Adverse reactions : תופעות לוואי

4.8    Undesirable effects

The frequency of adverse reactions reported is based on a cumulative database of 1,893 patients receiving single agent carboplatin 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 to < 1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data).

System Organ Class                     Frequency   MedDRA Term
Infections and infestations            Common      Infections*
Not known   Pneumonia
Neoplasms, benign, malignant and       Not known   Treatment-related secondary unspecified (incl. cysts and polyps)               malignancy
Blood and lymphatic system             Very common Thrombocytopenia, neutropenia, disorders                                          leukopenia, anaemia Common      Haemorrhage*
Not known   Bone marrow failure, febrile neutropenia, haemolytic-uraemic syndrome
Immune system disorders                Common      Hypersensitivity, anaphylactoid type reaction
Metabolism and nutrition disorders     Not known   Dehydration, anorexia, hyponatraemia, tumour lysis
Nervous system disorders               Common      syndrome peripheral, paraesthesia, Neuropathy decrease of osteotendinous reflexes,
sensory disturbance, dysgeusia

Carboplatin Teva EM 12/2023 Notification
                                                Not known  Cerebrovascular accident*, Reversible
Posterior Leukoencephalopathy
Syndrome (RPLS)#
Eye disorders                         Common      Visual disturbance, rare cases of loss of vision
Ear and labyrinth disorders           Common      Ototoxicity
Cardiac disorders                     Common      Cardiovascular disorder* Not known   Cardiac failure*, Kounis syndrome
Vascular disorders                    Not known   Embolism*, hypertension, hypotension
Respiratory, thoracic and             Common      Respiratory disorder, interstitial lung mediastinal disorders                             disease, bronchospasm Gastrointestinal disorders            Very common Vomiting, nausea, abdominal pain Common      Diarrhoea, constipation, mucous membrane disorder
Not known   Stomatitis, pancreatitis#
Skin and subcutaneous tissue          Common      Alopecia, skin disorder disorders                             Not known   Urticaria, rash, erythema, pruritus Musculoskeletal and connective        Common      Musculoskeletal disorder tissue disorders
Renal and urinary disorders            Common      Urogenital disorder General disorders and                  Common      Asthenia administration site conditions         Not known   Injection site necrosis, injection site reaction, injection site extravasation,
injection site erythema, malaise
Investigation                          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.
# Based on the post-marketing experience.

Description of selected adverse reactions
Blood and lymphatic system disorders
Myelosuppression is the dose-limiting toxicity of carboplatin. 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 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 

Carboplatin Teva EM 12/2023 Notification
reversible, have resulted in infectious and hemorrhagic complications in 4% and 5% of patients given carboplatin, respectively. These complications have led to death in less than 1% of patients.
Anaemia with haemoglobin values below 8 g/dL has been observed in 15% of patients with normal baseline values. The incidence of anaemia is increased with increasing exposure to carboplatin.


Gastrointestinal disorders
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. These effects usually disappear within 24 hours after treatment and are generally responsive to or prevented by antiemetic medication. Vomiting is more likely when carboplatin 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.

Nervous system disorders
Peripheral neuropathy (mainly paraesthesias and decrease of osteotendinous reflexes) has occurred in        4% of patients administered carboplatin. Patients older than 65 years and patients previously treated with cisplatin, as well as those receiving prolonged treatment with carboplatin, appear to be at increased risk.
Clinically significant sensory disturbances (i.e., 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 in combination. This may also be related to longer cumulative exposure.

Ear and labyrinth disorders
Auditory defects out of the speech range with impairments in the high-frequency range (4,000-8,000 Hz) were found in serial audiometric investigations with a frequency of 15%. Very rare cases of hypoacusia have been reported.
In patients with a hearing organ predamaged due to cisplatin, a further exacerbation in the hearing function sometimes occurs during treatment with carboplatin.

Renal and urinary disorders
When given in usual doses, development of abnormal renal function has been uncommon, despite the fact that carboplatin 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 of the patients. Creatinine clearance has proven to be the most sensitive renal function measure in patients receiving carboplatin. 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 therapy.

Electrolytes
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.

Hepatobiliary disorders
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 of the patients. In a limited series of patients receiving very high dosages of carboplatin and autologous bone marrow transplantation, severe elevation of liver function tests has occurred.
Cases of an acute, fulminant liver cell necrosis occurred after high-dosed administration of carboplatin.
Carboplatin Teva EM 12/2023 Notification

Immune system disorders
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.


Other undesirable effects
Secondary acute malignancies after cytostatic combination therapies containing carboplatin have been reported.
Alopecia, fever and chills, mucositis, asthenia, malaise as well as dysgeusia have occasionally been observed.
In isolated cases, a haemolytic-uraemic syndrome occurred.
Isolated cases of cardiovascular incidents (cardiac insufficiency, embolism) as well as isolated cases of cerebrovascular accidents have been reported.
Cases of hypertension have been reported.

Local reactions
Reactions at the site of injection (burning, pain, reddening, swelling, urticaria, necrosis in connection with extravasation) have been reported.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il.