Contents

Paclitaxel

Indication

1st-line & subsequent therapy for the treatment of advanced carcinoma of the ovary in combination w/ cisplatin. Adjuvant treatment of node +ve administered sequentially to standard doxorubicin-containing combination chemotherapy.

Dosage / Direction For Use

Primary treatment of ovarian cancer 135 mg/m2 infused over 24 hr, followed by cisplatin & repeated at 3-wk intervals. Alternatively 175 mg/m2 may be infused over 3 hr followed by cisplatin every 3 wk. Secondary treatment of ovarian cancer 135 or 175 mg/m2 infused over 3 hr once every 3 wk. Breast cancer 175 mg/m2 infused over 3 hr once every 3 wk is recommended for adjuvant treatment (for 4 courses), for 2nd-line monotherapy & for 1st-line treatment w/ trastuzumab; paclitaxel is given the day after the 1st dose of trastuzumab or immediately after subsequent doses if well-tolerated. When used 1st-line w/ doxorubicin, paclitaxel 220 mg/m2 infused over 3 hr once every 3 wk; the dose is given 24 hr after doxorubicin. Non-small cell lung cancer 135 mg/m2 over 24 hr or 175 mg/m2 over 3 hr, followed by cisplatin & repeated at 3-wk intervals. AIDS related Kaposi’s sarcoma (KS) 135 mg/m2 over 3 hr once every 3 wk. Alternatively, 100 mg/m2 over 3 hr every 2 wk may be given especially in patient w/ poor performance status.

Overdosage

–

Administration

–

Contraindication

Hypersensitivity.

Special Precaution

Severe hypersensitivity, anaphylaxis. Patients should be pretreated w/ corticosteroids, diphenhydramine & H2 antagonists to avoid fatal reactions. Neutropenia. Do not administer in patients w/ baseline neutrophil counts <1,500 cells/mm3 (<1,000 cells/mm3 for patients w/ KS). Frequent monitoring of blood counts should be instituted during treatment. Pregnancy & lactation.

Adverse Reactions

Bone marrow depression; peripheral neuropathy; hypersensitivity reactions w/ flushing, rash, dyspnoea, hypotension, chest pain & angioedema; alopecia, arthralgia & myalgia, GI disturbances, mucositis, bradycardia & ECG changes, nail dystrophies & elevation of liver enzyme values; infections.

Drug Interaction

Caution when in concomitant w/ CYP2C8 substrates (eg, repaglinide & rosiglitazone), inhibitors (eg, gemfibrozil) & inducers (eg, rifampin). Potential interactions w/ PIs (ritonavir, saquinavir, indinavir & nelfinavir).

Storage

Store at temperatures not exceeding 30°C.

Description

Each mL contains: Paclitaxel 6 mg.

Action

Pharmacology: Paclitaxel is a taxane originally derived from the bark of the Pacific yew tree Taxus brevifolia (Taxaceae), and now obtained semisynthetically from a taxane precursor derived from the needles of the European yew, Taxus baccata. Paclitaxel’s antineoplastic action arises from induction of microtubule formation and stabilization of microtubules, thereby disrupting normal cell division in the G2 and M phases of the cell cycle.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 or 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.Pharmacokinetics: Intravenous paclitaxel exhibits a biphasic decline in plasma concentrations with a mean terminal half-life of anywhere between about 3 and 50 hours. The pharmacokinetics are non linear. The steady-state volume of distribution is reported to range from 200 to 700 litres/m2, indicating extensive extravascular distribution, tissue binding, or both. Paclitaxel is 89% or more bound to plasma protein in vitro. The elimination of paclitaxel has not been fully elucidated; only about 1 to 12% of a dose is reported to be excreted in urine, as unchanged drug, indicating extensive non-renal clearance. Paclitaxel is metabolised in the liver, with the major metabolic pathway apparently mediated by the cytochrome P450 isoenzyme CYP2C8, although CYP3A4 may play a minor role. Metabolites are excreted in the faeces via the bile, the primary metabolite being 6 α-hydroxypaclitaxel. For patients with localised disease receiving bicalutamide alone, there was no significant difference in progression free survival. In these patients there was also a trend toward decreased survival compared with placebo patients (HP = 1.16; 95% Cl 0.99 to 1.37). In view of this, the benefit-risk profile for the use of bicalutamide is not considered favourable in this group of patients.Pharmacokinetics: Absorption and Distribution: Bicalutamide is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.The (S)-enantiomer is rapidly cleared relative to the (R)-enantiomer, the latter having a plasma elimination half-life of about 1 week.On daily administration of bicalutamide, the (R)-enantiomer accumulates about 10 fold in plasma as a consequence of its long half-life.Steady state plasma concentrations of the (R)-enantiomer of approximately 9 μg/mL are observed during daily administration of 50 mg doses of bicalutamide.At steady state the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.The pharmacokinetics of the (R)-enantiomer are unaffected by age, renal impairment or mild to moderate hepatic impairment. There is evidence that for subjects with severe hepatic impairment, the (R)-enantiomer is more slowly eliminated from plasma.Biotransformation and elimination: Bicalutamide is highly protein bound (racemate 96%, R-bicalutamide 99.6%) and extensively metabolised (via oxidation and glucuronidation): Its metabolites are eliminated via the kidneys and bile in approximately equal proportions.After excretion in the bile, hydrolysis of the glucuronides takes place. In the urine scarcely altered bicalutamide is found.In a clinical study the mean concentration of (R)-bicalutamide in semen of men receiving bicalutamide 150 mg was 4.9 μg/mL. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and equates to approximately 0.3 μg/kg.This is below that required to induce changes in offspring of laboratory animals.Toxicology: Preclinical safety data: Bicalutamide is a potent antiandrogen and a mixed function oxidase enzyme inducer in animals.Target organ changes, including tumour induction, in animals, are related to these activities. None of the findings in the preclinical testing is considered to have relevance to the treatment of advanced prostate cancer patients.