Ralenova

Ralenovae is indicated in the treatment of metastatic breast cancer, non-Hodgkin's lymphoma and adult acute non-lymphocytic leukaemia.

Ralenovae has also been used in the palliation of non-resectable primary hepatocellular carcinoma.

Ralenova is indicated for reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly abnormal between relapses). Ralenova is not indicated in the treatment of patients with primary progressive multiple sclerosis.

The clinical patterns of multiple sclerosis in the studies were characterized as follows: secondary progressive and progressive relapsing disease were characterized by gradual increasing disability with or without superimposed clinical relapses, and worsening relapsing-remitting disease was characterized by clinical relapses resulting in a step-wise worsening of disability.

Ralenova in combination with corticosteroids is indicated as initial chemotherapy for the treatment of patients with pain related to advanced hormone-refractory prostate cancer.

Ralenova in combination with other approved drug(s) is indicated in the initial therapy of acute nonlymphocytic leukemia (ANLL) in adults. This category includes myelogenous, promyelocytic, monocytic, and erythroid acute leukemias.

Posology

Metastatic breast cancer, Non-Hodgkin's lymphoma, Hepatoma:

Single Agent Dosage: The recommended initial dosage of Ralenovae as a single agent is 14 mg/m² of body surface area, given as a single intravenous dose which may be repeated at 21-day intervals. A lower initial dosage (12 mg/m² or less) is recommended for patients with inadequate bone marrow reserves e.g. due to prior chemotherapy or poor general condition.

Dosage modification and the timing of subsequent doses should be determined by clinical judgement depending on the degree and duration of myelosuppression. For subsequent courses the prior dose can usually be repeated if white blood cell and platelet counts have returned to normal levels after 21 days. The following table is suggested as a guide to dosage adjustment in the treatment of metastatic breast cancer, non-Hodgkin's lymphoma and hepatoma according to haematological nadir (which usually occurs about 10 days after dosing).

Combination Therapy: Ralenovae has been given as part of combination therapy. In metastatic breast cancer, combinations of Ralenovae with other cytotoxic agents including cyclophosphamide and 5-fluorouracil, or methotrexate and mitomycin C, have been shown to be effective. Reference should be made to the published literature for information on dosage modifications and administration. Ralenovae has also been used in various combinations for non-Hodgkin's lymphoma, however data are presently limited and specific regimens cannot be recommended.

As a guide, when Ralenovae is used in combination chemotherapy with another myelosuppressive agent, the initial dose of Ralenovae should be reduced by 2-4 mg/m² below the doses recommended for single agent use. Subsequent doses, as outlined in the table above, depend on the degree and duration of myelosuppression.

Adult acute non-lymphocytic leukaemia:

Single Agent Dosage in Relapse: The recommended dosage for remission induction is 12 mg/m² of body surface area, given as a single intravenous dose daily for five consecutive days (total of 60 mg/m²). In clinical studies with a dosage of 12 mg/m² daily for 5 days, patients who achieved a complete remission did so as a result of the first induction course.

Combination Therapy: Ralenovae has been used in combination regimens for the treatment of acute non-lymphocytic leukaemia (ANLL). Most clinical experience has been with Ralenovae combined with cytarabine. This combination has been used successfully for primary treatment of ANLL as well as in the treatment of relapse.

An effective regimen for induction in previously untreated patients has been Ralenovae 10-12 mg/m² IV for 3 days combined with cytarabine 100 mg/m² IV for 7 days (by continuous infusion). This is followed by second induction and consolidation courses as thought appropriate by the treating clinician. In clinical studies, duration of therapy in induction and consolidation courses with Ralenovae have been reduced to 2 days, and that of cytarabine to 5 days. However, modification to the above regimen should be carried out by the treating clinician depending on individual patient factors.

Efficacy has also been demonstrated with Ralenovae in combination with etoposide in patients who had relapsed or who were refractory to primary conventional chemotherapy. The use of Ralenovae in combination with etoposide, as with other cytotoxics, may result in greater myelosuppression than with Ralenovae alone.

Reference should be made to the published literature for information on specific dosage regimens. Ralenovae should be used by clinicians experienced in the use of chemotherapy regimens. Dosage adjustments should be made by the treating clinician as appropriate, taking into account toxicity, response and individual patient characteristics. As with other cytotoxic drugs, Ralenovae should be used with caution in combination therapy until wider experience is available.

Paediatrics: The safety and efficacy of Ralenovae in paediatric patients have not been established.

Method of administration

FOR INTRAVENOUS USE ONLY.

Dilute the required volume of Ralenovae Sterile Concentrate to at least 50 ml in either of the following infusion solutions: sodium chloride 0.9%, glucose 5%, or sodium chloride 0.18% and glucose 4%. Use Leur-lock fittings on all syringes and sets. Large bore needles are recommended to minimise pressure and the possible formation of aerosols. The latter may also be reduced by the use of a venting needle.

Administer the resulting solution over not less than 3 minutes via the tubing of a freely running intravenous infusion of the above fluids. Ralenovae should not be mixed with other drugs in the same infusion.

If extravasation occurs the administration should be stopped immediately and restarted in another vein. The non-vesicant properties of Ralenovae minimise the risk of severe local reaction following extravasation.

(See also WARNINGS)

Multiple Sclerosis

The recommended dosage of Ralenova is 12 mg/m² given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months. Left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of Ralenova and all subsequent doses. In addition, LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop at any time during treatment with Ralenova Ralenova should not be administered to multiple sclerosis patients with an LVEF < 50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of ≥ 140 mg/m². Complete blood counts, including platelets, should be monitored prior to each course of Ralenova and in the event that signs or symptoms of infection develop. Ralenova generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm³. Liver function tests should also be monitored prior to each course. Ralenova therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because Ralenova clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.

Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of Ralenova (see WARNINGS, Pregnancy).

Hormone-Refractory Prostate Cancer

Based on data from two Phase 3 comparative trials of Ralenova plus corticosteroids versus corticosteroids alone, the recommended dosage of Ralenova is 12 to 14 mg/m² given as a short intravenous infusion every 21 days.

Combination Initial Therapy for ANLL in Adults

For induction, the recommended dosage is 12 mg/m² of Ralenova daily on Days 1-3 given as an intravenous infusion, and 100 mg/m² of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1-7.

Most complete remissions will occur following the initial course of induction therapy. In the event of an incomplete antileukemic response, a second induction course may be given. Ralenova should be given for 2 days and cytarabine for 5 days using the same daily dosage levels.

If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves.

Consolidation therapy which was used in two large randomized multicenter trials consisted of Ralenova, 12 mg/m² given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m² for 5 days given as a continuous 24-hour infusion on Days 1-5. The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first. Severe myelosuppression occurred. (See CLINICAL PHARMACOLOGY)

Hepatic Impairment

For patients with hepatic impairment, there is at present no laboratory measurement that allows for dose adjustment recommendations. (See CLINICAL PHARMACOLOGY, Special Populations, Hepatic Impairment)

Preparation and Administration Precautions

Ralenova CONCENTRATE MUST BE DILUTED PRIOR TO USE.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

The dose of Ralenova should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP). Ralenova may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately. DO NOT FREEZE.

Ralenova should not be mixed in the same infusion as heparin since a precipitate may form. Because specific compatibility data are not available, it is recommended that Ralenova not be mixed in the same infusion with other drugs. The diluted solution should be introduced slowly into the tubing as a freely running intravenous infusion of 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP) over a period of not less than 3 minutes. Unused infusion solutions should be discarded immediately in an appropriate fashion. In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted Ralenova concentrate should be stored not longer than 7 days between 15°-25°C (59°-77°F) or 14 days under refrigeration. DO NOT FREEZE. CONTAINS NO PRESERVATIVE.

Care in the administration of Ralenova will reduce the chance of extravasation. Ralenova should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein. If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Care should be taken to avoid extravasation at the infusion site and to avoid contact of Ralenova with the skin, mucous membranes, or eyes. Ralenova SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY. If any signs or symptoms of extravasation have occurred, including burning, pain, pruritis, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein. During intravenous administration of Ralenova extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated. Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction.

Skin accidentally exposed to Ralenova should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.^1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

FOR INTRAVENOUS USE ONLY.

Ralenovae Sterile Concentrate is contraindicated in patients who have demonstrated prior hypersensitivity to Ralenovae hydrochloride, other anthracylines or any of its components. Use in patients with profound bone marrow suppression is a relative contraindication depending on the clinical circumstances.

Ralenovae Sterile Concentrate should not be used during pregnancy or lactation.

Ralenova is contraindicated in patients who have demonstrated prior hypersensitivity to it.

Special warnings

There may be an increased risk of leukaemia when Ralenovae is used as adjuvant treatment of non-metastatic breast cancer. In the absence of sufficient efficacy data, Ralenovae must not be used as adjuvant treatment of non-metastatic breast cancer.

Ralenovae should be used with caution in patients with myelosuppression or poor general condition.

Cases of functional cardiac changes, including congestive heart failure and decreases in left ventricular ejection fraction have been reported during Ralenovae therapy (see 4.8 Undesirable effects). These cardiac events have occurred most commonly in patients who have had prior treatment with anthracyclines, prior mediastinal/thoracic radiotherapy, or in patients with pre-existing heart disease. The concomitant administration of other cardiotoxic drugs may also increase the risk of cardiac toxicity. It is recommended that patients in these categories are treated with Ralenovae at full cytotoxic dosage and schedule. However, added caution is required in these patients and careful regular cardiac examinations are recommended from the initiation of treatment.

Cardiac monitoring should also be performed in patients without identifiable risk factors during therapy exceeding 160 mg/m² of Ralenovae, or during extended treatment.

Careful supervision is recommended when treating patients with hepatic insufficiency.

Topoisomerase II inhibitors, including Ralenovae hydrochloride, when used concomitantly with other antineoplastic agents (particularly anthracyclines) and/or radiotherapy, have been associated with the development of Acute Myeloid Leukaemia (AML) or Myelodysplastic Syndrome (MDS). Treatment with Ralenovae alone has also been associated with an increased risk of development of secondary acute myeloid leukaemia (see 4.8 Undesirable effects).

Sulphites can cause allergic-type reactions including anaphylactic symptoms and bronchospasm in susceptible people, especially those with a history of asthma or allergy.

Immunisation may be ineffective when given during Ralenovae therapy. Immunisation with live virus vaccines are generally not recommended.

There is no experience with the administration of Ralenovae Sterile Concentrate other than by the intravenous route. Safety for intrathecal use has not been established.

Precautions for use

Ralenovae is an active cytotoxic drug which should be used by clinicians who are familiar with the use of antineoplastic agents and have the facilities for regular monitoring of clinical, haematological and biochemical parameters during and after treatment.

Full blood counts should be undertaken serially during a course of treatment. Dosage adjustments may be necessary based on these counts (see Dosage section).

WARNINGS

WHEN Ralenova IS USED IN HIGH DOSES ( > 14 mg/m²/d x 3 days) SUCH AS INDICATED FOR THE TREATMENT OF LEUKEMIA, SEVERE MYELOSUPPRESSION WILL OCCUR. THEREFORE, IT IS RECOMMENDED THAT Ralenova BE ADMINISTERED ONLY BY PHYSICIANS EXPERIENCED IN THE CHEMOTHERAPY OF THIS DISEASE. LABORATORY AND SUPPORTIVE SERVICES MUST BE AVAILABLE FOR HEMATOLOGIC AND CHEMISTRY MONITORING AND ADJUNCTIVE THERAPIES, INCLUDING ANTIBIOTICS. BLOOD AND BLOOD PRODUCTS MUST BE AVAILABLE TO SUPPORT PATIENTS DURING THE EXPECTED PERIOD OF MEDULLARY HYPOPLASIA AND SEVERE MYELOSUPPRESSION. PARTICULAR CARE SHOULD BE GIVEN TO ASSURING FULL HEMATOLOGIC RECOVERY BEFORE UNDERTAKING CONSOLIDATION THERAPY (IF THIS TREATMENT IS USED) AND PATIENTS SHOULD BE MONITORED CLOSELY DURING THIS PHASE. Ralenova ADMINISTERED AT ANY DOSE CAN CAUSE MYELOSUPPRESSION.

General

Patients with preexisting myelosuppression as the result of prior drug therapy should not receive Ralenova unless it is felt that the possible benefit from such treatment warrants the risk of further medullary suppression.

The safety of Ralenova (mitoxantrone for injection concentrate) in patients with hepatic insufficiency is not established (see CLINICAL PHARMACOLOGY).

Safety for use by routes other than intravenous administration has not been established.

Ralenova is not indicated for subcutaneous, intramuscular, or intra-arterial injection. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection.

Ralenova must not be given by intrathecal injection. There have been reports of neuropathy and neurotoxicity, both central and peripheral, following intrathecal injection. These reports have included seizures leading to coma and severe neurologic sequelae, and paralysis with bowel and bladder dysfunction.

Topoisomerase II inhibitors, including Ralenova, have been associated with the development of secondary acute myeloid leukemia and myelosuppression.

Cardiac Effects

Because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin, the benefit-to-risk ratio of Ralenova therapy in such patients should be determined before starting therapy.

Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure can occur with Ralenova. Cardiac toxicity may be more common in patients with prior treatment with anthracyclines, prior mediastinal radiotherapy, or with preexisting cardiovascular disease. Such patients should have regular cardiac monitoring of LVEF from the initiation of therapy. Cancer patients who received cumulative doses of 140 mg/m² either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure. In comparative oncology trials, the overall cumulative probability rate of moderate or severe decreases in LVEF at this dose was 13%.

Multiple Sclerosis

Changes in cardiac function may occur in patients with multiple sclerosis treated with Ralenova. In one controlled trial (Study 1, see Clinical Trials, Multiple Sclerosis), two patients (2%) of 127 receiving Ralenova, one receiving a 5 mg/m² dose and the other receiving the 12 mg/m² dose, had LVEF values that decreased to below 50%. An additional patient receiving 12 mg/m², who did not have LVEF measured, had a decrease in another echocardiographic measurement of ventricular function (fractional shortening) that led to discontinuation from the trial (see ADVERSE REACTIONS, Multiple Sclerosis). There were no reports of congestive heart failure in either controlled trial.

MS patients should be assessed for cardiac signs and symptoms by history, physical examination, ECG, and quantitative LVEF evaluation using appropriate methodology (ex. Echocardiogram, MUGA, MRI, etc.) prior to the start of Ralenova therapy. MS patients with a baseline LVEF below the lower limit of normal should not be treated with Ralenova. Subsequent LVEF and ECG evaluations are recommended if signs or symptoms of congestive heart failure develop and prior to every dose administered to MS patients. Ralenova should not be administered to MS patients who experience a reduction in LVEF to below the lower limit of normal, to those who experience a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of 140 mg/m². MS patients should have yearly quantitative LVEF evaluation after stopping Ralenova to monitor for late-occurring cardiotoxicity.

Leukemia

Acute congestive heart failure may occasionally occur in patients treated with Ralenova for ANLL. In first-line comparative trials of Ralenova + cytarabine vs daunorubicin + cytarabine in adult patients with previously untreated ANLL, therapy was associated with congestive heart failure in 6.5% of patients on each arm. A causal relationship between drug therapy and cardiac effects is difficult to establish in this setting since myocardial function is frequently depressed by the anemia, fever and infection, and hemorrhage that often accompany the underlying disease.

Hormone-Refractory Prostate Cancer

Functional cardiac changes such as decreases in LVEF and congestive heart failure may occur in patients with hormone-refractory prostate cancer treated with Ralenova. In a randomized comparative trial of Ralenova plus low-dose prednisone vs low-dose prednisone, 7 of 128 patients (5.5 %) treated with Ralenova had a cardiac event defined as any decrease in LVEF below the normal range, congestive heart failure (n = 3), or myocardial ischemia. Two patients had a prior history of cardiac disease. The total Ralenova dose administered to patients with cardiac effects ranged from > 48 to 212 mg/m².

Among 112 patients evaluable for safety on the Ralenova + hydrocortisone arm of the CALGB trial, 18 patients (19%) had a reduction in cardiac function, 5 patients (5%) had cardiac ischemia, and 2 patients (2%) experienced pulmonary edema. The range of total Ralenova doses administered to these patients is not available.

Pregnancy

Ralenova may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant. Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents. Treatment of pregnant rats during the organogenesis period of gestation was associated with fetal growth retardation at doses > 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m² basis). When pregnant rabbits were treated during organogenesis, an increased incidence of premature delivery was observed at doses > 0.1 mg/kg/day (0.01 times the recommended human dose on a mg/m² basis). No teratogenic effects were observed in these studies, but the maximum doses tested were well below the recommended human dose (0.02 and 0.05 times in rats and rabbits, respectively, on a mg/m² basis). There are no adequate and well-controlled studies in pregnant women. Women with multiple sclerosis who are biologically capable of becoming pregnant should have a pregnancy test prior to each dose, and the results should be known prior to administration of the drug. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to the fetus.

Secondary Leukemia

Ralenova® therapy increases the risk of developing secondary leukemia in patients with cancer and in patients with multiple sclerosis.

In a study of patients with prostate cancer, acute myeloid leukemia occurred in 1% (5/487) of mitoxantrone-treated patients versus no cases in the control group (0/496) not receiving mitoxantrone at 4.7 years followup.

In a prospective, open-label, tolerability and safety monitoring study of Ralenova® treated MS patients followed for up to five years (median of 2.8 years), leukemia occurred in 0.6% (3/509) of patients. Publications describe leukemia risks of 0.25% to 2.8% in cohorts of patients with MS treated with Ralenova® and followed for varying periods of time. This leukemia risk exceeds the risk of leukemia in the general population. The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia.

In 1774 patients with breast cancer who received Ralenova concomitantly with other cytotoxic agents and radiotherapy, the cumulative risk of developing treatment-related acute myeloid leukemia was estimated as 1.1% and 1.6% at 5 and 10 years, respectively. The second largest report involved 449 patients with breast cancer treated with Ralenova, usually in combination with radiotherapy and/or other cytotoxic agents. In this study, the cumulative probability of developing secondary leukemia was estimated to be 2.2% at 4 years.

Secondary acute myeloid leukemia has also been reported in cancer patients treated with anthracyclines. Ralenova is an anthracenedione, a related drug. The occurrence of secondary leukemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of anthracyclines have been escalated.

Symptoms of acute leukemia may include excessive bruising, bleeding, and recurrent infections.

PRECAUTIONS

General

Therapy with Ralenova should be accompanied by close and frequent monitoring of hematologic and chemical laboratory parameters, as well as frequent patient observation.

Systemic infections should be treated concomitantly with or just prior to commencing therapy with Ralenova.

Information for Patients

See FDA-approved patient labeling (Medication Guide).

Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Ralenova and prior to each infusion. Review the Ralenova Medication Guide with every patient prior to initiation of treatment and periodically during treatment. Instruct patients that Ralenova should be taken only as prescribed.

Advise patients that Ralenova can cause myelosuppression and inform patients of the signs and symptoms of myelosuppression. Advise patients that Ralenova can cause congestive heart failure that may lead to death even in people who have never had heart problems before, and inform patients of the signs and symptoms of congestive heart failure. Advise patients receiving Ralenova to treat multiple sclerosis that they should receive cardiac monitoring prior to each Ralenova dose and yearly after stopping Ralenova.

Ralenova may impart a blue-green color to the urine for 24 hours after administration, and patients should be advised to expect this during therapy. Bluish discoloration of the sclera may also occur.

Laboratory Tests

A complete blood count, including platelets, should be obtained prior to each course of Ralenova and in the event that signs and symptoms of infection develop. Liver function tests should also be performed prior to each course of therapy. Ralenova therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because Ralenova clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.

In leukemia treatment, hyperuricemia may occur as a result of rapid lysis of tumor cells by Ralenova. Serum uric acid levels should be monitored and hypouricemic therapy instituted prior to the initiation of antileukemic therapy.

Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of Ralenova (see WARNINGS, Pregnancy).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Intravenous treatment of rats and mice, once every 21 days for 24 months, with Ralenova resulted in an increased incidence of fibroma and external auditory canal tumors in rats at a dose of 0.03 mg/kg (0.02 fold the recommended human dose, on a mg/m² basis), and hepatocellular adenoma in male mice at a dose of 0.1 mg/kg (0.03 fold the recommended human dose, on a mg/m² basis). Intravenous treatment of rats, once every 21 days for 12 months with Ralenova resulted in an increased incidence of external auditory canal tumors in rats at a dose of 0.3 mg/kg (0.15 fold the recommended human dose, on a mg/m² basis).

Mutagenesis

Ralenova was clastogenic in the in vivo rat bone marrow assay. Ralenova was also clastogenic in two in vitro assays; it induced DNA damage in primary rat hepatocytes and sister chromatid exchanges in Chinese hamster ovary cells. Ralenova was mutagenic in bacterial and mammalian test systems (Ames/Salmonella and E. coli and L5178Y TK+/-mouse lymphoma).

Special Populations

Hepatic Impairment

Patients with multiple sclerosis who have hepatic impairment should ordinarily not be treated with Ralenova. Ralenova should be administered with caution to other patients with hepatic impairment. In patients with severe hepatic impairment, the AUC is more than three times greater than the value observed in patients with normal hepatic function.

Pregnancy

Pregnancy Category D (see WARNINGS).

Nursing Mothers

Ralenova is excreted in human milk and significant concentrations (18 ng/mL) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from Ralenova, breast feeding should be discontinued before starting treatment.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Multiple Sclerosis: Clinical studies of Ralenova did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Hormone-Refractory Prostate Cancer: One hundred forty-six patients aged 65 and over and 52 younger patients ( < 65 years) have been treated with Ralenova in controlled clinical studies. These studies did not include sufficient numbers of younger patients to determine whether they respond differently from older patients. However, greater sensitivity of some older individuals cannot be ruled out.

Acute Nonlymphocytic Leukemia: Although definitive studies with Ralenova have not been performed in geriatric patients with ANLL, toxicity may be more frequent in the elderly. Elderly patients are more likely to have age-related comorbidities due to disease or disease therapy.

Cardiac monitoring should also be performed in patients without identifiable risk factors during therapy exceeding 160 mg/m² of Ralenovae, or during extended treatment.

Careful supervision is recommended when treating patients with hepatic insufficiency.

Topoisomerase II inhibitors, including Ralenovae hydrochloride, when used concomitantly with other antineoplastic agents (particularly anthracyclines) and/or radiotherapy, have been associated with the development of Acute Myeloid Leukaemia (AML) or Myelodysplastic Syndrome (MDS). Treatment with Ralenovae alone has also been associated with an increased risk of development of secondary acute myeloid leukaemia (see 4.8 Undesirable effects).

Sulphites can cause allergic-type reactions including anaphylactic symptoms and bronchospasm in susceptible people, especially those with a history of asthma or allergy.

Immunisation may be ineffective when given during Ralenovae therapy. Immunisation with live virus vaccines are generally not recommended.

There is no experience with the administration of Ralenovae Sterile Concentrate other than by the intravenous route. Safety for intrathecal use has not been established.

Precautions for use

Ralenovae is an active cytotoxic drug which should be used by clinicians who are familiar with the use of antineoplastic agents and have the facilities for regular monitoring of clinical, haematological and biochemical parameters during and after treatment.

Full blood counts should be undertaken serially during a course of treatment. Dosage adjustments may be necessary based on these counts (see Dosage section).

Animal data suggest that if used in combination with other antineoplastic agents, additive myelosuppression may be expected. This has been supported by available clinical data on combination regimens. When used in combination regimens, the initial dose of Ralenovae Sterile Concentrate should be reduced by 2-4 mg/m² below the dose recommended for single agent usage. (see Posology and method of administration).

Combining Ralenovae with potentially cardiotoxic drugs (anthracyclines) increases the risk of cardiac toxicity. The product must be used with caution in combination with immunosuppressive chemotherapy.

There are no adequate and well-controlled studies in pregnant women. Ralenovae should not normally be administered to patients who are pregnant. If the drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazard to the fetus. Women of childbearing potential and their partners should be advised to avoid becoming pregnant and use effective contraception during therapy and for at least six months after cessation of therapy.

Ralenovae is excreted in human milk and significant concentrations (18 ng/ml) have been reported for 28 days after the last administration. Because of the potential for serious adverse reactions in infants from Ralenovae, breast-feeding should be discontinued before starting treatment.

Not applicable.

Serious or Life Threatening Reactions:

Blood and lymphatic system disorders: Some degree of leucopenia is to be expected following recommended doses of Ralenovae. With the single dose every 21 days, suppression of WBC count below 1000/mm³ is infrequent. Leucopenia is usually transient reaching its nadir at about 10 days after dosing with recovery usually occurring by the 21^st day. Thrombocytopenia and anaemia occur less frequently. Myelosuppression may be more severe and prolonged in patients who have had extensive prior chemotherapy or radiotherapy or in debilitated patients.

Cardiac disorders: Congestive heart failure may occur during therapy with Ralenovae, or months to years after the end of treatment (see 4.4 Special Warnings and Special Precautions for Use). Some cases have been fatal. Treatment with digoxin and/or diuretics has been reported to be effective.

Other cardiovascular effects, which have been of clinical significance include decreased left ventricular ejection fraction, ECG changes and acute arrhythmia.

In patients with leukaemia an increase in the frequency of adverse cardiac events has been observed. The direct role of Ralenovae in these cases is difficult to assess, since some patients had received prior therapy with anthracyclines and since the clinical course in leukaemic patients is frequently complicated by anaemia, fever, sepsis and intravenous fluid therapy. Cardiomyopathy has been reported in rare instances.

Other Undesirable Effects:

Hepato-biliary disorders and Renal and urinary disorders: Ralenovae Sterile Concentrate may impart a blue-green colouration to the urine for 24 hours after administration, and patients should be advised to expect this during active therapy. Increased liver enzyme levels (with occasional reports of severe impairment of hepatic function in patients with leukaemia). Hyperuricaemia has also been reported. Elevated serum creatinine and blood urea nitrogen levels have been reported.

Skin and subcutaneous tissue disorders: Rash, onycholysis, blue discolouration of skin and nails and nail dystrophy has been reported occasionally. Alopecia may occur, but is most frequently of minimal severity and reversible on cessation of therapy

Eye Disorders: Reversible blue colouration of the sclerae has been reported. Conjunctivitis.

Respiratory disorders: Dyspnoea.

Gastrointestinal Disorders: Diarrhoea, anorexia, constipation, gastrointestinal bleeding, abdominal pain, stomatitis and mucositis. The most commonly encountered side effects are nausea and vomiting, although in the majority of cases these are mild and transient.

Neoplasms: Secondary acute myeloid leukaemia (see 4.4 Special Warnings and Special Precautions for Use)

General disorders and administration site conditions: Fever, fatigue and weakness.

Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning and/or blue discolouration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of infusion.

Nervous system disorders: Altered taste. Non-specific neurological side effects such as somnolence and mild paraesthesia have been reported.

Metabolism and nutrition disorders: Tumour lysis syndrome (characterised by hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia) has been observed rarely during single-agent chemotherapy with Ralenovae, as well as during combination chemotherapy.

Psychiatric disorders: Confusion, anxiety.

Reproductive system and breast disorders: Amenorrhoea.

In patients with leukaemia, the pattern of side-effects is generally similar, although there is an increase in both frequency and severity, particularly of stomatitis and mucositis. Nevertheless, overall, patients with leukaemia tolerate treatment with Ralenovae well.

Immune system disorders: Allergic reaction.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

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Ireland

HPRA Pharmacovigilance

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IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Multiple Sclerosis

Ralenova has been administered to 149 patients with multiple sclerosis in two randomized clinical trials, including 21 patients who received Ralenova in combination with corticosteroids.

In Study 1, the proportion of patients who discontinued treatment due to an adverse event was 9.7% (n = 6) in the 12 mg/m² Ralenova arm (leukopenia, depression, decreased LV function, bone pain and emesis, renal failure, and one discontinuation to prevent future complications from repeated urinary tract infections) compared to 3.1% (n = 2) in the placebo arm (hepatitis and myocardial infarction). The following clinical adverse experiences were significantly more frequent in the Ralenova groups: nausea, alopecia, urinary tract infection, and menstrual disorders, including amenorrhea.

Table 4a summarizes clinical adverse events of all intensities occurring in ≥ 5% of patients in either dose group of Ralenova and that were numerically greater on drug than on placebo in Study 1. The majority of these events were of mild to moderate intensity, and nausea was the only adverse event that occurred with severe intensity in more than one patient (three patients [5%] in the 12 mg/m² group). Of note, alopecia consisted of mild hair thinning.

Two of the 127 patients treated with Ralenova in Study 1 had decreased LVEF to below 50% at some point during the 2 years of treatment. An additional patient receiving 12 mg/m² did not have LVEF measured, but had another echocardiographic measure of ventricular function (fractional shortening) that led to discontinuation from the study.

Table 4a : Adverse Events of Any Intensity Occurring in ≥ 5% of Patients on Any Dose of Ralenova and That Were Numerically Greater Than in the Placebo Group Study 1

The proportion of patients experiencing any infection during Study 1 was 67% for the placebo group, 85% for the 5 mg/m² group, and 81% for the 12 mg/m² group. However, few of these infections required hospitalization: one placebo patient (tonsillitis), three 5 mg/m² patients (enteritis, urinary tract infection, viral infection), and four 12 mg/m² patients (tonsillitis, urinary tract infection [two], endometritis).

Table 4b summarizes laboratory abnormalities that occurred in ≥ 5% of patients in either Ralenova dose group, and that were numerically more frequent than in the placebo group.

Table 4b : Laboratory Abnormalities Occurring in ≥ 5% of Patients* on Either Dose of Ralenova and That Were More Frequent Than in the Placebo Group Study 1

There was no difference among treatment groups in the incidence or severity of hemorrhagic events.

In Study 2, Ralenova was administered once a month. Clinical adverse events most frequently reported in the Ralenova group included amenorrhea (53% of female patients), alopecia (33% of patients), nausea (29% of patients), and asthenia (24% of patients). Tables 5a and 5b respectively summarize adverse events and laboratory abnormalities occurring in > 5% of patients in the Ralenova group and numerically more frequent than in the control group.

Table 5a : Adverse Events of Any Intensity Occurring in > 5% of Patients* in the Ralenova Group and Numerically More Frequent Than in the Control Group Study 2

Table 5b : Laboratory Abnormalities Occurring in > 5% of Patients* in the Ralenova Group and Numerically More Frequent Than in the Control Group Study 2

Leukopenia and neutropenia were reported in the N +MP group (see Table 5b).

Neutropenia occurred within 3 weeks after Ralenova administration and was always reversible. Only mild to moderate intensity infections were reported in 9 of 21 patients in the N +MP group and in 3 of 21 patients in the MP group; none of these required hospitalization. There was no difference among treatment groups in the incidence or severity of hemorrhagic events. There were no withdrawals from Study 2 for safety reasons.

Leukemia

Ralenova has been studied in approximately 600 patients with acute nonlymphocytic leukemia (ANLL). Table 6 represents the adverse reaction experience in the large U.S. comparative study of mitoxantrone + cytarabine vs daunorubicin + cytarabine. Experience in the large international study was similar. A much wider experience in a variety of other tumor types revealed no additional important reactions other than cardiomyopathy (see WARNINGS). It should be appreciated that the listed adverse reaction categories include overlapping clinical symptoms related to the same condition, e.g., dyspnea, cough and pneumonia. In addition, the listed adverse reactions cannot all necessarily be attributed to chemotherapy as it is often impossible to distinguish effects of the drug and effects of the underlying disease. It is clear, however, that the combination of Ralenova + cytarabine was responsible for nausea and vomiting, alopecia, mucositis/stomatitis, and myelosuppression.

Table 6 summarizes adverse reactions occurring in patients treated with Ralenova + cytarabine in comparison with those who received daunorubicin + cytarabine for therapy of ANLL in a large multicenter randomized prospective U.S. trial.

Adverse reactions are presented as major categories and selected examples of clinically significant subcategories.

Table 6 : Adverse Events Occurring in ANLL Patients Receiving Ralenova or Daunorubicin

Hormone-Refractory Prostate Cancer

Detailed safety information is available for a total of 353 patients with hormone-refractory prostate cancer treated with Ralenova, including 274 patients who received Ralenova in combination with corticosteroids.

Table 7 summarizes adverse reactions of all grades occurring in ≥ 5% of patients in Trial CCI-NOV22.

Table 7 : Adverse Events of Any Intensity Occurring in ≥ 5% of Patients Trial CCI-NOV22

No nonhematologic adverse events of Grade 3/4 were seen in > 5% of patients.

Table 8 summarizes adverse events of all grades occurring in ≥ 5% of patients in Trial CALGB 9182.

Table 8 : Adverse Events of Any Intensity Occurring in ≥ 5 % of Patients Trial CALGB 9182

General

Allergic Reaction

Hypotension, urticaria, dyspnea, and rashes have been reported occasionally. Anaphylaxis/anaphylactoid reactions have been reported rarely.

Cutaneous

Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning, and/or blue discoloration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of the infusion.

Hematologic

Topoisomerase II inhibitors, including Ralenova, in combination with other antineoplastic agents or alone, have been associated with the development of acute leukemia (see WARNINGS).

Leukemia

Myelosuppression is rapid in onset and is consistent with the requirement to produce significant marrow hypoplasia in order to achieve a response in acute leukemia. The incidences of infection and bleeding seen in the U.S. trial are consistent with those reported for other standard induction regimens.

Hormone-Refractory Prostate Cancer

In a randomized study where dose escalation was required for neutrophil counts greater than 1000/mm³, Grade 4 neutropenia (ANC < 500 /mm³) was observed in 54% of patients treated with Ralenova + low-dose prednisone. In a separate randomized trial where patients were treated with 14 mg/m², Grade 4 neutropenia in 23% of patients treated with Ralenova + hydrocortisone was observed. Neutropenic fever/infection occurred in 11% and 10% of patients receiving Ralenova + corticosteroids, respectively, on the two trials. Platelets < 50,000/mm³ were noted in 4% and 3% of patients receiving Ralenova + corticosteroids on these trials, and there was one patient death on Ralenova + hydrocortisone due to intracranial hemorrhage after a fall.

Gastrointestinal

Nausea and vomiting occurred acutely in most patients and may have contributed to reports of dehydration, but were generally mild to moderate and could be controlled through the use of antiemetics. Stomatitis/mucositis occurred within 1 week of therapy.

Cardiovascular

Congestive heart failure, tachycardia, EKG changes including arrhythmias, chest pain, and asymptomatic decreases in left ventricular ejection fraction have occurred. (See WARNINGS)

Pulmonary

Interstitial pneumonitis has been reported in cancer patients receiving combination chemotherapy that included Ralenova.

There is no known specific antidote for Ralenovae Sterile Concentrate. Haemopoietic, gastrointestinal, hepatic or renal toxicity may be seen, depending on the dosage given and the physical condition of the patient. In cases of overdosage patients should be monitored closely and management should be symptomatic and supportive.

Fatalities have occurred on rare occasions as a result of severe leucopenia with infection in patients accidentally given single bolus injections of Ralenovae at over ten times the recommended dosage. Ralenovae Sterile Concentrate is extensively tissue-bound and peritoneal dialysis or haemodialysis is unlikely to be effective in managing overdose.

There is no known specific antidote for Ralenova. Accidental overdoses have been reported. Four patients receiving 140-180 mg/m² as a single bolus injection died as a result of severe leukopenia with infection. Hematologic support and antimicrobial therapy may be required during prolonged periods of severe myelosuppression.

Although patients with severe renal failure have not been studied, Ralenova is extensively tissue bound and it is unlikely that the therapeutic effect or toxicity would be mitigated by peritoneal or hemodialysis.

Pharmacokinetic studies in patients following intravenous administration of Ralenovae demonstrated a triphasic plasma clearance. Distribution to tissues is rapid and extensive. Elimination of the drug is slow with a mean half-life of 12 days (range 5-18) and persistent tissue concentrations. Similar estimates of half-life were obtained from patients receiving a single dose of Ralenovae every 21 days and patients dosed on 5 consecutive days every 21 days.

Ralenovae is excreted via the renal and hepatobiliary systems. Only 20-32% of the administered dose was excreted within the first five days after dosing (urine 6-11%, faeces 13-25%). Of the material recovered in the urine 65% was unchanged Ralenovae and the remaining 35% is primarily comprised of two inactive metabolites and their glucuronide conjugates. Approximately two thirds of the excretion occurred during the first day.

Pharmacokinetics of mitoxantrone in patients following a single intravenous administration of Ralenova® can be characterized by a three-compartment model. The mean alpha half-life of mitoxantrone is 6 to 12 minutes, the mean beta half-life is 1.1 to 3.1 hours and the mean gamma (terminal or elimination) half-life is 23 to 215 hours (median approximately 75 hours). Pharmacokinetic studies have not been performed in humans receiving multiple daily dosing. Distribution to tissues is extensive: steady-state volume of distribution exceeds 1,000 L/m². Tissue concentrations of mitoxantrone appear to exceed those in the blood during the terminal elimination phase. In the healthy monkey, distribution to brain, spinal cord, eye, and spinal fluid is low.

In patients administered 15-90 mg/m² of Ralenova intravenously, there is a linear relationship between dose and the area under the concentration-time curve (AUC).

Mitoxantrone is 78% bound to plasma proteins in the observed concentration range of 26455 ng/mL. This binding is independent of concentration and is not affected by the presence of phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin, or aspirin.

Metabolism and Elimination

Mitoxantrone is excreted in urine and feces as either unchanged drug or as inactive metabolites. In human studies, 11% and 25% of the dose were recovered in urine and feces, respectively, as either parent drug or metabolite during the 5-day period following drug administration. Of the material recovered in urine, 65% was unchanged drug. The remaining 35% was composed of monocarboxylic and dicarboxylic acid derivatives and their glucuronide conjugates. The pathways leading to the metabolism of Ralenova have not been elucidated.