Docetaxel - Indications, Dosage, and Contraindications

How Docetaxel Works?

Docetaxel works by interfering with a cell's internal framework, called microtubules, which are necessary for cell division and growth. By stabilizing these structures in a way that stops them from working, Docetaxel prevents cancer cells from dividing and causes them to die. This makes it an effective treatment for slowing down or stopping the spread of cancer.

Docetaxel is a Food and Drug Administration (FDA)-approved chemotherapy drug, which got its approval in 1996 and is used to treat various types of cancer. It is administered via intravenous infusion and inhibits the growth of cancer cells. It is used alone for breast cancer that has not responded to chemotherapy, as well as for non-small cell lung cancer (NSCLC) after platinum-based treatment fails.

What Is Docetaxel Used For?

Docetaxel is used for the treatment of the following cancers:

• Breast Cancer: Docetaxel injection is used for locally advanced or metastatic breast cancer if chemotherapy fails.

• Non-Small Cell Lung Cancer (NSCLC): Docetaxel injection is used for locally advanced or metastatic NSCLC if platinum therapy or Cisplatin fails.

• Hormone Refractory Prostate Cancer (HRPC): It is used along with Prednisone in androgen-independent metastatic prostate cancer.

• Stomach Cancer (Gastric Adenocarcinoma): The use of Docetaxel injection along with Cisplatin and Fluorouracil for untreated, advanced gastric adenocarcinoma, including the gastrointestinal junction.

• Squamous Cell Carcinoma of the Head and Neck Cancer: Docetaxel injection is used along with Cisplatin and Fluorouracil to induce a response in locally advanced squamous cell carcinoma of the head and neck.

Dosage and Administration:

1. Dosage Forms: Vials.

2. Dosage Strength: 20 mg/2 ml, 80 mg/8 ml, 160 mg/16 ml.

3. Administration: It is administered intravenously for one hour every three weeks.

• In hormone-refractory prostate cancer cases, 75 milligrams per square meter with 5 milligrams of Prednisone is given twice daily.

• In gastric adenocarcinoma and squamous cell carcinoma of the head and neck cancer, the use of 75 milligrams per square meter followed by Cisplatin 75 milligrams per square meter administered on day one, followed by Fluorouracil 750 milligrams per square meter per day for a 24-hour infusion for five days, with the end of Cisplatin infusion for four cycles.

• It is also administered as 75 milligrams per square meter following the Cisplatin 100 milligrams per square meter injection on the first day, followed by Fluorouracil 1000 milligrams per square meter per day in a 24-hour infusion on days one to four for three cycles.

• For all patients, the use of premedication with corticosteroids has to be given.

Who Should Not Use Docetaxel?

• Individuals allergic to Docetaxel, polysorbate 80, or any ingredients in the specific formulation.

• People with low levels of neutrophils (neutropenia) or other blood count abnormalities (low white blood cells, platelets, or red blood cells).

• Docetaxel should not be used during pregnancy.

Warnings and Precautions:

• Acute Myeloid Leukemia - Docetaxel, Doxorubicin, and Cyclophosphamide can show delayed myelodysplasia or myeloid leukemia.

• Cutaneous Reactions - The use of Docetaxel can cause reactions including erythema of the extremities, edema, and desquamation. If severe skin toxicity occurs, then it requires dose adjustments.

• Neurologic Reactions - There can be reactions like paresthesia, dysesthesia, and pain, and if severe neurosensory symptoms appear, then dose adjustment has to be made.

• Asthenia - If severe asthenia occurs after the use of Docetaxel, then discontinuation is advised.

• Pregnancy - If the patient is pregnant, Docetaxel is not used because it can cause fetal harm.

• Toxic Deaths - In breast cancer, the use of Docetaxel has caused death in some cases due to sepsis in the majority of cases. Death was reported in cases of non-small cell lung cancer who had a history of platinum chemotherapy and were then further treated with Docetaxel.

• Hepatic Impairments - The hepatic impairment patient should not be treated with Docetaxel injection, especially patients with combined abnormalities of transaminases and alkaline phosphatase.

• Hematologic Effects - Patients with severe neutropenia lasting 7 days or febrile neutropenia should receive a 25 percent reduction in the Docetaxel dose.

• Hypersensitivity Reactions - For patients experiencing severe hypersensitivity reactions with symptoms such as Docetaxel rash, erythema, hypotension, or bronchospasm on the first or second dose, or within 3 days of corticosteroid administration, discontinuation of the drug is an option.

• Fluid Retention - Severe fluid retention has been observed with Docetaxel, so premedication with oral corticosteroids is important before starting Docetaxel.

Special Considerations:

• Pregnancy - Docetaxel injection can cause fetal harm if used, so cautious use of Docetaxel during pregnancy is recommended.

• Nursing Mothers - Whether Docetaxel is excreted in human milk is unknown at this time, but many drugs are usually excreted in human milk. So, considering the possibilities of adverse outcomes in the breastfed baby, cautious use of Docetaxel is recommended.

• Pediatric Use - The safety and effectiveness of Docetaxel have not been determined in pediatric patients to date.

• Geriatric Use - Cautious use of Docetaxel is advised for geriatric patients after knowing their medical conditions.

• Hepatic Impairment - Anyone with an abnormal liver function test result should not receive Docetaxel injections.

For Patients:

What is Docetaxel?

Docetaxel is a chemotherapy drug that is available in injection form. It is used to treat various cancers, including breast, lung, prostate, stomach, and head and neck cancers. Docetaxel injection can be used alone or with other drugs like Cisplatin, Fluorouracil, or Prednisone to increase its effectiveness. While it primarily targets cancer cells, it may also affect normal cells, leading to side effects.

Why Is Docetaxel Prescribed?

Docetaxel injection has wide applications. It is prescribed to treat different cancers like breast cancer, lung cancer, prostate cancer, stomach cancer, and head and neck cancers. It works both in a single-drug regimen and a multi-drug regimen, where it can be given in combination with other cancer medicines. It belongs to the class of taxanes. Docetaxel acts on cancer cells by stopping their growth and spread.

How Should I Use Docetaxel?

Docetaxel injections are delivered into the veins (intravenously) by a doctor or healthcare professional. It is usually delivered within one hour every three weeks. The doctor will prescribe a corticosteroid premedication, such as Dexamethasone, to prevent adverse effects, and it is usually taken before each dose cycle.

What Docetaxel Precautions Should I Follow?

• Inform the doctor about allergic reactions to Docetaxel.

• Inform the doctor if you are taking any other medications, like antifungals.

• Avoid the use of alcohol while on Docetaxel injections.

• Take birth control measures if you are on Docetaxel to prevent unplanned pregnancies.

• Avoid breastfeeding while taking Docetaxel injection and for another two weeks following the final dose.

• Inform the doctor before surgery, including dental surgery.

• Docetaxel can cause drowsiness and can affect thinking and motor functions. So, avoid driving and other tasks that need concentration.

What are the Side Effects of Docetaxel?

The Docetaxel side effects can vary, and some common symptoms include:

• Vomiting.

• Constipation.

• Changes in taste.

• Extreme tiredness.

• Muscle, joint, or bone pain.

• Loss of hair.

• Changes in nails.

• Eye tearing is increasing.

• Sores in the mouth and throat.

• Redness, dryness, or swelling at the site of injection.

In some cases, serious Docetaxel side effects may occur, requiring immediate medical attention. These severe reactions can include:

• Blister on the skin.

• Numbness and tingling in the hands and feet.

• Burning sensation in hands and feet.

• Weakness in the hands and feet.

• Unusual bleeding or bruising.

• Nose bleeding.

• Blurred vision.

• Loss of vision.

• Stomach pain.

• Tenderness.

• Diarrhea.

• Fever.

What Are the Symptoms of Overdosage of Docetaxel?

Overdose symptoms are

• Seizures.

• Troublesome breathing.

• Sore throat.

• Fever.

• Chills.

• Sores in the mouth and throat.

• Skin irritation.

• Weakness.

• Numbness.

• Tingling.

• Burning sensation in hands and feet.

• Signs of infection.

What If the Patient Misses the Scheduled Docetaxel Dose?

If you forget to take the scheduled Docetaxel dose, then take it as soon as possible, but inform your doctor before taking the Docetaxel injection.

For Doctors:

Docetaxel:

Docetaxel is an anti-cancerous (anti-neoplastic) agent and belongs to the taxane class. It is formed by the needle biomass of yew plants. It has a chemical name (2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13 ester with 5 beta-20-epoxy-1,2alpha,4,7beta,10beta,13 alpha-hexahydroxy tax-11-en-9-one 4-acetate 2-benzoate. It appears as white powder, having a molecular weight of 807.88. It has an empirical formula of C43H53NO14. It is insoluble in water and lipophilic.

What Is the Clinical Pharmacology of Docetaxel?

• Mechanism of Action: Docetaxel acts by disrupting the microtubular network in cells, which is crucial for mitotic and interphase functions. Docetaxel further binds to free tubulin and promotes the assembly of tubulin to form stable microtubules. All these lead to the production of more stable microtubule bundles that inhibit cell mitosis. After binding to microtubules, Docetaxel does not alter the bonded microtubules.

• Absorption: Docetaxel is administered by injecting intravenously. An infusion takes one to two hours. Its pharmacokinetic profile has a three-compartment model, with half-lives for alpha 4 minutes, beta 36 minutes, and gamma 11.1 hours. Total clearance was 21 liters per hour per square meter.

• Distribution: A steady-state volume of distribution is 113 liters. The initial decline in the distribution of peripheral compartments and the late phase are due to Docetaxel's slow effect on the periphery.

• Metabolism: Docetaxel is metabolized by CYP3A4 and further by CYP3A4.

• Elimination: Docetaxel is eliminated in urine and feces, but the main route is fecal. In the seven days, urinary excretion is seven percent, and fecal excretion is 75 percent. Nearly 80 percent is excreted during 48 hours, as one major and three minor metabolites are formed.

• Effect of Age: Docetaxel does not show any influence on age differences.

• Effect of Gender: Docetaxel does not show any influence on gender.

• Hepatic Impairments: The mild-to-moderate hepatic-impaired patients have shown a reduction in body clearance of Doxetaxel by 27 percent and a 38 percent increase in systemic body values.

• Effect of Race: There are no significant differences in Docetaxel elimination across populations.

• Effect of Ketoconazole: The results of co-administration of Ketoconazole with Docetaxel showed a 49 percent reduction.

Nonclinical Toxicology:

• Carcinogenesis: The carcinogenic effect of Docetaxel has not been determined.

• Mutagenesis: Docetaxel has shown no mutagenic effects in tests conducted in mice.

• Impairment of Fertility: The use of Docetaxel has shown testicular atrophy in animals.

Indications and Usage:

• Breast Cancer: It is used in locally advanced or metastatic breast cancer patients after the failure of previous chemotherapy. And in combination with Doxorubicin and Cyclophosphamide in patients with operable node-positive breast cancer.

• Non-Small Cell Lung Cancer: It is also indicated for locally advanced or metastatic non-small cell lung cancer after the failure of platinum chemotherapy. It is also used alongside Cisplatin in patients who have not previously received chemotherapy. However, advances in immunotherapy for non-small cell lung cancer have made it a preferred option.

• Prostate Cancer: It is used in combination with Prednisolone in prostate cancer patients.

• Gastric Adenocarcinoma: It is used along with Cisplatin and Fluorouracil in patients with gastric adenocarcinoma.

• Head and Neck Cancer: It is used in combination with Cisplatin and Fluorouracil in patients with locally advanced squamous cell carcinoma of the head and neck.

Dosage and Administration:

• Dosage Form - The injection formulation is the recommended dosage form. Dosage is present in a clear, colorless, pale yellow solution. It is available in multiple-dose vials.

• Dosage Supplied - It is supplied as 20 milligrams per 2 milliliters, 80 milligrams per 8 milliliters, and 160 milligrams per 16 milliliters.

Administered:

• Breast Cancer: After the failure of previous chemotherapy, the recommended dose of Docetaxel injection is 60 milligrams per square meter to 100 milligrams per square meter delivered intravenously over one hour every three weeks, and for operable node-positive breast cancer, the dose is 75 milligrams per square meter, which is delivered in one hour after Doxorubicin (50 milligrams per square meter) and Cyclophosphamide 500 milligrams every three weeks for six courses.

• Non-Small Cell Lung Cancer: The patient is administered 75 milligrams per square meter intravenously over one hour for three weeks. One hundred milligrams per square meter in previously treated chemotherapy. In cases of co-administration with Cisplatin, Docetaxel is injected at 75 milligrams per square meter intravenously over one hour. followed by Cisplatin 75 milligrams per square meter over 30 to 60 minutes every three weeks.

• Prostate Cancer: The recommended dose of Docetaxel is 75 milligrams per square meter every three weeks, given for one hour intravenously. Prednisolone is also taken at five milligrams twice daily, taken orally.

• Gastric Adenocarcinoma: The recommended dose of Docetaxel is 75 milligrams per square given in one hour intravenously and, followed by a dose of Cisplatin 75 milligrams per square meter given intravenously for one to three hours, following Fluorouracil 750 milligram per square meter per day given intravenously over 24 hours for five days, starting at the end of Cisplatin, and treatment is given or repeated every three weeks.

• Head and Neck Cancer: Docetaxel is given 75 milligrams per square meter as a one-hour intravenous injection, followed by Cisplatin 75 milligrams per square meter over one hour, on the first day following Fluorouracil 750 milligrams per square meter for five days. It is repeated every three weeks for four cycles. For the patients who have undergone chemoradiotherapy, a 75 milligram per square meter Docetaxel dose on day one, followed by Cisplatin, which is given 100 milligrams per square meter in 30 minutes to three hours, followed by Fluorouracil 1000 milligrams per square meter per day from day one to four, which is repeated every three weeks for three cycles.

• Premedication Regimen: Oral corticosteroids are administered before administering Docetaxel injection to overcome fluid retention and hypersensitivity reactions.

Dosage Adjustments During Treatment:

• Breast Cancer: Patients who were given 100 milligrams per square meter might develop neutropenia (fewer than 500 neutrophils) for more than one week; in that case, the patient's dose should be adjusted from 100 to 75 milligrams per square meter. If the patient develops neutropenia symptoms, the dose has to be reduced to 55 to 75 milligrams per square meter. If the patient develops more than grade three peripheral neuropathy, then discontinuation of the drug must be done.

• Combination Therapy in Breast Cancers: If the patient is co-administered Docetaxel with Doxorubicin and Cyclophosphamide, then the neutrophil count might exceed 1500 cells per cubic millimeter. Then, in such cases, reduce the dosage of Docetaxel to 60 milligrams per square meter.

• Non-Small Cell Lung Cancer: With Docetaxel monotherapy, some patients experience neutropenia, so the dose must be reduced to 55 milligrams per square meter. In combination therapy, where the patient is given Cisplatin along with Docetaxel, the dose is reduced to 65 milligrams per square meter and then to 50 milligrams per square meter.

• Prostate Cancer: Docetaxel injections are reduced from 75 milligrams per square meter to 60 milligrams per square meter. If the patient continues to have a reaction, it has to be discontinued at last.

• Gastric Cancer and Head and Neck Cancer: Patients who have used Docetaxel in combination with Cisplatin and Fluorouracil for gastric cancers or head and neck cancers often develop neutropenia lasting for a week. If the febrile neutropenia episodes are becoming even more severe, then the injection has to be reduced to 60 milligrams per square meter. Further discontinuing the treatment has to be suggested if toxic results persist.

Administration Precautions:

• As it is an anticancer drug, cautious use of the drug while handling and preparing it is recommended.

• The gloves must be used while preparing the drug.

• If a Docetaxel injection accidentally comes into contact with the skin, wash it with soap and water.

• If this drug comes into contact with the mucosa, thoroughly wash it with water.

• Using the prepared infusion solution in contact with plasticized PVC equipment is not recommended.

• The final solution formed is stored in bags or bottles and delivered by polyethylene-lined administration sets.

Preparation and Administration:

The use of Docetaxel injection at 10 milligrams per milliliter does not require dilution with a diluent and is ready to be added to the infusion solution.

Infusion:

• The doctor aseptically takes the required amount of Docetaxel injection solution, 10 milligrams per milliliter, in the syringe and selects a 250 ml infusion bag or bottle; it is either Sodium chloride 0.9 percent solution or Dextrose 5 percent to form a final solution of 0.3 to 0.74 milligrams per milliliter.

• If the dose formed is greater than 200 mg of Docetaxel, then a larger volume of the infusion bag should be prepared at a concentration of 0.74 milligrams per milliliter.

• Mix the infusion bag or bottle thoroughly by inverting or rotating it in a controlled manner without any foaming. Shaking is also prevented during preparation and transportation.

• The docetaxel injection must be visually inspected before administration, and if the diluted solution is cloudy or contains precipitation, it must be discarded.

• The solution formed is infused intravenously for one hour at ambient room temperature, which is below 25 degrees Celsius.

• It is stored between 2 degrees Celsius to 25 degrees Celsius for stability. It remains stable for 4 hours in 0.9% sodium chloride or 5% dextrose. The use of it should be used within four hours. It should not be frozen.

Adverse Reactions:

• Body as a Whole: The patient might experience diffuse pain, chest pain, and radiation recall.

• Cardiovascular Changes: The patient may have atrial fibrillation, deep vein thrombosis, thrombophlebitis, pulmonary embolism, syncope, tachycardia, and myocardial infarction.

• Cutaneous Skin Changes: Lupus erythematosus or bullous eruptions like erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and scleroderma with peripheral lymphedema can occur in patients.

• Gastrointestinal Changes: The patient can experience abdominal pain, anorexia (loss of appetite), constipation, duodenal ulcers, gastrointestinal hemorrhage, and perforations.

• Hematologic Changes: Bleeding episodes with disseminated intravascular coagulation with sepsis or multiorgan failure have been reported.

• Hypersensitivity Reactions: Anaphylactic shock is rarely seen.

• Hepatic Changes: Hepatitis is seen.

• Neurologic Changes: Confusion, seizures, and loss of consciousness have been observed in patients.

• Ophthalmologic Changes: Conjunctivitis and lacrimation, with transient visual disturbances, are reported.

• Hearing Changes: Ototoxicity and hearing disorders, including hearing loss, are reported.

• Respiratory Changes: Dyspnea, acute pulmonary edema, acute respiratory distress syndrome, interstitial pneumonia, and pulmonary fibrosis with radiation pneumonitis have been seen.

• Renal Changes: Renal insufficiency and renal failure have been reported.

Overdosage:

No antidote for Docetaxel has been established to date for overdosage. In cases of overdosage, the patient is admitted to a specialized unit where the patient is closely observed and monitored by the medical staff. Some of the complications of overdosage are bone marrow suppression, peripheral neurotoxicity, mucositis, neutropenia, cutaneous reactions, and paresthesia.

Drug Interactions:

• Docetaxel, when coadministered with Ketoconazole, an inhibitor of CYP3A4, increases Docetaxel exposure.

• A protease inhibitor, Ritonavir, also increases Docetaxel exposure.

Clinical Studies:

• Breast Cancer: 2045 patients, including those treated and those untreated with chemotherapy. Among these, 965 had normal liver function, and 61 patients had abnormal liver function. Docetaxel, 100 milligrams per square meter, was administered, and 95 percent did not receive any hematopoietic support, indicating safety in patients treated with Docetaxel for breast cancer and other tumors.

• Hematologic and Other Toxicity: All the hematologic and other toxicities are increased when the dose is increased in patients who have increased liver function tests. The adverse reactions were observed in three populations. A normal liver function test was conducted on 730 patients given Docetaxel at 100 milligrams per square meter. Eighteen patients had abnormal liver function tests. One hundred seventy-four patients with normal liver function were given Docetaxel at 60 milligrams per square meter, but the studies were conducted on different Japanese racial groups. There are three-arm monotherapy trials with docetaxel at 60, 75, and 100 milligrams per square meter in breast cancer. Severe adverse reactions were seen in 49.0 percent of patients receiving 60 milligrams per square meter of Docetaxel, compared with 75 and 100 milligrams per square meter Docetaxel doses. Discontinuation occurred in 5.3% of patients receiving 60 milligrams per square meter, 16.5% receiving 100 milligrams per square meter, and 6.9% receiving 75 milligrams per square meter of Docetaxel. Death was reported in 4% of patients who received 60 milligrams per square meter, 5.3% in those who received 75 milligrams per square meter, and 1.6% in those who received 100 milligrams per square meter.

• Combination Therapy With Docetaxel in the Adjuvant Treatment of Breast Cancer: 744 patients were treated with Docetaxel 75 milligrams per square meter, administered every three weeks, along with Doxorubicin and Cyclophosphamide (TAC). Of the patients who were treated with Doxorubicin, Docetaxel, and Cyclophosphamide (FAC), 36 percent reported adverse reactions, and 26.6 percent of patients treated with Fluorouracil, Docetaxel, and Cyclophosphamide reported adverse reactions. Six percent of the patients discontinued the Doxorubicin, Docetaxel, and Cyclophosphamide, and 1.1 percent discontinued the Fluorouracil, Docetaxel, and Cyclophosphamide. Death was also reported in two cases.

• Monotherapy of Docetaxel: 176 patients who were treated with 75 milligrams per square meter had non-small cell lung carcinoma in two randomized controlled trials.

• Combination Therapy for Lung Cancer: 31 patients are treated with Docetaxel and Cisplatin, and 37 patients with Vinorelbine and Cisplatin. Deaths were reported in 9 patients (2.2 percent) in Docetaxel+Cisplatin and eight patients (2 percent) in Vinorelbine and Cisplatin.

• Prostate Cancer: 332 patients were treated with Docetaxel 75 mg/m² and treated every three weeks in combination with Prednisolone 5 mg taken orally two times a day.

• Gastric Cancer: 221 patients received Docetaxel 75 milligrams per square meter, along with Cisplatin and Fluorouracil, for gastric adenocarcinoma.

• Head and Neck Cancer: 174 patients were treated with 75 milligrams per meter of Docetaxel, Cisplatin, and Fluorouracil, followed by radiotherapy or chemotherapy.

Use in Specific Population:

• During Pregnancy: Docetaxel is not a medicine that is safe for pregnant women. As per the study results from animal studies, it can cause harm to the unborn baby, so it is not advisable.

• During Breastfeeding: Lactating women are generally not supposed to have Docetaxel, as its impact on lactating women and their fed child is unknown.

• Geriatric Population: Docetaxel recommendation for the elderly must be done very carefully. Proper dose adjustments are the key.

• Pediatric Population: While recommending Docetaxel for pediatric patients, keep in mind the alcohol content in the injection. The safety of Docetaxel when used as monotherapy or in multidrug therapy in pediatric patients was similar to that observed in adults. But its efficacy has not yet been evaluated.

• Hepatic Impairment: Both bilirubin level and ALT (alanine aminotransferase) level should be considered when advising on hepatic impairment. It shouldn't be considered for those with bilirubin above the upper limit of the normal range.