Pharmorubicin CS

Pharmorubicin CS Special Precautions

epirubicin

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma

Marketer:

DKSH
Full Prescribing Info
Special Precautions
Pharmorubicin should be administered only under the supervision of qualified physicians experienced in cytotoxic therapy.
Patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia and generalised infections) of prior cytotoxic treatment before beginning treatment with Pharmorubicin.
While treatment with high doses of Pharmorubicin (e.g., ≥90 mg/m2 every 3 to 4 weeks) causes adverse events generally similar to those seen at standard doses (e.g., <90 mg/m2 every 3 to 4 weeks), the severity of neutropenia and stomatitis/mucositis may be increased. In particular, treatment with high doses of the drug requires special attention for possible clinical complications due to profound myelosuppression.
Initial treatment with Pharmorubicin requires close observation of the patient and extensive laboratory monitoring including assessment of cardiac function (see Cardiac Function as follows). During each cycle of treatment patients must be carefully and frequently monitored. A blood count, renal and liver function tests should be carried out prior to each Pharmorubicin treatment.
The rate of administration is dependent on the size of the vein and the dosage. It is important that the dose be administered in not less than 3 to 4 minutes. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration.
Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid administration. A burning or stinging sensation may be indicative of perivenous infiltration and the infusion should be immediately terminated and restarted in another vein. Severe local tissue necrosis will occur if there is extravasation during administration. Venous sclerosis may result from injection into a small vessel or from repeated injections into the same vein.
Pharmorubicin must not be given by the intramuscular or subcutaneous route.
Pharmorubicin is not an antimicrobial agent.
Haematologic Toxicity: Myelosuppression very commonly accompanies effective Pharmorubicin treatment, and represents the acute dose-limiting toxicity of this drug. Haematologic profiles should be assessed before and during each cycle of therapy with epirubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leukopaenia and/or granulocytopaenia (neutropaenia) is the predominant manifestation of epirubicin haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leukopaenia and neutropaenia are generally more severe with high-dose schedules, reaching the nadir in most cases between days 10 and 14 after drug administration; this is usually transient with the WBC/neutrophil counts returning to normal values in most cases by day 21. Thrombocytopaenia and anaemia may also occur.
Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia or death.
Myelosuppression is more common in patients who have had extensive radiotherapy, bone marrow infiltration by tumour or impaired liver function (when appropriate dosage reduction has not been adopted) (see Dose Modifications, Other Special Populations under Dosage & Administration).
Secondary Leukaemia: Secondary leukaemia, with or without a pre-leukaemic phase, has been reported in patients treated with anthracyclines including epirubicin. Secondary leukaemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pre-treated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukaemias can have a 1- to 3-year latency period.
Cardiac Function: Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e., acute) or late (i.e., delayed) events. The cardiac abnormalities caused by treatment can be separated into 2 categories: ECG alterations and Congestive heart failure (CHF).
Early (i.e., Acute) Events: Early cardiotoxicity of epirubicin consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. ECG changes following Pharmorubicin treatment occur in about 10% of patients. Tachyarrhythmias, including premature ventricular contractions, ventricular tachycardia, and 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 a consideration for the discontinuation of epirubicin treatment.
Late (i.e., Delayed) Events: Delayed cardiotoxicity usually develops late in the course of therapy with Pharmorubicin or within 2 to 3 months after treatment termination, but later events several months to years after completion of treatment have also been reported. Cardiomyopathy induced by anthracyclines is associated with persistent QRS voltage reduction, prolongation beyond normal limits of the systolic time interval (PEP/LVET) and a reduction of the ejection fraction and/or signs and symptoms of CHF such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug. Pericardial effusion has also been described.
The risk of developing CHF increases rapidly with increasing total cumulative doses of epirubicin in excess of 900 mg/m2; this cumulative dose should only be exceeded with extreme caution.
Cardiac function should be assessed before patients undergo treatment with epirubicin and must be monitored throughout therapy to minimise the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of left ventricular ejection fraction (LVEF) during the course of treatment with prompt discontinuation of epirubicin at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.
Risk factors for cardiac toxicity include active or dormant cardiovascular disease, concomitant or previous radiation of the mediastinal-pericardial area, hypertensive cardiomyopathy, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic agents (e.g., trastuzumab, high dose cyclophosphamide or 5-fluorouracil). Anthracyclines including epirubicin should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored (see INTERACTIONS). Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. The half-life of trastuzumab is approximately 28 - 38 days and may persist in the circulation for up to 27 weeks. Therefore, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.
Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with epirubicin may occur at lower cumulative doses whether or not cardiac risk factors are present. It is probable that the toxicity of epirubicin and other anthracyclines or anthracenediones is additive.
Gastrointestinal: Epirubicin is emetigenic. Nausea and vomiting may be prevented or alleviated by the administration of appropriate antiemetic therapy.
Mucositis/stomatitis occurs frequently and generally appears early after drug administration, most commonly developing 5 to 10 days after treatment. It is painful and typically begins as a burning sensation in the mouth and pharynx. The mucositis may involve the vagina, rectum and oesophagus, and, if severe, may progress over a few days to mucosal ulcerations with a risk of secondary infection. Most patients recover from this adverse event by the third week of therapy.
Liver Function: The major route of elimination of epirubicin is the hepatobiliary system. Serum total bilirubin and AST levels should be evaluated before and during treatment with Pharmorubicin. Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients (see DOSAGE & ADMINISTRATION). Patients with severe hepatic impairment should not receive Pharmorubicin (see CONTRAINDICATIONS).
Renal Function: Moderate renal impairment does not appear to require a dose reduction in view of the limited amount of Pharmorubicin excreted by this route. However, serum creatinine should be assessed before and during therapy. Dosage adjustment is necessary in patients with serum creatinine >5 mg/dL (see DOSAGE & ADMINISTRATION).
Effects at Site of Injection: Phlebosclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Following the recommended administration procedures may minimise the risk of phlebitis/thrombophlebitis at the injection site (see Intravenous Administration under DOSAGE & ADMINISTRATION).
Extravasation: Extravasation of epirubicin during intravenous injection may produce local pain, severe tissue lesions (vesication, severe cellulitis) and necrosis. The recommended administration procedures should be followed (see Intravenous Administration under DOSAGE & ADMINISTRATION). Should signs or symptoms of extravasation occur during intravenous administration of epirubicin, the drug infusion should be immediately stopped.
Tumour-Lysis Syndrome: Epirubicin may induce hyperuricaemia because of the extensive purine catabolism that accompanies rapid drug-induced lysis of neoplastic cells (tumour-lysis syndrome). Blood uric acid levels, potassium, calcium phosphate and creatinine should be evaluated after initial treatment. Hydration, urine alkalinisation and prophylaxis with allopurinol to prevent hyperuricaemia may minimise potential complications of tumour-lysis syndrome.
Immunosuppressant Effects/Increased Susceptibility to Infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents, including epirubicin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving epirubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Other: As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidently reported with the use of Pharmorubicin.
Pharmorubicin may enhance radiation-induced toxicity such as skin reactions and mucositis and may potentiate the toxicity of other anticancer therapies. This has to be taken into account particularly when using the drug in high doses and the availability of supportive care and facilities has to be considered before initiating high dose-intensive regimens.
Epirubicin may impart a red colour to the urine for one-two days after administration. Patients should be advised that such an event is not a cause for alarm.
Intravesical Route: Administration of epirubicin may produce symptoms of chemical cystitis (such as dysuria, polyuria, nocturia, stranguria, haematuria, bladder discomfort, necrosis of the bladder wall) and bladder constriction. Special attention is required for catheterisation problems (e.g., uretheral obstruction due to massive intravesical tumours).
Use in Pregnancy (Category D): Women of child-bearing potential should be advised to avoid becoming pregnant during treatment and should use effective contraceptive methods.
There is no specific information available at present concerning the use of Pharmorubicin in human pregnancy. However, as it has been shown to be embryotoxic and fetotoxic in animals, it should not be used in patients who are pregnant or are likely to become pregnant.
Although no studies have been conducted with Pharmorubicin, it may be expected, like doxorubicin, to cause infertility during the period of drug administration. In women, Pharmorubicin may cause amenorrhoea. After termination of therapy, ovulation and menstruation may be expected to return in a few months, often accompanied by normal fertility. Premature menopause may also occur.
In male patients, oligospermia or azoospermia may be permanent, although fertility may return several years after ceasing therapy. Given the mutagenic potential of Pharmorubicin, the drug could induce chromosomal damage in human spermatozoa; therefore, males undergoing Pharmorubicin treatment should employ contraceptive measures.
Use in Lactation: It is likely that Pharmorubicin is excreted in breast milk, therefore, it is not recommended for nursing mothers unless the expected benefit outweighs any potential risk.
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