Oxaliplatin

Usage

Oxaliplatin is an antineoplastic chemotherapy drug, specifically a platinum-based alkylating agent. It is primarily used in combination with 5-fluorouracil (5-FU) and leucovorin (folinic acid) for:

• Adjuvant treatment: Stage III colon cancer after complete resection of the primary tumor.
• Treatment: Advanced colorectal cancer.
• Off Label uses include treatment of other cancers like breast, gastric, germ cell, head and neck, non-small cell lung cancer, non-Hodgkin’s Lymphoma, Mesothelioma, ovarian cancer, pancreatic cancer and prostate cancer.

It acts by binding to DNA, forming intrastrand and interstrand crosslinks, which inhibit DNA replication and transcription, ultimately leading to cell death. It primarily targets rapidly dividing cells, including cancer cells.

Alternate Names

While “oxaliplatin” is the generic name, it is marketed under brand names such as Eloxatin.

How It Works

Pharmacodynamics: Oxaliplatin exerts its cytotoxic effects by forming platinum-DNA adducts, primarily intrastrand crosslinks, which disrupt DNA replication and transcription. This ultimately triggers apoptosis (programmed cell death) in cancer cells. Its cytotoxic effect is cell-cycle nonspecific.

Pharmacokinetics:

• Absorption: Administered intravenously, therefore 100% bioavailable.
• Distribution: Widely distributed throughout the body, with a higher concentration found in erythrocytes, kidneys, liver and the gastrointestinal tract.
• Metabolism: Undergoes non-enzymatic conversion to active metabolites, including monoaquo- and diaquo-DACH-platinum. It also undergoes non-enzymatic biotransformation, involving the displacement of the labile oxalate ligand.
• Excretion: Primarily eliminated via renal excretion (approximately 50% within 3 days), with minimal fecal excretion. The terminal half-life of ultrafilterable platinum is around 273 hours (approximately 11 days). Approximately 90% of platinum in plasma is protein-bound one week after a 2-hour infusion of Oxaliplatin.

Mode of Action:

Oxaliplatin’s cytotoxicity is mainly due to the formation of covalent platinum-DNA adducts, which interfere with DNA repair mechanisms and ultimately cause cell death. Its mode of action differs from other platinum-based drugs because its bulky 1,2-diaminocyclohexane (DACH) carrier ligand, influencing the type of DNA adducts formed compared to cisplatin or carboplatin, thereby possibly explaining the lack of complete cross-resistance with these two other platinum-based drugs.

Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Not applicable in the classical sense, as its primary mechanism involves direct DNA interaction.

Dosage

Oxaliplatin is administered intravenously.

Standard Dosage

Adults:

• 85 mg/m² infused over 120 minutes, administered concurrently with leucovorin (200 mg/m² over 120 minutes) in separate bags using a Y-line. This is followed by 5-fluorouracil (400 mg/m² IV bolus, then 600 mg/m² as a 22-hour continuous infusion). This is administered on Day 1 of each 14-day cycle. The same regimen of leucovorin and 5-fluorouracil is administered on Day 2.
• Adjuvant treatment: Up to 12 cycles (6 months) or until unacceptable toxicity.
• Advanced colorectal cancer: Until disease progression or unacceptable toxicity.

Children:

There is no relevant indication for use of oxaliplatin in children. Safety and efficacy have not been established in this population.

Special Cases:

• Elderly Patients: No specific dose adjustment is required.
• Patients with Renal Impairment:
  • Mild to moderate: No dose adjustment.
  • Severe (creatinine clearance < 30 mL/min): Initial dose of 65 mg/m². Avoid use in severe renal impairment.
• Patients with Hepatic Dysfunction: Mild to moderate: No dose adjustment necessary. Severe hepatic impairment requires further investigation, and there is no established dose adjustment.
• Patients with Comorbid Conditions: Pre-existing cardiac conditions, electrolyte imbalances, pulmonary impairment, neurological disorders require careful monitoring.

Clinical Use Cases

Oxaliplatin is not typically used in clinical scenarios like intubation, surgical procedures, mechanical ventilation, intensive care unit (ICU) use, or emergency situations. It is primarily used for the cancer indications mentioned above.

Dosage Adjustments

• Neurosensory Toxicity:
  • Persistent Grade 2: Reduce dose to 75 mg/m² (adjuvant) or 65 mg/m² (advanced colorectal cancer).
  • Persistent Grade 3: Discontinue oxaliplatin.
• Hematologic Toxicity:
• After Grade 3/4 gastrointestinal toxicity, Grade 4 neutropenia/febrile neutropenia, or Grade 3/4 thrombocytopenia, reduce the dose to 75 mg/m² (adjuvant) or 65 mg/m² (metastatic), and 5-fluorouracil to 300mg/m² bolus then 500mg/m² over 22 hours in combination with leucovorin (200mg/m²) over 2 days, as tolerated. Delay subsequent doses until neutrophil count is ≥1.5 x 10⁹/L and platelet count ≥75 x 10⁹/L.
• Renal impairment (severe): Consider dose reduction or discontinuation.
• Acute neurological reactions: Prolonging the infusion time from 2 hours to 6 hours can be considered, as this can decrease the Cmax by approximately 30% and may lessen the severity of the acute toxicities.

Side Effects

Common Side Effects

• Nausea, vomiting, diarrhea
• Peripheral neuropathy (numbness, tingling, pain in extremities)
• Fatigue
• Stomatitis/Mucositis (mouth sores)
• Myelosuppression (decreased blood cell counts)

Rare but Serious Side Effects

• Anaphylactic reactions
• Posterior reversible encephalopathy syndrome (PRES)
• Pulmonary toxicity (including interstitial lung disease and pulmonary fibrosis)
• Hepatotoxicity
• QT prolongation, Torsades de pointes
• Rhabdomyolysis
• Hemorrhage

Long-Term Effects

• Peripheral neuropathy can persist after treatment.
• Secondary malignancies

Adverse Drug Reactions (ADR)

• Anaphylaxis
• Severe neutropenia
• PRES

Contraindications

• Hypersensitivity to oxaliplatin or other platinum-based drugs.
• Pre-existing peripheral sensory neuropathy interfering with function.
• Severe renal impairment.
• Myelosuppression.

Drug Interactions

• Aminoglycosides, amphotericin B and loop diuretics due to potentiation of oxaliplatin neurotoxicity.
• Other drugs that can prolong the QT interval.
• Live or live-attenuated vaccines.
• Nephrotoxins.
• Aluminum-containing IV sets can cause degradation of platinum compounds.
• Other medications metabolized by the liver need careful monitoring.

Pregnancy and Breastfeeding

• Pregnancy: Category D (oxaliplatin can cause fetal harm). Contraindicated in pregnancy. Advise women to avoid pregnancy during and for 9 months after treatment, and men for 6 months after treatment.
• Breastfeeding: Not recommended during and for 3 months after the final dose. Platinum is excreted in breast milk.

Drug Profile Summary

• Mechanism of Action: Platinum-based alkylating agent that forms DNA adducts, inhibiting DNA synthesis and leading to cell death.
• Side Effects: Nausea, vomiting, diarrhea, peripheral neuropathy, myelosuppression, fatigue. Serious: anaphylaxis, PRES, pulmonary toxicity, hepatotoxicity, QT prolongation.
• Contraindications: Hypersensitivity, pre-existing peripheral neuropathy, severe renal impairment, myelosuppression.
• Drug Interactions: Aminoglycosides, amphotericin B, live vaccines, other drugs that prolong the QT interval. Aluminum containing IV sets.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy. Not recommended while breastfeeding.
• Dosage: 85 mg/m² IV over 120 minutes every 2 weeks, in combination with 5-FU and leucovorin. Adjustments based on toxicity and renal function.
• Monitoring Parameters: Complete blood count (CBC) with differential, renal and liver function tests, neurological assessments, ECG (especially if risk factors for QT prolongation).

Popular Combinations

• 5-fluorouracil and leucovorin (FOLFOX regimen)

Precautions

• Pre-screen patients for hypersensitivity, renal and hepatic function, and baseline neurological status.
• Monitor for myelosuppression, peripheral neuropathy, allergic reactions, PRES, pulmonary and hepatotoxicity throughout the treatment course.
• Advise patients about potential long-term side effects, like persistent neuropathy.
• Contraception is essential in men and women of reproductive age.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Oxaliplatin?

A: The standard adult dosage is 85 mg/m² IV over 120 minutes every two weeks, given in combination with 5-FU and leucovorin. Dosage adjustments may be necessary based on patient-specific factors such as renal function and toxicity.

Q2: What are the most common side effects of Oxaliplatin?

A: The most common side effects include nausea, vomiting, diarrhea, peripheral sensory neuropathy (numbness, tingling, and pain in the extremities), fatigue, stomatitis, and myelosuppression.

Q3: What are the major contraindications for Oxaliplatin?

A: Oxaliplatin is contraindicated in patients with a history of hypersensitivity to oxaliplatin or other platinum compounds, pre-existing peripheral neuropathy that interferes with function, and severe renal impairment.

Q4: How should Oxaliplatin be administered?

A: Oxaliplatin is always administered intravenously via infusion over 120 minutes. It is never prepared or mixed with chloride-containing solutions (e.g., saline). It should always be administered before 5-FU.

Q5: How does Oxaliplatin interact with other drugs?

A: Oxaliplatin has clinically significant interactions with drugs such as aminoglycosides, amphotericin B, and other medications that prolong the QT interval. Concurrent use of these drugs might potentiate oxaliplatin’s toxicity. Aluminum-containing IV sets are contraindicated as they can cause degradation of the oxaliplatin.

Q6: Can Oxaliplatin be given during pregnancy or breastfeeding?

A: Oxaliplatin is contraindicated during pregnancy (Pregnancy Category D) and should not be used while breastfeeding.

Q7: What monitoring parameters are important for patients receiving Oxaliplatin?

A: Monitor patients for complete blood counts (CBC) with differential, renal and liver function tests, and neurological function. Electrocardiograms (ECGs) should be considered in patients at risk for QT interval prolongation.

Q8: What is the mechanism of action of Oxaliplatin?

A: Oxaliplatin is a platinum-based alkylating agent. It forms DNA adducts (primarily intrastrand crosslinks), which inhibit DNA replication and transcription, leading to cell death.

Q9: How should acute neurotoxicity be managed?

A: Acute neurotoxicity is characterized by sensory symptoms like paresthesia or dysesthesia. Management strategies include: dose reduction, symptomatic treatment, and prolonging the infusion duration (from 2 to 6 hours) to decrease peak plasma levels, possibly lessening the acute neurotoxic effects.

Q10: What are the dose reduction recommendations for hematological and gastrointestinal toxicities?

A: The dose should be reduced to 75 mg/m² (adjuvant) or 65 mg/m² (metastatic), and 5-fluorouracil to 300mg/m² bolus then 500mg/m² over 22 hours in combination with leucovorin (200mg/m²) over 2 days, as tolerated. Delay further doses until neutrophil counts recover to ≥1.5 x 10⁹/L and platelet counts to ≥75 x 10⁹/L.