Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: KEOCYT, Immeuble Cap Sud, 106 avenue Marx Dormoy, 92120 Montrouge, FRANCE
Many patients treated with Zanosar have experienced some degree of renal toxicity, as evidenced by an increase in plasma creatinine and proteinuria. The mechanisms of renal toxicity are still unclear but experimental and clinical data suggest tubular toxicity, such as tubular acidosis, low molecular weight proteinuria, hypokalemia and hypocalcaemia.
Such toxicity is dose-related and cumulative in most cases and may be severe or fatal. However, it can also appear after the first administration.
Renal function must be monitored immediately before and two weeks after each course of therapy. Routine surveillance consists of the measurement of plasma creatinine with the evaluation of glomerular filtration rate (GFR) by the Modification of Diet in Renal Diseases (MDRD) formula. Before the initiation of treatment (i.e. before the first cycle of therapy) and two to four weeks after the end of the last cycle of therapy, proteinuria and serum electrolytes should also be measured, in addition to plasma creatinine.
Reduction of the dose of Zanosar or discontinuation of treatment is mandatory in the presence of significant renal toxicity (see section 4.2).
Adequate hydration with at least one litre of sodium chloride 0.9% before the administration of Zanosar may help reduce the risk of toxicity to the renal tubular epithelium by decreasing renal and urinary concentration of the drug and its metabolites.
Use of Zanosar in patients with preexisting renal disease requires a judgment by the physician of the potential benefit of treatment as opposed to the known risk of serious renal damage.
This drug should not be used concomitantly with other potential nephrotoxic drugs.
Liver function tests should be done on a regular basis, to detect hepatic toxicity. Reduction of the dose or discontinuation should be considered in case of hepatic toxicity.
Complete blood counts should be done on a regular basis, to detect haematologic toxicity. Reduction of the dose or discontinuation should be considered in case of haematologic toxicity (usually due to the association of Zanosar with another chemotherapy).
Haematological toxicity has been rare, most often involving mild decreases in hematocrit values. However, fatal haematological toxicity with substantial reductions in leukocyte and platelet count has been observed.
Rare cases of myelodysplastic syndromes or acute myeloid leukemia have been reported in patients previously treated by a streptozocin-based chemotherapy, who received subsequent peptide receptor radionuclide therapy
The administration of live or live-attenuated vaccines in patients with chemotherapy-related immunodeficiency, including streptozocin, may provoke severe or life-threatening infections. Dead or inactivated vaccines can be administered; however, they can induce lower response in this population (see sections 4.3 and 4.5).
Streptozocin is associated with a high emetic potential which may be treatment-limiting. Antiemetic premedication is recommended to prevent nausea and vomiting.
Zanosar sterile powder is irritating to tissues. Extravasation may cause severe tissue lesions and necrosis.
In case of extravasation, administration should be stopped immediately. Healthcare professionals should take appropriate protection measures. The initial aim is to minimize the volume of extravasated product into the surrounding tissues and to aspirate as much as possible product from the cannula with a syringe. Cold packs should be applied and appropriate medical monitoring should be performed.
Live and live-attenuated vaccines: Concomitant use may induce fatal generalized vaccinal disease and is contraindicated (see section 4.3).
Immunosuppressive drugs: increased immunosuppression with a risk of lymphoproliferative disorders.
Vitamin K antagonists: The important intra-variability of the coagulation status and of the increased thrombotic and haemorrhagic risks during tumour diseases, and the potential interaction between oral anticoagulants and anticancer chemotherapy, require increased frequency of INR (International Normalised Ratio) monitoring, if it is decided to treat the patient with oral anticoagulants.
Nephrotoxic drugs: Zanosar should not be used in association with nephrotoxic drugs.
Zanosar is not recommended in women of childbearing potential not using contraception. An effective method of contraception should be used during treatment. A period of contraception post-treatment of 90 days for men, and 30 days for women should be applied.
There are no data from the use of Zanosar in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3).
Zanosar is not recommended during pregnancy.
Zanosar should be used in pregnancy only if the potential benefit to the mother outweighs the potential risks to the fetus.
It is unknown whether streptozocin and/or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Therefore, breast-feeding should be discontinued during treatment with Zanosar.
There are no data on fertility in humans. In non-clinical studies, streptozocin adversely affected fertility when administered to male and female rats (see section 5.3). Therefore, men being treated with streptozocin are advised not to attempt to father a child for 90 days after treatment and to seek advice on conservation of sperm prior to treatment.
Streptozocin may cause confusion, lethargy or depression.
Patients should be advised not to drive or use machines if they experience any adverse reaction that may affect their ability to perform these tasks.
The most common adverse reactions reported with Zanosar are gastrointestinal and renal disorders.
The former are not life threatening but can be disturbing for the patient and may result in treatment discontinuation if very severe; the latter are indolent but potentially serious.
The frequency and intensity of nausea and vomiting has decreased over time, due to the utilization of efficacious antiemetic drugs. Renal toxicity can be avoided or reduced with careful assessment of renal function before and during treatment, patient hydration during streptozocin administration, and dose adjustment in case of renal function impairment.
Streptozocin has the potential to cause hyperglycaemia due to its mechanism of action; however, glucose intolerance or diabetes have been rarely reported in clinical practice.
Myelotoxicity is usually mild and transient. Hepatic toxicity has been described, but not reported as a major issue during treatment.
Tabulated list of adverse reactions (from published data and post-marketing experience):
Adverse reactions are listed below by MedRA system organ class and frequency using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and not known (cannot be estimated from the available data).
Frequency not known: Decreased hematocrit, leukocytes and platelet counts
Frequency not known: glucose intolerance
Frequency not known: Confusion, lethargy, depression
Very common: Severe nausea and vomiting, Diarrhea
Frequency not known: Nephrogenic diabetes insipidus
Frequency not known: Elevated liver enzymes (SGOT and LDH), Hepatotoxicity, Hypoalbuminemia
Common: Renal toxicity-proteinuria, proximal tubular injury, phosphaturia, acute renal failure, Urinary disorders
Frequency not known: Fever, Injection site reactions
Patients treated with Zanosar have experienced nausea and vomiting. In the earliest studies, up to 80-90% of patients reported nausea and vomiting, while in the most recent ones, this percentage ranges from 23 to 37%. In the earliest studies, severe nausea and vomiting was reported in 20 to 41% of patients. In a randomized study published in 2014, grade 3-4 nausea and vomiting was reported in 4.6% of patients. Severe nausea and vomiting occasionally required discontinuation of drug therapy. Some patients experienced diarrhea.
Literature data suggest that renal and urinary disorders are frequent. Renal toxicity is dose-related and cumulative in most cases and may be severe or fatal.
However, an accurate incidence cannot be provided in the absence of recent prospective studies, using comprehensive toxicity reporting. In prospective studies published after 2000, no grade 3 to 5 toxicity was reported (See section 4.4).
Serum aminotransferase elevations can occur in up to two-thirds of patients treated with streptozocin, but the abnormalities are generally mild, transient and not associated with symptoms or jaundice. Rarely, severe cases have been reported (see section 4.4).
Acute haematological toxicity is rare, consisting most often of mild decreases in hematocrit values, leukocytes and platelets counts. However, fatal haematological toxicity with substantial reductions in leukocyte and platelet count has been observed. Haematological toxicity may increase the sensitivity to infections.
Rare cases of late haematological toxicity (myelodysplatic syndrome or acute myeloid leukemia) have been reported in patients previously treated by a streptozocin-based chemotherapy, who received subsequent peptide receptor radionuclide therapy.
Mild to moderate abnormalities of glucose tolerance have been noted in patients treated with Zanosar. These have generally been reversible.
Due to the mechanism of action of streptozocin, diabetes cannot be excluded.
Severe tissue necrosis has been described following extravasation. Burning sensation, extending from injection site to the arm has been reported in some patients following bolus administration.
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: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard, or search for MHRA Yellow Card in the Google Play or Apple App store.
This medicinal product must not be mixed with other medicinal products, especially other cytotoxic drugs, except those mentioned in section 6.6.
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