A Comprehensive Monograph on Oxaliplatin: Pharmacology, Clinical Efficacy, and Safety

Section I: Drug Identification and Physicochemical Properties

1.1 Overview and Classification

Oxaliplatin is a third-generation platinum coordination complex that functions as a potent antineoplastic agent.[1] It is categorized pharmacologically as an alkylating agent and is structurally defined as a diaminocyclohexane (DACH) platinum derivative.[2] This specific chemical lineage distinguishes it from its predecessors, cisplatin and carboplatin, granting it a unique profile of efficacy and toxicity.[1] As a small molecule drug, Oxaliplatin has become a cornerstone of modern chemotherapy, particularly in the management of colorectal cancer.[1]

1.2 Chemical Identity and Structure

The therapeutic activity and distinct clinical behavior of Oxaliplatin are direct consequences of its unique molecular architecture. Its formal International Union of Pure and Applied Chemistry (IUPAC) name is (SP-4-2)-[ethanedioato(2-)-kO1,kO2]-platinum.[6] It is also referred to as

cis-\ [oxalato(2-)- O,O'] platinum.[7]

Structurally, Oxaliplatin is an organoplatinum complex built around a central platinum (II) atom.[8] This platinum atom is coordinated with two distinct ligands that define its function:

1. 1,2-Diaminocyclohexane (DACH): A bulky, non-leaving side chain that replaces the two simple amine groups found on cisplatin. This modification is not merely incidental; it is the primary structural feature responsible for Oxaliplatin's enhanced cytotoxicity and, critically, its ability to overcome certain mechanisms of platinum resistance.[1]
2. Oxalate Ligand: A bidentate oxalate group that acts as a labile "leaving group." In the physiological environment of the body, this ligand is displaced, which is the essential step in activating the drug to its cytotoxic form.[8]

This structure-function relationship is central to understanding Oxaliplatin's clinical role. The DACH ligand sterically hinders the recognition of Oxaliplatin-DNA adducts by the cell's mismatch repair (MMR) machinery. MMR systems are a primary mechanism by which cancer cells develop resistance to cisplatin, as they recognize and excise cisplatin-DNA adducts, allowing the cell to survive. By evading this repair system, Oxaliplatin remains effective in tumors that are resistant to other platinum agents and establishes its own therapeutic niche, particularly in colorectal cancer, where cisplatin has limited activity.[1] This circumvention of a major resistance pathway explains why Oxaliplatin is not generally cross-resistant with its predecessors.[2] However, this structural advantage came with a physicochemical trade-off; the DACH group confers poor water solubility, a challenge that was addressed during its chemical development.[1]

1.3 Nomenclature and Identifiers

For precise identification in clinical, research, and regulatory contexts, Oxaliplatin is referenced by several standard identifiers.

Table 1: Oxaliplatin - Key Identifiers and Properties

Property	Value	Source(s)
Generic Name	Oxaliplatin	1
DrugBank ID	DB00526	1
CAS Number	61825-94-3	1
Molecular Formula	C8​H14​N2​O4​Pt	1
Average Molecular Weight	397.29 g/mol	1
IUPAC Name	(SP-4-2)-[ethanedioato(2-)-kO1,kO2]-platinum	6
Classification	Alkylating Agent, Platinum Compound	1
Key Brand Names	Eloxatin®, Elplat®, Dacotin®, Dacplat®	3

Additional synonyms include L-OHP, 1-OHP, Oxalatoplatin, Diaminocyclohexane Oxalatoplatinum, Ai Heng, JM-83, and RP-54780.[1]

1.4 Physical and Chemical Properties

Oxaliplatin is a synthetic compound that exists as a solid at room temperature.[6] Its average molecular weight is 397.29 g/mol, with a monoisotopic mass of 397.060149 Da.[1] The drug's solubility profile is a key consideration for its formulation and administration. It is only slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and is considered practically insoluble in ethanol and acetone.[9] For laboratory purposes, it is soluble in dimethyl sulfoxide (DMSO) up to 100 mM.[6] When stored properly under desiccating conditions at +4°C, the solid compound is stable for four years or more.[6]

1.5 Commercial Formulations and Brand Names

Commercially, Oxaliplatin is supplied as a sterile, preservative-free aqueous solution for intravenous injection, typically at a concentration of 5 mg/mL.[14] The formulation also contains inactive ingredients, including tartaric acid and sodium hydroxide, which serve as a buffering system, and Water for Injection.[9]

The most widely recognized global brand name is Eloxatin®, originally marketed by Sanofi.[2] Other major brand names developed in association with Debiopharm include Elplat®, Dacotin®, and Dacplat®.[3] With the expiration of its patents, numerous generic formulations have become available from manufacturers such as Teva, Hospira, and Ebewe, significantly reducing its cost.[16] This has led to broad global market penetration, with a variety of brand names available in different regions. For instance, in Bangladesh, brands include Oxaliplatin AqVida, Oxalotin, and Oxiplat, while AdvaCare Pharma markets a version called OxaliCare™.[17]

Section II: Clinical Pharmacology

2.1 Mechanism of Action

Oxaliplatin functions as a prodrug that must be activated within the body to exert its cytotoxic effects. This activation occurs through a rapid, non-enzymatic process in physiologic solutions, a key feature that distinguishes its pharmacology.[1] The labile oxalate ligand is displaced by water molecules, creating a series of transient but highly reactive, positively charged platinum species. These include monoaquo DACH platinum and diaquo DACH platinum.[1]

Once activated, these electrophilic platinum complexes seek out and form covalent bonds with macromolecules, with DNA being the primary therapeutic target.[1] The principal cytotoxic lesion is the formation of platinum-DNA adducts, which results in both intrastrand and interstrand DNA crosslinks.[1] These crosslinks are predominantly formed at the N7 position of purine bases, linking adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG).[1]

The formation of these bulky adducts creates a physical distortion in the DNA double helix. This distortion effectively blocks the molecular machinery responsible for DNA replication and transcription.[6] The inability of the cell to synthesize new DNA or transcribe genes into proteins triggers cell cycle arrest and, ultimately, initiates the process of programmed cell death, or apoptosis.[4] As previously noted, the unique three-dimensional conformation of the adducts formed by the bulky DACH ligand makes them poor substrates for the cell's mismatch repair (MMR) system. This evasion of a key DNA repair pathway is fundamental to Oxaliplatin's potent cytotoxicity and its activity against tumors that have developed resistance to cisplatin and carboplatin.[1]

2.2 Pharmacodynamics

The cytotoxic effects of Oxaliplatin are cell-cycle nonspecific, meaning it can damage and kill cancer cells at any point in their life cycle, which contributes to its broad efficacy.[5] A defining pharmacodynamic feature of Oxaliplatin is its powerful synergistic action when combined with fluoropyrimidines like 5-fluorouracil (5-FU).[1] This synergy, which is observed both

in vitro and in vivo, is the foundational principle of the highly effective FOLFOX and CAPOX chemotherapy regimens.[1] The enhanced effect is believed to be mechanistically based rather than the result of a pharmacokinetic interaction, with one proposed mechanism being the suppression of thymidylate synthase (the target of 5-FU) by Oxaliplatin.[11]

Patient response and susceptibility to toxicity are also influenced by individual genetic makeup. The field of pharmacogenomics has identified specific genetic variations that modulate the risk of Oxaliplatin-Induced Peripheral Neuropathy (OIPN), the drug's primary dose-limiting toxicity. Polymorphisms in the gene encoding glutathione S-transferase pi-1 (GSTP1), such as rs1695 and rs1138272, are significantly associated with an increased risk and greater severity of OIPN. The GSTP1 enzyme plays a dual role in both detoxifying the reactive metabolites of Oxaliplatin and modulating cellular pathways related to oxidative stress, providing a genetic explanation for the variability in neurotoxicity observed among patients.[4]

2.3 Pharmacokinetics (ADME)

The disposition of Oxaliplatin in the body is complex and characterized by extensive biotransformation and a multiphasic elimination pattern.

Table 2: Pharmacokinetic Parameters of Oxaliplatin

Parameter	Value	Source(s)
Cmax (at 85 mg/m²)	0.814 mcg/mL (ultrafilterable platinum)	10
Volume of Distribution (Vd)	~440 L	10
Plasma Protein Binding	>90% (irreversible)	1
Primary Metabolism	Rapid, extensive, non-enzymatic biotransformation	1
Primary Excretion Route	Renal (~54% of dose in urine over 5 days)	10
Half-life (t½) (ultrafilterable platinum)	t½α: ~0.43 hours (distribution) t½β: ~16.8 hours (distribution) t½γ: ~252-391 hours (terminal elimination)	1

Distribution

Following a standard 2-hour intravenous infusion, the distribution of platinum is rapid and extensive. Only about 15% of the administered platinum remains in the systemic circulation as active, ultrafilterable species; the remaining 85% is quickly distributed into tissues or eliminated in the urine.[10] The decline of this active fraction from the plasma is triphasic, marked by two initial distribution phases and a remarkably long terminal elimination phase.[1]

A critical pharmacokinetic feature is the extensive and irreversible binding of platinum to plasma proteins, primarily albumin and gamma-globulins, at levels exceeding 90%.[1] Platinum also binds irreversibly to erythrocytes, where it accumulates to approximately twice the plasma concentration but is considered pharmacologically inactive.[1] The large volume of distribution (~440 L) further confirms its widespread sequestration in body tissues.[10]

This pharmacokinetic profile directly informs the drug's toxicity. The extremely long terminal half-life and irreversible binding to tissues and proteins mean that while the active (ultrafilterable) drug does not accumulate in the plasma with repeated dosing, the total body burden of platinum does increase over time. This slow clearance and prolonged tissue exposure, particularly in the nervous system, provide the biological foundation for the cumulative, dose-dependent nature of chronic peripheral neuropathy, which is the principal factor limiting the total dose of Oxaliplatin a patient can receive.[2]

Metabolism

Oxaliplatin's metabolism is another of its defining characteristics. It undergoes rapid and extensive biotransformation, but this process is entirely non-enzymatic.[1] Up to 17 different platinum-containing derivatives have been identified in patient plasma, including several cytotoxic species (e.g., monochloro and dichloro DACH platinum) and various non-cytotoxic conjugated products.[1]

Crucially, there is no evidence of metabolism mediated by the cytochrome P450 (CYP450) enzyme system.[10] This "metabolic independence" is a significant clinical advantage. The CYP450 system is a major source of drug-drug interactions, as many medications can induce or inhibit these enzymes, unpredictably altering the concentration and toxicity of co-administered drugs. By bypassing this common metabolic pathway, Oxaliplatin's pharmacokinetic profile is more predictable and less susceptible to interactions with the wide array of concomitant medications (e.g., antiemetics, analgesics, antibiotics) that patients with cancer frequently require. This reliability is a key factor that has facilitated its role as a backbone agent in combination chemotherapy.[20]

Excretion

The primary route of elimination for platinum species derived from Oxaliplatin is renal excretion.[10] Studies tracking the administered dose show that approximately 54% is recovered in the urine within five days, whereas fecal excretion is minimal, accounting for only about 2%.[10] The renal clearance of ultrafilterable platinum is strongly correlated with the glomerular filtration rate (GFR), indicating that filtration by the kidneys is the principal mechanism of removal from the body.[20]

Section III: Clinical Applications and Therapeutic Efficacy

3.1 Approved Indications

The regulatory approvals for Oxaliplatin from major agencies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are specific and primarily focused on colorectal cancer. The approved indications are for its use in combination with infusional 5-fluorouracil and leucovorin (5-FU/LV) for:

• Adjuvant Treatment of Stage III Colon Cancer: For patients who have undergone complete surgical resection of the primary tumor, Oxaliplatin-based chemotherapy is used to eliminate micrometastatic disease and reduce the risk of cancer recurrence.[1]
• Treatment of Advanced (Metastatic) Colorectal Cancer: For patients with cancer that has spread to distant organs, Oxaliplatin-based regimens are a standard of care for both first-line (initial) and second-line (after progression on other therapies) treatment.[1]

3.2 Key Combination Regimens

Oxaliplatin is rarely used as a monotherapy; its clinical success is overwhelmingly derived from its use in combination regimens that leverage its synergistic activity with other cytotoxic agents.[1]

• FOLFOX: This is the quintessential Oxaliplatin-containing regimen, with the name being an acronym for its components: FOLinic acid (leucovorin), Fluorouracil, and OXaliplatin.[26] Leucovorin is not a cytotoxic agent itself but serves to enhance the activity of fluorouracil. FOLFOX is a global standard of care for colorectal cancer.[4] Several variations of the regimen exist (e.g., FOLFOX4, FOLFOX6, mFOLFOX6), which primarily differ in the specific doses and schedules of 5-FU and leucovorin administration.[26]
• CAPOX (or XELOX): This regimen offers an alternative to the infusional 5-FU used in FOLFOX. It combines CAPecitabine (Xeloda®), an oral fluoropyrimidine that converts to 5-FU in the body, with OXaliplatin.[5] This provides greater convenience for patients by replacing a continuous intravenous infusion with an oral tablet.
• Combinations with Targeted Agents: In the era of personalized medicine, Oxaliplatin-based backbones are frequently combined with targeted therapies. For example, bevacizumab (an anti-VEGF antibody that inhibits angiogenesis) or, in RAS wild-type tumors, cetuximab (an anti-EGFR antibody) may be added to FOLFOX or CAPOX to improve outcomes.[1]

3.3 Efficacy in Clinical Trials

The establishment of Oxaliplatin as a standard of care is supported by robust evidence from large, randomized clinical trials. In the setting of metastatic colorectal cancer, studies demonstrated that the FOLFOX regimen resulted in significantly higher tumor response rates and a longer time to disease progression compared to treatment with 5-FU/LV alone.[19] In the adjuvant setting for Stage III colon cancer, the addition of Oxaliplatin to 5-FU/LV was shown to significantly improve disease-free survival, effectively increasing the cure rate for these patients and transforming the standard of care.[3]

3.4 Off-Label and Investigational Uses

A notable paradox exists in the clinical use of Oxaliplatin: despite its narrow set of formal regulatory approvals, its recognized broad-spectrum activity has led to widespread off-label and investigational use across a multitude of other cancer types.[32] This practice stems from the understanding that its unique mechanism of overcoming platinum resistance could be beneficial in other malignancies where platinum agents are active. This extensive application beyond its label demonstrates a perception of clinical utility by oncologists that far exceeds its approved indications.

• Other Gastrointestinal (GI) Cancers: It is commonly used off-label in regimens for gastric, esophageal, and pancreatic cancers.[3]
• Other Solid Tumors and Hematologic Malignancies: Clinical trials have explored its use and shown promising results in non-Hodgkin's lymphoma, mesothelioma, and non-small cell lung cancer.[1] Compendial sources also support its use in biliary tract cancers, ovarian cancer, and refractory testicular cancer.[5] Its use in metastatic breast cancer has been studied, though with modest results in heavily pretreated populations.[32]
• Pediatric Oncology: In pediatric patients, Oxaliplatin is used off-label in combination regimens for the treatment of refractory or relapsed solid tumors, including neuroblastoma.[5]

Section IV: Dosage, Administration, and Patient Management

The clinical management of Oxaliplatin is a dynamic process heavily guided by the principle of mitigating its significant toxicities. Dosing and administration protocols are designed to maximize therapeutic benefit while proactively managing a challenging side effect profile.

4.1 Recommended Dosing and Administration

The standard recommended dose of Oxaliplatin is 85 mg/m², administered as an intravenous (IV) infusion once every two weeks as part of a 14-day cycle.[5]

Key administration parameters include:

• Infusion Duration: The infusion is typically administered over 120 minutes (2 hours).[34] As will be discussed, this duration may be extended to manage acute toxicities.
• Dilution: Oxaliplatin must be diluted prior to administration in 250 to 500 mL of 5% Dextrose in Water (D5W) to a final concentration no less than 0.2 mg/mL.[37]
• Incompatibilities: It is chemically incompatible with alkaline solutions and chloride ions. Therefore, it must not be diluted or mixed with saline (sodium chloride) solutions or administered through the same infusion line as alkaline drugs like basic solutions of 5-fluorouracil.[34]
• Equipment: Needles or IV administration sets containing aluminum parts must be avoided, as aluminum causes degradation of platinum compounds.[34]
• Premedication: To manage nausea and vomiting, premedication with antiemetics, such as 5-HT3 receptor antagonists (e.g., ondansetron) with or without a corticosteroid like dexamethasone, is recommended.[34] Unlike cisplatin, prehydration is not required for Oxaliplatin administration.[34]

4.2 Dose Modifications for Adverse Reactions

The clinical use of Oxaliplatin is characterized by a reactive approach to dosing, where adjustments are almost exclusively driven by the emergence of toxicity. The goal is to deliver the planned dose for as long as possible, with clear, guideline-based rules for dose reduction, delay, or discontinuation when adverse events occur.

Table 3: Dose Modifications for Key Adverse Reactions

Adverse Reaction	Severity	Recommended Dosage Modification (Adjuvant / Advanced Setting)	Source(s)
Peripheral Sensory Neuropathy	Persistent Grade 2	Consider reducing dose to 75 mg/m² (Adjuvant) or 65 mg/m² (Advanced)	34
	Persistent Grade 3	Consider discontinuing therapy	34
	Grade 4	Permanently discontinue therapy	36
Myelosuppression	Grade 4 Neutropenia or Grade 3-4 Thrombocytopenia	Delay next cycle until Neutrophils ≥1.5 × 10⁹/L and Platelets ≥75 × 10⁹/L. After recovery, reduce dose to 75 mg/m² (Adjuvant) or 65 mg/m² (Advanced).	34
Gastrointestinal Toxicity	Grade 3-4	After recovery, reduce Oxaliplatin dose to 75 mg/m² (Adjuvant) or 65 mg/m² (Advanced). Also reduce 5-FU dose.	35
Acute Toxicities (e.g., Infusion Reactions)	Non-life-threatening	Prolonging the infusion time from 2 hours to 6 hours may mitigate symptoms.	35

Permanent discontinuation of Oxaliplatin is mandated for several severe, non-negotiable toxicities, including any grade of hypersensitivity reaction, confirmed Posterior Reversible Encephalopathy Syndrome (PRES), confirmed interstitial lung disease or pulmonary fibrosis, and rhabdomyolysis.[24]

4.3 Use in Special Populations

• Renal Impairment: Since platinum is cleared by the kidneys, renal function is a critical consideration.
• Mild to Moderate Impairment (Creatinine Clearance [CrCl] 30-80 mL/min): No dose adjustment is formally recommended, though caution and close monitoring for increased toxicity are advised.[1]
• Severe Impairment (CrCl < 30 mL/min): A dose reduction to 65 mg/m² is required due to significantly decreased drug clearance and increased systemic exposure.[10]
• Hepatic Impairment: Studies have demonstrated that the clearance of Oxaliplatin is not significantly affected by hepatic dysfunction. Therefore, dose adjustments are not considered necessary for patients with impaired liver function when Oxaliplatin is used as a single agent.[20]
• Geriatric and Sex-Based Considerations: Age and sex have not been found to have a clinically significant impact on the pharmacokinetics of Oxaliplatin, and thus no dose adjustments are recommended based on these factors.[20]
• Pediatric Population: The safety and efficacy of Oxaliplatin in patients under the age of 18 have not been established through formal clinical trials.[34]

Section V: Safety Profile, Warnings, and Adverse Effects

The safety profile of Oxaliplatin is complex and is dominated by two distinct types of toxicity that require different clinical approaches: acute, immediate events that demand rapid intervention, and chronic, cumulative toxicities that necessitate long-term monitoring and proactive dose management.

5.1 Boxed Warning and Contraindications

Oxaliplatin carries a Boxed Warning from regulatory agencies regarding the risk of severe, life-threatening, and potentially fatal hypersensitivity reactions, including anaphylaxis. These reactions can occur within minutes of the start of an infusion and can happen during any cycle of treatment.[15]

Based on this risk, Oxaliplatin is absolutely contraindicated in the following populations:

• Patients with a known history of allergy or hypersensitivity reaction to Oxaliplatin or any other platinum-containing drug (e.g., cisplatin, carboplatin).[38]
• Individuals who are breastfeeding.[37]

5.2 Dose-Limiting Neurotoxicity (OIPN)

Oxaliplatin-Induced Peripheral Neuropathy (OIPN) is the most common and significant dose-limiting toxicity associated with the drug.[4] It manifests in two distinct forms:

Acute Neuropathy

This form of neurotoxicity is characterized by its rapid onset, typically occurring within hours to two days following an infusion.[41] It is generally reversible, with symptoms resolving within 14 days, but frequently recurs with subsequent doses.[43]

• Presentation: Symptoms are primarily sensory and include transient paresthesia (numbness, tingling), dysesthesia (abnormal sensations), and hypoesthesia (decreased sensation) in the hands, feet, and the perioral (around the mouth) or throat area.[43]
• Signature Symptom: The most characteristic and distressing symptom is pharyngolaryngeal dysesthesia, an acute, subjective sensation of the throat closing, difficulty swallowing, or shortness of breath, which occurs without any objective evidence of laryngeal spasm or respiratory compromise.[2] Other acute symptoms can include jaw spasm, abnormal tongue sensation, and dysarthria (difficulty speaking).[41]
• Cold Trigger: A hallmark of this acute neuropathy is that symptoms are precipitated or severely exacerbated by exposure to cold temperatures or cold objects.[22]

Chronic Cumulative Neuropathy

This form of neuropathy develops insidiously over multiple treatment cycles and its severity is directly related to the cumulative dose of Oxaliplatin received.[2]

• Presentation: It is a persistent (>14 days) sensory neuropathy characterized by paresthesias, sensory loss, and impaired proprioception (the sense of body position).[38] This loss of proprioception and fine motor control can severely interfere with activities of daily living, such as writing, buttoning clothes, or handling small objects, and can lead to difficulty walking and an increased risk of falls.[38]
• Progression and Reversibility: In most cases, severe (Grade 3) neuropathy evolves from milder (Grade 1 or 2) symptoms, highlighting the need for ongoing monitoring.[38] While the neuropathy is typically reversible after treatment is discontinued, recovery can be slow, often taking many months.[2]

5.3 Other Major Toxicities and Precautions

Beyond neurotoxicity, Oxaliplatin is associated with several other clinically significant risks that require careful monitoring and management.

• Hypersensitivity Reactions (HSRs): As highlighted in the boxed warning, HSRs are a major concern. They occur in approximately 10-12% of patients, with severe (Grade 3-4) anaphylactic reactions in 2-3%.[38] The risk increases with repeated exposure, often occurring after 4 to 6 cycles.[48] Manifestations range from mild rash and urticaria to life-threatening anaphylaxis with bronchospasm, hypotension, and angioedema.[25]
• Myelosuppression: Suppression of the bone marrow is very common and leads to neutropenia (low white blood cells), thrombocytopenia (low platelets), and anemia.[24] Grade 3-4 neutropenia is a frequent and serious event, which can lead to febrile neutropenia and life-threatening infections like sepsis or septic shock.[38]
• Pulmonary Toxicity: Although rare (<1% incidence), Oxaliplatin can cause interstitial lung disease and pulmonary fibrosis, which can be fatal. Any unexplained respiratory symptoms (e.g., non-productive cough, dyspnea) warrant immediate investigation and discontinuation of the drug until this toxicity is ruled out.[36]
• Hepatotoxicity: Elevations in liver function tests (AST, ALT, alkaline phosphatase) are common.[41] Rare but serious hepatic vascular disorders, such as veno-occlusive disease (sinusoidal obstruction syndrome), have also been reported and should be considered in patients with unexplained abnormal liver tests.[38]
• Posterior Reversible Encephalopathy Syndrome (PRES): This is a rare but serious neurological syndrome that requires immediate discontinuation of the drug. It presents with seizures, headache, altered mental status, and visual disturbances.[2]
• Cardiovascular Toxicity: Oxaliplatin can prolong the QT interval on an electrocardiogram, which creates a risk for serious ventricular arrhythmias, including the potentially fatal Torsade de Pointes. Caution and monitoring are required in patients with pre-existing cardiac conditions or those taking other QT-prolonging drugs.[37]
• Rhabdomyolysis: Rare cases of severe muscle breakdown (rhabdomyolysis), which can lead to acute kidney injury, have been reported and can be fatal.[24]

5.4 Common Adverse Effects

The following table summarizes the adverse effects of Oxaliplatin, categorized by system organ class and frequency.

Table 4: Summary of Adverse Effects by System Organ Class and Frequency

System Organ Class	Frequency	Adverse Effect(s)
Nervous System	Very Common (>10%)	Peripheral Sensory Neuropathy (92%), Pharyngolaryngeal Dysesthesia (38%), Headache, Dysgeusia
	Common (1-10%)	Dizziness, Insomnia, Depression
	Rare (<0.1%)	Posterior Reversible Encephalopathy Syndrome (PRES), Optic Neuritis, Dysarthria
Gastrointestinal	Very Common (>10%)	Nausea (74%), Diarrhea (67%), Vomiting (54%), Stomatitis/Mucositis (44%), Abdominal Pain, Constipation, Anorexia
	Common (1-10%)	Dyspepsia, Gastroesophageal Reflux, Dry Mouth
	Rare (<0.1%)	Colitis, Pancreatitis, Intestinal Obstruction
Hematological	Very Common (>10%)	Anemia (85%), Neutropenia (82%), Thrombocytopenia (77%), Leukopenia
	Common (1-10%)	Febrile Neutropenia, Sepsis
	Rare (<0.1%)	Immune Hemolytic Anemia, Immune-mediated Thrombocytopenia
Hepatic	Very Common (>10%)	Elevated Transaminases (AST/ALT), Elevated Alkaline Phosphatase
	Rare (<0.1%)	Veno-occlusive Disease (Sinusoidal Obstruction Syndrome)
General/Systemic	Very Common (>10%)	Fatigue (70%), Fever (29%), Pain, Edema
	Common (1-10%)	Allergic Reaction (10%), Injection Site Reaction
Dermatological	Very Common (>10%)	Alopecia, Skin Disorders, Sweating, Hand-Foot Syndrome
	Common (1-10%)	Rash, Pruritus, Dry Skin, Nail Changes
Respiratory	Very Common (>10%)	Dyspnea, Cough, Epistaxis
	Rare (<0.1%)	Interstitial Lung Disease, Pulmonary Fibrosis
Cardiovascular	Common (1-10%)	Flushing, Deep Vein Thrombosis, Hypertension, Hypotension
	Postmarketing (Rare)	QT Interval Prolongation, Ventricular Arrhythmias
Musculoskeletal	Very Common (>10%)	Back Pain, Myalgia, Arthralgia
	Postmarketing (Rare)	Rhabdomyolysis

Frequencies are based on combination therapy data and compiled from sources.[24]

5.5 Use in Pregnancy and Lactation

• Pregnancy: Oxaliplatin is classified as a drug that can cause fetal harm. Its mechanism of direct DNA damage, combined with evidence of teratogenicity and embryolethality in animal studies, indicates a significant risk to a developing fetus.[1] Women of reproductive potential must be advised of this risk and should use effective contraception during treatment and for at least 9 months after the final dose. Male patients with partners of reproductive potential should use effective contraception during treatment and for 6 months after the final dose.[50]
• Lactation: It is unknown whether Oxaliplatin or its metabolites are excreted in human milk. However, due to the high potential for serious adverse reactions in a breastfed infant, breastfeeding is contraindicated during Oxaliplatin therapy and for 3 months following the last dose.[25]

Section VI: Drug and Food Interactions

6.1 Drug-Drug Interactions

While Oxaliplatin's non-enzymatic metabolism spares it from many common pharmacokinetic interactions, several clinically significant interactions exist, primarily based on overlapping toxicities (pharmacodynamic interactions).

• Nephrotoxic Drugs: Because platinum is eliminated by the kidneys, co-administration of Oxaliplatin with other drugs known to be nephrotoxic (e.g., aminoglycoside antibiotics, amphotericin B) should be avoided. Such combinations can impair platinum clearance, leading to increased systemic exposure and heightened toxicity.[51]
• QT-Prolonging Drugs: Oxaliplatin has the potential to prolong the QT interval. Combining it with other medications that share this property (e.g., Class IA and III antiarrhythmics, certain antipsychotics, macrolide antibiotics) significantly increases the risk of life-threatening ventricular arrhythmias like Torsade de Pointes. This combination should be avoided or used only with extreme caution and intensive ECG monitoring.[37] Specific agents listed as contraindicated include dronedarone and pimozide.[56]
• Anticoagulants: In patients receiving Oxaliplatin-based chemotherapy (FOLFOX) concurrently with oral anticoagulants like warfarin, prolonged prothrombin time (PT) and International Normalized Ratio (INR) with associated hemorrhage have been reported. More frequent monitoring of coagulation parameters is necessary in these patients.[51]
• Live Vaccines: As a potent immunosuppressive agent, Oxaliplatin can diminish the immune response to vaccines and increase the risk of disseminated infection from live or live-attenuated vaccines (e.g., measles, mumps, rubella; rotavirus; intranasal influenza). Administration of live vaccines is contraindicated during and for at least three months following chemotherapy.[56]

6.2 Drug-Food Interactions

The interaction profile of Oxaliplatin with food is unique and clinically significant, though not in the traditional pharmacokinetic sense.

• Pharmacokinetic Interactions: There are no known direct interactions where food alters the absorption, metabolism, or excretion of Oxaliplatin.[57]
• Pharmacodynamic "Temperature" Interaction: The most critical interaction for patient management is not chemical but physical. Patients must be strictly counseled to avoid consuming cold foods and beverages and to avoid contact with cold objects (including ice) for several days following each infusion.[46] This is because cold temperatures are a direct physical trigger for the acute neurotoxicity symptoms, particularly the distressing pharyngolaryngeal dysesthesia. This is a crucial piece of patient education for preventing severe discomfort and anxiety.
• Symptom Management: General dietary advice is often given to help manage gastrointestinal side effects. To mitigate diarrhea, patients may be advised to avoid high-fiber foods. To manage nausea and vomiting, small, frequent meals and the avoidance of greasy or strongly aromatic foods are recommended.[46]

Section VII: Regulatory and Historical Context

7.1 Regulatory Approval History

The regulatory journey of Oxaliplatin illustrates its rapid ascent from a novel agent for refractory disease to a global standard of care, fundamentally reshaping the treatment landscape for colorectal cancer in the early 2000s.

• European Medicines Agency (EMA) and Europe:
• April 1996: First approved in France for the second-line treatment of metastatic colorectal cancer (mCRC).[60]
• July 1999: Gained broader European approval for first-line mCRC treatment through the Mutual Recognition Procedure.[60]
• September 2004: The indication was expanded to include the adjuvant treatment of Stage III colon cancer following complete tumor resection.[60]
• U.S. Food and Drug Administration (FDA):
• August 9, 2002: Received initial accelerated approval for the treatment of patients with mCRC whose disease had progressed on prior therapy (second-line treatment).[61]
• January 9, 2004: Granted full approval for the first-line treatment of advanced colorectal cancer when combined with 5-FU/LV, based on data showing superiority over the then-standard irinotecan-based regimen.[31]
• November 4, 2004: The approval was extended to the adjuvant setting for Stage III colon cancer, based on the landmark MOSAIC trial which demonstrated a significant improvement in disease-free survival.[31]

This stepwise progression—from second-line to first-line metastatic, and finally to the curative-intent adjuvant setting—occurred over a remarkably short period, reflecting the drug's clear and substantial clinical benefit over existing therapies.

7.2 Concluding Insights and Future Directions

Oxaliplatin's introduction into clinical practice represents a major advance in the history of oncology. Its development and strategic combination with fluoropyrimidines in regimens like FOLFOX dramatically improved outcomes for patients with colorectal cancer, more than doubling survival times in the metastatic setting and significantly increasing the cure rate for Stage III disease.[3] It remains a worldwide standard-of-care treatment for this malignancy.[3]

Future research directions are focused on several key areas. First is the continued exploration of Oxaliplatin's utility in other cancer types, building on the promising signals seen in gastric, pancreatic, and other solid tumors.[1] Second is its integration into novel combination regimens with next-generation targeted agents and immunotherapies, aiming to further enhance its efficacy.[28] Finally, and perhaps most critically, is the ongoing effort to mitigate its dose-limiting neurotoxicity. This includes research into effective neuroprotective agents, the identification of predictive biomarkers like GSTP1 polymorphisms to stratify patients by risk, and the development of alternative dosing strategies to allow for longer treatment durations with less cumulative toxicity.[4] The ability to successfully manage or prevent OIPN remains the greatest challenge and the most important frontier in optimizing the use of this powerful and transformative anticancer drug.

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