GemciMax^®

1. INDICATION:

Gemcitabine is a cytostatic (medicine against cancer). Gemcitabine inhibits the growth of cancer cells, finally leading to their extirpation. It may stop cancer cells from dividing and growing.

GEMCIMAX^® is used to treat different types of cancer:

1.1. GEMCIMAX^® is indicated for the treatment of locally advanced or metastatic bladder cancer in combination with cisplatin.

1.2.GEMCIMAX^® is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas.

1.3.GEMCIMAX^® in combination with cisplatin, is indicated as first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Gemcitabine monotherapy can be considered in elderly patients or those with performance status 2.

1.4. GEMCIMAX^® is indicated for the treatment of patients with locally advanced or metastatic epithelial ovarian carcinoma, in combination with carboplatin, in patients with relapsed disease following a recurrence-free interval of at least 6 months after platinum-based, first-line therapy.

1.5. GEMCIMAX^®, in combination with paclitaxel, is indicated for the treatment of patients with unresectable, locally recurrent or metastatic breast cancer who have relapsed following adjuvant/neoadjuvant chemotherapy. Prior chemotherapy should have included an anthracycline unless clinically contraindicated.

You should NOT be given GEMCIMAX^®
– if you are allergic to gemcitabine or any of the other ingredients of this medicine (sodium chloride, sodium hydroxide and/or hydrochloric acid)
– if you are breast-feeding.

Prolongation of the infusion time and increased dosing frequency have been shown to increase toxicity.
-Haematological toxicity
GEMCIMAX^® can suppress bone marrow function as manifested by leucopoenia, thrombocytopenia and anaemia.Patients receiving GEMCIMAX^® should be monitored prior to each dose for platelet, leucocyte and granulocyte counts. Suspension or modification of therapy should be considered when drug-induced bone marrow depression is detected. However, myelosuppression is short lived and usually does not result in dose reduction and rarely in discontinuation.
Peripheral blood counts may continue to deteriorate after GEMCIMAX^® administration has been stopped. In patients with impaired bone marrow function, the treatment should be started with caution.

As with other cytotoxic treatments, the risk of cumulative bone-marrow suppression must be considered when
GEMCIMAX^® treatment is given together with other chemotherapy.
-Hepatic and renal impairment
GEMCIMAX^® should be used with caution in patients with hepatic insufficiency or with impaired renal function as there is insufficient information from clinical studies to allow clear dose recommendation for this patient population.
Administration of GEMCIMAX^® in patients with concurrent liver metastases or a pre-existing medical history of hepatitis, alcoholism or liver cirrhosis may lead to exacerbation of the underlying hepatic impairment.
Laboratory evaluation of renal and hepatic function (including virological tests) should be performed periodically.
-Concomitant radiotherapy
Concomitant radiotherapy (given together or ≤ 7 days apart): Toxicity has been reported.
-Live vaccinations
Yellow fever vaccine and other live attenuated vaccines are not recommended in patients treated with GEMCIMAX^®

-Posterior reversible encephalopathy syndrome
Reports of posterior reversible encephalopathy syndrome (PRES) with potentially severe consequences have been reported in patients receiving gemcitabine as single agent or in combination with other chemotherapeutic agents. Acute hypertension and seizure activity were reported in most gemcitabine patients experiencing PRES, but other symptoms such as headache, lethargy, confusion and blindness could also be present. Diagnosis is optimally confirmed by magnetic resonance imaging (MRI). PRES was typically reversible with appropriate supportive measures. GEMCIMAX^® should be permanently discontinued and supportive measures implemented, including blood pressure control and antiseizure therapy, if PRES develops during therapy.
-Cardiovascular
Due to the risk of cardiac and/or vascular disorders with GEMCIMAX^®, particular caution must be exercised with patients presenting a history of cardiovascular events.
Capillary leak syndrome
Capillary leak syndrome has been reported in patients receiving gemcitabine as single agent or in combination with other chemotherapeutic agents.The condition is usually treatable if recognised early and managed appropriately, but fatal cases have been reported. The condition involves systemic capillary hyperpermeability during which fluid and proteins from the intravascular space leak into the interstitium. The clinical features include generalized oedema, weight gain, hypoalbuminaemia, severe hypotension, acute renal impairment and pulmonary oedema. GEMCIMAX^® should be discontinued and supportive measures implemented if capillary leak syndrome develops during therapy. Capillary leak syndrome can occur in later cycles and has been associated in the literature with adult respiratory distress syndrome.
-Pulmonary
Pulmonary effects, sometimes severe (such as pulmonary oedema, interstitial pneumonitis or adult respiratory distress syndrome (ARDS)) have been reported in association with gemcitabine therapy.
If such effects develop, consideration should be made to discontinuing GEMCIMAX^® therapy. Early use of supportive care measure may help ameliorate the condition.
-Renal
Haemolytic uraemic syndrome
Clinical findings consistent with the haemolytic uraemic syndrome (HUS) were rarely reported (post- marketing data) in patients receiving gemcitabine. HUS is a potentially life-threatening disorder. GEMCIMAX^® should be discontinued at the first signs of any evidence of microangiopathic haemolytic anaemia, such as rapidly falling haemoglobin with concomitant thrombocytopaenia, 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.
Fertility
In fertility studies gemcitabine caused hypospermatogenesis in male mice. Therefore, men being
treated with GEMCIMAX^® are advised not to father a child during and up to 6 months after treatment and to seek further advice regarding cryoconservation of sperm prior to treatment because of the possibility of infertility due to therapy with GEMCIMAX^®.

The only approved diluent for dilution of gemcitabine sterile concentrate is sodium chloride 9 mg/ml (0.9%) solution for injection (without preservative).

– Use aseptic techniques preparation for gemcitabine for intravenous infusion administration.

– Gemcitabine concentrate for solution for infusion is a clear, colorless to slightly yellow solution with a concentration of 100 mg/ml gemcitabine. The concentrate should be diluted with sterile sodium chloride 9 mg/ml (0.9%) solution for injection, without preservative to a final concentration of 0.1 to 10 mg/ml.

-Dilute Gemcitabine 200 with 250-400ml of sodium chloride 9 mg/ml (0.9%) and dilute Gemcitabine 1000 with 500ml of sodium chloride 9 mg/ml (0.9%)

– The total quantity of the Gemcitabine concentrate for solution for infusion required for an individual patient should be diluted into at least 250 ml of diluent. Further dilution with the same diluent can be done. Diluted solution is a clear colorless to slightly yellow solution.

To reduce the precipitation risk, Gemcitabine should be used as soon as possible after dilution,

After opening before dilution:

Each vial is for single use and should be used immediately after opening. If not used immediately, in-use storage times and conditions are the responsibility of the user.

After dilution:

Chemical and physical in-use stability after dilution in 0.9 % sodium chloride solution has been demonstrated for 3 days at 25°C and 2 °C to 8 °C.

From a microbiological point of view, the solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2° C to 8°C unless dilution has taken place in controlled and validated aseptic condition.

Like all medicines, GEMCIMAX^® can cause side effects, although not everybody gets them.

The most common side effects are hair loss and a reduced number of blood cells. After the end of treatment your hair should grow again and your blood count should return to normal.

• >10%:

Cardiovascular: Peripheral edema (20%), edema (13%)

Central nervous system: Drowsiness (11%)

Dermatologic: Skin rash (30%), alopecia (15%)

Gastrointestinal: Nausea and vomiting (69%), diarrhea (19%), stomatitis (11%)

Genitourinary: Proteinuria (45%), hematuria (35%)

Hematologic & oncologic: Anemia (68%; grade 3: 7%; grade 4: 1%), neutropenia (63%; grade 3: 19%; grade 4: 6%), thrombocytopenia (24%; grade 3: 4%; grade 4: 1%), hemorrhage (17%; grade 3: <1%; grade 4: <1%)

Hepatic: Increased serum ALT (68%; grade 3: 8%, grade 4: 2%), increased serum AST (67%; grade 3: 6%; grade 4: 2%), increased serum alkaline phosphatase (55%; grade 3: 7%; grade 4: 2%), increased serum bilirubin (13%; grade 3: 2%, grade 4: <1%)

Infection: Infection (16%)

Renal: Increased blood urea nitrogen (16%)

Respiratory: Dyspnea (23%; grade 3: 3%; grade 4: <1%), flu-like symptoms (19%)

Miscellaneous: Fever (41%)

• 1% to 10%:

Central nervous system: Paresthesia (10%; grade 3: <1%)

Local: Injection site reaction (4%)

Renal: Increased serum creatinine (8%)

Respiratory: Bronchospasm (<2%)

• <1%

postmarketing, and/or case reports (reported with single-agent use or with combination therapy): Adult respiratory distress syndrome, anaphylactoid reaction, anorexia, arthralgia, bullous skin disease, capillary leak syndrome, cardiac arrhythmia, cardiac failure, cellulitis, cerebrovascular accident, constipation, desquamation, digital vasculitis, gangrene of skin or other tissue, hemolytic-uremic syndrome, hepatic failure, hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease), hepatotoxicity (rare), hyperglycemia, hypertension, hypocalcemia, hypotension, increased gamma-glutamyl transferase, interstitial pneumonitis, myocardial infarction, neuropathy, petechiae, pruritus, pulmonary edema, pulmonary fibrosis, radiation recall phenomenon, renal failure, respiratory failure, reversible posterior leukoencephalopathy syndrome, sepsis, supraventricular cardiac arrhythmia, thrombotic thrombocytopenic purpura

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. Please report any adverse drug reactions via contacting Cedal Nano..⁽¹⁾

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Interaction means that different medicines may influence each other.

Radiotherapy

Concurrent (given together or ≤ 7 days apart) – Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of GEMCIMAX^®, frequency of GEMCIMAX^® administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. Pre-clinical and clinical studies have shown that gemcitabine has radiosensitising activity.

The optimum regimen for safe administration of gemcitabine with therapeutic doses of radiation has not yet been determined in all tumour types.

Non-concurrent (given >7 days apart)- Analysis of the data does not indicate any enhanced toxicity when gemcitabine is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that gemcitabine can be started after the acute effects of radiation have resolved or at least one week after radiation.

Radiation injury has been reported on targeted tissues (e.g. oesophagitis, colitis, and pneumonitis) in association with both concurrent and non-concurrent use of gemcitabine.

Vaccines (Inactivated)

 Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.

Vaccines (Live)

 Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants.

Chemotherapy drugs

When gemcitabine (1250 mg/m2 on Days 1 and 8) and cisplatin (75 mg/m2 on Day 1) were

administered in NSCLC patients, the clearance of gemcitabine on Day 1 was 128 L/hr/m2 and on

Day 8 was 107 L/hr/m2. Analysis of data from metastatic breast cancer patients shows that, on

average, gemcitabine has little or no effect on the pharmacokinetics (clearance and half-life) of

paclitaxel and paclitaxel has little or no effect on the pharmacokinetics of gemcitabine. Data

from NSCLC patients demonstrate that gemcitabine and carboplatin given in combination does

not alter the pharmacokinetics of gemcitabine or carboplatin compared to administration of either

single agent. However, due to wide confidence intervals and small sample size, interpatient

variability may be observed.

Others

Yellow fever and other live attenuated vaccines are not recommended due to the risk of systemic, possibly fatal, disease, particularly in immunosuppressed patients.

Pregnancy:

Pregnancy Category D

Based on the mechanism of action and on findings from animal reproduction studies, gemcitabine may cause fetal harm if administered during pregnancy. Women of reproductive potential should use effective contraception during treatment and for 6 months after the final GEMCIMAX^®  dose. Men with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the final dose.. If pregnancy occurs inform your doctor immediately.

Breastfeeding:

Tell your doctor if you are breast-feeding. You must discontinue breast-feeding during GEMCIMAX^® treatment.. Do not restart breast-feeding, unless your doctor has allowed you to

– Keep the medicine in the box until it is consumed.

– store the medicine at temperatures below 30° C and stored away from light and moisture.

– Keep the medicine out of the reach of children and pets.

– From a microbiological point of view, the solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2° C to 8°C unless dilution has taken place in controlled and validated aseptic condition.