Strigem

INSTRUCTIONS for medical use of the medicinal product stryGEM (StriGEM)

Composition:

Active substance: gemcitabine hydrochloride;

1 vial contains gemcitabine hydrochloride equivalent to 200 mg or 1000 mg of gemcitabine;

Excipients: mannitol (E 421), anhydrous sodium acetate, sodium hydroxide, hydrochloric acid diluted, water for injections.

Pharmaceutical form.

Lyophilisate for solution for infusion.

Main physicochemical characteristics: white lyophilized solid.

Pharmacotherapeutic group. Antineoplastic agents. Pyrimidine analogues. ATC code L01B C05.

Pharmacological Properties.

Pharmacodynamics.

Cytotoxic activity in cell cultures.

Gemcitabine exerts significant cytotoxic effects on various types of human cancer cells and cultured mouse cancer cells. Gemcitabine is cell-cycle phase-specific, primarily affecting cells undergoing DNA synthesis (S-phase), and under certain conditions, blocks cell progression through the G1/S phase boundary. The cytotoxic effect of gemcitabine in vitro is dependent on both concentration and duration of exposure.

Antitumor activity in preclinical models.

In animal tumor models, the antitumor activity of gemcitabine depends on the administration schedule. Daily administration of gemcitabine resulted in high animal mortality and minimal antitumor activity. However, when gemcitabine was administered every third or fourth day at non-lethal doses, it demonstrated significant antitumor activity against a broad spectrum of tumors in mice.

Mechanism of action.

Intracellular metabolism and mechanism of action.

Gemcitabine (dFdC) is a pyrimidine antimetabolite that is intracellularly metabolized by deoxycytidine kinase into active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is believed to result from inhibition of DNA synthesis by two active metabolites—diphosphate and triphosphate nucleosides. First, the diphosphate nucleoside inhibits ribonucleotide reductase, the enzyme responsible for catalyzing reactions that produce deoxynucleoside triphosphates (dCTP) required for DNA synthesis. Inhibition of this enzyme leads to reduced concentrations of deoxynucleosides in general, and particularly deoxycytidine triphosphates (dCTP). Second, dFdCTP competes with dCTP during DNA chain elongation (self-potentiation).

Additionally, a small amount of gemcitabine may incorporate into RNA. Thus, the reduction in intracellular dCTP concentration enhances the incorporation of gemcitabine triphosphate into the DNA chain. The epsilon DNA polymerases are unable to remove gemcitabine or repair the growing DNA strands. After incorporation of intracellular gemcitabine metabolites into the elongating DNA strands, one additional nucleotide is added, resulting in complete inhibition of further DNA synthesis ("masked chain termination") and programmed cell death known as apoptosis.

Pharmacokinetics.

Pharmacokinetics of gemcitabine were studied in 7 clinical trials involving 353 patients. The study population included 121 women and 232 men aged 29 to 79 years. Approximately 45% of these patients had non-small cell lung cancer, and 35% had pancreatic cancer. The following pharmacokinetic parameters were obtained after administration of doses ranging from 500 to 2592 mg/m², infused over time intervals of 0.4 to 1.2 hours.

Peak plasma concentrations (measured 5 minutes before the end of infusion) ranged from 3.2 to 45.5 µg/mL. Plasma concentrations of the main component after administration of a 1000 mg/m² dose infused over 30 minutes exceeded 5 µg/mL approximately 30 minutes after the end of infusion and remained above 0.4 µg/mL for up to 1 hour.

Distribution.

The volume of distribution in the central compartment is 12.4 L/m² in women and 17.5 L/m² in men (interindividual variability is 91.9%). The volume of distribution in the peripheral compartment was 47.4 L/m² and was independent of gender. Plasma protein binding is minimal and clinically negligible.

Elimination half-life.

The elimination half-life ranges from 42 to 94 minutes, depending on age and gender. After administration at recommended doses, elimination of gemcitabine is nearly complete within 5 to 11 hours after the start of infusion. When administered once weekly, gemcitabine does not accumulate.

Metabolism.

Gemcitabine is rapidly metabolized by cytidine deaminase in the liver, kidneys, blood, and other tissues. As a result of intracellular metabolism, gemcitabine monophosphate, diphosphate, and triphosphate (dFdCMP, dFdCDP, and dFdCTP, respectively) are formed. The active metabolites are considered to be dFdCDP and dFdCTP. These intracellular metabolites are not detectable in plasma or urine. The primary metabolite, 2'-deoxy-2',2'-difluorouridine (dFdU), is inactive and is found in plasma and urine.

Excretion.

Systemic clearance ranges from 29.2 to 92.2 L/h/m², depending on age and gender (interindividual variability is 52.2%). Clearance in women is approximately 25% lower than in men. Despite the rate of clearance, it decreases with age in both men and women. However, the lower clearance in women and men after administration of the recommended dose of 1000 mg/m² as a 30-minute infusion does not warrant dose reduction of gemcitabine.

Urinary excretion. Less than 10% of the administered dose is excreted unchanged.

Renal clearance ranges from 2 to 7 L/h/m².

Within one week after administration, 92% to 98% of the administered dose is excreted, with 99% eliminated in urine (primarily as dFdU) and 1% in feces.

Combination therapy with gemcitabine and paclitaxel.

Combination therapy with gemcitabine and paclitaxel does not affect the pharmacokinetics of either drug.

Combination therapy with gemcitabine and carboplatin.

Combination therapy with gemcitabine and carboplatin does not affect the pharmacokinetics of gemcitabine.

Renal impairment.

Moderate to mild renal impairment (glomerular filtration rate from 30 mL/min to 80 mL/min) does not have a clinically significant prolonged effect on the pharmacokinetics of gemcitabine.

Clinical characteristics.

Indications.

Bladder cancer. Strigem in combination with cisplatin is indicated for the treatment of patients with locally recurrent or metastatic bladder cancer.

Pancreatic cancer. Strigem is indicated for the treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas.

Non-small cell lung cancer. Strigem in combination with cisplatin is indicated as a first-line agent for the treatment of patients with locally advanced or metastatic non-small cell lung cancer. Strigem as monotherapy is indicated for the treatment of elderly patients and patients with a performance status of 2.

Ovarian cancer. Strigem in combination with carboplatin is indicated for the treatment of patients with locally advanced or metastatic epithelial ovarian carcinoma. Strigem is indicated for the treatment of patients with recurrent epithelial ovarian carcinoma after a remission period of at least 6 months following prior first-line platinum-based therapy.

Breast cancer. Strigem in combination with paclitaxel is indicated for the treatment of patients with unresectable, locally recurrent or metastatic breast cancer after prior adjuvant/neoadjuvant chemotherapy. Prior chemotherapy should include an anthracycline, unless contraindicated.

Bile duct cancer. Gemcitabine is indicated for the treatment of patients with bile duct cancer.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Breast-feeding period.

Special precautions.

Preparation of infusion solution.

As with other cytotoxic agents, great care should be taken in the preparation and administration of the infusion solution. The solution should be prepared in a safety cabinet using gloves and protective gowns. If work in a safety cabinet is not possible, a mask and protective goggles must be used.

Contact of the solution with the eyes may cause severe irritation. In such a case, the eyes should be immediately and thoroughly rinsed with water. If irritation persists, medical advice should be sought. In case of contact with the skin, the skin should be immediately washed with water.

Interaction with other medicinal products and other forms of interaction.

No specific interaction studies have been conducted.

Radiotherapy.

Concomitant radiotherapy (within or ≤7 days after). Toxicity associated with combined modality therapy depends on multiple factors, including the dose of gemcitabine, frequency of infusions, radiation dose, technique used, and the volume and site of irradiation.

Preclinical and clinical studies have shown that gemcitabine has radiosensitizing activity. In one trial, when Strigem at a dose of 1000 mg/m² was administered over a period of up to 6 weeks concurrently with thoracic radiotherapy in patients with non-small cell lung cancer, significant toxicity was observed in the form of severe and potentially life-threatening mucositis, particularly esophagitis and pneumonitis, especially in patients who received high-dose radiotherapy (median treatment volume of 4,795 cm³). Subsequent studies have suggested that lower doses of gemcitabine should be used with concomitant radiotherapy to achieve acceptable toxicity, as demonstrated in a phase II non-small cell lung cancer trial, where thoracic irradiation at 66 Gy was combined with gemcitabine (600 mg/m², 4 doses) and cisplatin (80 mg/m², 2 doses) over 6 weeks. The optimal regimen for safe use of Strigem with therapeutic radiation doses has not yet been established for all tumor types.

Non-concomitant radiotherapy (>7 days). Data analysis has not shown increased toxicity when Strigem is administered more than 7 days before or after radiation, except in cases of "radiation recall." Evidence suggests that gemcitabine administration can be initiated after acute radiation effects have subsided or at least one week after radiotherapy.

Tissue damage in previously irradiated areas (e.g., esophagitis, colitis, and pneumonitis) has been reported following administration of gemcitabine, both with concomitant and non-concomitant scheduling.

Others.

Concomitant administration of live attenuated vaccines, including yellow fever vaccine, is not recommended due to the risk of systemic, possibly fatal, disease, particularly in immunosuppressed patients.

Special precautions for use.

Prolonged infusion duration and increased dosing frequency may enhance toxicity.

Hematologic toxicity.

Gemcitabine can suppress bone marrow function, manifesting as leukopenia, thrombocytopenia, and anemia.

Patients receiving gemcitabine require monitoring of platelet count, white blood cells, and granulocytes prior to each dose. The dose of Strigemu may be reduced or administration delayed in case of bone marrow suppression (myelosuppression). However, myelosuppression is usually transient and most often does not necessitate dose reduction or discontinuation of therapy.

Peripheral blood cell counts may decrease even after discontinuation of gemcitabine therapy. Caution is advised when administering treatment to patients with impaired bone marrow function. As with other cytotoxic agents, the risk of cumulative bone marrow suppression should be considered when gemcitabine is administered in combination with other chemotherapeutic agents.

Hepatic impairment. The drug should be administered with caution in patients with hepatic or renal impairment, as insufficient data from clinical studies are available to recommend precise dosing for such patients. Administration of gemcitabine in patients with liver metastases, history of hepatitis or alcoholism, or hepatic cirrhosis may lead to worsening hepatic insufficiency. Periodic laboratory assessment of renal and hepatic parameters (including virological testing) is recommended.

Concomitant radiotherapy.

Toxicity has been reported during concomitant radiotherapy (either concurrently or within ≤ 7 days after administration).

Live vaccines.

Administration of the yellow fever vaccine and other live attenuated vaccines is not recommended in patients receiving gemcitabine therapy.

Posterior reversible encephalopathy syndrome (PRES).

Cases of posterior reversible encephalopathy syndrome (PRES), potentially with severe consequences, have been reported in patients receiving gemcitabine either as monotherapy or in combination with other chemotherapeutic agents. Most patients who developed PRES while receiving gemcitabine experienced acute arterial hypertension and epileptic seizures; other possible symptoms include headache, lethargy, confusion, and visual loss.

This condition (syndrome) is diagnosed by magnetic resonance imaging (MRI). Posterior reversible encephalopathy syndrome (PRES) is reversible with appropriate supportive measures. If PRES develops during gemcitabine therapy, treatment should be discontinued and supportive measures initiated, including blood pressure control and anticonvulsant therapy.

Cardiovascular system.

Due to the risk of cardiac or vascular disorders associated with gemcitabine use, special caution is required when prescribing Strigem to patients with a history of cardiovascular disease.

Capillary leak syndrome.

Capillary leak syndrome has been reported in patients receiving gemcitabine as monotherapy or in combination with other chemotherapeutic agents. With early detection and appropriate therapy, capillary leak syndrome is usually treatable; however, fatal outcomes have been reported. This condition arises from increased systemic vascular permeability, leading to leakage of fluid and proteins from the intravascular space into the interstitium. Clinical signs include generalized edema, weight gain, hypoalbuminemia, severe arterial hypotension, acute renal failure, and pulmonary edema. Drug administration should be discontinued at the first signs of capillary leak syndrome, and appropriate therapy initiated. Capillary leak syndrome may occur in later treatment cycles and is often associated with adult respiratory distress syndrome.

Respiratory system.

Pulmonary toxicity has been reported, sometimes severe (e.g., pulmonary edema, interstitial pneumonitis, or adult respiratory distress syndrome [ARDS]). If such events occur, discontinuation of Strigem therapy should be considered. Early symptomatic intervention may improve outcomes.

Urinary and reproductive system.

Hemolytic-uremic syndrome (HUS).

Clinical data related to HUS are rarely reported in post-marketing data from patients receiving Strigem. HUS is potentially life-threatening. Drug administration should be discontinued at the first signs of microangiopathic hemolytic anemia, such as rapid decline in hemoglobin accompanied by thrombocytopenia, elevated serum bilirubin, serum creatinine, blood urea, or lactate dehydrogenase. Renal failure may be irreversible even after discontinuation of therapy, and dialysis may become necessary.

Fertility.

Fertility studies in mice showed that gemcitabine causes hypospermatogenesis in males. Therefore, men receiving gemcitabine therapy should not plan to father children during treatment and for 6 months after therapy. Due to the potential for loss of fertility following gemcitabine therapy, men are advised to consider sperm preservation prior to initiating treatment.

Sodium.

One vial of Strigem, at doses of 200 mg and 1000 mg, contains 12.5 mg (0.54 mmol) and 62.5 mg (2.72 mmol) of sodium, respectively. This should be taken into account when prescribing the drug to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on the use of gemcitabine in pregnant women. Animal studies have shown reproductive toxicity. Considering the animal study results and the mechanism of action, gemcitabine should not be used during pregnancy except in cases of clear necessity. Women should be advised to avoid pregnancy during gemcitabine therapy and to inform their physician if they become pregnant while receiving gemcitabine.

Breastfeeding period.

It is unknown whether gemcitabine is excreted in human breast milk, and adverse reactions in breastfed infants cannot be excluded. Therefore, breastfeeding should be discontinued during gemcitabine therapy.

Fertility.

Fertility studies in mice showed that gemcitabine causes hypospermatogenesis in males. Therefore, men receiving gemcitabine therapy should not plan to father children during treatment and for 6 months after therapy. Due to the potential for loss of fertility following gemcitabine therapy, men are advised to consider sperm preservation prior to initiating treatment.

Ability to affect reaction rate when driving or operating machinery.

No studies have been conducted to evaluate the effect of gemcitabine on the ability to drive or operate machinery. Since Strigem may cause mild to moderate somnolence, particularly when combined with alcohol, patients should avoid operating technical equipment or driving until this effect subsides.

Method of Administration and Dosage.

Gemcitabine should be administered only by a physician experienced in anticancer chemotherapy.

Recommended Doses.

Bladder Cancer.

Combination therapy. Adults. The recommended dose of Strigem is 1000 mg/m² administered as a 30-minute intravenous infusion. This dose should be given on days 1, 8, and 15 of each 28-day cycle in combination with cisplatin. Cisplatin should be administered at the recommended dose of 70 mg/m² on day 1 after Strigem or on day 2 of each 28-day cycle. This 4-week cycle is then repeated. Dose reduction in each cycle or during any single cycle may be necessary depending on the degree of toxicity experienced by the patient.

Pancreatic Cancer.

Adults. The recommended dose of Strigem is 1000 mg/m² administered via 30-minute intravenous infusion once weekly for 7 weeks, followed by a one-week break. Subsequent cycles consist of weekly infusions for 3 consecutive weeks with a one-week break every 4th week. Dose reduction in each cycle or during any single cycle may occur depending on the degree of toxicity experienced by the patient.

Non-Small Cell Lung Cancer.

Monotherapy. Adults. The recommended dose is 1000 mg/m² administered as a 30-minute intravenous infusion once weekly for 3 weeks, followed by a one-week break. This 4-week cycle is repeated. Dose reduction in each cycle or during any single cycle may be performed depending on the degree of toxicity experienced by the patient.

Combination therapy. Adults. The recommended dose is 1250 mg/m² body surface area administered as a 30-minute intravenous infusion on days 1 and 8 of each 21-day cycle. The drug dose may be reduced in each cycle or during any single cycle depending on the degree of toxicity experienced by the patient. Cisplatin should be administered at a recommended dose of 75–100 mg/m² once every 3 weeks of the cycle.

Breast Cancer.

Combination therapy. Adults. Strigem in combination with paclitaxel is recommended to be administered as follows: paclitaxel (175 mg/m²) should be given on day 1 as a 3-hour intravenous infusion, followed by gemcitabine (1250 mg/m²) as a 30-minute intravenous infusion on days 1 and 8 of each 21-day cycle. The drug dose may be reduced in each cycle or during any single cycle depending on the degree of toxicity experienced by the patient. Prior to the first administration of the gemcitabine and paclitaxel combination, patients must have an absolute granulocyte count of at least 1,500 (×10⁹/L).

Ovarian Cancer.

Combination therapy. Adults. Strigem in combination with carboplatin is recommended to be administered at the following doses: gemcitabine 1000 mg/m² via 30-minute intravenous infusion on days 1 and 8 of a 21-day cycle. On day 1 of the cycle, after Strigem, carboplatin should be administered at a dose providing an AUC of 4 mg/mL*min. The dose may be reduced in each cycle or during any single cycle depending on the degree of toxicity experienced by the patient.

Bile Duct Cancer.

Monotherapy. Adults. The recommended dose of Strigem is 1000 mg/m² to be administered intravenously over 30 minutes. Infusion should be given once weekly for 3 consecutive weeks, followed by a one-week break. This 4-week cycle should be repeated. Dose reduction in each cycle or during any single cycle may occur depending on the extent of toxicity experienced by the patient.

Combination therapy. Adults. Strigem in combination with cisplatin: cisplatin 70 mg/m² is recommended to be administered on day 1 of the cycle via intravenous infusion, followed by Strigem at a dose of 1250 mg/m². Strigem should be administered on days 1 and 8 of each 21-day cycle via 30-minute intravenous infusion. This 3-week cycle should be repeated. Dose reduction in each cycle or during any single cycle may be performed depending on the degree of toxicity experienced by the patient.

Toxicity Monitoring and Dose Modifications Related to Toxicity.

Dose Modifications Related to Non-Hematological Toxicity.

Periodic physical examinations and monitoring of renal and liver function are required to detect non-hematological toxicity. Dose reduction in each cycle or during any single cycle may be performed depending on the degree of toxicity experienced by the patient.

In general, in the event of severe non-hematological toxicity (Grade III or IV), except for nausea or vomiting, the dose of Strigem may be reduced or administration delayed in the presence of hematological toxicity at the physician’s discretion. Treatment should be withheld until, in the physician’s opinion, the toxicity has been resolved.

Dose Modifications Related to Hematological Toxicity.

At the Start of a Treatment Cycle.

In patients receiving Strigem, platelet and granulocyte counts should be checked before each dose. The absolute granulocyte count prior to the start of a cycle should be at least 1,500 (×10⁹/L), and platelet count should be at least 100,000 (×10⁹/L).

During a Treatment Cycle.

If necessary, the dose of Strigem may be reduced or administration delayed in the presence of hematological toxicity according to the following criteria:

Table 1

Dose Modification of Strigem During a Treatment Cycle for the Indications: Bladder Cancer, Non-Small Cell Lung Cancer, Pancreatic Cancer under Monotherapy or Combination Therapy with Cisplatin

*Dosing should be withheld during the cycle until the absolute neutrophil count reaches at least 500 (x10⁶/L) and platelet count reaches 50,000 (x10⁶/L).

Table 2

Dose modification of Strigem during the treatment cycle based on indications: breast cancer when used in combination with paclitaxel

*Dose administration will not be resumed during the cycle. Treatment will be restarted on day 1 of the next cycle, once the absolute neutrophil count reaches at least 1,500 (x10⁶/L) and platelet count reaches 100,000 (x10⁶/L).

Table 3

Dose modification of Stirugem during the treatment cycle for the indication: ovarian cancer when used in combination with carboplatin

*Dose administration will not be resumed during the cycle. Treatment will be restarted on day 1 of the next cycle, once the absolute neutrophil count has recovered to at least 1500 (x10^6/L) and platelet count to 100,000 (x10^6/L).

Dose modification due to hematological toxicity during subsequent cycles, for all indications.

The dose of Strigem must be reduced to 75% of the initial dose administered at the beginning of treatment in case of the following hematological toxicities:

• Absolute neutrophil count < 500 x 10^6/L for more than 5 days.
• Absolute neutrophil count < 100 x 10^6/L for more than 3 days.
• Febrile neutropenia.
• Platelet count < 25,000 x 10^6/L.
• Delay of cycle due to toxicity manifestations exceeding 1 week.

Method of administration.

Strigem is well tolerated during infusion and can be administered on an outpatient basis. In case of hematoma development, infusion must be stopped immediately and resumed into another vein. Careful monitoring of the patient is required after infusion.

Special patient groups.

Patients with hepatic and renal impairment. The drug should be used with caution in patients with hepatic and renal impairment, as insufficient clinical data are available to recommend specific dosing regimens for these patients.

Elderly patients (˃65 years). The drug is well tolerated in patients aged 65 years and older. There is no evidence to suggest that dose adjustments are required for elderly patients beyond those already recommended for all patients.

Pediatric population. Gemcitabine is not recommended for use in children due to insufficient data on efficacy and safety in this patient group.

Instructions for solution preparation (and further dilution, if necessary). The only tested solvent for reconstitution of the sterile Strigem powder is 0.9% sodium chloride injection solution without preservatives.

Based on solubility data, the maximum concentration of Strigem after reconstitution should not exceed 40 mg/mL. Reconstitution at concentrations higher than 40 mg/mL may result in incomplete dissolution of the drug and should be avoided.

1. Solution preparation and further dilution, if necessary, must be performed under aseptic conditions.
2. To reconstitute the solution, add at least 5 mL of 0.9% sodium chloride injection solution without preservatives to the vial containing 200 mg of gemcitabine powder, or at least 25 mL of 0.9% sodium chloride injection solution without preservatives to the vial containing 1000 mg of gemcitabine powder. The total volume after reconstitution will be 5.26 mL (vials containing 200 mg gemcitabine) and 26.3 mL (vials containing 1000 mg gemcitabine). This provides a gemcitabine concentration of 38 mg/mL, accounting for the lyophilisate displacement volume. Shake to dissolve. The prepared solution may be further diluted with 0.9% sodium chloride injection solution without preservatives. The appropriate amount of the medicinal product can be administered immediately after preparation or further diluted with 0.9% sodium chloride injection solution. The resulting solution may be clear or slightly yellowish.
3. Parenteral preparations should be inspected visually for particulate matter and discoloration before administration. If particulate matter is present, the solution must not be used. Any unused portions of the medicinal product or waste materials should be disposed of in accordance with applicable regulations.

Pediatric population.

The safety and efficacy of gemcitabine in children have not been established.

Overdose.

There is no known antidote for gemcitabine overdose.

Clinically tolerable toxicity was observed with doses up to 5700 mg/m^2 administered as a 30-minute intravenous infusion every 2 weeks.

In case of suspected overdose, patient monitoring is required, appropriate blood tests should be performed, and symptomatic therapy should be administered as needed.

Adverse reactions.

Adverse reactions associated with Strigem therapy most commonly reported: nausea, with or without vomiting, elevation of liver transaminases (ALT and AST), as well as alkaline phosphatase, observed in approximately 60% of patients; proteinuria and hematuria reported in approximately 50% of patients; dyspnea observed in 10\–40% of patients (highest frequency observed in lung cancer patients); allergic skin rashes observed in 25% of patients, accompanied by pruritus in 10% of cases.

The frequency and severity of adverse reactions depend on the dose, rate of administration, and intervals between doses. Dose-dependent adverse reactions include decreased levels of thrombocytes, leukocytes, and granulocytes.

Data obtained from clinical studies.

Table 4 presents adverse reactions and their frequency observed during clinical studies. Within each group, adverse reactions are listed in order of decreasing severity, with frequency categories as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000).

Table 4

Combination use in breast cancer.

The frequency of hematological toxicity grade III and IV events, particularly neutropenia, increases with the combination of gemcitabine and paclitaxel, although the increased frequency of these adverse reactions is not associated with a higher incidence of infections or hemorrhagic events. Weakness and febrile neutropenia occur more frequently with the combination of gemcitabine and paclitaxel. Weakness not associated with anemia usually resolves after the first cycle of therapy.

Table 5

Grade III and IV adverse events with paclitaxel monotherapy compared to combination therapy with gemcitabine and paclitaxel

* Grade IV neutropenia lasting more than 7 days was observed in 12.6% of patients receiving combination therapy and in 5% of patients receiving paclitaxel alone.

Combination therapy in bladder cancer.

Table 6

Grade III and IV adverse events with M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) compared to combination therapy with gemcitabine and cisplatin

Combination therapy in ovarian cancer.

Table 7

Grade III and IV adverse reactions with carboplatin monotherapy compared to combination therapy with gemcitabine and carboplatin

The phenomenon of sensory neuropathy was also observed more frequently with combination therapy compared to carboplatin alone.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Incompatibilities.

The only tested solvent for reconstitution of the Strigem sterile powder is 0.9% sodium chloride injection solution without preservatives.

Packaging.

200 mg or 1000 mg of the drug in a glass vial stoppered with a rubber stopper and sealed with an aluminum crimp cap equipped with a flip-off cap ensuring first-opening control.

1 vial per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

MYLAN LABORATORIES LIMITED (OTL)

MYLAN LABORATORIES LIMITED (OTL)

Manufacturer's address and location of operations.

Plot No. 284-B, Bommasandra Jigani Link Road, Industrial Area, Anekal Taluk, Bangalore, Karnataka 560105, India (IND)

Marketing Authorisation Holder.

M.BIOTECH LTD

M.BIOTECH LTD

Address of the Marketing Authorisation Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom