Paclitaxel – Uses, Dosage, Side Effects, Interactions

Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist
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Drugs (A - Z)

Paclitaxel is an antineoplastic agent which acts as an inhibitor of cellular mitosis and which currently plays a central role in the therapy of ovarian, breast, and lung cancer. Therapy with paclitaxel has been associated with a low rate of serum enzyme elevations but has not been linked to cases of clinically apparent acute liver injury.

Nab-paclitaxel is a Cremophor EL-free, albumin-stabilized nanoparticle formulation of the natural taxane paclitaxel with antineoplastic activity. Paclitaxel binds to and stabilizes microtubules, preventing their depolymerization and so inhibiting cellular motility, mitosis, and replication. This formulation solubilizes paclitaxel without the use of the solvent Cremophor, thereby permitting the administration of larger doses of paclitaxel while avoiding the toxic effects associated with Cremophor.

Paclitaxel is a tetracyclic diterpenoid isolated originally from the bark of the Pacific yew tree, Taxus brevifolia. It is a mitotic inhibitor used in cancer chemotherapy. Note that the use of the former generic name ‘taxol’ is now limited, as Taxol is a registered trademark. It has a role as a microtubule-stabilizing agent, a metabolite, a human metabolite, and an antineoplastic agent. It is a tetracyclic diterpenoid and a taxane diterpenoid. It is functionally related to a vacation III.

Mechanism of Action

Paclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell’s ability to use its cytoskeleton flexibly. Specifically, paclitaxel binds to the β subunit of tubulin. Tubulin is the “building block” of microtubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel complex cannot disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) are necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis-stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function. Evidence suggests that paclitaxel also may induce cell death by triggering apoptosis. In addition, paclitaxel and docetaxel enhance the effects of ionizing radiation, possibly by blocking cells in the G2 phase, the phase of the cell cycle in which cells are most radiosensitive.

Paclitaxel is an antimicrotubule antineoplastic agent. Unlike some other common antimicrotubule agents (e.g., vinca alkaloids, colchicine, podophyllotoxin), which inhibit microtubule assembly, paclitaxel and docetaxel (a semisynthetic taxoid) promote microtubule assembly. Microtubules are organelles that exist in a state of dynamic equilibrium with their components, tubulin dimers. They are an essential part of the mitotic spindle and also are involved in the maintenance of cell shape and motility, and transport between organelles within the cell. By binding in a reversible, concentration-dependent manner to the beta-subunit of tubulin at the N-terminal domain, paclitaxel enhances the polymerization of tubulin, the protein subunit of the spindle microtubules, even in the absence of factors that are normally required for microtubule assembly (e.g., guanosine triphosphate [GTP]), and induces the formation of stable, nonfunctional microtubules. Paclitaxel promotes microtubule stability even under conditions that typically cause depolymerization in vitro (e.g., cold temperature, the addition of calcium, and the presence of antimitotic drugs). While the precise mechanism of action of the drug is not understood fully, paclitaxel disrupts the dynamic equilibrium within the microtubule system and blocks cells in the late G2 phase and M phase of the cell cycle, inhibiting cell replication.

Indications

  • Used in the treatment of Kaposi’s sarcoma and cancer of the lung, ovarian, and breast. Abraxane is specifically indicated for the treatment of metastatic breast cancer and locally advanced or metastatic non-small cell lung cancer.
  • Paper monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline-containing therapy is not indicated. Paper in combination with carboplatin is indicated for the first-line treatment of non-small cell lung cancer in adult patients who are not candidates for potentially curative surgery and/or radiation therapy.
  • Abraxane monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline-containing therapy is not indicated. Abraxane in combination with gemcitabine is indicated for the first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas. Abraxane in combination with carboplatin is indicated for the first-line treatment of non-small cell lung cancer in adult patients who are not candidates for potentially curative surgery and/or radiation therapy.
  • Apealea in combination with carboplatin is indicated for the treatment of adult patients with the first relapse of platinum‑sensitive epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer.,
  • advanced AIDS-related Kaposi’s sarcoma (AIDS-KS) who have failed prior liposomal anthracycline therapy;
  • metastatic carcinoma of the breast (MBC) who have failed, or are not candidates for standard anthracycline-containing therapy;
  • advanced carcinoma of the ovary (AOC) or with residual disease (> 1 cm) after initial laparotomy, in combination with cisplatin as first-line treatment;
  • metastatic carcinoma of the ovary (MOC) after the failure of platinum-containing combination therapy without taxanes as second-line treatment;
  • non-small cell lung carcinoma (NSCLC) who are not candidates for potentially curative surgery and/or radiation therapy, in combination with cisplatin.
  • Treatment of solid malignant tumor
  • Treatment of soft tissue sarcoma

Use in Cancer

Paclitaxel albumin-stabilized nanoparticle formulation is approved to be used alone or with other drugs to treat:

  • Breast cancer has relapsed or spread to other parts of the body after treatment with other chemotherapy.
  • Non-small cell lung cancer has spread. It is used with carboplatin as the first treatment in patients whose cancer cannot be treated with surgery or radiation therapy.
  • Pancreatic cancer has spread to other parts of the body. It is used with gemcitabine hydrochloride as the first treatment.

FDA Approved Indications

  • Adjuvant treatment for node-positive breast cancer 
  • Treatment of metastatic breast cancer after failure of combination chemotherapy that included an anthracycline 
  • Treatment of metastatic breast cancer that relapsed within six months of adjuvant chemotherapy that included an anthracycline 
  • Treatment of AIDS-related Kaposi sarcoma (second line)
  • Treatment of non-small cell lung cancer in combination therapy with cisplatin in patients who are not candidates for surgery and/or radiation therapy
  • Treatment of ovarian cancer in combination with cisplatin
  • Subsequent therapy for the treatment of advanced ovarian cancer in combination with cisplatin

Non-FDA Approved Indications

  • Treatment of metastatic or advanced bladder cancer in combination therapy with gemcitabine
  • Treatment of advanced cervical cancer in combination with topotecan, bevacizumab, and/or cisplatin
  • Preoperative management of esophageal and gastric cancers in combination with carboplatin and radiation therapy
  • Treatment of advanced head and neck cancer in combination with cisplatin
  • Neoadjuvant treatment in penile cancer with bulky regional lymph node metastases
  • Treating relapsed or refractory small-cell lung cancer
  • Treatment of advanced or unresectable angiosarcoma
  • Treatment of relapsed or refractory testicular germ cell tumors in combination with gemcitabine and oxaliplatin or ifosfamide and cisplatin
  • Treatment of advanced thymoma/thymic carcinoma in combination with carboplatin
  • Treatment of unknown primary adenocarcinoma in combination with carboplatin and/or etoposide 
  • Treatment of endometrial carcinoma
  • Treatment of metastatic or unresectable esophageal cancer
  • Treatment of metastatic or unresectable gastric cancer
  • Treatment of melanoma
  • Treatment of anaplastic thyroid cancer

Paclitaxel albumin-stabilized nanoparticle formulation is also being studied in the treatment of other types of cancer. Paclitaxel albumin-stabilized nanoparticle formulation is a form of paclitaxel contained in nanoparticles (very tiny particles of protein). The drug is also called nanoparticle paclitaxel and protein-bound paclitaxel. This form may work better than other forms of paclitaxel and have fewer side effects. For more information about paclitaxel that may apply to paclitaxel albumin-stabilized nanoparticle formulation,

Contraindications

  • Paclitaxel Injection, USP is contraindicated in patients who have a history of hypersensitivity reactions to paclitaxel or other drugs formulated in Polyoxyl 35 Castor Oil, NF.
  • Paclitaxel Injection, USP should not be used in patients with solid tumors who have baseline neutrophil counts of <1,500 cells/mm3 or in patients with AIDS-related Kaposi’s sarcoma with baseline neutrophil counts of <1,000 cells/mm3.
  • Due to the black box warning for hypersensitivity reactions and bone marrow suppression, paclitaxel should not be given to patients who have had a severe hypersensitivity reaction with paclitaxel, patients with solid tumors who have a baseline neutrophil count of fewer than 1500 cells/mm^3, or patients with AIDS-related Kaposi sarcoma if the baseline neutrophil count is less than 1000 cells/mm^3. Bone marrow suppression is dose-dependent and is dose-limiting toxicity. If it occurs, future doses should be reduced by 20% for severe neutropenia and consider supportive therapy (growth factor treatment).

Dosage

Ovarian Cancer

For previously untreated patients with cancer of the ovary:

  • 175 mg/m2 IV over 3 hours followed by cisplatin 75 mg/m2 IV every 3 weeks
    OR
  • 135 mg/m2 IV over 24 hours followed by cisplatin 75 mg/m2 IV every 3 weeks
  • 135 mg/m2 IV over 3 hours every 3 weeks
    OR
  • 175 mg/m2 IV over 3 hours every 3 weeks

Breast Cancer

After the failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy:

  • 175 mg/m2 IV over 3 hours every 3 weeks

Breast Cancer – Adjuvant

For adjuvant treatment of node-positive breast cancer:

  • 175 mg/m2 IV over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing chemotherapy

Kaposi’s Sarcoma

For patients with AIDS-Related Kaposi’s Sarcoma:

  • 135 mg/m2 IV over 3 hours every 3 weeks
    OR
  • 100 mg/m2 IV over 3 hours every 2 weeks

    Note: In patients with advanced HIV disease:1) Reduce the dose of dexamethasone as one of the premedication drugs (consult the manufacturer product information).2) Initiate or repeat treatment with this drug only if the neutrophil count is at least 1000 cells/mm3.3) Reduce the dose of subsequent courses of this drug by 20% for patients who experience severe neutropenia (a neutrophil count less than 500 cells/mm3 for a week or longer).4) Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

Liver Dose Adjustments

Dose adjustments for liver impairment
24-HOUR INFUSION:

  • Transaminase levels less than 2 x ULN and bilirubin levels less than or equal to 1.5 mg/dL: 135 mg/m2 IV
  • Transaminase levels 2 to less than 10 x ULN and bilirubin levels less than or equal to 1.5 mg/dL: 100 mg/m2 IV
  • Transaminase levels less than 10 x ULN and bilirubin levels 1.6 to 7.5 mg/dL: 50 mg/m2 IV
  • Transaminase levels greater than or equal to 10 x ULN or bilirubin levels greater than 7.5 mg/dL: Not recommended.

3-HOUR INFUSION:

  • Transaminase levels less than 10 x ULN and bilirubin levels less than or equal to 1.25 x ULN: 175 mg/m2 IV
  • Transaminase levels less than 10 x ULN and bilirubin levels 1.26 to 2 x ULN: 135 mg/m2 IV
  • Transaminase levels less than 10 x ULN and bilirubin levels 2.01 to 5 x ULN: 90 mg/m2 IV
  • Transaminase levels greater than or equal to 10 x ULN or bilirubin levels greater than 5 x ULN: Not recommended.

All patients should be premedicated prior to paclitaxel administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its equivalent) 50 mg I.V. 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) I.V. 30 to 60 minutes before paclitaxel.

For patients with carcinoma of the ovary the following regimen is recommended:

1)   For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered

  • Paclitaxel is administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or
  • Paclitaxel was administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin at a dose of 75 mg/m2.

2)   In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is paclitaxel 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following is recommended :

1)   For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide.

  • After the failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks is effective.
  • For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

For patients with AIDS-related Kaposi’s sarcoma, paclitaxel administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45–50 mg/m2/week). In the 2 clinical trials evaluating these schedules, the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low-performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended for these patients:

  • 1)   Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO);
  • 2)   Initiate or repeat treatment with paclitaxel only if the neutrophil count is at least 1,000 cells/mm3;
  • 3)   Reduce the dose of subsequent courses of paclitaxel by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and
  • 4)   Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

For the therapy of patients with solid tumors (ovary, breast and NSCLC), courses of paclitaxel should not be repeated until the neutrophil count is at least 1,500 cells/mm3 and the platelet count is at least 100,000 cells/mm3. Paclitaxel should not be given to patients with AIDS-related Kaposi sarcoma if the baseline or subsequent neutrophil count is less than 1,000 cells/mm3. For patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during Paclitaxel Injection, USP therapy should have dosage reduced by 20% for subsequent courses of paclitaxel. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Hepatic Impairment: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression . Recommendations for dosage adjustment for the first course of therapy are shown in Table 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

. Recommendations for Dosing in Patients with Hepatic Impairment Based on Clinical Trial Data

Degree of Hepatic Impairment

Recommended Paclitaxel Doc

Transaminase

Levels

Bilirubin Levels

24-Hour Infusion

<2 x ULN

and

≤1.5 mg/dL

135 mg/m2

2 to <10 x ULN

and

≤1.5 mg/dL

100 mg/m2

<10 x ULN

and

1.6-7.5 mg/dL

50 mg/m2

≥10 x ULN

or

>7.5 mg/dL

Not recommended

3-Hour Infusion

<10 x ULN

and

≤1.25 x ULN

175 mg/m2

<10 x ULN

and

1.26-2.0 x ULN

135 mg/m2

<10 x ULN

and

2.01-5.0 x ULN

90 mg/m2

≥10 x ULN

or

>5.0 x ULN

Not recommended

a   These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma).

b   Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design.

c   Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.

Preparation and Administration Precautions: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel Injection. If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Preparation for Intravenous Administration: Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2 mg/mL. The solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25°C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. N significant losses in potency have been noted following simulated delivery of the solution through I.V. tubing containing an in-line (0.22 micron) filter.

Data collected for the presence of the extractable plasticizer DEHP [di-(2-Ethylhexyl) phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended.

Paclitaxel solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.

Paclitaxel should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. The use of filter devices such as IVEX-2® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of paclitaxel since they can cause the stopper to collapse resulting in the loss of sterile integrity of the paclitaxel solution.

Stability: Unopened vials of Paclitaxel Injection, USP are stable until the date indicated on the package when stored between 20° to 25°C (68° to 77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration components in the paclitaxel vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25°C) and lighting conditions for up to 27 hours.

Side Effects

The Most Common

  • Occupational hepatotoxin – Secondary hepatotoxins: the potential for toxic effects in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.
  • Skin Sensitizer – An agent that can induce an allergic reaction in the skin.
  • Asthma – Reversible bronchoconstriction (narrowing of bronchioles) initiated by the inhalation of irritating or allergebeforets.
  • severe stomach pain or diarrhea;
  • cold symptoms such as stuffy nose, sneezing, sore throat;
  • flushing (warmth, redness, or tingly feeling);
  • numbness, tingling, or burning pain in your hands or feet;
  • severe redness or irritation, swelling or a hard lump, or other skin changes where the injection was given (may occur 7 to 10 days after an injection);
  • pain or burning when you urinate;
  • cough with mucus, chest pain, feeling short of breath;
  • chest pain, shortness of breath, fast orbeforeartbeats;
  • a light-headed feeling, like you might pass out;
  • severe headache, blurred vision, pounding in your neck or ears;
  • a seizure;
  • easy bruising, unusual bleeding, purple or red spots under your skin;
  • low red blood cells (anemia)–pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands and feet; or
  • low white blood cell counts–fever, mouth sores, skin sores, sore throat, cough, trouble breathing.

Common

  • fever, chills, or other signs of infection;
  • anemia;
  • feeling weak, tired, or light-headed;
  • bleeding;
  • trouble breathing or swallowing;
  • hair loss, skin rash, hives;
  • numbness, tingling, or burning;
  • swelling in your face, hands, or feet;
  • sores or white patches in or around yNon-PVC-containingr muscle pain;
  • nausea, vomiting, diarrhea; or
  • tenderness or irritation where the medicine was injected.

Rare

  • Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
  • cracked lips
  • diarrhea
  • difficulty with swallowing
  • hair loss
  • nausea or vomiting
  • numbness, burning or tingling in the hands or feet
  • pain in the joints or muscles, especially in the arms or legs
  • thinning of the hair

Drug Interactions

Food Interactions

  • Avoid echinacea. Co-administration may decrease the effectiveness of immunosuppressants, and echinacea may induce CYP3A4 increasing paclitaxel metabolism.
  • Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of paclitaxel.
  • Exercise caution with St. John’s Wort. This herb induces the CYP3A4 metabolism of paclitaxel and may reduce its serum concentration.

Pregnancy and Breast Beeding

Lactation

Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy.[1] Based on limited data, paclitaxel appears to be excreted into milk in relatively large amounts. It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence, but the duration of abstinence is not clear. Furthermore, milk paclitaxel levels appear to increase with repeated doses at weekly intervals. Some have suggested a breastfeeding abstinence period of 6 to 10 days,[2] although the manufacturer recommends that breastfeeding be discontinued during paclitaxel therapy and for 2 weeks after the last dose.

What special precautions should I follow?

Before receiving paclitaxel (with polyoxyethylated castor oil) injection,

  • tell your doctor and pharmacist if you are allergic to paclitaxel, docetaxel, any other medications, polyoxyethylated castor oil (Cremophor EL), or medications that contain polyoxyethylated castor oil such as cyclosporine injection (Sandimmune) or teniposide (Vumon). Ask your doctor or pharmacist if you do not know if a medication that you are allergic to contains polyoxyethylated castor oil.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: buspirone (Buspar); carbamazepine (Carbatrol, Equetro, Tegretol); certain medications used to treat human immunodeficiency virus (HIV) such as atazanavir (Reyataz, in Evotaz); indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra, in Viekira Pak), and saquinavir (Invirase); clarithromycin (Biaxin, in Prevpac); eletriptan (Relpax); felodipine; gemfibrozil (Lopid); itraconazole (Onmel, Sporanox); ketoconazole (Nizoral); lovastatin (Altoprev); midazolam; nefazodone; phenobarbital; phenytoin (Dilantin, Phenytek); repaglinide (Prandin, in Prandimet); rifampin (Rimactane, Rifadin, in Rifamate, in Rifater); rosiglitazone (Avandia, in Avandaryl, in Avandamet); sildenafil (Revatio, Viagra); simvastatin (Flolipid, Zocor, in Vytorin); telithromycin (Ketek; not available in the U.S.), and triazolam (Halcion); Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with paclitaxel, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • tell your doctor if you have or have ever had liver or heart disease.
  • tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant while you are receiving paclitaxel (with polyoxyethylated castor oil) injection. Talk to your doctor about birth control methods that you can use during your treatment. If you become pregnant while receiving paclitaxel (with polyoxyethylated castor oil) injection, call your doctor. Paclitaxel injection may harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed while you are receiving paclitaxel (with polyoxyethylated castor oil) injection.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are receiving a paclitaxel (with polyoxyethylated castor oil) injection.

Administer paclitaxel under the supervision of a healthcare provider experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Do not give paclitaxel therapy to patients with solid tumors who have baseline neutrophil counts of less than 1,500 cells/cu mm, and do not give to patients with AIDS-related Kaposi sarcoma if the baseline neutrophil count is less than 1,000 cells/cu mm. To monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, perform frequent peripheral blood cell counts on all patients receiving paclitaxel.

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2% to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. Pretreat all patients with corticosteroids, diphenhydramine, and H2 antagonists. Do not rechallenge patients who experience severe hypersensitivity reactions to paclitaxel with the drug.

WARNINGS

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2%-4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists. Patients who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the drug.

Bone marrow suppression (primarily neutropenia) is dose-dependent and is dose-limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. Paclitaxel should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3 (<1,000 cells/mm3 for patients with KS). Frequent monitoring of blood counts should be instituted during paclitaxel treatment. Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm3 (>1,000 cells/mm3 for patients with KS) and platelets recover to a level >100,000 cells/mm3.

Severe conduction abnormalities have been documented in <1% of patients during paclitaxel therapy and in some cases requiring pacemaker placement. If patients develop significant conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel.

An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of the drug in solution. Do not substitute for or with other paclitaxel formulations.

Pregnancy: Paclitaxel can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3.0 mg/kg/day (about 0.2 the daily maximum recommended human dose on an mg/m2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Maternal toxicity was also observed at this dose. No teratogenic effects were observed at 1.0 mg/kg/day (about 1/15 the daily maximum recommended human dose on an mg/m2 basis); teratogenic potential could not be assessed at higher doses due to extensive fetal mortality.

There are no adequate and well-controlled studies on pregnant women. If paclitaxel is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS

Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended. To minimize patient exposure to the plasticizer DEHP [di-(2-Ethylhexyl) phthalate], which may be leached from PVC infusion bags or sets, diluted Paclitaxel Injection, USP solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

Paclitaxel should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. The use of filter devices such as IVEX-2® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

Drug Interactions: In a Phase, I trial using escalating doses of paclitaxel (110-200 mg/m2) and cisplatin (50 or 75 mg/m2) given as sequential infusions, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence (i.e., paclitaxel before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when paclitaxel was administered following cisplatin.

The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering paclitaxel concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when paclitaxel is concomitantly administered with known substrates (eg, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (eg, rifampin and carbamazepine) of CYP3A4.

Caution should also be exercised when paclitaxel is concomitantly administered with known substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers (eg, rifampin) of CYP2C8.

Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials.

Reports in the literature suggest that plasma levels of doxorubicin (and its active metabolite doxorubicin) may be increased when paclitaxel and doxorubicin are used in combination.

Hematology: Paclitaxel therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. To monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel. Patients should not retreat with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of paclitaxel therapy, a 20% reduction in dose for subsequent courses of therapy is recommended.

For patients with advanced HIV disease and poor-risk AIDS-related Kaposi’s sarcoma, paclitaxel, at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1,000 cells/mm3.

Hypersensitivity Reactions: Patients with a history of severe hypersensitivity reactions to products containing Polyoxyl 35 Castor Oil, NF (e.g., cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with paclitaxel. To avoid the occurrence of severe hypersensitivity reactions, all patients treated with paclitaxel should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine, and H2 antagonists (such as cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel.

Cardiovascular: Hypotension, bradycardia, and hypertension have been observed during the administration of Paclitaxel Injection, USP, but generally do not require treatment. Occasionally paclitaxel infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities.  When paclitaxel is used in combination with doxorubicin for the treatment of metastatic breast cancer, monitoring of cardiac function is recommended.

Nervous System: Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of paclitaxel.

Paclitaxel contains Dehydrated Alcohol USP, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol.

Hepatic: There is limited evidence that the myelotoxicity of Paclitaxel may be exacerbated in patients with serum total bilirubin >2 times ULN. Extreme caution should be exercised when administering Paclitaxel to such patients, with dose reduction as recommended

Injection Site Reaction: Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e., “recall”, has been reported.

More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some cases, the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days.

Specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of paclitaxel has not been studied.

Paclitaxel is clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.

Administration of paclitaxel before and during mating produced impairment of fertility in male and female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum recommended human dose on an mg/m2 basis). At this dose, paclitaxel caused reduced fertility and reproductive indices, and increased embryo and fetotoxicity.

Pregnancy: 

Nursing Mothers: It is not known whether the drug is excreted in human milk. Following intravenous administration of carbon-14 labeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving paclitaxel therapy.

Pediatric Use: The safety and effectiveness of paclitaxel in pediatric patients have not been established.

There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical trial in pediatric patients in which paclitaxel was infused intravenously over 3 hours at doses ranging from 350 mg/m2 to 420 mg/m2. The toxicity is most likely attributable to the high dose of the ethanol component of the Paclitaxel Injection, USP vehicle given over a short infusion time. The use of concomitant antihistamines may intensify this effect. Although a direct effect of the paclitaxel itself cannot be discounted, the high doses used in this study (over twice the recommended adult dosage) must be considered in assessing the safety of paclitaxel for use in this population.

Geriatric Use: Of 2228 patients who received paclitaxel in 8 clinical studies evaluating its safety and effectiveness in the treatment of advanced ovarian cancer, breast carcinoma, or NSCLC, and 1570 patients who were randomized to receive paclitaxel in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older and 49 patients (1%) were 75 years or older. In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in elderly patients. In 2 clinical studies in NSCLC, the elderly patients treated with paclitaxel had a higher incidence of cardiovascular events. Estimates of efficacy appeared similar in elderly patients and younger patients; however, comparative efficacy cannot be determined with confidence due to the small number of elderly patients studied. In a study of first-line treatment of ovarian cancer, elderly patients had lower median survival than younger patients, but no other efficacy parameters favored the younger group. Table 9 presents the incidences of Grade IV neutropenia and severe neuropathy in clinical studies according to age.

Why is this medication prescribed?

Paclitaxel (with polyoxyethylated castor oil) is used alone or along with other chemotherapy medications to treat breast cancer, ovarian cancer (cancer that begins in the female reproductive organs where eggs are formed), and non-small cell lung cancer (NSCLC). Paclitaxel (with polyoxyethylated castor oil) injection is also used to treat Kaposi’s sarcoma (a type of cancer that causes patches of abnormal tissue to grow under the skin) in people who have acquired immunodeficiency syndrome (AIDS). Paclitaxel is in a class of medications called antimicrotubule agents. It works by stopping the growth and spread of cancer cells.

How should this medicine be used?

Paclitaxel (with polyoxyethylated castor oil) injection comes as a liquid to be injected over 3 or 24 hours intravenously by a doctor or nurse in a hospital or clinic. When paclitaxel (with polyoxyethylated castor oil) is used to treat breast cancer, ovarian cancer, or non-small cell lung cancer it is usually given once every 3 weeks. When paclitaxel (with polyoxyethylated castor oil) is used to treat Kaposi’s sarcoma, it may be given once every 2 or 3 weeks.

Your doctor may need to interrupt your treatment, reduce your dose, or stop your treatment depending on your response to the medication and any side effects that you experience. Be sure to tell your doctor how you are feeling during your treatment.

References

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