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oxaliplatin
Oxaliplatin is a platinum alkylating agent, which contains platinum complexed to oxalate and diaminocyclohexane (DACH) complex. Platinum complexes are formed intracellularly and bind to DNA, forming cross-links which inhibit DNA replication and transcription, leading to cytotoxic and antitumor effects. Cytotoxicity is cell-cycle nonspecific.
Cmax: reached at the end of 2-hour infusion of oxaliplatin at 85 mg/m2
At the end of a 2 hour infusion, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine.
Cross blood brain barrier? | No |
PPB | > 90 % (irreversible; also binds irreversibly to erythrocytes) |
Rapid and extensive nonenzymatic (no cytochrome P450-mediated metabolism) biotransformation to reactive platinum complexes.
Active metabolites |
Yes. Diaminocyclohexane (DACH) platinum complexes |
Inactive metabolites |
Yes, including one associated with neurotoxicity |
Triphasic elimination
Half-life | 391 hours (terminal) |
Urine |
54 % within 5 days |
Feces | 2% within 5 days |
-
Colorectal cancer
Refer to the product monograph for a full list and details of approved indications.
Other Uses:
- Pancreatic cancer
- Gastroesophageal cancer
- Biliary tract cancer
- GI neuroendocrine carcinoma
- Bladder cancer
- Testicular cancer
- Cancer of unknown primary origin
- Ovarian cancer
- Thyroid cancer
- Non-Hodgkin lymphoma
- T-cell lymphoma
Emetogenic Potential:
Extravasation Potential: Irritant
The following table lists adverse effects that occurred in ≥ 5% of patients who received adjuvant treatment in colorectal cancer, in a clinical study with oxaliplatin in combination with 5-FU/LV. Other adverse events, which may be severe, from other studies or post-marketing are also included.
ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
---|---|---|---|---|---|
Auditory | Hearing impaired (rare) | E D | |||
Cardiovascular | Arterial thromboembolism (rare) | E | |||
Hypertension (<5%) | I | ||||
Hypotension (<5%) | I | ||||
QT interval prolonged (rare) | E | ||||
Venous thromboembolism (<10%) | E | ||||
Dermatological | Alopecia (30%) (mostly mild) | D | |||
Hand-foot syndrome (7%) | E | ||||
Nail disorder (<5%) | E | ||||
Rash (14%) | E | ||||
Gastrointestinal | Abdominal pain (18%) | E | |||
Anorexia (13%) | E | ||||
Constipation (22%) | E | ||||
Diarrhea (56%) (11% severe) | E | ||||
Dyspepsia (8%) | E | ||||
GI obstruction (5%) | E | ||||
GI perforation (rare) | E | ||||
GI ulcer (duodenal – rare) | E | ||||
Mucositis (42%) | E | ||||
Nausea, vomiting (74%) (5% severe) | I E | ||||
Other - ischemia (rare; may be severe) | E | ||||
Weight changes (10%) | E | ||||
General | Edema (15%) | E | |||
Fatigue (44%) | E | ||||
Hematological | Disseminated intravascular coagulation (rare) | E | |||
Hemolysis (immune hemolytic anemia; rare) | I E | ||||
Hemolytic uremic syndrome / microangiopathic hemolytic anemia (rare) | E | ||||
Immune thrombocytopenic purpura (rare) | E | ||||
INR / prothrombin time increased (<5%) | E | ||||
Myelosuppression ± infection, bleeding (77%) (2% severe) | E | ||||
Hepatobiliary | ↑ LFTs (57%) (2% severe) | E | |||
Pancreatitis (rare) | E | ||||
Veno-occlusive disease (rare) | D | ||||
Hypersensitivity | Hypersensitivity (10%) (3% severe) | I E | |||
Injection site | Injection site reaction (11%) | I E | |||
Metabolic / Endocrine | Abnormal electrolyte(s) (11%) (↓ Ca, K, Na) | E | |||
Hyperglycemia (14%) | E | ||||
Musculoskeletal | Musculoskeletal pain (14%) | E | |||
Rhabdomyolysis (rare) | |||||
Nervous System | Ataxia (<5%) | I E | |||
Dizziness (<5%) | E | ||||
Dysgeusia (12%) | E | ||||
Guillain-Barre syndrome (rare) | E | ||||
Headache (7%) | E | ||||
Insomnia (<5%) | E | ||||
Optic neuritis (rare) | E | ||||
Pharyngolaryngeal dysesthesia (38%) | I | ||||
Posterior reversible encephalopathy syndrome (PRES) (rare) | E | ||||
Sensory neuropathy (92%) (including cranial neuropathy; 12% severe) | I E | ||||
Ophthalmic | Conjunctivitis (9%) | I | |||
Other (transient vision loss; rare) | E | ||||
Watering eyes (<5%) | I | ||||
Renal | Nephrotoxicity (<5%) (<1% severe) | E | |||
Respiratory | Cough, dyspnea (5%) | E | |||
Pneumonitis (<5%) | D | ||||
Urinary | Urinary symptoms (5%) | E |
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects associated with the of combination oxaliplatin/5FU/LV include sensory neuropathy, myelosuppression ± infection, bleeding, nausea, vomiting, ↑ LFTs, diarrhea, fatigue, mucositis, pharyngolaryngeal dysesthesia, alopecia and constipation.
Two different types of peripheral sensory neuropathy are associated with oxaliplatin. The first type is an acute presentation (within hours or 1 to 2 days of dosing), reversible (usually resolves within 14 days), and primarily peripheral, sensory neuropathy that frequently recurs with further dosing. Symptoms include sensory dysesthesia, paresthesia and hypoesthesia of the limbs, mouth, throat and larynx. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed.
Pharyngolaryngeal dysesthesia is common, with severe symptoms in 1-2% of patients shortly after drug infusion. Symptoms usually resolve within hours of onset. The feeling of difficulty in breathing or swallowing may be distressing to the patient. As symptoms may be precipitated or exacerbated by exposure to cold temperatures or objects, cold avoidance should be exercised. The second type of neuropathy is a more persistent (>14 days) presentation, characterized by paresthesias, dysesthesias, hypoesthesias and altered proprioception. It can interfere with daily activities (e.g. buttoning clothing, holding objects, writing) and occurs in most patients receiving oxaliplatin with 5-FU/LV. Lhermittes sign and urinary retention are seen rarely. Persistent neuropathy can occur without prior acute neuropathy event. Symptoms may improve in some patients upon discontinuation of oxaliplatin. Calcium gluconate 1 g and magnesium sulphate 1 g infusions pre ± post-oxaliplatin did not appear to be effective neuroprotective agents in a randomized study.
Anaphylaxis has been reported, including severe events in 2-3% of patients, and can occur during any cycle, but incidence increases as cycle number increases (generally after 6 cycles). In the post-marketing experience, some cases of anaphylaxis have been fatal. Patients should not be re-challenged if possible. If re-challenge is clinically necessary (ie. benefits of treatment outweigh risks and no other treatment option available), a desensitization protocol should be used.
Pneumonitis, including fatal cases, has been reported rarely, and presents with cough, dyspnea, crackles and pulmonary infiltrates.
Hepatotoxicity, transaminitis, VOD and nodular regenerative hyperplasia have been reported.
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
For adjuvant use, treatment is recommended for a total of 12 cycles.
Avoid mucositis prophylaxis with ice chip as cold temperatures can precipitate or exacerbate acute neurological symptoms.
Premedication (prophylaxis for infusion reactions):
- There is insufficient evidence that routine prophylaxis with pre-medications reduces IR rates.
- Consider corticosteroids and H1-receptor antagonists ± H2-receptor antagonists in high-risk patients (i.e. ≥ cycle 6, younger age, female gender, prior platinum exposure, platinum-free interval ≥ 3 years).
In Combination with 5-Fluorouracil and Leucovorin: 85 mg/m2 IV on day 1 every 2 weeks.
Modify according to protocol by which patient is being treated.
Consider dose reduction in subsequent cycles after recovery from Grade 3 or 4 hematological toxicities.
Neurotoxicity was graded based on the following scales from the adjuvant or metastatic colorectal cancer trials.
Neurotoxicity Grade |
Adjuvant
|
Metastatic
|
1
|
No change or none |
Resolved and did not interfere with functioning |
2
|
Mild paresthesias, loss of deep tendon reflexes |
Interfered with function but not daily activities |
3
|
Mild or moderate objective sensory loss, moderate paresthesias |
Pain or functional impairment that interfered with daily activities |
4
|
Severe objective sensory loss or paresthesias that interfere with function |
Persistent impairment that is disabling or life-threatening |
Toxicity Grade | Combinations - Adjuvant^ | Combinations - Palliative^ |
Persistent1 Grade 2 Neurotoxicity |
↓ from 85 → 75 mg/m2 |
↓ from 85 → 65 mg/m2 |
Transient1 Grade 3 Neurotoxicity | ↓ to 75mg/m2 | ↓ to 65mg/m2 |
Persistent1 Grade 3 Neurotoxicity or grade 4 | Discontinue | |
≥ Grade 3 GI toxicity (after prophylaxis) OR ≥ Grade 3 Platelets OR ≥ Grade 3 Neutropenia (including febrile neutropenia) |
↓ from 85 → 75 mg/m2 Reduce 5FU by 20% |
↓ from 85 → 65 mg/m2 Reduce 5FU by 20% |
Sepsis / septic shock | Discontinue | |
Other ≥ grade 3 toxicity 3 | Consider dose ↓ | |
Pharyngolaryngeal dysesthesia | Hold; then increase duration of next infusion to 6 hours4 | |
Pneumonitis | Hold, investigate; discontinue if confirmed. | |
Anaphylactic-like reaction | Discontinue | |
RPLS | ||
Hemolytic uremic syndrome or any signs of microangiopathic hemolytic anemia | ||
Disseminated intravascular coagulation (DIC) | ||
QT prolongation | ||
Intestinal ischemia or duodenal ulcer | ||
Symptoms of rhabdomyolysis |
^Do not re-treat until the ANC ≥ 1.5 x 109/L and the platelets ≥ 75 x 109/L, GI and neurotoxicities have resolved and other non-hematologic toxicities ≤ grade 1.
1 Transient = >7days - <1 cycle; persistent = ≥ 1 cycle
3 For skin toxicity, reduce 5FU dose only.
4 If oxygen saturation is normal, an anxiolytic agent may be given.
Management of Infusion-related reactions:
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
Grade | Management | Re-challenge |
1 or 2 |
Restart:
|
|
3 or 4 |
|
|
* Up to 50% of patients can experience recurrent reactions during re-challenge despite using pre-medications (e.g. corticosteroid and H1/H2-receptor antagonist).
Hepatic Impairment | Oxaliplatin Dose |
Mild to moderate | No adjustment required |
Severe | No information found |
Creatinine Clearance (mL/min)
|
Oxaliplatin
(% previous dose)
|
50 - 80
|
No adjustment required
|
30 - <50
|
Caution
|
<30
|
Discontinue
|
Patients ≥ 65 years had a higher incidence of GI toxicity, myelosuppression, syncope and fatigue. No dose adjustments were needed but caution should be exercised. Efficacy (on disease free survival benefit) in the adjuvant setting was not confirmed.
Women may be at higher risk of severe (grades 3-4) GI effects, fatigue or neutropenia in adjuvant treatment of colorectal cancer. In metastatic colorectal cancer, females were observed to have higher number of severe adverse effects than men across all treatment arms.
Safety and efficacy not established.
-
Oxaliplatin is administered by intravenous infusion.
-
Oxaliplatin should always be administered before fluorouracil.
-
May be mixed in 250-500 mL bag of D5W only. Do not mix with NS, chloride containing or alkaline solutions, or with fluorouracil.
-
Administer by slow infusion. Concentration must be between 0.2 to 0.7 mg/mL
-
Infuse IV over 2 hours. Increasing infusion time to 6 hours may decrease acute toxicity such as pharyngolaryngeal dysesthesia.
-
Do not mix oxaliplatin with other drugs in the same infusion bag or infusion line.
-
Infusion may be given at the same time as Leucovorin in separate D5W bags using a Y-site, providing trometamol is not used as an excipient. Do not administer concurrently with fluorouracil.
-
If another drug is given before oxaliplatin, flush infusion line with D5W before giving oxaliplatin. Flush the line with D5W after oxaliplatin before giving a subsequent drug (e.g. fluorouracil).
-
The compatibility of oxaliplatin solution for infusion has been tested with representative, PVC-based, administration sets.
-
Do not use with injection equipment containing aluminum, as this can degrade platinum compounds.
-
Unopened vials should be stored at 15-30°C; protect from light.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
-
Hypersensitivity to the drug or to other platinum agents (e.g. cisplatin, carboplatin) or to any component of the formulation.
-
Pregnancy and breastfeeding.
-
Severe renal impairment (CrCl < 30 mL/min).
-
Oxaliplatin may result in dizziness or visual disturbances (including transient vision loss) in some patients; patients should exercise caution in driving or operating machinery.
-
Do not give oxaliplatin intraperitoneally.
Other Drug Properties:
-
Carcinogenicity:
Yes
-
Fetotoxicity:
Yes
-
Mutagenicity:
Yes
-
Clastogenicity:
Yes
-
Teratogenicity:
Yes
-
Genotoxicity:
Yes
-
Embryotoxicity:
Yes
Oxaliplatin is contraindicated in pregnancy.
- Adequate contraception should be used by patients who can become pregnant and their partners during treatment, and for at least 9 months after the last dose.
- Adequate contraception should be used by patients who produce sperm and their partners during treatment, and for at least 6 months after the last dose.
-
Breastfeeding:
Breastfeeding is contraindicated during treatment and for 3 months after the last dose.
-
Fertility effects:
Yes
Oxaliplatin may cause irreversible infertility. Men are advised to seek counseling on sperm storage before starting treatment.
Drug interactions with CYP450 enzymes are unlikely.
AGENT | EFFECT | MECHANISM | MANAGEMENT |
---|---|---|---|
Anticoagulants | Occasionally associated with hemorrhage (in patients who received oxaliplatin plus 5-FU/leucovorin) | Prolong INR and prothrombin time | Monitor INR closely |
Fluorouracil | Possibly ↑ fluorouracil side effects with higher oxaliplatin dosage | ↑ Fluorouracil exposure (approximately 20%) observed at oxaliplatin 130mg/m2 q3w | Caution; interaction unlikely at oxaliplatin 85mg/m2 q2w |
Other nephrotoxic drugs | ↑ Incidence of renal impairment | ↓ Renal clearance | Monitor closely |
Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) | ↑ QTc-prolonging effect | Additive | Monitor closely |
Other drugs associated with rhabdomyolysis | ↑ Risk of rhabdomyolysis | Additive | Monitor closely |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
Monitor Type | Monitor Frequency |
---|---|
CBC |
Baseline and before each cycle |
Liver function tests |
Baseline and before each cycle |
Renal function tests |
Baseline and before each cycle |
Electrolytes, including magnesium |
Baseline and before each cycle |
INR, if patient on anticoagulants |
Baseline and as clinically indicated |
Clinical assessment of GI effects, neurotoxicity, infection, bleeding, thromboembolism, hypersensitivity, local reactions, respiratory or ophthalmic effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Haller D., Tabernero J., Maroun J et al. Capecitabine Plus Oxaliplatin Compared With Fluorouracil and Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer. Journal of Clinical Oncology 2011 29:11, 1465-1471
Loprinzi CL, Qin R, Dakhil SR, et al. Phase III randomized, placebo (PL)-controlled, double-blind study of intravenous calcium/magnesium (CaMg) to prevent oxaliplatin-induced sensory neurotoxicity (sNT), N08CB: An alliance for clinical trials in oncology study. J Clin Oncol 2013; 31 suppl; abstr 3501.
McEvoy GK, editor. AHFS Drug Information 2013. Bethesda: American Society of Health-System Pharmacists.
Product monograph: Oxaliplatin injection. Accord Healthcare Inc., November 27, 2018.
Product monograph: Oxaliplatin injection. Pfizer Canada ULC., May 2023.
October 2023 Modified Indications and Pregnancy/lactation sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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