Robol Special Precautions

CAUTION: Cytotoxic Agent: It is dangerous to take this preparation except under Medical Supervision.
General: ROBOL should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.
ROBOL is not an antimicrobial agent.
Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia and generalised infections) before beginning treatment with doxorubicin.
Initial treatment with ROBOL requires close observation of the patient and extensive laboratory monitoring.
It is strongly recommended therefore, that patients be hospitalised at least during the first phase of treatment. Blood count and liver function tests should be carried out prior to each ROBOL treatment.
ROBOL solution should be handled with care. If either of the preparations comes in contact with the skin or mucosa, the appropriate areas should be washed thoroughly with soap and water.
Warnings: 1. For intravenous or intravesical use only. Severe local tissue necrosis will occur if there is extravasation during administration. ROBOL must not be given by the intramuscular or subcutaneous route.
2. Serious irreversible myocardial toxicity with delayed congestive failure often unresponsive to any cardiac supportive therapy may be encountered as total dosage approaches 550 mg/m².
3. This toxicity may occur at lower cumulative doses in patients with prior mediastinal irradiation or on concurrent cyclophosphamide therapy.
4. Dosage should be reduced in patients with impaired hepatic function.
5. Severe myelosuppression may occur.
Cardiac Function: Special attention must be given to the cardiac toxicity exhibited by doxorubicin. 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: 1. ECG alterations and; 2. Congestive heart failure (CHF).
Early (i.e., Acute) Events: Early cardiotoxicity of doxorubicin consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes. 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 doxorubicin treatment. ECG changes following doxorubicin treatment occur in about 10% of patients at all dose levels of doxorubicin, are usually reversible and do not appear to be related to the subsequent development of congestive cardiac failure.
Late (i.e., Delayed) Events: Delayed cardiotoxicity usually develops late in the course of therapy with doxorubicin or within 2 to 3 months after treatment termination, but later events several months to years after completion of treatment have also been reported. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion and gallop rhythm. Subacute effects such as pericarditis/myocarditis have also been reported. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative doselimiting toxicity of the drug.
The following measures may identify patients with early cardiomyopathy: progressive flattening or inversion of the T-waves (mainly in the left precordial leads), low QRS voltage, prolonged systolic time interval, reduced ejection fraction (echocardiography or by cardiac pool scanning) or cardiac biopsy showing characteristic electromicroscopic changes. Cardiomyopathy induced by doxorubicin is frequently fatal. Cardiac failure is often not favourably affected by presently known medical or physical therapy for cardiac support. Early clinical diagnosis of drug induced heart failure appears to be essential for successful treatment with digitalis, diuretics, low salt diet and bed rest.
Although uncommon, acute left ventricular failure has occurred, particularly in patients who have received total dosage of the drug exceeding the currently recommended limit of 550 mg/m². For this reason, cardiac function should be assessed before patients undergo treatment with doxorubicin and must be carefully monitored throughout therapy to minimise the risk of incurring severe cardiac impairment. The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of doxorubicin 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. Severe cardiac toxicity may occur precipitously without antecedent ECG changes.
Baseline ECG and periodic follow-up ECG during, and immediately after drug therapy is an advisable precaution. Transient ECG changes, such as T-wave flattening, S-T depression and arrhythmias are not considered indications for suspension of doxorubicin therapy. A persistent reduction in the voltage of the QRS wave is presently considered more specifically predictive for cardiac toxicity. If this occurs, the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage.
A decrease of the LVEF is the most predictive event related to chronic, cumulative dose-dependent cardiomyopathy. When a pre-treatment (baseline) assessment of LVEF is available, this parameter can be used as an indicator of cardiac function throughout therapy.
Children and adolescents are at an increased risk for developing delayed cardiotoxicity following doxorubicin administration. Females may be at greater risk than males. Follow-up cardiac evaluations are recommended periodically to monitor for this effect.
As a general rule, in patients with normal baseline LVEF (≥50%), an absolute decrease of ≥10% or a decline below the 50% threshold level are indicative of a deterioration of cardiac function and the continuation of doxorubicin treatment under such conditions has to be carefully evaluated. The probability of developing impaired myocardial function based on a combined index of signs, symptoms and a decline in LVEF can be estimated to be around 1-2% at a cumulative dose of 300mg/m²; this probability slowly increases up to the total cumulative dose of 450-550 mg/m².
Thereafter, the risk of developing CHF increases more steeply, and it is recommended not to exceed the total cumulative dose of 550 mg/m².
Cardiac function must be carefully monitored in patients receiving high cumulative doses and in those with risk factors. However, cardiac toxicity with doxorubicin may occur at lower cumulative doses whether or not cardiac risk factors are present.
Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with anthracyclines or anthracenediones, concomitant use of drugs with the ability to suppress cardiac contractility or other cardioactive compounds (e.g. calcium channel blocking drugs) or concomitant use of other potentially cardiotoxic drugs (e.g. cyclophosphamide, 5-fluorouracil or trastuzumab).
Anthracyclines including doxorubicin 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 e.g. trastuzumab (variable half-life; washout period up to 7 months), may also be at an increased risk of developing cardiotoxicity. Note: Trastuzumab emtansine has a shorter half-life of approximately 4 days. The half-life of trastuzumab is variable. Trastuzumab may persist in the circulation for up to 7 months. Therefore, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.
For patients who have had mediastinal irradiation, concurrent high dose cyclophosphamide or hypertensive cardiomegaly it is recommended that the cumulative total lifetime dose of doxorubicin (including related drugs such as daunorubicin) be less than 450 mg/m² body surface area. Congestive heart failure and/or cardiomyopathy may be encountered several weeks after discontinuation of doxorubicin therapy.
The total (cumulative) dose levels of doxorubicin correlate with the incidence of drug induced congestive cardiac failure (cardiomyopathy). Limitation of the total dose of doxorubicin to 500 mg/m² reduces the risk of drug induced cardiomyopathy. At the cellular level, cardiotoxicity induced by doxorubicin is due to myocyte damage. Furthermore, as a consequence of the inhibition of cellular proliferation not only of neoplastic cells but also normal cells, cardiac muscle cells are unable to regenerate.
Microscopical examination of endocardial biopsies shows two major types of myocyte damage: 1. Cells totally or partially devoid of myofibrillar content, even though the nucleus and mitochondria are intact; 2. Vacuolar degeneration.
Damage to the myocardial muscle occurs with very little inflammatory reaction, muscle fibres appear to fade away. The clinical spectrum of doxorubicin toxicity ranges from subtle changes in ventricular function that can be detected only by sophisticated studies to gross congestive cardiomyopathy with symptoms and signs of advanced congestive heart failure.
It is probable that the toxicity of doxorubicin and other anthracyclines or anthracenediones is additive.
Animal studies have indicated a possible relationship between the inhibition by doxorubicin of the mitochondrial biosynthesis of Coenzyme Q 10 and cardiotoxicity induced by doxorubicin. Other studies have suggested that Vitamin E and other free radical acceptors may prevent doxorubicin toxicity.
Haematologic Toxicity: As with other cytotoxic agents, doxorubicin may produce myelosuppression. Haematologic profiles should be assessed before and during each cycle of therapy with doxorubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leucopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of doxorubicin haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leucopenia and neutropenia are generally more severe with high-dose schedules, reaching the nadir in most cases between days 10-14 after drug administration; this is usually transient with the WBC/neutrophil counts returning to normal values in most cases by day 21. White blood cell counts as low as 1000/mm³ are to be expected during treatment with appropriate doses of doxorubicin.
Myelosuppression accompanies effective doxorubicin treatment in almost 100% of patients. Leucopenia is the predominant effect with thrombocytopenia and anaemia occurring less frequently. Red blood cell and platelet levels should also be monitored.
Myelosuppression is more common in patients who have had extensive radiotherapy, bone infiltration by tumour, impaired liver function when appropriate dosage reduction has not been adopted (see Dosage & Administration) and simultaneous treatment with other myelosuppressive agents. Haematologic toxicity may require dose reduction, suspension or delay of ROBOL therapy.
When using doxorubicin as part of chemotherapy regimens which combine drugs of similar pharmacological effects (i.e. cytotoxicity) additive toxicity is likely to occur. Such additive toxicity has to be taken into consideration especially with regard to bone marrow function.
Doxorubicin is a powerful but temporary immunosuppressant agent. Appropriate measures should be taken to prevent secondary infection. Clinical consequences of severe myelosuppression include fever, infection, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia or death.
Secondary Leukaemia: Secondary leukaemia, with or without a pre-leukaemic phase, has been reported in patients treated with anthracyclines including doxorubicin. 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. This has been noted in the adjuvant and neoadjuvant setting. These leukaemias can have a 1- to 3-year latency period.
Gastrointestinal: Doxorubicin is emetogenic. Mucositis is a frequent and painful complication of doxorubicin treatment but is less common than myelosuppression. Mucositis/stomatitis generally appears early after drug administration, most commonly developing 5 to 10 days after treatment. It 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 risk of secondary infection. Most patients recover from this adverse event by the third week of therapy. Retrospective comparison of the incidence of mucositis suggests that it is less frequent as the intervals between doses increase. Mucositis may be severe in patients who have had previous irradiation to the mucosae.
Obesity: The systemic clearance of doxorubicin has been found to be reduced in obese patients; such patients have to be carefully monitored if undergoing treatment with the maximum recommended doses of the drug.
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 Dosage & Administration).
Extravasation: Extravasation of doxorubicin during intravenous injection may produce local pain (a burning or stinging sensation), severe tissue lesions (vesication, severe cellulitis) and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of doxorubicin, the drug infusion should be immediately stopped.
To minimise perivenous infiltration, see Dosage & Administration.
Tumour-Lysis Syndrome: Like other cytotoxic drugs, doxorubicin may induce hyperuricaemia as a consequence of the extensive purine catabolism that accompanies rapid drug-induced lysis of neoplastic cells (tumour-lysis syndrome). The clinician should monitor the patient's blood uric acid level, potassium, calcium phosphate and creatinine. Supportive and pharmacologic measures should be used to control this problem. 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 doxorubicin, may result in serious or fatal infections.
Vaccination with a live vaccine should be avoided in patients receiving doxorubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Other: Doxorubicin may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide induced haemorrhagic cystitis, mucositis induced by radiotherapy, and enhanced hepatotoxicity of 6-mercaptopurine have been reported. Radiation-induced toxicities (myocardium, mucosae, skin and liver) have also been reported.
As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of doxorubicin.
Doxorubicin imparts a red colouration to the urine for 1-2 days after administration and patients should be advised to expect this during active therapy.
Intravesical Route: Administration of doxorubicin by the intravesical route 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., urethral obstruction due to massive intravesical tumours). Urine cytologies and blood counts should be monitored monthly and cytoscopic examinations should be performed at regular intervals.
Instructions to be Given to Patients: 1. Patients should inform their physicians immediately if pain develops at the injection site.
2. Nausea and vomiting may be expected 3-6 hours after drug treatment, and may last for several hours.
3. Patients should be advised to expect a red colouration to the urine (not indicative of haematuria) for 1 to 2 days after each administration of ROBOL.
4. Alopecia (hair loss) should be expected 1 to 2 weeks after the initiation of ROBOL treatment. Hair loss may be complete but hair always returns after termination of treatment. NB. Scalp tourniquets inflated to above systolic blood pressure and left in situ for 30 minutes over the time of ROBOL treatment reduces the probability of alopecia.
5. Anorexia may be expected for 24 hours following each treatment and occasionally may persist for several days.
6. Hyperpigmentation, usually in the hands, nails and buccal mucosa may develop in patients receiving ROBOL. Patients should be advised that this condition does not usually improve after termination of treatment.
7. Infertility in both sexes is usual in patients receiving ROBOL. Amenorrhoea is frequent and in pre-menopausal women, regular menstruation usually returns a few months after termination of ROBOL therapy. This is often accompanied by normal fertility.
8. Male patients should be advised that oligospermia or azoospermia may be permanent. There is a possibility that fertility may return several years after ceasing therapy. Men undergoing ROBOL therapy should be advised to use effective contraceptive measures.
9. Patients should be instructed to inform their physicians of any prior abnormal heart or liver conditions, as this information is vital to the formulation of appropriate dosage regimes.
Effects on Laboratory Tests: No data available.
Use in Hepatic Impairment: The major route of elimination of doxorubicin is the hepatobiliary system. Toxicity to recommended doses of doxorubicin is enhanced by hepatic impairment. Therefore, prior to the individual dosing, evaluation of hepatic function is recommended using conventional clinical laboratory tests such as AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin and BSP (see Dosage & Administration). Serum total bilirubin levels should also be evaluated during treatment with doxorubicin. Patients with elevated bilirubin 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 doxorubicin (see Contraindications).
Changes in hepatic function induced by concomitant therapies, either given to achieve optimal antitumour efficacy or given for the pharmacological management of concomitant diseases, may affect doxorubicin metabolism, pharmacokinetics, therapeutic efficacy or toxicity.
Effects on ability to drive and use machines: The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
Use in the Elderly: No data available.
Use in Children: No data available.