Patient leaflets and SmPCs, drug interaction checker, official and paediatric dosages, pregnancy and breastfeeding guidance, and NHS pharmacy opening hours — all in one place.
Patient leaflets and SmPCs, drug interaction checker, official and paediatric dosages, pregnancy and breastfeeding guidance, and NHS pharmacy opening hours — all in one place.
The active ingredient of this medicine is oxaliplatin.
Oxaliplatin is used to treat cancer of the large bowel in adults (treatment of stage III colon
cancer after complete resection of primary tumour, metastatic cancer of colon and rectum). Oxaliplatin is used in combination with other anticancer medicines called 5-fluorouracil (5-FU) and folinic acid (FA).
Oxaliplatin is an anticancer drug and contains platinum.
You should not be given Oxaliplatin if: − you are allergic to oxaliplatin or to 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 − 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.
Warnings and precautions Talk to your doctor or nurse before you are given Oxaliplatin if: − you have ever suffered an allergic reaction to platinum-containing medicines such as
carboplatin, cisplatin. Allergic reactions can occur during any oxaliplatin infusion. − you have mild or moderate kidney problems − you have any liver problems or abnormal liver function test results during your treatment − 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 − you have recently received or plan to receive any vaccines. During treatment with
oxaliplatin, you should not have a vaccination with "live" or "attenuated" vaccines, such as yellow fever vaccine.
Children and adolescents Oxaliplatin should not be used in children and adolescents below 18 years of age.
Other medicines and Oxaliplatin Tell your doctor if you are using, have recently used or might use any other medicines.
Pregnancy, breast-feeding and fertility Pregnancy If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before you are given this medicine.
− 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 9 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 6 months after
treatment, and to take appropriate contraceptive measures during this time.
Driving and using machines Oxaliplatin treatment may result in an increased risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect walking and balance. If this happens, you should not drive or operate machinery. If you have vision problems during treatment with oxaliplatin, do not drive, operate machines, or engage in dangerous activities.
The following information is intended for healthcare professionals only:
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 and specialized personnel with knowledge of the medicines used, in conditions that guarantee the integrity of the 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 subsection "Disposal" below).
If oxaliplatin concentrate or solution for infusion comes into contact with the skin, the skin should be washed immediately and thoroughly with water.
If oxaliplatin concentrate or infusion solution comes into contact with mucous membranes, wash the mucous membranes immediately and thoroughly with water.
For intravenous infusion. Oxaliplatin is intended only for adults. Oxaliplatin concentrate for solution for infusion is administered by medical personnel and has to be dissolved and made into a solution before it can be injected into a vein.
Dose The dose of oxaliplatin is based on your body surface area. This is calculated from your height and weight. The usual dose for adults including the elderly is 85 mg/m2 of body surface area. The dose you receive will also depend on results of blood tests and whether you have previously experienced side effects with oxaliplatin.
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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 will be given by slow intravenous infusion (drip) into one of your veins 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.
Frequency of administration You should usually receive your infusion once every 2 weeks.
Duration of treatment The duration of 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 are given more Oxaliplatin than you should As this medicine is administered by a healthcare professional it is highly unlikely that you will be given too little or too much. 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 or nurse.
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.
Tell your doctor immediately if you notice any of the following: • 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, • Abnormal bruising, bleeding or signs of infection such as a sore throat and high temperature (due to a reduction in platelets or a reduction in white blood cells), • Persistent or severe diarrhoea or vomiting, • Presence of blood or dark brown coffee-coloured particles in your vomit, • Stomatitis/mucositis (sore lips or mouth ulcers), • Unexplained respiratory symptoms such as dry cough, difficulties in breathing, • 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), • Stroke symptoms (including sudden severe headache, confusion, trouble seeing in one or both eyes, numbness or weakness of face, arm or leg usually on one side, face drooping, trouble walking, dizziness, loss of balance and speech difficulty), • Extreme tiredness with decreased number of red blood cells, and shortness of breath (haemolytic anaemia), alone or combined with low platelet count and kidney disease where you pass little or no urine (symptoms of haemolytic-uraemic syndrome), which may be fatal.
Other known side effects of oxaliplatin are:
Very common (may affect more than 1 in 10 people) • Oxaliplatin can affect the nerves (peripheral 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 have difficulty in performing delicate tasks, such as buttoning clothes. Although in the majority of cases these symptoms resolve themselves 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
Special precautions for administration
• DO NOT use injection equipment containing aluminium. • DO NOT administer undiluted. • Only 50 mg/ml (5 %) glucose infusion solution is to be used as a diluent. DO NOT dilute for infusion with sodium chloride or chloride containing solutions. • DO NOT mix with any other medicinal products in the same infusion bag or administer simultaneously by the same infusion line. • DO NOT mix with alkaline drugs or solutions, in particular 5-fluorouracil, folinic acid preparations containing trometamol as an excipient and trometamol salts of other drugs. Alkaline drugs or solutions will adversely affect the stability of oxaliplatin.
Instruction for use with folinic acid (FA) (as calcium folinate or disodium folinate)
Oxaliplatin 85 mg/m2 intravenous infusion in 250 to 500 ml of 50 mg/ml (5 %) glucose solution is given at the same time as folinic acid intravenous infusion in 50 mg/ml (5 %) glucose solution, over 2 to 6 hours, using a Y-line placed immediately before the site of infusion. These two medicinal products should not be combined in the same infusion bag. Folinic acid must not contain trometamol as an excipient and must only be diluted using isotonic 50 mg/ml (5 %) glucose 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.
After oxaliplatin administration, flush the line and then administer 5-fluorouracil.
For additional information on drugs combined with oxaliplatin, see the corresponding manufacturer's summary of product characteristics.
Concentrate for solution for infusion
Inspect the medicinal product visually prior to use. Only clear solutions without particles should be used.
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 to you by your doctor 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), abnormal bleeding or bruising (due to a reduction in platelets). The reduction in white blood cells may make you prone to infections. Your doctor will take blood to check that you have sufficient blood cells before you start treatment and before each subsequent course.
• 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 your muscles, neck stiffness, abnormal tongue sensation possibly altering speech, stomatitis/mucositis (sore lips or mouth ulcers), • Stomach pain, • Abnormal bleeding including nose bleeds, • Coughing, difficulty in breathing, • Allergic reactions, skin rash which may be red and itchy, mild hair loss (alopecia), • Alteration in blood tests including those relating to abnormalities in liver function.
Common (may affect up to 1 in 10 people) • Infection due to a reduction in white blood cells, • 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 temperature > 38.3 °C or a prolonged temperature > 38 °C for more than one hour (febrile neutropenia), • Presence of blood or dark brown coffee-coloured particles in your vomit, • Indigestion and heartburn, hiccups, flushing, 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 insomnia, • Conjunctivitis and visual problems, • Decreased levels of calcium in the blood, • Fall.
Uncommon (may affect up to 1 in 100 people) • Serious infection of the blood (sepsis), which may be fatal, • Decreased blood pH (metabolic acidosis), • Difficulty in hearing, vertigo, ringing in ears, • Blockage or swelling of the bowel, • Nervousness.
Rare (may affect up to 1 in 1 000 people) • Loss of hearing, • Scarring and thickening in the lungs with difficulties in breathing, sometimes fatal (interstitial lung disease), • Reversible short-term loss of vision, • Unexpected bleeding or bruising due to widespread blood clots throughout the small blood vessels of the body (disseminated intravascular coagulation), which may be fatal.
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.
Not known (frequency cannot be estimated from the available data) • Allergic vasculitis (inflammation of blood vessels), • Auto-immune reaction leading to reduction of all blood cell lines (autoimmune pancytopenia), pancytopenia, • Serious infection of the blood and low blood pressure (septic shock), which may be fatal, • Convulsion (uncontrolled shaking of the body), • Spasm of the throat causing difficulty in breathing, • Pneumonia (serious lung infection), which may be fatal, • Extreme tiredness with decreased number of red blood cells, and shortness of breath (haemolytic anaemia), alone or combined with low platelet count and kidney disease where you pass little or no urine (symptoms of haemolytic-uraemic syndrome), which may be fatal, have been reported, • Abnormal heart rhythm (QT prolongation), that can be seen on electrocardiogram (ECG), which may be fatal, • Heart attack (myocardial infarction), pain or uncomfortable feeling in the chest (angina pectoris), • Muscle pain and swelling, in combination with weakness, fever, or red-brown urine (symptoms of muscle damage called rhabdomyolysis), which may be fatal, • Inflammation of the lining of the oesophagus – the tube that connects your mouth with your stomach – resulting in pain and swallowing difficulty (oesophageal inflammation),
Any concentrate that shows evidence of precipitation should not be used and should be destroyed with due regard to legal requirements for disposal of hazardous waste (see subsection "Disposal" below). For single use only. Any unused concentrate should be discarded (see subsection "Disposal" below).
Dilution for intravenous infusion
USE ONLY the recommended solvent (only 50 mg/ml (5 %) glucose infusion solution).
Withdraw the required amount of concentrate solution from the vial(s) and then dilute with 250 ml to 500 ml of a 50 mg/ml (5 %) glucose solution to give an oxaliplatin concentration between 0.2 mg/ml and 0.7 mg/ml; concentration range for which the physico-chemical stability of oxaliplatin has been demonstrated is between 0.2 mg/ml and 2 mg/ml.
Administer by intravenous infusion.
Chemical and physical in use stability has been demonstrated for 24 hours at 25 °C and 4 days at 2 to 8 °C when diluted with glucose 50 mg/ml (5 %) solution in concentrations between 0.2 mg/ml and 2 mg/ml.
From a microbiological point of view, the diluted product 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.
NEVER use sodium chloride or chloride containing solutions for dilution.
The compatibility of oxaliplatin solution for infusion has been tested with PVC-based administration sets.
Inspect the diluted solution visually prior to use. Only clear solutions without particles should be used. Any unused solution should be discarded (see subsection "Disposal" below).
• 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, • Risk of new cancers. Leukaemia, a form of blood cancer, has been reported in patients after taking oxaliplatin in combination with certain other medicines. Talk to your doctor about the potential for increased risk of this type of cancer when taking oxaliplatin and certain other medicines, • Non-cancerous abnormal liver nodules (focal nodular hyperplasia).
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Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.
Keep this medicine out of the sight and reach of children.
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.
This medicinal product does not require any special storage conditions.
Shelf life after dilution Chemical and physical in-use stability has been demonstrated for 24 hours at 25 °C and 4 days at 2 to 8 °C when diluted with glucose 50 mg/ml (5 %) solution in concentrations between 0.2 mg/ml and 2 mg/ml.
From a microbiological point of view, the diluted product 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.
Oxaliplatin must not come into contact with the eyes or the skin. If such an incident occurs,
inform your doctor or nurse immediately.
As soon as the infusion is finished, the unused medicine must be carefully discarded by the
doctor or the nurse.
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.
What Oxaliplatin contains − The active substance is oxaliplatin. Each ml of concentrate for solution for infusion contains 5 mg oxaliplatin. Each vial with 10 ml concentrate contains 50 mg oxaliplatin. Each vial with 20 ml concentrate contains 100 mg oxaliplatin. Each vial with 40 ml concentrate contains 200 mg oxaliplatin.
− The other ingredient is water for injections.
What Oxaliplatin looks like and contents of the pack This medicine is a concentrate for solution for infusion (sterile concentrate). It is a clear, colourless solution practically free from visible particles.
10 ml, 20 ml or 40 ml of solution in colourless glass vial, sealed with rubber stopper and aluminium flip-off seal. Vials are packed in outer cartons.
Pack sizes: 1 vial with 10 ml, 20 ml or 40 ml
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer AS KALCEKS Krustpils iela 71E, Rīga, LV-1057, Latvia Tel.: +371 67083320 E-mail: [email protected]
This leaflet was last revised in 01/2024
Infusion
The administration of oxaliplatin does not require prehydration.
Oxaliplatin diluted in 250 to 500 ml of a 50 mg/ml (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 infusion must precede the administration of 5-fluorouracil.
Disposal
Remnants of the medicinal product as well as all materials that have been used for dilution and administration must be destroyed according to hospital standard procedures applicable to cytotoxic agents and with due regard to current laws related to the disposal of hazardous waste.
Oxaliplatin 5 mg/ml concentrate for solution for infusion comes as infusion containing 5mg/ml. Always follow the dose your doctor or pharmacist has given you, and read the leaflet that comes with the medicine.
The active substance in Oxaliplatin 5 mg/ml concentrate for solution for infusion is oxaliplatin.
Medicines with the same active substance, strength and form include: Oxaliplatin 5 mg/ml concentrate for solution for infusion, Oxaliplatin 5 mg/ml concentrate for solution for infusion, Oxaliplatin 5mg/ml concentrate for solution for infusion. They are interchangeable only if your prescriber or pharmacist says so.
This leaflet reproduces the patient information leaflet approved for Oxaliplatin 5 mg/ml concentrate for solution for infusion, as published on the electronic medicines compendium (emc). The version printed inside your medicine’s packaging is the one that applies to you.
Whether a medicine is available over the counter or on prescription only depends on its licence. Check the leaflet, or ask your pharmacist — they can tell you straight away.
The text above reproduces the patient information leaflet approved for this medicine, restructured for easier reading.
Oxaliplatin in combination with 5-fluorouracil (5-FU) and folinic acid (FA) is indicated in adults for:
– Adjuvant treatment of stage III (Dukes C) colon cancer after complete resection of primary tumour.
– Treatment of metastatic colorectal cancer.
The preparation of injectable solutions of cytotoxic agents must be carried out by trained and specialized personnel with knowledge of the medicinal products 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 the hospital policy (see section 6.6).
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 concentrate for solution for infusion is administered as a 2 to 6 hour intravenous infusion in 250 to 500 ml of 50 mg/ml (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 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 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 infusion.
The administration of oxaliplatin does not require hyperhydration.
Oxaliplatin diluted in 250 to 500 ml of 50 mg/ml (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 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 diluted before use.
Only 50 mg/ml (5 %) glucose solution is to be used to dilute the concentrate for solution for infusion.
For instructions on dilution of the medicinal product before administration, see section 6.6.
Oxaliplatin is contraindicated in patients who:
– have a known history of hypersensitivity to oxaliplatin 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 x 109/l and/or platelet count of < 100 x 109/l.
– have a peripheral sensitive neuropathy with functional impairment prior to first course.
– have a severely impaired renal function (creatinine clearance < 30 ml/min) (see section 5.2).
Oxaliplatin concentrate for solution for infusion should only be used in specialised 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 infusion should be interrupted immediately and an appropriate symptomatic treatment started. Re-administration of oxaliplatin to such patients is contraindicated. Cross reactions, sometimes fatal, have been reported with all platinum compounds.
In case of oxaliplatin extravasation, the infusion 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 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.
Peripheral neuropathy
If neurological symptoms (paraesthesia, dysaesthesia) occur, the following recommended oxaliplatin dose 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. Localised moderate paraesthesias or paraesthesias 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, hypokalaemia, 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 x 109/l or platelets < 50 x 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 x 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 ºC or a sustained temperature > 38 ºC for more than one hour), or grade 3-4 thrombocytopenia (platelets < 50 x 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.
Respiratory disorders
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 lactate dehydrogenase (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). Caution should be exercised in patients with conditions that are associated with DIC such as infections, sepsis, etc.
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 hypokalaemia, 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).
Immunosuppressant effects/Increased susceptibility to infections
Administration of live or live attenuated vaccines in patients immunocompromised by chemotherapeutic agents, may results 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.
Hepatic impairment
In case of abnormal liver function test results, splenomegaly 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 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).
Other warnings
Peritoneal haemorrhage may occur when oxaliplatin is administered by intraperitoneal route (off-label route of administration).
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).
Vaccination with live or live attenuated vaccines should be avoided in patients receiving oxaliplatin (see section 4.4).
Pregnancy
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 9 months for women.
Breast-feeding
Excretion in breast milk has not been studied. Breast-feeding is contraindicated during oxaliplatin therapy (see section 4.3).
Fertility
Oxaliplatin may have an anti-fertility effect (see section 4.4).
Due to the potential genotoxic effects of oxaliplatin, appropriate contraceptive measures must be taken during and after cessation of therapy during 9 months for women and 6 months for men.
No studies on the effects on the ability to drive and use machines 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.
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.
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 according to the MedDRA convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data).
Further details are given after the table
System organ class
Very common
Common
Uncommon
Rare
Very rare
Not known***
Infections and infestations*
Infection
Rhinitis, upper respiratory tract infection, neutropenic sepsis
Sepsis +
Septic shock +
Blood and lymphatic system disorders*
Anaemia, neutropenia, thrombocytopenia, leukopenia, lymphopenia
Febrile neutropenia
Immuno-allergic thrombocytopenia, haemolytic anaemia****,
disseminated intravascular coagulation (DIC) +**
Haemolytic-uremic syndrome, autoimmune pancytopenia, pancytopenia, secondary leukaemia
Immune system disorders*
Allergy/allergic reaction ++
Metabolism and nutrition disorders
Anorexia, hyperglycaemia, hypokalaemia, hypernatraemia
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)**
Convulsions, ischemic or haemorrhagic cerebrovascular disorder
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
QT prolongation, which may lead to ventricular arrhythmias including Torsade de Pointes+**, 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**
Laryngospasm,
pneumonia and bronchopneumonia +
Gastrointestinal disorders*
Nausea, diarrhoea, vomiting, stomatitis/ mucositis, abdominal pain, constipation
Dyspepsia, gastroesophageal reflux, gastrointestinal haemorrhage, rectal haemorrhage
Ileus, intestinal obstruction
Colitis including Clostridioides difficile diarrhoea, pancreatitis
Intestinal ischemia +,
gastrointestinal ulcer and perforation+**,
oesophagitis
Hepatobiliary disorders
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
Focal nodular hyperplasia
Skin and subcutaneous tissue disorders
Skin disorder, alopecia
Skin exfoliation (i.e. Hand and Foot syndrome), rash erythematous, rash, hyperhidrosis, nail disorder
Hypersensitivity vasculitis
Musculoskeletal and connective tissue disorders
Back pain
Arthralgia, bone pain
Rhabdomyolysis +**
Renal and urinary disorders
Haematuria, dysuria, micturition frequency abnormal
Acute tubular necrosis, acute interstitial nephritis and acute renal failure
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.
*** Post-marketing experience.
**** Microangiopathic haemolytic anaemia associated with haemolytic uraemic syndrome (HUS) or Coombs positive haemolytic anaemia (see section 4.4).
+ Including fatal outcomes
++ Very common allergies/allergic reactions, occurring mainly during infusion, sometimes fatal. Common allergic reactions include skin rash, particularly urticaria, conjunctivitis and rhinitis. Common anaphylactic or anaphylactoid reactions include bronchospasm, angioedema, hypotension, sensation of chest pain and anaphylactic shock. Delayed hypersensitivity has also been reported with oxaliplatin hours or even days after the infusion.
+++ 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 / 5-FU/FA 85 mg/m2 every 2 weeks
Metastatic setting
Adjuvant setting
All grades
Grade 3
Grade 4
All grades
Grade 3
Grade 4
Anaemia
82.2
3
< 1
75.6
0.7
0.1
Neutropenia
71.4
28
14
78.9
28.8
12.3
Thrombocytopenia
71.6
4
< 1
77.4
1.5
0.2
Febrile neutropenia
5.0
3.6
1.4
0.7
0.7
0.0
Infections and infestations
Incidence by patient (%)
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
Immune system disorders
Incidence of allergic reactions by patient (%), by grade
Oxaliplatin and 5-FU/FA 85 mg/m2 every 2 weeks
Metastatic setting
Adjuvant setting
All grades
Grade 3
Grade 4
All grades
Grade 3
Grade 4
Allergic reactions/Allergy
9.1
1
< 1
10.3
2.3
0.6
Nervous system disorders
The dose limiting toxicity of oxaliplatin is neurological. It involves a sensory peripheral neuropathy characterised 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 paraesthesias of moderate intensity (2.3 %) or with paraesthesias 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 paraesthesia, dysaesthesia and hypoaesthesia. An acute syndrome of pharyngolaryngeal dysaesthesia 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 infusion helps to reduce the incidence of this syndrome (see section 4.4).
Occasionally other symptoms that have been observed include jaw spasm, muscle spasms, involuntary muscle contractions, myoclonus, coordination disorders, abnormal gait, 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.
Gastrointestinal disorders
Incidence by patient (%), by grade
Oxaliplatin/5-FU/FA 85 mg/m2 every 2 weeks
Metastatic setting
Adjuvant setting
All grades
Grade 3
Grade 4
All grades
Grade 3
Grade 4
Nausea
69.9
8
< 1
73.7
4.8
0.3
Diarrhoea
60.8
9
2
56.3
8.3
2.5
Vomiting
49.0
6
1
47.2
5.3
0.5
Mucositis / Stomatitis
39.9
4
< 1
42.1
2.8
0.1
Prophylaxis and/or treatment with potent antiemetic agents is indicated.
Dehydration, paralytic ileus, intestinal obstruction, hypokalaemia, metabolic acidosis and renal impairment may be caused by severe diarrhoea and/or emesis particularly when combining oxaliplatin with 5-fluorouracil (5-FU) (see section 4.4).
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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Symptoms
There is no known antidote to oxaliplatin. In cases of overdose, exacerbation of adverse events can be expected.
Management
Monitoring of haematological parameters should be initiated and symptomatic treatment given.
Ask anything about Oxaliplatin 5 mg/ml concentrate for solution for infusion. The assistant answers only from this leaflet — if the leaflet does not cover it, it will say so. It does not give medical advice.
Answers come from the patient leaflet published on the electronic medicines compendium (emc). They are not medical advice. Ask a pharmacist or your GP if you are unsure. For urgent help call NHS 111, or 999 in an emergency.
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