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PACLitaxel
Paclitaxel promotes assembly of microtubules and stabilizes them against depolymerization. It also inhibits cell replication by blocking cells in the late G2 and/or M phases of the cell cycle. Paclitaxel is obtained via a semi-synthetic process from Taxus baccata.
Extensive extravascular distribution and/or tissue binding.
| Cross blood brain barrier? | no |
| PPB | 89 % |
Hepatic metabolism (CYP 2C8 and CYP 3A4) and biliary secretion. Non-linear pharmacokinetics.
| Active metabolites | no information found |
| Inactive metabolites | Hydroxylated metabolites |
High concentrations found in bile; 71% excreted in feces in 120 hours (5% unchanged)
| Urine | 1.3 to 12.7 % as unchanged drug. |
| Half-life | 9.9 hours (3 hr infusion) |
Note: There are multiple generic brands, and not all of the indications listed below are contained in each product monograph. However, the indication is listed if approved for at least one generic brand
Health Canada Approvals:- Breast cancer (adjuvant and second-line metastatic)
- Non-small cell lung cancer (first-line advanced)
- Ovarian cancer (first-line combination, second-line metastatic)
- AIDS-related Kaposi’s sarcoma (advanced; refractory to liposomal anthracycline)
Other Uses:
- Breast cancer (neoadjuvant)
- Gastrointestinal cancer (anal, gastroesophageal)
- Genitourinary cancer (penile, prostate, bladder, testicular)
- Gynecological cancer (cervical, germ cell, gestational trophoblastic disease, vulvar, gynecological sarcoma, endometrial, fallopian tube, primary peritoneal)
- Head and neck cancer
- Thyroid cancer
- Thymoma
- Ewing's sarcoma
- Skin cancer (Merkel cell, Melanoma)
- Cancer of unknown primary origin
Emetogenic Potential:
Extravasation Potential: Irritant
The following data were based on clinical trials in ovarian and breast cancer patients, who were treated with single agent paclitaxel 175 mg/m2 IV over 3 hours.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (3%) (transient, including bradycardia) | I | |||
| Arterial thromboembolism (rare) | E | ||||
| Cardiotoxicity (rare) | E D | ||||
| ECG changes (14%) | E | ||||
| Hypotension (11%) | I | ||||
| Venous thromboembolism (rare) | E | ||||
| Dermatological | Alopecia (93%) (rarely permanent) | E | |||
| Nail disorder (2%) | E D | ||||
| Radiation recall reaction (rare) | I | ||||
| Rash (rare- may be severe) | I E | ||||
| Gastrointestinal | Dehydration | E | |||
| Diarrhea (25%) | I E | ||||
| GI obstruction (rare) | E | ||||
| GI perforation (rare) | E | ||||
| Mucositis (20%) | E | ||||
| Nausea, vomiting (44%) | I | ||||
| Typhlitis (rare) | I | ||||
| General | Edema (21%) | E | |||
| Fatigue (17%) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (grade 4 neutropenia 27%) | E | |||
| Hepatobiliary | ↑ LFTs (18%) (severe- rare) | E | |||
| Pancreatitis (rare) | E | ||||
| Hypersensitivity | Hypersensitivity (40%) (severe 1%) | I | |||
| Injection site | Injection site reaction (4%) (may be severe) | I | |||
| Musculoskeletal | Musculoskeletal pain (54%) (severe 12%) | E | |||
| Neoplastic | Secondary malignancy (rare) | L | |||
| Nervous System | Ataxia (rare) | E | |||
| Autonomic neuropathy (rare) | E | ||||
| Encephalopathy (rare) | E | ||||
| Optic neuritis / Ototoxicity (rare) | E | ||||
| Peripheral neuropathy (64%) (severe 4%) | E | ||||
| Seizure (rare) | E | ||||
| Syncope (rare) | E | ||||
| Ophthalmic | Cystoid macular edema (rare) | E | |||
| Eye disorders (visual disturbances- rare) | E | ||||
| Optic nerve disorder (rare) | E | ||||
| Respiratory | Pneumonitis (rare) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common adverse events are alopecia, peripheral neuropathy, musculoskeletal pain, nausea/vomiting, hypersensitivity, myelosuppression, diarrhea, edema, mucositis, ↑ LFTs.
Myelosuppression is dose and schedule-dependent but is not cumulative, with neutropenia being less common when paclitaxel was given as a 3-hour infusion as compared to a 24-hour infusion schedule. Toxicity may be more severe in HIV patients, especially infection (febrile neutropenia and opportunistic infections) and neutropenia.
Congestive heart failure (including LVEF decrease) has been reported in patients who have received other chemotherapy agents, especially anthracyclines.
Hypersensitivity reactions typically occur in early treatment courses and within the first hour of infusion. Dyspnea, flushing, chest pain and tachycardia were the most frequent manifestations. Reactions are neither dose-related nor dependent on prior exposure to paclitaxel, and may be caused by histamine release mediated by the Cremophor EL diluent. Because of the significant risk of hypersensitivity reactions, the patient must be monitored closely; a physician must be readily available, as well as emergency medications and resuscitation equipment. Anaphylaxis and severe hypersensitivity reactions (hypotension, angioedema, generalized urticaria) occur in 2% of patients and may rarely be fatal.
Myalgia and/or arthralgia tend to appear 2-3 days after paclitaxel administration and resolve within a few days, and do not appear to be dose-related. Non-steroidal anti-inflammatory drugs are successful in relieving these symptoms.
Peripheral neuropathy may be dose-limiting and is dose-related and cumulative. Common symptoms include numbness, tingling and/or burning pain in a glove-and-stocking distribution. Mild symptoms usually improve or resolve completely within several months after discontinuation of therapy. Pre-existing neuropathies are not a contraindication to treatment with paclitaxel.
Central neurotoxicity may occur and may be severe, especially in children treated at high dosage.
Hypotension and bradycardia have been observed during paclitaxel infusion and are usually asymptomatic, but not dose or schedule-dependent. Severe cardiovascular events, including death, have been reported; if these occur, appropriate action should be taken and the dose interrupted/discontinued; continuous electrocardiographic monitoring should be performed if patient receives subsequent paclitaxel therapy.
Cystoid macular edema (CME) has been reported in paclitaxel-treated patients, as well as with other taxanes. Patients who present with impaired vision during treatment should undergo a prompt ophthalmologic examination. Taxane-associated CME may not be associated with vascular leakage and is usually reversible upon taxane discontinuation. Treatment for CME may be required in some cases.
Paclitaxel has the potential to enhance radiation injury to tissues. While often called radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of paclitaxel. Recurrent injury to a previously radiated site may occur weeks to months following radiation. Recall skin reactions at a site of previous extravasation, after paclitaxel administration at a different site, have been reported rarely.
Refer also to protocol by which patient is being treated.
Pre-medications* (prophylaxis for infusion reaction):
Pre-Medications for Q3W paclitaxel:
- Dexamethasone 20 mg PO 12-and 6-hours OR Dexamethasone 20 mg IV 30 minutes pre-infusion†
- Diphenhydramine 25-50 mg IV/PO 30-60 minutes pre-infusion
- Ranitidine 50 mg IV OR Famotidine 20 mg IV 30-60 minutes pre-infusion
Pre-Medications for weekly paclitaxel: (To be given 30-60 minutes prior to paclitaxel infusion)
- Dexamethasone 10 mg IV, starting in cycle 1
- Diphenhydramine 25-50 mg IV/PO
- Ranitidine 50 mg IV OR Famotidine 20 mg IV
* Consider discontinuing pre-medications for paclitaxel if there was no IR in the first 2 doses.
† Oral and IV dexamethasone are both effective at reducing overall IR rates. Some evidence suggests that oral dexamethasone may be more effective for reducing severe reactions; however, adverse effects and compliance remain a concern.
Start treatment only in patients with neutrophils ≥ 1.5 x 109/L (≥ 1 x 109/L in AIDS-related Kaposi’s sarcoma) and platelet counts ≥ 100 x 109/L
Intravenous: 135 mg/m² over 3 hours every 3 weeks
Intravenous: 100 mg/m² over 3 hours every 2 weeks
|
Worst toxicity in previous cycle |
Dose of paclitaxel
|
|
Febrile neutropenia Grade 4 ANC ≥ 5-7 days Grade 4 thrombocytopenia
|
↓ by 20%* |
|
Grade 3 neurotoxicity or other toxicity
|
↓ by 20%* |
|
Grade 4 neurotoxicity or other toxicity, any grade cystoid macular edema
|
Discontinue |
|
*Patients should not be retreated with paclitaxel until neutrophils ≥ 1.5 x 109/L (≥ 1.0 x 109/L in AIDS-related Kaposi’s sarcoma) and platelet counts ≥ 100 x 109/L and other toxicity has recovered to ≤ grade 2
|
|
Management of Infusion-related reactions:
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
| Grade | Management | Re-challenge |
| 1 or 2 |
Restart:
|
|
| 3 or 4 |
|
|
Caution and dose reduction advised in patients with moderate to severe hepatic impairment.
Patients with hepatic impairment may be at risk of toxicity, especially severe myelosuppression.
Suggested are:
|
Bilirubin |
|
AST/ALT |
Dose (% usual dose) |
|
≤1.25 x ULN |
And |
2-10 x ULN |
75% |
|
1.26 to 2.5 x ULN |
And |
<10x ULN |
40% |
|
2.6 to 4 x ULN |
And |
<10x ULN |
25% |
| >4 x ULN | And/Or | ≥10 x ULN | Consider risk-benefit or Omit |
No adjustment required, but may consider for patients with HIV-AIDS if creatinine ≥ 2 x ULN
No adjustment required, but elderly patients are more at risk for severe toxicity.
Safety and efficacy have not been established. Children may be at a higher risk of severe and sometimes fatal neurologic toxicity, especially with high doses, possibly related to the ethanol content of paclitaxel infusions.
- In order to minimize patients’ exposure to DEHP leaching from PVC bags or sets, use polyolefin or polypropylene infusion bags and polyethylene-lined administration sets (with a 0.22 micron in-line filter).
- Dilute in 500-1000 mL Normal Saline or 5% Dextrose, in a final concentration of 0.3-1.2 mg/mL and infuse over 3 hours.
- For weekly dosing, may be infused over 1 hour - mix in 250mL bag as above (not approved by manufacturer).
- Extended infusion of paclitaxel is not recommended as primary prophylaxis to reduce paclitaxel IRs.
- Paclitaxel should be given before cisplatin, if given in combination (refer to drug interactions section)
- Excessive shaking, agitation, or vibration may induce precipitation and should be avoided
- Precipitation may rarely occur with infusions longer than 3 hours.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
- Patients with a history of severe hypersensitivity reactions to paclitaxel or other drugs formulated in Cremophor EL (polyethoxylated castor oil)
- Patients with severe baseline neutropenia (<1.5 x 109/L; < 1 x 109/L for patients with AIDS-related Kaposi’s)
- Paclitaxel contains ethanol, and is administered with agents such as antihistamines which cause drowsiness. Patients should be cautioned regarding driving and the use of machinery.
-
Embryotoxicity:
Yes
-
Fetotoxicity:
Yes
Paclitaxel is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose. -
Excretion into breast milk:
Probable
Breastfeeding is not recommended. -
Fertility effects:
Yes
The drugs listed in this table are based on drug interaction case reports, pharmacokinetic studies, or potential interactions. Paclitaxel clearance was not affected by cimetidine administration pre-treatment.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Cisplatin | ↑ myelosuppression if cisplatin given prior (within hours) to paclitaxel | ↓ paclitaxel clearance by 33% | Give paclitaxel before cisplatin |
| Cisplatin | May ↑ risk of renal failure in gynaecological cancers | Unknown | Caution |
| Doxorubicin (after prolonged paclitaxel infusions) | ↑ neutropenia and stomatitis | Higher plasma levels of doxorubicin and doxorubicinol | Caution |
| Epirubicin | ↑ systemic exposure to epirubicin or its metabolites. May be schedule-dependent. | Taxane or cremophor EL possibly compete with epirubicin for biliary excretion | Caution if used in combination; give epirubicin first |
| Cyclophosphamide (given after paclitaxel) | ↑ myelosuppression | Unknown | Caution |
| Radiation | Radiation pneumonitis | ↑ pulmonary effects | Avoid/caution |
| Carboplatin (given after paclitaxel) | ↓ thrombocytopenia | Unknown | Caution |
| CYP 2C8 substrates (i.e. paclitaxel, sorafenib, amiodarone) | May ↑/↓ effects of substrates or paclitaxel | Altered metabolism of CYP2C8 substrates or paclitaxel | Caution |
| CYP 3A4 substrates (i.e., verapamil, etoposide, dexamethasone, vincristine) | May ↑/↓ effects of substrates or paclitaxel | Altered metabolism of CYP3A4 substrates or paclitaxel | Caution |
| Inducers of CYP 2C8 (i.e., phenobarbital) | May ↓ paclitaxel levels and effects | ↑ metabolism of paclitaxel | Caution |
| CYP 2C8 inhibitors (i.e. gemfibrozil, montelukast) | May ↑ paclitaxel levels and effects | ↓ metabolism of paclitaxel | Caution |
| CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) | May ↓ paclitaxel levels and effects | ↑ metabolism of paclitaxel | Caution |
| CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) | May ↑ paclitaxel levels and effects | ↓ metabolism of paclitaxel | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and before each visit |
Liver function tests |
Baseline and before each cycle |
Renal function tests |
Baseline and as clinically indicated |
Blood pressure and pulse |
Per usual institutional protocol; also during infusion (more frequently during the first hour) |
| Continuous cardiac monitoring in patients who developed serious conduction abnormalities | During subsequent infusions |
Ophthalmology if visual impairment |
As clinically indicated |
Clinical assessment of bleeding, infection, diarrhea, musculoskeletal, neurologic (sensory), hypersensitivity, respiratory, thromboembolism |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
Renal function tests (AIDS-related Kaposi's sarcoma) |
Baseline and before each dose |
Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA).
Danesi R, Innocenti F, Fogli S, et al. Pharmacokinetics and pharmacodynamics of combination chemotherapy with paclitaxel and epirubicin in breast cancer patients. Br J Clin Pharmacol 2002; 53: 508–18.
Clin-Info: e-Compendium of Pharmaceuticals and Specialties. Accessed October 27, 2009.
Esposito M, Venturini M, Vannozzi MO, et al. Comparative effects of paclitaxel and docetaxel on the metabolism and pharmacokinetics of epirubicin in breast cancer patients. J Clin Oncol 1999; 17:1132-40.
Floyd J, Mirza I, Sachs B, et al. Hepatotoxicity of chemotherapy. Semin Oncol 2006;33(1):50-67.
Fogli S, Danesi R, Gennari A, et al. Gemcitabine, epirubicin and paclitaxel: pharmacokinetic and pharmacodynamic interactions in advanced breast cancer. Annals of Oncology 2002; 13: 919–27.
Gill PS, Tulpule, A, Espina BM, et al. Paclitaxel is safe and effective in the treatment of advanced AIDS-Related Kaposi’s sarcoma. J Clin Oncol 1999; 17: 1876-83.
Grasselli G, Vigano L, Capri G, et al. Clinical and pharmacologic study of the epirubicin and paclitaxel combination in women with metastatic breast cancer. J Clin Oncol 2001; 19:2222-31.
King PD and Perry MC. Hepatotoxicity of chemotherapy. The Oncologist 2001;6:162-176.
McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 1191-205.
Prevezas C, Matard B, Pinquier L, et al. Irreversible and severe alopecia following docetaxel or paclitaxel cytotoxic therapy for breast cancer. British Journal of Dermatology 2009; 160(4): 883-5.
Product Monograph: Taxol® (paclitaxel) Bristol-Myers Squibb Inc (Canada), February 22, 2010.
Product Monograph: Paclitaxel for injection. Hospira Healthcare Corp. (Canada), October 28, 2013.
Superfin D, Iannucci AA, Davies AM, et al. Commentary: Oncologic drugs in patients with organ dysfunction: a summary. Oncologist 2007;12(9):1070-83.
Venturini M, Lunardi G, Del Mastro L, et al. Sequence effect of epirubicin and paclitaxel treatment on pharmacokinetics and toxicity. J Clin Oncol 2000; 18: 2116-25.
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