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12 CLINICAL PHARMACOLOGY

12 CLINICAL PHARMACOLOGY

12.1 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.

12.3 Pharmacokinetics

Absorption

The pharmacokinetics of docetaxel has been evaluated in cancer patients after administration of 20 mg/m2 to 115 mg/m2 in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m2 to 115 mg/m2 with infusion times of 1 to 2 hours.

Docetaxel’s pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with initial rapid distribution phase and the late (terminal) phase.

Distribution

Mean steady state volume of distribution was 113 L. Docetaxel is approximately 94% protein bound in vitro, mainly to α1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was approximately 97%. Dexamethasone does not affect the protein binding of docetaxel.

Elimination

With extended plasma sampling up to 8 to 22 days post infusion, the estimated mean total body clearance was 18 L/h/m2 (range of means: 14 to 23) and mean terminal elimination half-life was 116 hours (range of means: 92 to 135).

Metabolism

Docetaxel is metabolized by the CYP3A4 isoenzyme in vitro [see Drug Interactions (7)].

Excretion

In three cancer patients urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively, within 7 days. About 80% of the radioactivity recovered in feces was excreted during the first 48 hours as 1 major and 3 minor metabolites with less than 8% as unchanged drug.

Specific Populations

Effect of Age

A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m2. Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel was not influenced by age.

Effect of Gender

The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel.

Hepatic Impairment

The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with Docetaxel Injection. Patients with severe hepatic impairment have not been studied [see Warnings and Precautions (5.2), Use in Specific Populations (8.6)].

Effect of Race

Mean total body clearance for Japanese patients dosed at the range of 10 mg/m2 to 90 mg/m2 was similar to that of European/American populations dosed at 100 mg/m2, suggesting no significant difference in the elimination of docetaxel in the two populations.

Drug Interaction Studies

Effect of Ketoconazole

The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/m2 intravenous) alone or docetaxel (10 mg/m2 intravenous) in combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 3-week washout period. The results of this study indicated that the mean dose-normalized AUC of docetaxel was increased 2.2-fold and its clearance was reduced by 49% when docetaxel was coadministered with ketoconazole [see Dosage and Administration (2.7), Drug Interactions (7)].

Effect of Combination Therapies

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Dexamethasone: Docetaxel total body clearance was not modified by pretreatment with dexamethasone.
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Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar to that previously observed following monotherapy with docetaxel. The pharmacokinetic profile of cisplatin in combination therapy with docetaxel was similar to that observed with cisplatin alone.
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Cisplatin and Fluorouracil: The combined administration of docetaxel, cisplatin and fluorouracil in 12 patients with solid tumors had no influence on the pharmacokinetics of each individual drug.
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Prednisone: A population pharmacokinetic analysis of plasma data from 40 patients with metastatic castration-resistant prostate cancer indicated that docetaxel systemic clearance in combination with prednisone is similar to that observed following administration of docetaxel alone.
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Cyclophosphamide and Doxorubicin: A study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug interactions between docetaxel (75 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) when administered in combination. The coadministration of docetaxel had no effect on the pharmacokinetics of doxorubicin and cyclophosphamide when the three drugs were given in combination compared to coadministration of doxorubicin and cyclophosphamide only. In addition, doxorubicin and cyclophosphamide had no effect on docetaxel plasma clearance when the three drugs were given in combination compared to historical data for docetaxel monotherapy.
Medication Guide

MEDICATION GUIDE

This Patient Information has been approved by the U.S. Food and Drug Administration.

Revised: May 2023

Patient Information
Docetaxel (doe-se-TAKS-el) Injection
for intravenous use

What is the most important information I should know about Docetaxel Injection?
Docetaxel Injection can cause serious side effects, including death.

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The chance of death in people who receive Docetaxel Injection is higher if you:
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have liver problems
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receive high doses of Docetaxel Injection
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have non-small cell lung cancer and have been treated with chemotherapy medicines that contain platinum
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Docetaxel Injection can affect your blood cells. Your healthcare provider should do routine blood tests during treatment with Docetaxel Injection. This will include regular checks of your white blood cell counts. If your white blood cells are too low, your healthcare provider may not treat you with Docetaxel Injection until you have enough white blood cells. People with low white blood cell counts can develop life-threatening infections. The earliest sign of infection may be fever. Follow your healthcare provider's instructions for how often to take your temperature during treatment with Docetaxel Injection. Call your healthcare provider right away if you have a fever.
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Swelling (inflammation) of the small intestine and colon. This can happen at any time during treatment and could lead to death as early as the first day you get symptoms. Tell your healthcare provider right away if you develop new or worse symptoms of intestinal problems, including stomach (abdominal) pain or tenderness or diarrhea, with or without fever.
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Severe allergic reactions are medical emergencies that can happen in people who receive Docetaxel Injection and can lead to death. You may be at higher risk of developing a severe allergic reaction to Docetaxel Injection if you are allergic to paclitaxel. Your healthcare provider will monitor you closely for allergic reactions during your Docetaxel Injection infusion.
Tell your healthcare provider right away if you have any of these signs of a severe allergic reaction:
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trouble breathing
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sudden swelling of your face, lips, tongue, throat, or trouble swallowing
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hives (raised bumps), rash, or redness all over your body
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Your body may hold too much fluid (severe fluid retention) during treatment with Docetaxel Injection. This can be life threatening. To decrease the chance of this happening, you must take another medicine, a corticosteroid, before each Docetaxel Injection treatment. You must take the corticosteroid exactly as your healthcare provider tells you. Tell your healthcare provider or nurse before your Docetaxel Injection treatment if you forgot to take your corticosteroid dose or do not take it as your healthcare provider tells you. Tell your healthcare provider right away if you have swelling in your legs or feet, weight gain or shortness of breath.
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Risk of new cancers. An increase in new (second) cancers has happened in people treated with Docetaxel Injection together with certain other anticancer treatments. This includes certain blood cancers, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), non-Hodgkin's Lymphoma (NHL), and kidney cancer.
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Changes in blood counts due to leukemia and other blood disorders may occur years after treatment with Docetaxel Injection.
 
Your healthcare provider will check you for new cancers during and after your treatment with Docetaxel Injection.
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Severe skin problems.
Tell your healthcare provider right away if you have any of these signs of a severe skin reaction:
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redness and swelling of your arms and legs.
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blistering, peeling, or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet) with or without a rash. You may also have flu-like symptoms such as fever, chills, or muscle aches.
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red, scaly rash all over your body with blisters, small red or white bumps under the skin that contain pus (pustules), and fever.

What is Docetaxel Injection?
Docetaxel Injection is a prescription anticancer medicine used to treat certain people with:

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breast cancer
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non-small cell lung cancer
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prostate cancer
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stomach cancer
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head and neck cancer

It is not known if Docetaxel Injection is effective in children.

Do not receive Docetaxel Injection if you:

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have a low white blood cell count.
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have had a severe allergic reaction to:
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docetaxel, the active ingredient in Docetaxel Injection, or
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any other medicines that contain polysorbate 80. Ask your healthcare provider or pharmacist if you are not sure.

See "What is the most important information I should know about Docetaxel Injection?" for the signs and symptoms of a severe allergic reaction.
See the end of this Patient Information for a complete list of the ingredients in Docetaxel Injection.

Before you receive Docetaxel Injection, tell your healthcare provider about all of your medical conditions, including if you:

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are allergic to any medicines, including paclitaxel. See "Do not receive Docetaxel Injection if you".
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have liver problems
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have kidney problems
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are pregnant or plan to become pregnant. Docetaxel Injection can harm your unborn baby. You should not become pregnant during treatment with Docetaxel Injection. Tell your healthcare provider if you become pregnant or you think you may be pregnant during treatment with Docetaxel Injection.
Females who are able to become pregnant:
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Your healthcare provider will check to see if you are pregnant before you start treatment with Docetaxel Injection.
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You should use effective birth control (contraception) during treatment with Docetaxel Injection and for 2 months after the last dose.
 
Males with female partners who are able to become pregnant should use effective birth control during treatment with Docetaxel Injection and for 4 months after the last dose.
 
Talk to your healthcare provider if you have questions about birth control options that are right for you.
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are breastfeeding or plan to breastfeed. It is not known if Docetaxel Injection passes into your breast milk. Do not breastfeed during treatment with Docetaxel Injection and for 1 week after the last dose.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Docetaxel Injection may affect the way other medicines work, and other medicines may affect the way Docetaxel Injection works.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How will I receive Docetaxel Injection?

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Docetaxel Injection will be given to you as an intravenous (IV) injection into your vein, usually over 1 hour.
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Docetaxel Injection is usually given every 3 weeks.
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Your healthcare provider will decide how long you will receive treatment with Docetaxel Injection.
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Your healthcare provider will check your blood cell counts and other blood tests during your treatment with Docetaxel Injection to check for side effects of Docetaxel Injection.
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Your healthcare provider may stop your treatment, change the timing of your treatment, or change the dose of your treatment if you have certain side effects while receiving Docetaxel Injection.

What are the possible side effects of Docetaxel Injection?
Docetaxel Injection may cause serious side effects including death.

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See "What is the most important information I should know about Docetaxel Injection?"
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Neurologic problems. Neurologic symptoms are common in people who receive Docetaxel Injection but can be severe. Tell your healthcare provider right away if you have numbness, tingling, or burning in your hands or feet (peripheral neuropathy) or weakness of your legs, feet, arms, or hands (motor weakness).
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Vision problems including blurred vision or loss of vision. Tell your healthcare provider right away if you have any vision changes.
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Docetaxel Injection contains alcohol. The alcohol content in Docetaxel Injection may impair your ability to drive or use machinery right after receiving Docetaxel Injection. Consider whether you should drive, operate machinery or do other dangerous activities right after you receive Docetaxel Injection treatment.
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Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, or heart problems, and may lead to death. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with Docetaxel Injection. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with Docetaxel Injection, including:
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nausea
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vomiting
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confusion
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shortness of breath
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irregular heartbeat
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dark or cloudy urine
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reduced amount of urine
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unusual tiredness
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muscle cramps
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You may experience side effects of Docetaxel Injection that may impair your ability to drive, use tools, or operate machines. If this happens, do not drive or use any tools or machines before discussing with your healthcare provider.

The most common side effects of Docetaxel Injection include:

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infections
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low white blood cells (help fight infections), low red blood cells (anemia), and low platelets (help blood to clot)
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allergic reactions (See "What is the most important information I should know about Docetaxel Injection?")
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changes in your sense of taste
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shortness of breath
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constipation
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decreased appetite
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changes in your fingernails or toenails
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swelling of your hands, face, or feet
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feeling weak or tired
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joint and muscle pain
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nausea and vomiting
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diarrhea
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mouth or lip sores
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hair loss: in some people, permanent hair loss has been reported
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redness of the eye, excess tearing
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skin reactions at the site of Docetaxel Injection administration such as increased skin pigmentation, redness, tenderness, swelling, warmth or dryness of the skin
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tissue damage if Docetaxel Injection leaks out of the vein into the tissues

Tell your healthcare provider if you have a fast or irregular heartbeat, severe shortness of breath, dizziness or fainting during your infusion. If any of these events occurs after your infusion, get medical help right away.
Docetaxel Injection may affect fertility in males. Talk to your healthcare provider if this is a concern for you.
These are not all of the possible side effects of Docetaxel Injection. For more information, ask your healthcare provider or pharmacist.
Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of Docetaxel Injection.
Medicines are sometimes prescribed for purposes other than those listed in this Patient Information. You can ask your pharmacist or healthcare provider for information about Docetaxel Injection that is written for health professionals.

What are the ingredients in Docetaxel Injection?
Active ingredient: docetaxel (anhydrous)
Inactive ingredients: (10 mg injection): polysorbate 80, anhydrous citric acid, dehydrated alcohol and polyethylene glycol.

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Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA
LAB-1366-5.0

For more information, call 1-800-441-4100, or go to www.pfizer.com

Every three-week injection of Docetaxel Injection for breast, non-small cell lung and stomach, and head and neck cancers
Take your oral corticosteroid medicine as your healthcare provider tells you.

Oral corticosteroid dosing:
Day 1                       Date:                        Time:                        AM                        PM
Day 2                       Date:                        Time:                        AM                        PM

(Docetaxel Injection Treatment Day)
Day 3                       Date:                        Time:                        AM                        PM

Every three-week injection of Docetaxel Injection for prostate cancer
Take your oral corticosteroid medicine as your healthcare provider tells you.

Oral corticosteroid dosing:
Date:                        Time:                       
Date:                        Time:                       

(Docetaxel Injection Treatment Day)
                                Time:                       

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