Paclitor

FDA-Approved Indications:

• Ovarian Cancer:
• First-line treatment of advanced ovarian carcinoma in combination with a platinum-based compound (e.g., cisplatin or carboplatin).
• Second-line treatment of metastatic ovarian carcinoma after failure of initial chemotherapy.
• Breast Cancer:
• Adjuvant treatment following standard combination chemotherapy.
• Metastatic breast cancer as monotherapy or in combination with other agents (e.g., trastuzumab, doxorubicin).
• Non-Small Cell Lung Cancer (NSCLC):
• First-line treatment (with cisplatin) of locally advanced or metastatic NSCLC in patients not eligible for curative surgery and/or radiotherapy.
• AIDS-Related Kaposi's Sarcoma:
• Treatment after failure of prior liposomal anthracycline therapy.

Clinically Accepted Off-Label Uses:

• Pancreatic Cancer: In combination with gemcitabine.
• Cervical Cancer: As part of combination regimens in advanced or recurrent disease.
• Esophageal, Bladder, Head and Neck, and Prostate Cancers: In palliative or neoadjuvant settings.
• Triple-Negative Breast Cancer (TNBC): Often used in neoadjuvant protocols.

Route of Administration: Intravenous infusion only.
Pre-medication: Required to reduce hypersensitivity—typically includes dexamethasone, diphenhydramine, and H2 blocker (e.g., ranitidine).

Adult Dosage:

• Ovarian Cancer:
• 175 mg/m² IV over 3 hours every 3 weeks, in combination with cisplatin.
• Alternatively, 135 mg/m² IV over 24 hours every 3 weeks.
• Breast Cancer (Metastatic):
• 175 mg/m² IV over 3 hours every 3 weeks, as monotherapy.
• 80–100 mg/m² weekly dosing often used in clinical practice.
• NSCLC:
• 175 mg/m² IV over 3 hours on Day 1, followed by cisplatin 75 mg/m² every 21 days.
• Kaposi’s Sarcoma (AIDS-related):
• 135 mg/m² IV over 3 hours every 3 weeks, or
• 100 mg/m² every 2 weeks.

Special Populations:

• Pediatrics: Not routinely recommended; investigational dosing protocols exist.
• Elderly: Start at lower doses; monitor closely for myelosuppression and neuropathy.
• Hepatic Impairment:
• Mild-to-moderate: Dose reduction by 20–25% may be necessary.
• Severe impairment: Contraindicated if total bilirubin >5 mg/dL.
• Renal Impairment: No dose adjustment usually required; minimal renal clearance.

Paclitaxel is a cytotoxic agent that interferes with the normal function of microtubule breakdown during cell division. It promotes microtubule polymerization and stabilizes them against depolymerization, preventing the normal dynamic reorganization required for mitosis. This leads to the formation of dysfunctional microtubule bundles, mitotic arrest at the G2/M phase of the cell cycle, and subsequent apoptosis of cancer cells. Its action is highly effective in rapidly dividing tumor cells.

• Absorption: Complete (100%) after IV infusion.
• Distribution: Extensive; volume of distribution >300 L/m². Plasma protein binding: ~89–98%.
• Metabolism: Primarily hepatic via cytochrome P450 enzymes—mainly CYP2C8 and CYP3A4.
• Elimination:
• ~70–90% excreted via feces (biliary route).
• <10% via kidneys.
• Half-life: Multi-phasic elimination
• Initial phase: ~0.3–1 hour
• Terminal phase: ~20–30 hours
• Bioavailability: Not applicable (IV only).
• Onset of Action: Days to weeks, depending on tumor response.

• Pregnancy:
• Former FDA Category D.
• Evidence of fetal harm including embryotoxicity and fetal death in animal studies. Should not be used during pregnancy unless the potential benefits justify the risks.
• Effective contraception is advised during treatment and for 6 months after the final dose.
• Lactation:
• Unknown if excreted in human milk; due to potential for serious adverse effects in nursing infants, breastfeeding is contraindicated during therapy and for at least 2 weeks after the final dose.

• Class: Antineoplastic (chemotherapeutic) agent
• Subclass: Taxane derivative (Microtubule-stabilizing agent)

• Hypersensitivity to paclitaxel or formulation excipients (e.g., polyoxyethylated castor oil – Cremophor EL)
• Severe baseline neutropenia (ANC <1500/mm³ in solid tumors; <1000/mm³ in Kaposi’s sarcoma)
• Severe hepatic impairment
• Pregnancy and breastfeeding
• Concurrent use with live or live-attenuated vaccines in immunocompromised patients

• Severe hypersensitivity reactions: Can be life-threatening. Requires pre-medication.
• Myelosuppression: Major dose-limiting toxicity. Monitor blood counts before and after each cycle.
• Peripheral neuropathy: Dose- and duration-dependent. May require dose reduction or discontinuation.
• Hepatic impairment: Increased risk of toxicity. Frequent liver function monitoring is essential.
• Cardiac toxicity: Bradycardia, hypotension, and conduction abnormalities may occur.
• Extravasation risk: May cause tissue necrosis. Ensure proper IV line placement.
• Infection risk: Monitor for signs of febrile neutropenia or sepsis.
• Use in elderly: Greater sensitivity to adverse effects; adjust dose cautiously.

Common Side Effects:

• Hematologic: Neutropenia, leukopenia, anemia, thrombocytopenia
• Gastrointestinal: Nausea, vomiting, diarrhea, mucositis
• Neurologic: Peripheral neuropathy, paresthesia, sensory loss
• Dermatologic: Alopecia, rash
• Musculoskeletal: Arthralgia, myalgia

Serious/Rare Side Effects:

• Severe hypersensitivity reactions (e.g., anaphylaxis)
• Cardiac arrhythmias
• Hepatotoxicity
• Pulmonary toxicity (e.g., interstitial pneumonitis)
• Severe infection or febrile neutropenia
• Injection site reactions including necrosis (with extravasation)

• CYP450 Interactions:
• Substrate of CYP2C8 and CYP3A4
• CYP3A4 inhibitors (e.g., ketoconazole, verapamil): ↑ plasma levels and toxicity risk
• CYP inducers (e.g., rifampin, phenytoin): ↓ efficacy
• Other Drug Interactions:
• Cisplatin: Administer paclitaxel before cisplatin to reduce myelosuppression.
• Doxorubicin: Use with caution—may increase cardiotoxicity.
• Live vaccines: Avoid during and after therapy due to immunosuppression.
• Anticoagulants or antiplatelets: Increased bleeding risk in thrombocytopenia.

• Weekly paclitaxel dosing regimens are now commonly recommended in breast and ovarian cancer for improved tolerability and comparable efficacy.
• Albumin-bound paclitaxel (nab-paclitaxel) is increasingly used due to reduced hypersensitivity risk (no Cremophor EL).
• NCCN and ESMO guidelines continue to support paclitaxel for multiple tumor types.
• Ongoing studies are exploring its use in combination immunotherapies and dose-dense regimens for high-risk cancers.

• Unopened Vials:
• Store at 20°C to 25°C (68°F to 77°F); excursions allowed between 15–30°C.
• Protect from light. Do not freeze.
• After Dilution:
• Stable for up to 6 hours at room temperature.
• Refrigerated solutions (2°C to 8°C): Use within 24 hours.
• Use non-DEHP IV sets and containers due to leaching risk from Cremophor EL.
• Handling Precautions:
• Cytotoxic—handle with gloves, mask, and gown.
• Dispose of unused product and waste according to hazardous drug protocols.