ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Prialt 25 micrograms/ml solution for infusion
2.
One ml solution contains 25 μg ziconotide (as acetate).
Each vial contains 500 μg ziconotide (as acetate).
For a full list of excipients, see section 6.1.
3.
Solution for infusion.
Clear, colourless solution, free of visible particles.
4.
Ziconotide is indicated for the treatment of severe, chronic pain in adults who require intrathecal (IT)
analgesia.
Treatment with ziconotide should only be undertaken by physicians experienced in intrathecal (IT)
administration of medicinal products.
Adults (including the elderly ≥ 65 years of age)
Dosing of ziconotide should be initiated at 2.4 μg/day and titrated on an individual patient basis
according to the patient’s analgesic response and adverse reactions. Patients should be titrated in dose
increments of ≤ 2.4 μg/day, up to a maximum dose of 21.6 μg/day. The minimal interval between
dose increases is 24 hours; the recommended interval, for safety reasons, is 48 hours or more. If
necessary the dose can be decreased by any amount (including stopping the infusion) for the
management of adverse reactions. Approximately 75% of patients who respond satisfactorily to
treatment require a dose of ≤ 9.6 μg/day.
Ziconotide must be administered as a continuous infusion via an intrathecal catheter, using an external
or internally implanted mechanical infusion pump capable of delivering an accurate infusion volume.
As the risk of meningitis secondary to prolonged catheterisation of the intrathecal space is greater with
an external catheter infusion system, internal systems are recommended to administer ziconotide for
prolonged periods. An external catheter system should only be used when an internal system cannot
be implanted.
When low doses of ziconotide are required, for example when initiating titration, ziconotide must be
diluted before use with preservative-free sodium chloride 9 mg/ml (0.9%) solution for injection. (See
section 6.6).
2
Use in paediatric patients (< 18 years of age)
Prialt is not recommended for use in children below 18 years due to a lack of data on safety and
efficacy. There is no experience in children.
Use in patients with impaired hepatic function
Studies have not been conducted in patients with impaired hepatic function. Caution should be
exercised when ziconotide is administered to patients with impaired hepatic function.
Use in patients with impaired renal function
Studies have not been conducted in patients with impaired renal function. Caution should be exercised
when ziconotide is administered to patients with impaired renal function.
Prialt is for intrathecal use only.
For instructions for use and handling, see section 6.6.
Hypersensitivity to the active substance or to any of the excipients.
Ziconotide is contraindicated in combination with IT chemotherapy (see section 4.5).
Long-term use
Although ziconotide has been studied in long-term, open label efficacy and safety clinical trials,
controlled studies of longer than 3 weeks duration have not been conducted (see section 5.1). Possible
long-term local toxic effects on the spinal cord have not been excluded and preclinical data in this
respect are limited (see section 5.3). Therefore, caution is needed during long-term treatment.
Route of administration
The administration of medicinal products by the intrathecal (IT) route carries the risk of potentially
serious infections, such as meningitis, which may be life threatening. Meningitis due to the entrance
of organisms along the catheter track or inadvertent contamination of the infusion system is a known
complication of intrathecal medicinal product administration, especially with external systems.
Patients and physicians must be vigilant for typical symptoms and signs of meningitis.
The optimal intrathecal placement of the catheter tip has not been established. Lower catheter tip
placement, e.g. at the lumbar level, may reduce the incidence of ziconotide-related neurological
adverse reactions. Therefore, catheter tip placement should be carefully considered to allow adequate
access to spinal nociceptive segments whilst minimising medicinal product concentrations at cerebral
levels.
Only a small number of patients have received systemic chemotherapy and IT ziconotide. Caution
should be exercised when ziconotide is administered to patients who are receiving systemic
chemotherapy (see section 4.5).
Elevations in creatine kinase
Elevations in creatine kinase, which are usually asymptomatic, are common amongst patients on
intrathecal ziconotide. Progressive elevation of the creatine kinase is uncommon. However
monitoring of creatine kinase is recommended. In the event of progressive elevation, or clinically
significant elevation in association with clinical features of myopathy or rhabdomyolysis,
discontinuation of ziconotide should be considered.
3
Hypersensitivity reactions
Hypersensitivity reactions including anaphylaxis have not been observed during clinical trials and the
immunogenicity of ziconotide administered by the IT route appears to be low. However, the potential
for severe allergic reactions cannot be excluded.
Cognitive and neuropsychiatric adverse reactions
Cognitive and neuropsychiatric adverse reactions, particularly confusion, are common in patients
treated with ziconotide. Cognitive impairment typically appears after several weeks of treatment.
Episodes of acute psychiatric disturbances, such as hallucinations, paranoid reactions, hostility,
delirium, psychosis and manic reactions have been reported in patients treated with ziconotide. The
ziconotide dose should be reduced or discontinued if signs or symptoms of cognitive impairment or
neuropsychiatric adverse reactions develop, but other contributing causes should also be considered.
The cognitive effects of ziconotide are typically reversible within 1 - 4 weeks after discontinuation of
the medicinal product, but may persist in some cases.
In patients with severe chronic pain there is a higher incidence of suicide and suicide attempts than in
the general population. Ziconotide may cause or worsen depression with the risk of suicide in
susceptible patients.
Depression of Central Nervous System
Patients have experienced depressed levels of consciousness while receiving ziconotide. The patient
usually remains conscious and breathing is not depressed. The event may be self limited, but
ziconotide should be discontinued until the event resolves. The re-introduction of ziconotide is not
recommended in these patients. Withdrawal of concomitant Central Nervous System (CNS)
depressant medicinal products should also be considered as they may contribute to the reduced level of
arousal.
Specific clinical medicinal product interaction studies have not been conducted with ziconotide.
However, low plasma ziconotide concentrations, metabolism by ubiquitous peptidases and relatively
low plasma protein binding (see section 5.2) make metabolic-based interactions or plasma protein
displacement type interactions between ziconotide and other medicinal products unlikely.
No clinical data are available on the interaction between IT chemotherapy and IT ziconotide.
Ziconotide is contraindicated in combination with IT chemotherapy (see section 4.3).
Only a small number of patients have received systemic chemotherapy and IT ziconotide. Caution
should be exercised when ziconotide is administered to patients who are receiving systemic
chemotherapy (see section 4.4).
Medicinal products that affect specific peptidases/proteases would not be expected to impact upon
ziconotide plasma exposure. Based on very limited clinical investigations, both angiotensin
converting enzyme inhibitors (e.g., benazepril, lisinopril and moexipril) and HIV protease inhibitors
(e.g., ritonavir, saquinavir, indinavir), have no readily apparent effect on plasma ziconotide exposure.
Ziconotide does not interact with opiate receptors. If discontinuing opiates when initiating ziconotide
therapy, opiate withdrawal should be gradual. For patients being withdrawn from IT opiates, the IT
opiate infusion dose should be gradually tapered over a few weeks and replaced with a
pharmacologically equivalent dose of oral opiates. Adding IT ziconotide to stable doses of IT
morphine (see section 5.1), is possible but requires special attention, as a high rate of neuropsychiatric
adverse reactions (confusion/thinking abnormal, paranoid reactions and hallucinations, and abnormal
gait), some of them serious, was observed in Study 202 despite a low dose of ziconotide. Vomiting
and anorexia, and peripheral oedema were also observed when IT ziconotide was added to IT
morphine. The addition of IT morphine to stable doses of IT ziconotide is better tolerated (pruritis has
been reported). (See section 5.1).
4
An increased incidence of somnolence has been observed when ziconotide is administered
concomitantly with systemic baclofen, clonidine, bupivacaine or propofol thus for the time being their
simultaneous use is discouraged.
No data are available regarding the concomitant use of partial opioid agonists (e.g. buprenorphine)
with ziconotide.
There are no adequate data from the use of ziconotide in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Ziconotide
should not be used during pregnancy unless clearly necessary.
It is not known whether ziconotide is excreted in breast milk, therefore it should not be administered to
breast-feeding women unless clearly necessary.
No studies on the effects on the ability to drive and use machines have been performed.
Ziconotide may cause confusion, somnolence and other neurological adverse reactions, therefore
patients must be advised not to drive or operate machines if affected.
The safety of ziconotide administered as a continuous intrathecal infusion has been evaluated in more
than 1,400 patients participating in acute and chronic pain clinical trials. The duration of treatment has
ranged from one-hour bolus infusion to continuous use for more than 6 years. The median exposure
time was 43 days. The infusion dose rate ranged from 0.03 - 912 μg/day, with a median final dose rate
of 7.2 μg/day.
In clinical trials, 88% of patients experienced adverse drug reactions (ADRs). The most commonly
reported ADRs reported in long-term clinical trials were dizziness (42%), nausea (30%), nystagmus
(23%), confusional state (25%), gait abnormal (16%), memory impairment (13%), vision blurred
(14%), headache (12%), asthenia (13%), vomiting (11%), and somnolence (10%). Most ADRs were
mild to moderate in severity and resolved over time.
All ADRs reported in the intrathecal clinical trials with ziconotide (short- and long-term exposure) are
listed below in order of frequency.
Very Common (
≥
1/10)
Common (
≥
1/100 to < 1/10)
Uncommon (
≥
1/1,000 to < 1/100)
Infections and infestations
Uncommon:
sepsis, meningitis
Metabolism and nutrition disorders
Common:
appetite decreased, anorexia
Psychiatric disorders
Very common:
confusional state
5
Common:
anxiety, auditory hallucination, insomnia, agitation, disorientation, hallucination, visual
hallucination, depression, paranoia, irritability, depression aggravated, nervousness, affect lability,
mental status changes, anxiety aggravated, confusion aggravated
Uncommon:
delirium, psychotic disorder, suicidal ideation, suicide attempt, thought blocking,
abnormal dreams
Nervous system disorders
Very common:
dizziness, nystagmus, memory impairment, headache, somnolence
Common:
dysarthria, amnesia, dysgeusia, tremor, balance impaired, ataxia, aphasia, burning
sensation, sedation, paraesthesia, hypoaesthesia, disturbance in attention, speech disorder, areflexia,
coordination abnormal, dizziness postural, cognitive disorder, hyperaesthesia, hyporeflexia, ageusia,
depressed level of consciousness, dysaesthesia, parosmia, mental impairment
Uncommon:
incoherence, loss of consciousness, coma, stupor, convulsions, cerebrovascular accident,
encephalopathy
Eye disorders
Very common:
vision blurred
Common:
diplopia, visual disturbance, photophobia
Ear and labyrinth disorders
Common:
vertigo, tinnitus
Cardiac disorders
Uncommon:
atrial fibrillation
Vascular disorders
Common:
orthostatic hypotension, hypotension
Respiratory, thoracic and mediastinal disorders
Common:
dyspnoea
Uncommon:
respiratory distress
Gastrointestinal disorders
Very common:
nausea, vomiting
Common:
diarrhoea, dry mouth, constipation, nausea aggravated, upper abdominal pain
Uncommon:
dyspepsia
Skin and subcutaneous tissue disorders
Common:
pruritus, sweating increased
Uncommon:
rash
6
Musculoskeletal and connective tissue disorders
Common:
pain in limb, myalgia, muscle spasms, muscle cramp, muscle weakness, arthralgia,
peripheral swelling
Uncommon:
rhabdomyolysis, myositis, back pain, muscle twitching, neck pain
Renal and urinary disorders
Common:
urinary retention, urinary hesitation, dysuria, urinary incontinence
Uncommon:
acute renal failure
General disorders and administration site conditions
Very Common:
gait abnormal, asthenia
Common:
fatigue, pyrexia, lethargy, oedema peripheral, rigors, fall, chest pain, feeling cold, pain,
feeling jittery, pain exacerbated
Uncommon:
difficulty in walking
Investigations
Common:
blood creatine phosphokinase increased, weight decreased
Uncommon:
electrocardiogram abnormal, aspartate aminotransferase increased, blood creatine
phosphokinase MM increased, body temperature increased
Specific comments and particular caution regarding meningitis, elevations of creatine kinase, and CNS
adverse events can be found in Section 4.4.
In intravenous infusion studies, healthy male volunteers received ziconotide at doses of up to
70,000 μg/day or 3,200 times the maximum recommended daily intrathecal infusion dose. Postural
hypotension was observed in almost all subjects who received high intravenous doses of ziconotide.
The maximum recommended intrathecal dose is 21.6 μg/day. The maximum intended intrathecal dose
of ziconotide in clinical trials was 912 μg/day following upward titration over 7 days.
In one clinical study a male cancer patient received an accidental IT ziconotide overdose of 744 μg
over a 24-hour period (31 μg/hour) and resumed treatment at the intended dose after experiencing a
reduction in Visual Analog Scale of Pain Intensity (VASPI) from 82 to 2.5 mm. In some patients who
received intrathecal doses greater than the maximum recommended dose, exaggerated
pharmacological effects, e.g., ataxia, nystagmus, dizziness, stupor, depressed level of consciousness,
muscle spasms, confusional state, sedation, hypotension, aphasia, speech disorder, nausea and
vomiting were observed. There was no indication of respiratory depression. Most patients under
observation recovered within 24 hours of withdrawal of the medicinal product.
General medical supportive measures should be administered to patients who receive an overdose until
the exaggerated pharmacological effects of the medicinal product have resolved.
7
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics; Other analgesics and antipyretics ATC code: N02BG08
This medicinal product has been authorised under “Exceptional Circumstances”. This means that due
to the rarity of the disease it has not been possible to obtain complete information on this medicinal
product. The European Medicines Agency (EMEA) will review any new information, which may
become available every year and this SPC will be updated as necessary.
Ziconotide is a synthetic analogue of a ω-conopeptide, MVIIA, found in the venom of the
Conus
magus
marine snail. It is an N-type calcium channel blocker (NCCB). NCCs regulate
neurotransmitter release in specific neuronal populations responsible for the spinal processing of pain.
In binding to these neuronal NCCs ziconotide inhibits the voltage sensitive calcium current into
primary nociceptive afferents terminating in the superficial layers of the dorsal horn of the spinal cord.
In turn, this inhibits their release of neurotransmitters (including Substance P) and therefore, the spinal
signalling of pain.
Though statistically significant relationships and reasonable correlation between cerebrospinal fluid
(CSF) exposure (AUC, C
max
) and clinical response measures have been observed following 1 hour IT
administration, no well-defined dose-concentration-response relationships have yet been identified.
Many responsive patients obtain near-maximal analgesia within a few hours of delivery of an
appropriate dose. However, maximal effects may be delayed for approximately 24 hours in some
patients. Given the occurrence of analgesia and adverse drug reactions at similar doses, the
recommended interval between dose increases is 48 hours or more. If necessary the dose can be
decreased by any amount (including stopping the infusion) for the management of adverse drug
reactions.
Nervous system adverse reactions, particularly dizziness, nausea and abnormal gait appear to be
correlated with CSF exposure, though a definitive relationship has not been established.
Low plasma exposure occurs during IT infusion due to the low recommended IT infusion rates and
relatively rapid plasma clearance (see section 5.2). Therefore, pharmacological effects related to
systemic exposure should be minimal.
The median dose at response is approximately 6.0 μg/day and approximately 75% of responsive
patients require ≤ 9.6 μg/day. To limit the occurrence of serious adverse drug reactions, a maximum
dose of 21.6 μg/day is recommended. However, in clinical trials it has been observed that patients
who tolerate doses of 21.6 μg/day following slow titration over a 3 to 4-week period, generally tolerate
higher doses up to 48.0 μg/day.
There is no evidence of the development of pharmacological tolerance to ziconotide in patients.
However, in view of limited data, the development of tolerance cannot be excluded. Examination of
the patency of the intrathecal catheter should be considered if the required ziconotide dose continually
increases and there is no benefit or increase in drug reactions.
There were three placebo-controlled clinical trials of IT ziconotide.
Two short-term studies, 95-001 (malignant pain) and 96-002 (non malignant pain), involving
366 patients, demonstrated the efficacy of IT ziconotide in severe chronic pain using the percent
change in Visual Analog Scale of Pain Intensity (VASPI) as the primary efficacy measure. These
studies were of short duration, 5 and 6 days respectively, and used a more rapid dose escalation and
higher doses than recommended in Section 4.2.
8
Efficacy results from study 95-001
Initial Treatment Assignment
Parameter
Ziconotide (n = 71)
Placebo (n = 40)
p-value
Mean VASPI score at
baseline in mm (SD)
74.1 (± 13.82)
77.9 (± 13.60)
_
Mean VASPI score at end of
initial titration in mm (SD)
35.7 (± 33.27)
61.0 (± 22.91)
_
% improvement in VASPI
score at end of initial titration
(SD)
51.4 (± 43.63)
18.1 (± 28.28)
< 0.001
Responder
a
n (%)
34 (47.9%)
7 (17.5%)
0.001
Dose at end of titration
(μg/hr)
0.91
0.60
0.074 - 9.36
a
Responders were defined as those patients who 1) experienced a ≥ 30% drop in VASPI score
compared to baseline; 2) had stable or decreased concomitant opioid analgesics; and 3) had opiate type
unchanged from preinfusion if receiving opiates.
SD – Standard Deviation.
Mean
Median
Range
Efficacy results from study 96-002
Initial Treatment Assignment
Parameter
Ziconotide (n = 169)
b
Placebo (n = 86)
p-value
Mean VASPI score at
baseline in mm (SD)
80.1 (± 15.10)
76.9 (± 14.58)
_
Mean VASPI score at end of
initial titration in mm (SD)
54.4 (± 29.30)
71.9 (± 30.93)
_
% improvement in VASPI
score at end of initial titration
(SD)
31.2 (± 38.69)
6.0 (± 42.84)
< 0.001
Responder
a
n (%)
57 (33.7%)
11 (12.8%)
< 0.001
Dose at end of titration
(μg/hr)
1.02
0.50
0.019 - 9.60
Mean
Median
Range
a
Responders were defined as those patients who 1) experienced a ≥ 30% drop in VASPI score
compared to baseline; 2) had stable or decreased concomitant opioid analgesics; and 3) had opiate type
unchanged from preinfusion if receiving opiates.
b
164 patients provided VASPI scores for ziconotide at the end of titration.
SD – Standard Deviation.
The aetiologies of pain in studies 95-001 (malignant pain) and 96-002 (non-malignant pain) were
varied and included bone pain (n = 38) mostly due to bone metastases (n = 34), myelopathy (n = 38),
half of whom had spinal cord injury with paralysis (n = 19), neuropathy (n = 79), radiculopathy
(n = 24), spinal pain (n = 91) mostly due to failed back surgery (n = 82), and other aetiologies
(n = 82). Some patients had more than one cause of pain. The efficacy of IT ziconotide was apparent
in all groups.
Study 301 (n = 220) was of longer duration (21 days), involved more cautious up-titration and lower
doses of IT ziconotide, and enrolled the most refractory population of patients studied in the three
studies. All patients in the 301 study had failed IT therapy with combinations of analgesics and their
physicians considered that 97% of the patients were refractory to currently available treatments. The
9
majority had spinal pain (n = 134), especially failed back surgery (n = 110); a lower proportion had
neuropathy (n = 36). Only five had malignant pain. The primary endpoint was the percent change in
VASPI score. The efficacy of IT ziconotide in study 301 was lower than in the previous two,
short-term studies. The frequency and severity of adverse events were also lower.
Efficacy results from study 301
Initial Treatment Assignment
Parameter
Ziconotide (n = 112)
Placebo (n = 108)
p-value
Mean VASPI score at baseline
in mm (SD)
80.7 (± 14.98)
80.7 (± 14.91)
-
Mean VASPI score at end of
initial titration in mm (SD)
67.9 (± 22.89)
74.1 (± 21.28)
_
% improvement in VASPI score
at end of initial titration (SD)
14.7 (± 27.71)
7.2 (± 24.98)
0.0360
Responder
a
n (%)
18 (16.1%)
13 (12.0%)
0.390
Dose at end of titration (μg/hr)
Mean
Median
Range
0.29
0.25
0.0 - 0.80
a
Responders were defined as those who experienced a ≥ 30% drop in VASPI score compared to
baseline.
SD – Standard Deviation.
Combination studies with IT Morphine
Clinical studies 201 and 202 indicate that the combination of IT ziconotide and IT morphine may
effectively reduce pain and decrease systemic opioid use over a sustained period of time for patients
whose pain was inadequately controlled with their maximum tolerated dose of IT ziconotide (median
8.7 μg/day, mean 25.7 μg/day – study 201) or with IT morphine (study 202) alone. When adding IT
ziconotide to stable doses of IT morphine, as with the initiation of IT ziconotide monotherapy, the
appearance of psychotic adverse events (e.g., hallucinations, paranoid reactions) or discontinuation
due to increased adverse events may occur. (see section 4.5).
5.2 Pharmacokinetic properties
The CSF pharmacokinetics of ziconotide have been studied following one-hour IT infusions of
1 - 10 μg of ziconotide in patients with chronic pain. The plasma pharmacokinetics following
intravenous doses (0.3 – 10 μg/kg/24 hr) were also studied. IT and intravenous pharmacokinetics data
are summarised below.
CSF and Plasma Pharmacokinetics of Ziconotide [mean ± SD (median)]
Route of
administration
Fluid
matrix
Number
of
patients
CL (ml/min)
Vd (ml)
t
½
(hr)
Intrathecal
CSF
23
0.38 ± 0.56
(0.26)
155 ± 263
(99)
4.6 ± 0.9
(4.5)
Intravenous
Plasma
21
270 ± 44
(260)
30,460 ± 6,366
(29,320)
1.3 ± 0.3
(1.3)
CL = clearance; Vd = distribution volume; t½ = half life
Absorption:
Following one-hour IT administration (1 – 10 μg), both cumulative exposure (AUC;
range: 83.6 – 608 ng/h/ml) and peak exposure (C
max
; range: 16.4 – 132 ng/ml) values were variable
and dose-dependent, but appeared only approximately dose-proportional. Plasma concentrations
10
following continuous (≥ 48 h) IT infusion (≤ 21.6 μg/day) appear to be relatively low and typically
undetectable (i.e., about 80% of plasma samples collected from pain patients contain no quantifiable
medicinal product; < 0.04 ng/ml). No accumulation of ziconotide in plasma following long-term IT
administration (up to 9 months) has been observed.
Distribution:
Median ziconotide CSF volume of distribution (Vd: 99 ml) is between the spinal cord
CSF volume (approximately 75 ml) and total CSF volume (approximately 130 ml). Ziconotide
appears to distribute mainly within the CSF until transferred to the systemic circulation. Upon
reaching the systemic circulation, ziconotide appears to be more extensively distributed, based on a
plasma distribution volume of approximately 30 l and is only about 53% bound (non-specifically) to
human plasma proteins.
Biotransformation:
Ziconotide is a peptide consisting of 25 naturally-occurring amino acids of the
L-configuration, and does not appear to be appreciably metabolised in the CSF. Following passage
into the systemic circulation, ziconotide is expected to be primarily susceptible to proteolytic cleavage
by various ubiquitous peptidases/proteases present in most organs (e.g., kidney, liver, lung, muscle,
etc.), and thus degraded to peptide fragments and its individual constituent free amino acids. The
generated free amino acids are expected to be taken up by cellular carrier systems and either subjected
to normal intermediary metabolism or used as substrates for constitutive biosynthetic processes. Due
to the wide distribution of these peptidases it is not expected that hepatic or renal impairment would
affect the systemic clearance of ziconotide. The biological activity of the various expected proteolytic
degradation products has not been assessed. It is unlikely that the degradation products of ziconotide
will have significant biological activity, as peptides consisting of the individual peptide loop structures
have been found to have binding affinities for N-type voltage sensitive calcium channels that are
several orders of magnitude lower than that of the parent (ziconotide) compound.
Elimination:
Mean ziconotide CL (0.38 ml/min) approximates adult human CSF turnover rate
(0.3 - 0.4 ml/min). Hence, ziconotide appears to be mainly eliminated from the CSF (mean
t
½
= 4.6 hr) by bulk flow of CSF out of the CNS through the arachnoid villi with subsequent transfer
into the systemic circulation. Very low circulating plasma concentrations of ziconotide may be
observed following IT administration due to both the low IT infusion rate and relatively rapid plasma
clearance. The mean plasma elimination half-life (t
½
) is 1.3 hr. Ziconotide is a relatively small
molecular weight peptide (MW = 2,639) and is filtered by the kidney glomerulus, but only minimal
amounts of ziconotide (< 1%) are recovered in human urine following intravenous infusion. This is
because almost all of the filtered active substance is rapidly endocytosed and ultimately transported
back to the systemic circulation.
Specific populations:
Although only limited data are available, there is no obvious effect of race,
height, weight, gender or age on CSF ziconotide exposure after IT administration. No formal studies
assessing the impact of renal or hepatic dysfunction have been conducted; however, given that
peptidases are present in various body organs, it is not anticipated that renal or hepatic dysfunction
will significantly impact systemic exposure of ziconotide.
5.3 Preclinical safety data
Preclinical toxic effects related to ziconotide administration were observed only at exposures
considered sufficiently in excess of the human exposure to indicate little risk in clinical use.
In subchronic continuous intrathecal infusion studies in rats and dogs, behavioural effects were seen at
doses ≥ 8-fold the maximum recommended clinical intrathecal infusion dose of 21.6 μg/day (on a
mg/kg basis). These effects were defined by exaggerated pharmacological actions of ziconotide and
not by neurotoxic lesions or target organ toxicity. Observations included transient and reversible
neurological effects consisting of tremors, uncoordinated movements and hyper- and hypoactivity.
The long-term consequences to neuronal function of continuous N-type calcium-channel block have
not been demonstrated in experimental animals. Changes in neurological signalling have not been
studied in experimental animals. Ziconotide did not induce bacterial gene mutation and was not
11
genotoxic. Chronic animal studies have not been performed to assess the carcinogenic potential of
ziconotide. However, ziconotide did not induce cell transformation in the
in vitro
Syrian hamster
embryo (SHE) assay and did not increase cell proliferation (pre-neoplastic lesion formation) or
apoptosis after subchronic intrathecal exposure in dogs.
In rat fertility studies, there were no effects in males while reductions in corpora lutea; implantation
sites and number of live embryos were observed in females. No adverse effects on female
reproduction and post-natal development in rats were seen at systemic exposures up to 2,300 times
human exposures at the maximum recommended intrathecal dose.
Ziconotide was not teratogenic in rats and rabbits at exposures < 100 times human plasma levels.
These results do not indicate a significant risk to humans due to the relatively high systemic exposures
needed to elicit these effects in rats and rabbits.
6.
6.1 List of excipients
Methionine
Sodium chloride
Water for injections
Hydrochloric acid (pH adjuster)
Sodium hydroxide (pH adjuster)
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
3 years
Chemical and physical in use stability has been demonstrated for 60 days at 37°C.
From a microbiological point of view, if the product is diluted it should be transferred to the infusion
pump 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°C – 8°C, unless dilution
has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vial in the outer carton in order to protect
from light.
For storage conditions of the diluted medicinal product, see section 6.3.
12
6.5 Nature and contents of container
Single-use Type I glass vials with butyl rubber stoppers coated with fluorinated polymer.
Each vial contains 20 ml solution for infusion.
One vial per carton.
6.6 Special precautions for disposal and other handling
If dilution is required, Prialt must be diluted aseptically with preservative-free sodium chloride
9 mg/ml (0.9%) solution for injection before use. The concentration of the solution used in the
infusion pump must be no lower than 5 μg/ml ziconotide in an external pump and 25 μg/ml in an
internal pump.
Strict aseptic procedures must be used during the preparation and handling of the solution for infusion
and refilling of the pump. The patient and health-care providers must be familiar with the handling of
the external or internal infusion system and be aware of the need to guard against infection.
Prialt has been shown to be chemically and physically compatible with the implantable Synchromed
pump and the external CADD-Micro pump at the concentration levels indicated above. Chemical and
physical in-use stability has been demonstrated for 14 days at 37ºC in the Synchromed pump when the
pump has not previously been exposed to the medicinal product. The initial fill must therefore be
replaced after 14 days.
Prialt was stable for 60 days at 37°C in the Synchromed pump previously exposed to the medicinal
product. Stability has been demonstrated for 21 days at room temperature in the CADD-Micro pump.
Specific instructions for using the pumps must be obtained from the manufacturer. CE marked pumps
equivalent to the Synchromed and CADD-Micro pump should be used to deliver Prialt. Pumps
previously used to deliver other medicinal products must be washed out three times with sodium
chloride 9 mg/ml (0.9%) solution for injection (preservative-free) before being filled with Prialt. The
introduction of air into the pump reservoir or cartridge should be minimized, as oxygen can degrade
ziconotide.
Prior to initiation of therapy, an internal pump must be rinsed three times with 2 ml of Prialt at
25 μg/ml. The concentration of Prialt in a naïve pump may be reduced due to adsorption onto the
surfaces of the device, and/or dilution by the residual space of the device. Because of this, after the
first use of Prialt, the reservoir should be emptied and refilled after 14 days. Subsequently the pump
should be emptied and refilled every 60 days.
Prialt is a clear and colourless solution. It should be inspected visually for particulate matter and
discolouration prior to administration. The solution should not be used if discoloured or cloudy or if
particulate matter is observed.
For single use only. Any unused solution should be discarded according to local regulations.
13
7.
Eisai Ltd.,
European Knowledge Centre
Mosquito Way
Hatfield
Herts
AL10 9SN
United Kingdom
8.
EU/1/04/302/004 – 20 ml solution for infusion
9.
Date of first authorisation: 20/03/2006
Date of latest renewal: 12/01/2010
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA) www.emea.europa.eu
14
1.
Prialt 100 micrograms/ml solution for infusion
2.
One ml solution contains 100 μg ziconotide (as acetate).
1 ml vial: Each vial contains 100 μg ziconotide (as acetate).
2 ml vial: Each vial contains 200 μg ziconotide (as acetate).
5 ml vial: Each vial contains 500 μg ziconotide (as acetate).
For a full list of excipients, see section 6.1.
3.
Solution for infusion.
Clear, colourless solution, free of visible particles.
4.
Ziconotide is indicated for the treatment of severe, chronic pain in adults who require intrathecal (IT)
analgesia.
Treatment with ziconotide should only be undertaken by physicians experienced in intrathecal (IT)
administration of medicinal products.
Adults (including the elderly ≥ 65 years of age)
Dosing of ziconotide should be initiated at 2.4 μg/day and titrated on an individual patient basis
according to the patient’s analgesic response and adverse reactions. Patients should be titrated in dose
increments of ≤ 2.4 μg/day, up to a maximum dose of 21.6 μg/day. The minimal interval between
dose increases is 24 hours; the recommended interval, for safety reasons, is 48 hours or more. If
necessary the dose can be decreased by any amount (including stopping the infusion) for the
management of adverse reactions. Approximately 75% of patients who respond satisfactorily to
treatment require a dose of ≤ 9.6 μg/day.
Ziconotide must be administered as a continuous infusion via an intrathecal catheter, using an external
or internally implanted mechanical infusion pump capable of delivering an accurate infusion volume.
As the risk of meningitis secondary to prolonged catheterisation of the intrathecal space is greater with
an external catheter infusion system, internal systems are recommended to administer ziconotide for
prolonged periods. An external catheter system should only be used when an internal system cannot
be implanted.
When low doses of ziconotide are required, for example when initiating titration, ziconotide must be
diluted before use with preservative-free sodium chloride 9 mg/ml (0.9%) solution for injection. (see
section 6.6).
15
Use in paediatric patients (< 18 years of age)
Prialt is not recommended for use in children below 18 years due to a lack of data on safety and
efficacy. There is no experience in children.
Use in patients with impaired hepatic function
Studies have not been conducted in patients with impaired hepatic function. Caution should be
exercised when ziconotide is administered to patients with impaired hepatic function.
Use in patients with impaired renal function
Studies have not been conducted in patients with impaired renal function. Caution should be exercised
when ziconotide is administered to patients with impaired renal function.
Prialt is for intrathecal use only.
For instructions for use and handling, see section 6.6.
Hypersensitivity to the active substance or to any of the excipients.
Ziconotide is contraindicated in combination with IT chemotherapy (see section 4.5).
Long-term use
Although ziconotide has been studied in long-term, open label efficacy and safety clinical trials,
controlled studies of longer than 3 weeks duration have not been conducted (see section 5.1). Possible
long-term local toxic effects on the spinal cord have not been excluded and preclinical data in this
respect are limited (see section 5.3). Therefore, caution is needed during long-term treatment.
Route of administration
The administration of medicinal products by the intrathecal (IT) route carries the risk of potentially
serious infections, such as meningitis, which may be life threatening. Meningitis due to the entrance
of organisms along the catheter track or inadvertent contamination of the infusion system is a known
complication of intrathecal medicinal product administration, especially with external systems.
Patients and physicians must be vigilant for typical symptoms and signs of meningitis.
The optimal intrathecal placement of the catheter tip has not been established. Lower catheter tip
placement, e.g. at the lumbar level, may reduce the incidence of ziconotide-related neurological
adverse reactions. Therefore, catheter tip placement should be carefully considered to allow adequate
access to spinal nociceptive segments whilst minimising medicinal product concentrations at cerebral
levels.
Only a small number of patients have received systemic chemotherapy and IT ziconotide. Caution
should be exercised when ziconotide is administered to patients who are receiving systemic
chemotherapy (see section 4.5).
Elevations in creatine kinase
Elevations in creatine kinase, which are usually asymptomatic, are common amongst patients on
intrathecal ziconotide. Progressive elevation of the creatine kinase is uncommon. However
monitoring of creatine kinase is recommended. In the event of progressive elevation, or clinically
16
significant elevation in association with clinical features of myopathy or rhabdomyolysis,
discontinuation of ziconotide should be considered.
Hypersensitivity reactions
Hypersensitivity reactions including anaphylaxis have not been observed during clinical trials and the
immunogenicity of ziconotide administered by the IT route appears to be low. However, the potential
for severe allergic reactions cannot be excluded.
Cognitive and neuropsychiatric adverse reactions
Cognitive and neuropsychiatric adverse reactions, particularly confusion, are common in patients
treated with ziconotide. Cognitive impairment typically appears after several weeks of treatment.
Episodes of acute psychiatric disturbances, such as hallucinations, paranoid reactions, hostility,
delirium, psychosis and manic reactions have been reported in patients treated with ziconotide. The
ziconotide dose should be reduced or discontinued if signs or symptoms of cognitive impairment or
neuropsychiatric adverse reactions develop, but other contributing causes should also be considered.
The cognitive effects of ziconotide are typically reversible within 1 - 4 weeks after discontinuation of
the medicinal product, but may persist in some cases.
In patients with severe chronic pain there is a higher incidence of suicide and suicide attempts than in
the general population. Ziconotide may cause or worsen depression with the risk of suicide in
susceptible patients.
Depression of Central Nervous System
Patients have experienced depressed levels of consciousness while receiving ziconotide. The patient
usually remains conscious and breathing is not depressed. The event may be self limited, but
ziconotide should be discontinued until the event resolves. The re-introduction of ziconotide is not
recommended in these patients. Withdrawal of concomitant Central Nervous System (CNS)
depressant medicinal products should also be considered as they may contribute to the reduced level of
arousal.
Specific clinical medicinal product interaction studies have not been conducted with ziconotide.
However, low plasma ziconotide concentrations, metabolism by ubiquitous peptidases and relatively
low plasma protein binding (see section 5.2) make metabolic-based interactions or plasma protein
displacement type interactions between ziconotide and other medicinal products unlikely.
No clinical data are available on the interaction between IT chemotherapy and IT ziconotide.
Ziconotide is contraindicated in combination with IT chemotherapy (see section 4.3).
Only a small number of patients have received systemic chemotherapy and IT ziconotide. Caution
should be exercised when ziconotide is administered to patients who are receiving systemic
chemotherapy (see section 4.4).
Medicinal products that affect specific peptidases/proteases would not be expected to impact upon
ziconotide plasma exposure. Based on very limited clinical investigations, both angiotensin
converting enzyme inhibitors (e.g., benazepril, lisinopril and moexipril) and HIV protease inhibitors
(e.g., ritonavir, saquinavir, indinavir), have no readily apparent effect on plasma ziconotide exposure.
Ziconotide does not interact with opiate receptors. If discontinuing opiates when initiating ziconotide
therapy, opiate withdrawal should be gradual. For patients being withdrawn from IT opiates, the IT
opiate infusion dose should be gradually tapered over a few weeks and replaced with a
pharmacologically equivalent dose of oral opiates. Adding IT ziconotide to stable doses of IT
morphine (see section 5.1), is possible but requires special attention, as a high rate of neuropsychiatric
adverse reactions (confusion/thinking abnormal, paranoid reactions and hallucinations, and abnormal
gait), some of them serious, was observed in Study 202 despite a low dose of ziconotide. Vomiting
and anorexia, and peripheral oedema were also observed when IT ziconotide was added to IT
17
morphine. The addition of IT morphine to stable doses of IT ziconotide is better tolerated (pruritis has
been reported). (See section 5.1).
An increased incidence of somnolence has been observed when ziconotide is administered
concomitantly with systemic baclofen, clonidine, bupivacaine or propofol thus for the time being their
simultaneous use is discouraged.
No data are available regarding the concomitant use of partial opioid agonists (e.g. buprenorphine)
with ziconotide.
There are no adequate data from the use of ziconotide in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Ziconotide
should not be used during pregnancy unless clearly necessary.
It is not known whether ziconotide is excreted in breast milk, therefore it should not be administered to
breast-feeding women unless clearly necessary.
No studies on the effects on the ability to drive and use machines have been performed.
Ziconotide may cause confusion, somnolence and other neurological adverse reactions, therefore
patients must be advised not to drive or operate machines if affected.
The safety of ziconotide administered as a continuous intrathecal infusion has been evaluated in more
than 1,400 patients participating in acute and chronic pain clinical trials. The duration of treatment has
ranged from one-hour bolus infusion to continuous use for more than 6 years. The median exposure
time was 43 days. The infusion dose rate ranged from 0.03 - 912 μg/day, with a median final dose rate
of 7.2 μg/day.
In clinical trials, 88% of patients experienced adverse drug reactions (ADRs). The most commonly
reported ADRs reported in long-term clinical trials were dizziness (42%), nausea (30%), nystagmus
(23%), confusional state (25%), gait abnormal (16%), memory impairment (13%), vision blurred
(14%), headache (12%), asthenia (13%), vomiting (11%), and somnolence (10%). Most ADRs were
mild to moderate in severity and resolved over time.
All ADRs reported in the intrathecal clinical trials with ziconotide (short- and long-term exposure) are
listed below in order of frequency.
Very Common (≥ 1/10)
Common (≥ 1/100 to < 1/10)
Uncommon (≥ 1/1,000 to < 1/100)
Infections and infestations
Uncommon:
sepsis, meningitis
Metabolism and nutrition disorders
Common:
appetite decreased, anorexia
18
Psychiatric disorders
Very common:
confusional state
Common:
anxiety, auditory hallucination, insomnia, agitation, disorientation, hallucination, visual
hallucination, depression, paranoia, irritability, depression aggravated, nervousness, affect lability,
mental status changes, anxiety aggravated, confusion aggravated
Uncommon:
delirium, psychotic disorder, suicidal ideation, suicide attempt, thought blocking,
abnormal dreams
Nervous system disorders
Very common:
dizziness, nystagmus, memory impairment, headache, somnolence
Common:
dysarthria, amnesia, dysgeusia, tremor, balance impaired, ataxia, aphasia, burning
sensation, sedation, paraesthesia, hypoaesthesia, disturbance in attention, speech disorder, areflexia,
coordination abnormal, dizziness postural, cognitive disorder, hyperaesthesia, hyporeflexia, ageusia,
depressed level of consciousness, dysaesthesia, parosmia, mental impairment
Uncommon:
incoherence, loss of consciousness, coma, stupor, convulsions, cerebrovascular accident,
encephalopathy
Eye disorders
Very common:
vision blurred
Common:
diplopia, visual disturbance, photophobia
Ear and labyrinth disorders
Common:
vertigo, tinnitus
Cardiac disorders
Uncommon:
atrial fibrillation
Vascular disorders
Common:
orthostatic hypotension, hypotension
Respiratory, thoracic and mediastinal disorders
Common:
dyspnoea
Uncommon:
respiratory distress
Gastrointestinal disorders
Very common:
nausea, vomiting
Common:
diarrhoea, dry mouth, constipation, nausea aggravated, upper abdominal pain
Uncommon:
dyspepsia
Skin and subcutaneous tissue disorders
19
Common:
pruritus, sweating increased
Uncommon:
rash
Musculoskeletal and connective tissue disorders
Common:
pain in limb, myalgia, muscle spasms, muscle cramp, muscle weakness, arthralgia,
peripheral swelling
Uncommon:
rhabdomyolysis, myositis, back pain, muscle twitching, neck pain
Renal and urinary disorders
Common:
urinary retention, urinary hesitation, dysuria, urinary incontinence
Uncommon:
acute renal failure
General disorders and administration site conditions
Very Common:
gait abnormal, asthenia
Common:
fatigue, pyrexia, lethargy, oedema peripheral, rigors, fall, chest pain, feeling cold, pain,
feeling jittery, pain exacerbated
Uncommon:
difficulty in walking
Investigations
Common:
blood creatine phosphokinase increased, weight decreased
Uncommon:
electrocardiogram abnormal, aspartate aminotransferase increased, blood creatine
phosphokinase MM increased, body temperature increased
Specific comments and particular caution regarding meningitis, elevations of creatine kinase, and CNS
adverse events can be found in Section 4.4.
In intravenous infusion studies, healthy male volunteers received ziconotide at doses of up to
70,000 μg/day or 3,200 times the maximum recommended daily intrathecal infusion dose. Postural
hypotension was observed in almost all subjects who received high intravenous doses of ziconotide.
The maximum recommended intrathecal dose is 21.6 μg/day. The maximum intended intrathecal dose
of ziconotide in clinical trials was 912 μg/day following upward titration over 7 days.
In one clinical study a male cancer patient received an accidental IT ziconotide overdose of 744 μg
over a 24-hour period (31 μg/hour) and resumed treatment at the intended dose after experiencing a
reduction in Visual Analog Scale of Pain Intensity (VASPI) from 82 to 2.5 mm. In some patients who
received intrathecal doses greater than the maximum recommended dose, exaggerated
pharmacological effects, e.g., ataxia, nystagmus, dizziness, stupor, depressed level of consciousness,
muscle spasms, confusional state, sedation, hypotension, aphasia, speech disorder, nausea and
vomiting were observed. There was no indication of respiratory depression. Most patients under
observation recovered within 24 hours of withdrawal of the medicinal product.
General medical supportive measures should be administered to patients who receive an overdose until
the exaggerated pharmacological effects of the medicinal product have resolved.
20
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics; Other analgesics and antipyretics ATC code: N02BG08
This medicinal product has been authorised under “Exceptional Circumstances”. This means that due
to the rarity of the disease it has not been possible to obtain complete information on this medicinal
product. The European Medicines Agency (EMEA) will review any new information, which may
become available every year and this SPC will be updated as necessary.
Ziconotide is a synthetic analogue of a ω-conopeptide, MVIIA, found in the venom of the
Conus
magus
marine snail. It is an N-type calcium channel blocker (NCCB). NCCs regulate
neurotransmitter release in specific neuronal populations responsible for the spinal processing of pain.
In binding to these neuronal NCCs ziconotide inhibits the voltage sensitive calcium current into
primary nociceptive afferents terminating in the superficial layers of the dorsal horn of the spinal cord.
In turn, this inhibits their release of neurotransmitters (including Substance P) and therefore, the spinal
signalling of pain.
Though statistically significant relationships and reasonable correlation between cerebrospinal fluid
(CSF) exposure (AUC, C
max
) and clinical response measures have been observed following 1 hour IT
administration, no well-defined dose-concentration-response relationships have yet been identified.
Many responsive patients obtain near-maximal analgesia within a few hours of delivery of an
appropriate dose. However, maximal effects may be delayed for approximately 24 hours in some
patients. Given the occurrence of analgesia and adverse drug reactions at similar doses, the
recommended interval between dose increases is 48 hours or more. If necessary the dose can be
decreased by any amount (including stopping the infusion) for the management of adverse drug
reactions.
Nervous system adverse reactions, particularly dizziness, nausea and abnormal gait appear to be
correlated with CSF exposure, though a definitive relationship has not been established.
Low plasma exposure occurs during IT infusion due to the low recommended IT infusion rates and
relatively rapid plasma clearance (see section 5.2). Therefore, pharmacological effects related to
systemic exposure should be minimal.
The median dose at response is approximately 6.0 μg/day and approximately 75% of responsive
patients require ≤ 9.6 μg/day. To limit the occurrence of serious adverse drug reactions, a maximum
dose of 21.6 μg/day is recommended. However, in clinical trials it has been observed that patients
who tolerate doses of 21.6 μg/day following slow titration over a 3 to 4-week period, generally tolerate
higher doses up to 48.0 μg/day.
There is no evidence of the development of pharmacological tolerance to ziconotide in patients.
However, in view of limited data, the development of tolerance cannot be excluded. Examination of
the patency of the intrathecal catheter should be considered if the required ziconotide dose continually
increases and there is no benefit or increase in drug reactions.
There were three placebo-controlled clinical trials of IT ziconotide.
Two short-term studies, 95-001 (malignant pain) and 96-002 (non malignant pain), involving
366 patients, demonstrated the efficacy of IT ziconotide in severe chronic pain using the percent
change in Visual Analog Scale of Pain Intensity (VASPI) as the primary efficacy measure. These
studies were of short duration, 5 and 6 days respectively, and used a more rapid dose escalation and
higher doses than recommended in Section 4.2.
21
Efficacy results from study 95-001
Initial Treatment Assignment
Parameter
Ziconotide (n = 71)
Placebo (n = 40)
p-value
Mean VASPI score at
baseline in mm (SD)
74.1 (± 13.82)
77.9 (± 13.60)
_
Mean VASPI score at end of
initial titration in mm (SD)
35.7 (± 33.27)
61.0 (± 22.91)
_
% improvement in VASPI
score at end of initial titration
(SD)
51.4 (± 43.63)
18.1 (± 28.28)
< 0.001
Responder
a
n (%)
34 (47.9%)
7 (17.5%)
0.001
Dose at end of titration
(μg/hr)
0.91
0.60
0.074 - 9.36
a
Responders were defined as those patients who 1) experienced a ≥ 30% drop in VASPI score
compared to baseline; 2) had stable or decreased concomitant opioid analgesics; and 3) had opiate type
unchanged from preinfusion if receiving opiates.
SD – Standard Deviation.
Mean
Median
Range
Efficacy results from study 96-002
Initial Treatment Assignment
Parameter
Ziconotide (n = 169)
b
Placebo (n = 86)
p-value
Mean VASPI score at
baseline in mm (SD)
80.1 (± 15.10)
76.9 (± 14.58)
_
Mean VASPI score at end of
initial titration in mm (SD)
54.4 (± 29.30)
71.9 (± 30.93)
_
% improvement in VASPI
score at end of initial titration
(SD)
31.2 (± 38.69)
6.0 (± 42.84)
< 0.001
Responder
a
n (%)
57 (33.7%)
11 (12.8%)
< 0.001
Dose at end of titration
(μg/hr)
1.02
0.50
0.019 - 9.60
Mean
Median
Range
a
Responders were defined as those patients who 1) experienced a ≥ 30% drop in VASPI score
compared to baseline; 2) had stable or decreased concomitant opioid analgesics; and 3) had opiate type
unchanged from preinfusion if receiving opiates.
b
164 patients provided VASPI scores for ziconotide at the end of titration.
SD – Standard Deviation.
The aetiologies of pain in studies 95-001 (malignant pain) and 96-002 (non-malignant pain) were
varied and included bone pain (n = 38) mostly due to bone metastases (n = 34), myelopathy (n = 38),
half of whom had spinal cord injury with paralysis (n = 19), neuropathy (n = 79), radiculopathy
(n = 24), spinal pain (n = 91) mostly due to failed back surgery (n = 82), and other aetiologies
(n = 82). Some patients had more than one cause of pain. The efficacy of IT ziconotide was apparent
in all groups.
Study 301 (n = 220) was of longer duration (21 days), involved more cautious up-titration and lower
doses of IT ziconotide, and enrolled the most refractory population of patients studied in the three
studies. All patients in the 301 study had failed IT therapy with combinations of analgesics and their
physicians considered that 97% of the patients were refractory to currently available treatments. The
22
majority had spinal pain (n = 134), especially failed back surgery (n = 110); a lower proportion had
neuropathy (n = 36). Only five had malignant pain. The primary endpoint was the percent change in
VASPI score. The efficacy of IT ziconotide in study 301 was lower than in the previous two,
short-term studies. The frequency and severity of adverse events were also lower.
Efficacy results from study 301
Initial Treatment Assignment
Parameter
Ziconotide (n = 112)
Placebo (n = 108)
p-value
Mean VASPI score at baseline
in mm (SD)
80.7 (± 14.98)
80.7 (± 14.91)
-
Mean VASPI score at end of
initial titration in mm (SD)
67.9 (± 22.89)
74.1 (± 21.28)
_
% improvement in VASPI score
at end of initial titration (SD)
14.7 (± 27.71)
7.2 (± 24.98)
0.0360
Responder
a
n (%)
18 (16.1%)
13 (12.0%)
0.390
Dose at end of titration (μg/hr)
Mean
Median
Range
0.29
0.25
0.0 - 0.80
a
Responders were defined as those who experienced a ≥ 30% drop in VASPI score compared to
baseline.
SD – Standard Deviation.
Combination studies with IT Morphine
Clinical studies 201 and 202 indicate that the combination of IT ziconotide and IT morphine may
effectively reduce pain and decrease systemic opioid use over a sustained period of time for patients
whose pain was inadequately controlled with their maximum tolerated dose of IT ziconotide (median
8.7 μg/day, mean 25.7 μg/day – study 201) or with IT morphine (study 202) alone. When adding IT
ziconotide to stable doses of IT morphine, as with the initiation of IT ziconotide monotherapy, the
appearance of psychotic adverse events (e.g., hallucinations, paranoid reactions) or discontinuation
due to increased adverse events may occur. (see section 4.5).
5.2 Pharmacokinetic properties
The CSF pharmacokinetics of ziconotide have been studied following one-hour IT infusions of
1 - 10 μg of ziconotide in patients with chronic pain. The plasma pharmacokinetics following
intravenous doses (0.3 – 10 μg/kg/24 hr) were also studied. IT and intravenous pharmacokinetics data
are summarised below.
CSF and Plasma Pharmacokinetics of Ziconotide [mean ± SD (median)]
Route of
administration
Fluid
matrix
Number
of
patients
CL (ml/min)
Vd (ml)
t
½
(hr)
Intrathecal
CSF
23
0.38 ± 0.56
(0.26)
155 ± 263
(99)
4.6 ± 0.9
(4.5)
Intravenous
Plasma
21
270 ± 44
(260)
30,460 ± 6,366
(29,320)
1.3 ± 0.3
(1.3)
CL = clearance; Vd = distribution volume; t½ = half life
Absorption:
Following one-hour IT administration (1 – 10 μg), both cumulative exposure (AUC;
range: 83.6 – 608 ng/h/ml) and peak exposure (C
max
; range: 16.4 – 132 ng/ml) values were variable
and dose-dependent, but appeared only approximately dose-proportional. Plasma concentrations
23
following continuous (≥ 48 h) IT infusion (≤ 21.6 μg/day) appear to be relatively low and typically
undetectable (i.e., about 80% of plasma samples collected from pain patients contain no quantifiable
medicinal product; < 0.04 ng/ml). No accumulation of ziconotide in plasma following long-term IT
administration (up to 9 months) has been observed.
Distribution:
Median ziconotide CSF volume of distribution (Vd: 99 ml) is between the spinal cord
CSF volume (approximately 75 ml) and total CSF volume (approximately 130 ml). Ziconotide
appears to distribute mainly within the CSF until transferred to the systemic circulation. Upon
reaching the systemic circulation, ziconotide appears to be more extensively distributed, based on a
plasma distribution volume of approximately 30 l and is only about 53% bound (non-specifically) to
human plasma proteins.
Biotransformation:
Ziconotide is a peptide consisting of 25 naturally-occurring amino acids of the
L-configuration, and does not appear to be appreciably metabolised in the CSF. Following passage
into the systemic circulation, ziconotide is expected to be primarily susceptible to proteolytic cleavage
by various ubiquitous peptidases/proteases present in most organs (e.g., kidney, liver, lung, muscle,
etc.), and thus degraded to peptide fragments and its individual constituent free amino acids. The
generated free amino acids are expected to be taken up by cellular carrier systems and either subjected
to normal intermediary metabolism or used as substrates for constitutive biosynthetic processes. Due
to the wide distribution of these peptidases it is not expected that hepatic or renal impairment would
affect the systemic clearance of ziconotide. The biological activity of the various expected proteolytic
degradation products has not been assessed. It is unlikely that the degradation products of ziconotide
will have significant biological activity, as peptides consisting of the individual peptide loop structures
have been found to have binding affinities for N-type voltage sensitive calcium channels that are
several orders of magnitude lower than that of the parent (ziconotide) compound.
Elimination:
Mean ziconotide CL (0.38 ml/min) approximates adult human CSF turnover rate
(0.3 - 0.4 ml/min). Hence, ziconotide appears to be mainly eliminated from the CSF (mean
t
½
= 4.6 hr) by bulk flow of CSF out of the CNS through the arachnoid villi with subsequent transfer
into the systemic circulation. Very low circulating plasma concentrations of ziconotide may be
observed following IT administration due to both the low IT infusion rate and relatively rapid plasma
clearance. The mean plasma elimination half-life (t
½
) is 1.3 hr. Ziconotide is a relatively small
molecular weight peptide (MW = 2,639) and is filtered by the kidney glomerulus, but only minimal
amounts of ziconotide (< 1%) are recovered in human urine following intravenous infusion. This is
because almost all of the filtered active substance is rapidly endocytosed and ultimately transported
back to the systemic circulation.
Specific populations:
Although only limited data are available, there is no obvious effect of race,
height, weight, gender or age on CSF ziconotide exposure after IT administration. No formal studies
assessing the impact of renal or hepatic dysfunction have been conducted; however, given that
peptidases are present in various body organs, it is not anticipated that renal or hepatic dysfunction
will significantly impact systemic exposure of ziconotide.
5.3 Preclinical safety data
Preclinical toxic effects related to ziconotide administration were observed only at exposures
considered sufficiently in excess of the human exposure to indicate little risk in clinical use.
In subchronic continuous intrathecal infusion studies in rats and dogs, behavioural effects were seen at
doses ≥ 8-fold the maximum recommended clinical intrathecal infusion dose of 21.6 μg/day (on a
mg/kg basis). These effects were defined by exaggerated pharmacological actions of ziconotide and
not by neurotoxic lesions or target organ toxicity. Observations included transient and reversible
neurological effects consisting of tremors, uncoordinated movements and hyper- and hypoactivity.
The long-term consequences to neuronal function of continuous N-type calcium-channel block have
not been demonstrated in experimental animals. Changes in neurological signalling have not been
studied in experimental animals. Ziconotide did not induce bacterial gene mutation and was not
24
genotoxic. Chronic animal studies have not been performed to assess the carcinogenic potential of
ziconotide. However, ziconotide did not induce cell transformation in the
in vitro
Syrian hamster
embryo (SHE) assay and did not increase cell proliferation (pre-neoplastic lesion formation) or
apoptosis after subchronic intrathecal exposure in dogs.
In rat fertility studies, there were no effects in males while reductions in corpora lutea; implantation
sites and number of live embryos were observed in females. No adverse effects on female
reproduction and post-natal development in rats were seen at systemic exposures up to 2,300 times
human exposures at the maximum recommended intrathecal dose.
Ziconotide was not teratogenic in rats and rabbits at exposures < 100 times human plasma levels.
These results do not indicate a significant risk to humans due to the relatively high systemic exposures
needed to elicit these effects in rats and rabbits.
6.
6.1 List of excipients
Methionine
Sodium chloride
Water for injections
Hydrochloric acid (pH adjuster)
Sodium hydroxide (pH adjuster)
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
3 years
Chemical and physical in use stability has been demonstrated for 60 days at 37°C.
From a microbiological point of view, if the product is diluted it should be transferred to the infusion
pump 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°C – 8°C, unless dilution
has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vial in the outer carton in order to protect
from light.
For storage conditions of the diluted medicinal product, see section 6.3.
25
6.5 Nature and contents of container
Single-use Type I glass vials with butyl rubber stoppers coated with fluorinated polymer.
Each vial contains 1, 2 or 5 ml solution for infusion.
One vial per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
If dilution is required, Prialt must be diluted aseptically with preservative-free sodium chloride
9 mg/ml (0.9%) solution for injection before use. The concentration of the solution used in the
infusion pump must be no lower than 5 μg/ml ziconotide in an external pump and 25 μg/ml in an
internal pump.
Strict aseptic procedures must be used during the preparation and handling of the solution for infusion
and refilling of the pump. The patient and health-care providers must be familiar with the handling of
the external or internal infusion system and be aware of the need to guard against infection.
Prialt has been shown to be chemically and physically compatible with the implantable Synchromed
pump and the external CADD-Micro pump at the concentration levels indicated above. Chemical and
physical in-use stability has been demonstrated for 14 days at 37ºC in the Synchromed pump when the
pump has not previously been exposed to the medicinal product. The initial fill must therefore be
replaced after 14 days.
Prialt was stable for 60 days at 37°C in the Synchromed pump previously exposed to the medicinal
product. Stability has been demonstrated for 21 days at room temperature in the CADD-Micro pump.
Specific instructions for using the pumps must be obtained from the manufacturer. CE marked pumps
equivalent to the Synchromed and CADD-Micro pump should be used to deliver Prialt. Pumps
previously used to deliver other medicinal products must be washed out three times with sodium
chloride 9 mg/ml (0.9%) solution for injection (preservative-free) before being filled with Prialt. The
introduction of air into the pump reservoir or cartridge should be minimized, as oxygen can degrade
ziconotide.
Prior to initiation of therapy, an internal pump must be rinsed three times with 2 ml of Prialt at
25 μg/ml. The concentration of Prialt in a naïve pump may be reduced due to adsorption onto the
surfaces of the device, and/or dilution by the residual space of the device. Because of this, after the
first use of Prialt, the reservoir should be emptied and refilled after 14 days. Subsequently the pump
should be emptied and refilled every 60 days.
Prialt is a clear and colourless solution. It should be inspected visually for particulate matter and
discolouration prior to administration. The solution should not be used if discoloured or cloudy or if
particulate matter is observed.
For single use only. Any unused solution should be discarded according to local regulations.
7.
Eisai Ltd.,
European Knowledge Centre
Mosquito Way
Hatfield
26
Herts
AL10 9SN
United Kingdom
8.
EU/1/04/302/001 – 1 ml solution for infusion.
EU/1/04/302/002 – 2 ml solution for infusion.
EU/1/04/302/003 – 5 ml solution for infusion.
9.
Date of first authorisation: 21/02/2005
Date of latest renewal: 12/01/2010
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA) www.emea.europa.eu
27
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
28
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Eisai Manufacturing Limited
European Knowledge Centre
Mosquito Way
Hatfield
Herts
AL10 9SN
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2.)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
The MAH will continue to submit yearly PSURs, unless otherwise specified by the CHMP.
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of studies within the
specified time frame, the results of which shall form the basis of the annual reassessment of the
benefit/risk profile.
Clinical aspects
A post-marketing registry study (PRIME) – will be performed. This will be an open-label
registry, which will provide long-term efficacy and safety data for IT ziconotide given to
patients experiencing severe, chronic malignant and non-malignant pain. Analyses of patient
outcomes by pain aetiology (malignant, non-malignant), pain mechanism (neuropathic, non-
neuropathic), and pain severity (VASPI score above or below 50 mm at baseline) will be
conducted. The registry will help to define the use of ziconotide in the clinical setting e.g.
optimal dosing regimen, the possible development of tolerance. The use of ziconotide in
combination with morphine or baclofen, rescue medication, the evaluation of health related
quality of life, and the analysis of adverse events will also be taken into account. Enrollment
into the registry will continue until at least 150 patients have received Prialt. The MAH should
provide annual updates of the enrollment of patients in the PRIME registry at the time of the
annual re-assessment and interim analysis as well. This study commenced in March 2008.
The MAH should submit the final study report to the CHMP and consider the need for a
submission of a variation to the SPC for any significant results arising from this study.
29
ANNEX III
LABELLING AND PACKAGE LEAFLET
30
A. LABELLING
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Prialt 25 micrograms/ml solution for infusion
ziconotide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml contains 25 micrograms ziconotide (as acetate), (500 micrograms per vial)
3.
LIST OF EXCIPIENTS
methionine, sodium chloride, water for injections, hydrochloric acid and sodium hydroxide.
4.
Solution for infusion.
1 vial of 20 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intrathecal use only
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
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial in the outer carton in order to protect
from light.
32
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Eisai Ltd.
Mosquito Way
Hatfield
Herts
AL10 9SN
United Kingdom
EU/1/04/302/004
13. BATCH NUMBER
Lot
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
33
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
Prialt 25 μg/ml
Intrathecal infusion
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
20 ml
6.
OTHER
34
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Prialt 100 micrograms/ml solution for infusion
ziconotide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml:
Each ml contains 100 micrograms ziconotide (as acetate), (100 micrograms per vial)
2 ml:
Each ml contains 100 micrograms ziconotide (as acetate), (200 micrograms per vial)
5 ml:
Each ml contains 100 micrograms ziconotide (as acetate), (500 micrograms per vial)
3.
LIST OF EXCIPIENTS
methionine, sodium chloride, water for injections, hydrochloric acid and sodium hydroxide.
4.
Solution for infusion.
1 ml:
1 vial of 1 ml
2 ml:
1 vial of 2 ml
5 ml:
1 vial of 5 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intrathecal use only
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.
35
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial in the outer carton in order to protect
from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Eisai Ltd.
Mosquito Way
Hatfield
Herts
AL10 9SN
United Kingdom
1 ml:
EU/1/04/302/001
2 ml:
EU/1/04/302/002
5 ml:
EU/1/04/302/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
36
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
37
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
Prialt 100 μg/ml
Intrathecal infusion
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 ml:
1 ml
2 ml:
2 ml
5 ml:
5 ml
6.
OTHER
38
B. PACKAGE LEAFLET
39
PACKAGE LEAFLET: INFORMATION FOR THE USER
Prialt 25 micrograms/ml solution for infusion
Ziconotide
Read all of this leaflet carefully before you start using this medicine.
-
If you have any further questions, ask your doctor.
-
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.
In this leaflet
:
1.
What Prialt is and what it is used for
3.
How to use Prialt
4.
Possible side effects
5.
How to store Prialt
6.
Further information
1.
WHAT PRIALT IS AND WHAT IT IS USED FOR
Prialt belongs to a group of medicines, called analgesics or ‘painkillers’. Prialt is used for the
treatment of long-term pain when your existing treatment is not effective or causes severe side effects.
2.
BEFORE YOU USE PRIALT
Do not use Prialt
-
If you are allergic (hypersensitive) to ziconotide or any of the other ingredients of Prialt.
Take special care with Prialt
-
The effects of long-term treatment of Prialt are uncertain at this time and the possibility of toxic
effects on the spinal cord have not yet been ruled out. In case of a need for long term treatment,
monitoring may be necessary (as decided by your doctor).
-
If you are receiving Prialt via a pump worn outside your body, it is important you check once
daily for any signs of infection at the point where the tube enters your body.
-
If you observe any signs of infection around the tube, such as skin redness, swelling, pain or
discharge, you must tell your doctor immediately and seek treatment for the infection.
-
If you develop any tenderness in the area around the tube without signs of infection, you should
seek advice from your doctor as soon as possible as tenderness may be an early sign of
infection.
-
If you are receiving Prialt via a pump worn outside your body and any part of the infusion
tubing becomes disconnected, you must contact your doctor immediately.
-
If you have any of the following symptoms: high temperature, headache, stiff neck, tiredness,
confusion, feeling sick, vomiting or occasional fits, these may be signs of meningitis. You must
tell your doctor immediately if you experience any of the above symptoms.
-
If you notice any adverse change in your thinking, mood or memory, please tell your doctor.
-
You may have an increased level of an enzyme called creatine kinase in your blood and
although this does not usually cause any symptoms or problems, your doctor is likely to monitor
its level. In addition, you may also occasionally experience muscular problems. If such is the
40
-
Keep this leaflet. You may need to read it again.
2.
Before you use Prialt
-
If you are receiving an anticancer medicine into the space around your spinal cord.
-
If you are receiving chemotherapy please tell your doctor.
-
Severe allergic reactions have not been seen in clinical studies so far, however it is not yet
possible to say for certain that a severe allergic reaction will not happen when you are given
Prialt. You should tell your doctor immediately if you experience any of the following
symptoms after receiving your treatment; sudden wheeziness, difficulty in breathing, pain in the
chest, swelling of eyelids, face or lips, rash or itching (especially affecting the whole body).
-
In patients that suffer from severe long term pain, there is a higher likelihood of suicide and
attempted suicide than in the general population.
Prialt may also cause or worsen depression in
people that are already susceptible.
-
You may experience drowsiness or may not be fully aware of your surroundings whilst
receiving treatment. If this happens, you should immediately notify your doctor, as he/she may
decide to halt your Prialt treatment.
-
Not recommended for use in children and adolescents.
Taking other medicines
Please tell your doctor if you are taking or have recently taken any other medicines (for example,
baclofen, clonidine, bupivacaine or propofol), including medicines obtained without a prescription.
You may feel drowsy if you are given Prialt with certain other medicines used to treat pain.
Pregnancy and breast-feeding
If you are pregnant, think you may be pregnant, or are breast-feeding ask your doctor for advice before
taking any medicine.
Prialt should not be used during pregnancy or breast-feeding unless clearly necessary.
Driving and using machines
The use of Prialt has been reported to cause confusion and drowsiness. Ask your doctor for advice
before you drive or operate machinery.
3.
HOW TO USE PRIALT
Your treatment with Prialt will be managed by a doctor who has experience of giving medicines into
the space around the spinal cord, and in the use of internal and external infusion pumps.
Prialt is given as a very slow continuous injection into the space surrounding the spinal cord. The
medicine will be administered continuously from a pump either implanted into your abdominal wall or
placed externally in a belt pouch. Your doctor will discuss with you the kind of pump that will be
most suitable for you and when you need to have your pump refilled.
The recommended starting dose is no more than 2.4 micrograms per day. Your doctor will adjust the
dose of Prialt according to the severity of your pain in dose increments of ≤ 2.4 micrograms/day. The
maximum dose is 21.6 micrograms/day. At the start of your treatment your doctor may increase your
dose every 1 to 2 days or more. If needed, the dose may be decreased or injection stopped if the side
effects are too great.
If you feel that you are still in too much pain while taking Prialt, or that the side effects are too great,
talk to your doctor.
Before giving you Prialt, your doctor might decide to slowly stop giving you opiates (other types of
medicinal product which are used to treat pain) into your spinal cord and instead replace with
alternative pain medicinal products.
If you use more Prialt than you should
41
case, you should immediately notify your doctor, as he/she may decide to halt your Prialt
treatment.
If you receive more Prialt than your doctor intended, you may feel unwell with signs such as
confusion, problems with speech, word finding difficulties, excessive shaking, light-headedness,
excessive sleepiness, feeling or being sick. If this happens, consult your doctor or hospital
immediately.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Prialt can cause side effects, although not everybody gets them.
The frequency of possible side effects listed below is defined using the following convention:
Very common (affects more than 1 user in 10)
Common (affects 1 to 10 users in 100)
Uncommon (affects 1 to 10 users in 1,000)
Very common
:
Confusion, dizziness, blurred vision, headache, rapid back-and-forth movement of the eyes, loss or
impairment of memory (forgetfulness), difficulty walking, vomiting, nausea, general weakness and
drowsiness.
Common
: Decreased appetite, anxiety or worsened anxiety, hallucinations, inability to fall or stay
asleep, agitation, disorientation, depression or worsened depression, nervousness, mood swings,
mental status changes (thinking abnormal, confusion), paranoia, irritability, worsened confusion,
difficulty with learning, memory or thinking, reflexes absent or impaired, problems expressing or
understanding words, slurred speech, difficulty with speech or loss of ability to speak, sluggishness,
balance or coordination impaired, burning sensation, increased pain sensitivity, reduced level of
consciousness (unresponsive or almost unconscious), sedation, difficulty in concentrating, problems
with the sense of smell, odd or no sense of taste, shaking, pins and needles, double vision, visual
disturbance, intolerance to light, tinnitus (ringing in the ears), dizziness or spinning sensation,
lightheadedness or dizziness when standing, low blood pressure, shortness of breath, dry mouth,
abdominal pain, worsened nausea, diarrhoea, constipation, sweating, itching, muscle weakness, muscle
spasms, muscle cramp, muscle or joint pain, difficult or painful urination, difficulty starting or
controlling urination, feeling jittery, falling, pain or pain exacerbated, fatigue, feeling cold, swelling of
the face, legs or feet, chest pain, fever, blood chemistry changes, mental impairment and weight
decreased.
Uncommon
Infection of the blood stream, meningitis, delirium (feeling of mental confusion), psychotic disorder
(abnormal thinking and perceptions), suicidal thought or attempt, thought disorders, abnormal dreams,
incoherence (inability to make sense), loss of consciousness, coma, stupor (unresponsive/difficult to
arouse), convulsions (fits), stroke, encephalopathy (brain disorder), abnormal heart rhythm, difficulty
breathing, indigestion,
rash, muscle breakdown (rhabdomyolysis), muscle inflammation, back pain,
muscle twitching, neck pain, acute kidney failure, abnormal heart trace measurements (ECG), raised
body temperature.
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 pharmacist.
5.
HOW TO STORE PRIALT
Keep out of the reach and sight of children.
Do not use Prialt after the expiry date stated on the label and carton after EXP. The expiry date refers
to the last day of that month.
Store unopened vial in refrigerator (2°C – 8°C).
42
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
Chemical and physical in use stability has been demonstrated for 60 days at 37°C.
From a microbiological point of view, if the product is diluted it should be transferred to the infusion
pump 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°C – 8°C, unless dilution
has taken place in controlled and validated aseptic conditions.
6.
FURTHER INFORMATION
What Prialt contains
-
The active substance is ziconotide. One ml solution contains 25 micrograms ziconotide (as
acetate). One vial of 20 ml contains 500 micrograms.
-
The other ingredients are methionine, sodium chloride, water for injections, hydrochloric acid
and sodium hydroxide.
What Prialt looks like and contents of the pack
Prialt is a solution for infusion. The solution is clear and colourless. Prialt is supplied in packs
containing a single vial of 20 ml.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Eisai Ltd.
Mosquito Way
Herts
AL10 9SN
United Kingdom
Manufacturer:
Eisai Manufacturing Limited
Mosquito Way
Herts
AL10 9SN
United Kingdom
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Eisai Europe Ltd.
Tél/Tel: + 32 (0) 2 735 45 34
Luxembourg/Luxemburg
Eisai Europe Ltd.
Tél/Tel: + 32 (0) 2 735 45 34
(Belgique/Belgien)
България
Eisai Ltd.
Teл.: + 44 208 600 1400
(Великобритания (Обединеното кралство))
Magyarország
Eisai GesmbH
Tel.: + 36 1 230 43 20
43
Hatfield
Hatfield
Česká republika
Eisai GesmbH organizační složka
Tel: + 420 242 485 839
Malta
Associated Drug Company Ltd
Tel: +356 (0) 227 780 00
Danmark
NordicInfu Care
Tlf: + 46 (0)8 601 24 40
(Sverige)
Nederland
Eisai Europe Ltd.
Tel: + 32 (0) 2 735 45 34
(België/Belgique)
Deutschland
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
Norge
NordicInfu Care
Tlf: + 46 (0)8 601 24 40
(Sverige)
Eesti
Eisai Ltd.
Tel: + 44 208 600 1400
(Ühendkuningriik)
Österreich
Eisai GesmbH
Tel: + 43 (0) 1 535 1980-0
Ελλάδα
Arriani Pharmaceuticals S.A.
Τηλ: +30 210 668 3000
Polska
Eisai Ltd.
Tel.: + 44 208 600 1400
(Wielka Brytania)
España
Eisai Farmacéutica, S.A.
Tel: +(34) 91 455 94 55
Portugal
Eisai Farmacêutica,
Unipessoal Lda
Tel: + 351 214 875 540
France
Eisai SAS
Tél: + (33) 1 47 67 00 05
România
Eisai Ltd.
Tel: + 44 208 600 1400
(Marea Britanie)
Ireland
Eisai Ltd.
Tel: + 44 208 600 1400
(United Kingdom)
Slovenija
Eisai Ltd.
Tel: + 44 208 600 1400
(Velika Britanija)
Ísland
NordicInfu Care
Sími: + 46 (0)8 601 24 40
(Svíþjóð)
Slovenská republika
Eisai GesmbH organizační složka
Tel: + 420 242 485 839
(Česká republika)
Italia
Eisai S.r.l.
Tel: + 39 02 5181401
Suomi/Finland
NordicInfu Care
Puh/Tel: + 46 (0)8 601 24 40
(Ruotsi/Sverige)
Κύπρος
Arriani Pharmaceuticals S.A.
Τηλ: +30 210 668 3000
Sverige
NordicInfu Care
Tel: + 46 (0)8 601 24 40
44
Latvija
Eisai Ltd.
Tel: + 44 208 600 1400
(Lielbritānija)
United Kingdom
Eisai Ltd.
Tel: 0208 600 1400
Lietuva
Eisai Ltd.
Tel. + 44 208 600 1400
(Jungtinė Karalystė)
This leaflet was last approved in {MM/YYY}.
This medicine has been authorised under “Exceptional Circumstances”. This means that because of the
rarity of the disease it has been impossible to get complete information on this medicine. The European
Medicines Agency (EMEA) will review any new information on the medicine every year and this leaflet
will be updated as necessary.
Detailed information on this medicine is available on the European Medicines Agency (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:
Instructions for use and handling
Prialt is supplied as a clear, colourless solution in single use vials. It should be inspected visually for
particulate matter and discolouration prior to administration. The solution should not be used if
discoloured or cloudy or if particulate matter is observed.
For single use only. Any unused solution should be discarded according to local regulations.
If dilution is required, Prialt must be diluted aseptically with preservative-free sodium chloride
9 mg/ml (0.9%) solution for injection before use. The concentration of the solution used in the
infusion pump must be no lower than 5 μg/ml ziconotide in an external pump and 25 μg/ml in an
internal pump.
Strict aseptic procedures must be used during the preparation and handling of the solution for infusion
and refilling of the pump. The patient and health-care providers must be familiar with the handling of
the external or internal infusion system and be aware of the need to guard against infection.
Prialt has been shown to be chemically and physically compatible with the implantable Synchromed
pump and the external CADD-Micro pump at the concentration levels indicated above. Chemical and
physical in-use stability has been demonstrated for 14 days at 37ºC in the Synchromed pump when the
pump has not previously been exposed to the medicinal product. The initial fill must therefore be
replaced after 14 days.
Prialt was stable for 60 days at 37°C in the Synchromed pump previously exposed to the medicinal
product. Stability has been demonstrated for 21 days at room temperature in the CADD-Micro pump.
Specific instructions for using the pumps must be obtained from the manufacturer. CE marked pumps
equivalent to the Synchromed and CADD-Micro pump should be used to deliver ziconotide. Pumps
previously used to deliver other medicinal products must be washed out three times with sodium
chloride 9 mg/ml (0.9%) solution for injection (preservative-free) before being filled with ziconotide.
The introduction of air into the pump reservoir or cartridge should be minimized, as oxygen can
degrade ziconotide.
45
Prior to initiation of therapy, an internal pump must be rinsed three times with 2 ml of the solution at
25 μg/ml. The concentration of Prialt in a naïve pump may be reduced due to adsorption onto the
surfaces of the device, and/or dilution by the residual space of the device. Because of this, after the
first use of Prialt, the reservoir should be emptied and refilled after 14 days. Subsequently the pump
should be emptied and refilled every 60 days.
46
PACKAGE LEAFLET: INFORMATION FOR THE USER
Prialt 100 micrograms/ml solution for infusion
Ziconotide
Read all of this leaflet carefully before you start using this medicine.
-
If you have any further questions, please ask your doctor.
-
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.
In this leaflet
1.
What Prialt is and what it is used for
3.
How to use Prialt
4.
Possible side effects
5.
How to store Prialt
6.
Further information
1.
WHAT PRIALT IS AND WHAT IT IS USED FOR
Prialt belongs to a group of medicines, called analgesics or ‘painkillers’. Prialt is used for the
treatment of long-term pain when your existing treatment is not effective or causes severe side effects.
2.
BEFORE YOU USE PRIALT
Do not use Prialt
-
If you are allergic (hypersensitive) to ziconotide or any of the other ingredients of Prialt.
Take special care with Prialt
-
The effects of long-term treatment of Prialt are uncertain at this time and the possibility of toxic
effects on the spinal cord have not yet been ruled out. In case of a need for long term treatment,
monitoring may be necessary (as decided by your doctor).
-
If you are receiving Prialt via a pump worn outside your body, it is important you check once
daily for any signs of infection at the point where the tube enters your body.
-
If you observe any signs of infection around the tube, such as skin redness, swelling, pain or
discharge, you must tell your doctor immediately and seek treatment for the infection.
-
If you develop any tenderness in the area around the tube without signs of infection, you should
seek advice from your doctor as soon as possible as tenderness may be an early sign of
infection.
-
If you are receiving Prialt via a pump worn outside your body and any part of the infusion
tubing becomes disconnected, you must contact your doctor immediately.
-
If you have any of the following symptoms: high temperature, headache, stiff neck, tiredness,
confusion, feeling sick, vomiting or occasional fits, these may be signs of meningitis. You must
tell your doctor immediately if you experience any of the above symptoms.
-
If you notice any adverse change in your thinking, mood or memory, please tell your doctor.
-
If you are receiving chemotherapy please tell your doctor.
-
You may have an increased level of an enzyme called creatine kinase in your blood and
although this does not usually cause any symptoms or problems, your doctor is likely to monitor
its level. In addition, you may also occasionally experience muscular problems. If such is the
47
-
Keep this leaflet. You may need to read it again.
2.
Before you use Prialt
-
If you are receiving an anticancer medicine into the space around your spinal cord.
-
Severe allergic reactions have not been seen in clinical studies so far, however it is not yet
possible to say for certain that a severe allergic reaction will not happen when you are given
Prialt. You should tell your doctor immediately if you experience any of the following
symptoms after receiving your treatment; sudden wheeziness, difficulty in breathing, pain in the
chest, swelling of eyelids, face or lips, rash or itching (especially affecting the whole body).
-
In patients that suffer from severe long term pain, there is a higher likelihood of suicide and
attempted suicide than in the general population.
Prialt may also cause or worsen depression in
people that are already susceptible.
-
You may experience drowsiness or may not be fully aware of your surroundings whilst
receiving treatment. If this happens, you should immediately notify your doctor, as he/she may
decide to halt your Prialt treatment.
-
Not recommended for use in children and adolescents.
Taking other medicines
Please tell your doctor if you are taking or have recently taken any other medicines (for example,
baclofen, clonidine, bupivacaine or propofol), including medicines obtained without a prescription.
You may feel drowsy if you are given Prialt with certain other medicines used to treat pain.
Pregnancy and breast-feeding
If you are pregnant, think you may be pregnant, or are breast-feeding ask your doctor for advice before
taking any medicine.
Prialt should not be used during pregnancy or breast-feeding unless clearly necessary.
Driving and using machines
The use of Prialt has been reported to cause confusion and drowsiness. Ask your doctor for advice
before you drive or operate machinery.
3.
HOW TO USE PRIALT
Your treatment with Prialt will be managed by a doctor who has experience of giving medicines into
the space around the spinal cord, and in the use of internal and external infusion pumps.
Prialt is given as a very slow continuous injection into the space surrounding the spinal cord. The
medicine will be administered continuously from a pump either implanted into your abdominal wall or
placed externally in a belt pouch. Your doctor will discuss with you the kind of pump that will be
most suitable for you and when you need to have your pump refilled.
The recommended starting dose is no more than 2.4 micrograms per day. Your doctor will adjust the
dose of Prialt according to the severity of your pain in dose increments of ≤ 2.4 micrograms/day. The
maximum dose is 21.6 micrograms/day. At the start of your treatment your doctor may increase your
dose every 1 to 2 days or more. If needed, the dose may be decreased or injection stopped if the side
effects are too great.
If you feel that you are still in too much pain while taking Prialt, or that the side effects are too great,
talk to your doctor.
Before giving you Prialt, your doctor might decide to slowly stop giving you opiates (other types of
medicinal product which are used to treat pain) into your spinal cord and instead replace with
alternative pain medicinal products.
If you use more Prialt than you should
If you receive more Prialt than your doctor intended, you may feel unwell with signs such as
confusion, problems with speech, word finding difficulties, excessive shaking, light-headedness,
48
case, you should immediately notify your doctor, as he/she may decide to halt your Prialt
treatment.
excessive sleepiness, feeling or being sick. If this happens, consult your doctor or hospital
immediately.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Prialt can cause side effects, although not everybody gets them.
The frequency of possible side effects listed below is defined using the following convention:
Very common (affects more than 1 user in 10)
Common (affects 1 to 10 users in 100)
Uncommon (affects 1 to 10 users in 1,000)
Very common
:
Confusion, dizziness, blurred vision, headache, rapid back-and-forth movement of the eyes, loss or
impairment of memory (forgetfulness), difficulty walking, vomiting, nausea, general weakness and
drowsiness.
Common
:
Decreased appetite, anxiety or worsened anxiety, hallucinations, inability to fall or stay asleep,
agitation, disorientation, depression or worsened depression, nervousness, mood swings, mental status
changes (thinking abnormal, confusion), paranoia, irritability, worsened confusion, difficulty with
learning, memory or thinking, reflexes absent or impaired, problems expressing or understanding
words, slurred speech, difficulty with speech or loss of ability to speak, sluggishness, balance or
coordination impaired, burning sensation, increased pain sensitivity, reduced level of consciousness
(unresponsive or almost unconscious), sedation, difficulty in concentrating, problems with the sense of
smell, odd or no sense of taste, shaking, pins and needles, double vision, visual disturbance,
intolerance to light, tinnitus (ringing in the ears), dizziness or spinning sensation, lightheadedness or
dizziness when standing, low blood pressure, shortness of breath, dry mouth, abdominal pain,
worsened nausea, diarrhoea, constipation, sweating, itching, muscle weakness, muscle spasms, muscle
cramp, muscle or joint pain, difficult or painful urination, difficulty starting or controlling urination,
feeling jittery, falling, pain or pain exacerbated, fatigue, feeling cold, swelling of the face, legs or feet,
chest pain, fever, blood chemistry changes, mental impairment and weight decreased.
Uncommon
Infection of the blood stream, meningitis, delirium (feeling of mental confusion), psychotic disorder
(abnormal thinking and perceptions), suicidal thought or attempt, thought disorders, abnormal dreams,
incoherence (inability to make sense), loss of consciousness, coma, stupor (unresponsive/difficult to
arouse), convulsions (fits), stroke, encephalopathy (brain disorder), abnormal heart rhythm, difficulty
breathing, indigestion,
rash, muscle breakdown (rhabdomyolysis), muscle inflammation, back pain,
muscle twitching, neck pain, acute kidney failure, abnormal heart trace measurements (ECG), raised
body temperature.
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 pharmacist.
5.
HOW TO STORE PRIALT
Keep out of the reach and sight of children.
Do not use Prialt after the expiry date stated on the label and carton after EXP. The expiry date refers
to the last day of that month.
Store unopened vial in refrigerator (2°C – 8°C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
49
Chemical and physical in use stability has been demonstrated for 60 days at 37°C.
From a microbiological point of view, if the product is diluted it should be transferred to the infusion
pump 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°C – 8°C, unless dilution
has taken place in controlled and validated aseptic conditions.
6.
FURTHER INFORMATION
What Prialt contains
-
The active substance is ziconotide.
-
One ml solution contains 100 micrograms ziconotide (as acetate).
-
One vial of 1 ml contains 100 micrograms; one vial of 2 ml contains 200 micrograms; one vial
of 5 ml contains 500 micrograms.
-
The other ingredients are methionine, sodium chloride, water for injections, hydrochloric acid
and sodium hydroxide.
What Prialt looks like and contents of the pack
Prialt is a solution for infusion. The solution is clear and colourless. Prialt is supplied in packs
containing a single vial of either 1 ml, 2 ml or 5 ml. Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Eisai Ltd.
Mosquito Way
Herts
AL10 9SN
United Kingdom
Manufacturer:
Eisai Manufacturing Limited
Mosquito Way
Herts
AL10 9SN
United Kingdom
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Eisai Europe Ltd.
Tél/Tel: + 32 (0) 2 735 45 34
Luxembourg/Luxemburg
Eisai Europe Ltd.
Tél/Tel: + 32 (0) 2 735 45 34
(Belgique/Belgien)
България
Eisai Ltd.
Teл.: + 44 208 600 1400
(Великобритания (Обединеното кралство))
Magyarország
Eisai GesmbH
Tel.: + 36 1 230 43 20
50
Hatfield
Hatfield
Česká republika
Eisai GesmbH organizační složka
Tel: + 420 242 485 839
Malta
Associated Drug Company Ltd
Tel: +356 (0) 227 780 00
Danmark
NordicInfu Care
Tlf: + 46 (0)8 601 24 40
(Sverige)
Nederland
Eisai Europe Ltd.
Tel: + 32 (0) 2 735 45 34
(België/Belgique)
Deutschland
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
Norge
NordicInfu Care
Tlf: + 46 (0)8 601 24 40
(Sverige)
Eesti
Eisai Ltd.
Tel: + 44 208 600 1400
(Ühendkuningriik)
Österreich
Eisai GesmbH
Tel: + 43 (0) 1 535 1980-0
Ελλάδα
Arriani Pharmaceuticals S.A.
Τηλ: +30 210 668 3000
Polska
Eisai Ltd.
Tel.: + 44 208 600 1400
(Wielka Brytania)
España
Eisai Farmacéutica, S.A.
Tel: +(34) 91 455 94 55
Portugal
Eisai Farmacêutica,
Unipessoal Lda
Tel: + 351 214 875 540
France
Eisai SAS
Tél: + (33) 1 47 67 00 05
România
Eisai Ltd.
Tel: + 44 208 600 1400
(Marea Britanie)
Ireland
Eisai Ltd.
Tel: + 44 208 600 1400
(United Kingdom)
Slovenija
Eisai Ltd.
Tel: + 44 208 600 1400
(Velika Britanija)
Ísland
NordicInfu Care
Sími: + 46 (0)8 601 24 40
(Svíþjóð)
Slovenská republika
Eisai GesmbH organizační složka
Tel: + 420 242 485 839
(Česká republika)
Italia
Eisai S.r.l.
Tel: + 39 02 5181401
Suomi/Finland
NordicInfu Care
Puh/Tel: + 46 (0)8 601 24 40
(Ruotsi/Sverige)
Κύπρος
Arriani Pharmaceuticals S.A.
Τηλ: +30 210 668 3000
Sverige
NordicInfu Care
Tel: + 46 (0)8 601 24 40
51
Latvija
Eisai Ltd.
Tel: + 44 208 600 1400
(Lielbritānija)
United Kingdom
Eisai Ltd.
Tel: 0208 600 1400
Lietuva
Eisai Ltd.
Tel. + 44 208 600 1400
(Jungtinė Karalystė)
This leaflet was last approved in {MM/YYY}.
This medicine has been authorised under “Exceptional Circumstances”. This means that because of the
rarity of the disease it has been impossible to get complete information on this medicine. The European
Medicines Agency (EMEA) will review any new information on the medicine every year and this leaflet
will be updated as necessary.
Detailed information on this medicine is available on the European Medicines Agency (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:
Instructions for use and handling
Prialt is supplied as a clear, colourless solution in single use vials. It should be inspected visually for
particulate matter and discolouration prior to administration. The solution should not be used if
discoloured or cloudy or if particulate matter is observed.
For single use only. Any unused solution should be discarded according to local regulations.
If dilution is required, Prialt must be diluted aseptically with preservative-free sodium chloride
9 mg/ml (0.9%) solution for injection before use. The concentration of the solution used in the
infusion pump must be no lower than 5 μg/ml ziconotide in an external pump and 25 μg/ml in an
internal pump.
Strict aseptic procedures must be used during the preparation and handling of the solution for infusion
and refilling of the pump. The patient and health-care providers must be familiar with the handling of
the external or internal infusion system and be aware of the need to guard against infection.
Prialt has been shown to be chemically and physically compatible with the implantable Synchromed
pump and the external CADD-Micro pump at the concentration levels indicated above. Chemical and
physical in-use stability has been demonstrated for 14 days at 37ºC in the Synchromed pump when the
pump has not previously been exposed to the medicinal product. The initial fill must therefore be
replaced after 14 days.
Prialt was stable for 60 days at 37°C in the Synchromed pump previously exposed to the medicinal
product. Stability has been demonstrated for 21 days at room temperature in the CADD-Micro pump.
Specific instructions for using the pumps must be obtained from the manufacturer. CE marked pumps
equivalent to the Synchromed and CADD-Micro pump should be used to deliver ziconotide. Pumps
previously used to deliver other medicinal products must be washed out three times with sodium
chloride 9 mg/ml (0.9%) solution for injection (preservative-free) before being filled with ziconotide.
The introduction of air into the pump reservoir or cartridge should be minimized, as oxygen can
degrade ziconotide.
52
Prior to initiation of therapy, an internal pump must be rinsed three times with 2 ml of the solution at
25 μg/ml. The concentration of Prialt in a naïve pump may be reduced due to adsorption onto the
surfaces of the device, and/or dilution by the residual space of the device. Because of this, after the
first use of Prialt, the reservoir should be emptied and refilled after 14 days. Subsequently the pump
should be emptied and refilled every 60 days.
53
Source: European Medicines Agency
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