Cephalon Pharma (Ireland) Ltd

TRISENOX^® 1 mg/ml, concentrate for solution for infusion

One ml of TRISENOX contains 1 mg of Arsenic trioxide

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion

Sterile, clear, colourless, aqueous solution.

TRISENOX is indicated for induction of remission and consolidation in adult patients with relapsed/refractory acute promyelocytic leukaemia (APL), characterised by the presence of the t(15;17) translocation and/or the presence of the Pro-Myelocytic Leukaemia/Retinoic-Acid-Receptor-alpha (PML/RAR-alpha) gene. Previous treatment should have included a retinoid and chemotherapy.

The response rate of other acute myelogenous leukaemia subtypes to TRISENOX has not been examined.

Posology

TRISENOX must be administered under the supervision of a physician who is experienced in the management of acute leukaemias and the special monitoring procedures described in Section 4.4 must be followed. The same dose is recommended for adults, and elderly.

Induction treatment schedule

TRISENOX must be administered intravenously at a fixed dose of 0.15 mg/kg/day given daily until the bone marrow remission is achieved (less than 5% blasts present in cellular bone marrow with no evidence of leukaemic cells). If bone marrow remission has not occurred by day 50, dosing must be discontinued.

Consolidation schedule

Consolidation treatment must begin 3 to 4 weeks after completion of induction therapy. TRISENOX is to be administered intravenously at a dose of 0.15 mg/kg/day for 25 doses given 5 days per week, followed by 2 days interruption, repeated for 5 weeks.

Dose delay, modification and reinitiation

Treatment with TRISENOX must be interrupted, adjusted, or discontinued before the scheduled end of therapy at any time that a toxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteria is observed and judged to be possibly related to TRISENOX treatment. Patients who experience such reactions that are considered TRISENOX related must resume treatment only after resolution of the toxic event or after recovery to baseline status of the abnormality that prompted the interruption. In such cases, treatment must resume at 50% of the preceding daily dose. If the toxic event does not recur within 3 days of restarting treatment at the reduced dose, the daily dose can be escalated back to 100% of the original dose. Patients who experience a recurrence of toxicity must be removed from treatment.

For ECG and electrolytes abnormalities, see section 4.4.

Patients with hepatic and/or renal impairment

Since limited data are available across all hepatic impairment groups and across all renal impairment groups, caution is advised in the use of TRISENOX in patients with hepatic and/or renal impairment.

Paediatric population

The safety and efficacy of TRISENOX in children aged up to 17 years has not been established. Currently available data for children aged 5 to 16 years are described in section 5.1 but no recommendation on a posology can be made. No data are available for children under 5 years of age.

Method of administration

TRISENOX must be administered intravenously over 1-2 hours. The infusion duration may be extended up to 4 hours if vasomotor reactions are observed. A central venous catheter is not required. Patients must be hospitalised at the beginning of treatment due to symptoms of disease and to ensure adequate monitoring

Hypersensitivity to the active substance or to any of the excipients.

Clinically unstable APL patients are especially at risk and will require more frequent monitoring of electrolyte and glycaemia levels as well as more frequent haematologic, hepatic, renal and coagulation parameter tests.

Leukocyte Activation Syndrome (APL Differentiation Syndrome): 27% of patients with APL treated with TRISENOX have experienced symptoms similar to a syndrome called the retinoic-acid-acute promyelocytic leukaemia (RA-APL) or APL differentiation syndrome, characterised by fever, dyspnoea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis. This syndrome can be fatal. The management of the syndrome has not been fully studied, but high-dose steroids have been used at the first suspicion of the APL differentiation syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome (unexplained fever, dyspnoea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intravenously twice a day) must be immediately initiated, irrespective of the leukocyte count and continued for at least 3 days or longer until signs and symptoms have abated. The majority of patients do not require termination of TRISENOX therapy during treatment of the APL differentiation syndrome. It is recommended that chemotherapy not be added to treatment with steroids since there is no experience with administration of both steroids and chemotherapy during treatment of the leukocyte activation syndrome due to TRISENOX. Post-marketing experience suggests that a similar syndrome may occur in patients with other types of malignancy. Monitoring and management for these patients should be as described above.

Electrocardiogram (ECG) Abnormalities: Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. Previous treatment with anthracyclines may increase the risk of QT prolongation. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging medicinal products (such as class Ia and III antiarrythmics (e.g. quinidine, amiodarone, sotalol, dofetilide), antipsychotics (e.g. thioridazine), antidepressants (e.g. amitriptyline), some macrolides (e.g. erythromycine), some antihistamines (e.g. terfenadine and astemizole), some quinolone antibiotics (e.g. sparfloxacin), and other individual drugs known to increase QT interval (e.g. cisapride)), a history of torsade de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, amphotericin B or other conditions that result in hypokalemia or hypomagnesaemia. In clinical trials, 40% of patients treated with TRISENOX experienced at least one QT corrected (QTc) interval prolongation greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after TRISENOX infusion, and then returned to baseline by the end of 8 weeks after TRISENOX infusion. One patient (receiving multiple, concomitant medicinal products, including amphotericin B) had asymptomatic torsade de pointes during induction therapy for relapsed APL with arsenic trioxide.

ECG and Electrolyte Monitoring Recommendations: Prior to initiating therapy with TRISENOX, a 12-lead ECG must be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine must be assessed; preexisting electrolyte abnormalities must be corrected and, if possible, medicinal products that are known to prolong the QT interval must be discontinued. Patients with risk factors of QTc prolongation or risk factors of torsade de pointes should be monitored with continuous cardiac monitoring (ECG). For QTc greater than 500 msec, corrective measures must be completed and the QTc reassessed with serial ECGs prior to considering using TRISENOX. During therapy with TRISENOX, potassium concentrations must be kept above 4 mEq/l and magnesium concentrations must be kept above 1.8 mg/dl. Patients who reach an absolute QT interval value > 500 msec must be reassessed and immediate action must be taken to correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending TRISENOX therapy must be considered. If syncope, rapid or irregular heartbeat develops, the patient must be hospitalised and monitored continuously, serum electrolytes must be assessed, TRISENOX therapy must be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities are corrected, and the syncope and irregular heartbeat cease. There are no data on the effect of TRISENOX on the QTc interval during the infusion. Electrocardiograms must be obtained twice weekly, and more frequently for clinically unstable patients, during induction and consolidation.

Dose and delay modification: Treatment with TRISENOX must be interrupted, adjusted, or discontinued before the scheduled end of therapy at any time that a toxicity grade 3 or greater on the National Cancer Institute Common Toxicity Criteria, is observed and judged to be possibly related to TRISENOX treatment (see section 4.2).

Laboratory tests: The patient's electrolyte and glycaemia levels, as well as haematologic, hepatic, renal and coagulation parameter tests must be monitored at least twice weekly, and more frequently for clinically unstable patients during the induction phase and at least weekly during the consolidation phase.

Patients with renal or hepatic impairment:

Since limited data are available across all renal impairment groups, caution is advised in the use of TRISENOX in patients with renal impairment. The experience in patients with severe renal impairment is insufficient to determine if dose adjustment is required.

The use of TRISENOX in patients on dialysis has not been studied.

Patients with hepatic impairment:

Since limited data are available across all hepatic impairment groups, caution is advised in the use of TRISENOX in patients with hepatic impairment. The experience in patients with severe hepatic impairment is insufficient to determine if dose adjustment is required.

Elderly patients: There is limited clinical data on the use of TRISENOX in the elderly population. Caution is needed in these patients.

Hyperleukocytosis: Treatment with TRISENOX has been associated with the development of hyperleukocytosis ( 10 x 10³/μl) in some patients. There did not appear to be a relationship between baseline white blood cell (WBC) counts and development of hyperleukocytosis nor did there appear to be a correlation between baseline WBC count and peak WBC counts. Hyperleukocytosis was never treated with additional chemotherapy and resolved on continuation of TRISENOX. WBC counts during consolidation were not as high as during induction treatment and were < 10 x 10³/μl, except in one patient who had a WBC count of 22 x 10³/ μl during consolidation. Twenty patients (50%) experienced leukocytosis; however, in all these patients, the WBC count was declining or had normalized by the time of bone marrow remission and cytotoxic chemotherapy or leukopheresis was not required.

No formal assessments of pharmacokinetic interactions between TRISENOX and other therapeutic medicinal products have been conducted. QT/QTc prolongation is expected during treatment with TRISENOX, and torsade de pointes and complete heart block have been reported. Patients who are receiving, or who have received, medicinal products known to cause hypokalemia or hypomagnesaemia, such as diuretics or amphotericin B, may be at higher risk for torsade de pointes. Caution is advised when TRISENOX is coadministered with other medicinal products known to cause QT/QTc interval prolongation such as macrolide antibiotics, the antipsychotic thioridazine, or medicinal products known to cause hypokalemia or hypomagnesaemia. Additional information about QT prolonging medicinal agents, is provided in Section 4.4. The influence of TRISENOX on the efficacy of other antileukaemic medicinal products is unknown.

Contraception in males and females

Men and women of childbearing potential must use effective contraception during treatment with TRISENOX.

Pregnancy

Arsenic trioxide has been shown to be embryotoxic and teratogenic in animal studies (see section 5.3). There are no studies in pregnant women using TRISENOX. If this medicinal product is used during pregnancy or if the patient becomes pregnant while taking this product, the patient must be informed of the potential harm to the foetus.

Breastfeeding

Arsenic is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from TRISENOX, breastfeeding must be discontinued prior to and throughout administration.

Fertility

No clinical or non-clinical fertility studies have been conducted with TRISENOX.

No studies on the effects on the ability to drive and use machines have been performed.

Related adverse events of CTC grade 3 and 4 occurred in 37% of patients in clinical trials. The most commonly reported reactions were hyperglycaemia, hypokalaemia, neutropenia, and increased alanine amino transferase (ALT). Leukocytosis occurred in 50% of patients with APL, as determined by haematology assessments.

Serious adverse reactions were common (1-10%) and not unexpected in this population. Those serious adverse reactions attributed to TRISENOX included APL differentiation syndrome (3), leukocytosis (3), prolonged QT interval (4, 1 with torsade de pointes), atrial fibrillation/atrial flutter (1), hyperglycaemia (2) and a variety of serious adverse reactions related to haemorrhage, infections, pain, diarrhoea, nausea.

In general, treatment-emergent adverse events tended to decrease over time, perhaps accounted for by amelioration of the underlying disease process. Patients tended to tolerate consolidation and maintenance treatment with less toxicity than in induction. This is probably due to the confounding of adverse events by the uncontrolled disease process early on in the treatment course and the myriad concomitant medicinal products required to control symptoms and morbidity.

The following undesirable effects have been reported in clinical trials and/or post-marketing experience. Undesirable effects are listed below as MedDRA preferred term by system organ class and frequencies observed during TRISENOX clinical trials in 52 patients with refractory/relapsed APL. Frequencies are defined as: very common1/10, common1/100 to <1/10, uncommon1/1000 to <1/100, not known (cannot be estimated from available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

During TRISENOX treatment, 14 of the 52 patients in the APL studies had one or more symptoms of APL differentiation syndrome, characterised by fever, dyspnoea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis (see section 4.4). Twenty-seven patients had leukocytosis (WBC 10 x 10³/μl) during induction, 4 of whom had values above 100,000/μl. Baseline white blood cell (WBC) counts did not correlate with development of leukocytosis on study, and WBC counts during consolidation therapy were not as high as during induction. In these studies, leukocytosis was not treated with chemotherapeutic medicinal products. Medicinal products that are used to lower the white blood cell count often exacerbate the toxicities associated with leukocytosis, and no standard approach has proven effective. One patient treated under a compassionate use program died from cerebral infarct due to leukocytosis, following treatment with chemotherapeutic medicinal products to lower WBC count. Observation is the recommended approach with intervention only in selected cases.

Mortality in the pivotal studies from disseminated intravascular coagulation (DIC) associated haemorrhage was very common (> 10%), which is consistent with the early mortality reported in the literature.

Arsenic trioxide can cause QT interval prolongation (see section 4.4). QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging medicinal products, a history of torsade de pointes, preexisting QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalaemia or hypomagnesaemia. One patient (receiving multiple, concomitant medicinal products, including amphotericin B) had asymptomatic torsade de pointes during induction therapy for relapsed APL with arsenic trioxide. She went onto consolidation without further evidence of QT prolongation.

Peripheral neuropathy, characterised by paresthesia/dysesthesia, is a common and well known effect of environmental arsenic. Only 2 patients discontinued treatment early due to this adverse event and one went on to receive additional TRISENOX on a subsequent protocol. Forty-four percent of patients experienced symptoms that could be associated with neuropathy; most were mild to moderate and were reversible upon cessation of treatment with TRISENOX.

In post marketing experience, a differentiation syndrome, like retinoic acid syndrome, has also been reported for the treatment of malignancies other than APL with TRISENOX.

If symptoms suggestive of serious acute arsenic toxicity (e.g. convulsions, muscle weakness and confusion) appear, TRISENOX must be immediately discontinued and chelating therapy with penicillamine at a daily dose 1 gm per day may be considered. The duration of treatment with penicillamine must be evaluated taking into account the urinary arsenic laboratory values. For patients who cannot take oral medication, dimercaprol administered at a dose of 3 mg/kg intramuscularly every 4 hours until any immediately life-threatening toxicity has subsided may be considered. Thereafter, penicillamine at a daily dose 1 gm per day may be given. In the presence of coagulopathy, the oral administration of the chelating agent Dimercaptosuccinic Acid Succimer (DCI) 10 mg/kg or 350 mg/m² every 8 hours during 5 days and then every 12 hours during 2 weeks is recommended. For patients with severe, acute arsenic overdose, dialysis should be considered.

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX27

Mechanism of action: The mechanism of action of TRISENOX is not completely understood. Arsenic trioxide causes morphological changes and deoxyribonucleic acid (DNA) fragmentation characteristic of apoptosis in NB4 human promyelocytic leukaemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein Pro-Myelocytic Leukaemia/Retinoic Acid Receptor-alpha (PML/RAR alpha).

Clinical trials: TRISENOX has been investigated in 52 APL patients, previously treated with an anthracycline and a retinoid regimen, in two open-label, single-arm, non-comparative studies. One was a single investigator clinical study (n=12) and the other was a multicentre, 9-institution study (n=40). Patients in the first study received a median dose of 0.16 mg/kg/day of TRISENOX (range 0.06 to 0.20 mg/kg/day) and patients in the multicentre study received a fixed dose of 0.15 mg/kg/day. TRISENOX was administered intravenously over 1 to 2 hours until the bone marrow was free of leukaemic cells, up to a maximum of 60 days. Patients with complete remission received consolidation therapy with TRISENOX for 25 additional doses over a 5 week period. Consolidation therapy began 6 weeks (range, 3-8) after induction in the single institution study and 4 weeks (range, 3-6) in the multicentre study. Complete remission (CR) was defined as the absence of visible leukaemic cells in the bone marrow and peripheral recovery of platelets and white blood cells.

Patients in the single centre study had relapsed following 1-6 prior therapy regimens and 2 patients had relapsed following stem cell transplantation. Patients in the multicentre study had relapsed following 1-4 prior therapy regimens and 5 patients had relapsed following stem cell transplantation. The median age in the single centre study was 33 years (age range 9 to 75). The median age in the multicentre study was 40 years (age range 5 to 73).

The results are summarised in the table below.

The single institution study included 2 paediatric patients (< 18 years old), both of whom achieved CR. The multicentre trial included 5 paediatric patients (< 18 years old), 3 of whom achieved CR. No children of less than 5 years of age were treated.

In a follow-up treatment after consolidation, 7 patients in the single institution study and 18 patients in the multicentre study received further maintenance therapy with TRISENOX. Three patients from the single institution study and 15 patients from the multicentre study had stem cell transplants after completing TRISENOX. The Kaplan-Meier median CR duration for the single institution study is 14 months and has not been reached for the multicentre study. At last follow-up, 6 of 12 patients in the single institution study were alive with a median follow-up time of 28 months (range 25 to 29). In the multicentre study 27 of 40 patients were alive with a median follow-up time of 16 months (range 9 to 25). Kaplan-Meier estimates of 18-month survival for each study are shown below.

Cytogenetic confirmation of conversion to a normal genotype and Reverse Transcriptase - Polymerase Chain Reaction (RT-PCR) detection of PML/RARα conversion to normal are shown in the table below.

Cytogenetics after TRISENOX therapy:

Responses were seen across all age groups tested, ranging from 6 to 75 years. The response rate was similar for both genders. There is no experience on the effect of TRISENOX on the variant APL containing the t(11;17) and t(5;17) chromosomal translocations.

Paediatric population

The experience in children is limited. Of 7 patients under 18 years of age (range 5 to 16 years) treated with TRISENOX at the recommended dose of 0.15 mg/kg/day, 5 patients achieved a complete response (see section 4.2).

The inorganic, lyophilized form of arsenic trioxide, when placed into solution, immediately forms the hydrolysis product arsenious acid (As^III). As^III is the pharmacologically active species of arsenic trioxide.

Linearity/non-linearity:

In the total single dose range of 7 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) appears to be linear. The decline from peak plasma concentration of As^III occurs in a biphasic manner and is characterized by an initial rapid distribution phase followed by a slower terminal elimination phase. After administration at 0.15 mg/kg on a daily (n=6) or twice-weekly (n=3) regimen, an approximate 2-fold accumulation of As^III was observed as compared to a single infusion. This accumulation was slightly more than expected based on single-dose results.

Distribution:

The volume of distribution (V_d) for As^III is large (>400 L) indicating significant distribution into the tissues with negligible protein binding. V_d is also weight dependent, increasing with increasing body weight. Total arsenic accumulates mainly in the liver, kidney, and heart and, to a lesser extent, in the lung, hair, and nails.

Biotransformation:

The metabolism of arsenic trioxide involves oxidation of arsenious acid (As^III), the active species of arsenic trioxide, to arsenic acid (As^V), as well as oxidative methylation to monomethylarsonic acid (MMA^V) and dimethylarsinic acid (DMA^V) by methyltransferases, primarily in the liver. The pentavalent metabolites, MMA^V and DMA^V, are slow to appear in plasma (approximately 10-24 hours after first administration of arsenic trioxide), but due to their longer half-life, accumulate more upon multiple dosing than does As^III. The extent of accumulation of these metabolites is dependent on the dosing regimen. Approximate accumulation ranged from 1.4- to 8-fold following multiple as compared to single dose administration. As^V is present in plasma only at relatively low levels.

In vitro enzymatic studies with human liver microsomes revealed that arsenic trioxide has no inhibitory activity on substrates of the major cytochrome P450 enzymes such as 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, 4A9/11. Drugs that are substrates for these P450 enzymes are not expected to interact with TRISENOX.

Elimination:

Approximately 15% of the administered TRISENOX dose is excreted in the urine as unchanged As^III. The methylated metabolites of As^III (MMA^V, DMA^V) are primarily excreted in the urine. The plasma concentration of As^III declines from peak plasma concentration in a biphasic manner with a mean terminal elimination half-life of 10 to 14 hours. The total clearance of As^III over the single-dose range of 7-32 mg (administered as 0.15 mg/kg) is 49 L/h and the renal clearance is 9 L/h. Clearance is not dependent on the weight of the subject or the dose administered over the dose range studied. The mean estimated terminal elimination half-lives of the metabolites MMA^V and DMA^V are 32 hours and 70 hours, respectively.

Renal Impairment:

Plasma clearance of As^III was not altered in patients with mild renal impairment (creatinine clearance of 50-80 mL/min) or moderate renal impairment (creatinine clearance of 30-49 mL/min). The plasma clearance of As^III in patients with severe renal impairment (creatinine clearance less than 30 mL/min) was 40% lower when compared with patients with normal renal function (see section 4.4).

Systemic exposure to MMA^V and DMA^V tended to be larger in patients with renal impairment; the clinical consequence of this is unknown but no increased toxicity was noted.

Hepatic Impairment:

Pharmacokinetic data from patients with hepatocellular carcinoma having mild to moderate hepatic impairment indicate that As^III or As^V do not accumulate following twice-weekly infusions. No clear trend toward an increase in systemic exposure to As^III, As^V, MMA^V or DMA^V was observed with decreasing level of hepatic function as assessed by dose-normalized (per mg dose) AUC.

Limited reproductive toxicity studies of arsenic trioxide in animals indicate embryotoxicity and teratogenicity (neural tube defects, anophthalmia and microphthalmia) at administration of 1-10 times the recommended clinical dose (mg/m²). Fertility studies have not been conducted with TRISENOX.

Arsenic compounds induce chromosomal aberrations and morphological transformations of mammalian cells in vitro and in vivo. No formal carcinogenicity studies of arsenic trioxide have been performed. However, arsenic trioxide and other inorganic arsenic compounds are recognised as human carcinogens.

sodium hydroxide

hydrochloric acid as pH adjuster

water for injections

In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

4 years.

After dilution in intravenous solutions, TRISENOX is chemically and physically stable for 24 hours at 15-30°C and 48 hours at refrigerated (2-8°C) temperatures. From a microbiological point of view, the product must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Do not freeze.

Type I borosilicate glass ampoule of 10 ml. Each pack contains 10 ampoules

 Preparation of TRISENOX

Aseptic technique must be strictly observed throughout handling of TRISENOX since no preservative is present.

TRISENOX must be diluted with 100 to 250 ml of glucose 50 mg/ml (5%) solution for injection or sodium chloride 9 mg/ml (0.9%) solution for injection immediately after withdrawal from the ampoule. For single use only. Unused portions of each ampoule must be discarded properly. Do not save any unused portions for later administration.

TRISENOX must not be mixed with or concomitantly administered in the same intravenous line with other medicinal products.

TRISENOX must be administered intravenously over 1-2 hours. The infusion duration may be extended up to 4 hours if vasomotor reactions are observed. A central venous catheter is not required.

The diluted solution must be clear and colourless. All parenteral solutions must be inspected visually for particulate matter and discoloration prior to administration. Do not use the preparation if foreign particulate matter is present.

 Procedure for proper disposal

Any unused product, any items that come into contact with the product, and waste material must be disposed of in accordance with local requirements.

Cephalon Europe

5 Rue Charles Martigny

94700 Maisons Alfort

France

EU/1/02/204/001

Date of first authorisation: 05 March 2002

Date of latest renewal: 05 March 2007

November 2011