Docetaxel - Indications, Dosage, and Contraindications

Overview:

Docetaxel is used to treat many types of cancers like breast cancer, head and neck cancer, stomach cancer, and prostate cancer. It is used as a chemotherapy drug. It can be used alone or in combination with other chemotherapeutic drugs. Chemotherapy destroys cancer cells, and Docetaxel is an anticancer drug used to destroy cancer cells.

What Are the Indications of Docetaxel?

Docetaxel is indicated for:

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

• Non-Small Cell Lung Cancer (NSCLC) - Docetaxel 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.

• Gastric Adenocarcinoma (GC) - The use of Docetaxel along with Cisplatin and Fluorouracil for untreated, advanced gastric adenocarcinoma, including gastrointestinal junction.

• Squamous Cell Carcinoma of the Head and Neck Cancer - Docetaxel is used along with Cisplatin and Fluorouracil for the induction of the locally advanced squamous cell carcinoma of the head and neck.

Dosage and Administration:

Dosage Forms: Vials.

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

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

• Breast cancer is locally advanced or metastatic in 60 milligrams per square to 100 milligrams per meter square single agent.

• Breast cancer adjuvant in 75 milligrams per meter square administered after one hour of Doxorubicin 50 milligrams per meter square and Cyclophosphamide 500 milligrams per meter square after every three weeks for six cycles.

• Non-small cell lung cancer is administered after platinum therapy failure, and Docetaxel is used as a 75 milligrams per meter square single agent.

• Non-small cell lung cancer, the use of Docetaxel with 75 milligrams per meter square followed by Cisplatin 75 milligrams per meter square.

• In hormone-refractory prostate cancer cases, 75 milligrams per meter square 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 meter square followed by Cisplatin 75 milligrams per meter square administered both on day one followed by Fluorouracil 750 milligrams per meter square per day for 24 hours infusion for five days with the end of Cisplatin infusion for four cycles.

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

• For all the patients, the use of premedication of corticosteroids is done.

Contraindications:

• Docetaxel is contraindicated in cases with hypersensitivity of Docetaxel.

• It is also contraindicated in cases with neutrophil counts of less than 1500 cells per millimeter square.

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 that include erythema of extremities along with edema and desquamation may occur. If severe skin toxicity occurs, then it requires a dose adjustment.

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

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

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

• Toxic Deaths - In breast cancers, 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 cases 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 as patients with combined abnormalities of transaminases and alkaline phosphatase.

• Hematologic Effects - The patients who are facing severe neutropenia, which lasts for seven days, or febrile neutropenia, are administered a 25 percent reduction in the dose of Docetaxel injection.

• Hypersensitivity Reactions - For patients suffering from severe hypersensitivity reactions with symptoms like rash, erythema, hypotension, or bronchospasm in the first or second dose or within three days of corticosteroids, discontinuation is the option.

• Fluid Retention - Severe fluid retention has been seen in cases of Docetaxel, so premedication with oral corticosteroids is important before starting the Docetaxel.

Special Considerations:

• Pregnancy - Docetaxel injection can cause fetal harm on use, so cautious use of Docetaxel during pregnancy is done.

• Nursing Mothers - Docetaxel is excreted in human milk or not is unknown till now, but many drugs usually get excreted in human milk. Therefore, severe adverse reactions can occur in nursing mothers on use, so cautious use of Docetaxel is done.

• Pediatric Use - The safety and effectiveness of Docetaxel is not determined till now in pediatric patients.

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

• Hepatic Impairments - The patient with an abnormal liver function test should not receive any Docetaxel injections.

For Patients:

Why Is Docetaxel Used?

Docetaxel injection is used to treat different cancers like breast cancer, lung, prostate, stomach, head, and neck cancers. It can be used alone or in combination with other drugs. It belongs to the class taxanes. It acts on cancer cells by stopping their growth and spread.

How Is Docetaxel Given?

Docetaxel injections are available in the form of liquids that are delivered into the veins (intravenously). It is usually delivered over one hour every three weeks. The doctor will give a premedication of corticosteroids such as Dexamethasone to prevent the patient from any adverse effects, and it is usually taken before every dose cycle.

What Are the Precautions Taken While Using Docetaxel?

• The patient should inform the doctor about allergic reactions to Docetaxel.

• The patient should inform the doctor if the patient is taking any other medications like antifungals.

• The patient should avoid the use of alcohol while being on Docetaxel injection usage.

• The patient should avoid pregnancy if the patient is under Docetaxel usage.

• The patient should not breastfeed while taking Docetaxel injection and after two weeks till the final dose.

• The patient should inform the doctor before surgery, including dental surgery.

• The use of Docetaxel can cause drowsiness and can affect thinking and motor functions. So, the patient should avoid driving and other tasks that need concentration.

What Are the Side Effects of Docetaxel?

Side effects of Docetaxel are:

• 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.

Serious side effects are observed in some cases with some symptoms. If such symptoms appear, then the patient requires immediate medical attention. Some severe side effects are:

• Blister on the skin.

• Numbness and tingling in the hands and feet.

• Burning sensation in hands and feet.

• Weakness in 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?

Overdosage symptoms are:

• Seizures.

• Troublesome breathing.

• Sore throat.

• Fever.

• Chills.

• Sores in mouth and throat.

• Skin irritation.

• Weakness.

• Numbness.

• Tingling.

• Burning sensation in hands and feet.

• Signs of infection.

What If the Patient Misses the Scheduled Dose?

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

For Doctors:

Docetaxel:

Docetaxel is an anti-cancerous or anti-neoplastic agent and belongs to a class of taxanes. 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 is present in 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 disturbing the microtubular network present in the cells, which is important for mitotic and interphase functions. Docetaxel further binds to free tubulin and provides the assembly of tubulin to form stable microtubules. All these lead to the production of microtubule bundles with stabilization that inhibits cell mitosis. After binding to microtubules, Docetaxel does not alter the bonded microtubules.

• Absorption: Docetaxel is administered by injecting the injection intravenously. It takes infusion times of one to two hours. It has a three-compartment with half-lives for alpha for 4 minutes, the beta for 36 min, and gamma for 11.1 hours phases. Total clearance was 21 liters per hour per meter per square.

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

• Metabolism: Docetaxel is metabolized by CYP3A4 isoenzymes and further metabolized by cytochrome P4503A4.

• Elimination: Docetaxel is eliminated in urine and feces, but the main elimination is by fecal. In the seven days, urinary 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 influences on age differences.

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

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

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

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

Nonclinical Toxicology:

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

• Mutagenesis: Docetaxel has shown no mutagenic effects on the test done on 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 along with Cisplatin in patients who have not received chemotherapy earlier.

• 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 - Injections. 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 meter square to 100 milligrams per meter square delivered intravenously over one hour every three weeks, and for operable node-positive breast cancer, the dose is 75 milligrams per meter square which are delivered in one hour after Doxorubicin 50 milligrams per meter square, and Cyclophosphamide 500 milligram in every three weeks for six courses.

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

• Prostate Cancer: The recommended dose of Docetaxel is 75 milligrams per meter square 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 meter square for one to three hours intravenous infusion following Fluorouracil 750 milligram per meter square per day in 24-hour intravenous injection are given for five days, starting at the end of Cisplatin and treatment is given or repeated in every three weeks.

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

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

Dosage Adjustments During Treatment:

• Breast Cancer: The patients who were given 100 milligrams per square meter can have neutropenia (less than 500 neutrophils cells) for more than one week, then the patient dosage is adjusted from 100 to 75 milligrams per square meter. If the patient carries these symptoms further, the dose is shifted to 75 to 55 milligrams per meter square. If in case the patient develops more than grade three peripheral neuropathy, then discontinuation of the drug is done.

• Combination Therapy in Breast Cancers: If the patient is co-administered Docetaxel with Doxorubicin and Cyclophosphamide, then the neutrophil can be more than 1500 cells per millimeter cube or three to four stomatitis, then such patients should reduce the dosage of Docetaxel to 60 milligrams per meter square.

• Non-Small Cell Lung Cancer: In monotherapy of Docetaxel, the patient faces neutropenia, then the dose is reduced to 55 milligrams per meter square. And in combination therapy, the patient who is given Cisplatin along with Docetaxel they are reducing the dosage to 65 milligrams per meter square, further reduced to 50 milligrams per meter square.

• Prostate Cancer: Docetaxel injections are reduced to 60 from 75 milligrams per meter square. And if the patient continues to face a reaction, it is discontinued at last.

• Gastric Cancer and Head and Neck Cancer: Patient who has injected Docetaxel in combination with Cisplatin and Fluorouracil in gastric cancers or head and neck cancers are observed for neutropenia lasting for a week. If the febrile neutropenia episodes are even becoming severe, the injection is reduced to 60 milligrams per square meter. Further discontinuing the treatment if toxic results persist.

Administration Precautions:

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

• The gloves are used while preparing for the drug.

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

• If these drugs come in contact with mucosa, thoroughly wash them with water.

• Using the prepared solution for infusion to 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 of 10 milligrams per milliliter does not require the previous dilution with a diluent, and thus it is ready to add to the infusion solution to infuse.

Infusion:

• The doctor aseptically takes the required amount of Docetaxel injection solution 10 milligrams per milliliter in the syringe and injection 250 ml infusion bags or bottle selected, and 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 milliliters.

• If the dose formed is greater than 200 mg of Docetaxel, then a larger volume of infusion bag to have 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.

• Docetaxel injection is inspected visually before administering, and if the diluted solution is not clear or has precipitation, then it needs to be discarded.

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

• It is stored between 2 degrees Celsius to 25-degree Celsius for stability. It remains stable for four hours in 0.9 percent Sodium Chloride or 5 percent Dextrose. The use of it should be done within four hours. It should not be frozen.

Adverse Reaction:

• Body As a Whole: The body has diffuse pain, chest pain, and radiation recall phenomenon.

• Cardiovascular Changes: The patient can 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 suffer from abdominal pain, anorexia, 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 with 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 failures have been reported.

Overdosage:

No antidote for Docetaxel has been established till now for its 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 reaction, and paresthesia.

Drug Interactions:

• Docetaxel, on concomitant administration with Ketoconazole, an inhibitor of CYP3A4, increases Docetaxel exposure.

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

Clinical Studies:

• Breast Cancer: 2045 patients, including the patients that are treated and are untreated with chemotherapy. Among these, 965 were with normal liver function, and 61 patients with abnormal liver function. Docetaxel, 100 milligrams per meter square, was delivered, and 95 percent did not receive any hematopoietic support, which shows safety in patients who are delivered Docetaxel for breast cancer and other tumors.

• Hematologic and Other Toxicity: All the hematologic and other toxicity is increased when the dose is increased in the patients who are having increased liver function tests. The adverse reactions were observed in three populations. Normal liver function test 730 patients given Docetaxel 100 milligrams per meter square. Eighteen patients with abnormal liver function tests. One hundred seventy-four patients were given Docetaxel at 60 milligrams per square meter with normal liver functions, but studies were on different races of Japanese.

• There are three arm monotherapy trials, with Docetaxel 60 milligrams per meter square, 75 milligrams per meter square, and 100 milligrams per meter square in breast cancer. Severe adverse reactions were seen in 49.0 percent of patients with 60 Docetaxel milligrams per meter square on comparing it with 75 and 100 milligrams per meter square Docetaxel doses. Discontinuation was carried out in 5.3 percent of patients who were given 60 milligrams per meter square, 16.5 percent reported 100 milligrams per meter square dose, and 6.9 percent in 75 milligrams per meter square Docetaxel. Death was reported in 4 percent of patients in 60 milligrams per meter square, 5.3 percent in 75 milligrams per meter square, and 1.6 percent in 100 milligrams per meter square.

• Combination Therapy With Docetaxel in the Adjuvant Treatment of Breast Cancer: 744 patients were treated with Docetaxel 75 milligrams per meter square which was delivered every three weeks along with Doxorubicin and Cyclophosphamide (TAC). Of the patient who was treated with Doxorubicin Docetaxel+Cyclophosphamide (FAC) among these, 36 percent reported adverse reactions, and 26.6 percent of patients were treated with Fluorouracil+Docetaxel Cyclophosphamide reported adverse reactions. 6 percent of the patients discontinued the Doxorubicin+Docetaxel+Cyclophosphamide, and 1.1 percent discontinued the Fluorouracil+Docetaxel+Cyclophosphamide. Death was also reported in two cases.

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

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

• Prostate Cancer: Combination Therapy with Docetaxel: 332 patients were treated with Docetaxel 75 milligrams per meter square and treated every three weeks in combination with Prednisolone 5 mg taken orally two times a day.

• Gastric Cancer: Combination Therapy with Docetaxel: 221 patients were administered Docetaxel 75 milligrams per meter square along with Cisplatin and Fluorouracil in gastric adenocarcinoma.

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