Oxaliplatin (Eloxatin) is a platinum-based chemotherapeutic drug that is used in the treatment of metastatic colonic cancer and other cancers.

Oxaliplatin Uses (Indications):

• As adjuvant therapy in stage III Colon Cancer:

  • After complete resection of primary tumor, treatment of stage III colon cancer (in combination with infusional fluorouracil and leucovorin).

• Advanced Colorectal cancer:

  • Treatment of advanced colorectal cancer (in combination with infusional fluorouracil & leucovorin).

• Off Label Use of Oxaliplatin in Adults:

  • Advanced Biliary adenocarcinoma;
  • Refractory Chronic lymphocytic leukemia
  • Esophageal cancer
  • Gastric cancer
  • Refractory Neuroendocrine tumors (carcinoid)
  • Relapsed or refractory Non Hodgkin lymphoma,
  • Advanced Ovarian cancer
  • Advanced or metastatic Pancreatic cancer,
  • Adjuvant therapy in potentially curable Pancreatic cancer,
  • Refractory Testicular cancer,
  • Recurrent or refractory Unknown primary cancer

Oxaliplatin Dose in Adults

Note:

• Oxaliplatin is associated with a moderate emetic potential.
• To prevent nausea and vomiting, antiemetics are recommended.

Oxaliplatin Dose in the treatment of advanced Biliary adenocarcinoma (off-label): IV:

• GEMOX regimen:

  • Until disease progression or unacceptable toxicity, 100 milligram/m² on day two every 2 weeks (in combination with gemcitabine).

• CAPOX regimen:

  • Until disease progression or unacceptable toxicity, 130 milligram/m² on day 1 every three weeks (in combination with capecitabine).

Oxaliplatin Dose in the treatment of fludarabine-refractory chronic lymphocytic leukemia (off-label): IV

• OFAR regimen:

  • 25 milligram/m²/day for four days every 4 weeks (in combination with fludarabine, cytarabine, and rituximab) for up to six cycles.

Oxaliplatin Dose in the treatment of Advanced Colorectal cancer:

• IV:
• Until disease progression or unacceptable toxicity, 85 milligram/m² every 2 weeks (in combination with infusional fluorouracil/leucovorin).

Oxaliplatin dose in the treatment of Advanced Colorectal cancer (off-label dosing/ combinations):

• IV:

  • 85 milligram/m² every 2 weeks in combination with fluorouracil/leucovorin/irinotecan (Falcone 2007) or
  • 130 milligram/m² every three weeks in combination with capecitabine.

Oxaliplatin Dose in the treatment of Stage III Colon cancer (adjuvant therapy):

• IV:

  • 85 milligram/m² every two weeks (in combination with infusional fluorouracil/leucovorin) for six months (12 cycles; in combination with infusional fluorouracil/leucovorin).

Adjuvant therapy duration in completely resected stage III colon cancer (off-label):

• Low risk (T1, T2, or T3 and N1):

  • A duration of therapy of 3 or 6 months of oxaliplatin (when used in combination with infusional fluorouracil and leucovorin) may be provided.
  • In the subgroup of patients with T1, T2, or T3 and N1 stage III colon cancer, a pooled analysis of 6 phase III studies demonstrated noninferiority (based on 3-year disease-free survival) with a 3-month (compared to a 6month) adjuvant oxaliplatin-based treatment duration.

• High risk (T4 and/or N2):

  • The duration of therapy of six months of oxaliplatin (when used in combination with infusional fluorouracil and leucovorin) should be provided.
  •  In the subgroup of patients with T4 & N2 stage III colon cancer, in a pooled analysis of 6 phase III studies, superior disease-free survival has been demonstrated with 6 months (compared to 3 months) of adjuvant oxaliplatin-based therapy.

Oxaliplatin Dose in the adjuvant therapy of Colon cancer (off-label dosing/combinations):

• IV:

  • 85 milligram/m² /dose on days 1, 15, and 29 of an 8-week treatment cycle in combination with fluorouracil/leucovorin or
  • 130 milligram/m² every three weeks in combination with capecitabine.

Oxaliplatin Dose in the treatment of Esophageal/ gastric cancers (off-label):

• IV:

  • 130 milligram/m² on day 1 every three weeks (in combination with epirubicin and either capecitabine or fluorouracil) for up to 8 cycles (Cunningham 2008) or 85 milligram/m² on day 1 every 2 weeks (in combination with docetaxel, leucovorin, and fluorouracil) for up to 8 cycles or
  • 85 milligram/m² on day 1 every 2 weeks (in combination with leucovorin and fluorouracil; FOLFOX4) for 6 cycles.

or

Oxaliplatin Dose in the treatment of Gastric cancer:

• IV:

  • 130 milligram/m² on day 1 every three weeks (in combination with capecitabine) for 8 cycles (Bang 2012)

or

Oxaliplatin dose in the advanced palliative treatment of Gastroesophageal cancer:

• Frail and/or elderly patients:

  • A dose optimization study which examined 60 percent, 80 percent or 100 percent of a 130 milligram per m² dose once every 21 days (in combination with capecitabine) found that the 60 percent dose was not inferior (for progression-free survival) & had less toxicity compared to the full dose.

Oxaliplatin Dose in the treatment of Refractory Neuroendocrine tumors (carcinoid) (off-label):

• IV:
  • 130 milligrams per m² on day one every three weeks (in combination with capecitabine) for up to six cycles.

Oxaliplatin Dose in the treatment of relapsed/refractory Non-Hodgkin lymphoma (off-label):

• IV:
  • 100 milligram/m² on day one every three weeks (in combination with gemcitabine and rituximab).

Oxaliplatin Dose in the treatment of advanced Ovarian cancer (off-label):

• IV:
• Until disease progression or unacceptable toxicity, 130 milligram/m² once every 3 weeks.

Oxaliplatin Dose in the treatment of advanced or metastatic pancreatic cancer (off-label):

• IV:
  • Until disease progression or unacceptable toxicity, 85 milligram/m² every 2 weeks (in combination with fluorouracil, leucovorin, and irinotecan; FOLFIRINOX regimen) for up to 6 months or
  • 110 to 130 milligram/m² on day one every three weeks (in combination with capecitabine).

Oxaliplatin Dose in the adjuvant therapy of potentially curable pancreatic cancer (off-label):

Note:

• If recovery is complete, American Society of Clinical Oncology (ASCO) guidelines recommend 6 months of adjuvant therapy.
• A total of 6 months of adjuvant therapy (including the preoperative regimen) is recommended if preoperative chemotherapy therapy was received.

• mFOLFIRINOX regimen:

  • IV:
  • 85 milligram/m² every two weeks (in combination with fluorouracil, leucovorin, and irinotecan; modified FOLFIRINOX regimen) for 24 weeks (Conroy 2018).
  • According to ASCO guidelines, mFOLFIRINOX is the preferred first-line adjuvant regimen for a potentially curable disease.

Oxaliplatin Dose in the treatment of refractory testicular cancer (off-label):

• IV:
• 130 milligram/m² every 3 weeks in combination with gemcitabine or 130 milligrams/m² on day one every three weeks (in combination with gemcitabine and paclitaxel) for up to 8 cycles.

Oxaliplatin Dose in the treatment of recurrent or refractory Unknown primary cancer (off-label):

• IV:
• Until clinical benefit is no longer realized, 30 milligram/m² on day 1 of a 21-day cycle (in combination with capecitabine) for 6 cycles or may continue.

Oxaliplatin Dose in Childrens

• Refer to individual protocols; details concerning dosing in combination regimens should also be consulted.

Oxaliplatin Dose in the treatment of refractory or relapsed solid tumors:

• Limited data are available.
• Several regimens reported.
• Efficacy results highly variable.
• Has shown limited activity in pediatric patients (primarily some delayed tumor progression reported) and an acceptable safety profile.
• Should not be used first-line.
• Reserved for refractory cases.
• Prior to and during administration, patients should be hydrated (eg, 3 L/m² /day).

• Lam 2015; McGregor 2009:

  • Children and Adolescents:
  • IV:
  • 130 milligram/m² over two hours on day one in combination with etoposide with/without ifosfamide every 21 days.

• Geoerger 2011; Macy 2013:

  • Children and Adolescents:
  • IV:
  • In combination with gemcitabine or fluorouracil/leucovorin, 100 milligram/m² over 2 hours on day 1 of a 14-day cycle.

• Hartmann 2011:

  • Children and Adolescents:
  • IV:
  • 85 milligram/m² over two hours on day 1 in combination with irinotecan (day 1) & gemcitabine (day 1 and 8).

Oxaliplatin dose in the treatment of refractory or relapsed Neuroblastoma:

Limited data available; efficacy results highly variable; should not be used first-line; reserved for a refractory case.

• Children ≥2 years and Adolescents:

  • IV:
  • 105 milligrams/m² on day one in combination with doxorubicin on a 21-day cycle.

Oxaliplatin Dosing adjustments for toxicity:

• • The presented dosing adjustments are based on experience in adult patients.
  • If available, refer to specific protocol management in pediatric patients.

  • Adult:

    • Acute toxicities:

      • Acute toxicities may be mitigated by longer infusion time (6 hours) (eg, pharyngolaryngeal dysesthesia).

    • Neurosensory events:

      • Persistent (>7 days) grade 2 neurosensory events:
        • Adjuvant treatment of stage 3 colon cancer:
        • Reduce dose to 75 milligram/m².
      • Advanced colorectal cancer:
        • Reduce dose to 65 milligram/m².
        • Despite dose reduction, consider withholding oxaliplatin for grade two neuropathy lasting >7 days.
      • Persistent (>7 days) grade 3 neurosensory events:
        • Consider discontinuing oxaliplatin.

    • Gastrointestinal toxicity (grade 3/4) occurring despite prophylactic treatment:

      • Adjuvant treatment of stage 3 colon cancer:
      • Until recovery from toxicity, delay the next dose, then reduce dose to 75 milligram/m².
      • Advanced colorectal cancer:
        • Until recovery from toxicity, delay the next dose, then reduce dose to 65 milligram/m².

    • Hematologic toxicity (grade 4 neutropenia, febrile neutropenia, or grade 3/4 thrombocytopenia):

      • Adjuvant treatment of stage 3 colon cancer:
        • Until neutrophils recover to ≥1,500/mm³ and platelets recover to ≥75,000/mm³, delay the next dose, then reduce dose to 75 mg/m².
      • Advanced colorectal cancer:
        • •  Until neutrophils recover to ≥1,500/mm³ and platelets recover to ≥75,000/mm³, delay the next dose, then reduce dose to 65 milligram/m².

    • Pulmonary toxicity (unexplained respiratory symptoms, including nonproductive cough, dyspnea, crackles, pulmonary infiltrates):

      • Until interstitial lung disease or pulmonary fibrosis has been excluded, discontinue.

    • Rhabdomyolysis:

      • Discontinue for signs/symptoms of rhabdomyolysis.

    • Sepsis or septic shock:

      • Withhold treatment.

Pregnancy Risk Factor D

• Animal reproduction studies showed that adverse reactions were only one-tenth the human equivalent.
• Effective contraception should be used during treatment to prevent pregnancy.
• Before undergoing therapy, both males and females with reproductive potential who are interested in having children should think about fertility preservation.

Use of oxyliplatin while breastfeeding

• It is unknown if breast milk contains oxaliplatin.
• It is important to decide whether to stop breast-feeding or discontinue oxaliplatin treatment.
• This decision will be made taking into consideration the importance of the mother's treatment.

Oxaliplatin Dose in Kidney Disease:

• Manufacturer's labeling:

  • CrCl ≥30 mL/minute:

  • No dosage adjustment is necessary.

  • CrCl <30 mL/minute:

  • Reduce dose from 85 milligram/m to 65 milligram/m .

• Alternate recommendations:

  • CrCl ≥20 mL/minute:

    • In a study with a limited number of patients with mild to moderate impairment, defined by the authors as CrCl 20-59 mL/min (determined using 24-hour urine collection), oxaliplatin was well tolerated, suggesting a dose reduction may not be necessary for patients with CrCl ≥20 mL/min receiving every-3-week dosing (dose range: 80 -130 milligram/m² every three weeks).

Oxaliplatin Dose in Liver Disease:

• Mild, moderate, or severe impairment:

  • No dosage adjustment necessary.

Common Side Effects of Oxaliplatin:

• Central Nervous System:

  • Peripheral Neuropathy
  • Fatigue
  • Pain
  • Headache
  • Insomnia

• Gastrointestinal:

  • Nausea
  • Diarrhea
  • Vomiting
  • Abdominal Pain
  • Constipation
  • Anorexia
  • Stomatitis

• Hematologic & Oncologic:

  • Anemia
  • Thrombocytopenia
  • Leukopenia

• Hepatic:

  • Increased Serum AST
  • Increased Serum ALT
  • Increased Serum Bilirubin

• Neuromuscular & Skeletal:

  • Back Pain

• Respiratory:

  • Dyspnea
  • Cough

• Miscellaneous:

  • Fever

Less Common Side Effects Of Oxaliplatin:

• Cardiovascular:

  • Edema
  • Chest Pain
  • Peripheral Edema
  • Flushing
  • Thromboembolism

• Central Nervous System:

  • Rigors
  • Dizziness

• Dermatologic:

  • Skin Rash
  • Alopecia
  • Palmar-Plantar Erythrodysesthesia

• Endocrine & Metabolic:

  • Dehydration
  • Hypokalemia

• Gastrointestinal:

  • Dyspepsia
  • Dysgeusia
  • Flatulence
  • Hiccups
  • Mucositis
  • Dysphagia
  • Gastroesophageal Reflux Disease

• Genitourinary:

  • Dysuria

• Hematologic & Oncologic:

  • Neutropenia

• Hypersensitivity:

  • Hypersensitivity Reaction

• Local:

  • Injection Site Reaction

• Neuromuscular & Skeletal:

  • Arthralgia

• Ocular:

  • Abnormal Lacrimation

• Renal:

  • Increased Serum Creatinine

• Respiratory:

  • Upper Respiratory Tract Infection
  • Rhinitis
  • Epistaxis
  • Pharyngitis
  • Pharyngolaryngeal Dysesthesia

Contraindications to Oxaliplatin:

• Hypersensitivity to oxaliplatin or other platinum-containing compounds or any component in the formulation

Canadian labelingAdditional contraindications not listed in the US labeling:

• Pregnancy and breastfeeding
• Severe renal impairment (CrCl >30 mL/minute).

Warnings and precautions

• Suppression of bone marrow

  • Fluorouracil, leucovorin and fluorouracil are combined to produce Grade 3 and 4. This is often associated with oxaliplatin.
  • Some fatalities have been reported from sepsis, neutropenic and septic shock caused by oxaliplatin.
  • Do not start oxaliplatin treatment until neutrophils are at least 1500/mm3.
  • For sepsis and septic shock, withhold treatment
  • Reduce the dose after you have recovered from neutropenia (grade 4 neutropenia) or neutropenic fever.

• Cardiotoxicity

  • Postmarketing surveillance has shown QT prolongation, ventricular arrhythmias and fatal torsades-de-pointes.
  • ECG monitoring is recommended for patients with heart disease.
  • Bradyarrhythmias and concomitant medication are known to prolong QT (including class III and IV antiarrhythmics) and electrolyte abnormalities.
  • Patients with congenital long QT syndrome should be avoided.
  • You should check potassium and magnesium levels before and after treatment.
  • Before treatment begins, correct hypokalemia and hypomagnesemia.

• Extravasation

  • Oxaliplatin is an irritant that has the same properties as vesicant.
  • Before and during infusion, make sure you have the proper needle/catheter placement.
  • Avoid excessive use.

• Toxicity to the GI:

  • Oxaliplatin has moderate emetic properties.
  • Antiemetics can be used to prevent nausea and vomiting.
  • Fluorouracil is often associated with GI adverse events.
  • Fluorouracil and Leucovorin can increase the risk of GI toxicity when oxaliplatin are administered together.
  • Reports of stomatitis and mucositis as well as GI bleeding and obstruction have been made.

• Hypersensitivity and anaphylactoid reactions [US Boxed Warning]

  • Anaphylactic reactions to oxaliplatin have been reported. (may occur within minutes after administration).
  • You can manage your symptoms with epinephrine or contortionists and discontinuation.
  • Also, oxygen and bronchodilators were used.
  • It has been reported that Grade 3 and 4 hypersensitivity have been observed.
  • Allergy reactions can be similar to those reported with other platinum analogs and may occur with any cycle.
  • Reactions are common after several cycles.
  • In retrospective reviews, reaction occurred in a median of 7-9 cycles with an onset time of 5 to 70 minutes.
  • The symptoms include bronchospasm, erythema and hypotension (rare), pruritus and/or urticaria.
  • Patients who have not been treated previously have experienced flushing and diaphoresis as well as chest pain, hypotension, syncope and shortness of breath.
  • According to the manufacturer, re-challenge should not be done (deaths from anaphylaxis have been linked to platinum derivatives).
  • Patients who have experienced mild hypersensitivity have seen their reactions recur at a greater severity.
  • For patients with severe hypersensitivity, rechallenge was performed (with 2 to3 days of antihistamine/corticosteroid premedication and prolonged infusion time). It allowed for 2 to4 additional oxaliplatin cycles.
  • However, nearly two-thirds (33%) of patients were unable to re-challenge because of the severity of their initial reaction.

• Hepatotoxicity

  • Reports of hepatotoxicity, including rare cases of hepatitis or hepatic failure, have been made.
  • A liver biopsy revealed peliosis and idiopathic portal hypertension (including nodular regeneration hyperplasia), sinusoidal changes, perisinusoidal fibrisis and veno-occlusive lesion.
  • Portal hypertension and increased liver function should be considered in patients who have hepatic vessels disorders, including veno-occlusive diseases.

• Neuropathy

  • There may be two types of peripheral sensory neuropathy:
  • The first type of neuropathy, which is primarily characterized by peripheral symptoms and may be exacerbated or exacerbated by cold (may include Pharyngolaryngeal Dyesthesia), is an acute presentation. It can resolve in as little as one to two days.
  • Avoid cold foods/beverages and ice chips during or shortly after oxaliplatin injections.
  • This acute neuropathy often recurs with subsequent doses.
  • Cold-triggered neuropathy can last up to seven days after oxaliplatin is administered.
  • The second type of neuropathy is more severe (>14 days), and interferes with daily activities such as writing, buttoning, or swallowing.
  • These symptoms can improve for some patients if the treatment is stopped.
  • In a retrospective assessment of patients who received oxaliplatin to treat colorectal cancer, the incidence of peripheral sensor neuropathy was comparable between diabetics and non-diabetic (Ramanathan 2010,).
  • Numerous retrospective studies, as well as a small underpowered randomized trial, have shown the benefits of calcium and magnesium infusions prior to and after oxaliplatin. Administration may decrease the risk of cumulative sensory neuropathy.
  • A double-blind, placebo-controlled, randomized study of patients with colorectal carcinoma showed that calcium and magnesium did not have any benefit in preventing sensory neuropathy, or decreasing discontinuation rates for oxaliplatin.

• Toxicity in the lungs:

  • This condition may lead to pulmonary fibrisis, which can be fatal.
  • Withhold treatment of unexplained symptoms, such as crackles, dyspnea and nonproductive cough until interstitial lung disease (or pulmonary Fibrosis) is excluded.

• Reversible posterior Leukoencephalopathy Syndrome:

  • Reversible posterior Leukoencephalopathy Syndrome (RPLS) has been described.
  • Seizures, blurred vision, blindness, and other vision problems are some of the symptoms.
  • Hypertension may be a possible cause.
  • Brain imaging confirms diagnosis.

• Rhabdomyolysis

  • Rhabdomyolysis, including fatal cases, has been reported with oxaliplatin.
  • Stop if you experience rhabdomyolysis symptoms.

• Renal impairment

  • Patients with impaired renal function should be cautious.
  • It is possible to experience increased toxicities.
  • Reduce the initial dose if you have severe impairment.

Oxaliplatin: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring Parameters:

• CBC with differential, blood chemistries, including serum creatinine, ALT, AST & bilirubin (prior to each cycle), electrolytes, including potassium and magnesium (prior to & periodically during treatment).
• INR & prothrombin time (in patients on oral anticoagulant therapy).
• Prior to each dose, go for neurologic evaluation and periodically thereafter.
• Hypersensitivity.
• Respiratory effects.
• RPLS

How to administer Oxaliplatin?

IV:

• Give an IV infusion for up to 2 hours.
• Infusions should be extended to 6 hours for acute toxicities.

Rate off-label:

• It was used a fixed infusion rate (1 milligram/m2/min) and it did not show statistically significant differences in hypersensitivity reactions.
• Before administering any concomitant medication flush the infusion line with D.W.
• Avoid cold exposure, ice chips and cold drinks (may worsen acute neurological symptoms).
• Use aluminum-containing needles and administration sets only.
• When using oxaliplatin in combination with a fluoropyrimidine (eg 5-FU), infuse it first.
• Oxaliplatin has moderate emetic properties.
• Antiemetics can be used to prevent nausea and vomiting.
• It is characterized by vesicant-like properties.
• Before and during infusion, make sure you have the proper needle/catheter placement.
• Avoid excessive use.
• Check the IV site for redness or swelling.

Extravasation management

• If extravasation occurs, stop infusion immediately.
• Extravasated solution should be gently aspirated (do not flush the line).
• Take out needle/cannula.
• Elevate extremes
• Information conflicts relating to cold or warm compresses.
• Applying cold compresses to the skin may reduce cell injury and local vasoconstriction.
• It can also cause or exacerbate peripheral nerve damage.
• Warm compresses can increase drug removal locally, but may also increase cell uptake and injury (de Lemos 2005).

Mechanism of action of Oxaliplatin:

• Oxaliplatin is a platinum derivative and an alkylating agent.
• The platinum compound forms cross-links with DNA after intracellular hydrolysis.
• This inhibits DNA replication and transcription and causes cell death.
• Cytotoxicity can be defined as cell-cycle nonspecific.

Protein binding:

• >90 percent primarily albumin & gamma globulin (irreversible binding to platinum)

Metabolism:

• Nonenzymatic (rapid and extensive), forms active & inactive derivatives

Half-life elimination: Children:

• Oxaliplatin ultra-filterable platinum (terminal):
• Median:
  • 293 hours.
• Range:
  • 187-662 hours.

Adults:

• Oxaliplatin ultra-filterable platinum:
• Distribution:
• Alpha phase:
• 0.4 hours
• Beta phase:
• 16.8 hours
• Terminal:
• 391 hours

Excretion:

• Urine (~54 percent)
• Feces (~2 percent)

International Brands of Oxaliplatin:

• Eloxatin
• ACT Oxaliplatin
• Eloxatin
• PMS-Oxaliplatin
• TARO-Oxaliplatin
• Ai Heng
• Crisapla
• Dacotin
• Dacplat
• Eloxatin
• Eloxatine
• Elplat
• Entia
• Henplatin
• Kebir
• Liplatin
• Loxatron
• Meslatin
• Olatin
• Olipcis
• Oplat
• Oxalatin
• Oxalee
• Oxalem
• Oxalip
• Oxalitan
• Oxalitin
• Oxalotin
• Oxaltic
• Oxaltie
• Oxapla
• Oxaplat
• Oxaplin
• Oxerin
• Oxitan
• Oxitel
• Oxol
• Planitox
• Platinox
• Pleoxtin
• Plusplatin
• Ranxor
• Rexta
• Riptam
• Sanroxa
• Sindoxplatin
• Sinoxal
• X-Plat
• Xaliplat
• Xaloplat
• Zildox
• Zolaxat

Oxaliplatin Brand Names in Pakistan: