Medicinal Products

ELOXATINE 5 mg / mL

Generic drug of the therapeutic class: Oncology and Hematology
active ingredients: Oxaliplatin
laboratory: Sanofi-Aventis France

Solution for solution for IV infusion
Box of 1 bottle of 20 ml
All forms

Indication

Oxaliplatin in combination with 5-fluorouracil (5FU) and folinic acid (AF) is indicated in:

· Adjuvant treatment of stage III colon cancer (stage C Dukes) after complete resection of the initial tumor,

· The treatment of metastatic colorectal cancers.

Dosage ELOXATINE 5 mg / mL Concentrate for solution for infusion IV Box of 1 vial of 20 ml

The preparation of injectable cytotoxic solutions must be carried out by specialized and trained personnel, with knowledge of the drugs used, under conditions ensuring the integrity of the drug, the protection of the environment and especially the protection of the personnel handling them. according to the hospital conduct. It requires a preparation room reserved for this purpose. It is forbidden to smoke, eat or drink in this room (see section Instructions for use, handling and disposal ).

Dosage

RESERVED FOR ADULTS

The recommended dose of oxaliplatin as adjunctive therapy is 85 mg / m 2 intravenously repeated every two weeks for 12 cycles (6 months).

The recommended dose of oxaliplatin for the treatment of metastatic colorectal cancer is 85 mg / m 2 intravenously repeated every two weeks until disease progression or onset of unacceptable toxicity.

The dose will be adjusted according to the tolerance (see section Warnings and precautions for use ).

Administration of oxaliplatin should always precede that of fluoropyrimidines, that is, 5-fluorouracil (5-FU).

Oxaliplatin is administered as a 2 to 6 hour IV infusion in 250 to 500 ml of 5% glucose solution (50 mg / ml) to obtain a concentration of between 0.2 mg / ml and 0.7 mg / ml; 0.7 mg / ml corresponds to the highest concentration observed in clinical practice for a dose of 85 mg / m 2 of oxaliplatin.

Oxaliplatin was most often administered in combination with fluorouracil (5-FU) as a continuous infusion. For repeated treatment every 2 weeks, a regimen with 5-fluorouracil (5-FU) bolus and continuous infusion was used.

Populations at risk

· Renal insufficiency:

Oxaliplatin should not be administered in patients with severe renal impairment (see sections Contraindications and Pharmacokinetic Properties ).

In patients with mild to moderate impairment of renal function, the recommended dose of oxaliplatin is 85 mg / m 2 .

(See sections Warnings and Precautions and Pharmacokinetic Properties ).

· Hepatic impairment:

In a phase I study that included patients with varying degrees of hepatic impairment, the frequency and severity of hepatobiliary disease appeared to be related to disease progression and initial abnormalities of liver function.

During clinical development, no dose adjustment was performed in patients with liver function abnormalities.

· Elderly subjects:

Severe toxicity of oxaliplatin alone or in combination with 5-fluorouracil (5-FU) has not been observed in subjects over 65 years of age. As a result, no adjustment of the dose is necessary in the elderly.

· Pediatric patients:

There is no indication to justify the use of oxaliplatin in children. The efficacy of oxaliplatin alone in children with solid tumors has not been established (see section 5.1 ).

Administration mode

Oxaliplatin is administered as an intravenous infusion.

Administration of oxaliplatin does not require hyperhydration.

Oxaliplatin diluted in 250-500 ml of 5% glucose solution (50 mg / ml), in order to obtain a concentration greater than or equal to 0.2 mg / ml, must be perfused by the central venous or venous route. peripheral for a period of 2 to 6 hours and always prior to 5-fluorouracil (5-FU).

In case of extravasation, the administration must be stopped immediately.

Handling modalities

Oxaliplatin should be diluted before administration. Only 5% glucose solution (50 mg / ml) should be used for dilution of the solution for infusion (see section Instructions for use, handling and disposal ).

Against indications

Oxaliplatin is contraindicated in patients:

· Having a known history of hypersensitivity to oxaliplatin,

· Who are breastfeeding,

· With bone marrow failure before the first treatment cycle (neutrophils <2x10 9 / l and / or platelets <100x10 9 / l),

· Presenting peripheral sensory neuropathy with functional impairment before the first treatment cycle,

· With severe renal impairment (creatinine clearance <30 ml / min). (see section Pharmacokinetic properties ).

Eloxatin side effects

The most common adverse events in the combination of oxaliplatin with 5-fluorouracil / folinic acid (5-FU / AF) are gastrointestinal (diarrhea, nausea, vomiting and mucositis), hematologic (neutropenia, thrombocytopenia) and neurological (acute sensory peripheral neuropathy and dose-cumulative).

Overall, these adverse events were more frequent and severe with oxaliplatin in combination with 5-FU / AF than with 5-FU / AF alone.

The frequencies presented in the table below are derived from clinical studies in metastatic treatment and adjuvant therapy (including 416 and 1108 patients in the oxaliplatin + 5-FU / AF arm) and experience since the the market.

The frequencies mentioned in the table have been defined using the following criteria: very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10000, <1/1000), very rare (<1/10000), and of undetermined frequency (can not be estimated from the available data).

Further information is given after the table.

Frequency

Very common

Frequent

Little

Rare

Class-organ system

frequent

investigations

· Elevation of liver enzymes

· Elevation of alkaline phosphatases

· Elevation of bilirubin

· Elevation of LDH

· Weight gain (adjuvant treatment)

· Elevation of creatinine

· Weight loss (metastatic treatment)

Hematological and lymphatic system disorders *

· Anemia

· Neutropenia

· Thrombocytopenia

· Leukopenia

· Lymphopenia

· Febrile neutropenia

· Immune allergic thrombocytopenia

· Hemolytic anemia

Nervous system disorders *

· Sensory peripheral neuropathy

Sensory disorders

· Alteration of taste

· Headache

· Dizziness

· Motor neuritis

· Meningism

· Dysarthria

· Posterior reversible leukoencephalopathy Synd syndrome (SLPR)

(see section 4.4)

Eye disorders

· Conjunctivitis

· Visual disturbances

· Transient decrease in visual acuity

· Visual field disorders

· Optic neuritis

· Temporary loss of vision, reversible upon discontinuation of treatment

Affections of the ear and labyrinth

· Ototoxicity

· Deafness

Respiratory, thoracic and mediastinal disorders

· Dyspnea

· Cough

· Epistaxis

· Hiccup

· Pulmonary embolism

Interstitial pneumonitis, sometimes fatal

· Pulmonary fibrosis **

Gastrointestinal disorders *

· Nausea

· Diarrhea

· Vomiting

· Stomatitis / Mucites

· Abdominal pain

· Constipation

· Dyspepsia

· Gastroesophageal reflux

· Gastrointestinal bleeding

· Rectorragies

· Ileus

· Intestinal obstruction

· Colitis including Clostridium difficile diarrhea

· Pancreatitis

Renal and urinary disorders

· Hematuria

· Dysuria

· Frequent and abnormal urination

Skin and subcutaneous tissue disorders

· Skin disorders

· Alopecia

· Skin exfoliation (ie hand-foot syndrome)

· Rash erythematosus

· Rash

· Hypersudation

· Dagger disorders

Musculoskeletal and systemic disorders

· Back pain

· Arthralgia

· Bone pain

Metabolism and nutrition disorders

· Anorexia

· Hyperglycemia

· Hypokalemia

· Hypernatremia

· Dehydration

· Metabolic acidosis

Infections and infestations *

· Infection

· Rhinitis

· Upper respiratory tract infection

· Septic neutropenia

Vascular disorders

· Haemorrhages

· Flushing

· Deep thrombophlebitis

· Hypertension

General disorders and administration site conditions

· Tired

· Fever ++

· Asthenia

· Pain

· Injection site reaction +++

Immune system disorders *

· Allergy / allergic reactions +

Psychiatric disorders

· Depression

· Insomnia

· Nervousness

* See detailed heading below.

** See section Warnings and precautions for use

+ Allergic reactions / allergies very frequent occurring mainly during infusion, sometimes fatal (frequent allergic reactions such as rash especially urticaria, conjunctivitis, rhinitis). Frequent anaphylactic or anaphylactoid reactions including bronchospasm, angiodemesis, hypotension, chest pain sensation, and anaphylactic shock).

++ Very frequent fevers, either of infectious origin (with or without febrile neutropenia), or isolated of immunological origin.

+++ Injection site reaction including local pain, redness, swelling and thrombosis. Extravasation may also cause local pain and inflammation, which can be severe and lead to complications including necrosis, particularly when oxaliplatin is perfused via the peripheral venous route (see section 4.4 ). .

Blood and lymphatic system disorders

Incidence per patient (%), by grade

Oxaliplatin combined with 5-FU / folinic acid 85 mg / m 2 every 2 weeks

Metastatic treatment

Adjuvant treatment

All grades

Grade 3

Grade 4

All grades

Grade 3

Grade 4

Anemia

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

Septic neutropenia

1.1

0.7

0.4

1.1

0.6

0.4

Experience since placing on the market, of undetermined frequency:

Uremic hemolytic syndrome.

Immune system disorders

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

Oxaliplatin associated with 5-FU / folinic acid

Metastatic treatment

Adjuvant treatment

85 mg / m 2 every 2 weeks

All grades

Grade 3

Grade 4

All grades

Grade 3

Grade 4

Allergic reactions / allergies

9.1

1

<1

10.3

2.3

0.6

Affection of the nervous system

The limiting toxicity of oxaliplatin is neurological. It is essentially a sensitive peripheral neuropathy characterized by dysaesthesia and / or paresthesia of extremities accompanied or not by cramps, often triggered by cold. These symptoms occur in up to 95% of treated patients. The duration of these symptoms, generally regressive between the cycles of treatment, increases with the repetition of these.

The occurrence of pain and / or functional discomfort requires, depending on the duration of the symptoms, the adjustment of the dose, or even the cessation of treatment (see section Warnings and precautions for use ).

This functional discomfort, which includes difficulties during the execution of precise gestures, is a possible consequence of the sensory impairment. The risk of persistent symptoms for a cumulative dose of 850 mg / m 2 (10 cycles) is approximately 10% and 20% for a cumulative dose of 1020 mg / m 2 (12 cycles).

In the majority of cases, neurological signs and symptoms improve or resolve completely when treatment is stopped.

In the adjuvant treatment of colon cancer, 6 months after stopping treatment, 87% of patients have no symptoms or moderate symptoms. After more than 3 years of follow-up, approximately 3% of patients presenting with localized persistent paresthesia of moderate intensity (2.3%) are paresthesia that can interfere with functional activities (0.5%).

Acute neurosensory manifestations have been reported (see section 5.3 ). They begin in the hours following administration and often occur during exposure to the cold. They are usually characterized by transient paresthesia, dysesthesia or hypoesthesia. An acute syndrome of pharyngolaryngeal dysaesthesia occurs in 1% - 2% of patients and is characterized by subjective sensations of dysphagia or dyspnea / choking sensation without objective sign of respiratory distress (without cyanosis or hypoxia) or by laryngospasm or bronchospasm (without stridor or whistling);

Although antihistamines and bronchodilators have been administered in these situations, this symptomatology is rapidly reversible even in the absence of any treatment. The prolongation of the duration of the infusion in the following cycles favors the decrease of the incidence of this syndrome (see section Warnings and precautions for use ).

Occasionally other symptoms have been observed: jaw contracture, muscle spasms, involuntary muscle contractions, myoclonus, coordination disorder, abnormal gait, ataxia, balance disorder, constriction of the throat or chest, oppression, discomfort, pain. In addition, cranial nerve involvement may be associated or occur in isolation such as eyelid ptosis, diplopia, aphonia, dysphonia, hoarseness sometimes described as vocal cord paralysis, lingual dysesthesia or dysarthria sometimes described as aphasia, neuralgia of the trigeminal, facial pain, ocular, decreased visual acuity, visual field disturbances.

Other neurologic symptoms such as dysarthria, loss of osteotendinous reflexes and a sign of Lhermitte have been reported during treatment with oxaliplatin. Isolated cases of optic neuritis have been reported.

Experience since placing on the market, of undetermined frequency:

Convulsion.

Gastrointestinal disorders

Incidence per patient (%), by grade

Oxaliplatin combined with 5-FU / folinic acid 85 mg / m 2 every 2 weeks

Metastatic treatment

Adjuvant treatment

All grades

Grade 3

Grade 4

All grades

Grade 3

Grade 4

nausea

69.9

8

<1

73.7

4.8

0.3

diarrhea

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

Preventive and / or curative treatment with potent antiemetic agents is indicated.

Dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and impaired renal function may be caused by severe diarrhea and / or vomiting, especially when oxaliplatin is combined with 5-fluorouracil (5). -FU) (see section Warnings and precautions for use ).

Hepatobiliary disorders

Very rare (<1 / 10, 000):

Sinusoidal liver obstruction syndrome, also known as hepatic veno-occlusive disease, or histological abnormalities related to this type of syndrome, including peliosis of the liver, nodular regenerative hyperplasia, perisinusoidal fibrosis. Clinical manifestations may result in 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.

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