Oxaliplatin 100mg powder for injection Taj Pharma

  1. Name of the medicinal product

Oxaliplatin  50 mg powder for injection Taj Pharma
Oxaliplatin  100 mg powder for injection Taj Pharma

  1. Qualitative and quantitative composition

a) Oxaliplatin  50 mg powder for injection Taj Pharma
Each sterile lyophilized vial contains:
Oxaliplatin USP                                        50mg
Lactose Monohydrate USNF                    450mg

b) Oxaliplatin  100 mg powder for injection Taj Pharma
Each sterile lyophilized vial contains:
Oxaliplatin USP                                        100mg
Lactose Monohydrate USNF                    900mg

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Powder for injection.

  1. 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 (Dukes’ C) colon cancer after complete resection of primary tumour

– treatment of metastatic colorectal cancer.

4.2 Posology and method of administration

Posology

FOR ADULTS ONLY

The recommended dose for oxaliplatin in adjuvant setting is 85 mg/m² intravenously repeated every two 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 until disease progression or unacceptable toxicity.

Dosage given should be adjusted according to tolerability (see section 4.4).

Oxaliplatin should always be administered before fluoropyrimidines – i.e. 5-fluorouracil.

Oxaliplatin is administered as a 2- to 6-hour intravenous injection in 250 to 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 oxaliplatin dose of 85 mg/m².

Oxaliplatin was mainly used in combination with continuous injection 5-fluorouracil based regimens. For the two-weekly treatment schedule 5-fluorouracil regimens combining bolus and continuous injection were used.

Special Populations

Renal impairment:

Oxaliplatin must not be administered in patients with severe renal impairment (see sections 4.3 and 5.2). In patients with mild to moderate renal impairment, the recommended dose of oxaliplatin is 85 mg/m² (see sections 4.4 and 5.2).

Hepatic impairment:

In a phase I study including patients with several levels of hepatic impairment, frequency and severity of hepato-biliary 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.

Paediatric population:

There is no relevant indication for use of oxaliplatin in children. The effectiveness of oxaliplatin single agent in the paediatric populations with solid tumours has not been established (see section 5.1).

Method of administration

Oxaliplatin is administered by intravenous injection.

The administration of oxaliplatin does not require hyperhydration.

Oxaliplatin diluted in 250 to 500 ml of 5% glucose solution to give a concentration not less than 0.2 mg/ml must be infused via a central venous line or peripheral vein over 2 to 6 hours.

Oxaliplatin injection must always precede the administration of 5-fluorouracil.

Instruction for use

Oxaliplatin must be diluted before use. Only 5% glucose diluent is to be used to dilute the powder for injection product. (For instructions on dilution of the medicinal product before administration, see section 6.6).

In the event of extravasation, administration must be discontinued immediately.

4.3 Contraindications

Oxaliplatin is contraindicated in patients who:

– have a known history of hypersensitivity to the active substance or to any of the excipients listed in section 6.1

– are breast feeding

– have myelosuppression prior to starting first course, as evidenced by baseline neutrophils <2×109/l and/or platelet count of <100×109l

– 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) (see section 5.2).

4.4 Special warnings and precautions for use

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

Renal impairment

Patients with mild to moderate renal impairment should be closely monitored for adverse reactions and the dose adjusted according to toxicity (see section 5.2).

Hypersensitivity reactions

Special surveillance should be ensured for patients with a history of allergic manifestations to other products containing platinum. In case of anaphylactic manifestations the injection should be interrupted immediately and an appropriate symptomatic treatment started. Re-administration of oxaliplatin is contra-indicated. Cross reactions, sometimes fatal, have been reported with all platinum compounds.

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

Neurological symptoms

Neurological toxicity of oxaliplatin should be carefully monitored, especially if co-administered with other medications 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 injection, the next oxaliplatin injection should be administered over 6 hours.

Peripheral neuropathy

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

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Cases of Reversible Posterior Leukoencephalopathy Syndrome (RPLS also known as PRES, Posterior Reversible Encephalopathy Syndrome) have been reported in patients receiving oxaliplatin in combination chemotherapy. RPLS is a rare, reversible, rapidly evolving neurological condition, which can include seizure, hypertension, headache, confusion, blindness, and other visual and neurological disturbances (see section 4.8). Diagnosis of RPLS is based upon confirmation by brain imaging, preferably MRI (Magnetic Resonance Imaging).

Nausea, vomiting, diarrhoea, dehydration and haematological changes

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.

Cases of intestinal ischemia, including fatal outcomes, have been reported with oxaliplatin treatment. In case of intestinal ischemia, oxaliplatin treatment should be discontinued and appropriate measures initiated (see section 4.8).

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 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. Myelosuppressive effects may be additive to those of concomitant chemotherapy. Patient with severe and persistent myelosuppression are at high risk of infectious complications. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin including fatal outcomes (see section 4.8). If any of these events occurs, oxaliplatin should be discontinued.

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 x 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), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count < 1.0 x 109/L, temperature > 38.3°C or a sustained temperature > 38°C for more than one hour), or 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.

Pulmonary

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).

Blood disorders

Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect (frequency not known). Oxaliplatin should be discontinued at the first signs of any evidence of microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood urea nitrogen, or LDH. Renal failure may not be reversible with discontinuation of therapy and dialysis may be required. Disseminated intravascular coagulation (DIC), including fatal outcomes, has been reported in association with oxaliplatin treatment. If DIC is present, oxaliplatin treatment should be discontinued and appropriate treatment should be administered (see section 4.8).

QT prolongation

QT prolongation may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes, which can be fatal (see section 4.8). The QT interval should be closely monitored on a regular basis before and after administration of oxaliplatin. Caution should be exercised in patients with a history or a predisposition for prolongation of QT, those who are taking medicinal products known to prolong QT interval, and those with electrolyte disturbances such as hypokalemia, hypocalcaemia, or hypomagnesaemia. In case of QT prolongation, oxaliplatin treatment should be discontinued (see sections 4.5 and 4.8).

Rhabdomyolysis

Rhabdomyolysis has been reported in patients treated with oxaliplatin, including fatal outcomes. In case of muscle pain and swelling, in combination with weakness, fever or darkened urine, oxaliplatin treatment should be discontinued. If rhabdomyolysis is confirmed, appropriate measures should be taken. Caution is recommended if medicinal products associated with rhabdomyolysis are administered concomitantly with oxaliplatin (see sections 4.5 and 4.8).

Gastrointestinal ulcer/ Gastrointestinal ulcer haemorrhage and perforation

Oxaliplatin treatment can cause gastrointestinal ulcer and potential complications, such as gastrointestinal haemorrhage and perforation, which can be fatal. In case of gastrointestinal ulcer, oxaliplatin treatment should be discontinued and appropriate measures taken (see section 4.8).

Hepatic

In case of abnormal liver function test results or portal hypertension which does not obviously result from liver metastases, very rare cases of drug-induced hepatic vascular disorders should be considered.

Pregnancy

For use in pregnant women, see section 4.6.

Fertility

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).

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.

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.

Caution is advised when oxaliplatin treatment is co-administered with other medicinal products known to cause QT interval prolongation. In case of combination with such medicinal products, the QT interval should be closely monitored (see section 4.4).

Caution is advised when oxaliplatin treatment is administered concomitantly with other medicinal products known to be associated with rhabdomyolysis (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

There is no data from the use of oxaliplatin in pregnant women. Animal studies, have shown reproductive toxicity (see section 5.3).

Oxaliplatin is not recommended during pregnancy and in women of childbearing potential not using contraception.

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.

Breastfeeding

It is unknown whether oxaliplatin is excreted in human milk.

Oxaliplatin is contra-indicated during breast-feeding (see section 4.3).

Fertility

Oxaliplatin may have an anti-fertility effect (see section 4.4).

Contraception in males and females

Due to the potential genotoxic effects of oxaliplatin, appropriate contraceptive measures must be taken during and after cessation of therapy during 4 months for women and 6 months for men.

4.7 Effects on 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 patients’ 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.

4.8 Undesirable effects

Summary of the safety profile

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.

Tabulated list of adverse reactions

The frequencies reported in the table below are derived from clinical trials in the 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, ≤1/100), rare (≥1/10000, ≤1/1000), very rare (≤1/10000), not known (cannot be estimated from the available data).

Further details are given after the table.

MedDRA system organ classes Very common Common Uncommon Rare Not known
Infections and infestations Infection Rhinitis

Upper respiratory tract infection

Neutropenic sepsis+

Sepsis +
Blood and lymphatic system disorders* Anaemia

Neutropenia

Thrombocytopenia

Leukopenia

Lymphopenia

Febrile neutropenia Immunoallergic thrombocytopenia

Haemolytic anaemia

Immune system disorders* Allergy/allergic reaction ++
Metabolism and nutrition disorders Anorexia

Hyperglycaemia

Hypokalaemia

Hyponatraemia

Dehydration

Hypocalcaemia

Metabolic acidosis
Psychiatric disorders Depression

Insomnia

Nervousness
Nervous system disorders*- Peripheral sensory neuropathy

Sensory disturbance

Dysgeusia

Headache

Dizziness

Motor neuritis

Meningism

Dysarthria

Reversible Posterior Leukoencephalopathy syndrome (RPLS, or PRES) (see section 4.4)

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
Cardiac disorders Acute coronary syndrome, including myocardial infarction and coronary arteriospasm and angina pectoris in patients treated with oxaliplatin in combination with 5-FU and bevacizumab
Vascular disorders Haemorrhage

Flushing

Deep vein thrombosis

Hypertension

Respiratory, thoracic and mediastinal disorders Dyspnoea

Cough

Epistaxis

Hiccups

Pulmonary embolism

Interstitial lung disease

Pulmonary fibrosis**

Gastrointestinal disorders* Nausea

Diarrhoea

Vomiting

Stomatitis /Mucositis

Abdominal pain

Constipation

Dyspepsia

Gastroesophageal reflux

Gastrointestinal haemorrhage

Rectal haemorrhage

Ileus

Intestinal obstruction

Colitis including clostridium difficile diarrhoea

Pancreatitis

Oesophagitis
Skin and subcutaneous tissue disorders Skin disorders

Alopecia

Skin exfoliation (i.e. Hand & Foot syndrome)

Rash erythematous

Rash

Hyperhidrosis

Nail disorder

Musculo-skeletal and connective tissue disorders Back pain Arthralgia

Bone pain

Renal and urinary disorders Haematuria

Dysuria

Micturition frequency abnormal

General disorders and administration site conditions Fatigue

Fever+++

Asthenia

Pain

Injection site reaction++++

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)

Injury, poisoning and procedural complications Fall

* See detailed section below

** See section 4.4.

+ including fatal outcomes

++ Very common allergies/allergic reactions, occurring mainly during injection, sometimes fatal. Common allergic reactions include skin rash, particularly urticaria, conjunctivitis ,and rhinitis. Common anaphylactic or anaphylactoid reactions include bronchospasm, angiooedema, hypotension, sensation of chest pain and anaphylactic shock. Delayed hypersensitivity has also been reported with oxaliplatin hours or even days after the injection.

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

++++ Injection site reactions including local pain, redness, swelling and thrombosis have 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 (see section 4.4).

Description of selected adverse reactions

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 Gr 3 Gr 4 All grades Gr 3 Gr 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

Rare (>1/10000, <1/1000)

Disseminated intravascular coagulation (DIC), including fatal outcomes (see section 4.4).

Post marketing experience with frequency unknown

Hemolytic uremic syndrome, autoimmune pancytopenia.

Infections and infestations

Incidence by patient (%), by grade

Oxaliplatin and 5-FU/FA

85 mg/m² every 2 weeks

Metastatic Setting Adjuvant Setting
All grades All grades
Sepsis (including sepsis and neutropenic sepsis) 1.5 1.7

Post-marketing experience with frequency not known

Septic shock, including fatal outcomes.

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 Gr 3 Gr 4 All grades Gr 3 Gr 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, 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 the 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 1% – 2% of patients 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). Although antihistamines and bronchodilators have been administered in such cases, the symptoms are rapidly reversible even in the absence of treatment. Prolongation of the injection helps to reduce the incidence of this syndrome (see section 4.4). 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, throat or chest tightness/ pressure/ discomfort/pain. In addition, cranial nerve dysfunctions may be associated with above mentioned events, 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, visual field disorders.

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.

Post marketing experience with frequency unknown

Convulsion

Cardiac disorders

Post-marketing experience with frequency not known

QT prolongation, which may lead to ventricular arrhythmias including Torsade de Pointes, which may be fatal (see section 4.4).

Respiratory, thoracic and mediastinal disorders

Post-marketing experience with frequency not known:

Laryngospasm

Gastrointestinal disorders

Incidence by patient (%), by grade

Oxaliplatin and 5-FU/FA

85 mg/m² every 2 weeks

Metastatic Setting Adjuvant Setting
All grades Gr 3 Gr 4 All grades Gr 3 Gr 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 antiemetic agents is 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 (5 FU) (see section 4.4).

Post marketing experience with frequency not known

Intestinal ischaemia, including fatal outcomes (see section 4.4).

Gastrointestinal ulcer and perforation, which can be fatal (see section 4.4).

Hepato-biliary disorders

Very rare (≤ 1/10000)

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

Musculoskeletal and connective tissue disorders

Post-marketing experience with frequency not known

Rhabdomyolysis, including fatal outcomes (see section 4.4).

Skin and subcutaneous tissue disorders

Post-marketing experience with frequency not known

Hypersensitivity vasculitis.

Renal and urinary disorders

Very rare (≤ 1/10000)

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

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.

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other antineoplastic agents, platinum compounds

Mechanism of action

Oxaliplatin is an antineoplastic 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 is a single enantiomer, (SP-4-2)-[(1R,2R)-Cyclohexane-1,2-diamine-kN, kN‘] [ethanedioato(2-)-kO1, kO2] platinum.

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.

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 anti-tumour effects.

Clinical and efficacy and safety

In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85 mg/m2 repeated every two weeks) combined with 5-fluorouracil/folinic acid (5-FU/FA) is reported in three clinical studies:

– in front-line treatment, the 2-arm comparative phase III EFC2962 study randomised 420 patients either to 5-FU/FA alone (LV5FU2, N=210) or the combination of oxaliplatin with 5-FU/FA (FOLFOX4, N=210)

– in pretreated patients, the comparative three arms phase III study EFC4584 randomised 821 patients refractory to an irinotecan (CPT-11) + 5-FU/FA combination either to 5-FU/FA alone (LV5FU2, N=275), oxaliplatin single agent (N=275), or combination of oxaliplatin with 5-FU/FA (FOLFOX4, N=271).

– finally, the uncontrolled phase II EFC2964 study included patients refractory to 5-FU/FA alone, that were treated with the oxaliplatin and 5-FU/FA combination (FOLFOX4, N=57).

The two randomised 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-FU/FA alone. In EFC4584 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

Response rate, %

(95% CI)

independent radiological review ITT analysis

LV5FU2 FOLFOX4 Oxaliplatin Single agent
Front-line treatment

EFC2962

22 (16-27) 49 (42-56) NA*
Response assessment every 8 weeks P value = 0.0001
Pretreated patients

EFC4584 (refractory to CPT-11 + 5-FU/FA)

0.7 (0.0-2.7) 11.1 (7.6-15.5) 1.1 (0.2-3.2)
Response assessment every 6 weeks P value < 0.0001
Pretreated patients
EFC2964 NA* 23 NA*
(refractory to 5-FU/FA) (13-36)
Response assessment every 12weeks

* NA : Not Applicable

Median Progression Free Survival (PFS) / Median Time to Progression (TTP) FOLFOX4 versus LV5FU2

Median PFS/TTP

Months (95% CI)

independent radiological review ITT analysis

LV5FU2 FOLFOX4 Oxaliplatin Single agent
Front-line treatment

EFC2962 (PFS)

6.0 (5.5-6.5) 8.2 (7.2-8.8) NA*
Log-rank P value = 0.0003
Pretreated patients

EFC4584 (TTP)

(refractory to CPT-11 + 5-FU/FA)

2.6 (1.8-2.9) 5.3 (4.7-6.1) 2.1 (1.6-2.7)
Log-rank P value < 0.0001
Pretreated patients
EFC2964 NA* 5.1 NA*
(refractory to 5-FU/FA) (3.1-5.7)

*NA : Not Applicable

Median Overall Survival (OS) under FOLFOX4 versus LV5FU2

Median OS, months

(95% CI)

ITT analysis

LV5FU2 FOLFOX4 Oxaliplatin Single agent
Front-line treatment

EFC2962

14.7 (13.0-18.2) 16.2 (14.7-18.2) NA*
Log-rank P value = 0.12
Pretreated patients

EFC4584

(refractory to CPT-11 + 5-FU/FA)

 

8.8

(7.3-9.3)

 

9.9

(9.1-10.5)

 

8.1

(7.2-8.7)

Log-rank P value = 0.09
Pretreated patients
EFC2964 NA* 10.8 NA*
(refractory to 5-FU/FA) (9.3-12.8)

*NA : Not Applicable

In pretreated patients (EFC4584), who were symptomatic at baseline, a higher proportion of those treated with oxaliplatin and 5-FU/FA experienced a significant improvement of their disease related symptoms compared to those treated with 5-FU/FA alone (27.7% versus 14.6% p = 0.0033).

In non-pretreated patients (EFC2962), no statistically significant difference between the two treatment groups was found for any of the quality of life dimensions. However, the quality of life scores were generally better in the control arm for measurement of global health status and pain and worse in the oxaliplatin arm for nausea and vomiting. In the adjuvant setting, the MOSAÏC comparative phase III study (EFC3313) randomised 2246 patients (899 stage II/Dukes’ B2 and 1347 stage III/Dukes’ C) further to complete resection of the primary tumour of colon cancer either to 5-FU/FA alone (LV5FU2, N=1123 ( B2/C = 448/675) or to combination of oxaliplatin and 5-FU/FA (FOLFOX4, N=1123 (B2/C) = 451/672).

EFC 3313 3-year disease free survival (ITT analysis )* for the overall population.

Treatment arm FOLFOX4 LV5FU2 FOLFOX4
Percent 3-year disease free survival (95% CI) 73.3 (70.6-75.9) 78.7 (76.2-81.1)
Hazard ratio (95% CI) 0.76 (0.64-0.89)
Stratified log rank test P=0.0008

* median follow up 44.2 months (all patients followed for at least 3 years)

The study demonstrated an overall significant advantage in 3-year disease free survival for the oxaliplatin and 5-FU/FA combination (FOLFOX4) over 5-FU/FA alone (LV5FU2).

EFC 3313 3-year disease free survival (ITT analysis )* according to stage of disease.

Patient stage Stage II

(Dukes’ B2)

Stage III

(Dukes’ C)

Treatment arm LV5FU2 FOLFOX4 LV5FU2 FOLFOX4
Percent 3-year disease 84.3 87.4 65.8 72.8
Free survival (80.9-87.7) (84.3-90.5) (62.2-69.5) (69.4-76.2)
(95% CI)
Hazard ratio (95% CI) 0.79 (0.57-1.09) 0.75 (0.62 – 0.90)
Log-rank test P=0.151 P=0.002

* median follow up 44.2 months (all patients followed for at least 3 years)

Overall Survival (ITT analysis)

At time of the analysis of the 3-year disease free survival, which was the primary endpoint of the MOSAIC trial, 85.1% of the patients were still alive in the FOLFOX4 arm versus 83.8% in the LV5FU2 arm. This translated into an overall reduction in mortality risk of 10% in favour of FOLFOX4 not reaching statistical significance (hazard ratio = 0.90). The figures were 92.2% versus 92.4% in the stage II (Dukes’ B2) sub-population (hazard ratio = 1.01) and 80.4% versus 78.1% in the stage III (Dukes’ C) sub-population (hazard ratio = 0.87), for FOLFOX4 and LV5FU2, respectively.

Paediatric population

Oxaliplatin single agent has been evaluated in paediatric population in 2 Phase I (69 patients) and 2 Phase II (166 patients) studies. A total of 235 paediatric patients (7 months – 22 years of age) with solid tumours have been treated. The effectiveness of oxaliplatin single agent in the paediatric populations treated has not been established. Accrual in both Phase II studies was stopped for lack of tumour response.

5.2 Pharmacokinetic properties

The pharmacokinetics of individual active compounds have not been determined. The pharmacokinetics of ultrafiltrable platinum, representing a mixture of all unbound, active and inactive platinum species, following a two-hour injection of oxaliplatin at 130 mg /m² every three weeks for 1 to 5 cycles and oxaliplatin at 85 mg/m² every two weeks for 1 to 3 cycles are as follows:

Summary of Platinum Pharmacokinetic Parameter Estimates in Ultrafiltrate Following Multiple Doses of Oxaliplatin at 85 mg/m2 Every Two Weeks or at 130 mg/m2 Every Three Weeks

Dose

85 mg/m²

Cmax

μg/mL

AUC 0-48

μg.h/mL

AUC

μg.h/mL

1/2α

h

1/2β

h

1/2γ

h

Vss

L

CL

L/h

Mean 0.814 4.19 4.68 0.43 16.8 391 440 17.4
SD 0.193 0.647 1.40 0.35 5.74 406 199 6.35
130 mg/m²
Mean 1.21 8.20 11.9 0.28 16.3 273 582 10.1
SD 0.10 2.40 4.60 0.06 2.90 19.0 261 3.07

Mean AUC0-48, and Cmax values were determined on Cycle 3 (85 mg/m²) or cycle 5 (130 mg/m²).

Mean AUC, Vss, CL, and CLR0-48 values were determined on Cycle 1.

Cend, Cmax, AUC, AUC0-48, Vss and CL values were determined by non-compartmental analysis.

t1/2α, t1/2β, and t1/2γ, were determined by compartmental analysis (Cycles 1-3 combined).

At the end of a 2-hour injection, 15% of the administered platinum is present in the systemic circulation, the remaining 85% being rapidly distributed into tissues or eliminated in the urine. Irreversible binding to red blood cells and plasma, results in half-lives in these matrices that are close to the natural turnover of red blood cells and serum albumin. No accumulation was observed in plasma ultrafiltrate following 85 mg/m² every two weeks or 130 mg/m² every three weeks and steady state was attained by cycle one in this matrix. Inter- and intra-subject variability is generally low.

Biotransformation in vitro is considered to be the result of non-enzymatic degradation and there is no evidence of cytochrome P450-mediated metabolism of the diaminocyclohexane (DACH) ring.

Oxaliplatin undergoes extensive biotransformation in patients, and no intact drug was detectable in plasma ultrafiltrate at the end of a 2h-injection. Several cytotoxic biotransformation products including the monochloro-, dichloro- and diaquo-DACH platinum species have been identified in the systemic circulation together with a number of inactive conjugates at later time points. Platinum is predominantly excreted in urine, with clearance mainly in the 48 hours following administration. By day 5, approximately 54% of the total dose was recovered in the urine and < 3% in the faeces.

The effect of renal impairment on the disposition of oxaliplatin was studied in patients with varying degrees of renal function. Oxaliplatin was administered at a dose of 85 mg/m2 in the control group with a normal renal function (CLcr > 80 ml/min, n=12) and in patients with mild (CLcr = 50 to 80 ml/min, n=13) and moderate (CLcr = 30 to 49 ml/min, n=11) renal impairment, and at a dose of 65 mg/m2 in patients with severe renal impairment (CLcr < 30 ml/min, n=5). Median exposure was 9, 4, 6, and 3 cycles, respectively, and PK data at cycle 1 were obtained in 11, 13, 10, and 4 patients respectively.

There was an increase in plasma ultrafiltrate (PUF) platinum AUC, AUC/dose and a decrease in total and renal CL and Vss with increasing renal impairment especially in the (small) group of patients with severe renal impairment: point estimate (90% CI) of estimated mean ratios by renal status versus normal renal function for AUC/dose were 1.36 (1.08, 1.71), 2.34 (1.82, 3.01) and 4.81 (3.49, 6.64) for patients with mild and moderate and in severe renal failure respectively.

Elimination of oxaliplatin is significantly correlated with the creatinine clearance. Total PUF platinum CL was respectively 0.74 (0.59, 0.92), 0.43 (0.33, 0.55) and 0.21 (0.15, 0.29) and for Vss respectively 0.52 (0.41, 0.65), 0.73 (0.59, 0.91) and 0.27 (0.20, 0.36) for patients with mild, moderate and severe renal failure respectively. Total body clearance of PUF platinum was therefore reduced by respectively 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 (see sections 4.2, 4.3 and 4.4).

5.3 Preclinical safety data

The target organs identified in preclinical species (mice, rats, dogs, and/or monkeys) in single- and multiple-dose studies included the bone marrow, the gastrointestinal system, the kidney, the testes, the nervous system, and the heart. The target organ toxicities observed in animals are consistent with those produced by other platinum-containing drugs and DNA-damaging, cytotoxic drugs used in the treatment of human cancers with the exception of the effects produced on the heart. Effects on the heart were observed only in the dog and included electrophysiological disturbances with lethal ventricular fibrillation. Cardiotoxicity is considered specific to the dog not only because it was observed in the dog alone but also because doses similar to those producing lethal cardiotoxicity in dogs (150 mg/m²) were well-tolerated by humans. Preclinical studies using rat sensory neurons suggest that the acute neurosensory symptoms related to Oxaliplatin may involve an interaction with voltage-gated Na+ channels.

Oxaliplatin was mutagenic and clastogenic in mammalian test systems and produced embryo-fetal toxicity in rats. Oxaliplatin is considered a probable carcinogen, although carcinogenic studies have not been conducted.

  1. Pharmaceutical particulars

6.1 List of excipients

Lactose Monohydrate USNF.

6.2 Incompatibilities

This medicinal product should not be mixed with other medicinal products except for those mentioned in section 6.6.

6.3 Shelf life

18 months

After dilution in 5% glucose, chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (15-25°C) or for 48 hours under refrigeration (2°C-8°C).

From a microbiological point of view, the injection preparation should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not store above 25°C.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Oxaliplatin 5mg/ml powder for injection is supplied in colourless type I moulded glass vials with 20mm grey bromobutyl rubber stoppers provided with a 20mm blood-red flip-off aluminium seal (50mg/10ml), a dark blue flip-off aluminium seal (100mg/20ml) or a light yellow flip-off aluminium seal (200mg/40ml) and a tamper proof sleeved cap.

Pack sizes:

50 mg/10 ml and 100 mg/20 ml: 30 ml vial

200 mg/40 ml: 50 ml vial

1 or 5 vials per carton.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

As with other potentially toxic compounds, caution should be exercised when handling and preparing oxaliplatin solutions.

Instructions for handling

The handling of this cytotoxic agent by healthcare personnel requires every precaution to guarantee the protection of the handler and his surroundings.

The preparation of injectable solutions of cytotoxic agents must be carried out by trained specialist personnel with knowledge of the medicines 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 medicines, in accordance with the hospital policy. It requires a preparation area reserved for this purpose. It is forbidden to smoke, eat or drink in this area.

Personnel must be provided with appropriate handling materials, notably long sleeved gowns, protection masks, caps, protective goggles, sterile single-use gloves, protective covers for the work area, containers and collection bags for waste.

Excreta and vomit must be handled with care.

Pregnant women must be warned to avoid handling cytotoxic agents.

Any broken container must be treated with the same precautions and considered as contaminated waste. Contaminated waste should be incinerated in suitably labelled rigid containers. See below chapter “Disposal”.

If oxaliplatin powder for injection or injection solution, should come into contact with skin, wash immediately and thoroughly with water.

If oxaliplatin powder for injection or injection solution, should come into contact with mucous membranes, wash immediately and thoroughly with water.

Special precautions for administration

– DO NOT use injection equipment containing aluminium.

– DO NOT administer undiluted.

– Only glucose 5 % (50 mg/ml) injection solution is to be used as a diluent. DO NOT dilute for injection with sodium chloride or chloride containing solutions.

– DO NOT mix with any other medicinal products in the same injection bag or administer simultaneously by the same injection line.

– 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 others active substances. Alkaline medicinal products or solutions will adversely affect the stability of oxaliplatin.

Instruction for use with folinic acid (as calcium folinate or disodium folinate)

Oxaliplatin 85 mg/m² intravenous injection in 250 to 500 ml of glucose 5 % (50 mg/ml) solution is given at the same time as folinic acid (FA) intravenous injection in glucose 5 % solution, over 2 to 6 hours, using a Y-line placed immediately before the site of injection.

These two medicinal products should not be combined in the same injection bag. Folinic acid (FA) must not contain trometamol as an excipient and must only be diluted using isotonic glucose 5 % solution, never in alkaline solutions or sodium chloride or chloride containing solutions.

Instruction for use with 5 fluorouracil (5 FU)

Oxaliplatin should always be administered before fluoropyrimidines – i.e. 5 fluorouracil (5 FU).

After oxaliplatin administration, flush the line and then administer 5 fluorouracil (5 FU).

For additional information on medicinal products combined with oxaliplatin, see the corresponding manufacturer’s summary of product characteristics.

Powder for injection

Inspect visually prior to use. Only clear solutions without particles should be used.

The medicinal product is for single use only. Any unused powder for injection should be discarded.

Instructions for dilution

Withdraw the required amount of powder for injection from the vial(s) and then dilute with 250 ml to 500 ml of a 5% glucose solution to give an oxaliplatin concentration between not less than 0.2 mg/ml and 0.7 mg/ml. The concentration range for which the physico-chemical stability of oxaliplatin has been demonstrated is 0.2 mg/ml to 0.7 mg/ml.

Administer by intravenous injection.

Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (15-25°C) or for 48 hours under refrigeration (2°C-8°C). From a microbiological point of view, this injection preparation should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8°C unless dilution has taken place in controlled and validated aseptic conditions.

Inspect visually prior to use. Only clear solutions without particles should be used.

The medicinal product is for single use only. Any unused injection solution should be discarded.

NEVER use sodium chloride or chloride containing solutions for dilution.

The compatibility of oxaliplatin solution for injection has been tested with representative, PVC based, administrative sets.

Injection

The administration of oxaliplatin does not require prehydration.

Oxaliplatin diluted in 250 to 500 ml of a 5% glucose solution to give a concentration not less than 0.2 mg/ml must be infused either by peripheral vein or central venous line over 2 to 6 hours. When oxaliplatin is administered with 5-fluorouracil, the oxaliplatin injection must precede the administration of 5-fluorouracil.

Disposal

Any unused medicinal product or waste material should be disposed of according to standard procedures applicable to cytotoxic agents in accordance with local requirements.

7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

Oxaliplatin  100 mg powder for injection Taj Pharma

Package leaflet: Information for the user

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Oxaliplatin is and what it is used for
    2. What you need to know before you use Oxaliplatin
    3. How to use Oxaliplatin
    4. Possible side effects
    5. How to store Oxaliplatin
    6. Contents of the pack and other information
  2. What Oxaliplatin is and what it is used for

Oxaliplatin is an anticancer drug that contains platinum.

Oxaliplatin is used to treat metastatic (advanced) cancer of the colon (large bowel) or rectum (back passage), or as additional treatment following surgery to remove a tumour (growth) in the colon. It is used in combination with other anticancer agents, 5-fluorouracil and folinic acid.

  1. What you need to know before you use Oxaliplatin

You should not be given Oxaliplatin if

  • you are allergic to oxaliplatin or any of the other ingredients of this medicine (listed in section 6)
  • you are breast feeding
  • you already have a reduced number of blood cells (white blood cells and/or platelets)
  • you already have tingling and numbness in the fingers and/or toes, and have difficulty performing delicate tasks, such as buttoning clothes
  • you have severe kidney problems.

Even if you are male, please ensure that you read the section of this leaflet that concerns pregnancy and breast-feeding.

Warnings and precautions

Talk to your doctor or pharmacist before using Oxaliplatin if

  • you have ever suffered an allergic reaction to platinum-containing medicines such as carboplatin or cisplatin
  • you have moderate kidney problems, you have any liver problems or abnormal liver function test results during your treatment
  • if you have or had heart disorders such as an abnormal electrical signal called prolongation of the QT interval, an irregular heartbeat, or a family history of heart problems.

If any of the following applies to you at any time, tell your doctor immediately. Your doctor may need to treat you for these events. Your doctor may need to reduce the dose of Oxaliplatin, or delay or stop your treatment with Oxaliplatin.

  • If you have an unpleasant sensation in the throat, in particular when swallowing, and have a sensation of shortness of breath, during the treatment, tell your doctor.
  • If you have nerve problems in your hands or feet, such as numbness or tingling, or decreased sensations in your hands or feet, tell your doctor.
  • If you have headache, altered mental functioning, seizures and abnormal vision from blurriness to vision loss, tell your doctor.
  • If you feel or are sick (nausea or vomiting), tell your doctor.
  • If you have severe diarrhoea, tell your doctor.
  • If you have sore lips or mouth ulcers (mucositis/ stomatitis), tell your doctor.
  • If you have diarrhoea, or a reduction in white blood cells or platelets, tell your doctor. Your doctor may reduce the dose of Oxaliplatin or postpone your treatment with Oxaliplatin.
  • If you have unexplained respiratory symptoms such as cough, or any difficulties in breathing, tell your doctor. Your doctor may stop your treatment with Oxaliplatin.
  • If you develop an extreme tiredness, shortness of breath, or kidney disease where you pass little or no urine (symptoms of acute renal failure), tell your doctor.
  • If you have fever (temperature greater than or equal to 38°C), or chills, which could be signs of infection, tell your doctor immediately. You may be at risk of getting an infection of the blood.
  • If you have fever > 38°C, tell your doctor. Your doctor may determine you also have a reduction in white blood cells.
  • If you experience unexpected bleeding or bruising (disseminated intravascular coagulation), tell your doctor as these could be signs of blood clots throughout the small vessels of your body.
  • If you faint (lose consciousness) or have an irregular heartbeat while being given Oxaliplatin, tell your doctor immediately as this may be a sign of a serious heart condition.
  • If you experience muscle pain and swelling, in combination with weakness, fever, or red-brown urine, tell your doctor. These could be signs of muscle damage (rhabdomyolysis) and could lead to kidney problems or other complications.
  • If you have abdominal pain, nausea, bloody vomit or vomit that looks like “coffee-grounds”, or dark-coloured/ tarry stools, which may be signs of an ulcer of the bowel (gastrointestinal ulcer, with potential bleeding or perforation), tell your doctor.
  • If you have abdominal (tummy) pain, bloody diarrhoea, and nausea and/or vomiting, which may be caused by a reduction of blood flow to your gut wall (intestinal ischaemia), tell your doctor.

Other medicines and Oxaliplatin

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

Pregnancy, breast-feeding and fertility

Pregnancy

  • It is not recommended that you become pregnant during treatment with oxaliplatin and must use an effective method of contraception. Female patients should take appropriate contraceptive measures during and after cessation of therapy continuing for 4 months.
  • If you are pregnant or planning a pregnancy it is very important that you discuss this with your doctor before you receive any treatment.
  • If you get pregnant during your treatment, you must immediately inform your doctor.

Breast-feeding

  • You must not breast-feed while you are treated with oxaliplatin.

 

Fertility

  • Oxaliplatin may have an anti-fertility effect, which could be irreversible. Male patients should seek advice on conservation of sperm prior to treatment.
  • Male patients are advised not to father a child during treatment and until 6 months after treatment, and to take appropriate contraceptive measures during this time.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Oxaliplatin may result in increased risk of dizziness, nausea and vomiting and other neurological symptoms that may affect walking and balance. If this happens to you, you should not drive or operate machinery. If you have vision problems whilst being given Oxaliplatin do not drive, operate heavy machines or engage in dangerous activities.

  1. How to use Oxaliplatin

Oxaliplatin may only be given to adults.

For single use only.

Dosage

The dose of Oxaliplatin is based on your body surface area (calculated from your height and weight).

The dose will also depend on results of blood tests and whether you have previously experienced side effects with Oxaliplatin.

The recommended dose for adults including the elderly is 85 mg/m² of body surface.

Method and route of administration

  • Oxaliplatin will be prescribed for you by a specialist in cancer treatment.
  • You will be treated by a healthcare professional, who will have made up the required dose of Oxaliplatin.
  • Oxaliplatin is given by slow injection into one of your veins (an intravenous infusion) over a 2 to 6 hour period.
  • Oxaliplatin will be given to you at the same time as folinic acid and before the infusion of 5- fluorouracil.
  • The needle must remain in the vein while the drug is being given. If the needle comes out or becomes loose, or the solution is going into the tissue outside the vein (you may feel discomfort or pain) – tell the nurse or doctor immediately.

Frequency of administration

You should usually receive your infusion once every two weeks.

Duration of treatment

The duration of the treatment will be determined by your doctor.

Your treatment will last a maximum of 6 months when used after complete resection of your tumour.

If you use more Oxaliplatin than you should

As this medicine is administered by a healthcare professional, it is highly unlikely that you will be given too much or too little.

In case of overdose, you may experience increased side effects. Your doctor may give you appropriate treatment for these side effects.

If you have any further questions on the use of this medicine, ask your doctor.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. If you experience any side effect it is important that you inform your doctor before your next treatment.

You will find described below the side effects that you could experience.

Most serious side effects

Tell your doctor immediately if you notice any of the following:

Very common: may affect more than 1 in 10 people

  • allergies/allergic reactions, occurring mainly during infusion, sometimes fatal
  • stomatitis / mucositis (sore lips or mouth ulcers)
  • low platelet count, abnormal bruising (thrombocytopenia). Your doctor will take blood to check that you have sufficient blood cells before you start treatment and before each subsequent course.
  • unexplained respiratory symptoms such as dry cough, difficulties in breathing or crackles.

Common: may affect up to 1 in 10 people

  • serious infection of the blood in addition to a reduction in white blood cells (neutropenic sepsis), which may be fatal
  • reduction in white blood cells accompanied by fever > 38.3°C or a prolonged fever > 38°C for more than one hour (febrile neutropenia)
  • symptoms of an allergic or anaphylactic reaction with sudden signs such as rash, itching or hives on the skin, difficulties in swallowing, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing, extreme tiredness (you may feel you are going to faint). In the majority of cases, these symptoms occurred during the infusion or immediately after but delayed allergic reactions have also been observed hours or even days after the infusion.
  • fall.

Uncommon: may affect up to 1 in 100 people

  • serious infection of the blood (sepsis), which may be fatal.

Rare: may affect up to 1 in 1,000 people

  • unexpected bleeding or bruising due to widespread blood clots throughout the small blood vessels of the body (disseminated intravascular coagulation), which may be fatal
  • abnormal bruising, bleeding or signs of infection such as a sore throat and high temperature
  • persistent or severe diarrhoea or vomiting
  • reversible short-term loss of vision
  • a group of symptoms such as headache, altered mental functioning, seizures and abnormal vision from blurriness to vision loss (symptoms of reversible posterior leukoencephalopathy syndrome, a rare neurological disorder)
  • extreme tiredness with decreased number of red blood cells, and shortness of breath (haemolytic anaemia), alone or combined with low platelet count, abnormal bruising (thrombocytopenia) and kidney disease where you pass little or no urine (symptoms of Haemolytic-uraemic syndrome)
  • scarring and thickening in the lungs with difficulties in breathing, sometimes fatal (interstitial lung disease).

Very rare: may affect up to 1 in 10,000 people

  • kidney disease where you pass little or no urine (symptoms of acute renal failure)
  • vascular disorders of the liver (symptoms include abdominal pain and swelling, weight gain and tissue swelling of the feet, ankles or other parts of the body).

Not known: frequency cannot be estimated from the available data

  • serious infection of the blood and low blood pressure (septic shock), which may be fatal
  • abnormal heart rhythm (QT prolongation), that can be seen on electrocardiogram (ECG), which may be fatal
  • muscle pain and swelling, in combination with weakness, fever, or red-brown urine (symptoms of muscle damage called rhabdomyolysis), which may be fatal
  • abdominal pain, nausea, bloody vomit or vomit that looks like “coffee grounds”, or dark-coloured/ tarry stools (symptoms of gastrointestinal ulcer, with potential bleeding or perforation), which may be fatal
  • decreased blood flow to the intestine/bowel (intestinal ischaemia), which may be fatal
  • spasm of the throat causing difficulty in breathing
  • auto-immune reaction leading to reduction of all blood cell lines (autoimmune pancytopenia) (symptoms include easy bleeding, easy bruising, shortness of breath, extreme lethargy and weakness, and an increased risk of infection due to the immune compromised state)
  • myocardial infarction (heart attack), angina pectoris (pain or uncomfortable feeling in the chest)
  • oesophageal inflammation (inflammation of the lining of the esophagus – the tube that connects your mouth with your stomach – resulting in pain and swallowing difficulty).

All other known side effects

Very common: may affect more than 1 in 10 people

  • Oxaliplatin can affect the nerves (peripheral sensory neuropathy). You may feel a tingling and/or numbness in the fingers, toes, around the mouth or in the throat which may sometimes occur in association with cramps. These effects are often triggered by exposure to cold e.g. opening a refrigerator or holding a cold drink. You may also experience difficulties in performing delicate tasks, such as buttoning clothes. Although in the majority of cases these symptoms disappear completely there is a possibility of persistent symptoms of peripheral sensory neuropathy after the end of the treatment.
  • Some people have experienced a tingling shock-like sensation passing down the arms or trunk when the neck is flexed.
  • Oxaliplatin can sometimes cause an unpleasant sensation in the throat, in particular when swallowing and give the sensation of shortness of breath. This sensation, if it happens, usually occurs during or within hours of the infusion and may be triggered by exposure to the cold. Although unpleasant, it will not last long and goes away without the need for any treatment. Your doctor may decide to alter your treatment as a result.
  • Oxaliplatin may cause diarrhoea, mild nausea (feeling sick and vomiting (being sick); however medication to prevent the sickness is usually given before treatment and may be continued after treatment.
  • Oxaliplatin causes temporary reduction in the number of blood cells. The reduction of red cells may cause anaemia (a reduction of red cells).
  • sensation of discomfort close to or at the injection site during the infusion
  • fever, rigors (tremors), mild or severe tiredness, body pain
  • weight changes, loss or lack of appetite, taste disorders, constipation
  • headache, back pain
  • swelling of the nerves to the muscles, neck stiffness, abnormal tongue sensation possibly altering speech
  • stomach pain
  • abnormal bleeding including nose bleeds
  • allergic reactions, skin rash including red and itchy skin, mild hair loss (alopecia)
  • alteration in blood tests including those relating to abnormalities on liver function.

Common: may affect up to 1 in 10 people

  • infection due to a reduction in white blood cells
  • indigestion and heart burn, hiccups, flushing and dizziness
  • increased sweating and nail disorders, flaking skin
  • chest pain
  • lung disorders and runny nose
  • joint pain and bone pain
  • pain on passing urine and changes in kidney function, changes of frequency of urination, dehydration
  • blood in the urine/stools, swelling of the veins, clots in the lung
  • high blood pressure
  • depression and sleeplessness
  • conjunctivitis and visual problems.

Uncommon: may affect up to 1 in 100 people

  • blockage or swelling of the bowel
  • nervousness.

Rare: may affect up to 1 in 1,000 people

  • loss of hearing.

Not known: frequency cannot be estimated from the available data

  • convulsion
  • allergic vasculitis (inflammation of blood vessels).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

  1. How to store Oxaliplatin

Keep this medicine out of the sight and reach of children.

Do not store above 25°C.

Do not use this medicine after the expiry date which is stated on the label and carton after EXP.

The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

  1. Contents of the pack and other information
  • The active substance is oxaliplatin.
  • A vial of 20 ml of concentrate contains 100 mg oxaliplatin.

7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

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Taj Generics (Taj Pharma) provides a wide range of products to the Indian market, including an extensive range of generics and specialty products; Our products cover a vast array of therapeutic categories, and we offer an extensive range of dosage forms and delivery systems including oral solids, controlled-release, steriles, injectables, topicals, liquids, transdermals, semi-solids and high-potency products. Our Generics portfolio offers over 1500 products in the major therapeutic areas of gastro-intestinal, cardiovascular, pain management, oncology, anti-infectives, paediatrics and dermatology.