PACLITAXEL-SAIDAL

Paclitaxel is a chemotherapeutic agent marketed under the brand name Taxol among others.

Used as a treatment for various cancers, paclitaxel is a mitotic inhibitor that was first isolated in from the bark of the Pacific yew tree which contains endophytic fungi that synthesize paclitaxel.

It is available as an intravenous solution for injection and the newer formulation contains albumin-bound paclitaxel marketed under the brand name Abraxane.

Used in the treatment of

Kaposi's sarcoma and cancer of the lung, ovarian, and breast.

Abraxane® is specfically indicated for the treatment of metastatic breast cancer and locally advanced or metastatic non-small cell lung cancer.

Paclitaxel is a taxoid antineoplastic agent indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary, and other various cancers including breast cancer.

Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization.

This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions.

In addition, paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the maximum plasma concentration (Cmax) is 195 ng/mL, while the AUC is 6300 ng•h/mL.

In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6a-hydrox-ypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3'-p-hydroxypaclitaxel and 6a, 3'-p-dihydroxypaclitaxel, by CYP3A4.

Hover over products below to view reaction partners Paclitaxel 6α, 3'-p-dihydroxypaclitaxel 6α-hydroxypaclitaxel 3′-p-hydroxypaclitaxel.

In 5 patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine.

When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the elimination half=life is 52.7 hours.

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Rat (ipr) LD 50 =32530 µg/kg. Symptoms of overdose include bone marrow suppression, peripheral neurotoxicity, and mucositis.

Overdoses in pediatric patients may be associated with acute ethanol toxicity.

Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in to 4% of patients receiving paclitaxel in clinical trials.

Fatal reactions have occurred in patients despite premedication.

All patients should be pretreated with corticosteroids, diphenhydramine, and H 2 antagonists. See DOSAGE AND ADMINISTRATION.

Patients who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the drug.

Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting toxicity.

Neutrophil nadirs occurred at a median of 11 days.

Paclitaxel should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm 3 (<1,000 cells/mm for patients with KS).

Frequent monitoring of blood counts should be instituted during paclitaxel treatment.

Patients should not be re-treated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm 3 (>1,000 cells/mm for patients with KS) and platelets recover to a level >100,000 cells/mm 3.

Severe conduction abnormalities have been documented in <1% of patients during paclitaxel therapy and in some cases requiring pacemaker placement.

If patients develop significant conduction abnormalities during paclitaxel infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel.

Paclitaxel can cause fetal harm when administered to a pregnant woman.

Administration of paclitaxel during the period of organogenesis to rabbits at doses of 3 mg/kg/day (about 0.2 the daily maximum recommended human dose on a mg/m 2 basis) caused embryo.

• and fetotoxicity, as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths.

Maternal toxicity was also observed at this dose.

No teratogenic effects were observed at 1 mg/kg/day (about 1/15 the daily maximum recommended human dose on a mg/m 2 basis); teratogenic potential could not be assessed at higher doses due to extensive fetal mortality.

There are no adequate and well-controlled studies in pregnant women.

If paclitaxel is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

Women of child-bearing potential should be advised to avoid becoming pregnant.

Paclitaxel is contraindicated in patients who have a history of hypersensitivity reactions to paclitaxel or other drugs formulated in polyoxyl 35 castor oil.

Paclitaxel should not be used in patients with solid tumors who have baseline neutrophil counts of <1,500 cells/mm 3 or in patients with AIDS-related Kaposi's sarcoma with baseline neutrophil counts of <1,000 cells/mm 3.

Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended.

In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

All patients should be premedicated prior to paclitaxel administration in order to prevent severe hypersensitivity reactions.

Such premedication may consist of dexamethasone 20 mg PO administered approximately and 6 hours before paclitaxel, diphenhydramine (or its equivalent) 50 mg I.V. 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) I.V. 30 to 60 minutes before paclitaxel.

For patients with carcinoma of the ovary the following regimen is recommended: For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks.

In selecting the appropriate regimen, differences in toxicities should be considered.

Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m 2 followed by cisplatin at a dose of 75 mg/m 2;or Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m 2 followed by cisplatin at a dose of 75 mg/m 2.

In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear.

The recommended regimen is paclitaxel 135 mg/m 2 or 175 mg/m 2 administered intravenously over 3 hours every 3 weeks.

For patients with carcinoma of the breast, the following is recommended: For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, at a dose of 175 mg/m 2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy.

The clinical trial used 4 courses of doxorubicin and cyclophosphamide.

After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m 2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.

For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m 2 followed by cisplatin, 75 mg/m 2.

For patients with AIDS-related

Kaposi’s sarcoma, paclitaxel administered at a dose of 135 mg/m 2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m 2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity to 50 mg/m 2 /week).

In the 2 clinical trials evaluating these schedules, the former schedule (135 mg/m 2 every 3 weeks) was more toxic than the latter.

In addition, all patients with low performance status were treated with the latter schedule (100 mg/m 2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients: Reduce the dose of dexamethasone as of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO); Initiate or repeat treatment with paclitaxel only if the neutrophil count is at least 1,000 cells/mm 3; Reduce the dose of subsequent courses of paclitaxel by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm for a week or longer); and Initiate concomitant hematopoietic growth factor (G-CSF) as clinicallyindicated.

For the therapy of patients with solid tumors (ovary, breast and NSCLC), courses of paclitaxel should not be repeated until the neutrophil count is at least 1,500 cells/mm and the platelet count is at least 100,000 cells/mm 3.

Paclitaxel should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1,000 cells/mm 3.

Patients who experience severe neutropenia (neutrophil <500 cells/mm for a week or longer) or severe peripheral neuropathy during paclitaxel therapy should have dosage reduced by 20% for subsequent courses of paclitaxel.

The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Paclitaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised in handling paclitaxel.

The use of gloves is recommended.

If paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water.

Following topical exposure, events have included tingling, burning and redness.

If paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water.

Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression.

Recommendations for dosage adjustment for the first course of therapy are shown in TABLE for both 3.

• and 24-hour infusions.

Further dose reduction in subsequent courses should be based on individual tolerance.

Patients should be monitored closely for the development of profound myelosuppression.

TABLE 17.

RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATIC IMPAIRMENT BASED ON CLINICAL TRIAL DATA a Degree of Hepatic Impairment Recommended Paclitaxel Dose c Transaminase Bilirubin Levels b Levels 24-Hour Infusion <2 x ULN and ≤1.5 mg/dL 135 mg/m 2 2 to <10 x ULN and ≤1.5 mg/dL 100 mg/m 2 <10 x ULN and 1.6 to 7.5 mg/dL 50 mg/m 2 ≥10 x ULN or >7.5 mg/dL Not recommended 3-Hour Infusion <10 x ULN and ≤1.25 x ULN 175 mg/m 2 <10 x ULN and 1.26 to 2 x ULN 135 mg/m 2 <10 x ULN and 2.01 to 5 x ULN 90 mg/m 2 ≥10 x ULN or >5.0 x ULN Not recommended a These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m 2 over 24 hours or 175 mg/m 2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma). b Differences in criteria for bilirubin levels between the 3.

• and 24-hour infusion are due to differences in clinical trial design. c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.

Procedures for proper handling and disposal of anticancer drugs should be considered.

Several guidelines on this subject have been published. 1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing paclitaxel Injection.

Following topical exposure, events have included tingling, burning, and redness.

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

Paclitaxel must be diluted prior to infusion.

Paclitaxel should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2 mg/mL.

The solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25°C) and room lighting conditions.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle.

No significant losses in potency have been noted following simulated delivery of the solution through I.V. tubing containing an in-line (0.22 micron) filter.

Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl) phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers.

Consequently, the use of plasticized PVC containers and administration sets is not recommended.

Paclitaxel solutions should be prepared and stored in glass, polypropylene, or polyolefin containers.

Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.

Paclitaxel should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns.

Use of filter devices such as

IVEX-2® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

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

Unopened vials of paclitaxel are stable until the date indicated on the package when stored between 20° to 25°C (68° to 77°F), in the original package.

Neither freezing nor refrigeration adversely affects the stability of the product.

Upon refrigeration components in the paclitaxel vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation.

There is no impact on product quality under these circumstances.

If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded.

Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25°C) and lighting conditions for up to 27 hours.

Injection, USP (6 mg/mL) is a clear, colorless to slightly yellow viscous solution and supplied as follows: NDC 62332-620-05 30 mg/5 mL Multidose vial individually packaged in a carton.

NDC 62332-621-17 100 mg/16.7 mL Multidose vial individually packaged in a carton.

NDC 62332-622-50 300 mg/50 mL Multidose vial individually packaged in a carton.

Store the vials in original cartons between 20° to 25°C (68° to 77°F). .

Retain in the original package to protect from light.

ADMINISTRATION, Preparation and Administration Precautions.

See WARNINGS section.

It is not known whether the drug is excreted in human milk.

Following intravenous administration of carbon-14 labeled paclitaxel to rats on days to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving paclitaxel therapy.

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

There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical trial in pediatric patients in which paclitaxel was infused intravenously over 3 hours at doses ranging from 350 mg/m to 420 mg/m 2.

The toxicity is most likely attributable to the high dose of the ethanol component of the paclitaxel vehicle given over a short infusion time.

The use of concomitant antihistamines may intensify this effect.

Although a direct effect of the paclitaxel itself cannot be discounted, the high doses used in this study (over twice the recommended adult dosage) must be considered in assessing the safety of paclitaxel for use in this population.

Of 2228 patients who received paclitaxel in 8 clinical studies evaluating its safety and effectiveness in the treatment of advanced ovarian cancer, breast carcinoma, or NSCLC, and 1,570 patients who were randomized to receive paclitaxel in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older and 49 patients (1%) were 75 years or older.

In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in elderly patients.

In 2 clinical studies in NSCLC, the elderly patients treated with paclitaxel had a higher incidence of cardiovascular events.

Estimates of efficacy appeared similar in elderly patients and in younger patients; however, comparative efficacy cannot be determined with confidence due to the small number of elderly patients studied.

In a study of first-line treatment of ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters favored the younger group.

TABLE 9 presents the incidences of Grade IV neutropenia and severe neuropathy in clinical studies according to age.

TABLE 9.

SELECTED ADVERSE EVENTS IN GERIATRIC PATIENTS RECEIVING PACLITAXEL IN CLINICAL STUDIES Patients (n/total [%]) Neutropenia (Grade IV) Peripheral Neuropathy (Grades III/IV) INDICATION Age (y) Age (y) (Study/Regimen) ≥65 <65 ≥65 <65 OVARIAN Cancer (Intergroup First-Line/T175/3 c75 a ) 34/83 78/252 24/84 b 46/255 b (GOG-111 First-Line/T135/24 c75 a ) 48/61 106/129 3/62 2/134 (Phase 3 Second-Line/T175/3 c ) 5/19 21/76 1/19 0/76 (Phase 3 Second-Line/T175/24 c ) 21/25 57/79 0/25 2/80 (Phase 3 Second-Line/T135/3 c ) 4/16 10/81 0/17 0/81 (Phase 3 Second-Line/T135/24 c ) 17/22 53/83 0/22 0/83 (Phase 3 Second-Line Pooled) 47/82 141/319 1/83 2/320 Adjuvant BREAST Cancer (Intergroup/AC followed by T d ) 56/102 734/1468 5/102 e 46/1468 e BREAST Cancer after Failure of Initial Therapy (Phase 3/T175/3 c ) 7/24 56/200 3/25 12/204 (Phase 3/T135/3 c ) 7/20 37/207 0/20 6/209 Non-Small Cell LUNG Cancer (ECOG/T135/24 c75 a ) 58/71 86/124 9/71 f 16/124 f (Phase 3/T175/3 c80 a ) 37/89 56/267 11/91 11/271 * p<0.05 a Paclitaxel dose in mg/m 2 /infusion duration in hours; cisplatin doses in mg/m 2. b Peripheral neuropathy was included within the neurotoxicity category in the Intergroup First-Line Ovarian Cancer study. c Paclitaxel dose in mg/m 2 /infusion duration in hours. d Paclitaxel (T) following 4 courses of doxorubicin and cyclophosphamide (AC) at a dose of 175 mg/m 2 /3 hours every 3 weeks for 4 courses. e Peripheral neuropathy reported as neurosensory toxicity in the Intergroup Adjuvant Breast Cancer study. f Peripheral neuropathy reported as neurosensory toxicity in the ECOG NSCLC study.