PACLIT(Paclitaxel lnjection USP) lnjection 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. Paclitaxel is a natural product with antitumor activity and is obtained via a semi-synthetic process from Taxus baccata. It represents first agent from novel class of taxoids. The clinical development of Paclitaxel was initially hampered by hypersensitivity reactions. Current dosage regimens with premedication have reduced their incidence.

The chemical name for Paclitaxel is 5β,20-Epoxy-l,2α,4,7β,10β,13α-hexahydroxytax-l l-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.

Paclitaxel has the following structural formula:

Paclitaxel is a white to off-white crystalline powder with the empirical formula C₄₇H₅₁NO₁₄ and a molecular weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216-217°C.

CLINICAL PHARMACOLOGY

Mode of action : Paclitaxel is a novel antimicrotubule, antineoplastic agent. Paclitaxel exerts its effects on microtubules and their protein subunits, the tubulin diamers. Microtubules serve as facilitators of intracellular transport and maintain the integrity and function of cells. Paclitaxel promotes microtubule assembly by enchancing the action of tubulin diamers, stabilizing existing microtubules resulting in the inhibition of the normal dynamic reorganization of the microtubular 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, resulting in the breakage of chromosomes. The G, and M-phases of the cell cycle are affected.

Pharmacokinetics : Paclitaxel given by I.V.administration exhibits a biphasic decline. Paclitaxel dose not appear to cross the blood-brain barrier to an appreciable amount; However it does distribute to ascitic fluid. Ascitic fluid concentration can be 40% above serum concentration. It gets 89-98% bound to serum proteins. The presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine does not affect protein binding of Paclitaxel. In Vitro studies with human liver microsomes and tissue slices showed that Paclitaxel gets metabolized primarily to 6a-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3′-p-hydroxypaclitaxel and 6a,3′-p-dihydroxypaclitaxel, by CYP3A4. The effect of renal or hepatic dysfunction on the disposition of Paclitaxel has not been investigated. Hepatic metabolism and biliary excretion are likely routes of elimination given that only 10% of Paclitaxel is eliminated unchanged in the urine, and high concentrations of the drug have been found in bile. Nonlinear clearance has been observed. The elimination half-life ranges from 1.3-8.6 hours, without dose dependency. After intravenous administration of 15-275 mg/m² doses of Paclitaxel as 1, 6, or 24 hour infusions, mean values for cumulative urinary recovery of unchanged drug ranges from 1.3 to 12.6% of the dose, indicating extensive non-renal clearance.

DRUG INTERACTIONS

Cisplatin : Administration of cisplatin prior to paclitaxel treatment leads to greater myelosuppression than administering it after. In patients receiving cisplatin prior to paclitaxel, there is about a 33% decrease in paclitaxel clearance.

Product is for single use in one patient only.

All patients should be premedicated before paclitaxel is administered to prevent severe hypersensitivity reactions. Before every treatment cycle patients should be premedicated with dexamethasone 20 mg orally, 12 and 6 hours prior to starting the paditaxel infusion; promethazine 25 to 50 mg intravenously or other suitable H1-antagonist, 30 minutes prior to starting the paclitaxel infusion: and cimetidine 300 mg or ranitidine 50 mg by intravenous infusion over 15 minutes, starting 30 minutes prior to the paclitaxel infusion.

For primary treatment of ovarian cancer: it is recommended that paclitaxel be used at a dose of 135 mg/m², administered intravenously over three hours, followed by cisplatin 75 mg/m². The infusion should be repeated every three weeks.

For the treatment of metastaticovarian cancer or metastatic breast cancer: it is recommended that paclitaxel be used as a single agent at a dose of 175 mg/m². Paclitaxel should be administered as an intravenous infusion over three hours. The infusion should be repeated every three weeks as tolerated. Patients have tolerated treatment with up to nine cycles of paclitaxel therapy, but the optimal course of therapy remains to be established.

For primary or secondary treatment of NSCLC (non-small cell lung cancer): the recommended dose of paclitaxel is 175 mg/m² administered intravenously over three hours with a three week interval between courses.

For node positive breast cancer: the recommended dose of paclitaxel is 175 mg/m² administered intravenously over three hours every three weeks for four courses following doxorubicin and cyclophosphamide combination therapy.

For overexpression of HER-2 breast cancer: paclitaxel 175 mg/m² administered intravenously over three hours with a three weeks interval between courses for six cycles. Herceptin 2 mg/kg administered intravenously once a week until progression of disease after an initial loading dose of 4 mg/kg body weight.

Repetition of a course of paclitaxel is not recommended until the patient’s neutrophil count is at least 1500 cells/mm³ and the platelet count is at least 100,000 cells/mm³, If there is severe neutropenia (neutrophil count less than 0.5 x 109 cells/L for seven or more days) or severe peripheral neuropathyduring paclitaxel therapy, the dose of paclitaxel in subsequent courses should be reduced by 20%.

Preparation for intravenous administration: Paclitaxel Injection must be diluted prior to intravenous infusion. it should be diluted in glucose 5% or sodium chloride 0.9% intravenous infusion. Dilution should be made to afinal concentration of 0.3 to 1.2 mg/mL.

After the final dilution of Paclitaxel Injection USP, the bottte should be swirled gently to disperse the paclitaxel. Do not shake.

Avoid contact of paclitaxel solutions with plasticised polyvinyl chloride (PVC) equipment, infusion lines or devices used when preparing infusion solutions. Prepare and store diluted paclitaxel solutions in glass or polyethylene containers, These precautions are toavoid leaching of the plasticiser DEHP (di-[2-ethylhexyl] phthalate) from PVC infusion bags or sets. Paclitaxel solutions should be administered through polyethylene lined administration sets (e.g. Gemini 20 giving set) using an IMED pump.

To reduce microbiological hazard, use as soon as practicable after reconstitution/preparation. If storage is necessary, hold at 2-8°C for not more than 24 hours after preparation. Administration should be completed within 24 hours of preparation of the infusion and any residue discarded according to the guidelines for the disposal of cytotoxic drugs.

Facilities preparing paclitaxel solutions reconstituted under controlled aseptic conditions for IV infusion, may apply a shelf life of 14 days at 2 to 8°C (refrigerate: do not freeze) when diluted with glucose 5% or sodium chloride 0.9% for intravenous infusion and stored in glass or polyethylene containers. Diluted solutions prepared this way have been shown to be chemically stable for these periods. Administration should be completed within 24 hours of the start of the infusion and any residue discarded according to the guidelines for the disposal of cytotoxic drugs.

Filtration: Amicroporous membrane of 0.22 microns or less in size is recommended as the in-line filter for all infusions of paclitaxel, The IMED 0.2 micron add on filter set composed of polysulfone and the IVEX II 0.2 micron filter composed of cellulose have both been found to be suitable for Paclitaxel injection USP.

Preparation and administration precautions: Paclitaxel is a cytotoxic anti-cancer drug and, as with other potentially toxic compounds, caution should be exercised in handling Paclitaxel. The use of gloves is recommended. Following topical exposure, tingling. burning and redness have been observed. If Paclitaxel solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Paclitaxel contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, Dyspnoea, chest pain, burning eyes, sore throat and nausea have been reported.

Handling and disposal: The published guidelines related to procedures for the proper handiing and disposal of cytotoxic drugs should be followed.

CONTRAINDICATIONS
Patients with a known hypersensitivity to Paclitaxel or other drugs formulated in Cremophor® ELP (Polyoxyethylated castor oil)

Paclitaxel 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.

Paclitaxel should be administered under the supervision of a physician experienced in the use of cancer cytotoxic agents. Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available.

Patients must be pretreated with corticosteroids, antihistamines and H. antagonists. Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2%-4% of patients receiving Paclitaxel in clinical trials.
Fatal reactions have occurred in patients despite premedication. All patients should be pretreated with corticosteroids. diphenhydramine, and H2 antagonists. Severe myelosuppression may occur.

Paclitaxel therapy should not be given to patients with solid tumors who have baseline neutrophil counts of less than 1,500 cells/mm³ and should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline neutrophil count is less than cells/mm³. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Paclitaxel.

Paclitaxel should be given before cisplatin when used in combination.

The frequency and severity of adverse events have been generally similar for patients receiving Paclitaxel for the treatment of ovarian or breast carcinoma or for Kaposi’s sarcoma but patients with AIDS-related Kaposi’s sarcoma may have more frequent and severe hematologic toxicity, infections, febrile neutropenia and GI toxicities. These patients require a lower dose intensity and supportive care.

Blood : Bone marrow suppression is the major dose-limiting toxicity of Paclitaxel Neutropenia, the most important hematologic toxicity, is dose and schedule dependent and is generally rapidly reversible. The use of more supportive therapy including G-CSF, is recommended in case of severe neutropenia. 12% of all treatment courses report fever. Anemia (Hb<11 g/dl) is observed in 78% of all patients and is severe (Hb<8 g/dl) in 16% of the cases.

Hypersensitivity Reactions : The frequency and severity hypersensitivity are observed in 20% and in 41% of all patients. The most frequent symptoms observed are dyspnea, flushing, chest pain and tachycardia. Rare reports of chills and reports of back pain have been received.

Cardiovascular : Hypotension, during the first 3 hours of infusion, occurs in 12% of all patients and 3% of all courses administered. Significant cardiovascular events possibly related to Paclitaxel occur in approximately 1% of all patients. These events include syncope, rhythm abnormalities, hypertension and venous thrombosis. The arrhythmias include asymptomatic ventricular tachycardia bigeminy and complete AV block requiring pacemaker placements. ECG abnormalities are noted in 23% of the patients. Congestive heart failure has been reported typically in patients who have received other chemotherapy, notably anthracyclines.

Central Nervous System : The frequency and severity of neurologic manifestation are dose-dependent. Peripheral neuropathy isobserved in 60% of all patients (3% severe) and in 52% (2% severe) of the patients without pre-existing neuropathy. The frequency increases with cumulative dose. Neurologic symptoms are observed in 27% of the patients after the first course of treatment and in 34-51% from course 2 to 10. Other serious neurologic events have been rare (< 1%) and include grand malseizures, syncope, ataxia and neuroencephalopathy. Reversible autonomic neuropathy resulting in paralytic ileus have also been observed in rare cases.

Gastrointestinal : Mild to moderate nausea/ vomiting, diarrhoea and mucositis are reported by 52%, 38% and 31% of all patients, respectively. Mucosities is schedule dependent and occurs more frequently with the 24 hour than with the 3-hour infusion. Rare reports of intestinal obstruction, intestinal perforation, pancreatitis ischemiccoiitis, and dehydration have been received.

Kidney / Genitourinary : Urinary tract infections are frequently reported infectious complications. Among the patients treated for Kaposi’s sarcoma with Paclitaxel, renal toxicity of grade III or |IV severity has been reported.

Liver : No relationship is observed between liver function abnormalities. Among patients with normal baseline liver function 7%, 22% and 19% had elevations in bilirubin, alkaline phosphatase and AST (SGOT), respectively. Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been documented.

Respiratory : Upper respiratory tract infections do occur. Rare reports of interstitial pneumonia, lung fibrosis and pulmonary embolism have been received. Rare reports of radiation pneumonitis have been received in patients receiving concurrent radiotherapy.

Musculoskeletal : 60% of all patients treated experience arthralgia/ myalgia, 8% experience severe symptoms. The symptoms are usually transient, occur 2-3 days after Paclitaxel administration, and resolve within a few days. The frequency and severity of musculoskeletal symptoms remain unchanged throughout the treatment period.

Injection site reactions : These include reactions secondary to extravasation, are usually mild and consist of erythema. tenderness, skin discoloration, or swelling at the injection site. These are observed more frequently with the 24-hour infusion than with the 3 hour infusion. Rare reports of more severe events such as phlebitis. cellulitis. induration, skin exfoliation, necrosis and fibrosis have been documented. It is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Other Clinical Events : Alopecia is observed in almost all (87%) of the patients Nail changes are uncommon (2%). Edema has been reported in 21% of all patients. Rare reports of skin abnormalities related to radiation recall as well as reports of maculopapular rash and pruritus have been documented.