Neoquabin

Each vial contains Epirubicin HCl 10 mg, 50 mg.

ATC Code: L01D B.
Pharmacology: Pharmacodynamics: The mechanism of action of Epirubicin is related to its ability to bind to DNA. Cell culture studies have shown rapid cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis. Epirubicin has proved to be active on a wide spectrum of experimental tumours including L1210 and P388 leukaemias, sarcomas SA180 (solid and ascitic forms), B16 melanoma, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38. It has also shown activity against human tumours transplanted into athymic nude mice (melanoma, mammary lung, prostatic and ovarian carcinomas).
Pharmacokinetics: In patients with normal hepatic and renal function, plasma levels after intravenous injection of 60-150 mg/m² of the drug follow a tri-exponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours. These doses are within the limits of pharmacokinetic linearity both in terms of plasma clearance values and metabolic pathway. The major metabolites that have been identified are epirubicinol (13-OH epirubicin) and glucuronides of epirubicin and epirubicinol.
The 4'-O-glucuronidation distinguishes epirubicin from doxorubicin and may account for the faster elimination of epirubicin and its reduced toxicity. Plasma levels of the main metabolite, the 13-OH derivative (epirubicinol) are consistently lower and virtually parallel those of the unchanged drug.
Epirubicin is eliminated mainly through the liver; high plasma clearance values (0.9 L/min) indicate that this slow elimination is due to extensive tissue distribution. Urinary excretion accounts for approximately 9-10% of the administered dose in 48 hours.
Biliary excretion represents the major route of elimination, about 40% of the administered dose being recovered in the bile in 72 hours. The drug does not cross the blood brain barrier.

Epirubicin has produced responses in a wide range of neoplastic conditions, including breast, ovarian, gastric, lung, liver and colorectal carcinomas, malignant lymphomas, leukemias, multiple myeloma and soft tissue sarcoma.
Intravesical administration of epirubicin has been found to be beneficial in the treatment of superficial bladder cancer (carcinoma-in-situ) and in the prophylaxis of recurrences after transurethral resection.

Epirubicin hydrochloride is administered intravenously by injection in a solution of sodium chloride 0.9% or water for injections into a fast-running infusion of sodium chloride 0.9% or glucose 5% over 3 to 5 minutes, or by infusion over up to 30 minutes. It is given as a single agent in usual doses of 60 to 90 mg per m² body surface as a single dose every 3 weeks; this dose may be divided over 2 or 3 days if desired. High dose regimens of 120 mg or more per m² every 3 weeks, or 45 mg per m² for 3 consecutive days every 3 weeks have been used. A regimen of 20 mg as a single weekly dose has also been tried and is reported to be associated with lower toxicity. Doses should be reduced if epirubicin is given with other antineoplastics, and should be halved in patients with moderate liver dysfunction serum bilirubin concentrations of 14-30 μg per mL while those with severe liver impairment (serum bilirubin greater than 30 μg per mL) should be given a quarter of the usual dose. Reduced doses are also recommended in those whose bone marrow function is impaired by age or previous chemotherapy or radiotherapy. A total cumulative dose of 0.9 to 1 g per m² should not generally be exceeded because of the risk of cardiotoxicity.
Epirubicin has also been given by intravesical instillation in the local treatment of bladder cancer. Instillation of 50 mg weekly as a 0.1% solution for 8 weeks has been suggested reduced to 30 mg weekly. If chemical cystitis develops for carcinoma in-situ, the dose may be increased, if tolerated to 80 mg weekly. For the prophylaxis of recurrence in patients who have undergone transurethral resection. 50 mg weekly for 4 weeks, followed by 50 mg instilled once a month for 11 months is the suggested regimen.
Blood counts should be made routinely during treatment with epirubicin and cardiac function should be carefully monitored. Liver function should be assessed before and if possible during therapy. Or as prescribed by the physician.

Very high single doses of epirubicin may be expected to cause acute myocardial degeneration within 24 hours and severe myelosuppression within 10-14 days. Treatment should aim to support the patient during this period and should utilise such measures as blood transfusion and reverse barrier nursing. Delayed cardiac failure has been seen with the anthracyclines up to 6 months after the overdose. Patients should be observed carefully and should, if signs of cardiac failure arise, be treated along conventional lines.

Patients with a current or previous history of cardiac impairment; Patients known to have hypersensitivity to the drug; Patients already treated with maximal cumulative doses of other anthracyclines such as Epirubicin (500 mg/m2-Surface area) or daunorubicin (25 mg/kg: total dose); Patients with heart disease.

Patients with hepatic dysfunction; Patients with renal dysfunction; Patients with myelosuppression; Patients with infectious complication; The elderly; Patients with chickenpox. (The fatal systemic disorder may occur.); Patients with experience the heart failure of the type described for other anthracyclines.
General: EPIRUBICIN Injection should be administered only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Before initial treatment with epirubicin, patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment. Also, initial treatment with EPIRUBICIN should be preceded by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and creatinine; and cardiac function as measured by left ventricular ejection function (LVEF). Patients should be carefully monitored during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to epirubicin.
Cardiotoxicity is a known risk of anthracycline treatment. Anthracycline-induced cardiac toxicity may be manifested by early (or acute) or late (delayed) events. Early cardiac toxicity of epirubicin consists mainly of sinus tachycardia and/or ECG abnormalities such as non-specific ST-T wave changes, but tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not considered an indication for the suspension of epirubicin treatment. Delayed cardiac toxicity results from a characteristic cardiomyopathy that is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF) such as tachycardia, dyspnea, pulmonary edema, dependent edema, hepatomegaly, ascites, pleural effusion, gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy. This toxicity appears to be dependent on the cumulative dose of EPIRUBICIN and represents the cumulative dose-limiting toxicity of the drug. If it occurs, delayed cardiotoxicity usually develops late in the course of therapy with EPIRUBICIN or within 2 to 3 months after completion of treatment, but later events (several months to years after treatment termination) have been reported.
In a retrospective survey, including 9144 patients, mostly with solid tumors in advanced stages, the probability of developing CHF increased with increasing cumulative doses of EPIRUBICIN. The estimated risk of epirubicin-treated patients developing clinically evident CHF was 0.9% at a cumulative dose of 550 mg/m², 1.6% at 700 mg/m², and 3.3% at 900 mg/m². The risk of developing CHF in the absence of other cardiac risk factors increased steeply after an epirubicin cumulative dose of 900 mg/m².
In another retrospective survey of 469 epirubicin-treated patients with metastatic or early breast cancer, the reported risk of CHF was comparable to that observed in the larger study of over 9000 patients.
Given the risk of cardiomyopathy, a cumulative dose of 900 mg/m² EPIRUBICIN should be exceeded only with extreme caution. Risk factors (active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility) may increase the risk of cardiac toxicity. Although not formally tested, it is probable that the toxicity of epirubicin and other anthracyclines or anthracenediones is additive. Cardiac toxicity with EPIRUBICIN may occur at lower cumulative doses whether or not cardiac risk factors are present.
Although endomyocardial biopsy is recognized as the most sensitive diagnostic tool to detect anthracycline-induced cardiomyopathy, this invasive examination is not practically performed on a routine basis. Electrocardiogram (ECG) changes such as dysrhythmias, a reduction of the QRS voltage, or a prolongation beyond normal limits of the systolic time interval may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity. The risk of serious cardiac impairment may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of EPIRUBICIN at the first sign of impaired function. The preferred method for repeated assessment of cardiac function is evaluation of LVEF measured by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent through follow-up. In patients with risk factors, particularly prior anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict and the risk-benefit of continuing treatment with EPIRUBICIN in patients with impaired cardiac function must be carefully evaluated. Special attention must be given to the infection and bleeding tendency exhibited by Epirubicin.
In case of prescription to a child and a patient with generative power, consider effect on sexual gland.
Cautions of Application: Epirubicin must not be given by the intramuscular or subcutaneous route.
Avoid intraperitoneal prescribing because of danger of intestinal obstruction.
Since intravenous administration may cause vascular pain, phlebitis, thrombus, site of injection and administration method should be cautioned, and administered as slow as possible.
Induration, necrobiosis may occur due to extravasation of the solution in intravenous injection.
Therefore, intravenous administration should be cautioned not to leak the solution.
Because stability may be reduced due to pH change in dissolving, avoid using together other medicine and dissolve in water for injection or a saline solution for injection.
Reconstituted solution should be used immediately.
Others: Epirubicin imparts a red coloration to the urine after administration and patients should be advised to expect this during active therapy. Tumors have been reported in the animal test with rat intravenously. Epirubicin is recognized as mutagenic for bacterium. Acute leukemia and preleukemia myelodysplastic syndrome (MSD) is reported to the patients with concomitant administration of Epirubicin and other antineoplastics.
Use in Pregnancy & Lactation: There is conclusive information as to whether Epirubicin may adversely affect human fertility or cause teratogenesis.
Experimental data, however, suggest that Epirubicin may harm the fetus and should, therefore, not be administered to pregnant women or to mothers who are breast feeding.
Use in Children: Use in children should be cautioned about manifestation of adverse effects.

There is conclusive information as to whether Epirubicin may adversely affect human fertility or cause teratogenesis.
Experimental data, however, suggest that Epirubicin may harm the fetus and should, therefore, not be administered to pregnant women or to mothers who are breast feeding.

Cardiogenic: Cardiotoxicity may be manifested in tachycardia, including supraventricular tachycardia, arrhythmia, abdominal pain, and ECG changes. Routine ECG monitoring is recommended and caution should be exercised in patients with impaired cardiac function.
Hematologic: Anemia, bleeding, leukocytopenia, and thrombopenia.
Hypersensitivity: Fever, chills, and urticaria have been reported occasionally. Anaphylaxis may occur.
Hepatic: Hepatic impairment has been reported occasionally.
Renal: Occasionally, proteinuria has been reported.
Gastrointestinal: Acute nausea and vomiting occurs frequently and may be severe. Mucositis (stomatitis and esophagitis) may occur 5 to 10 days after administration. Anorexia and diarrhea have been occasionally reported.
Cutaneous: Reversible complete alopecia occurs in most cases. Hyperpigmentation of nail beds and dermal creases have been reported in a few cases.
CNS: Fatigue and headache occurs frequently.
Urinary system: Cystic stimulation symptoms (oliguria, urodynia, urocystitis, hematuria) by vesicoclysis therapy.
Respiratory system: Pneumothorax during treatment which metastasize to the lungs.
Other: Febricity, occasionally facial edema may occur.

Epirubicin when used in combination with other cytotoxic drugs may show on-treatment additive toxicity, especially hematologic and gastrointestinal effects.
Concomitant use of Epirubicin with other cardioactive compounds that could cause heart failure (e.g., calcium channel blockers), requires close monitoring of cardiac function throughout treatment.
There are few data regarding the co administration of radiation therapy and epirubicin. In adjuvant trials of epirubicin-containing CEF-120 or FEC-100 chemotherapies, breast irradiation was delayed until after chemotherapy was completed. This practice resulted in no apparent increase in local breast cancer recurrence relative to published accounts in the literature. A small number of patients received epirubicin-based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of epirubicin with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation. Administration of Epirubicin after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.
Epirubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity.

Store at temperatures between 2°C and 8°C.

Cytotoxic Chemotherapy

L01DB03 - epirubicin ; Belongs to the class of cytotoxic antibiotics, anthracyclines and related substances. Used in the treatment of cancer.

Rx