Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Accord Healthcare Limited, 319 Pinner Road, North Harrow, Middlesex, HA1 4HF, United Kingdom
Carboplatin is contraindicated in:
Dosage adjustment may allow use in the presence of mild impairment (see section 4.2).
Myelosuppression as a result of carboplatin treatment is closely related to the renal clearance of the drug. Therefore, in patients with abnormal renal function, or who are receiving concomitant therapy with nephrotoxic drugs, myelosuppression, especially thrombocytopenia, may be more severe and prolonged.
The occurrence, severity and protraction of toxicity is likely to be greater in patients who have received extensive prior treatment with the drug for their disease or with cisplatin, have poor performance status and are advanced in years. Renal function parameters should be assessed prior to, during and after carboplatin therapy Initial carboplatin dosages in these groups of patients should be appropriately reduced (see section 4.2) and the effects carefully monitored through frequent blood counts between courses. Myelosuppressive effects may be additive to those of concomitant chemotherapy.
Peripheral blood counts (including platelets, white blood cells and haemoglobin) should be followed during and after therapy. Combination therapy with other myelosuppressive drugs may require modification of dosage/timing of schedules in order to minimize additive effects.
Carboplatin courses should not, in general, be repeated more frequently than every 4 weeks in order to ensure that the nadir in blood counts has occurred and there has been recovery to a satisfactory level.
Patients with severe and persistant myelosuppression are at high risk of infectious complications including fatal outcomes (see section 4.8). If any of these events occurs, carboplatin should be interrupted and dose modification or discontinuation should be considered.
As with other platinum-based drugs, allergic reactions appearing most often during administration may occur and necessitate discontinuation of infusion. Patients should be observed carefully and an appropriate symptomatic treatment (including antihistamines, adrenaline and/or glucocorticoids) must also be initiated in such cases. Cross reactions, sometimes fatal, have been reported with all the platinum compounds (see sections 4.3 and 4.8).
The vial stopper contains dry natural rubber (a derivative of latex), which may cause allergic reactions.
In patients with impaired renal function, the effect of carboplatin on the haemotopoietic system is more pronounced and longer-acting than in patients with normal renal function. In this risk group, therapy with carboplatin must be performed with special caution (see section 4.2).
Carboplatin should only be administered under the supervision of a qualified physician who is experienced in the use of chemotherapeutic agents. Diagnostic and treatment facilities should be readily available for management of therapy and possible complications.
Peripheral blood counts, renal and hepatic function tests should be monitored closely. Blood counts should be performed prior to commencement of carboplatin therapy and at weekly intervals thereafter. The drug should be discontinued if abnormal depression of the bone marrow or abnormal renal or hepatic function is seen.
Leukopenia, neutropenia, and thrombocytopenia are dose-dependent and dose-limiting. Peripheral blood counts should be monitored during carboplatin treatment. This will monitor toxicity and help determine the nadir and recovery of haematological parameters and assist in subsequent dosage adjustments. Median day of nadir is day 21 in patients receiving single agent carboplatin and day 15 in patients receiving carboplatin in combination with other chemotherapeutic agents. In general, single intermittent courses of carboplatin should not be repeated until leukocyte, neutrophil, and platelet counts have returned to normal. Lowest levels of platelets are generally seen between days 14 and 21 of initial therapy. A greater reduction is seen in patients who previously received extensive myelosuppressive chemotherapy. Lowest levels of white cells occur generally between days 14 and 28 of initial therapy. If neutrophil levels fall below 2000 cells/mm³ or platelets are less than 100,000 cells/mm³ then postponement of carboplatin therapy until bone barrow recovery is evident, should be considered. This recovery usually takes 5 to 6 weeks. Transfusions may be necessary and dosage reductions recommended for subsequent treatment.
Anaemia is frequent and cumulative, however rarely requires a transfusion.
Haemolytic-uraemic syndrome (HUS) is a life-threatening side effect. Carboplatin 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.
Haemolytic anaemia with the presence of serologic drug-induced antibodies has been reported in patients treated with carboplatin. This event can be fatal.
Acute promyelocytic leukaemia and myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) have been reported years after therapy with carboplatin and other antineoplastic treatments.
Cases of hepatic venoocclusive disease (sinusoidal obstruction syndrome) have been reported, some of which were fatal. Patients should be monitored for signs and symptoms of abnormal liver function or portal hypertension which do not obviously result from liver metastases.
In post marketing experience tumour lysis syndrome (TLS) has been reported in patients following the use of carboplatin alone or in combination with other chemotherapeutic agents. Patient at high risk of TLS, such as patients with high proliferative rate, high tumor burden, and high sensitivity to cytotoxic agents, should be monitored closely and appropriate precaution taken.
The incidence and severity of nephrotoxicity may increase in patients who have impaired kidney function before carboplatin treatment. It is not clear whether an appropriate hydration programme might overcome such an effect but dosage reduction or discontinuation of therapy is required in the presence of severe alteration in renal function test. Impairment of renal function is more likely in patients who have previously experienced nephrotoxicity as a result of Cisplatin therapy.
Although peripheral neurologic toxicity is generally common and mild, limited to paresthesia and decreases in osteotendinous reflexes, its frequency is increased in patients older than 65 years and/or in patients previously treated with cisplatin. Monitoring and neurological examinations should be carried out at regular intervals.
Visual disturbances, including loss of vision, have been reported after the use of carboplatin in doses higher than those recommended in patients with renal impairment. Vision appears to recover totally or to a significant extent within weeks of stopping these high doses.
Cases of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) have been reported in patients receivingcarboplatin in combination chemotherapy. RPLS is a rare, reversible (after treatment discontinuation), 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)
In studies involving combination therapy with carboplatin and cyclophosphamide, elderly patients treated with carboplatin were more likely to develop severe thrombocytopenia than younger patients. Because renal function is often decreased in the elderly, renal function should be considered when determining dosage.
Auditory defects have been reported during carboplatin therapy. Ototoxicity may be more pronounced in children and is more likely seen in patients previously treated with cisplatin. Cases of hearing loss with a delayed onset have been reported in pediatric patients. A long-term audiometric follow-up in this population is recommended.
Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including carboplatin may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving carboplatin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Aluminium containing equipment should not be used during preparation and administration of Carboplatin (See section 4.5).
Carboplatin may interact with aluminium to form a black precipitate. Needles, syringes, catheters or IV administration sets that contain aluminium parts which may come into contact with carboplatin, should not be used for the preparation or administration of the drug.
Due to the increase of thrombotic risk in cases of tumoral diseases, the use of anticoagulative treatment is frequent. The high intra-individual variability of the coagulabilty during diseases, and the possibility of interaction between oral anticoagulants and anticancer chemotherapy, may require an increase in frequency of INR monitoring if a patient is treated with oral anticoagulants.
Concomitant use contraindicated:
Yellow fever vaccine: risk of generalized disease mortal (see section 4.3).
Concomitant use not recommended:
Concomitant use to take into consideration:
Ciclosporin (and by extrapolation tacrolimus and sirolimus): Excessive immunosuppression with risk of lymphoproliferation.
Concurrent therapy with nephrotoxic drugs or ototoxic drugs such as amino glycosides, vancomycin, capreomycin and diuretics, may increase or exacerbate toxicity, particularly in renal failure patients, due to Carboplatin induced changes in renal clearance.
Loop diuretics: The concomitant use of carboplatin with loop diuretic should be approached with caution due to the cumulative nephrotoxicity and ototoxicity.
Combination therapy with other myelosuppressive agents may require dose changes or rescheduling of doses in order to minimize the additive myelosuppressive effects.
Carboplatin can cause foetal harm when administered to a pregnant woman. Carboplatin has been shown to be embryotoxic and teratogenic in rats receiving the drug during organogenesis. No controlled studies in pregnant women have been conducted.
Safe use of carboplatin in pregnancy has not been established. Both men and women receiving carboplatin should be informed of the potential risk of adverse effects on reproduction (see section 5.3). Women of childbearing potential should be advised to avoid becoming pregnant by using effective contraception and should be fully informed of the potential hazard to the foetus should they become pregnant during carboplatin therapy. Carboplatin should not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the foetus.
It is not known whether Carboplatin is excreted in breast milk.
To avoid possible harmful effects in the infant, breast-feeding must be stopped during carboplatin therapy.
Gonadal suppression resulting in amenorrhoea or azospermia may occur in patients receiving antineoplastic therapy. These effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian functional impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.
Men of sexually mature age treated with carboplatin are advised not to father a child during treatment and up to 6 months afterwards. Male patients should seek advice about sperm preservation prior to initiation of the therapy because of the possibility of irreversible infertility due to therapy with carboplatin.
No studies of the effects on the ability to drive and use machines have been performed. However, carboplatin may cause nausea, vomiting, vision abnormalities and ototoxicity; therefore, patients should be warned of the potential effect of these events on the ability to drive or to use machines.
The frequency of adverse reactions reported is based on a cumulative database of 1,893 patients receiving single agent carboplatin injection and post-marketing experience.
The list is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, ≤1/100), rare (≥1/10,000, ≤1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data)
Not known: Treatment related secondary malignancy
Common: Infections*
Not known: Pneumonia
Very common: Thrombocytopenia, neutropenia, leukopenia, anaemia
Common: Haemorrhage*
Not known: Bone marrow failure, haemolytic-uraemic syndrome
Rare: febrile neutropenia,
Common: Hypersensitivity, anaphylactoid type reaction
Not known: Dehydration, anorexia, Tumor lysis syndrome
Rare: hyponatraemia
Common: Neuropathy peripheral, paraesthesia, decrease of osteotendinous reflexes, sensory disturbance, dysgeusia
Not known: Cerebrovascular accident*, Reversible Posterior Leukoencephalopathy Syndrome (RPLS).
Common: Visual disturbance (incl. rare cases of loss of vision)
Common: Ototoxicity
Common: Cardiovascular disorder*
Not known: Cardiac failure*
Not known: Embolism*, hypertension, hypotension
Common: Respiratory disorder, interstitial lung disease, bronchospasm
Very common: Vomiting, nausea, abdominal pain
Common: Diarrhoea, constipation, mucous membrane disorder
Not known:__ Stomatitis, Pancreatitis.
Common: Alopecia, skin disorder
Not known: Urticaria, rash, erythema, pruritus
Common: Musculoskeletal disorder
Common: Urogenital disorder
Common: Asthenia
Not known: Injection site necrosis, injection site reaction, injection site extravasation, injection site erythema, malaise
Very Common: Creatinine renal clearance decreased, blood urea increased, blood alkaline phosphatase increased, aspartate aminotransferase increased, liver function test abnormal, blood sodium decreased, blood potassium decreased, blood calcium decreased, blood magnesium decreased.
Common: Blood bilirubin increased, blood creatinine increased, blood uric acid increased
* Fatal in <1%, fatal cardiovascular events in <1% included cardiac failure, embolism, and cerebrovascular accident combined.
Myelosuppression is the dose-limiting toxicity of carboplatin injection. In patients with normal baseline values, thrombocytopenia with platelet counts below 50,000/mm³ occurs in 25% of patients, neutropenia with granulocyte counts below 1,000/mm³ in 18% of patients, and leukopenia with WBC counts below 2,000/mm³ in 14% of patients. The nadir usually occurs on day 21. Myelosuppression can be worsened by combination of carboplatin injection with other myelosuppressive compounds or forms of treatment.
Myelotoxicity is more severe in previously treated patients, in particular in patients previously treated with cisplatin and in patients with impaired kidney function. Patients with poor performance status have also experienced increased leukopenia and thrombocytopenia. These effects, although usually reversible, have resulted in infectious and hemorrhagic complications in 4% and 5% of patients given carboplatin injection, respectively. These complications have led to death in less than 1% of patients.
Anaemia with haemoglobin values below 8g/dl has been observed in 15% of patients with normal baseline values. The incidence of anaemia is increased with increasing exposure to carboplatin injection.
Myelosuppression may be more severe and prolonged in patients with impaired renal function, extensive prior treatment, poor performance status and age above 65.
At maximum tolerated dosages of carboplatin administered as a single agent, thrombocytopenia, with nadir platelet counts of less than 50 × 109/l, occurs in about a third of the patients. The nadir usually occurs between days 14 and 21, with recovery within 35 days from the start of therapy.
Leukopenia has also occurred in approximately 20% of patients but its recovery from the day of nadir (day 14-28) may be slower and usually occurs within 42 days from the start of therapy. Neutropenia with granulocyte counts below 1 × 109/l occurs in approximately one fifth of patients. Haemoglobin values below 9.5 mg/100ml have been observed in 48% of patients with normal base-line values.
Secondary acute malignancies after cytostatic combination therapies containing carboplatin have been reported.
Very rare: Pulmonary fibrosis manifested by tightness of the chest and dyspnoea. This should be considered if a pulmonary hypersensitivity state is excluded (see General disorders below).
Vomiting occurs in 65% of patients, in one-third of whom it is severe. Nausea occurs in an additional 15%. Previously treated patients (in particular patients previously treated with cisplatin) appear to be more prone to vomiting. Nausea and vomiting are generally delayed until 6 to 12 hours after administration of carboplatin, are readily controlled or prevented with antiemetic s and disappear within 24hours. Vomiting is more likely when carboplatin injection is given in combination with other emetogenic compounds.
The other gastrointestinal complaints corresponded to pain in 8% of patients, diarrhoea, and constipation in 6% of patients. Cramps have also been reported.
Peripheral neuropathy (mainly paresthesias and decrease of osteotendinous reflexes) has occurred in 4% of patients administered carboplatin injection. Patients older than 65 years and patients previously treated with cisplatin, as well as those receiving prolonged treatment with carboplatin injection, appear to be at increased risk.
Clinically significant-sensory disturbances (ie, visual disturbances and taste modifications) have occurred in 1% of patients.
The overall frequency of neurologic side effects seems to be increased in patients receiving carboplatin injection in combination. This may also be related to longer cumulative exposure. Parasthesias present prior to treatment, especially if caused by cisplatin, may persist or worsen during carboplatin therapy (see section 4.4).
Visual disturbances, including sight loss, are usually associated with high dose therapy in renally impaired patients.
Very common: A subclinical decrease in hearing acuity in the high frequency range (4000-8000 Hz), determined by audiogram, occurred in 15% of patients. Very rare cases of hypoacusia have been reported.
Common: Tinnitus was also commonly reported. Hearing loss as a result of cisplatin therapy may give rise to persistent or worsening symptoms. At higher than recommended doses, in common with other ototoxic agents, clinically significant hearing loss has been reported to occur in paediatric patients when carboplatin is administered.
Modification of liver function in patients with normal baseline values was observed, including elevation of total bilirubin in 5%, SGOT in 15%, and alkaline phosphatase in 24% of patients. These modifications were generally mild and reversible in about one-half the patients.
In a limited series of patients receiving very high dosages of carboplatin injection and autologous bone marrow transplantation, severe elevation of liver function tests has occurred.
Cases of an acute, fulminant liver cell necrosis occured after high-dose administration of carboplatin.
When given in usual doses, development of abnormal renal function has been uncommon, despite the fact that carboplatin injection has been administered without high-volume fluid hydration and/or forced diuresis. Elevation of serum creatinine occurs in 6% of patients, elevation of blood urea nitrogen in 14%, and of uric acid in 5% of patients. These are usually mild and are reversible in about one-half the patients. Creatinine clearance has proven to be the most sensitive renal function measure in patients receiving carboplatin injection. Twenty-seven percent (27%) of patients who have a baseline value of 60 mL/min or greater, experience a reduction in creatinine clearance during carboplatin injection therapy. Impairment of renal function is more likely in patients who have previously experienced nephrotoxicity as a result of cisplatin therapy.
Very common: Renal toxicity is usually not dose-limiting in patients receiving carboplatin, nor does it require preventive measures such as high volume fluid hydration or forced diuresis.
Common: Renal function impairment, as defined by a decrease in the creatinine clearance below 60 ml/min.
Anaphylactic-type reactions, sometimes fatal, may occur in the minutes following injection of the product: facial oedema, dyspnoea, tachycardia, low blood pressure, urticaria, anaphylactic shock, bronchospasm.
Fever with no apparent cause has also been reported.
Erythematous rash, fever and pruritis have been observed. These were reactions similar to those seen after cisplatin therapy but in a few cases no cross-reactivity was present.
Decreases in serum sodium, potassium, calcium, and magnesium occur in 29%, 20%, 22%, and 29% of patients, respectively. In particular, cases of early hyponatraemia have been reported. The electrolyte losses are minor and mostly take a course without any clinical symptoms.
Isolated cases of cardiovascular incidents (cardiac insufficiency, embolism) as well as isolated cases of cerebrovascular accidents have been reported.
Reactions at the site of injection (burning, pain, reddening, swelling, urticaria, necrosis in connection with extravasation) have been reported.
Fever, chills and mucositis have occasionally been observed.
Very common: The alkaline phosphatase level is increased more frequently than SGOT, SGPT or total bilirubin The majority of these abnormalities regress spontaneously during the course of treatment.
Rare: Severe hepatic dysfunction (including acute liver necrosis) has been reported after administration of higher than recommended carboplatin dosages.
Reporting suspected adverse reactions after authorization 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 Yellow Card Scheme; Website: www.mhra.gov.uk/yellowcard.
This medicinal product must not be mixed with other medicinal product except those mentioned in section 6.6.
Carboplatin may interact with aluminium to form a black precipitate. Needles, syringes, catheters or intravenous sets containing aluminium parts that may come into contact with carboplatin should not be used for preparation or administration of carboplatin. Precipitation can lead to a reduction of the antineoplastic activity.
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