Paclitaxel - Indications, Dosage, Precautions, and Side Effects

Overview:

Paclitaxel is a type of chemotherapy drug called taxanes. Taxanes meddle with networks in a cell called microtubules that assist in moving chromosomes during mitosis (a process of cell division). Paclitaxel blocks the growth of cancer cells and other separating cells by thwarting cell division. A class of chemotherapy drugs is taxane; providers utilize it to treat ovarian, prostate, and breast cancer, among other cancer types. They prevent cell division, also known as mitosis, the process by which cancer cells make more cancer cells. They destroy cancer cells and slow down the tumor growth. Taxanes comprises Paclitaxel, Cabazitaxel, and Docetaxel. Taxanes appear inherently in Yew trees. The first taxane, Paclitaxel, was extracted from the bark of the Western Yew tree. It is one of the two chemotherapy drug classes that develop from plants. The second type is called Vinca alkaloids. Vinca alkaloids appear innately in periwinkle plants.

How Does the Paclitaxel Work?

Paclitaxel meddles with the regular function of microtubule development. Whereas drugs like Colchicine cause the depolymerization of microtubules in vivo (a process taking place in a living organism), Paclitaxel stops their function by harboring the opposite effect; it hyper-stabilizes their structure. This step obliterates the cell's ability to use its cytoskeleton easily. Especially, Paclitaxel binds with the beta subunit of tubulin. Tubulin is also known as the building block of microtubules, and the binding of Paclitaxel locks these building blocks in place. The resultant microtubule or the Paclitaxel complex cannot be dismantled. This adversely impacts cell function because the lengthening and shortening of microtubules (termed dynamic instability) is required for their function as a cell's transportation highway. For example, chromosomes rely upon this property of microtubules at the time of mitosis. Further research has revealed that Paclitaxel influences programmed cell death (apoptosis) of cancerous cells by binding to Bcl-2 (B-cell leukemia 2), an apoptosis-stopping protein, thus stopping its function.

How Is Paclitaxel Used?

Paclitaxel (with poly-oxyethylene castor oil) injection comes as a liquid to be injected intravenously over three hours or 24 hours by a nurse or doctor in a hospital set-up or clinic. When Paclitaxel (with polyoxyethylene castor oil) treats ovarian, breast, or non-small cell lung cancer, it is usually administered once every three weeks. When Paclitaxel (with polyoxyethylene castor oil) is used to manage Kaposi's sarcoma medically, it can be given once every two or three weeks. The doctor may need to interrupt the patient's treatment, reduce the dose, or stop the treatment depending on the patient's response to the medication and any side effects that the patient experiences. One should be sure to tell the doctor how one feels during the treatment. One should ask the pharmacist or doctor for a document from the manufacturer related to information about the medication for the patient.

Dosage:

1. Ovarian Cancer (Adult):

Previously Untreated Patients:

175 mg/m2 IV (intravenous) over three hours pursued by Cisplatin 75 mg/m2 IV every three weeks.

Or

135 mg/m2 IV (intravenous) over 24 hours pursued by Cisplatin 75 mg/m2 IV every three weeks.

Previously Treated Patients:

135 mg/m2 IV (intravenous) over three hours every three weeks.

Or

175 mg/m2 IV (intravenous) over three hours every three weeks.

2. Breast Cancer (Adult):

After the failure of initial chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy:

175 mg/m2 IV (intravenous) over three hours every three weeks.

3. Breast Cancer Adjuvant (Adult):

For adjuvant treatment of node-positive breast cancer:

175 mg/m2 IV over three hours every three weeks for four courses distributed sequentially to doxorubicin-containing chemotherapy.

4. Non-small Cell Lung Cancer (Adult):

135 mg/m2 IV over 24 hours, followed by cisplatin mg/m2 IV every three weeks.

5. Kaposi's Sarcoma:

For patients with AIDS-related Kaposi's sarcoma:

135 mg/m2 IV over three hours every three weeks.

Or

100 mg/m2 IV over three hours every two weeks.

6. For Patients With Solid Tumors (Ovary, Breast, and NSCLC (Non-small Cell Lung Cancer):

Courses must only be repeated once the platelet count is at least 100,000 cells/mm3 and the neutrophil count is at least 1500 cells/mm3.

Dosage Form:

For Injectable Suspension for Intravenous Use:

White to yellow, sterile lyophilized powder comprising 100 mg of Paclitaxel formulated as albumin-bound particles in a single-dose vial for reconstitution.

The Direction of Administration:

• Follow the advised dosage for Paclitaxel.

• The medication has to be administered in a professional set-up like a hospital by a trained nurse or a doctor.

• While administering the drug and after the administration, one should look for any hypersensitivity reaction in the patient.

• If the patient is sensitive to Paclitaxel, do not re-administer the medication.

• Closely monitor the infusion site for drug infiltration or extravasation during administration. Restricting the infusion of Paclitaxel to 30 minutes may lessen the risk of infusion-related reactions.

• One should consider premedication for patients who are sensitive to the medication.

Warnings:

• This drug has to be only given under the charge of a physician experienced in using cancer chemotherapeutic agents in medical set-ups adequately equipped to control complications.

• Severe hypersensitivity and anaphylaxis reactions characterized by dyspnea (labored or difficult breathing) and low blood pressure (hypotension) needing treatment, angioedema (swelling that occurs rapidly beneath the skin or the mucosa), and generalized urticaria (a reaction in the form of a red round rash, welts which itch intensely) occurred in two to five percent of patients acquiring this drug in clinical trials. Fatal reactions may occur despite premedication. All patients must be pretreated with diphenhydramine, corticosteroids, and H2 antagonists. Patients who encounter severe hypersensitivity reactions should avoid being rechallenged with the drug.

• This medicine should be avoided given to patients with solid tumors who have baseline neutrophil counts of shorter than 1500 cells/mm3 and should not be given to patients with AIDS (acquired immunodeficiency syndrome) -related Kaposi's sarcoma if the baseline neutrophil count is smaller than 1000 cells/mm3. To observe the happening of bone marrow suppression, primarily neutropenia, which can be severe and result in infection, it is suggested that periodic peripheral blood cell counts be performed on all patients acquiring this drug.

For Patients:

What Are the Different Types of Cancers?

Cancer is not a single entity but rather a set of diseases, all of which force cells in the body to change and expand out of control. Cancers are classified according to the fluid or tissue category from which they form or the site in the body where they first grew. In addition, some cancers are of hybrid types. Carcinoma, lymphoma, sarcoma, leukemia, and myeloma are cancers.

Things to Consider:

Before the Administration of the Drug:

• The doctor and pharmacist, if you are allergic to Paclitaxel, Docetaxel, any other medications, polyoxyethylene castor oil, or medications that contain poly-oxyethylene castor oil such as cyclosporine injection or Teniposide. The doctor or pharmacist should be asked if the patient does not know if a medication they are allergic to contains polyoxyethylene castor oil.

• The doctor and pharmacist should be told what prescription and nonprescription vitamins, nutritional supplements, medications, and herbal products the patients intend to take. The patient should be sure to note any of the following: Buspirone, Carbamazepine, certain medications used to treat human immunodeficiency viruses (HIV) such as Indinavir, Ritonavir, Atazanavir, Nelfinavir, and Saquinavir, Lovastatin Midazolam; Nefazodone, Phenobarbital, Phenytoin, Repaglinide, Rifampin, Rosiglitazone, Sildenafil, Simvastatin, Telithromycin, Clarithromycin, Eletriptan, Ketoconazole, Felodipine, Gemfibrozil, Itraconazole, and Triazolam.

• The doctor may need to change the doses of the medications or monitor the patient carefully for side effects. Many other medications may also interact with Paclitaxel. Be sure to tell your doctor about all your medications, even those that do not occur on this list.

• The doctor should know if the patient ever had or has any liver or heart disease.

• The doctor should be informed if the patient is pregnant or plans to become pregnant. The patient should avoid becoming pregnant while receiving the injection of Paclitaxel (with poly-oxyethylated castor oil). Talk to the doctor about birth control methods that the patient can use during the treatment. The doctor should be called if the patient becomes pregnant while receiving Paclitaxel (with polyoxyethylene castor oil) injection. Paclitaxel injection has the potential to harm the fetus.

• The doctor should be informed if the patient is breastfeeding. The patient should avoid breastfeeding while receiving the injection of Paclitaxel (with poly-oxyethylated castor oil).

• If the patient has dental surgery, the doctor or dentist should be informed that the patient is receiving an injection of Paclitaxel (with polyoxyethylene castor oil).

How to Administer Paclitaxel?

• Aseptically, reconstitute each vial by injecting 20 mL of 0.9 percent Sodium Chloride Injection, USP (United States Pharmacopeia).

• Slowly inject the 20 milliliters of 0.9 percent Sodium Chloride Injection, USP, over a minimum of 60 seconds. Use the sterile syringe to handle the solution flow onto the vials inside where the walls get covered.

• Avoid injecting the 0.9 percent Sodium Chloride Injection, USP, straight onto the lyophilized cake, as this will lead to foaming.

• Once the injection is done, allow the vial to sit for at least five minutes to ensure proper wetting of the lyophilized powder or cake.

• Gently stir, and the vial slowly should be moved upside down for at least two minutes until the total dissolution of any powder or cake appears.

• The formation of the foam should be avoided.

• If clumping or foaming appears, the solution should be stood for at least 15 minutes until the foam lessens.

After the Administration of the Drug:

• Paclitaxel should be administered at certified healthcare facilities.

• The patient should be observed every day for at least six to eight days at the certified healthcare facility after administration for any signs or symptoms of toxicity.

• The patient should be instructed to remain around or near the certified healthcare facility for about a few weeks after the infusion of Paclitaxel.

What Side Effects Can Paclitaxel Medication Cause?

Paclitaxel (with poly-oxyethylated castor oil) can cause side effects. Tell the doctor if any of these symptoms are extreme or do not go away.

• Pain, swelling, redness, or sores in the site where the medication was injected.

• Burning, numbness, or tingling in the hands or feet.

• Joint pain or muscle pain.

• Diarrhea.

• Vomiting.

• Nausea.

• Hair loss.

• Oral ulcers.

Some side effects can be severe. If the patient experiences any of these symptoms or those listed in the important warning section, call the doctor immediately or get emergency medical treatment:

• Shortness of breath.

• Pale skin.

• Extreme tiredness

• Unusual bleeding and bruising.

• Chest pain.

• Irregular or slow heartbeat.

How Effective Is Paclitaxel?

Paclitaxel, given weekly, has been used with merit in treating advanced breast cancer as single-agent therapy, in combination with chemotherapy, radiotherapy, and immunomodulating drugs, such as Trastuzumab. Many of the patients in these studies have received previous chemotherapy regimens. Nevertheless, response rates with weekly Paclitaxel of up to 87 percent have been achieved with single-agent therapy, up to 88 percent with combination therapy, and up to 100 percent when united with radiotherapy. Paclitaxel administered weekly with the humanized monoclonal antibody against HER2 (human epidermal growth factor receptor 2), Trastuzumab, has response rates of 51 to 83 percent in patients with aggressive HER2-positive tumors. Paclitaxel is linked with moderate toxicity. The primary dose-limiting toxicities are neutropenia (when a person has too few neutrophils white blood cells) and peripheral neuropathy, which usually can be managed.

How Is Paclitaxel Manufactured and Supplied?

Paclitaxel for injectable suspension (Paclitaxel protein-bound particles for injectable suspension) (albumin‑bound) is Paclitaxel developed as albumin‑bound nanoparticles with a mean particle size of around 130 nanometers. Paclitaxel exists in the particles in a non-crystalline, amorphous state. Paclitaxel is an inhibitor of microtubules.

Paclitaxel is delivered as a whitish-yellow or a completely white or yellow, lyophilized, sterile powder for reconstitution with 20 milliliters of 0.9 % Sodium Chloride Injection, USP initial to intravenous infusion. Each single‑dose vial contains 100 milligrams of Paclitaxel (bound to human albumin) and approximately 900 milligrams of human albumin (containing sodium caprylate and sodium acetyl-tryptophanate). Each milliliter (mL) of reconstituted suspension contains 5 milligrams of Paclitaxel composed of albumin‑bound particles. Paclitaxel is free of solvents.

How to Store and Dispose of Paclitaxel?

Paclitaxel for injectable suspension (Paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is a white to yellow, lyophilized sterile powder supplied as NDC: 68817-134-50 100 mg of paclitaxel in a single-dose vial, individually packaged in a carton.

Storage is in the vials in actual cartons at 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit). The medications should be retained in the original package to protect them from bright light. Paclitaxel is a cytotoxic drug. Applicable special handling and disposal procedures should be followed.

What Should Be Done in the Case of Paclitaxel Overdose?

In case of an overdose, the poison control helpline should be called if there. Information about it is also available online. If the victim collapses, has a seizure, has breathing trouble, or cannot be aroused, one should immediately call emergency services.

What Should Be Done if a Dose of Paclitaxel Is Missed?

The medical staff or the healthcare facility should be contacted if a dose is missed in chemotherapy.

What Other General Information Should Be Known About Paclitaxel?

Axicabtagene may cause side effects that can be fatal or life-threatening, so the patient should call or visit the healthcare provider or get help on an emergency basis. It is essential to tell the physician or anybody from the medical staff that the patient has received Axicabtagene and show them the patient's wallet card. The healthcare provider possibly gives the patient other medicines to treat the side effects.

For Doctors:

Pharmacology:

• Mechanism of Action: Paclitaxel is a microtubule inhibitor that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability inhibits the normal dynamic reorganization of the microtubule network, which is essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

• Pharmacokinetics: The pharmacokinetics of total Paclitaxel following thirty minutes and three hours of infusions of Paclitaxel at dose levels of 80 to 375 mg/m2 (0.31 to 1.15 times the highest recommended dosage) were determined in clinical studies. Dose levels of mg/m2 refer to milligrams of Paclitaxel in Paclitaxel. Following intravenous administration of Paclitaxel to patients with solid tumors, Paclitaxel plasma concentrations declined biphasically, the initial rapid decline characterizing distribution to the peripheral compartment and the slower second phase representing drug elimination.

Warning and Precautions Before Prescribing:

• Severe myelosuppression (primarily neutropenia) is the dose-limiting toxicity and dose-dependent of Paclitaxel. In clinical studies, Grade 3 to 4 neutropenia occurred in 35 % of patients with metastatic breast cancer (MBC), 48 % with non-small cell lung cancer (NSCLC), and 39 % with pancreatic cancer.

• In patients with adenocarcinoma of the pancreas, withhold Paclitaxel and Gemcitabine if the ANC (absolute neutrophil count) is less than 500 cells/mm3 or platelets is less than 50,000 cells/mm3 and delay at the beginning of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on day one of the cycle. The treatment should be resumed with an appropriate dose reduction if recommended.

• Sensory neuropathy is dose- and schedule-dependent. If greater than or equal to Grade 3, sensory neuropathy develops, the Paclitaxel should be withheld in the treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to less than or equal to Grade 1 for NSCLC and pancreatic cancer, followed by a dose reduction for all subsequent courses of Paclitaxel.

• Sepsis appeared in five percent of patients with or without neutropenia who received Paclitaxel with Gemcitabine in combination. The presence of a biliary stent or biliary obstruction was a risk factor for severe or fatal sepsis. If a patient becomes febrile (febrile means sudden onset of fever) (regardless of ANC), the treatment should be initiated with a broad spectrum.

• Based on the findings in animals and the mechanism of action, Paclitaxel can cause fetal harm when given to a pregnant woman. In animal reproduction studies, administration of formulated Paclitaxel albumin-bound particles to rats in pregnancy at doses less than the highest recommended human dose, based on the body surface area, caused embryo-fetal toxicities, comprising intrauterine mortality, reduced numbers of live fetuses, increased resorptions, and malformations.

Indications and Uses:

• Metastatic Breast Cancer: Paclitaxel is given for treating breast cancer after failure of combination chemotherapy for metastatic diseases or relapse within six months of adjuvant chemotherapy. Before, therapy should have comprised an anthracycline unless clinically contraindicated.

• Non-small Cell Lung Cancer: Paclitaxel is suggested for the first-line treatment of advanced local or metastatic non-small cell lung cancer, combined with Carboplatin, in patients not candidates for radiation therapy or curative surgery.

• Adenocarcinoma of the Pancreas: Paclitaxel is suggested for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, given in combination with Gemcitabine.

Dosage and Strength Forms:

For injectable suspension for intravenous use: White to yellow, lyophilized sterile powder containing 100 milligrams of Paclitaxel formulated as albumin-bound particles in a single-dose vial for reconstitution.

Dosage and Administration:

Paclitaxel, like Abraxane, should not be substituted with other Paclitaxel formulations. Various formulations of Paclitaxel have different dosages and administration instructions from each other. The infusion site should be monitored for extravasation or drug infiltration during administration. Limiting the infusion of Paclitaxel to half an hour may lessen the risk of infusion-related reactions. The premedication should be considered in patients who have had hypersensitivity reactions previously to Paclitaxel. Rechallenging should be avoided in patients who experience a severe hypersensitivity reaction to Paclitaxel.

• Recommended Dosage for Metastatic Breast Cancer: After the collapse of combination chemotherapy for metastatic breast cancer or relapse within six months of adjuvant chemotherapy, the suggested regimen for Paclitaxel is 260 mg/m2 distributed intravenously over half an hour every three weeks.

• Recommended Dosage for Non-small Cell Lung Cancer: The recommended dose of Paclitaxel is 100 mg/m2 given as an intravenous infusion over half an hour on days first, eighth, and fifteenth of each 21-day cycle. Carboplatin on the first day of each 21-day cycle immediately after Paclitaxel.

• Recommended Dosage for Adenocarcinoma of the Pancreas: The recommended dose of Paclitaxel is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day cycle. Administer gemcitabine immediately after Paclitaxel on days first, eighth, and fifteenth of every 28-day cycle.

Preparation:

• Aseptically, reconstitute each vial by injecting 20 mL of 0.9 % Sodium Chloride Injection, USP.

• Slowly inject the 20 milliliters of 0.9 % sodium chloride Injection, USP, over a minimum of 60 seconds, using the sterile syringe so that the solution flows onto the inside of the wall.

• Do not inject the 0.9 % sodium chloride injection, USP, directly onto the lyophilized cake, as this will result in foaming.

• Once the injection is complete, allow the vial to sit for at least 5 minutes to wet the lyophilized cake/powder properly.

• Gently swirl and/or invert the vial slowly for at least 2 minutes until any cake/powder is completely dissolved.

• Avoid the generation of foam.

• If foaming or clumping occurs, stand the solution for at least 15 minutes until the foam subsides.

Administration:

• Each milliliter of the reconstituted formulation will contain 5 mg/mL Paclitaxel. The reconstituted suspension has to be milky and homogenous with no visible particulates. If particulates or settling are visible, the vial should be gently moved upside down to ensure complete resuspension before use.

• The reconstituted suspension should be discarded if precipitates are observed. Any unused portion should be discarded, too.

• The exact calculation of the total dosing volume of 5 mg/mL suspension required for the patient and gradual withdrawal of the dosing volume of the reconstituted suspension from the vial(s) into a syringe:

• Dosing volume (milliliters) = Total dose (mg)/5 (mg/mL).

• Inject the appropriate amount of reconstituted Paclitaxel into a sterile and empty intravenous bag [plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type intravenous bag].

• The usage of specialized (di(2-ethylhexyl)phthalate) DEHP-free solution containers or administration sets is optional to organize or administer Paclitaxel infusions.

• The use of medical devices containing silicone oil as a lubricant (i.e., syringes and intravenous bags) to administer and reconstitute Paclitaxel may result in the formation of proteinaceous strands.

Contraindications:

• Baseline neutrophil counts of less than 1,500 cells/mm3.

• A history of severe hypersensitivity reactions to Paclitaxel.

Drug Interactions:

Other drugs can affect Paclitaxel, including prescription and over-the-counter medicines, vitamins, and herbal supplements. The physician should be told about all the current medications or any medication the patient starts or stops using. CYP2C8 and CYP3A4 catalyze the Paclitaxel metabolism. Caution should be exerted when distributing Paclitaxel concomitantly with medicines that induce or inhibit CYP2C8 or CYP3A4.

Other Specifications:

• In Pregnancy: Based on its findings in animals and the mechanism of action, Paclitaxel can lead to fetal harm when administered to a pregnant woman. There is no available human data on Paclitaxel use in pregnant women to report the drug-associated risk.

• In Lactating Period: There is no data on the presence of Paclitaxel in human milk or its effect on the child on breastfeeding or milk production. In animal studies, Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because of the possibility of severe adverse reactions in a breastfed child from Paclitaxel, advise lactating women not to breastfeed during the treatment with Paclitaxel and for two weeks after the last dose is given.

• In Pediatric Patients: Safety and efficacy in pediatric patients have yet to be documented.