X-PLAT Injection (Oxaliplatin)

Table of Content

Black Box Warning

Anaphylactic Reactions

Anaphylactic reactions to oxaliplatin have been reported, and may occur within minutes of oxaliplatin administration. Epinephrine, corticosteroids and antihistamines have been employed to alleviate symptoms of anaphylaxis.

Composition

X-PLAT 50 mg Injection
Each ml contains:
Oxaliplatin ….......... 2 mg

X-PLAT 100 mg Injection
Each ml contains:
Oxaliplatin …........... 2 mg

Dosage Form

Concentrate for solution for infusion

Pharmacology

Pharmacodynamics

Oxaliplatin is an anti-neoplastic active substance belonging to a new class of platinum-based compounds in which the platinum atom is complexed with 1,2 diaminocyclohexane (‘DACH’) and an oxalate group.

Oxaliplatin exhibits a wide spectrum of both in vitro cytotoxicity and in vivo anti-tumour activity in a variety of tumour model systems, including human colorectal cancer models. Oxaliplatin also demonstrates in vitro and in vivo activity in various cisplatin-resistant models.

Oxaliplatin undergoes non-enzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo- and diaquo-DACH platinum, which covalently bind with macromolecules. Both inter- and intra-strand Pt-DNA cross-links are formed. Cross-links are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These cross-links inhibit DNA replication and transcription resulting in the disruption of DNA synthesis, leading to cytotoxic and anti-tumour effects. Cytotoxicity is cell-cycle nonspecific. In vivo studies have shown the anti-tumour activity of oxaliplatin against colon carcinoma. In combination with 5-fluorouracil, oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumour models (HT29 , GR and L1210 ).

Pharmacokinetics

The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. The decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t½α; 0.43 hours and t½β; 16.8 hours) and a long terminal elimination phase (t½γ; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour intravenous infusion of oxaliplatin at a dose of 85 mg/m2 expressed as ultrafilterable platinum were a Cmax of 0.814 mcg/mL and a volume of distribution of 440 L. Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC0-48 hr) assessed over three cycles was moderate to low (23% and 6%, respectively). A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.

Distribution

At the end of a 2-hour infusion of oxaliplatin, 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. In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m2 every 2 weeks.

Metabolism

Oxaliplatin undergoes rapid and extensive non-enzymatic biotransformation. There is no evidence of cytochrome P450 (CYP450)-mediated metabolism in vitro.

Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro-DACH platinum, dichloro-DACH platinum, and monoaquo- and diaquo-DACH platinum) and a number of non-cytotoxic, conjugated species.

Elimination

The major route of platinum elimination is renal excretion. At 5 days after a single 2-hour infusion of oxaliplatin, urinary elimination accounted for about 54% of the platinum eliminated, with faecal excretion accounting for only about 2%. Platinum was cleared from plasma at a rate (10–17 L/hour) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/hour). There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal clearance of ultrafilterable platinum is significantly correlated with the GFR.

Special Populations

Renal Impairment

The AUC0-48 hr of platinum in the plasma ultrafiltrate increases as renal function decreases. The AUC0-48 hr of platinum in patients with mild (creatinine clearance 50 to 80 mL/min), moderate (CLcr 30 to <50 mL/min) and severe renal (CLcr <30 mL/min) impairment is increased by about 60%, 140% and 190%, respectively, compared to patients with normal renal function (CLcr >80 mL/min).

There was decrease in total and renal CL and Vss with increasing renal impairment especially in the (small) group of patients with severe renal impairment.

Total body clearance of plasma ultrafiltrate (PUF) platinum was reduced by 26% in mild, 57% in moderate, and 79% in severe renal impairment compared to patients with normal function.

Renal clearance of PUF platinum was reduced in patients with impaired renal function by 30% in mild, 65% in moderate, and 84% in severe renal impairment compared to patients with normal function.

There was an increase in beta half life of PUF platinum with increasing degree of renal impairment mainly in the severe group. Despite the small number of patients with severe renal dysfunction, these data are of concern in patients in severe renal failure and should be taken into account when prescribing oxaliplatin in patients with renal impairment.

Drug–Drug Interactions

No pharmacokinetic interaction between 85 mg/m2 of oxaliplatin and infusional 5-fluorouracil has been observed in patients treated every 2 weeks, but increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 of oxaliplatin administered every 3 weeks. In vitro, platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron and paclitaxel. In vitro, oxaliplatin is not metabolized by, nor does it inhibit, human CYP450 isoenzymes. No CYP450-mediated drug–drug interactions are, therefore, anticipated in patients.

Since platinum-containing species are eliminated primarily through the kidneys, clearance of these products may be decreased by co-administration of potentially nephrotoxic compounds, although this has not been specifically studied.

Indications

X-PLAT Injection, used in combination with infusional 5-fluorouracil and folinic acid  or leucovorin, is indicated for the following:

  • Adjuvant treatment of stage III (Duke's C) colon cancer in patients who have undergone complete resection of the primary tumour.
  • Treatment of metastatic colorectal cancer.

Dosage and Administration 

X-PLAT Injection should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

X-PLAT Injection should always be administered before the fluoropyrimidines, i.e., 5-fluorouracil.

Dosage

Administer X-PLAT Injection in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles).

X-PLAT Injection is administered as a 2- to 6-hour intravenous infusion in 250–

500 ml of 5% glucose solution to give a concentration between 0.2 mg/ml and 0.70 mg/ml; 0.70 mg/ml is the highest concentration in clinical practice for an X-PLAT Injection dose of 85 mg/m².

Day 1: X-PLAT Injection 85 mg/m2 intravenous infusion in 250–500 mL 5% Dextrose Injection and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, both given over 2–6 hours at the same time in separate bags, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2–4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, (recommended) as a 22-hour continuous infusion.

Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2–4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, (recommended) as a 22-hour continuous infusion.

The administration of X-PLAT Injection does not require pre-hydration. Premedication with anti-emetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

Dose Modification Recommendations

Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests. Prolongation of infusion time for X-PLAT Injection from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

Adjuvant Therapy in Patients with Stage III Colon Cancer

Neuropathy and other toxicities were graded using the National Cancer Institute Common Toxicity Criteria (NCI CTC) scale, Version 1.  

For patients who experience persistent grade 2 neurosensory events that do not resolve, a dose reduction of X-PLAT Injection to 75 mg/m2 should be considered. For patients with persistent grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.

A dose reduction of X-PLAT Injection to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 infusion for 22 hours is recommended for patients after recovery from grade 3/4 gastrointestinal events (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until neutrophils are ≥1.5 × 109/L and platelets are ≥75 × 109/L.

Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer

Neuropathy was graded using a study-specific neurotoxicity scale. Other toxicities were graded by the NCI CTC, Version 2.0.

For patients who experience persistent grade 2 neurosensory events that do not resolve, a dose reduction of X-PLAT Injection to 65 mg/m2 should be considered. For patients with persistent grade 3 neurosensory events, discontinuing of therapy should be considered. The 5-fluorouracil/leucovorin regimen need not be altered.

A dose reduction of X-PLAT Injection to 65 mg/m2 and 5-fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 (22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal events (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until neutrophils are ≥1.5 × 109/L and platelets are ≥75 × 109/L.

Preparation of Infusion Solution

Concentrate Solution for Infusion

  • Do not freeze the concentrated solution and protect it from light.
  • Dilution must never be performed with a sodium chloride solution or other chloride-containing solutions.
  • The solution must be diluted in an infusion solution of 250–500 mL of 5% Dextrose Injection.
  • After dilution with 250–500 mL of 5% Dextrose Injection, the shelf-life is 6 hours at room temperature (20–25°C ) or up to 24 hours under refrigeration (2–8°C ). After dilution, protection from light is not required.
  • X-PLAT Injection is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection prior to administration of any concomitant medication.
  • Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration and discarded if present.
  • Needles or intravenous administration sets containing aluminium parts that may come in contact with X-PLAT Injection should not be used for the preparation or mixing of the drug. Aluminium has been reported to cause degradation of platinum compounds.
  • The medicinal product is for single use only. Any unused infusion solution should be discarded.

Contraindications 

X-PLAT Injection should not be administered to patients with a history of known allergy to X-PLAT Injection or other platinum compounds.

X-PLAT is contraindicated in patients who

  • Have a known history of hypersensitivity to X-PLAT Injection or other platinum compounds;
  • Are breastfeeding;
  • Have myelosuppression prior to starting the first course, as evidenced by baseline neutrophils <2 × 109/l and/or platelet count of <100 ×109/l;
  • Have a peripheral sensitive neuropathy with functional impairment prior to the first course; and,
  • Have a severely impaired renal function (creatinine clearance less than 30 ml/min).

Warnings and Precautions

Oxaliplatin concentrate for solution for infusion should only be used in specialized departments of oncology and should be administered under the supervision of an experienced oncologist.

Drug Interactions

No specific CYP450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 oxaliplatin and 5-fluorouracil/leucovorin has been observed in patients treated every 2 weeks. Increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 oxaliplatin dosed every 3 weeks. Because platinum-containing species are eliminated primarily through the kidneys, clearance of these products may be decreased by co-administration of potentially nephrotoxic compounds; although, this has not been specifically studied.

Allergic Reactions

See Boxed Warning.

Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to oxaliplatin has been observed in 2–3% of colon cancer patients. These allergic reactions, which can be fatal, can occur within minutes of administration and at any cycle, and were similar in nature and severity to those reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus and, rarely, bronchospasm and hypotension. The symptoms associated with hypersensitivity reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the face, diarrhoea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. These reactions are usually managed with standard epinephrine, corticosteroid and antihistamine therapy. Rechallenge is contraindicated in these patients.

In case of anaphylactic manifestations the infusion should be interrupted immediately and an appropriate symptomatic treatment started. Re-administration of oxaliplatin to such patients is contraindicated. Cross-reactions, sometimes fatal, have been reported with all platinum compounds. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.

In case of oxaliplatin extravasation, the infusion must be stopped immediately and usual local symptomatic treatment initiated.

Neuropathy

Oxaliplatin is associated with two types of neuropathy:

An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or 1–2 days of dosing, that resolves within 14 days, and that frequently recurs with further dosing. The symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as transient paraesthesia, dysaesthesia and hypoaesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed. The acute, reversible pattern of sensory neuropathy was observed in about 56% of study patients who received oxaliplatin with 5-fluorouracil/leucovorin. In any individual cycle, acute neurotoxicity was observed in approximately 30% of patients. In adjuvant patients, the median cycle of onset for grade 3 peripheral sensory neuropathy was 9 in the previously treated patients; the median number of cycles administered on the oxaliplatin with 5-fluorouracil/leucovorin combination arm was 6.

An acute syndrome of pharyngolaryngeal dysaesthesia seen in 1–2% (grade 3/4) of patients previously untreated for advanced colorectal cancer and the previously treated patients, is characterized by subjective sensations of dysphagia or dyspnoea, without any laryngospasm or bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the infusion of oxaliplatin injection because cold temperature can exacerbate acute neurological symptoms. For patients who develop acute laryngopharyngeal dysaesthesia, during or within the hours following the 2-hour infusion, the next oxaliplatin infusion should be administered over 6 hours.

  • A persistent (>14 days), primarily peripheral, sensory neuropathy that is usually characterized by paraesthesias, dysaesthesias and hypoaesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty in walking from impaired proprioception). These forms of neuropathy occurred in 48% of the study patients receiving oxaliplatin with 5-fluorouracil/leucovorin. Persistent neuropathy can occur without any prior acute neuropathy event. The majority of the patients (80%) who developed grade 3 persistent neuropathy progressed from prior grade 1 or 2 events. These symptoms may improve in some patients upon discontinuation of oxaliplatin.

In the adjuvant colon cancer trial, neuropathy was graded using a prelisted module derived from the neurosensory section of the NCI CTC scale, Version 1, as follows:

 Table 1: NCI CTC grading for neuropathy in adjuvant patients
 

Grade

Definition

Grade 0

No change or none

Grade 1

Mild paraesthesias, loss of deep tendon reflexes

Grade 2

Mild or moderate objective sensory loss, moderate paraesthesias

Grade 3

Severe objective sensory loss or paraesthesias that interfere with function

Grade 4

Not applicable

Peripheral sensory neuropathy was reported in adjuvant patients treated with the oxaliplatin combination with a frequency of 92% (all grades) and 13% (grade 3). At the 28-day follow-up after the last treatment cycle, 60% of all patients had any grade (grade 1=40%, grade 2=16%, grade 3=5%) peripheral sensory neuropathy decreasing to 39% at 6 months follow-up (grade 1=31%, grade 2=7%, grade 3=1%) and 21% at 18 months of follow-up (grade 1=17%, grade 2=3%, grade 3=1%).

In the advanced colorectal cancer studies, neuropathy was graded using a study-specific neurotoxicity scale, which was different from the NCI CTC scale, Version 2.0.

Table 2: Grading scale for paraesthesias/dysaesthesias in advanced colorectal cancer patients
 

Grade

Definition

Grade 1

Resolved and did not interfere with functioning

Grade 2

Interfered with function but not daily activities

Grade 3

Pain or functional impairment that interfered with daily activities

Grade 4

Persistent impairment that is disabling or life-threatening

Overall, neuropathy was reported in patients previously untreated for advanced colorectal cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 74% (all grades) and 7% (grade 3/4) of events. Information regarding reversibility of neuropathy was not available from the trial for patients who had not been previously treated for colorectal cancer.

Patients should be informed of the possibility of persistent symptoms of peripheral sensory neuropathy after the end of the treatment. Localized moderate paraesthesia or paraesthesia that may interfere with functional activities can persist after up to 3 years following treatment cessation in the adjuvant setting.

If neurological symptoms (paraesthesia, dysaesthesia) occur, the following recommended oxaliplatin dosage adjustment should be based on the duration and severity of these symptoms:

  • If symptoms last longer than 7 days and are troublesome, the subsequent oxaliplatin dose should be reduced from 85 to 65 mg/m2 (metastatic setting) or 75 mg/m2 (adjuvant setting).
  • If paraesthesia without functional impairment persists until the next cycle, the subsequent oxaliplatin dose should be reduced from 85 to 65 mg/m2 (metastatic setting) or 75 mg/m2 (adjuvant setting).
  • If paraesthesia with functional impairment persists until the next cycle, oxaliplatin should be discontinued.
  • If these symptoms improve following discontinuation of oxaliplatin therapy, resumption of therapy may be considered.

Neutropenia

Grade 3 or 4 neutropenia occurred in 41-44% of patients with colorectal cancer treated with oxaliplatin combination with 5-flurouracil (5-FU) and leucovorin compared to 5% with 5-FU plus leucovorin alone. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin, including fatal outcomes. Delay oxaliplatin until neutrophils are ≥ 1.5 x 109 /L. Withhold oxaliplatin for sepsis or septic shock. Dose reduce oxaliplatin after recovery from Grade 4 neutropenia or febrile neutropenia.

Pulmonary Toxicity

Oxaliplatin has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnoea was 7.4% (any grade) and <1% (grade 3) with no grade 4 events in the oxaliplatin plus infusional 5-fluorouracil/leucovorin arm, compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5-fluorouracil/leucovorin alone arm in adjuvant colon cancer patients. In this study, 1 patient died from eosinophilic pneumonia in the oxaliplatin combination arm. The combined incidence of cough, dyspnoea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the oxaliplatin plus 5-fluorouracil/leucovorin arm, compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-fluorouracil/leucovorin arm of unknown duration for patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, dyspnoea, crackles or radiological pulmonary infiltrates, oxaliplatin injection should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.

Hepatotoxicity

Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% versus 34%) and alkaline phosphatase (42% versus 20%) was observed more commonly in the oxaliplatin combination arm than in the control arm. The incidence of increased bilirubin was similar in both arms. Changes noted on liver biopsies included peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered and, if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases.

Cardiovascular Toxicity

QT prolongation and ventricular arrhythmias including fatal Torsade de Pointes have been reported in postmarketing experiences following oxaliplatin administration. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating oxaliplatin and monitor these electrolytes periodically during therapy. Avoid oxaliplatin in patients with congenital long QT syndrome

Rhabdomyolysis

Rhabdomyolysis, including fatal cases, has been reported in patients treated with oxaliplatin. Discontinue oxaliplatin if any signs or symptoms of rhabdomyolysis occur.

Thromboembolism

The incidence of thromboembolic events in adjuvant patients with colon cancer was 6% (1.8% grade 3/4) in the infusional 5-fluorouracil/leucovorin arm and 6% (1.2% grade 3/4) in the oxaliplatin and infusional 5-fluorouracil/leucovorin combined arm, respectively. The incidence was 6 and 9% of the patients previously untreated for advanced colorectal cancer and previously treated patients in the oxaliplatin and 5-fluorouracil/leucovorin combination arm, respectively.

Reversible Posterior Leukoencephalopathy Syndrome

Cases of reversible posterior leukoencephalopathy syndrome (RPLS; also known as PRES ) has been observed in clinical trials (< 0.1%) and postmarketing experience. RPLS is a rare, reversible and rapidly evolving neurological condition, which can include seizure, hypertension, headache, confusion, blindness, and other visual and neurological disturbances. Diagnosis of RPLS is based upon confirmation by brain imaging, preferably magnetic resonance imaging (MRI).

Nausea, Vomiting, Diarrhoea, Dehydration and Haematological Changes

Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic and/or therapeutic anti-emetic therapy.

Dehydration, paralytic ileus, intestinal obstruction, hypokalaemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis, particularly when combining oxaliplatin with 5-fluorouracil.

If haematological toxicity occurs (neutrophils <1.5 × 109/l or platelets <50 × 109/l), administration of the next course of therapy should be postponed until the haemotological values return to acceptable levels. A full blood count with white cell differentials should be performed prior to start of therapy and before each subsequent course.

Patients must be adequately informed of the risk of diarrhoea/emesis, mucositis/stomatitis and neutropenia after oxaliplatin and 5-fluorouracil administration so that they can urgently contact their treating physician for appropriate management.

If mucositis/stomatitis occurs with or without neutropenia, the next treatment should be delayed until recovery from mucositis/stomatitis to grade 1 or less and/or until the neutrophil count is 1.5 × 109/l.

For oxaliplatin combined with 5-fluorouracil (with or without folinic acid), the usual dose adjustments for 5-fluorouracil associated toxicities should apply.

If grade 4 diarrhoea, grade 3–4 neutropenia (neutrophils <1.0 × 109/l), grade 3–4 thrombocytopenia (platelets <50 × 109/l) occur, the dose of oxaliplatin should be reduced from 85 to 65 mg/m² (metastatic setting) or 75 mg/m² (adjuvant setting), in addition to any 5-fluorouracil dose reductions required.

Immunosuppressant Effects/Increased Susceptibility to Infections

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including oxaliplatin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving oxaliplatin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Recommended Laboratory Tests

Standard monitoring of the white blood cell count with differential, haemoglobin, platelet count and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each oxaliplatin injection.

There have been reports, while under study and from postmarketing surveillance, of prolonged prothrombin time and international normalized ratio (INR) occasionally associated with haemorrhage in patients who received oxaliplatin injection plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving oxaliplatin injection plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.

Renal Impairment

In patients with normal renal function or mild to moderate renal impairment, the recommended dose of oxaliplatin is 85 mg/m2. In patients with severe renal impairment, the initial recommended oxaliplatin dose should be reduced to 65 mg/m2.

The combination of oxaliplatin injection and 5-fluorouracil/leucovorin should be used with caution in patients with pre-existing renal impairment since the primary route of platinum elimination is renal. Clearance of ultrafilterable platinum is decreased in patients with mild, moderate and severe renal impairment. A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.

Hepatic Impairment 

In a Phase I study including patients with several levels of hepatic impairment, the frequency and severity of hepatobiliary disorders appeared to be related to progressive disease and impaired liver function tests at baseline. No specific dose adjustment for patients with abnormal liver function tests was performed during clinical development.

Fertility

Male patients treated with oxaliplatin are advised not to father a child during and up to 6 months after treatment and to seek advice on conservation of sperm prior to treatment because oxaliplatin may have an anti-fertility effect, which could be irreversible.

Women should not become pregnant during treatment with oxaliplatin and should use an effective method of contraception

Pregnancy

Pregnancy Category D

To date, there is no available information on safety of use in pregnant women. In animal studies, reproductive toxicity was observed. Consequently, oxaliplatin is not recommended during pregnancy and in women of childbearing potential not using contraceptive measures.

The use of oxaliplatin should only be considered after suitably appraising the patient of the risk to the foetus, and with the patient's consent.

Appropriate contraceptive measures must be taken during and after cessation of therapy for up to 4 months for women and 6 months for men.

Oxaliplatin may have an anti-fertility effect.

Lactation

Excretion in breast milk has not been studied. Breastfeeding is contraindicated during oxaliplatin therapy.

Paediatric Use 

The effectiveness of oxaliplatin in children has not been established.

Geriatric Use

No significant effect of age on the clearance of ultrafilterable platinum has been observed.

No increase in severe toxicities was observed when oxaliplatin was used as a single agent or in combination with 5-fluorouracil in patients over the age of 65. In consequence no specific dose adaptation is required for elderly patients.

Patients ≥ 65 years of age receiving the oxaliplatin combination therapy experienced more grade 3-4 granulocytopenia than patients < 65 years of age (45% versus 39%). The incidence of diarrhea, dehydration, hypokalemia, leucopenia, fatigue and syncope were higher in patients ≥65 years old. No adjustment to starting dose was required in patients ≥65 years old.

Effects on the Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However oxaliplatin treatment resulting in an increase risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect gait and balance may lead to a minor or moderate influence on the ability to drive and use machines.

Vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), may affect a patient's ability to drive and use machines. Therefore, patients should be warned of the potential effect of these events on the ability to drive or use machines.

Undesirable Effects 

The most frequent adverse events of oxaliplatin in combination with 5-fluorouracil/folinic acid (5-FU/FA) were gastrointestinal (diarrhoea, nausea, vomiting and mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute and dose-cumulative peripheral sensory neuropathy). Overall, these adverse events were more frequent and severe with oxaliplatin and the 5-FU/FA combination than with 5-FU/FA alone.

The frequencies reported in Table 3 below are derived from clinical trials in the metastatic and adjuvant settings (having included 416 and 1,108 patients, respectively, in the oxaliplatin plus 5-FU/FA treatment arms) and from postmarketing experience.  

Frequencies in this table are defined using the following convention: very common (1/10), common (1/100 to <1/10), uncommon="" 000="" to="" rare="" very="" not="" known="" cannot="" be="" estimated="" from="" the="" available="" p="">

MedDRA Organ System Class

Very Common

Common

Uncommon

Rare

Investigations

 Hepatic enzyme increase

 Blood alkaline phosphatase increase

 Blood bilirubin increase

 Blood lactate dehydrogenase increase

 Weight increase (adjuvant setting)

 Blood creatinine increase

 Weight decrease (metastatic setting)

 

 

Blood and Lymphatic System Disorders

 Anaemia

 Neutropenia

 Thrombocytopenia  Leucopenia

 Lymphopenia

 

 

 Immunoallergic thrombocytopenia

 Haemolytic anaemia

Nervous System Disorders

 Peripheral sensory neuropathy

 Sensory disturbance

 Dysgeusia

 Headache

Dizziness

 Motor neuritis

 Meningism

 

 Dysarthria

Eye Disorders

 

 Conjunctivitis

 Visual disturbance

 

 Visual acuity reduced transiently

 Visual field disturbances

 Optic neuritis

 Transient vision loss, reversible following therapy discontinuation

Ear and Labyrinth Disorders

 

 

 Ototoxicity

 Deafness,

 Transient vision loss, reversible following therapy discontinuation

Respiratory, Thoracic and Mediastinal Disorders

 Dyspnoea

 Cough

 Hiccups

 

 Interstitial lung disease, sometimes fatal

 Pulmonary fibrosis

Gastrointestinal Disorders

 Nausea

 Diarrhoea

 Vomiting

 Stomatitis/ mucositis

 Abdominal pain

 Constipation

 Dyspepsia

Gastro esophageal reflux

 Gastrointestinal haemorrhage

 Rectal haemorrhage

 Ileus

 Intestinal obstruction

 Colitis, including Clostridium difficile-associated diarrhoea

Renal and Urinary Disorders

 

Haematuria

 Dysuria

 Micturition frequency abnormal

 

 

Skin and Subcutaneous Tissue Disorders

 Skin disorder

 Alopecia

 Skin exfoliation (i.e., hand and foot syndrome)

 Rash erythematous

 Rash

 Hyperhidrosis

 Nail disorder

 

 

Musculoskeletal and Connective Tissue Disorders

 Back pain

 Arthralgia

 Bone pain

 

 

Metabolism and Nutrition Disorders

 Anorexia

 Glycaemia abnormalities

 Hypokalaemia

 Natraemia abnormalities

 Dehydration

 Metabolic acidosis

 

Infections and Infestations

Infection

 Rhinitis

 Upper respiratory tract infection

 Febrile neutropenia/neutropenic sepsis

 

 

Vascular Disorders

 Epistaxis

 Haemorrhage

 Flushing

Deep-vein thrombosis

 Pulmonary embolism

 Hypertension

 

 

General Disorders and Administration Site Conditions

 Fatigue

 Fever++

 Asthenia

 Pain

 Injection site reaction+++

 

 

 

Immune System Disorders

 Allergy/allergic reaction+

 

 

 

Psychiatric Disorders

 

 Depression

 Insomnia

 Nervousness

 

+ Common allergic reactions such as skin rash (particularly urticaria), conjunctivitis, rhinitis. Common anaphylactic reactions, including broncospasm, sensation of chest pain, angioedema, hypotension and anaphylactic shock.

++ Very common fever, rigors (tremors), either from infection (with or without febrile neutropenia) or possibly from immunological mechanism.

+++ Injection site reaction, including local pain, redness, swelling and thrombosis has been reported. Extravasation may also result in local pain and inflammation, which may be severe and lead to complications, including necrosis, especially when oxaliplatin is infused through a peripheral vein.

Blood and Lymphatic System Disorders

Incidence by patient (%), by grade

Oxaliplatin and 5-FU/FA 85 mg/m² every 2 weeks

Metastatic Setting

Adjuvant Setting

All grades

Grade 3

Grade 4

All grades

Grade 3

Grade 4

Anaemia

82.2

3

<1

75.6

0.7

0.1

Neutropenia

71.4

28

14

78.9

28.8

12.3

Thrombocytopenia

71.6

4

<1

77.4

1.5

0.2

Febrile neutropenia

5.0

3.6

1.4

0.7

0.7

0.0

Neutropenic sepsis

1.1

0.7

0.4

1.1

0.6

0.4

Immune System Disorders

Incidence of allergic reactions by patient (%), by grade

Oxaliplatin and 5-FU/FA 85 mg/m² every 2 weeks

Metastatic Setting

Adjuvant Setting

All grades

Grade 3

Grade 4

All grades

Grade 3

Grade 4

Allergic reactions/allergy

9.1

1

<1

10.3

2.3

0.6

Nervous System Disorders

The dose-limiting toxicity of oxaliplatin is neurological. It involves a sensory peripheral neuropathy characterized by dysaesthesia and/or paraesthesia of the extremities with or without cramps, often triggered by the cold. These symptoms occur in up to 95% of patients treated. The duration of these symptoms, which usually regress between courses of treatment, increases with the number of treatment cycles.

The onset of pain and/or a functional disorder are indications, depending on the duration of the symptoms or dose adjustment or even treatment discontinuation.

This functional disorder includes difficulties in executing delicate movements and is a possible consequence of sensory impairment. The risk of occurrence of persistent symptoms for a cumulative dose of 850 mg/m² (10 cycles) is approximately 10% and 20% for a cumulative dose of 1,020 mg/m² (12 cycles).

In the majority of cases, the neurological signs and symptoms improve or totally recover when treatment is discontinued. In the adjuvant setting of colon cancer, 6 months after treatment cessation, 87% of patients had no or mild symptoms. After up to 3 years of follow-up, about 3% of patients presented either with persisting localized paraesthesias of moderate intensity (2.3%) or with paraesthesias that may interfere with functional activities (0.5%).

Acute neurosensory manifestations have been reported. They start within hours of administration and often occur on exposure to cold. They usually present as transient paraesthesia, dysaesthesia and hypoaesthesia. An acute syndrome of pharyngolaryngeal dysaesthesia occurs in 1–2% of patients, and is characterized by subjective sensations of dysphagia or dyspnoea/feeling of suffocation, without any objective evidence of respiratory distress (no cyanosis or hypoxia) or of laryngospasm or bronchospasm (no stridor or wheezing). Although antihistamines and bronchodilators have been administered in such cases, the symptoms are rapidly reversible even in the absence of treatment. Prolongation of the infusion helps to reduce the incidence of this syndrome. Occasionally, other symptoms that have been observed include jaw spasm/muscle spasms/muscle contractions — involuntary/muscle twitching/myoclonus, coordination abnormal/gait abnormal/ ataxia/ balance disorders, and throat or chest tightness/ pressure/ discomfort/pain. In addition, cranial nerve dysfunctions may be associated, or also occur as an isolated event such as ptosis, diplopia, aphonia/dysphonia/hoarseness (sometimes described as vocal cord paralysis), abnormal tongue sensation or dysarthria (sometimes described as aphasia), trigeminal neuralgia/facial pain/eye pain, decrease in visual acuity, and visual field disorders. Other neurological symptoms such as dysarthria, loss of deep-tendon reflex and Lhermitte's sign, cranial nerve palsies and fasciculations were reported during treatment with oxaliplatin. Isolated cases of optic neuritis have been reported.

Gastrointestinal Disorders

Incidence by patient (%), by grade

Oxaliplatin and 5-FU/FA 85 mg/m² every 2 weeks

Metastatic Setting

Adjuvant Setting

All grades

Grade 3

Grade 4

All grades

Grade 3

Grade 4

Nausea

69.9

8

<1

73.7

4.8

0.3

Diarrhoea

60.8

9

2

56.3

8.3

2.5

Vomiting

49.0

6

1

47.2

5.3

0.5

Mucositis/stomatitis

39.9

4

<1

42.1

2.8

0.1

Prophylaxis and/or treatment with potent anti-emetic agents are indicated.

Dehydration, paralytic ileus, intestinal obstruction, hypokalaemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis, particularly when combining oxaliplatin with 5-fluorouracil.

Hepatobiliary Disorders

Very rare (<1/10,000)

Liver sinusoidal obstruction syndrome, also known as veno-occlusive disease of the liver, or pathological manifestations related to such liver disorder, including peliosis hepatis, nodular regenerative hyperplasia and perisinusoidal fibrosis. Clinical manifestations may be portal hypertension and/or increased transaminases.

Renal and Urinary Disorders

Very rare (<1/10,000)

Acute tubular necrosis, acute interstitial nephritis and acute renal failure.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of oxaliplatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole

Angio-oedema, anaphylactic shock.

Central and Peripheral Nervous System Disorders

Loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations, convulsion.

Liver and Gastrointestinal System Disorders

Severe diarrhoea/vomiting resulting in hypokalaemia, colitis (including Clostridium difficile-associated diarrhoea), metabolic acidosis; ileus; intestinal obstruction, pancreatitis; veno-occlusive disease of the liver (also known as sinusoidal obstruction syndrome); and perisinusoidal fibrosis, which rarely may progress.

Hearing and Vestibular System Disorders

Deafness.

Platelet, Bleeding and Clotting Disorders

Immuno-allergic thrombocytopenia.

Prolongation of prothrombin time and of INR in patients receiving anticoagulants.

Red Blood Cell Disorders

Haemolytic uraemic syndrome, immuno-allergic haemolytic anaemia.

Renal Disorders

Acute tubular necrosis, acute interstitial nephritis and acute renal failure.

Respiratory System Disorders

Pulmonary fibrosis, and other interstitial lung diseases (sometimes fatal).

Vision Disorders

Decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following therapy discontinuation).

Undesirable Effects 

The most frequent adverse events of oxaliplatin in combination with 5-fluorouracil/folinic acid (5-FU/FA) were gastrointestinal (diarrhoea, nausea, vomiting and mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute and dose-cumulative peripheral sensory neuropathy). Overall, these adverse events were more frequent and severe with oxaliplatin and the 5-FU/FA combination than with 5-FU/FA alone.

The frequencies reported in Table 3 below are derived from clinical trials in the metastatic and adjuvant settings (having included 416 and 1,108 patients, respectively, in the oxaliplatin plus 5-FU/FA treatment arms) and from postmarketing experience.  

Frequencies in this table are defined using the following convention: very common (1/10), common (1/100 to <1/10), 000="" available="" be="" cannot="" estimated="" from="" known="" not="" p="" rare="" the="" to="" uncommon=" " very="">If you experience any side effects, talk to your doctor or pharmacist or write to

drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024.  

 

By reporting side effects, you can help provide more information on the safety of this product.

Overdosage 

There is no known antidote for oxaliplatin injection overdose. In addition to thrombocytopenia, the anticipated complications of an oxaliplatin injection overdose include hypersensitivity reaction, myelosuppression, nausea, vomiting, diarrhoea and neurotoxicity.

In cases of overdose, exacerbation of adverse events can be expected. Monitoring of haematological parameters should be initiated and symptomatic treatment given.

Incompatibility

The diluted medicinal product should not be mixed with other medications in the same infusion bag or infusion line. Oxaliplatin can be co-administered with folinic acid.

  • DO NOT mix with alkaline medicinal products or solutions, in particular 5-fluorouracil, folinic acid preparations containing trometamol as an excipient and trometamol salts of other drugs. Alkaline drugs or solutions will adversely affect the stability of oxaliplatin.
  • DO NOT dilute oxaliplatin with saline or other solutions containing chloride ions (including calcium, potassium or sodium chloride).
  • DO NOT mix with other medicinal products in the same infusion bag or infusion line.
  • DO NOT use injection equipment containing aluminium.

Shelf-Life

2 years

Storage and Handling Instructions

Store below 25°C. Protect from light. Do not freeze.

Packaging Information

X-PLAT 50 mg:  Vial of 25 ml

X-PLAT 100 mg: Vial of 50 ml

Last Updated: Nov 2017

Last Reviewed: Jan 2018

 

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