ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
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 children, 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.
Paediatric use
:
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. Safety and effectiveness in paediatric patients under 5 years of age have not been
studied.
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.
Method of administration
2
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 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)
:
Twenty-five percent 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. erythromycin), 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
3
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 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, Version 2 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.
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 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 10
3
/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 10
3
/μl, except in
one patient who had a WBC count of 22 x 10
3
/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.
4
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.
Arsenic trioxide has been shown to be embryotoxic and teratogenic in animal studies (see 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. Men, and women of childbearing potential must use effective
contraception during treatment with TRISENOX.
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.
No studies on the effects on the ability to drive and use machines have been performed.
Related adverse reactions 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, rather than adverse event reports.
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 table below lists the related grade 3 and 4 adverse drug reactions for the 107 patients treated with
TRISENOX in clinical trials (frequencies defined as: common ≥1/100 to <1/10, uncommon ≥ 1/1,000
to < 1/100).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
System Organ Class
Common
Uncommon
Blood and lymphatic system
disorders
Neutropenia
Thrombocytopenia
Febrile neutropenia
Leucocytosis
Leucopenia
Metabolism and nutrition
Hyperglycaemia
Hypermagnesaemia
5
System Organ Class
Common
Uncommon
disorders
Hypokalaemia
Hypernatraemia
Ketoacidosis
Nervous system disorders
Paraesthesia
Cardiac disorders
Pericardial effusion
Tachycardia
Vascular disorders
Vasculitis
Respiratory, thoracic and
mediastinal disorders
Pleuritic pain
Dyspnoea
Pulmonary alveolar
haemorrhage
Pleural effusion
Hypoxia
Gastrointestinal disorders
Diarrhoea
Skin and subcutaneous
tissue disorders
Pruritus
Erythema
Musculoskeletal and
connective tissue disorders
Bone pain
Arthralgia
Myalgia
General disorders and
administration site
conditions
Pyrexia
Fatigue
Chest pain
Pain
Investigations
ECG QT prolonged
ALT increased
Aspartate amino transferase
increased
Hyperbilirubinaemia
Hypomagnesaemia
During TRISENOX treatment, 13 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 10
3
/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.
6
The following adverse events have been identified during the post-approval use of TRISENOX and
have been included following consideration of the observed frequency, seriousness and possible causal
relationship to TRISENOX. They are listed below by system organ class and frequency (frequencies
are defined as: uncommon (≥1/1,000 to <1/100), not known (cannot be estimated from the available
data).
System Organ Class
Uncommon
Not known
Infection and Infestations
Sepsis
Pneumonia
Herpes zoster
Blood and Lymphatics System
Disorders
Anaemia
Pancytopenia
Metabolism and Nutrition
Disorders
Dehydration
Fluid retention
Psychiatric Disorders
Confusional state
Nervous System Disorders
Convulsions
Dizziness
Eye Disorders
Vision blurred
Cardiac Disorders
Cardiac failure
Ventricular tachycardia
Ventricular extrasystoles
Vascular Disorders
Hypotension
Respiratory, Thoracic and
Mediastinal Disorders
Pneumonitis
Differentiation syndrome
Gastrointestinal Disorders
Vomiting
Abdominal pain
Skin and Subcutaneous Disorders Face oedema
Rash
Renal and Urinary Disorders
Renal failure
General Disorders and
Administration Site Conditions
Oedema
Chills
Investigations
Blood creatinine increased
Weight increased
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
penicilamine 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/m
2
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
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX27
7
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.
Single Centre Trial
N=12
Multicentre Trial
N=40
TRISENOX Dose,
mg/kg/day
(Median, Range)
0.16 (0.06 – 0.20)
0.15
Complete Remission
11 (92%)
34 (85%)
Time to Bone Marrow
Remission (Median)
32 days
35 days
Time to CR (Median)
54 days
59 days
18-Month Survival
67%
66%
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.
8
100%
80%
60%
40%
20%
Single Center
Multicenter Study
At Risk
12
40
Deaths
6
13
18-Month
67%
66%
0%
0
6
12
18
24
30
36
Months
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
Single Centre Pilot Trial
N with CR = 11
Multicentre Trial
N with CR = 34
Conventional
Cytogenetics
[t(15;17)]
Absent
Present
Not evaluable
8 (73%)
1 (9%)
2 (18%)
31 (91%)
0%
3 (9%)
RT-PCR for PML/
RARα
8 (73%)
3 (27%)
0
27 (79%)
4 (12%)
3 (9%)
Negative
Positive
Not evaluable
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.
5.2
Pharmacokinetic properties
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.
9
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.
Metabolism:
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.
10
5.3
Preclinical safety data
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.
6.1
List of excipients
sodium hydroxide
hydrochloric acid as pH adjuster
water for injections
6.2
Incompatibilities
In the absence of incompatibility studies, this medicinal product must not be mixed with other
medicinal products except those mentioned in 6.6.
6.3
Shelf life
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.
6.4
Special precautions for storage
Do not freeze.
6.5
Nature and contents of container
Type I borosilicate glass ampoule of 10 ml. Each pack contains 10 ampoules.
6.6
Special precautions for disposal and other handling
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%) injection or sodium
chloride 9 mg/ml (0.9%) 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.
11
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 last renewal: 05 March 2007
12
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
13
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Almac Pharma Services Limited,
Almac House,
20 Seagoe Industrial Estate,
Craigavon,
BT63 5QD,
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
14
ANNEX III
LABELLING AND PACKAGE LEAFLET
15
A. LABELLING
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
{CARTON LABEL}
1.
TRISENOX 1 mg/ml, concentrate for solution for infusion
Arsenic trioxide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One ml contains 1 mg of arsenic trioxide
3.
LIST OF EXCIPIENTS
Other ingredients:
sodium hydroxide
hydrochloric acid
water for injections
4.
concentrate for solution for infusion
10 ampoules of 10 ml (10 mg/10 ml)
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use, single use only
Must be diluted before use – Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
Read the leaflet for the shelf-life of the diluted product
17
9.
SPECIAL STORAGE CONDITIONS
Do not freeze
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Cephalon Europe
5 Rue Charles Martigny
94700 Maisons Alfort
FRANCE
EU/1/02/204/001
13. BATCH NUMBER
Lot: {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
<Justification for not including Braille accepted>
18
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
{AMPOULE LABEL}
1.
TRISENOX
1 mg/ml, concentrate for solution for infusion
Arsenic trioxide
Intravenous use
2.
METHOD OF ADMINISTRATION
Single use only, must be diluted – see leaflet
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot: {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
10 ml
6.
OTHER
19
B. PACKAGE LEAFLET
20
PACKAGE LEAFLET: INFORMATION FOR THE USER
TRISENOX 1 mg/ml, concentrate for solution for infusion
Arsenic trioxide
Read all of this leaflet carefully before you start using this medicine.
- Keep this leaflet. You may need to read it again.
- If you have further questions, please ask your doctor or your pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or your pharmacist.
In this leaflet:
1.
What TRISENOX is and what it is used for
2.
Before you use TRISENOX
3.
How to use TRISENOX
5.
How to store TRISENOX
6.
Further information
1.
WHAT TRISENOX IS AND WHAT IT IS USED FOR
TRISENOX is used in patients with acute promyelocytic leukaemia (APL) whose disease has not
responded to other therapies. APL is a unique type of myeloid leukaemia, a disease in which abnormal
white blood cells and abnormal bleeding and bruising occur.
2.
BEFORE YOU USE TRISENOX
TRISENOX must be injected under the supervision of a physician experienced in the treatment of
acute leukaemias.
Do not use TRISENOX
- if you are hypersensitive (allergic) to arsenic trioxide or any of the other ingredients of
TRISENOX.
Take special care with TRISENOX
Please tell your doctor immediately if you have any of the following symptoms: shortness of breath,
fever, sudden weight gain, fainting, water retention or palpitations (strong heartbeat you can feel in
your chest). .
Your doctor must check your blood to be sure that you do not have low amounts of potassium or
magnesium before your first dose of TRISENOX. You should also have a 12-lead electrocardiogram
performed before your first dose. Blood tests should be repeated twice weekly while you are receiving
TRISENOX. In addition, you will receive electrocardiograms twice weekly. If you are at risk for a
certain type of abnormal heart rhythm (e.g. torsade de pointes or QTc prolongation) your heart will be
monitored continuously.
You must tell your doctor if you have impaired kidney or liver function.
Using other medicines
Please tell your doctor if you are taking any of various types of medicines which could cause a change
in the rhythm of your heartbeat. These include:
•
some types of antiarrhythmics (drugs used to correct irregular heart beats, e.g.
quinidine, amiodarone, sotalol, dofetilide)
•
antipsychotics (e.g. thioridazine)
antidepressants (e.g. amitriptyline)
•
21
4.
Possible side effects
•
some types of antibiotics (e.g. erythromycin and sparfloxacin)
•
some antihistamines (e.g. terfenadine and astemizole)
•
any medicines that cause a decrease in magnesium or potassium in your blood (e.g.
amphotericin B)
•
cisapride (a medicine used to relieve certain stomach problems).
The effect of these medicines on your heartbeat can be made worse by TRISENOX. You must be sure
to tell your doctor about all medicines you are taking.
Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without prescription.
no restrictions on your food or drink are needed while you are receiving TRISENOX.
Pregnancy
Ask your doctor or pharmacist for advice before taking any medicine. TRISENOX may cause harm to
the foetus when used by pregnant women. If you are able to become pregnant, you must use effective
birth control during treatment with TRISENOX. If you are pregnant or you become pregnant during
the treatment with TRISENOX, you must ask your doctor for advice.
Men should also use effective contraception during treatment with TRISENOX.
Breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine. Arsenic will be present in the
milk of TRISENOX patients who are breast-feeding. Because of the potential for serious side-effects
in nursing infants from TRISENOX, do not breast-feed while on TRISENOX.
Driving and using machines
The effect of TRISENOX on your ability to drive is not known. If you experience discomfort or if
you feel unwell after a TRISENOX injection, you should wait until the symptoms go away before
driving or using machines.
Important information about some of the ingredients of TRISENOX
Trisenox contains less than 1 mmol sodium (23 mg) per dose i.e. essentially ‘sodium-free’.
3.
HOW TO USE TRISENOX
Your doctor will dilute TRISENOX with 100 to 250 ml of glucose 50 mg/ml (5%) injection, or
sodium chloride 9 mg/ml (0.9%) injection.
Your doctor will infuse TRISENOX through a tube into a blood vessel over 1-2 hours, but the infusion
may last longer if side-effects like flushing and dizziness occur.
Your doctor will give you TRISENOX once every day as a single infusion each day. In your first
treatment cycle, you may be treated every day up to 50 days at most, or until your doctor determines
that your disease is better. If your disease responds to TRISENOX, you will be given a second
treatment cycle of 25 doses, one infusion every weekday for 5 weeks. Your doctor will decide exactly
how long you must continue on therapy with TRISENOX.
Each TRISENOX ampoule must be used only once and does not contain any preservatives. Unused
portions of each ampoule must be discarded properly.
22
Using TRISENOX with food and drink
-
Do not save any unused portions for later use.
TRISENOX must not be mixed with, or infused through the same tube with other medicinal products.
If your doctor gives you more TRISENOX than he/she should
You may experience convulsions, muscle weakness and confusion. If this happens, treatment with
TRISENOX must be stopped immediately and your doctor will treat the arsenic overdose.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, TRISENOX can have side effects.
While on treatment with TRISENOX, you may experience some of the following reactions:
common side effects (greater than or equal to 1 in 100 but less than 1 in 10): fatigue (weariness),
increased blood sugar, shortness of breath, cough, headache.
uncommon side effects (greater than or equal to 1 in 1000 but less than 1 in 100): increased white
blood cell count, Herpes zoster, pneumonia, sepsis, anaemia, dehydration, confusion, blurry vision,
cardiac failure, hypotension, pneumonitis, chills, renal failure, increased weight, nausea, vomiting,
diarrhoea, stomach ache, oedema (water retention), rash or itching, change in your heart rhythm or
dizziness.
Frequency unknown: decreased blood cell counts, a syndrome including fever, together with difficulty
in breathing, coughing and chest pain. If you experience these symptoms, you should inform your
doctor immediately.
Other side effects not mentioned above may also occur in some patients.
Tell your doctor immediately if you experience shortness of breath, fever, sudden weight gain, water
retention, fainting or palpitations (strong heartbeat you can feel in your chest).
If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.
5.
HOW TO STORE TRISENOX
Keep out of the reach and sight of children
Do not use after the expiry date stated on the ampoule label.
Do not freeze
After dilution, if not used immediately, in-use storage times and conditions before use are the
responsibility of your doctor and would normally not be longer than 24 hours at 2ºC – 8ºC, unless
dilution has taken place in a sterile environment.
Do not use TRISENOX if you notice foreign particulate matter or if discolouration is present.
6.
FURTHER INFORMATION
What TRISENOX contains
-
The active substance is arsenic trioxide 1 mg/ml
-
The other ingredients are sodium hydroxide, hydrochloric acid and water for injections
What TRISENOX looks like and contents of the pack
- TRISENOX is a concentrate for solution for infusion. TRISENOX is supplied in glass ampoules
as a concentrated, sterile, clear, colourless, aqueous solution that is prepared and diluted at the hospital
23
and given as an infusion into a blood vessel. Each carton contains 10 single-use glass ampoules. Each
ampoule contains 10 mg of arsenic trioxide.
Marketing Authorisation Holder and Manufacturer
- Marketing Authorisation Holder:
Cephalon Europe, 5 Rue Charles Martigny, 94700 Maisons Alfort, FRANCE
- Manufacturer:
Almac Pharma Services Limited, Almac House, 20 Seagoe Industrial Estate, Craigavon, BT63 5QD,
United Kingdom
This leaflet was last approved in {MM/YYYY}
Detailed information on this medicine is available on the EMEA web site:http://www.emea.europa.eu
There are also links to other websites about rare diseases and treatments.
<--------------------------------------------------------------------------------------------------------------------------
----
The following information is intended for medical or healthcare professionals only:
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%) injection or sodium
chloride 9 mg/ml (0.9%) 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.
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.
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.
24
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/trisenox.html
Copyright © 1995-2021 ITA all rights reserved.