Paxoll

Paxoll

paclitaxel

Manufacturer:

Venus Remedies

Distributor:

Cosma Medical
Full Prescribing Info
Contents
Paclitaxel.
Description
PAXOLL (Paclitaxel) injection is a clear colorless to slightly yellow viscous solution. It is supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion PAXOLL is available in 30 mg (5 mL), 100 mg (16.7 mL), 260 mg (43.4 mL) and 300 mg (50 mL) multidose vials.
Action
Pharmacology: 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.
Following intravenous administration of PAXOLL, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.
Pharmacokinetic parameters of paclitaxel following 3-and 24-hour infusions of PAXOLL at dose levels of 135 and 175 mg/m2 are determined in a Phase 3 randomized study in ovarian cancer patients. It appeared that with the 24-hour infusion of PAXOLL, a 30% increase in dose (135 mg/m2 versus 175 mg/m2) increased the Cmax by 87%, whereas the AUC(0-∞) remained proportional. However, with a 3-hour infusion for a 30% increase in dose, the Cmax and AUC(0-∞) are increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state with the 24-hour infusion of PAXOLL ranged from 227 to 688 L/m2, indicating extensive extravascular distribution and/or tissue binding of paclitaxel.
The pharmacokinetics of paclitaxel are also evaluated in adult cancer patients who received single doses of 15-135 mg/m2 given by 1-hour infusions (n=15), 30-275 mg/m2 given by 6-hour infusions (n=36), and 200-275 mg/m2 given by 24-hour infusions (n=54) in Phase 1 and 2 studies.
Indications/Uses
PAXOLL is indicated, after failure of first-line or subsequent chemotherapy for the treatment of metastatic carcinoma of the ovary. PAXOLL is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. Paxoll in combination with cisplatin is indicated for the first-line treatment of non-small cell lung carcinoma (NSCLC) in patients who are not candidates for potentially curative surgery or radiation therapy. PAXOLL is indicated for the second-line treatment of AIDS-related Kaposi's sarcoma.
Dosage/Direction for Use
All patients should be premedicated prior to PAXOLL administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before PAXOLL, diphenhydramine (or its equivalent) 50 mg I.V. 30 to 60 minutes prior to PAXOLL, and cimetidine (300 mg) or ranitidine (50 mg) I.V. 30 to 60 minutes before PAXOLL. In patients previously treated with chemotherapy for ovarian cancer, the recommended regimen is PAXOLL 175 mg/m2 administered intravenously over 3 hours every 3 weeks. For patients with carcinoma of the breast, PAXOLL at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective after failure of chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. In patients previously untreated with chemotherapy for non-small cell lung carcinoma (NSCLC), the recommended regimen is 175 mg/m2 administered intravenously over 3 hours every 3 weeks follow by a platinum compound. A more myelosuppressive regimen of PAXOLL may be 135 mg/m2 administered intravenously over 24 hours every 3 weeks follow by a platinum compound. For patients with AIDS­ related Kaposi's sarcoma, PAXOLL administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45-50 mg/m2/week). Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients: Reduce the dose of dexamethasone as one of the three premedication drugs to 10 mg PO (instead of 20 mg PO); Initiate or repeat treatment with PAXOLL only if the neutrophil count is at least 1000 cells/mm3; Reduce the dose of subsequent courses of PAXOLL by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer. For the therapy of patients with solid tumors (ovary and breast), courses of PAXOLL should not be repeated until the neutrophil count is at least 1,500 cells/mm3 and the platelet count is at least 100,000 cells/mm3 and PAXOLL should not be given to patients with AIDS­ related Kaposi's sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm3 patients who experience severe neutropenia (neutrophil <500 cells/mm3 for week or longer) or severe peripheral neuropathy during PAXOLL therapy should have dosage reduced by 20% for subsequent courses of PAXOLL. The incidence of neurotoxicity and the severity of neutropenia increase with dose.
Patients with hepatic impairment may be at increased risk of toxicity particularly grade 3 to 4 myelosuppression. Recommendations for dosage adjustment for the first course of therapy are shown in the table for 3-and 24-hour infusion. Monitor patients closely for the development of profound myelosuppression.

Click on icon to see table/diagram/image

Preparation for Intravenous Administration: PAXOLL must be diluted prior to infusion PAXOLL 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. Upon preparation, solution may show haziness, which is attributed to the formulation vehicle.
Stability: Unopened vials of PAXOLL injection are stable until the date indicated on the package when stored between 20°C-25°C (68°-77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration components in the PAXOLL 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.
Overdosage
There is no known antidote for PAXOLL overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis.
Contraindications
PAXOLL is contraindicated in patients who have a history of hypersensitivity reactions to PAXOLL or other drugs formulated in polyoxyethylated castor oil. PAXOLL should not be used in patients with solid tumors who have baseline neutrophil counts of <1500 cells/mm3 or in patients with AIDS-related Kaposi's sarcoma with baseline neutrophil counts of <1000 cells/mm3.
Warnings
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea, hypotension requiring treatment, angioedema, and generalized urticaria have been observed in 2% of patients receiving PAXOLL. Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists. Patients who experience severe hypersensitivity reactions to PAXOLL should not be rechallenged with the drug.
Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose­ limiting toxicity. PAXOLL should not be administered to patients with baseline neutrophil counts of less than 1500 cells/mm3 (<1000 cells/mm3 for patients with KS). Frequent monitoring of blood counts should be instituted during Paxoll treatment. Patients should not be re-treated with subsequent cycles of PAXOLL until neutrophils recover to a level >1500 cells/mm3 (>1000 cells/mm3 for patients with KS) and platelets recover to a level >100,000 cells/mm3. If patients develop significant conduction abnormalities during Paxoll infusion, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with PAXOLL.
Special Precautions
Note: Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. Diluted PAXOLL solutions should be stored in bottles (glass, polypropylene) and administered through polyethylene lined administration sets.
Hematology: PAXOLL therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In case of severe neutropenia (<500 cells/mm3 during a course of Paxoll, a 20% reduction in dose for subsequent courses of therapy is recommended. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving PAXOLL.
Preparation and Administration Precautions: PAXOLL is a cytotoxic anticancer drug, caution should be exercised in handling PAXOLL. The use of gloves is recommended. If PAXOLL solution comes in contact with the skin wash the area immediately and thoroughly with soap and water. If PAXOLL contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning sensation in eyes, sore throat, and nausea have been reported.
Cardiovascular: Hypotension, bradycardia, and hypertension have been observed during administration of PAXOLL but generally do not require treatment. In severe cases, PAXOLL infusion may need to be interrupted of discontinued at the discretion of treating physician.
Nervous System: Although, the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual PAXOLL contains dehydrated alcohol USP, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol.
Hepatic: There is evidence that the toxicity of PAXOLL is enhanced in patients with elevated liver enzymes. Caution should be exercised when administering PAXOLL. Patients with hepatic impairment may be at increased risk of toxicity particularly grade III-IV myelosuppression.
Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of PAXOLL has not been studied.
Paclitaxel has been shown to be clastogenic in vitro (chromosome aberration in human lymphocytes) and in vivo (micronucleus test in mice) Paclitaxel is not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay. Administration of paclitaxel prior to and during mating produced impairment of fertility in male and female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum recommended human dose on a mg/m2 basis). At this dose, paclitaxel caused reduced fertility and reproductive indices, and increased embryo-and fetotoxicity.
Effect on ability to drive and to use machines: Since PAXOLL contains ethanol, consideration should be given to the possibility of CNS and other effects.
Use in Children: The safety and effectiveness of PAXOLL in pediatric patients have not been established. There have been reports of central nervous system toxicity.
Use In Pregnancy & Lactation
Pregnancy: PAXOLL can cause harm to foetus when administered to a pregnant woman. Teratogenic potential could not be assessed at higher doses due to extensive fetal mortality. Woman of childbearing potential should be advised to avoid becoming pregnant during therapy with PAXOLL.
Lactation: It is not known whether the drug is excreted in human milk. 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 PAXOLL therapy.
Side Effects
Toxicity is more pronounced in the studies utilizing PAXOLL at a dose of 135 mg/m2 every 3 weeks than in the study utilizing PAXOLL at a dose of 100 mg/m2 every 2 weeks. Notably, severe neutropenia, febrile neutropenia, and opportunistic infections are more common with the former dose and schedule. Patients with AIDS-related Kaposi's sarcoma have more frequent and severe hematologic toxicity, infections, and febrile neutropenia. These patients require a lower dose intensity and supportive care.
Hematologic: Bone marrow suppression is the major dose-limiting toxicity of PAXOLL. Neutropenia, the most important hematologic toxicity, is dose and schedule dependent and is generally rapidly reversible. Among patients treated in the Phase III study in patients of ovarian cancer with a 3-hour infusion, neutrophil counts declined below 500 cells/mm3 in 13% of the patients treated with a dose of 135 mg/m2 compared to 27% at a dose of 175 mg/m2 (p=0.05). In the same study, severe neutropenia (<500 cells/mm3) is more frequent with the 24-hour than with the 3-hour infusion; infusion duration had a greater impact on myelosuppression than dose.
Fever is frequent episodes of sepsis, pneumonia, peritonitis and UTI and upper respiratory tract infections were the most frequently reported complications. The use of supportive therapy, including G-CSF, is recommended for patients who have experienced severe neutropenia. Thrombocytopenia is uncommon, and almost never severe (<50,000 cells/mm3). Anemia (Hb < 11 g/dL) is observed in 78% of all patients and is severe (Hb <8 g/dL) in 16% of the cases. No consistent relationship between dose of schedule and the frequency of anemia is observed.
Hypersensitivity Reactions (HSRs): The frequency and severity of HSRs are not affected by the dose or schedule of PAXOLL administration. Severe symptoms occurred generally within the first hour of PAXOLL infusion. The most frequent symptoms observed during these severe reactions were dyspnea, flushing chest pain and tachycardia. The minor hypersensitivity reactions consisted mostly of flushing rash, hypotension, dyspnea, tachycardia and hypertension. The frequency of hypersensitivity reactions remained relatively stable during the entire treatment period. Rare reports of chills and reports of back pain in association with hypersensitivity reactions have been received as proof of the continuing surveillance of PAXOLL safety.
Cardiovascular: Hypotension and bradycardia during the first 3 hours of infusion.
Significant cardiovascular events include syncope, rhythm abnormalities, hypertension and venous thrombosis. The arrhythmias included asymptomatic ventricular tachycardia, bigeminy and complete AV block requiring pacemaker placement.
Electrocardiogram (ECG) abnormalities are common among patients at baseline. The most frequently reported ECG modifications are non-specific repolarization abnormalities, sinus bradycardia, sinus tachycardia and premature beats. Among patients with normal ECGs at initiation of therapy, prior therapy with anthracyclines did not influence the frequency of ECG abnormalities. Cases of myocardial infarction have been reported rarely. Congestive heart failure has been reported typically in patients who have received other chemotherapy, notably anthracyclines. Rare reports of atrial fibrillation and supra-ventricular tachycardia have been received as proof of the continuing surveillance of PAXOLL safety.
Respiratory: Rare reports of interstitial pneumonia, lung fibrosis and pulmonary embolism have been reported as proof of the continuing surveillance of PAXOLL safety.
Rarely radiation pneumonitis has also been reported in patients receiving concurrent radiotherapy.
Neurologic: The frequency and severity of neurologic manifestations are dose­ dependent, but are not influenced by infusion duration. Peripheral neuropathy is observed without pre-existing neuropathy. The frequency of peripheral neuropathy increased with cumulative dose. Pre-existing neuropathies resulting from prior therapies are not a contraindication for PAXOLL therapy. Other than peripheral neuropathy, serious neurologic events following PAXOLL administration have been rare (<1%) and have included grand mal seizures, syncope, ataxia and neuroencephalopathy. Rare reports of autonomic neuropathy resulting in paralytic ileus and motor neuropathy with resultant minor distal weakness. Optic nerve and/or visual disturbance have been reported in patients who have received higher doses than those recommended.
Ototoxicity such as hearing loss and tinnitus has also been reported.
Arthralgia/Myalgia: There is no consistent relationship between dose or schedule of PAXOLL and the frequency or severity of arthralgia/myalgia. The symptoms are usually transient, occurring two or three days after PAXOLL administration and resolving within a few days.
Hepatic: No relationship is observed between liver function abnormalities and either dose or schedule of PAXOLL administration. Among patients with normal therapy liver function elevations in bilirubin, alkaline phosphatase and AST (SGOT) have been observed. Prolonged exposure to PAXOLL is not associated with any cumulative hepatic toxicity. Hepatic necrosis and hepatic encephalopathy leading to death have been reported rarely.
Renal: Among the patients treated for Kaposi's sarcoma with PAXOLL, renal toxicity grade III or IV has been observed. Renal insufficiency with elevations of serum creatinine have been reported.
Gastrointestinal (GI): Nausea/vomiting, diarrhea and mucositis have been reported. Rarely intestinal obstruction, perforation, pancreatitis, ischemicolitis, and dehydration have been observed. Neutropenic enterocolitis (typhilitis) has also been reported.
Injection Site Reaction: Injection site reactions, including reactions secondary to extravasation, are usually mild and consisted of erythema, tenderness. skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. More severe events such as phlebitis, cellulitis induration skin exfoliation, necrosis and fibrosis have been reported.
Other Clinical Events: Alopecia is observed in almost all the patients. Transient skin changes, nail changes, edema is reported and none of these patients required treatment discontinuation. Maculopapular rash, pruritus, Stevens-Jonson syndrome, and toxic epidermal necrolysis have been reported rarely. Asthenia and malaise have also been reported.
Drug Interactions
Using escalating doses of PAXOLL (110-200 mg/m2) and cisplatin (50 or 75 mg/m2) given as sequential infusions, myelosuppression is more profound when PAXOLL is­ given after cisplatin than with the alternate sequence (i.e., PAXOLL before cisplatin). The metabolism of PAXOLL is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering PAXOLL concomitantly with known substrates, inducers or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination, which result in neutropenic and stomatitis episodes.
Storage
Store the vials in original cartons between 20°-25°C (68°-77°F). Retain in the original package to protect from light.
ATC Classification
L01CD01 - paclitaxel ; Belongs to the class of plant alkaloids and other natural products, taxanes. Used in the treatment of cancer.
Presentation/Packing
Inj (vial) 30 mg/5 mL x 1's. 100 mg/16.7 mL x 1's. 260 mg/43.4 mL x 1's. 300 mg/50 mL x 1's.
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