation studies in animals have been conducted. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Docetaxel Injection and for 1 week after the last dose.

Females and Males of Reproductive Potential

Docetaxel can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of Docetaxel Injection.

Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of Docetaxel Injection.

Based on findings in animal studies, Docetaxel Injection may impair fertility in males of reproductive potential

Pediatric Use: The efficacy of docetaxel in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of docetaxel in pediatric patients receiving monotherapy or TCF was consistent with the known safety profile in adults.

Geriatric Use: In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients.

Overdosage

There is no known antidote for Docetaxel Injection overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.

In two reports of overdose, one patient received 150 mg/m2 and the other received 200 mg/m2 as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.

Storage

Store at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from light.

After first use and following multiple needle entries and product withdrawals, Docetaxel Injection multiple-dose vials are stable for up to 28 days when stored between 2°C and 8°C (36°F and 46°F) and protected from light.

Handling and Disposal

Docetaxel is a hazardous drug. Follow applicable special handling and disposal procedures.

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