1. Name Of The Medicinal Product
Oxaliplatin Hospira 5 mg/ml Powder for Solution for Infusion
2. Qualitative And Quantitative Composition
One ml of reconstituted solution contains oxaliplatin 5 mg.
50 mg vial: each vial contains 50 mg oxaliplatin for reconstitution in 10 ml of solvent.
100 mg vial: each vial contains 100 mg oxaliplatin for reconstitution in 20 ml of solvent.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for solution for infusion.
A white to off-white powder
4. Clinical Particulars
4.1 Therapeutic Indications
Oxaliplatin in combination with 5-fluorouracil (5-FU) and folinic acid (FA) is indicated for:
• Adjuvant treatment of stage III (Duke's C) colon cancer after complete resection of primary tumour
• Treatment of metastatic colorectal cancer.
4.2 Posology And Method Of Administration
The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist personnel with knowledge of the medicinal product used, in conditions that guarantee the integrity of the medicinal product, the protection of the environment and in particular the protection of the personnel handling the medicinal products, in accordance with hospital policy. It requires a preparation area reserved for this purpose. It is forbidden to smoke, eat or drink in this area.
Posology
FOR ADULTS ONLY
The recommended dose for oxaliplatin in adjuvant setting is 85 mg/m² intravenously repeated every 2 weeks for 12 cycles (6 months).
The recommended dose for oxaliplatin in treatment of metastatic colorectal cancer is 85 mg/m² intravenously repeated every 2 weeks.
Dosage given should be adjusted according to tolerability (see section 4.4).
Oxaliplatin should always be administered before fluoropyrimidines – i.e. 5 fluorouracil (5 FU).
Oxaliplatin is administered as a 2- to 6-hour intravenous infusion in 250 to 500 ml of glucose 5% solution (50 mg/ml) 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 oxaliplatin dose of 85 mg/m2.
Oxaliplatin was mainly used in combination with continuous infusion 5-fluorouracil based regimens. For the two-weekly treatment schedule 5-fluorouracil regimens combining bolus and continuous infusion were used.
Special Populations
- Renal impairment:
Oxaliplatin has not been studied in patients with severe renal impairment (See section 4.3).
In patients with moderate renal impairment, treatment may be initiated at the normally recommended dose (see section 4.4). There is no need for dose adjustment in patients with mild renal dysfunction.
- Hepatic impairment:
In a phase I study including patients with several levels of hepatic impairment, 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.
- Elderly patients:
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.
Method of administration
Oxaliplatin is administered by intravenous infusion.
The administration of oxaliplatin does not require hyperhydration.
Oxaliplatin diluted in 250 to 500 ml of glucose 5% solution (50 mg/ml) to give a concentration not less than 0.2 mg/ml must be infused either via a peripheral vein or central venous line over 2 to 6 hours. Oxaliplatin infusion must always precede the administration of 5-fluorouracil.
In the event of extravasation, administration must be discontinued immediately.
Instructions for use:
Oxaliplatin must be reconstituted and further diluted before use. Only glucose 5% (50 mg/ml) diluent is to be used to reconstitute and then dilute the freeze-dried medicinal product. (See section 6.6).
4.3 Contraindications
Oxaliplatin is contraindicated in patients who
- have a hypersensitivity to oxaliplatin or to the excipient.
- are breast feeding.
- have myelosuppression prior to starting first course, as evidenced by baseline neutrophils <2x109/l and/or platelet count of <100x109l.
- have a peripheral sensitive neuropathy with functional impairment prior to first course.
- have a severely impaired renal function (creatinine clearance less than 30 ml/min).
4.4 Special Warnings And Precautions For Use
Oxaliplatin should only be used in specialised departments of oncology and should be administered under the supervision of an experienced oncologist.
Due to limited information on safety in patients with moderately impaired renal function, administration should only be considered after suitable appraisal of the benefit/risk for the patient.
In this situation, renal function should be closely monitored and dose adjusted according to toxicity.
Patients with a history of allergic reaction to platinum compounds should be monitored for allergic symptoms. In case of an anaphylactic-like reaction to oxaliplatin, the infusion should be immediately discontinued and appropriate symptomatic treatment initiated. Oxaliplatin rechallenge is contra-indicated.
In case of oxaliplatin extravasation, the infusion must be stopped immediately and usual local symptomatic treatment initiated.
Neurological toxicity of oxaliplatin should be carefully monitored, especially if co-administered with other medicinal products with specific neurological toxicity. A neurological examination should be performed before each administration and periodically thereafter.
For patients who develop acute laryngopharyngeal dysaesthesia (see section 4.8), during or within the hours following the 2-hour infusion, the next oxaliplatin infusion should be administered over 6 hours.
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 seven 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.
Patients should be informed of the possibilities of persistent symptoms of peripheral sensory neuropathy after the end of the treatment. Localised moderate parasthesias or parasthesias that may interfere with functional activities can persist after up to 3 years following treatment cessation in the adjuvant setting.
Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic and/or therapeutic anti-emetic therapy (see section 4.8.).
Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with 5-fluorouracil.
If haematological toxicity occurs (neutrophils < 1.5x109/l or platelets < 50x109/l), administration of the next course of therapy should be postponed until haematological values return to acceptable levels. A full blood count with white cell differential 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 9/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 < 1.0x109/l), grade 3-4 thrombocytopenia (platelets < 50x109/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.
In the case of unexplained respiratory symptoms such as non-productive cough, dyspnoea, crackles or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further pulmonary investigations exclude an interstitial lung disease (see section 4.8).
In cases of abnormal test results of liver function or portal hypertension, which obviously not depend on liver metastases, very rare cases of drug induced hepatic vascular disorder should be considered.
For use in pregnant women see section 4.6.
Genotoxic effects were observed with oxaliplatin in the preclinical studies. Therefore 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 (see section 4.6).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
In patients who have received a single dose of 85 mg/m2 of oxaliplatin, immediately before administration of 5-fluorouracil, no change in the level of exposure to 5-fluorouracil has been observed.
In vitro, no significant displacement of oxaliplatin binding to plasma proteins has been observed with the following agents: erythromycin, salicylates, granisetron, paclitaxel, and sodium valproate.
4.6 Pregnancy And Lactation
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 during 4 months for women and 6 months for men.
Excretion in breast milk has not been studied. Breast-feeding is contra-indicated during oxaliplatin therapy.
Oxaliplatin may have an anti-fertility effect (see section 4.4).
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machinery have been performed. However, oxaliplatin treatment resulting in an increased 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.
4.8 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 5-FU/FA combination than with 5-FU/FA alone.
The frequencies reported in the table below are derived from clinical trials in metastatic and adjuvant settings (having included 416 and 1108 patients respectively in the oxaliplatin + 5-FU/FA treatment arms) and from post marketing experience.
Frequencies in this table are defined using the following convention: very common (>1/10), common (> 1/100, <1/10), uncommon (> 1/1000, > 1/10000,
Further details are given after the table.
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* See detailed section below
** See section 4.4 'Special warnings and precaution for use'
+ Common allergic reactions such as skin rash (particularly urticaria), conjunctivitis, rhinitis. Common anaphylactic reactions, including broncospasm, angioedema, hypotension and anaphylactic shock.
++ Very common fever, either from infection (with or without febrile neutropenia) or isolated fever from immunological mechanism.
+++ Extravasation may result in local pain and inflammation which may be severe and lead to complications, especially when oxaliplatin is infused through a peripheral vein (see 4.4).
Hepatobiliar disorders
Very rare (<1/10,000):
Liver sinusoidal obstruction syndrome, also known as veno-occlusive liver disease or pathological manifestations related to such liver disorders, including peliosis hepatis, nodular regenerative hyperplasia, perisinusoidal fibrosis. Clinical manifestations may be portal hypertension and/or elevation of transaminases.
Renal and urinary disorders
Very rare (<1/10,000):
Acute tubulo-interstitial nephropathy leading to acute renal failure.
Haematological toxicity:
Incidence by patient (%), by grade
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Digestive toxicity:
Incidence by patient (%), by grade
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Prophylaxis and/or treatment with potent antiemetic agents is indicated.
Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea/emesis particularly when combining oxaliplatin with 5-fluorouracil (see section 4.4).
Nervous system:
The dose limiting toxicity of oxaliplatin is neurological. It involves a sensory peripheral neuropathy characterised by dysaesthesia and/or parasthesia 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, for dose adjustment, or even treatment discontinuation (see section 4.4).
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 1020 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 paresthesias of moderate intensity (2.3%) or with paresthesias that may interfere with functional activities (0.5%).
Acute neurosensory manifestations (see section 5.3) have been reported. They start within hours of administration and often occur on exposure to cold. They usually present as transient paresthesia, dysesthesia and hypoesthesia. An acute syndrome of pharyngolaryngeal dysesthesia occurs in between 1% - 2%, and is characterised 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);abnormal tongue sensation, dysarthria and a feeling of chest pressure have also been observed. 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 (see section 4.4). Occassionally other symptoms that have been observed include jaw spasm/muscle spasms/muscle spasms/muscle contractions – involuntary/muscle twitching/myoclonus, coordination abnormal. In addition, cranial nerve dysfunctions may be associated, or also occur as an isolated event.
Other neurological symptoms such as dysarthria, loss of deep tendon reflex and Lhermitte's sign were reported during treatment with oxaliplatin. Isolated cases of optic neuritis have been reported.
Allergic reactions:
Incidence by patient (%), by grade
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4.9 Overdose
There is no known antidote to oxaliplatin. In cases of overdose, exacerbation of adverse events can be expected. Monitoring of haematological parameters should be initiated and symptomatic treatment given.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Other antineoplastic agents, platinum compounds.
ATC code : L01XA 03
Oxaliplatin is an antineoplastic drug 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 is a single enantiomer, the Cis -[oxalato ( trans-l-1,2- DACH ) platinum].
Oxaliplatin exhibits a wide spectrum of both in vitro cytotoxicity and in vivo antitumour 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.
A synergistic cytotoxic action has been observed in combination with 5-fluorouracil both in vitro and in vivo.
Studies on the mechanism of action of oxaliplatin, although not completely elucidated, show that the aqua-derivatives resulting from the biotransformation of oxaliplatin, interact with DNA to form both inter and intra-strand cross-links, resulting in the disruption of DNA synthesis leading to cytotoxic and antitumour effects.
In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85mg/m2 repeated every two weeks) combined with 5-fluorouracil/folinic acid is reported in three clinical studies:
- In front-line treatment, the 2-arm comparative phase III EFC2962 study randomized patients either to 5-fluorouracil/folinic acid alone (LV5FU2) or the combination of oxaliplatin with 5-fluorouracil/folinic (FOLFOX4, N=210)
- In pretreated patients the comparative 3-arm EFC4584 study randomized patients refractory to an irinotecan (CPT-11) + 5-fluorouracil/folinic combination either to 5-fluorouracil/folinic acid alone (LV5FU2), oxaliplatin single agent, or combination of oxaliplatin with 5-fluorouracil/folinic (FOLFOX4, N=275)
- Finally, the non controlled phase II EFC2964 study included patients refractory to 5-fluorouracil/folinic acid alone, that were treated with the oxaliplatin and 5-fluorouracil/folinic acid combination (FOLFOX4, N=57)
The two randomized clinical trials, EFC2962 in front-line therapy and EFC4584 in pretreated patients, demonstrated a significantly higher response rate and a prolonged progression free survival (PFS)/time to progression (TTP) as compared to treatment with 5-fluorouracil/folinic acid alone. IN EFC 4584 performed in refractory pretreated patients, the difference in median overall survival (OS) between the combination of oxaliplatin and 5-FU/FA did not reach statistical significance.
Response rate under FOLFOX4 versus LV5FU2
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