PACLITAXEL

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) NSC 125973
2) Taxol
3) Taxol A
4) CAS 33069-62-4

1.2.1) MOLECULAR FORMULA
1) PACLITAXEL: C(47)H(51)NO(14) (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009)

Available Forms Sources

1) PACLITAXEL: Intravenous paclitaxel is a clear, colorless to slightly yellow viscous solution. It is supplied as a sterile nonaqueous solution intended for dilution in a suitable parenteral fluid prior to IV infusion. Each mL of sterile non-pyrogenic solution contains 6 mg of paclitaxel, 527 mg of polyoxyethylated castor oil (Cremophor(R) EL) and 49.7% (v/v) dehydrated alcohol, USP (Prod Info TAXOL(R) IV injection, 2010).
2) PACLITAXEL PROTEIN-BOUND for injectable suspension is an albumin-bound form of paclitaxel with a mean particle size of approximately 130 nanometers. Paclitaxel exists in the particles in a noncrystalline, amorphous state. It is supplied as a white to yellow, sterile, lyophilized powder for reconstitution with 20 mL of 0.9% sodium chloride injection prior to IV infusion. Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin; each mL of reconstituted suspension contains 5 mg paclitaxel (Prod Info ABRAXANE(R) intravenous suspension, 2009).
3) INTRAPERITONEAL ADMINISTRATION

a) In 2006, the National Cancer Institute issued a Clinical Announcement suggesting that intraperitoneal (IP) administration be the standard of care for women with advanced ovarian cancer (Rowan, 2009). The National Comprehensive Cancer Network (2007) has incorporated the use of IP chemotherapy as part of its guidelines for ovarian cancer and recommends its use as initial therapy for patients with smaller than 1 cm optimally debulked stage III disease and all stage II patients. Several randomized controlled trials have been conducted and reported the use of paclitaxel and carboplatin as part of the treatment regimens. Some studies suggest that patients receiving IP therapy have improved survival and have lived a year longer than patients receiving intravenous chemotherapy (Rowan, 2009; Landrum et al, 2008)

1) There have been reports of similar toxicity (ie, hematologic, gastrointestinal, neurologic) with IP therapy as observed with intravenous administration. Intraperitoneal port complications (eg, infection, inflow obstruction, port blockage, abdominal pain or bowel injury) and inadequate technical experience with the procedure have also been associated with discontinuation of therapy. Based on several studies, IP treatment was discontinued in 13% of patients and up to 34% of patients in one study (Bunting et al, 2009).

1) NATURAL SOURCES

a) Paclitaxel has been isolated in the leaves/needles/bark of Taxus brevifolia, Taxus canadensis, Taxus cuspidata cv Capitata, and Taxus X media cv Hicksii and Taxus media (Prod Info ABRAXANE(R) intravenous suspension, 2009; Witherup et al, 1990).

1) The paclitaxel content varies by species, season harvested, and handling procedures (Wheeler et al, 1992).
2) Average amounts of paclitaxel in various parts of Taxus brevifolia are as follows (Vidensek et al, 1992):

a) Bark: 0.015%
b) Branches: 0.0017%
c) Leaves/Needles: 0.0015%
d) Roots: 0.004%
e) Seedlings: 0.0058%
f) Twigs: 0.0012%
g) Wood: 0.0006%

3) Paclitaxel is difficult to obtain from the bark of Taxus brevifolia so production of paclitaxel analogs and the preparation of paclitaxel from baccatin (from the leaves) has been investigated to increase the supply of paclitaxel (Blume, 1989; Kingston et al, 1990).
4) A single cancer patient may require 1200 to 1500 mg of paclitaxel over a course of treatment. It takes 25,000 pounds of Pacific yew bark to create 1000 mg of finished paclitaxel (Anon, 1992).

b) Paclitaxel is also obtained via a semisynthetic process from Taxus baccata (Prod Info TAXOL(R) IV injection, 2010).

1) PACLITAXEL: Paclitaxel is indicated for the following (Prod Info TAXOL(R) IV injection, 2010):

a) As a first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary
b) Adjuvant treatment of node-positive breast cancer administered sequentially with doxorubicin combination chemotherapy
c) Treatment of breast cancer after failure of combination therapy for metastatic disease or relapse within 6 months of adjuvant therapy
d) Used in combination with cisplatin for the first-line treatment of non-small cell lung cancer in patients that are not candidates for potentially curative surgery and/or radiation therapy
e) As a second-line therapy in the treatment of AIDS-related Kaposi's sarcoma

2) PACLITAXEL PROTEIN-BOUND: Paclitaxel protein-bound particles for injectable suspension is used in the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy (Prod Info ABRAXANE(R) intravenous suspension, 2009).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Paclitaxel is an antineoplastic agent commonly used alone or in combination with other antineoplastic agents to treat cancers of the breast, ovaries or lung. It is also used as a second-line therapy in the treatment of AIDS-related Kaposi's sarcoma. It has also been used in the treatment of the following: bladder cancer, esophageal cancer, gastric cancer, head and neck cancers, melanoma, non-melanoma skin cancers, testicular cancer, thymomas, uterine cancers, and cancers of unknown primary site. Typically, it is administered intravenously, but it has also been administered via the intraperitoneal route for the treatment of ovarian cancer.
B) PHARMACOLOGY: Paclitaxel is a microtubule inhibitor; it binds to tubulin and promotes its assembly into microtubules while inhibiting disassembly. The stabilization that occurs produces inhibition of mitotic and interphase cellular functions.
C) TOXICOLOGY: Paclitaxel inhibits normal interphase and mitotic cellular function, causing cell death. Overdose effects are seen primarily in rapidly dividing cells (ie, bone marrow suppression, gastrointestinal tract).
D) EPIDEMIOLOGY: Inadvertent overdose or exposure is uncommon.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: Bone marrow suppression is the major dose-limiting toxicity of paclitaxel therapy. In a summary of adverse effects in patients with solid tumors treated with single-agent paclitaxel, moderate neutropenia (less than 2000/mm(3)) occurred in 90% of cases with severe neutropenia (less than 500/mm(3)) reported in 52% of cases. Leukopenia (less than 4000/mm(3); 90%), anemia (less than 11 g/dL; 78%), and thrombocytopenia (less than 100,000/mm(3); 20%) were observed following single-agent paclitaxel, but symptoms were not severe (less than grade 3) in most cases. In addition, peripheral neuropathy (60%), myalgias/arthralgias (60%), nausea/vomiting (38%), diarrhea (31%), and mucositis (87%) were also common events observed with single-agent paclitaxel. In an adjuvant breast carcinoma study, patients receiving combination therapy with cyclophosphamide, doxorubicin and paclitaxel, experienced more episodes of grade 3/4 neurosensory toxicity, myalgia/arthralgia, neurologic pain (5% vs 1%) and flu-like symptoms (5% vs 3%), and hyperglycemia (3% vs 1%). Hypersensitivity reactions (41%) are more frequently observed with the Cremophor EL formulation even with premedication; fatalities have occurred in a small number of cases. Injection site reactions usually produce mild symptoms. Other frequent events: fever, edema, asthenia, malaise and edema.
2) PEDIATRIC: Based on limited studies, children receiving paclitaxel were more likely to develop neurotoxic effects (ie, somnolence, mild agitation, coma) shortly after exposure; neutropenia was not found to be the dose-limiting toxicity.
3) INFREQUENT: Cardiovascular events (bradycardia, hypotension, hypertension, ECG abnormalities), liver injury, infections, anorexia, and confusion are not commonly observed with single-agent therapy. Severe injection site reactions (ie, phlebitis, cellulitis, and necrosis) are more often seen with longer infusions.
4) INTRAPERITONEAL: Systemic toxicity occurs similar to that seen with intravenous therapy, along with occasional port complications including infection, inflow obstruction or blockage, abdominal pain, and bowel injury.
5) DERMAL: Tingling, redness or burning of the skin. INHALATION: May produce dyspnea, chest pain, burning eyes, sore throat, and nausea.

F) WITH POISONING/EXPOSURE

1) OVERDOSE: Data are limited. Overdose effects are expected to be an extension of adverse events and include bone marrow suppression, peripheral neurotoxicity, and mucositis. Events may take several days up to a week or more to develop. Since paclitaxel is often combined with other chemotherapeutic agents, certain toxicities may be more severe (ie, hematologic, gastrointestinal) depending on the agent(s) used. Acute ethanol toxicity (for ethanol-containing formulation) may develop, primarily in children.
2) MILD TO MODERATE TOXICITY: Early symptoms (within hours to days) may include nausea/vomiting and diarrhea. CNS function may be altered by ethanol toxicity. Other common events may include mucositis, myalgias/arthralgias, and peripheral neurotoxicity (usually sensory).
3) SEVERE TOXICITY: Myelosuppression (primarily neutropenia) is likely to develop and may be severe (grade 3 or higher). Anemia, thrombocytopenia, and febrile neutropenia may also develop. Myelotoxicity may be exacerbated by patients with abnormal liver function (total bilirubin of greater than 2 times the upper limit of normal).

0.2.20)

A) Paclitaxel is classified as FDA pregnancy category D. In animal studies in rats and rabbits, paclitaxel was embryotoxic and fetotoxic. At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans.

0.2.21)

A) At the time of this review, the manufacturers do not report any carcinogenic potential.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) Paclitaxel is typically available for intravenous use.
B) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

0.4.4)

A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

0.4.6)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is primarily symptomatic and supportive, there is no antidote. Early signs of toxicity may include nausea/vomiting and diarrhea, that can be severe. It may be necessary to treat with multiple concomitant agents, from different drug classes, in patients with persistent symptoms. BONE MARROW SUPPRESSION: Neutropenia should be anticipated. Colony stimulating factor (filgrastim or sargramostim) should be initiated as soon as possible after exposure. Patients with severe neutropenia should be in protective isolation. PERIPHERAL NEUROPATHY: Likely to develop in overdose. Monitor and treat symptoms. Effects are usually reversible, but may persist for long periods. MYALGIAS: Initially treat with acetaminophen (NSAIDs if the patient is not thrombocytopenic). Glutamine and gabapentin have been used with some success to treat persistent symptoms. PEDIATRIC: Based on limited data, children may be more likely to develop neurotoxicity (ie, somnolence, agitation, seizures, coma) following exposure.

B) MANAGEMENT OF SEVERE TOXICITY

1) NEUTROPENIA: Bone marrow suppression (ie, neutropenia) may be severe. Neutropenia is the dose-dependent and the dose-limiting toxicity in therapy. Colony stimulating factor (filgrastim or sargramostim) should be initiated as soon as possible. Place patients with severe neutropenia in protective isolation. Platelet and red cell transfusions may be necessary. Aggressively treat with antiemetics. Replace fluids and electrolytes as indicated. Closely monitor patients for hypotension, bradycardia and other cardiac dysrhythmias. Monitor liver enzymes and renal function. PEDIATRIC: Based on limited data, children may be more likely to develop neurotoxicity (ie, somnolence, agitation, seizures, coma) following exposure.

C) DECONTAMINATION

1) PREHOSPITAL: Not indicated since overdose is unlikely because paclitaxel is administered by the intravenous route.
2) HOSPITAL: Activated charcoal and/or gastric lavage are not indicated since overdose most often occurs by the intravenous route.

D) AIRWAY MANAGEMENT

1) Consider orotracheal intubation in patients with significant CNS depression or respiratory failure.

E) HYPERSENSITIVITY REACTION

1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.

F) ANTIDOTE

1) There is no known antidote for paclitaxel.

G) MYELOSUPPRESSION

1) Severe neutropenia should be anticipated following a significant exposure. Place patients in protective isolation. Give colony stimulating factor as soon as possible. Closely monitor CBC with differential daily until patient recovery. Filgrastim: 5 mcg/kg/day IV or subQ (preferred route). Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily.

H) NEUTROPENIA

1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).

I) FEBRILE NEUTROPENIA

1) If fever (38.3 C) develops during the neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.

J) VOMITING

1) Treat nausea and vomiting with high-dose dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, promethazine or prochlorperazine), 5-HT3 serotonin antagonists (eg, ondansetron, dolasetron, or granisetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and/or antipsychotics (eg, haloperidol). Diphenhydramine may be required to prevent dystonic reactions from dopamine antagonists, phenothiazines, or antipsychotics. Replace fluid and electrolytes as needed. Monitor liver and renal function closely.

K) MUCOSITIS/STOMATITIS

1) Ice chips (ie, cryotherapy) may help minimize symptoms. Palifermin, a keratinocyte growth factor, is indicated for the prevention of chemotherapy-induced oral mucositis. Treat mild symptoms of pain or xerostomia with bland rinses (ie, normal saline or sodium bicarbonate). Treat salivary gland dysfunction or xerostomia with sugarless candy/mints, pilocarpine/cevimeline, bethanechol, topical fluorides or remineralizing agents. Treat moderate pain symptoms with topical anesthetics (ie, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin) and mucosal coating agents (benzydamine) as needed. Moderate to severe symptoms may require systemic analgesics. Prophylactic treatment to prevent infection is suggested; topical or systemic treatment may be indicated. It may affect the entire gastrointestinal tract and lead to significant morbidity and mortality in some cases. Lower GI symptoms can include: diarrhea, abdominal pain, hemorrhagic diarrhea, and in rare cases, neutropenic enterocolitis. These events may occur several days after exposure. Treatment should include fluid and nutritional replacement and appropriate antibiotic therapy. Palifermin is indicated to reduce the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. In patients with severe paclitaxel overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.

L) PERIPHERAL AXONAL NEUROPATHY

1) Peripheral neurotoxicity should be anticipated in overdose. Paclitaxel-induced neurotoxicity can produce distal symmetrical polyneuropathy (sensory greater than motor). Monitor and treat symptoms as indicated. Pain is sometimes present. Amitriptyline may be used for neuropathic symptoms. In general, symptoms are reversible, but may persist for long periods.

M) EXTRAVASATION INJURY

1) Paclitaxel is both an irritant and vesicant. If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Administer hyaluronidase (see dosing below). Elevate the affected area. Apply cold compresses on the area for 15 to 20 minutes each hour for 4 hours or at least 4 times daily. Administer analgesia for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (ie, antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy. HYALURONIDASE: Local injection of hyaluronidase (150 to 300 Units diluted in 3 mL of saline subQ or intradermally) has been suggested by some authors to treat paclitaxel-induced extravasations. Impaired healing has been suggested with the use of hyaluronidase. Another source recommended hyaluronidase 1500 Units in 2 mL water for injection using the pin cushion technique; however, routine use is probably not warranted.

N) INTRATHECAL INJECTION

1) No clinical reports available, information derived from experience with other antineoplastics. Keep patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or lactated ringers through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hr). FFP (25 mL FFP/liter NS or LR) or albumin 5% have also been used for perfusion; may be useful because of high protein binding of paclitaxel. Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.

O) ENHANCED ELIMINATION

1) Paclitaxel is highly protein-bound with a large volume of distribution, but after large doses the distribution is saturable so the drug stays in the central compartment longer. Theoretically, plasmapheresis or plasma exchange might effectively remove significant quantities of paclitaxel, if performed soon after a large overdose. There are no reports of the use of plasmapheresis to treat paclitaxel overdose.

P) PATIENT DISPOSITION

1) HOME CRITERIA: There is no data to support home management. Patients with a paclitaxel overdose need to be admitted.
2) OBSERVATION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), daily monitoring of CBC with differential until bone marrow suppression is resolved, along with monitoring of serum electrolytes, renal function and hepatic enzymes (alkaline phosphatase, SGOT and SGPT) and bilirubin.
3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with a paclitaxel overdose. Consultation with an infectious disease specialist with experience treating immunosuppressed and myelosuppressive patients may also be beneficial.
4) TRANSFER CRITERIA: Patients with severe overdose or profound neutropenia may benefit from a transfer to a bone marrow transplant or cancer treatment center.

Q) PITFALLS

1) Symptoms in patients may be delayed (particularly myelosuppression), so reliable follow-up is imperative. Patients taking these medications may have severe comorbidities and access to other drugs with significant toxicity. Ethanol intoxication may contribute to CNS toxicity, particularly in children.

R) PHARMACOKINETICS

1) Paclitaxel is highly protein-bound (89% to 98%). The volume of distribution is high (227 to 688 L/m(2)) with therapeutic doses. Terminal half-life ranged from 13.1 to 52.7 hours following doses of 135 to 175 mg mg/m(2) for the paclitaxel liposome formulation and was about 27 hours for the protein-bound formulation. Serum concentrations of paclitaxel decline rapidly following intravenous infusion. Distribution and elimination can be saturated after large doses.

S) DIFFERENTIAL DIAGNOSIS

1) Differential diagnosis includes other chemotherapeutic agents.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.3)

A) WITH THERAPEUTIC USE

1) Fever was is relatively common during paclitaxel therapy and was observed in animal studies (Prod Info TAXOL(R) IV injection, 2010; Anon, 1988; Ohnuma et al, 1985)

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) PHOTOPSIA

a) Six of 25 patients receiving paclitaxel infusions, at doses of 250 to 275 mg/m(2) of body surface area over a 3-hour period, experienced seeing flashing lights across the entire visual field. This effect began during the last 30 minutes of the infusion and the duration was from 15 minutes to 3 hours.

1) The photopsia recurred upon rechallenge at the same or slightly lower dose (275 to 250 mg/m(2) of body surface area), but did not occur in doses less than 250 mg/m(2) of body surface area (Seidman et al, 1994).

2) GLAUCOMA

a) CASE REPORT: A 31-year-old woman developed visual loss and wide angle glaucoma after the fifth cycle of docetaxel. Glaucoma recurred in the third cycle after she was switched to paclitaxel. Both times glaucoma developed after the onset of diffuse fluid retention (Fabre-Guillevin et al, 1999).

3) LENS TOXICITY (ANIMAL STUDIES)

a) Paclitaxel has been used experimentally to inhibit the development of tractional retinal detachments in proliferative vitreoretinopathy in rabbits.

1) When injected intravitreally into rabbit eyes (in 30% DMSO), severe toxicity to the lens and retina was seen at concentrations of 10(-2) Molar. It was estimated that a safe concentration in this model was 10(-5) Molar or less (Daniels et al, 1989).

3.4.4)

A) WITH THERAPEUTIC USE

1) OTOTOXICITY

a) There have been rare reports of ototoxicity (ie, hearing loss, tinnitus) during postmarketing surveillance (Prod Info TAXOL(R) IV injection, 2010).

Cardiovascular

3.5.2)

A) CARDIOVASCULAR FINDING

1) WITH THERAPEUTIC USE

a) Hypotension, bradycardia, and hypertension may develop during therapy with single-agent paclitaxel, but usually requires no intervention.
b) Bradycardia may be observed within the first several hours of therapy. The prior use of anthracyclines did not affect the development of hypotension or bradycardia (Prod Info TAXOL(R) IV injection, 2010).
c) ECG changes may develop, but are usually not dose-limiting. Patients often remain asymptomatic. Severe conduction abnormalities have been reported in less than 1% of patients receiving single-agent paclitaxel, with some patients requiring pacemaker placement (Prod Info TAXOL(R) IV injection, 2010).
d) Cases of atrial fibrillation and supraventricular tachycardia have been reported infrequently with administration of single-agent paclitaxel (Prod Info TAXOL(R) IV injection, 2010).

B) BRADYCARDIA

1) WITH THERAPEUTIC USE

a) Transient asymptomatic bradycardia has developed infrequently with single-agent paclitaxel therapy. The prior use of anthracyclines did not affect the development of hypotension or bradycardia (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009). The Cremophor vehicle does not appear to be implicated (Rowinsky et al, 1990).
b) INCIDENCE: Bradycardia occurred in 3% of all patients during the first 3 hour infusion of single-agent paclitaxel. The prior use of anthracyclines did not affect the development of hypotension or bradycardia (Prod Info TAXOL(R) IV injection, 2010).

C) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) SUMMARY: Hypotension has been reported infrequently in patients receiving single-agent paclitaxel therapy (Prod Info TAXOL(R) IV injection, 2010).
b) In a pooled analysis from 10 clinical studies in women with ovarian and breast cancer, 12% of patients who received single-agent paclitaxel (n=532) experienced hypotension during the first 3 hours of the infusion. One patient treated with paclitaxel 175 mg/m(2) IV over 24 hr experienced syncope, progressive hypotension, and died (Prod Info TAXOL(R) IV injection, 2010).
c) In 2 open-label, phase 2 studies evaluating single-agent paclitaxel as a second-line treatment for AIDS-related Kaposi sarcoma, hypotension occurred in 17% and 9% of patients who received paclitaxel 135 mg/m(2) IV over 3 hr every 3 weeks (n=29) and 100 mg/m(2) IV over 3 hr every 2 weeks (n=56), respectively (Prod Info TAXOL(R) IV injection, 2010).

D) VENTRICULAR ARRHYTHMIA

1) WITH THERAPEUTIC USE

a) Severe conduction abnormalities are rare and have been reported in less than 1% of patients receiving single-agent paclitaxel (Prod Info TAXOL(R) IV injection, 2010).
b) Ventricular tachycardia and ventricular ectopy have been reported in patients receiving paclitaxel and cisplatin (Rowinsky et al, 1990). In a Phase 3 study, significant cardiovascular events occurred in 12% to 13% of patients with non-small cell lung cancer treated with paclitaxel and cisplatin (Prod Info TAXOL(R) IV injection, 2010).

E) ATRIOVENTRICULAR BLOCK

1) WITH THERAPEUTIC USE

a) SUMMARY: Rare cases of cardiovascular toxicity have been observed with single-agent paclitaxel therapy (McGuire et al, 1989).
b) CASE REPORT: Progressive atrioventricular block culminating in third-degree block and a 7-second episode of asystole developed in an ovarian cancer patient treated with single-agent paclitaxel. The patient had been previously treated with doxorubicin and a history of coronary artery disease (McGuire et al, 1989).
c) CASE REPORT: Another patient developed Wenckebach syndrome during several infusions of paclitaxel alone. The syndrome resolved within 3 to 4 hours after discontinuation of the infusion (McGuire et al, 1989).

F) MYOCARDIAL INFARCTION

1) WITH THERAPEUTIC USE

a) Myocardial infarction has been reported rarely with single-agent paclitaxel use (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009).
b) In a phase II trial of weekly paclitaxel and trastuzumab in patients with HER2-positive metastatic breast cancer (n=95), patients with a history of significant cardiac disease or a left ventricular ejection fraction (LVEF) of less than 50% were excluded. Seven patients with a prior anthracycline exposure of 400 mg/m(2) or less developed an asymptomatic decrease in LVEF of greater than 20% from baseline. Three patients developed serious cardiac complications. One patient with a prior cumulative doxorubicin exposure of 615 mg/m(2) and an LVEF of less than 50% at study entry had a decrease of LVEF to 10% after 7 weeks of therapy. The second patient had a cumulative doxorubicin exposure of 240 mg/m(2) prior to therapy and developed an acute myocardial infarction with a LVEF of 35% to 40% after 8 months of therapy. She had another myocardial infarction with a LVEF of 30% 2 months later and recovered. LVEF remained low but she maintained stable disease after 3 months of weekly paclitaxel. A third patient who had received adjuvant therapy consisting of 4 courses of paclitaxel followed by 4 courses of fluorouracil, doxorubicin, and cyclophosphamide was hospitalized 6 months after study entry for influenza and pneumonia requiring mechanical ventilation for respiratory failure; she had a massive myocardial infarction and died of acute respiratory failure (Seidman et al, 2001).
c) Chest pain and a fatal myocardial infarction was reported during paclitaxel infusions of a patient with atherosclerotic cardiovascular disease (Rowinsky et al, 1990).
d) CASE REPORT: A 67-year-old woman developed tachypnea, respiratory distress, confusion, and chest pain approximately 15 hours after beginning a 24-hour infusion of paclitaxel 225 mg. Lab analysis showed elevated cardiac enzyme levels. An electrocardiogram showed ST elevation with pathological Q waves, and an echocardiogram showed severe global left ventricular dysfunction consistent with an acute inferior myocardial infarction. Despite discontinuation of paclitaxel therapy, the patient died 13 hours later (Hekmat, 1996).

G) CONGESTIVE HEART FAILURE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 36-year-old woman was given a 3-hour infusion of paclitaxel 135 mg/m(2) of body surface area, and 2 days later developed dyspnea and generalized edema, which suggested congestive heart failure. The patient died 5 days after the paclitaxel infusion. Electron microscopy detected structural changes in the myocardium, possibly caused by the paclitaxel treatment. These structural changes could have precipitated the congestive heart failure (Jekunen et al, 1994).

Respiratory

3.6.2)

A) RESPIRATORY FINDING

1) WITH THERAPEUTIC USE

a) Respiratory failure and pleural effusion have been reported rarely with paclitaxel therapy (Prod Info TAXOL(R) IV injection, 2010).

B) INTERSTITIAL PNEUMONIA

1) WITH THERAPEUTIC USE

a) Interstitial pneumonia has been reported with paclitaxel therapy (Prod Info TAXOL(R) IV injection, 2010).
b) CASE REPORTS: Seven patients receiving concomitant radiation and paclitaxel (50 to 86 mg/m(2)) for non-small cell lung cancer developed moderate to severe interstitial pneumonia, secondary to lymphocytopenia. One of these patients had pneumocystis carini pneumonia and 4 others had mild to moderate pulmonary infections. Pulmonary infiltrates were unilateral and outside the irradiation field in all patients, ruling out the possibility of T-cell-mediated hypersensitivity, which usually occurs bilaterally (Reckzeh et al, 1996).
c) CASE REPORT: A 71-year-old Japanese man with adenocarcinoma of the lung was started on paclitaxel 80 mg/m(2) on day 1 and 8. Premedication therapy included dexamethasone, diphenhydramine and ranitidine. Twelve days after therapy the patient complained of chills. Physical exam included fine crackles in the left lung and a CT scan of chest showed ground-glass opacities consistent with interstitial pneumonia. Methylprednisolone 1 g/day for 3 days was started immediately and repeated 5 days later for persistent symptoms and radiologic findings. Cyclophosphamide (750 mg/day) was added on day 31. A repeat CT showed extensive areas of ground-glass opacities with interlobular septal thickening and traction bronchiectasis. The patient further deteriorated and required mechanical ventilation; the patient died on day 128 (from initiation of chemotherapy) of respiratory failure due to interstitial pneumonia and lung cancer (Suzaki et al, 2006).

1) MECHANISM: The development of interstitial pneumonia is thought to be due to a cell-mediated immunologic reaction, which can be diagnosed by a drug lymphocyte stimulation test along with bronchoalveolar lavage or findings from a transbronchial lung biopsy. In this case, the patient was too ill to undergo these studies (Suzaki et al, 2006).

C) PNEUMONIA

1) WITH THERAPEUTIC USE

a) Lipid pneumonia was reported in a lung cancer patient given paclitaxel in a Cremophor(R) base (Brandwein et al, 1988).

D) ACUTE LUNG INJURY

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 59-year-old woman developed tachypnea and cyanosis 7 days after a paclitaxel infusion of 160 mg/m(2) of body surface area. The patient died shortly afterwards. Autopsy determined that the immediate cause of death was acute pulmonary edema (Alagaratnam, 1993).

E) FIBROSIS OF LUNG

1) WITH THERAPEUTIC USE

a) Lung fibrosis has been reported infrequently with paclitaxel therapy (Prod Info TAXOL(R) IV injection, 2010).
b) Bilateral interstitial infiltrates and subsequent irreversible lung fibrosis are described in a 59-year-old male with chronic obstructive pulmonary disease receiving paclitaxel (200 mg/m(2) over 3 hours), carboplatin, and radiation for non-small-cell lung cancer. Five weeks after initiating drug therapy, treatment was discontinued and the patient hospitalized for fever and cough. Computerized tomography (CT) revealed interstitial basal infiltrates with a "ground-glass" image outside the radiation field. Infectious and neoplastic etiologies were ruled out. Symptoms were significantly improved after 2 days of methylprednisolone (32 milligrams/day). Repeat CT after 2 weeks demonstrated improvement in the interstitial injury but the appearance of lung fibrosis at the bases outside the radiation field was evident. Methylprednisolone and supplemental oxygen were continued for a total of 2 months. At 14 months, the patient was alive and well, but fibrosis persisted on follow-up CT scan (Sotiriou & Klastersky, 1998).

F) PNEUMONITIS

1) WITH THERAPEUTIC USE

a) PACLITAXEL: Acute bilateral pneumonitis occurred in 3 patients approximately 30 minutes to 5 hours after receiving intravenous infusions of paclitaxel in a Cremophor EL(R) diluent. The patients experienced coughing, dyspnea, and tachypnea and chest X-rays revealed bilateral interstitial infiltrates. Each patient received parenteral corticosteroid therapy; the infiltrates resolved 24 to 96 hours later. It is unclear whether the pneumonitis was an anaphylactoid response or a direct effect of the paclitaxel treatment; Cremophor EL(R) has also been associated with hypersensitivity reactions (Khan et al, 1997).

1) INCIDENCE: Acute bilateral pneumonitis occurs in less than 1% of patients receiving paclitaxel therapy (Khan et al, 1997).

Neurologic

3.7.2)

A) PERIPHERAL AXONAL NEUROPATHY

1) WITH THERAPEUTIC USE

a) CHEMOTHERAPY-INDUCED PERIPHERAL NEUROTOXICITY

1) PREDOMINANT CLINICAL FEATURES: Paclitaxel-induced neurotoxicity can produce distal symmetrical polyneuropathy (sensory greater than motor) (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009; Cavaletti et al, 2008). It occurs frequently with therapy and appears dependent on cumulative dose (Prod Info TAXOL(R) IV injection, 2010). Pain is sometimes present. The target of the neurotoxicity is the axons and possibly the dorsal root ganglia. An early feature of peripheral toxicity is that all sensory modalities are affected along with loss of deep tendon reflexes. Motor impairment is usually a rare finding. Myalgia is common, but distal neuropathic pain rarely develops (Cavaletti et al, 2008).

a) Sensory neuropathy, usually beginning in the hands and feet or sometimes in the mouth and tongue, was reported in patients taking paclitaxel with or without other neurotoxic drugs. Neurotoxic effects have been cumulative, worsening after multiple courses of therapy (Lipton et al, 1989; Rowinsky et al, 1990; Sahenk et al, 1994; Van Gerven et al, 1994; Cavaletti et al, 1995).

1) Symptoms included burning dysesthesias of the feet, glove-and-stocking distribution sensory loss, numbness, and lancing pain in the back or extremities (Park et al, 2008; Lipton et al, 1989).

2) INCIDENCE: Severe dose-dependent neurotoxicity occurs in 10% to 30% of patients (Park et al, 2008). Any grade peripheral neuropathy: 42% to 79% (Prod Info TAXOL(R) IV injection, 2010).
3) DOSE RANGE: Doses over 300 mg/m(2), but may occur at lower doses (Park et al, 2008).
4) CUMULATIVE DOSE EFFECT: Cumulative neurotoxicity typically occurs at doses above 200 to 250 mg/m(2) (Park et al, 2008).
5) PATHOLOGY: Taxane-induced neurotoxicity has been associated with microtubule damage resulting in dysfunction of axonal transport. It has been noted that paclitaxel interferes with microtubule dynamics, damaging the mitotic spindle and resulting in apoptosis (Park et al, 2008).
6) RECOVERY: Paclitaxel-induced neurotoxicity may be dose-limiting. In general, the clinical features are reversible over several weeks to several months (Cavaletti et al, 2008; Wiernik et al, 1987a; Donehower et al, 1987; Rowinsky et al, 1990)although some studies report that symptoms can persist long-term (Park et al, 2008). Nerve conduction studies are suggested to evaluate patients treated with taxanes (Cavaletti et al, 2008).
7) CASE REPORT: A patient developed tingling and numbness of feet and legs after receiving paclitaxel therapy (175 to 250 mg/m(2)). The patient reported residual numbness and weakness in the feet 5 years after completing paclitaxel therapy (Kaplan et al, 1993).
8) CASE REPORT: A 50-year-old woman developed a hypersensitivity reaction, consisting of chest tightness, facial flushing, and light-headedness, as well as arm numbness and tingling several minutes after starting her first infusion of paclitaxel 175 mg/m(2). The symptoms completely resolved after the infusion was stopped. Eighteen hours later, the patient experienced severe bilateral upper and lower extremity pain accompanied by right arm numbness and loss of function. Symptoms resolved the following day (McCauley et al, 1994).

b) PHANTOM PAIN

1) Phantom limb pain has been reported as a manifestation of paclitaxel-induced neuropathy in 3 patients with remote amputations (Khattab et al, 2000).

B) SEIZURE

1) WITH THERAPEUTIC USE

a) Grand mal seizures have been reported rarely (less than 1% of patients) following paclitaxel administration (Prod Info TAXOL(R) IV injection, 2010).
b) (Slichenmyer & Von Hoff, 1990; Rowinsky et al, 1990). In clinical trials, seizures have also been reported in children (Doz et al, 2001).

C) COMA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Coma was reported in 5 patients following high-dose paclitaxel infusions, 600 mg/m(2) or greater, as part of a chemotherapy regimen. The onset of coma began 2 to 16 days after paclitaxel treatment with death occurring in 3 of the 5 patients. Multiple small infarcts in the cerebral parenchyma were observed during autopsy of one of the patients. The autopsy of a second patient, who received whole brain irradiation prior to administration of paclitaxel, showed diffuse white matter atrophy with no residual tumor lesions (Nieto et al, 1999).
b) PEDIATRIC: In a phase 1 trial and pharmacological study of a 3-hour paclitaxel (containing 50% cremophor EL and 50% ethanol) infusion in children (=17) with refractory solid tumors, acute neurologic toxicity was dose-limiting (at doses of 350 mg/m(2) and 420 mg/m(2)) and included coma, agitation, and somnolence. It was uncertain what role paclitaxel, the solvent or ethanol ol had in the development of acute neurologic toxicity, but the study was discontinued. Due to the adverse events observed, the authors could not recommend the use of a 3-hour infusion every 3 weeks in children (Doz et al, 2001).

D) DROWSY

1) WITH THERAPEUTIC USE

a) PEDIATRIC: In a phase 1 trial and pharmacological study of a 3-hour paclitaxel (containing 50% cremophor EL and 50% ethanol) infusion in children (=17) with refractory solid tumors, acute neurologic toxicity was dose-limiting (at doses of 350 mg/m(2) and 420 mg/m(2)) and included coma, agitation, and somnolence. It was uncertain what role paclitaxel, the solvent, or ethanol had in the development of acute neurologic toxicity, but the study was discontinued. Due to the adverse events observed, the authors could not recommend the use of a 3-hour infusion every 3 weeks in children (Doz et al, 2001).

E) ALCOHOL INTOXICATION

1) WITH THERAPEUTIC USE

a) CASE REPORT: Acute ethanol intoxication was reported in a 57-year-old woman following diphenhydramine premedication and intravenous administration of high-dose paclitaxel, 600 mg infused over 3 hours. The patient's symptoms included agitation, ataxia, slurred speech, vertigo, and hallucinations. Lab analysis showed a blood alcohol concentration of 97.8 mg/dL (0.098%). It was speculated that the ethanol intoxication was due to the 49.7% ethanol contained in the paclitaxel formulation with the effects aggravated by the diphenhydramine effects on the CNS (Wilson et al, 1997).
b) CASE SERIES: In a small study of outpatients treated with paclitaxel (n=36) or docetaxel (n=16), 5 patients reported a "drunken sensation" after receiving the paclitaxel infusion. Both paclitaxel and docetaxel contain ethanol as a diluent. Blood alcohol concentrations measured by breathalyzer after infusion were noted to be greater than 0.15 mg/L in 20 patients treated with paclitaxel. No significant blood alcohol concentrations were noted with docetaxel (Komagata et al, 2005).

2) WITH POISONING/EXPOSURE

a) Acute ethanol toxicity may develop in children or adults following an overdose of paclitaxel (ethanol-containing formulation) (Prod Info TAXOL(R) IV injection, 2010).

F) NEUROPATHY

1) WITH THERAPEUTIC USE

a) CASE REPORTS: Two cases of autonomic neuropathy occurred following paclitaxel therapy. One patient was diabetic and one was not; however, both patients experienced generalized weakness and orthostatic hypotension (Jerian et al, 1993).

G) MUSCLE WEAKNESS

1) WITH THERAPEUTIC USE

a) Proximal muscle weakness has been described occasionally in paclitaxel-treated patients (McGuire et al, 1989; Slichenmyer & Von Hoff, 1990; Rowinsky et al, 1990).

H) BEHAVIOR SHOWING REDUCED MOTOR ACTIVITY

1) WITH THERAPEUTIC USE

a) Mild to severe motor dysfunction was described occasionally in paclitaxel-treated patients (McGuire et al, 1989; Slichenmyer & Von Hoff, 1990).

I) OPTIC NEURITIS

1) WITH THERAPEUTIC USE

a) Nine of 47 patients experienced scintillating scotomata as small luminous dots in the visual fields of both eyes following paclitaxel infusion of 175 to 225 mg/m(2) of body surface area. Three of the 9 patients also reported a reduction of vision at the 225 mg/m(2) of body surface area dose.

1) Recordings of visual evoked potentials (VEP) abnormalities suggested an involvement of the optic nerve (Capri et al, 1994).

b) Visual field loss, which resolved after completion of therapy, developed in 3 of 12 patients receiving paclitaxel 400 mg/m(2) in one study (De Giorgi et al, 2000). It was felt to be secondary to optic neurotoxicity.

J) TOXIC ENCEPHALOPATHY

1) WITH THERAPEUTIC USE

a) Neuroencephalopathy has been reported in less than 1% of patients following paclitaxel administration (Prod Info TAXOL(R) IV injection, 2010).
b) At least 2 cases have been described in which confusion and behavioral changes appeared 3 to 7 days after a 3-hr infusion of paclitaxel (175 mg/m(2)). Symptoms resolved after 6 to 48 hours, but reappeared following repeated exposure (Perry & Warner, 1996).
c) Six patients out of 129 in a high-dose paclitaxel protocol (600 mg/m(2) with stem cell support) developed encephalopathy starting 7 to 23 days after paclitaxel therapy; 2 had also received whole brain irradiation. They presented with rapid obtundation, coma, confusion, and paranoid ideation. Three patients recovered and 3 died of irreversible coma. Autopsy on 2 of the patients revealed generalized white matter atrophy and multiple parenchymal infarcts, respectively. In the third death no autopsy was performed, but MRI prior to death showed white matter atrophy. MRI results on the 3 surviving patients were normal (Nieto et al, 1999).

K) CRANIAL NERVE DISORDER

1) WITH THERAPEUTIC USE

a) CASE REPORT: Bilateral facial nerve palsy developed in a 62-year-old woman receiving paclitaxel. She also demonstrated severe sensory motor neuropathy of the hands and feet, mouth and face (Lee et al, 1999).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) SUMMARY: In a summary of patients (n=812) with solid tumors receiving paclitaxel alone, nausea/vomiting occurred in 52% of patients (Prod Info TAXOL(R) IV injection, 2010).

B) DIARRHEA

1) WITH THERAPEUTIC USE

a) SUMMARY: In a summary of patients (n=812) with solid tumors receiving paclitaxel alone, diarrhea occurred in 38% of patients (Prod Info TAXOL(R) IV injection, 2010).

C) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE

1) WITH THERAPEUTIC USE

a) SUMMARY: In a summary of patients (n=812) with solid tumors receiving paclitaxel alone, mucositis occurred in 31% of patients (Prod Info TAXOL(R) IV injection, 2010).
b) CHARACTERISTICS: Mucositis is a potentially severe complication (Rowinsky et al, 1990; Slichenmyer & Von Hoff, 1990). It is characterized by ulcerations of the lips, pharynx, oral cavity, esophagus (Hruban et al, 1989), and dysphagia.
c) ONSET: Oropharyngeal ulcerations usually occur 3 to 7 days after treatment, and subside within 1 week (Rowinsky et al, 1989).
d) In a pooled analysis from 10 clinical studies in women with ovarian (n=493) and breast (n=319) cancer, 31% of patients who received single-agent paclitaxel experienced mucositis. In these studies, mucositis appeared to be schedule dependent and occurred more frequently with the 24-hour infusion than with the 3-hour infusion(Prod Info TAXOL(R) IV injection, 2010).

D) DRUG-INDUCED ILEUS

1) WITH THERAPEUTIC USE

a) Autonomic neuropathy resulting in paralytic ileus has been reported rarely with paclitaxel use in postmarketing surveillance (Prod Info TAXOL(R) IV injection, 2010).
b) Adynamic ileus, associated with severe, generalized weakness has been reported in diabetic patients treated with paclitaxel. This may have been an additional complication of autonomic neuropathy (Wiernik et al, 1987).

E) PERFORATION OF INTESTINE

1) WITH THERAPEUTIC USE

a) Intestinal perforation has been reported with paclitaxel use (Prod Info TAXOL(R) IV injection, 2010).
b) MECHANISM: The mechanism of action is not well understood, but paclitaxel may act directly on compromised gastrointestinal epithelium and induce mitotic arrest, thereby reducing the reparative capacity of the tissue. Typically, symptoms (ie, fever, neutropenia and abdominal pain) begin about 2 weeks after cycle 1 or 2. Although not frequently reported, mortality has approached 50%. Based on limited data, it is uncertain whether intraperitoneal paclitaxel administration may result in bowel injury (Landrum et al, 2008).
c) CASE SERIES: Four of 79 patients receiving paclitaxel infusions to treat refractory platinum-resistant ovarian cancer, experienced gastrointestinal perforation 13 to 16 days after receiving paclitaxel. One patient receiving intraperitoneal therapy developed symptoms, while the other cases occurred following intravenous administration (Seewaldt et al, 1993).
d) CASE REPORTS: Three patients developed colonic perforation 4 to 15 days after paclitaxel infusion therapy. Two of the 3 patients died (Rose & Piver, 1995).

F) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE

1) WITH THERAPEUTIC USE

a) CASE REPORTS: Two patients developed typhlitis after receiving combined treatment with paclitaxel and doxorubicin. Typhlitis is a necrotizing inflammation of the cecum that may extend into the ileum and the ascending colon.

1) Both patients experienced fever, diarrhea, grade 4 neutropenia (absolute neutrophil count less than 500/microliter), and moderate to severe abdominal pain. CT scans confirmed the diagnosis of typhlitis (Pestalozzi et al, 1993).

G) COLITIS

1) WITH THERAPEUTIC USE

a) A case series described 5 patients with neutropenic enterocolitis associated with paclitaxel or docetaxel therapy. All presented with neutropenic fever, abdominal pain with rebound tenderness, and diarrhea. Abdominal CT showed thickening of the colon wall and pericolic edema, and a pericolic abscess was present in 3 patients. All patients recovered with broad spectrum antibiotics and G-CSF (Kouroussis et al, 2000).
b) Pseudomembranous colitis was reported in one patient receiving paclitaxel (Ang et al, 2000).

H) PANCREATITIS

1) WITH THERAPEUTIC USE

a) Pancreatitis has been reported infrequently with paclitaxel use (Prod Info TAXOL(R) IV injection, 2010).
b) CASE REPORT: A 44-year-old woman developed pancreatitis ( nausea, vomiting, abdominal pain, hypotension, glucose 1740 mg/dL, amylase 250 Units/L, lipase 2247 Units/L, enlarged and inflamed pancreas on CT) 1 month after receiving paclitaxel-cremophor (Mills et al, 2000).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH THERAPEUTIC USE

a) Mild elevations of liver enzymes and bilirubin have been observed during paclitaxel administration (Prod Info ABRAXANE(R) intravenous suspension, 2009). In most cases, no relationship was found between the dose of paclitaxel and liver function abnormalities (Prod Info TAXOL(R) IV injection, 2010)
b) Elevated liver enzymes and bilirubin have been reported at a clinically significantly higher rate with paclitaxel administration in Kaposi sarcoma patients compared with solid tumor patients (Prod Info TAXOL(R) IV injection, 2010).
c) In women with ovarian and breast cancer who received single-agent paclitaxel (n=812), bilirubin elevations occurred in 7% of patients (n=765), alkaline phosphatase elevations were reported in 22% of patients (n=575), and AST levels were increased in 19% of patients (n=591) in a pooled analysis from 10 clinical studies (Prod Info TAXOL(R) IV injection, 2010).

B) HEPATIC NECROSIS

1) WITH THERAPEUTIC USE

a) Based on ongoing surveillance, there have been rare reports of hepatic necrosis and hepatic encephalopathy leading to death during paclitaxel therapy (Prod Info ABRAXANE(R) intravenous suspension, 2009).
b) CASE REPORT: A 47-year-old woman with disseminated breast cancer unresponsive to previous chemotherapy regimens was treated with paclitaxel at a dose of 175 mg/m(2). She was discharged in good condition. Prior to treatment her liver function enzymes (AST 339 U/L, ALT 56 U/L, LDH 1349 U/L, alkaline phosphatase 319 U/L, gamma-glutamyltranspeptidase 417 U/L and bilirubin 54 micromol/L) were significantly elevated due to hepatic metastases. Twenty-four hours after treatment the patient was readmitted in stupor. A cerebral CT scan was negative for cerebral metastases and an EEG showed symmetric, high-voltage, slow-wave pattern suggestive of metabolic encephalopathy. Liver enzymes were further elevated (AST 714 U/L, ALT 99 U/L, LDH 3415 U/L bilirubin 86 micromol/L); serum concentrations of alkaline phosphatase and gamma-glutamyltranspeptidase were essentially unchanged. An ammonia level was not obtained. The patient became comatose and died within 48 hours of readmission; no aggressive measures were performed. A temporal association between paclitaxel administration and the rapid onset of neurologic decline and laboratory and diagnostic findings suggest hepatic coma was attributable to paclitaxel (Feenstra et al, 1997).

Genitourinary

3.10.2)

A) ABNORMAL RENAL FUNCTION

1) WITH THERAPEUTIC USE

a) Creatinine elevations were reported in 11% of patients treated with paclitaxel; 1% of cases were severe. There were no reports of dose reduction or discontinuation (Prod Info ABRAXANE(R) intravenous suspension, 2009).
b) In 2 open-label, phase 2 studies evaluating single-agent paclitaxel as second-line treatment for AIDS-related Kaposi sarcoma, creatine elevations occurred in 34% of patients who received paclitaxel 135 mg/m(2) IV over 3 hr every 3 weeks (n=29) and 18% of patients who received 100 mg/m(2) IV over 3 hr every 2 weeks (n=56). Additionally, severe creatine elevations were reported in 7% and 5% of patients who received 135 mg/m(2) IV over 3 hr every 3 weeks and 100 mg/m(2) IV over 3 hr every 2 weeks, respectively (Prod Info TAXOL(R) IV injection, 2010).

B) MALIGNANT TUMOR OF OVARY

1) WITH THERAPEUTIC USE

a) INTRAPERITONEAL ADMINISTRATION

1) In 2006, the National Cancer Institute issued a Clinical Announcement suggesting that intraperitoneal (IP) administration be the standard of care for women with advanced ovarian cancer (Rowan, 2009).
2) Systemic toxicity is similar to that observed with intravenous paclitaxel (ie, hematologic, gastrointestinal, neurologic). Intraperitoneal port complications (eg, infection, inflow obstruction, port blockage, abdominal pain or bowel injury) have also been reported (Bunting et al, 2009).

Hematologic

3.13.2)

A) NEUTROPENIA

1) WITH THERAPEUTIC USE

a) SUMMARY

1) Neutropenia has been the primary dose-limiting toxic effect of paclitaxel therapy (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009; Kris et al, 1986; Grem et al, 1987; Einzig et al, 1991; Legha et al, 1990).
2) Neutropenia has been reported with paclitaxel use in several clinical studies and is a dose-dependent and dose-limiting toxicity. Neutrophils nadirs occur at a median of 11 days (Prod Info TAXOL(R) IV injection, 2010).
3) INCIDENCE: Any neutropenic event: 78% to 98%. Grade 4 neutropenia: 14% to 81% (neutrophils less than 500 cells/mm(3)) (Prod Info TAXOL(R) IV injection, 2010).
4) ONSET/DURATION: Reductions in neutrophil counts are usually observed by day 8, with nadirs occurring on days 8 to 11; recovery is rapid, being evident by days 15 to 21 (Rowinsky et al, 1990).
5) CUMULATIVE EFFECTS: Paclitaxel-related neutropenia has not been cumulative in most patients. Neutrophil count nadirs generally remain unchanged during subsequent courses of therapy, suggesting that paclitaxel may not produce irreversible hematopoietic stem cell toxicity (Rowinsky et al, 1990; McGuire et al, 1989).
6) RISK FACTORS: The extent of prior chemotherapy and/or irradiation is the major clinical risk factor for the development of neutropenia with paclitaxel therapy (Donehower et al, 1987; McGuire et al, 1989; Slichenmyer & Von Hoff, 1990).

b) CLINICAL STUDIES

1) In 2 multicenter, randomized, phase 3 studies evaluating paclitaxel in combination with cisplatin as first-line treatment for ovarian cancer, neutropenia (neutrophils less than 2000/mm(3)) occurred in 91% of women who received paclitaxel 175 mg/m(2) IV over 3 hr (n=339) and in 96% of women who received paclitaxel 135 mg/m(2) IV over 24 hr (n=196). Additionally, grade 4 neutropenia (neutrophils less than 500/mm(3)) was experienced by 33% and 81% of patients who received paclitaxel 175 mg/m(2) IV over 3 hr and 135 mg/m(2) IV over 24 hr, respectively (Prod Info TAXOL(R) IV injection, 2010).
2) In a randomized, phase 3 study evaluating single-agent paclitaxel as second-line treatment for ovarian cancer, neutropenia (neutrophils less than 2000/mm(3)) was reported in 78%, 98%, 78%, and 98% of women who received paclitaxel 175 mg/m(2) IV over 3 hr (n=95), 175 mg/m(2) IV over 24 hr (n=105), 135 mg/m(2) IV over 3 hr (n=98), and 135 mg/m(2) IV over 24 hr (n=105), respectively. Additionally grade 4 neutropenia (neutrophils less than 500/mm(3)) was experienced by 27%, 75%, 14%, and 67% of women in the paclitaxel 175 mg/m(2) IV over 3 hr, 175 mg/m(2) IV over 24 hr, 135 mg/m(2) IV over 3 hr, and 135 mg/m(2) IV over 24 hr arms, respectively. The incidence of neutropenia did not appear to increase with cumulative exposure; additionally, neutropenia did not occur more frequently or severely in patients previously treated with radiation therapy (Prod Info TAXOL(R) IV injection, 2010).
3) In a phase 3 study evaluating the addition of 4 cycles of paclitaxel following doxorubicin and cyclophosphamide for the adjuvant treatment of breast cancer, 50% of women who received paclitaxel 175 mg/m(2) IV over 3 hr every 3 weeks (n=1570) experienced grade 4 neutropenia (neutrophils less than 500/mm(3)). Additionally, in a subgroup of women in this study who received intense monitoring (n=159), grade 4 neutropenia occurred in 76% of women who received paclitaxel (Prod Info TAXOL(R) IV injection, 2010).

B) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) SUMMARY: In a summary of patients (n=812) with solid tumors receiving paclitaxel alone, leukopenia occurred in 90% of patients (leukocyte count of less than 4000/mm(3); 17% of patients had a leukocyte count of less 1000/mm(3) (Prod Info TAXOL(R) IV injection, 2010).

C) FEBRILE NEUTROPENIA

1) WITH THERAPEUTIC USE

a) SUMMARY: Febrile neutropenia develops infrequently in most patients treated with paclitaxel (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009).
b) In 2 multicenter, randomized, phase 3 studies evaluating paclitaxel in combination with cisplatin as first-line treatment for ovarian cancer, febrile neutropenia was reported in 4% and 15% of patients who received paclitaxel 175 mg/m(2) IV over 3 hr (n=339) and 135 mg/m(2) IV over 24 hr (n=196), respectively (Prod Info TAXOL(R) IV injection, 2010).
c) In a multicenter, randomized, phase 3 study evaluating single-agent paclitaxel for treatment of breast cancer after failure of 1 or 2 chemotherapy regimens or within 6 months of adjuvant chemotherapy, febrile neutropenia was reported in 2% of women who received paclitaxel 175 mg/m(2) IV over 3 hr (n=229) or 135 mg/m(2) IV over 3 hr (n=229) (Prod Info TAXOL(R) IV injection, 2010).
d) In 2 open-label, phase 2 studies evaluating single-agent paclitaxel as a second-line treatment for AIDS-related Kaposi sarcoma, febrile neutropenia occurred in 55% and 9% of patients who received paclitaxel 135 mg/m(2) IV over 3 hr every 3 weeks (n=29) and 100 mg/m(2) IV over 3 hr every 2 weeks (n=56), respectively (Prod Info TAXOL(R) IV injection, 2010).
e) Fever and sepsis have been reported in association with neutropenia induced by paclitaxel. Sepsis has been reported in 3 of 281 courses of paclitaxel therapy (2 of which were fatal) in heavily pretreated patients with advanced ovarian carcinoma. In this study, 213 of the 281 courses of therapy were associated with grade 3 or 4 neutropenia, however, only 14 patients (21 of 281 courses) required hospitalization for febrile neutropenia (McGuire et al, 1989a).

D) ANEMIA

1) WITH THERAPEUTIC USE

a) SUMMARY: Among all patients treated with paclitaxel who had a normal baseline hemoglobin level, 69% became anemic, while 7% developed severe anemia. Transfusions were necessary in 12% of patients with a normal hemoglobin at baseline (Prod Info TAXOL(R) IV injection, 2010).

E) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) SUMMARY

1) Thrombocytopenia may develop with paclitaxel therapy (Prod Info ABRAXANE(R) intravenous suspension, 2009). Bleeding episodes when they did occur were usually unrelated to paclitaxel therapy (Prod Info TAXOL(R) IV injection, 2010).
2) INCIDENCE: The incidence can vary widely and is usually not severe (less than 50,000 cells/mm(3)) (Prod Info TAXOL(R) IV injection, 2010).

F) THROMBOEMBOLUS

1) WITH THERAPEUTIC USE

a) Three patients developed thromboses following 4 to 5 cycles of paclitaxel, 175 mg/m(2) of body surface area (Sevelda et al, 1994).

Dermatologic

3.14.2)

A) INJECTION SITE REACTION

1) WITH THERAPEUTIC USE

a) SUMMARY: Injection site reactions occur infrequently (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009).
b) Mild injection site reactions, including erythema, tenderness, skin discoloration, and swelling at injection site, have occurred with paclitaxel administration. Injection-site reactions have been reported more frequently with 24-hour infusions than with 3-hour infusions and are sometimes delayed by a week to 10 days (Prod Info TAXOL(R) IV injection, 2010).

B) EXTRAVASATION INJURY

1) WITH THERAPEUTIC USE

a) Extravasation reactions may occur; however, specific treatment for paclitaxel extravasation reactions is unknown (Prod Info TAXOL(R) IV injection, 2010).
b) CASE REPORT: Paclitaxel extravasated in the arm of a 53-year-old woman and caused grade 4 injury (based on Southwest Oncology Group Common Toxicity Criteria), requiring surgical debridement and treatment with cephalexin and silver sulfadiazine cream 11 days after exposure to paclitaxel. The drug was infused in the dorsum of the left forearm, 400 mg through a peripheral line over 24 hours. The patient complained of erythema and pain at the infusion site 3 days after the infusion. The wound began healing by day 15 and continued to heal properly at day 50. Prolonged infusions of paclitaxel are not recommended due to the risk of extravasation and necrosis (Herrington & Figueroa, 1997).
c) CASE REPORT: A 52-year-old ovarian cancer patient developed recall soft tissue ulceration at the site of prior subcutaneous paclitaxel injections while receiving IV paclitaxel several weeks later. Unable to obtain paclitaxel commercially, the patient sought homeopathic treatment by a practitioner using unapproved chemical paclitaxel. About 15 subcutaneous injections of paclitaxel 0.1 milligram were placed in the abdominal wall. Weeks later, the patient enrolled in a formal study, without disclosing her prior exposure, and was given 175 mg/m(2) as a 3-hour infusion. Erythematous nodules appeared on the abdomen after the first infusion, becoming progressively ulcerated with subsequent doses. Despite the patient's eventual disclosure of subcutaneous exposure to paclitaxel, investigators continued to treat her because of a partial remission. Three ulcerated nodules were surgically excised, although residual inflammation did not completely resolve until therapy was discontinued. The patient relapsed and died 5 months later (du Bois et al, 1996).
d) CASE REPORT: Recall of a soft tissue injury occurred in a 49-year-old female following IV administration of paclitaxel at a different site. Initially, the patient experienced edema, cellulitis, erythema, induration, tenderness and bullae following paclitaxel extravasation in the left hand; this reaction resolved over 2 weeks. With a subsequent paclitaxel dose administered in the left lower leg, the soft tissue injury recurred in the left hand; no reaction occurred in the left-lower-leg administration site. The recall reaction resolved over 7 days (Shapiro & Richardson, 1994).

C) ERUPTION

1) WITH THERAPEUTIC USE

a) Erythema, tenderness, and discomfort have occurred during paclitaxel infusion (Rowinsky et al, 1990).
b) Fixed drug eruptions have been reported with paclitaxel therapy (Baykal et al, 2000; Chu et al, 2000).

D) DERMATITIS

1) WITH THERAPEUTIC USE

a) Dermatitis, consisting of erythema with subsequent desquamation, occurred in patients who received radiotherapy and then were given a paclitaxel infusion up to 6 months later. The dermatitis appeared from 3 hours to 5 days after the paclitaxel infusion (Raghavan et al, 1993; Shenkier & Gelmon, 1994; Phillips et al, 1995).

E) CELLULITIS

1) WITH THERAPEUTIC USE

a) Rare reports of more severe events such as phlebitis, cellulitis, skin exfoliation, necrosis, and fibrosis have been reported (Prod Info TAXOL(R) IV injection, 2010; (CDER, 1997)).
b) Cellulitis has been associated with soft tissue infiltration (Rowinsky et al, 1990; Herrington & Figueroa, 1997a).
c) Three patients developed painful, erythematous, indurated nodules at the site of paclitaxel extravasation (Ajani et al, 1994).
d) CASE REPORT: A 49-year-old woman developed erythema, induration, tenderness and bullae without bacterial infection at the site of extravasation following her sixth cycle of paclitaxel administered into a vein in the left hand. The reaction gradually subsided over the next 14 days. Eight hours after administration of the seventh cycle of paclitaxel into the vein in the lower left limb, the patient again developed cellulitis. The reaction gradually resolved after 7 days (Shapiro & Richardson, 1994a).

F) ALOPECIA

1) WITH THERAPEUTIC USE

a) Alopecia is common with paclitaxel therapy (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009). Scalp hair loss usually occurs 14 to 21 days posttreatment, and is abrupt, often being complete within a day. Loss of other body hair has also been reported (Rowinsky et al, 1990; Rowinsky et al, 1989). It is reversible (Donehower et al, 1987) .

G) NAIL FINDING

1) WITH THERAPEUTIC USE

a) Onycholysis has been reported after paclitaxel therapy (Almagro et al, 2000; Hussain et al, 2000; Flory et al, 1999).

Musculoskeletal

3.15.2)

A) MUSCLE PAIN

1) WITH THERAPEUTIC USE

a) Arthralgia and/or myalgia are commonly reported with paclitaxel therapy (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009). There was no consistent relationship between dose or schedule of paclitaxel and the frequency or severity of arthralgia/myalgia (Prod Info TAXOL(R) IV injection, 2010)
b) PRESENTATION: Myalgias typically involve shoulder and paraspinous muscles; arthralgias are in large joints of the arms and legs. They are usually observed on the second or third posttreatment day; resolution is often within a few days (Prod Info TAXOL(R) IV injection, 2010; Slichenmyer & Von Hoff, 1990).

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) SUMMARY: Hypersensitivity reactions have occurred in up to 41% of all patients; reactions were severe in less than 2% of patients. Severe hypersensitivity reactions (ie, dyspnea, flushing, chest pain, and tachycardia), including anaphylaxis usually occur within the first hour of therapy. There have been rare reports of chills and shock. Some fatalities have occurred despite premedication (Prod Info TAXOL(R) IV injection, 2010).
b) ONSET: Approximately 75% of reactions have been observed within 10 minutes of initiation of paclitaxel infusion; most within 2 to 3 minutes; the remainder of reactions developed 30 to 90 minutes into the infusion (Weiss et al, 1990).
c) POSSIBLE RISK FACTOR: Patients with a history of allergy to bee stings may have a high incidence of hypersensitivity reactions to paclitaxel (Grosen et al, 2000).
d) CASE REPORT: Bronchospasm developed in a 43-year-old man during an infusion of paclitaxel. He was successfully treated with inhaled bronchodilators and epinephrine. The patient was then treated with etoposide and cisplatin during the second cycle of chemotherapy. The patient developed severe bronchospasm during the first etoposide infusion. Again, he was treated with inhaled bronchodilators and epinephrine.

1) These episodes of anaphylaxis suggest the possibility of cross-hypersensitivity between etoposide and paclitaxel (Friedland et al, 1993).

Reproductive

3.20.1)

3.20.2)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the teratogenic potential of paclitaxel (Prod Info TAXOL(R) IV injection, 2010).

B) LACK OF EFFECT

1) In a systematic review, 92.3% of neonates were born healthy following second- or third-trimester exposure (gestational age range, 16 to 30 weeks) to 2 to 5 cycles of paclitaxel- (n=12) or docetaxel- (n=1) based chemotherapy during treatment for maternal ovarian cancer (n=11) or dysgerminoma (n=1). One postpartum death occurred in a 5-day-old docetaxel-exposed infant, which was attributed to congenital abnormalities diagnosed before chemotherapy initiation. One paclitaxel-exposed infant developed intrauterine growth restriction. All infants were born prematurely (mean gestational age, 37.5 weeks; range, 34 to 38 weeks) via cesarean section with a mean weight of 2381 g (range, 1900 to 2800). One paclitaxel case study with an 11-year followup found a case of attention deficit disorder in a pair of twins, while the remaining studies showed no long-term developmental effects (median followup, 20 months) (Zagouri et al, 2012).

C) ANIMAL STUDIES

1) Rabbits administered 1 mg/kg/day (approximately 1/15 the daily maximum recommended human dose on a mg/m(2) basis) of paclitaxel showed no signs of teratogenic effects. Teratogenic potential could not be evaluated at higher doses because of the high rate of mortality at higher doses (Prod Info TAXOL(R) IV injection, 2010).

3.20.3)

A) LACK OF INFORMATION

1) At the time of this review, no data were available by the manufacturers to assess the potential effects of exposure to paclitaxel or paclitaxel protein-bound agents during pregnancy in humans (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009).

B) PREGNANCY CATEGORY

1) The manufacturers have classified paclitaxel or paclitaxel protein-bound as FDA pregnancy category D (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009).

C) SYSTEMIC REVIEW

D) ANIMAL STUDIES

1) PACLITAXEL PROTEIN-BOUND

a) Rats administered paclitaxel protein-bound particles during gestation days 7 to 17 at doses of 6 mg/m(2) (approximately 2% of the daily maximum recommended human dose based on body surface area) experienced embryo- and fetotoxicities. Adverse effects included intrauterine death, up to a 5-fold increase in resorptions, fewer litters and live fetuses, reduced fetal body weight and increased fetal anomalies. Anomalies were characterized as soft tissue and skeletal malformations, such as eye bulge, folded retina, micropthalmia, and dilation of brain ventricles. Lower doses of 3 mg/m(2) (approximately 1% of the daily maximum recommended human dose) also produced soft tissue and skeletal malformations, but at a lower rate (Prod Info ABRAXANE(R) intravenous suspension, 2009).

2) PACLITAXEL

a) Rabbits administered paclitaxel at doses of 3 mg/kg/day (approximately 0.2 the daily maximum recommended human dose on a mg/m(2) basis) during organogenesis developed embryo- and fetotoxicities. Events included intrauterine mortality, increased resorptions and fetal deaths. Maternal toxicity was also observed at this dose (Prod Info TAXOL(R) IV injection, 2010).

3.20.4)

A) BREAST MILK

1) It is not known whether paclitaxel is distributed into human breast milk. At the time of this review, no data were available to assess the potential effects of exposure to these agents during lactation in humans (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009).
2) Due to the potential for adverse effects in the nursing infant, breastfeeding is not recommended while the mother is undergoing treatment with paclitaxel (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009).
3) Paclitaxel has been detected in the breast milk of a lactating woman receiving adjuvant chemotherapy (ie, carboplatin and paclitaxel) (Griffin et al, 2012).

B) CASE REPORT

1) Both carboplatin and paclitaxel were found in the breast milk of a 40-year-old lactating woman following adjuvant chemotherapy treatment. The patient was administered 6 weekly doses of IV carboplatin 233 mg (AUC, 1.5) and IV paclitaxel 56.1 mg (30 mg/m(2)) approximately 30 minutes apart. Both carboplatin and paclitaxel were detected in breast milk samples collected during the sixth chemotherapy session. Carboplatin had a relative infant dose of 2% of the maternal dose and continued to be measurable after 316 hours, while paclitaxel had a relative infant dose of 16.7% and was measurable for at least 172 hours. The possible transfer of metabolites were not measured (Griffin et al, 2012).

C) ANIMAL STUDIES

1) Studies conducted in rats indicate that paclitaxel is excreted into rat milk (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009).

Carcinogenicity

3.21.2)

A) At the time of this review, the manufacturers do not report any carcinogenic potential.

3.21.3)

A) LACK OF INFORMATION

1) At the time of this review, the carcinogenic potential of paclitaxel or paclitaxel protein-bound has not been studied (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009).

3.21.4)

A) LACK OF INFORMATION

1) The carcinogenic potential of paclitaxel or paclitaxel protein-bound has not been studied (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Obtain CBC with differential daily to evaluate for bone marrow suppression (primarily neutropenia). Neutrophil nadirs usually occur at a median of 11 days. Serial counts should be monitored until patient recovery.
B) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
C) Closely monitor liver enzymes, renal function, fluid status and electrolytes. Ensure adequate hydration and correct electrolyte abnormalities as needed.
D) Serum lipids and creatine phosphokinase should be monitored periodically.
E) Monitor vital signs, including temperature.
F) Obtain an ECG. Continuous cardiac monitoring is indicated in patients with evidence of conduction abnormalities.
G) Clinically evaluate patients for the development of mucositis and/or peripheral neuropathy.

4.1.2)

A) HEMATOLOGIC

1) Complete blood counts with differential and platelets should be monitored to evaluate for bone marrow suppression following overdose.
2) Neutrophil nadirs usually occur at a median of 11 days with therapeutic use (Prod Info TAXOL(R) IV injection, 2010).
3) In therapeutic use, neutropenia appears to be dose and schedule dependent and rapidly reversible. Anemia is commonly reported, but is usually not severe (Hgb less 8 g/dL). Thrombocytopenia is uncommon and is rarely found to be severe (less than 50,000 cells/mm(3)) (Prod Info TAXOL(R) IV injection, 2010).

B) BLOOD/SERUM CHEMISTRY

1) Monitor serum triglyceride levels, CPK levels, renal function tests, and liver enzymes.

4.1.4)

A) OTHER

1) ECG

a) Obtain an ECG. Continuous cardiac monitoring may be indicated in patients with evidence of conduction abnormalities.

2) NERVE CONDUCTION STUDIES

a) Nerve conduction studies may be useful in evaluating patients with sensory or motor neuropathies. Paclitaxel-induced neurotoxicity can produce distal symmetrical polyneuropathy (sensory greater than motor) (Cavaletti et al, 2008).

1) Typically, in a taxane-treated patient, the results show evidence of a reduction in sensory (rarely motor) potential amplitudes. A mild reduction in sensory and motor conduction velocity may also be present, suggesting axonal damage as the primary pathologic change. These findings have not been confirmed because taxanes are usually given in combination with other agents (Cavaletti et al, 2008).

3) PERIPHERAL NERVOUS SYSTEM EVALUATION

a) NERVE GROWTH FACTOR vs PHYSICAL EVALUATION: In a study of 34 women with locally advanced cervical carcinoma treated with either paclitaxel plus cisplatin or paclitaxel plus ifosphamide who had received 3 and 5 cycles of therapy, circulating nerve growth factor (NGF), a neurotrophic factor of the neurotrophin family, was associated with clinical neurologic status. The study showed that a decrease in circulating NGF was highly correlated with the degree of chemotherapy-induced peripheral neuropathy (CIPN); however, it was not found to be a biological predictor of final neurologic outcome in these patients. The clinical course of CIPN and final neurologic outcome was found to be reliably predicted by a thorough clinical evaluation of the peripheral nervous system. In particular, changes in vibration sensibility (ie, vibration impairment) and deep tendon reflexes were found to be early predictors of outcome of CIPN (Cavaletti et al, 2004).

4) DRUG LYMPHOCYTE STIMULATION TEST

a) Paclitaxel-induced interstitial pneumonia is thought to be due to a cell-mediated immunologic reaction, which can be diagnosed by a drug lymphocyte stimulation test along with findings from a bronchoalveolar lavage or transbronchial lung biopsy (Suzaki et al, 2006).

Treatment

Life Support

Patient Disposition

6.3.2)

6.3.2.2) HOME CRITERIA/PARENTERAL

A) There is no data to support home management. Patients with paclitaxel overdose need to be admitted.

6.3.2.3) CONSULT CRITERIA/PARENTERAL

A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with a paclitaxel overdose. Consultation with an infectious disease specialist with experience treating immunosuppressed and myelosuppressive patients may also be beneficial.

6.3.2.4) PATIENT TRANSFER/PARENTERAL

A) Patients with large overdose or severe neutropenia might benefit from transfer to a bone marrow transplant or oncology treatment center.

6.3.2.5) OBSERVATION CRITERIA/PARENTERAL

A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), daily monitoring of CBC with differential until bone marrow suppression is resolved, and monitoring of serum electrolytes, renal function, and hepatic enzymes (ie, bilirubin, alkaline phosphatase and SGOT).

Monitoring

Oral Exposure

6.5.1)

A) SUMMARY

1) Activated charcoal and gastric lavage are generally not indicated, since overdose most often occurs by the intravenous route.

6.5.3)

A) GENERAL TREATMENT

1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

1) Paclitaxel is highly protein-bound with a large volume of distribution, but after large doses distribution is can be saturated so drug stays in central compartment longer. Theoretically, plasmapheresis or plasma exchange might effectively remove significant quantities of paclitaxel if performed soon after large overdose. There are no reports of the use of plasmapheresis to treat paclitaxel overdose.

Abstracts

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) DISEASE STATE

1) BREAST CANCER, METASTATIC

a) PACLITAXEL: The recommended dose is 175 mg/m(2) IV over 3 hours every 3 weeks (Prod Info paclitaxel intravenous injection, 2014).
b) PACLITAXEL, PROTEIN-BOUND: The recommended dose is 260 mg/m(2) IV over 30 minutes every 3 weeks (Prod Info ABRAXANE(R) intravenous injection suspension, 2014).

2) BREAST CANCER, OPERABLE

a) PACLITAXEL: The recommended dose for node-positive breast cancer is 175 mg/m(2) IV over 3 hours every 3 weeks for 4 courses sequentially with doxorubicin-containing chemotherapy (Prod Info paclitaxel intravenous injection, 2014; Prod Info TAXOL(R) IV injection, 2010).

3) OVARIAN CARCINOMA

a) PACLITAXEL: The recommended dose is 135 mg/m(2) IV over 24 hours or 175 mg/m(2) IV over 3 hours every 3 weeks, followed by cisplatin in previously untreated patients. In previously treated patients, the recommended dose is 135 mg/m(2) or 175 mg/m(2) IV over 3 hours every 3 weeks; an optimal regimen has not been determined (Prod Info paclitaxel intravenous injection, 2014; Prod Info TAXOL(R) IV injection, 2010).

4) PANCREATIC ADENOCARCINOMA, METASTATIC

a) PACLITAXEL, PROTEIN-BOUND: The recommended dose is 125 mg/m(2) IV over 30 to 40 minutes on days 1, 8, and 15 of each 28-day cycle immediately followed by gemcitabine on days 1, 8, and 15 of each 28-day cycle (Prod Info ABRAXANE(R) intravenous injection suspension, 2014).

5) KAPOSI'S SARCOMA, AIDS-RELATED

a) PACLITAXEL: The recommended dose is 135 mg/m(2) IV over 3 hours every 3 weeks or as 100 mg/m(2) IV over 3 hours every 2 weeks (dose intensity is 45 to 50 mg/m(2)/week) (Prod Info paclitaxel intravenous injection, 2014; Prod Info TAXOL(R) IV injection, 2007).

6) NON-SMALL CELL LUNG CANCER

a) PACLITAXEL: The recommended dose is 135 mg/m(2) IV over 24 hours, followed by cisplatin, every 3 weeks (Prod Info paclitaxel intravenous injection, 2014; Prod Info TAXOL(R) IV injection, 2010).
b) PACLITAXEL, PROTEIN-BOUND: The recommended dose is 100 mg/m(2) IV over 30 minutes on days 1, 8, and 15 of each 21-day cycle, in combination with carboplatin, in patients who are not candidates for radiation therapy or curative surgery (Prod Info ABRAXANE(R) intravenous injection suspension, 2014).

7.2.2)

A) The safety and efficacy of paclitaxel has not been established in pediatric patients (Prod Info paclitaxel intravenous injection, 2014; Prod Info ABRAXANE(R) intravenous injection suspension, 2014; Prod Info TAXOL(R) IV injection, 2010).
B) In a phase 1 dose escalation study of paclitaxel, 31 children (described as patients less than 23 years old with refractory solid tumors and normal renal function) were given starting doses of 200 mg/m(2) followed by incremental increases (ie, 240, 390, 350, and 420 mg/m(2)) as a 24-hour infusion. In this study, toxicity was not significantly correlated with dosage. The median dosage that produced no adverse events was 350 mg/m(2), which is greater than the usual dosage for treatment of solid tumors in adults (ie, 110 to 250 mg/m(2)) (Sonnichsen et al, 1994).
C) In a phase 1 trial and pharmacological study of a 3-hour paclitaxel (containing 50% cremophor EL and 50% ethanol) infusion in children (=17) with refractory solid tumors, acute neurologic toxicity was dose-limiting (at doses of 350 mg/m(2) and 420 mg/m(2)) and included coma, agitation, and somnolence. It was uncertain what role paclitaxel, the solvent, or ethanol had in the development of acute neurologic toxicity, but the study was discontinued. Due to the adverse events observed, the authors could not recommend the use of a 3-hour infusion every 3 weeks in children (Doz et al, 2001).

Minimum Lethal Exposure

1) A minimum lethal dose has not been reported in the literature.

1) A 59-year-old woman was given paclitaxel infusion of 160 mg/m(2) of body surface area to treat breast cancer. Seven days after the infusion, the patient developed tachypnea and cyanosis and died shortly thereafter (Alagaratnam, 1993).
2) A 36-year-old woman was given a 3-hour infusion of paclitaxel 135 mg/m(2) of body surface area; and 2 days later, she developed dyspnea and generalized edema, suggestive of congestive heart failure. The patient died 5 days after the infusion (Jekunen et al, 1994).

Maximum Tolerated Exposure

1) Doses of 200 mg/m(2) of body surface area or greater are likely to produce moderate to severe neutropenia (Finley & Rowinsky, 1994).

1) The incidence of neuropathy appears to be dose related. Most cases have been reported with doses exceeding 170 mg/m(2) (Wiernik et al, 1987; Slichenmyer & Von Hoff, 1990).
2) Clinically definite or probable peripheral neurotoxicity has been reported in 55% of patients treated with doses of 200 mg/m(2) or greater (Lipton et al, 1989).

1) Three patients developed thromboses after 4 or 5 cycles of paclitaxel 175 mg/m(2) of body surface area (Sevelda et al, 1994).

1) Alopecia is observed in virtually all patients treated with paclitaxel in doses greater than 130 to 150 mg/m(2) (Donehower et al, 1987; Rowinsky et al, 1990).

1) In a phase 1 trial and pharmacological study of a 3-hour paclitaxel (containing 50% cremophor EL and 50% ethanol) infusion in children (=17) with refractory solid tumors, acute neurologic toxicity was dose-limiting (at doses of 350 mg/m(2) and 420 mg/m(2)) and included coma, agitation, and somnolence. It was uncertain what role paclitaxel, the solvent, or ethanol had in the development of acute neurologic toxicity, but the study was discontinued. Due to the adverse events observed, the authors could not recommend the use of a 3-hour infusion every 3 weeks in children (Doz et al, 2001).

Toxicity Information

7.7.1)

A) LD50- (INTRAPERITONEAL)MOUSE:

1) 128 mg/kg (RTECS, 2001)

B) LD50- (INTRAPERITONEAL)RAT:

1) 32.5 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

1) Unlike other antimicrotubule agents that induce microtubule disassembly (eg, vinca alkaloids and colchicine), paclitaxel promotes the assembly of microtubules from tubulin dimers, and stabilize microtubules by preventing depolymerization (Prod Info TAXOL(R) IV injection, 2010; Manfredi et al, 1982; Manfredi & Horwitz, 1984; Schiff et al, 1979; Hamel et al, 1981; Rowinsky et al, 1990; Rowinsky et al, 1989; Lipton et al, 1989; (CDER, 1997)).
2) Other potential mechanisms of cytotoxicity include inhibition of DNA synthesis and/or inhibition of cell migration (Slichenmyer & Von Hoff, 1990).
3) Preclinical studies with paclitaxel have demonstrated a broad spectrum of antineoplastic activity. Significant antitumor activity has been observed in solid tumor models (B16 melanoma, MX-1 human mammary xenograft)(Slichenmyer & Von Hoff, 1990; Rowinsky et al, 1990).
4) The drug has also shown activity against intraperitoneally implanted P388 and L1210 murine leukemias, human CX-1 colon cancer xenografts, and LX-1 lung tumor xenografts (Rowinsky et al, 1990).

Toxicologic Mechanism

1) Reactions to paclitaxel do not appear to be solely mediated by IgE, as over 50% of reactions have occurred during the first administration of paclitaxel. Direct release of mast cell mediators has been suggested, similar to anaphylactoid reactions to radiocontrast media (Weiss et al, 1990).
2) Hypersensitivity reactions have occurred with both types of paclitaxel (protein-bound formulation that is albumin bound and paclitaxel containing a vehicle of purified (Cremophor EL(R)) a polyoxyethylated castor oil and ethanol) (Prod Info TAXOL(R) IV injection, 2010; Prod Info ABRAXANE(R) intravenous suspension, 2009) . In clinical trials, anaphylaxis and severe hypersensitivity have occurred in 2% to 4% of patients receiving paclitaxel (Prod Info TAXOL(R) IV injection, 2010).

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

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PACLITAXEL

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Hematologic

Dermatologic

Musculoskeletal

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Life Support

Patient Disposition

Monitoring

Oral Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography