Stribicin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Stribicin (STRIBICIN)

Composition:

Active ingredient: epirubicin;

1 ml contains epirubicin hydrochloride 2.0 mg;

Excipients: sodium chloride, diluted hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear red-colored solution.

Pharmacotherapeutic group.

Antineoplastic and immunomodulating agents. Cytotoxic antibiotics and related substances. ATC code L01D B03.

Pharmacological properties.

Pharmacodynamics.

Streptozocin exhibits activity against a broad spectrum of experimental tumors, including leukemias (L1210, P388), sarcomas (SA180, solid and ascitic forms), melanoma (B16), breast cancer, Lewis lung cancer, colon cancer (38), as well as against human tumors transplanted into thymus-deficient mice (melanoma, breast, lung, prostate, and ovarian cancers).

Pharmacokinetics.

In patients with normal hepatic and renal function, plasma levels of Streptozocin after intravenous administration of 60–150 mg/m² show a triphasic decline, characterized by a very rapid initial phase and a slow terminal phase with a mean elimination half-life of approximately 40 hours.

These doses fall within the linear range of pharmacokinetics with respect to both plasma clearance and metabolic profile. Plasma levels of the main metabolite (13-OH derivative) were consistently lower and nearly parallel to those of the unchanged drug. The drug is primarily eliminated via the liver; the high plasma clearance (0.9 L/min) indicates that the slow elimination is due to extensive tissue distribution. Streptozocin does not cross the blood-brain barrier.

Clinical characteristics.

Indications.

Streptozin is effective in the treatment of a wide spectrum of neoplasms, including breast cancer, malignant lymphomas, soft tissue sarcomas, gastric cancer, liver cancer, pancreatic cancer, rectal cancer, head and neck cancer, lung cancer, ovarian cancer, leukemia.

Intravesical administration of Streptozin is indicated for the treatment of superficial bladder cancer (transitional cell carcinoma, in situ carcinoma) and for the prevention of recurrence after transurethral resection.

Contraindications.

Hypersensitivity to the active substance or to any excipients, other anthracyclines or anthracenediones.

Breastfeeding period.

Active bone marrow suppression due to previous treatments with other antineoplastic agents or radiotherapy.

Intravenous administration is contraindicated in patients:

• with cardiomyopathies, recent myocardial infarction, severe arrhythmia, unstable angina, persistent myelosuppression;
• with severe hepatic dysfunction;
• with acute generalized infection;
• previously treated with maximum cumulative doses of epirubicin and/or other anthracyclines and anthracenediones (see section "Special precautions").

Intravesical administration is contraindicated in patients with urinary tract infections, invasive tumor invading the bladder wall, bladder inflammation, and in patients with hematuria. Special caution is required in case of difficulties with catheterization (e.g., urethral obstruction caused by significant intravesical neoplasm).

Special safety precautions.

The following precautions should be taken when using all antineoplastic agents.

Personnel must be adequately trained in the techniques of dilution and administration.

Pregnant individuals must not be involved in handling the drug.

Personnel handling the drug must wear protective clothing: protective goggles, protective gown, disposable gloves, and mask.

The working area must be equipped for drug reconstitution (preferably with a vertical laminar airflow system); the work surface must be covered with absorbent plastic-backed paper.

All materials used during drug administration or cleanup, including gloves, must be collected in disposable bags for toxic waste and disposed of by high-temperature incineration.

In case of accidental contact of the drug with skin or eyes, the affected skin area must be immediately washed thoroughly with plenty of water and soap, and eyes must be rinsed with sodium bicarbonate solution. Affected areas must be carefully examined by a specialist.

In case of accidental contamination of surfaces with the drug solution, surfaces must be washed with a 1% sodium hypochlorite solution, followed by copious amounts of water.

All materials used for cleanup must be destroyed as described above.

Treatment with Streptozin must be administered only by qualified physicians experienced in the use of antineoplastic agents.

Preparation of solution.

Streptozin should be diluted in 0.9% sodium chloride solution or sterile water for injection. The vial contents are under negative pressure. To prevent aerosol formation during reconstitution, caution must be exercised after inserting the needle into the vial. Inhalation of the drug aerosol during solution preparation must be avoided.

From a microbiological standpoint, the reconstituted solution should be used immediately. If immediate use is not possible, the solution must be used within 24 hours when stored at 2–8 °C.

During storage of the infusion solution in the refrigerator, the drug may gelatinize. The consistency is restored within 2–4 hours at room temperature (not above 25 °C) with gentle shaking of the vial.

Dilution table for solutions used for bladder instillation.

Table 1.

Interaction with other medicinal products and other forms of interaction.

Streptecin can also be used in combination with other antineoplastic agents in chemotherapy. Additive toxicity may develop, particularly affecting the bone marrow, hematopoietic organs, and gastrointestinal tract (see section "Special precautions"). The use of epirubicin in combination chemotherapy together with other potentially cardiotoxic agents, as well as concomitant use of other cardioactive drugs (e.g., calcium channel blockers), requires careful monitoring of cardiac function throughout the treatment course.

Streptecin is extensively metabolized in the liver. Changes in liver function caused by concomitant therapy may influence the metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity of epirubicin (see section "Special precautions").

Anthracyclines, including epirubicin, should not be used in combination with other cardiotoxic medicinal products unless careful monitoring of cardiac function is performed (see section "Special precautions"). Patients receiving anthracyclines after discontinuation of treatment with other cardiotoxic agents, particularly those with a long elimination half-life such as trastuzumab, may also be at increased risk of developing cardiotoxicity. The reported half-life of trastuzumab is approximately 28–38 days, and the drug may remain in circulation for up to 27 weeks. Therefore, whenever possible, physicians should avoid initiating anthracycline-based therapy within 27 weeks after discontinuation of trastuzumab treatment. If anthracyclines have been administered previously, careful monitoring of cardiac function is recommended.

Administration of live vaccines should be avoided in patients receiving epirubicin. Inactivated or killed vaccines may be administered, although such vaccines may be less effective.

Concomitant administration of cimetidine results in a 50% increase in the area under the curve (AUC) of Streptecin; therefore, cimetidine should be discontinued during epirubicin treatment.

Administration of paclitaxel prior to Streptecin may lead to increased plasma concentrations of unchanged epirubicin and its metabolites; however, these metabolites are neither toxic nor active. Concurrent administration of paclitaxel or docetaxel after Streptecin infusion did not affect the pharmacokinetics of Streptecin. This combination can be used with a multi-step administration schedule of the two drugs. Infusion of epirubicin and paclitaxel should be administered with an interval of at least 24 hours between the two agents.

Dexverapamil may alter the pharmacokinetics of Streptecin and possibly enhance its myelosuppressive effect.

In one study, docetaxel was found to increase plasma concentrations of epirubicin metabolites when administered immediately after Streptecin.

Quinine may accelerate the initial distribution of Streptecin from blood into tissues and may affect the distribution of Streptecin into erythrocytes.

Concomitant administration of α2b-interferon may result in a shortened terminal elimination half-life and reduced total clearance of epirubicin.

Potential for severe impairment of hematopoiesis should be considered in patients previously or concurrently treated with agents affecting the bone marrow (i.e., cytostatic agents, sulfonamides, chloramphenicol, phenytoin, amidepyrine derivatives, antiretroviral agents).

Enhanced myelosuppression is possible in patients who have received combination therapy with an anthracycline and dexrazoxane.

Special precautions.

Epirubicin should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy.

Prior to initiating epirubicin treatment, patients should have recovered from acute toxicities (e.g., stomatitis, neutropenia, thrombocytopenia, and generalized infections) resulting from prior cytotoxic therapy.

High-dose epirubicin treatment (e.g., > 90 mg/m² every 3–4 weeks) generally causes the same adverse effects observed with standard doses (< 90 mg/m² every 3–4 weeks); however, the severity of neutropenia and stomatitis/mucositis may increase. High-dose epirubicin therapy requires special attention to potential clinical complications associated with profound myelosuppression.

Cardiac function. Treatment with anthracyclines carries a risk of cardiotoxicity, which may manifest as early (i.e., acute) or late (i.e., delayed) effects.

Early (i.e., acute) effects. Early manifestations of epirubicin cardiotoxicity primarily include sinus tachycardia and/or electrocardiogram (ECG) changes such as non-specific S-T segment and T-wave changes. Cases of tachyarrhythmias, including premature ventricular contractions, ventricular tachycardia, bradycardia, atrioventricular block, and intraventricular block, have also been reported. These effects are generally not predictive of subsequent development of delayed cardiotoxicity, are rarely clinically significant, and usually should not be considered an indication for discontinuation of epirubicin therapy.

Late (i.e., delayed) effects. Delayed cardiotoxicity usually develops at the end of an epirubicin treatment course or within 2–3 months after therapy completion, although later occurrences (months or even years after treatment) have also been reported. Delayed cardiomyopathy is characterized by a decrease in left ventricular ejection fraction (LVEF) and/or symptoms of congestive heart failure (CHF), such as dyspnea, pulmonary edema, orthostatic edema, cardiomegaly, and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm.

Life-threatening congestive heart failure (CHF) is the most severe form of anthracycline-induced cardiomyopathy and reflects the drug's dose-limiting toxicity.

The risk of developing CHF increases rapidly with cumulative epirubicin doses exceeding 900 mg/m²; exceeding this cumulative dose should be done only with extreme caution (see section "Pharmacodynamics").

Cardiac function should be assessed before initiating epirubicin therapy and carefully monitored during treatment to minimize the risk of severe cardiac failure.

The risk can be reduced by regular monitoring of left ventricular ejection fraction (LVEF) during treatment, with prompt discontinuation of epirubicin at the first signs of functional impairment. Appropriate quantitative methods for serial cardiac assessment (LVEF evaluation) include multigated radionuclide angiography (MUGA) or echocardiography (Echocardiography). Baseline cardiac evaluation using ECG and MUGA scan or echocardiography is recommended, especially for patients with risk factors that increase the likelihood of cardiotoxicity. LVEF should be reassessed periodically using MUGA or echocardiography, particularly when higher cumulative anthracycline doses are administered. Appropriate techniques should be used for ongoing follow-up assessment.

Due to the potential risk of cardiomyopathy, exceeding a cumulative epirubicin dose of 900 mg/m² should be done with extreme caution.

Risk factors for cardiotoxicity may be present in patients with active or occult cardiovascular disease, in patients who have previously or concurrently received mediastinal/pericardial radiotherapy, in patients previously treated with other anthracyclines or anthracenediones, and with concomitant use of other drugs that may depress myocardial contractility or are cardiotoxic (e.g., trastuzumab) (see section "Interaction with other medicinal products and other forms of interaction"); elderly patients are also at increased risk.

Heart failure (New York Heart Association [NYHA] class II–IV) has been observed in patients receiving trastuzumab monotherapy or combination therapy with anthracyclines such as epirubicin. It may range from mild to severe and has been associated with fatal outcomes.

Trastuzumab and anthracyclines, such as epirubicin, should not be used in combination outside of well-controlled clinical trials with careful monitoring of cardiac function. Patients previously treated with anthracyclines are also at increased risk of developing cardiotoxicity when receiving trastuzumab, although the risk is lower than with concurrent trastuzumab and anthracycline use.

Since the reported half-life of trastuzumab is approximately 4–5 weeks (28–38 days), trastuzumab may remain in circulation for up to 20–27 weeks after discontinuation. Patients receiving anthracyclines such as epirubicin after stopping trastuzumab may therefore be at increased risk of cardiotoxicity. Thus, physicians should, whenever possible, avoid anthracycline-based therapy for at least 27 weeks after stopping trastuzumab. If anthracyclines such as epirubicin are used, careful monitoring of cardiac function is recommended.

If symptoms of heart failure occur during trastuzumab use following epirubicin treatment, standard heart failure medications should be administered.

Particular attention should be paid to monitoring cardiac function in patients receiving high cumulative doses and in those with risk factors. However, epirubicin-related cardiotoxicity may occur at lower cumulative doses, regardless of the presence or absence of risk factors.

The toxicity of epirubicin and other anthracyclines or anthracenediones is likely additive.

Hematological toxicity. Like other cytotoxic agents, epirubicin may cause myelosuppression. Hematological parameters should be evaluated before and during each cycle of epirubicin treatment, including differential leukocyte count. Dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) are the predominant manifestations of epirubicin hematological toxicity and the most common dose-limiting acute toxicity of this drug.

Leukopenia and neutropenia are generally more severe with higher doses, reaching their nadir between days 10 and 14 after drug administration; they are usually transient, with leukocyte and neutrophil counts returning to normal by day 21 in most cases.

Thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.

Secondary leukemia. Cases of secondary leukemia, with or without a pre-leukemic phase, have been reported in patients treated with anthracyclines, including epirubicin. Secondary leukemia occurs more frequently when these drugs are used in combination with DNA-damaging antineoplastic agents, in combination with radiotherapy, after intensive prior cytotoxic therapy, or with high anthracycline doses. Such leukemias may be preceded by a latent period of 1 to 3 years (see section "Pharmacodynamics").

Gastrointestinal reactions. Epirubicin is emetogenic. Mucositis/stomatitis typically develops shortly after administration of the drug; in severe cases, it may progress over several days and lead to ulceration of the mucous membranes. This adverse effect usually resolves within 3 weeks of treatment.

Hepatic function. The hepatobiliary system is the primary route of epirubicin elimination. Total serum bilirubin and aspartate aminotransferase levels should be assessed before and during epirubicin therapy. In patients with elevated bilirubin or aspartate aminotransferase levels, drug clearance may be reduced, leading to increased overall toxicity. Dose reduction is recommended for such patients (see sections "Method of administration and dosage" and "Pharmacokinetics"). Epirubicin should not be administered to patients with severe hepatic impairment (see section "Contraindications").

Renal function. Serum creatinine levels should be regularly monitored before and during treatment. Dose adjustment is required for patients with serum creatinine levels > 5 mg/dL (see section "Method of administration and dosage").

Injection site reactions. Phlebitis may occur following injection into small vessels or repeated injections into the same vein. Adherence to recommended administration techniques helps minimize the risk of phlebitis/thrombophlebitis at the injection site (see section "Method of administration and dosage").

Extravasation. Extravasation of epirubicin during intravenous administration may cause local pain, severe tissue damage (blistering, severe subcutaneous inflammation), and tissue necrosis. If signs of extravasation occur during intravenous infusion of epirubicin, the infusion should be stopped immediately. The adverse effects of anthracycline extravasation can be prevented or minimized by immediate specific therapy, e.g., with dexrazoxane (see relevant instructions for use). Patient discomfort may be alleviated by cooling the injection site and maintaining a cooled state, using hyaluronic acid and DMSO. Close follow-up monitoring is essential, as tissue necrosis may develop weeks later. In case of extravasation, consultation with a plastic surgeon regarding possible resection of the affected area is recommended.

Other. As with other cytotoxic agents, isolated cases of thrombophlebitis and thromboembolism, including pulmonary embolism (in some cases fatal), have been reported during epirubicin use.

Tumor lysis syndrome. Epirubicin may cause hyperuricemia due to extensive purine catabolism accompanying rapid lysis of neoplastic cells induced by the drug (tumor lysis syndrome). Therefore, serum levels of uric acid, potassium, calcium phosphate, and creatinine should be monitored during treatment. Hydration, urine alkalinization, and prophylactic allopurinol to prevent hyperuricemia may minimize potential complications of tumor lysis syndrome.

Immunosuppression/increased susceptibility to infections. Administration of live or attenuated live vaccines to patients whose immune system is compromised by chemotherapeutic agents, including epirubicin, may result in severe or fatal infections (see section "Interaction with other medicinal products and other forms of interaction"). Live vaccines should be avoided in patients receiving epirubicin. Inactivated or killed vaccines may be administered, although they may be less effective.

Effect on reproductive function. Epirubicin may cause genotoxic effects. Men and women receiving epirubicin should use appropriate contraceptive methods. Patients desiring children should be advised, if possible, to consider genetic counseling after completion of treatment with this drug.

Additional warnings and precautions for other routes of administration

Intravesical administration. Administration of epirubicin may cause symptoms of chemical cystitis (e.g., dysuria, polyuria, nocturia, stranguria, hematuria, voiding disorders, bladder wall necrosis) and bladder shrinkage. Special attention should be paid to catheterization issues (e.g., urethral obstruction due to large intravesical tumors).

Use during pregnancy or breastfeeding.

Pregnancy

Women of reproductive potential should be advised to avoid pregnancy and to use effective contraception during treatment.

Animal experimental data suggest that epirubicin may cause fetal harm when administered to pregnant women.

If StriBicin is used during pregnancy or if a patient becomes pregnant while receiving this drug, she should be informed of the potential risk to the fetus.

There are no studies in pregnant women. StriBicin should be used during pregnancy only if the potential benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding

It is unknown whether epirubicin is excreted in human milk. Because many drugs, including anthracyclines, are excreted in breast milk and due to the potential for serious adverse reactions in nursing infants caused by StriBicin, women should discontinue breastfeeding before starting the drug.

Fertility

StriBicin may cause chromosomal damage in human spermatozoa. Men receiving StriBicin therapy should use effective contraception and, if appropriate and feasible, seek advice on sperm preservation due to the possibility of irreversible infertility induced by therapy.

StriBicin may cause amenorrhea and premature menopause in women.

Ability to affect reaction speed when driving or operating machinery.

StriBicin does not affect the ability to drive or operate machinery.

Method of Administration and Dosage.

Intravenous administration.

Dosing regimen for standard dosage.

When Streptozin is used as a single-agent antineoplastic therapy, the recommended dose for adults is 60–90 mg/m² of body surface area, administered by intravenous injection over 5–10 minutes, repeated every 21 days, depending on hematological/bone marrow status.

Dosing regimen for high-dose administration.

Lung cancer.

For high-dose monotherapy in the treatment of lung cancer, Streptozin should be administered according to the following regimens:

• Small cell lung cancer in previously untreated patients: 120 mg/m² on Day 1 every 3 weeks;
• Non-small cell lung cancer (epidermoid, squamous, and adenocarcinoma) in previously untreated patients: 135 mg/m² on Day 1 or 45 mg/m² on Days 1, 2, and 3 every 3 weeks.

Breast cancer.

Doses up to 135 mg/m² (with Streptozin monotherapy) and up to 120 mg/m² (with combination therapy), administered every 3–4 weeks, have been effective and well tolerated in patients with breast cancer.

For adjuvant therapy in early-stage breast cancer, recommended doses range from 100 mg/m² to 120 mg/m² every 3–4 weeks.

The drug should be administered by intravenous injection over 5–10 minutes or by intravenous infusion over no more than 30 minutes.

Lower doses (60–75 mg/m² or 105–120 mg/m² in high-dose regimens) are recommended for patients with reduced bone marrow reserve due to prior chemotherapy and/or radiotherapy, elderly patients, or patients with tumor infiltration of the bone marrow. The total dose per cycle may be divided and administered over 2–3 consecutive days.

When used in combination with other antineoplastic agents, doses of Streptozin should be appropriately reduced.

Since the primary route of elimination is the hepatobiliary system, the dose of Streptozin should be reduced in patients with impaired liver function to avoid increased overall toxicity.

In general, if bilirubin levels are between 1.4–3 mg/100 mL and bromsulfalein (BSP) retention is 9–15%, half the usual dose is recommended.

If bilirubin levels and BSP retention exceed these values, one-quarter of the usual dose is recommended.

Mild renal impairment is not a sufficient reason to alter the recommended doses due to the low level of renal excretion of Streptozin.

Intravesical administration.

For the treatment of patients with transitional cell papillary carcinoma, weekly instillations of 50 mg are recommended, repeated for 8 weeks. In case of local toxicity (chemical cystitis), the dose should be reduced to 30 mg. For the treatment of carcinoma in situ, the dose may be increased to 80 mg according to individual patient tolerance.

For the prevention of recurrence after transurethral resection of superficial tumors, weekly instillations of 50 mg are recommended for 4 weeks, followed by monthly instillations of the same dose for up to one year.

Method of administration.

Streptozin is ineffective when administered orally and must not be administered intramuscularly or intrathecally.

Intravenous administration.

Intravenous injection should last 5–10 minutes and should be given through an intravenous infusion set with a pre-connected flask of physiological saline, ensuring that the needle is properly placed in the vein. This technique reduces the risk of drug extravasation and allows for flushing the vein with 0.9% sodium chloride solution at the end of administration. Leakage of Streptozin from the vein during injection may lead to tissue damage and even necrosis. Venous sclerosis may occur as a result of injection into small blood vessels or repeated injections into the same vein.

Intravesical administration.

The Streptozin solution administered via catheter should remain in the bladder for 1 hour, after which the patient should empty the bladder. During instillation, the patient should turn from side to side to ensure more uniform distribution of the drug solution over the bladder walls.

Children.

The efficacy and safety of the drug for the treatment of children have not been studied.

Overdose.

Acute overdose of epirubicin causes severe myelosuppression (mainly leukopenia and thrombocytopenia), gastrointestinal toxicity (mainly mucositis), and acute cardiac complications. Cases of latent heart failure associated with anthracycline use have been reported from several months to several years after completion of therapy (see section "Special precautions"). Patients should be carefully monitored. If symptoms of heart failure occur, patients should be treated with conventional methods.

Treatment is symptomatic. Epirubicin is not eliminated by dialysis.

Adverse reactions

The following adverse reactions have been observed during treatment with Streptozocin, with the following frequencies: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (≤ 1/10000), not known (cannot be estimated from the available data).

Adverse reactions may occur in more than 10% of patients. The most common adverse effects include myelosuppression, gastrointestinal adverse reactions, anorexia, alopecia, and infections.

Table 2

Intravesical administration

Since only a small amount of the active substance is absorbed after intravesical administration, severe systemic adverse reactions, as well as allergic reactions to this medicinal product, are rare. Local reactions such as burning sensation and increased urinary frequency (polyuria) are usually observed.

Occasionally, bacterial or chemical cystitis may occur (see section "Special precautions for use"). These adverse reactions are generally reversible.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging, protected from light, at 2–8 °C.

Do not freeze.

Keep out of reach of children.

Incompatibilities.

Streptocin should not be mixed with heparin due to their chemical incompatibility, which may lead to precipitation.

Packaging.

25 mL or 100 mL of the medicinal product are contained in amber glass bottles stoppered with a rubber stopper and sealed with an aluminum crimp cap equipped with a flip-off cap ensuring tamper-evidence.

One bottle is placed in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

MYLAN LABORATORIES LIMITED (OTL)

MYLAN LABORATORIES LIMITED (OTL)

Manufacturer's address and place of business.

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

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

Marketing authorization holder.

M.Biotech Ltd

M.Biotech Ltd

Address of the marketing authorization holder.

Gladstone House, 77–79 High Street, Egham TW20 9GH, Surrey, United Kingdom