4.1. Therapeutic indications

Zanosar is indicated for the systemic treatment of adult patients with inoperable, advanced or metastatic, progressive and/or symptomatic, well-differentiated, G1 or G2 neuroendocrine tumours of pancreatic origin, in combination with 5-Fluorouracil (see section 5.1).

4.2. Posology and method of administration

Zanosar should only be administered under the supervision of a physician experienced in the use of anti-cancer chemotherapeutic agents.

The patient should have access to a facility with a laboratory and supportive resources sufficient to monitor drug tolerance and to protect and maintain a patient compromised by drug toxicity.

Posology

The dose is based on the body surface area (m2).

Two different dosage schedules can be used:

Six-weekly regimen - 500 mg/m2/day, intravenously for 5 consecutive days every 6 weeks until maximum benefit is obtained or until treatment-limiting toxicity is observed. Dose escalation on this schedule is not recommended.

Three-weekly regimen – 500 mg/m2/day, intravenously for 5 consecutive days during cycle 1, followed by 1000 mg/m2 every 3rd week during the subsequent cycles.

Other dosing regimens, with similar dose intensity, have been used in clinical studies with comparable efficacy and safety results. However, a single dose of 1500 mg/m2 of body surface area should not be exceeded (renal toxicity).

The optimal duration of maintenance therapy with Zanosar has not been established.

For patients with functional tumours, serial monitoring of biological markers allows a determination of biochemical response to therapy. For patients with either functional or nonfunctional tumours, response to therapy can be determined by measurable reductions of tumour size on imaging.

Renal, hepatic and haematological function must be closely monitored before, during and after treatment, as well as blood glucose levels (see section 4.4). Dose adjustment or discontinuation of the drug may be indicated, depending upon the degree of toxicity noted.

Antiemetic premedication is recommended to prevent nausea and vomiting.

Method of administration

Zanosar should be administered intravenously by infusion (See section 6.6). The duration of infusion should be between 30 minutes and 4 hours.

The administration of Zanosar requires hyperhydration (see section 4.4).

This medicinal product is vesicant in nature and as such should be administered with caution through a free-flowing line.

In the event of extravasation, the administration should be discontinued immediately.

Special populations:

Patients with renal impairment:

Based on clinical practice, the dose of Zanosar should be adapted according to renal function: dose reduction or treatment discontinuation is mandatory in the presence of significant renal toxicity.

Estimated Glomerular Filtration Rate (GFR)

> 60 ml/min

≤ 60 ml/min and > 45 ml/min

≤ 45 ml/min and > 30 ml/min

≤ 30 ml/min

Dose of Zanosar

Full dose

Dose reduced by 50%

Evaluation of the benefit/risk ratio

Contra indicated (see sections 4.3 and 4.4)

If GFR is comprised between 30 and 45 ml/min, the benefit/risk ratio should be thoroughly evaluated in a multidisciplinary approach, which includes soliciting a nephrologist's opinion and balancing the potential benefit against the known risk of serious renal damage.

Hepatic impairment:

Dose reduction should be considered in cases of hepatic impairment (see section 4.4).

Elderly population:

The safety and efficacy of Zanosar in patients aged ≥ 65 years have not been established. Regimen selection for elderly patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapies.

Paediatric population:

The safety and efficacy of Zanosar in patients below 18 years have not been established.

For precautions to be taken before handling or administering the medicinal product, see section 6.6.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• Renal failure (GFR < 30 ml/min) (see section 4.4)

• Live and live-attenuated vaccines

• Breastfeeding

4.4. Special warnings and precautions for use

Renal Toxicity :

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.

Hepatotoxicity:

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.

Haematologic 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 haematocrit 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

Immunosuppressive effects, increased sensitivity to infections:

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).

Nausea and vomiting:

Streptozocin is associated with a high emetic potential which may be treatment-limiting. Antiemetic premedication is recommended to prevent nausea and vomiting.

Injection-Site reactions:

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.

Sodium:

This medicinal product contains 30,1mg sodium per vial equivalent to 1,5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

Contraception:

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.

Pregnancy:

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 foetus.

Lactation:

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.

Fertility:

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 MedDRA 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).

MedDRA system organ class

Very common adverse reactions

Common adverse reactions

Frequency not known

Blood and lymphatic system disorders

Decreased haematocrit, leukocytes and platelet counts

Metabolism and nutrition disorders

glucose intolerance

Nervous system disorders

Confusion, lethargy, depression

Gastrointestinal disorders

Severe nausea and vomiting,

Diarrhoea

Nephrogenic diabetes insipidus

Hepatobiliary disorders

Elevated liver enzymes (SGOT and LDH) Hepatotoxicity

Hypoalbuminemia

Renal and urinary disorders

Renal toxicity – proteinuria, proximal tubular injury, phosphaturia, acute renal failure

Urinary disorders

General disorders and administration site conditions

Fever,

Injection site reactions

Gastrointestinal disorders:

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 diarrhoea.

Renal and urinary disorders:

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).

Hepatobiliary disorders:

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).

Blood and lymphatic system disorders:

Acute haematological toxicity is rare, consisting most often of mild decreases in haematocrit 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.

Metabolism and nutrition disorders (see section 5.1):

Mild to moderate glucose intolerance has been noted in patients treated with Zanosar. These have generally been reversible.

Due to the mechanism of action of streptozocin, diabetes cannot be excluded.

General disorders and administration site conditions:

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 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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no specific antidote for overdose with Zanosar and treatment of overdose should consist of supportive measures. Overdose should be avoided by carefully calculating the dose to be administered.