Oxaliplatin

Oxaliplatin is an antineoplastic medicine of the platinum-compound class. The platinum atom is complexed with 1,2-diaminocyclohexane (DACH) and an oxalate group, and oxaliplatin is a single enantiomer. It has a broad spectrum of cytotoxic activity in vitro and of antitumour activity in vivo, including in human colorectal cancer models and in several cisplatin-resistant models.

Mechanism of Action

• Activation: in physiological solutions oxaliplatin is converted non-enzymatically, by displacement of the labile oxalate ligand, into several transient reactive species, including monoaquo and diaquo DACH platinum.
• DNA cross-links: these derivatives bind covalently to DNA and form intrastrand and interstrand platinum–DNA cross-links, mainly between adjacent guanines (GG), adjacent adenine–guanine pairs (AG) and guanines separated by one nucleotide (GNG). The cross-links inhibit DNA replication and transcription.
• Cell cycle: the cytotoxicity is not specific to a phase of the cell cycle.
• Synergy with 5-fluorouracil: oxaliplatin and 5-fluorouracil (5-FU) show synergistic cytotoxicity in vitro and in vivo, and together they were more antiproliferative than either alone in several tumour models.
• Cisplatin resistance: activity has also been shown in several cisplatin-resistant models in vitro and in vivo.
• The mechanism has not been fully clarified, but the hydrated derivatives formed during biotransformation are thought to account for the cytotoxic and antitumour activity.

Pharmacokinetics

• What is measured: the pharmacokinetics of the individual active compounds have not been determined. The figures describe ultrafiltrable platinum, a mixture of all unbound active and inactive platinum species.
• Exposure: after a 2-hour infusion of 85 mg/m² every two weeks, mean peak ultrafiltrable platinum is about 0.814 μg/mL and AUC0–48 about 4.19 μg·h/mL. No accumulation occurs with 85 mg/m² every two weeks, steady state is reached in cycle 1, and variability between and within patients is generally low.
• Distribution: at the end of a 2-hour infusion about 15% of the platinum dose is in the circulation, and the other 85% distributes rapidly into tissues or is excreted in urine. The steady-state volume of distribution is about 440 L. Platinum binds irreversibly to plasma proteins (more than 90%, mainly albumin and gamma-globulins) and accumulates about 2-fold in red blood cells, where it appears to have no relevant activity. Half-lives in these matrices are close to the natural turnover of red cells and serum albumin.
• Metabolism: biotransformation is extensive and non-enzymatic. There is no evidence of cytochrome P450-mediated metabolism of the DACH ring. Up to 17 platinum-containing derivatives have been seen in plasma ultrafiltrate, including cytotoxic species (monochloro, dichloro, monoaquo and diaquo DACH platinum) and non-cytotoxic conjugates. No unchanged oxaliplatin was detectable in ultrafiltrate at the end of a 2-hour infusion.
• Elimination: ultrafiltrable platinum declines in three phases, with half-lives of about 0.43 hours, 16.8 hours and a long terminal phase of about 391 hours; mean clearance is about 17.4 L/h. Elimination is mainly renal: within five days of a single 2-hour infusion about 54% of the platinum was found in urine and only about 2% in faeces. Renal clearance of ultrafiltrable platinum is significantly correlated with glomerular filtration rate.
• Special populations: severe renal impairment (creatinine clearance below 30 mL/min) is a contraindication; see Administration and Dosage for mild to moderate renal impairment, hepatic impairment and age.

Oxaliplatin is used in combination with 5-fluorouracil (5-FU, a fluoropyrimidine) and folinic acid, for adults, as:

• Adjuvant treatment of stage III (Dukes C) colon cancer, after complete resection of the primary tumour.
• Treatment of metastatic colorectal cancer.

• History of hypersensitivity to oxaliplatin or to any of the excipients.
• Breastfeeding.
• Myelosuppression before the first cycle, shown by baseline neutrophils below 2 × 10⁹/L and/or platelets below 100 × 10⁹/L.
• Peripheral sensory neuropathy with functional impairment before the first cycle.
• Severe renal impairment (creatinine clearance below 30 mL/min).

The most frequent reactions of oxaliplatin with 5-FU and folinic acid are gastrointestinal (diarrhoea, nausea, vomiting, mucositis), haematological (neutropenia, thrombocytopenia) and neurological (acute and cumulative-dose peripheral sensory neuropathy). They were generally more frequent and more severe with oxaliplatin plus 5-FU/folinic acid than with 5-FU/folinic acid alone. Frequencies come from studies in metastatic cancer (416 patients) and adjuvant treatment (1,108 patients) with oxaliplatin plus 5-FU/folinic acid, and from post-marketing data.

Very common (≥1/10): infection; anaemia, neutropenia, thrombocytopenia, leukopenia, lymphopenia; allergy/allergic reaction; anorexia, hyperglycaemia, hypokalaemia, hypernatraemia; peripheral sensory neuropathy, sensory disturbance, taste disturbance, dysgeusia, headache; dyspnoea, cough, epistaxis; nausea, diarrhoea, vomiting, stomatitis/mucositis, abdominal pain, constipation; skin disorder, alopecia; back pain; fatigue, fever, asthenia, pain, administration-site reaction; increased liver enzymes, alkaline phosphatase, bilirubin and lactate dehydrogenase; weight increase (adjuvant treatment).

Common (≥1/100 to <1/10): rhinitis, upper respiratory tract infection, neutropenic sepsis (including fatal cases); febrile neutropenia; dehydration, hypocalcaemia; depression, insomnia; dizziness, motor neuritis, meningism; conjunctivitis, visual disturbance; haemorrhage, flushing, deep vein thrombosis, hypertension; hiccups, pulmonary embolism; dyspepsia, gastro-oesophageal reflux, gastrointestinal and rectal haemorrhage; skin exfoliation (hand-foot syndrome), erythematous rash, rash, hyperhidrosis, nail disorder; arthralgia, bone pain; haematuria, dysuria, abnormal urinary frequency; increased blood creatinine, weight loss (metastatic treatment); fall.

Uncommon (≥1/1,000 to <1/100): sepsis (including fatal cases); metabolic acidosis; nervousness; ototoxicity; ileus, intestinal obstruction.

Rare (≥1/10,000 to <1/1,000): immuno-allergic thrombocytopenia, haemolytic anaemia; dysarthria, posterior reversible encephalopathy syndrome (PRES); temporarily reduced visual acuity, visual field disturbance, optic neuritis, transient vision loss that reverses after treatment stops; deafness; interstitial lung disease (sometimes fatal), pulmonary fibrosis; colitis including Clostridium difficile diarrhoea, pancreatitis; disseminated intravascular coagulation (including fatal cases).

Very rare (<1/10,000): hepatic sinusoidal obstruction syndrome (veno-occlusive disease) and related liver changes such as peliosis hepatis, nodular regenerative hyperplasia and perisinusoidal fibrosis; acute tubular necrosis, acute interstitial nephritis and acute renal failure.

Not known: acute coronary syndrome (myocardial infarction, coronary vasospasm, angina pectoris) in patients given oxaliplatin with 5-FU and bevacizumab; oesophagitis; focal nodular hyperplasia of the liver; haemolytic uraemic syndrome, autoimmune pancytopenia, pancytopenia, secondary leukaemia; septic shock (including fatal cases); convulsions, ischaemic and haemorrhagic cerebrovascular disorder; QT prolongation with ventricular arrhythmia including torsade de pointes; laryngospasm, pneumonia and bronchopneumonia (including fatal cases); intestinal ischaemia (including fatal cases), gastrointestinal ulcer and perforation; rhabdomyolysis (including fatal cases); hypersensitivity vasculitis.

Reported frequencies of the main reactions with oxaliplatin 85 mg/m² plus 5-FU/folinic acid every two weeks (all grades, metastatic and adjuvant treatment): neutropenia 71.4% and 78.9%, anaemia 82.2% and 75.6%, thrombocytopenia 71.6% and 77.4%, nausea 69.9% and 73.7%, diarrhoea 60.8% and 56.3%, vomiting 49.0% and 47.2%, mucositis/stomatitis 39.9% and 42.1%, allergic reaction 9.1% and 10.3%. Grade 3 neutropenia occurred in 28% and 28.8% and grade 4 in 14% and 12.3%; grade 3 diarrhoea in 9% and 8.3% and grade 4 in 2% and 2.5%.

Neurological toxicity: the dose-limiting toxicity is a peripheral sensory neuropathy with dysaesthesia and/or paraesthesia of the extremities, with or without cramps, often worsened by cold. Symptoms occur in up to 95% of treated patients, usually clear between cycles, and last longer as cycles accumulate. Persistent symptoms occur in about 10% of patients at a cumulative dose of 850 mg/m² (10 cycles) and 20% at 1,020 mg/m² (12 cycles). Six months after adjuvant treatment stopped, 87% of patients had no or mild symptoms, and after up to 3 years of follow-up about 3% had persistent localised paraesthesia of moderate intensity (2.3%) or paraesthesia that may interfere with functional activities (0.5%). Acute neurosensory symptoms start within hours of administration and often follow cold exposure; an acute pharyngolaryngeal dysaesthesia (a subjective sensation of difficulty swallowing or breathing, without objective respiratory distress) occurs in 1–2% of patients and clears quickly, and a longer infusion lowers its incidence.

Important serious reactions: anaphylactic reactions, neutropenic sepsis and septic shock, haemolytic uraemic syndrome, disseminated intravascular coagulation, QT prolongation, rhabdomyolysis, interstitial lung disease, intestinal ischaemia, gastrointestinal ulcer with perforation or haemorrhage, hepatic sinusoidal obstruction syndrome and PRES.

• 5-fluorouracil: after a single oxaliplatin dose of 85 mg/m² given immediately before 5-FU, exposure to 5-FU did not change.
• Protein binding: in vitro, erythromycin, salicylates, granisetron, paclitaxel and sodium valproate did not significantly displace oxaliplatin from plasma proteins.
• Medicines that prolong the QT interval: use caution, and monitor the QT interval closely if they are combined with oxaliplatin.
• Medicines associated with rhabdomyolysis: use caution.
• Neurotoxic medicines: neurological toxicity needs particular monitoring when oxaliplatin is given with medicines that are themselves neurotoxic.
• Other myelosuppressive chemotherapy: the bone marrow effects of oxaliplatin may add to those of concomitant chemotherapy.
• Live or live-attenuated vaccines: avoid in patients receiving oxaliplatin; inactivated vaccines may be given, but the response may be reduced.
• Diluent: only 5% glucose should be used to dilute the concentrate.

Oxaliplatin is for adults only. Its use should be restricted to specialised medical oncology units, under the supervision of an experienced clinical oncologist. It is given as an intravenous infusion, diluted in 250–500 mL of 5% glucose to a concentration of not less than 0.2 mg/mL (the highest concentration used in practice for an 85 mg/m² dose is 0.70 mg/mL), through a central or peripheral vein over 2 to 6 hours. No hyperhydration is needed. Oxaliplatin must always be given before the fluoropyrimidine (5-fluorouracil). If extravasation occurs, stop the infusion immediately.

Recommended Dose

• Adjuvant treatment of stage III colon cancer: 85 mg/m² intravenously every two weeks for 12 cycles (6 months).
• Metastatic colorectal cancer: 85 mg/m² intravenously every two weeks until disease progression or unacceptable toxicity.
• Oxaliplatin has been used mainly with 5-FU in continuous-infusion regimens; for the two-weekly regimen, 5-FU was given as a bolus plus continuous infusion. The dose is adjusted to tolerability.

Dose Adjustments for Side Effects

• Neurological symptoms: if paraesthesia or dysaesthesia lasts more than seven days and is troublesome, reduce the next dose from 85 to 65 mg/m² (metastatic treatment) or 75 mg/m² (adjuvant treatment). The same reduction applies if paraesthesia without functional impairment persists to the next cycle. If paraesthesia with functional impairment persists to the next cycle, stop treatment. If symptoms improve after stopping, resumption may be considered.
• Acute pharyngolaryngeal dysaesthesia: if it occurs during or in the hours after a 2-hour infusion, make the next infusion last 6 hours.
• Blood counts: if neutrophils are below 1.5 × 10⁹/L or platelets below 50 × 10⁹/L, delay the next cycle until values return to acceptable levels. A full blood count with differential is done before starting and before each cycle.
• Mucositis or stomatitis (with or without neutropenia): delay the next treatment until it falls to grade 1 or below and/or neutrophils are at least 1.5 × 10⁹/L.
• Grade 4 diarrhoea, grade 3–4 neutropenia (neutrophils below 1.0 × 10⁹/L), febrile neutropenia or grade 3–4 thrombocytopenia (platelets below 50 × 10⁹/L): reduce oxaliplatin from 85 to 65 mg/m² (metastatic treatment) or 75 mg/m² (adjuvant treatment), in addition to any reduction needed for 5-FU. The usual dose adjustments for 5-FU toxicities are followed when it is given with oxaliplatin.
• See Special Instructions for the events that call for interruption or stopping.

Special Populations

• Renal impairment: do not give in severe impairment (creatinine clearance below 30 mL/min). In mild to moderate impairment the recommended dose is 85 mg/m², with close monitoring for adverse reactions and dose adjustment to toxicity.
• Hepatic impairment: in a phase I study, the frequency and severity of hepatobiliary disorders seemed related to disease progression and previous liver function abnormalities. No specific dose adjustment was made in patients with abnormal liver function tests during clinical development.
• Elderly: no increase in severe toxicity was seen in patients over 65 years, with oxaliplatin alone or with 5-FU, so no specific adjustment is needed.
• Children and adolescents: oxaliplatin is not specifically indicated in children. The efficacy of oxaliplatin alone in paediatric populations with solid tumours has not been established.

Specialised Setting

Oxaliplatin should be used only in specialised medical oncology units, under an experienced clinical oncologist.

Hypersensitivity and Extravasation

Patients with a history of allergic reactions to other platinum products need special clinical monitoring. If anaphylactic-type reactions appear, stop the infusion immediately and start appropriate symptomatic treatment; giving oxaliplatin again is contraindicated in these patients. Cross-reactions, sometimes fatal, have been reported with all platinum compounds. If extravasation occurs, stop the infusion and apply the usual local symptomatic treatment.

Neurological Toxicity and Peripheral Neuropathy

Neurological toxicity needs particular monitoring, especially with other neurotoxic medicines. A neurological examination should be done regularly before and after each administration. Dose adjustments for neuropathy are described above. Patients should be told that peripheral neuropathy symptoms may persist after treatment ends: moderate localised paraesthesia, or paraesthesia that interferes with functional activities, can continue for up to 3 years after adjuvant treatment.

Posterior Reversible Encephalopathy Syndrome (PRES)

PRES, also called reversible posterior leukoencephalopathy syndrome, has been reported in patients given oxaliplatin with chemotherapy. It is a rare, reversible condition of rapid neurological evolution that can include seizures, hypertension, headache, confusion, blindness and other visual and neurological disturbances. The diagnosis is confirmed by brain imaging, preferably MRI.

Nausea, Vomiting, Diarrhoea and Dehydration

Gastrointestinal toxicity calls for prophylactic and/or therapeutic antiemetic treatment, and potent antiemetics are strongly recommended. Severe diarrhoea or vomiting can lead to dehydration, paralytic ileus, intestinal obstruction, hypokalaemia, metabolic acidosis and renal impairment, particularly when oxaliplatin is combined with 5-FU. Intestinal ischaemia, including fatal cases, has been reported; if it occurs, stop oxaliplatin and start appropriate measures. Patients should be told about the risk of diarrhoea and vomiting, mucositis/stomatitis and neutropenia so that they can contact their prescriber urgently.

Haematological Toxicity and Infections

Patients with severe, persistent myelosuppression are at high risk of infection. Sepsis, neutropenic sepsis and septic shock, including fatal cases, have been reported; if any occurs, stop oxaliplatin. Haemolytic uraemic syndrome is a life-threatening reaction of unknown frequency: stop treatment at the first evidence of microangiopathic haemolytic anaemia, such as a rapid fall in haemoglobin with thrombocytopenia and a rise in bilirubin, creatinine, blood urea nitrogen or LDH. Renal failure can be irreversible and dialysis may be needed. Disseminated intravascular coagulation, including fatal cases, has been reported; stop treatment if it occurs, and take care in patients with related conditions such as infection or sepsis.

Lung Symptoms

If unexplained respiratory symptoms appear (non-productive cough, dyspnoea, crackles or radiological infiltrates), withhold oxaliplatin until further tests have ruled out interstitial lung disease.

QT Prolongation

QT prolongation can raise the risk of ventricular arrhythmias, including torsade de pointes, which can be fatal. Monitor the QT interval closely and regularly, before and after administration. Take care in patients with a history of or predisposition to QT prolongation, those taking QT-prolonging medicines and those with electrolyte disturbances such as hypokalaemia, hypocalcaemia or hypomagnesaemia. Interrupt oxaliplatin if the QT interval is prolonged.

Rhabdomyolysis, Gastrointestinal Ulcer and the Liver

Rhabdomyolysis, including fatal cases, has been reported. If muscle pain and swelling occur with weakness, fever or dark urine, stop oxaliplatin and take suitable measures if it is confirmed. Oxaliplatin can cause gastrointestinal ulcer with haemorrhage and perforation, which can be fatal; if an ulcer occurs, stop oxaliplatin. Abnormal liver function tests, splenomegaly or portal hypertension that are not clearly due to liver metastases should raise suspicion, in very rare cases, of drug-induced hepatic vascular disorders.

Vaccines and Immunosuppression

Live or live-attenuated vaccines given to patients made immunocompromised by chemotherapy can cause serious or fatal infections, so avoid them during oxaliplatin treatment. Inactivated or killed-virus vaccines can be given, but the response may be reduced.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: no safety information is available in pregnant women, and animal studies showed reproductive toxicity. Oxaliplatin is not recommended in pregnancy or in women of childbearing potential who are not using contraception. It should be considered only after the patient has been properly informed of the risk to the foetus and has given consent.
• Contraception: women should use adequate contraception during therapy and for 4 months after it ends. Because of potentially genotoxic effects, contraception is advised for 6 months after the end of treatment in men.
• Breastfeeding: excretion in milk has not been studied; oxaliplatin is contraindicated while breastfeeding.
• Fertility: oxaliplatin may have an anti-fertility effect that could be irreversible. Men are advised not to father a child during treatment or for up to 6 months afterwards, and to seek advice on sperm preservation before treatment.
• Route: peritoneal haemorrhage can occur if oxaliplatin is given intraperitoneally, which is not an authorised route.

Lactose

Each mL of the concentrate contains 45 mg lactose monohydrate (180 mg in the 4 mL vial, 450 mg in 10 mL, 900 mg in 20 mL and 1,800 mg in 40 mL).

Effect on Driving

No studies on the ability to drive or use machines have been done. The increased risk of dizziness, nausea and vomiting and of other neurological symptoms that can affect gait and balance may have a minimal to moderate influence on the ability to drive and use machines.

Store below 25 °C. Keep the vial in the outer carton to protect it from light. Refrigeration is not required.

After dilution in 5% glucose, the infusion solution is physically and chemically stable for 24 hours at 2–8 °C and for 6 hours at 25 °C. From a microbiological point of view, use it immediately. Otherwise in-use storage times and conditions are the user’s responsibility and should normally not exceed 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.

The vials are clear Type I glass with a bromobutyl rubber stopper, aluminium seal and polypropylene snap cap, in packs of one 4, 10, 20 or 40 mL vial; not all sizes may be marketed.

2 years before the vial is opened (Oxaliplatino Teva 5 mg/mL concentrate for solution for infusion). For the diluted solution, see Storage Conditions.

Prescription only (Rx), for use in specialised medical oncology units under the supervision of an experienced clinical oncologist. Oxaliplatin is given as an intravenous infusion, so it is supplied to the hospital or clinic that administers it. It does not need cold-chain delivery; store below 25 °C.