PRIALT 25mcg / ml infusion solution medication leaflet

Prialt 25 micrograms/ml solution for infusion

One ml solution contains 25 μg ziconotide (as acetate).

Each 20 ml vial contains 500 μg ziconotide (as acetate).

For the full list of excipients, see section 6.1.

Solution for infusion (infusion).

Clear, colourless solution.

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 basisaccording to the patient’s analgesic response and adverse reactions. Patients should be titrated in doseincrements of ≤ 2.4 μg/day, up to a maximum dose of 21.6 μg/day. The minimal interval betweendose increases is 24 hours; the recommended interval, for safety reasons, is 48 hours or more. Ifnecessary the dose can be decreased by any amount (including stopping the infusion) for themanagement of adverse reactions. Approximately 75% of patients who respond satisfactorily totreatment require a dose of ≤ 9.6 μg/day.

Studies have not been conducted in patients with impaired renal function. Caution should be exercisedwhen ziconotide is administered to patients with impaired renal function.

Studies have not been conducted in patients with impaired hepatic function. Caution should beexercised when ziconotide is administered to patients with impaired hepatic function.

The safety and efficacy of ziconotide in children aged 0 to 18 years have not been established.

No data are available.

Intrathecal use.

Ziconotide must be administered as a continuous infusion via an intrathecal catheter, using an externalor 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 withan external catheter infusion system, internal systems are recommended to administer ziconotide forprolonged periods (see section 4.4). An external catheter system should only be used when an internalsystem cannot be implanted.

When low doses of ziconotide are required, for example when initiating titration, ziconotide must bediluted before use with preservative-free sodium chloride 9 mg/ml (0.9%) solution for injection.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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). Possiblelong-term local toxic effects on the spinal cord have not been excluded and preclinical data in thisrespect are limited (see section 5.3). Therefore, caution is needed during long-term treatment.

Risk of infection

The administration of medicinal products by the intrathecal (IT) route carries the risk of potentiallyserious infections, such as meningitis, which may be life threatening. Meningitis due to the entranceof organisms along the catheter track or inadvertent contamination of the infusion system is a knowncomplication 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 tipplacement, e.g. at the lumbar level, may reduce the incidence of ziconotide-related neurologicaladverse reactions. Therefore, catheter tip placement should be carefully considered to allow adequateaccess to spinal nociceptive segments whilst minimising medicinal product concentrations at cerebrallevels.

Only a small number of patients have received systemic chemotherapy and IT ziconotide. Cautionshould be exercised when ziconotide is administered to patients who are receiving systemicchemotherapy (see section 4.5).

Elevations in creatine kinase

Elevations in creatine kinase, which are usually asymptomatic, are common amongst patients onintrathecal ziconotide. Progressive elevation of the creatine kinase is uncommon. However,monitoring of creatine kinase is recommended. In the event of progressive elevation, or clinicallysignificant elevation in association with clinical features of myopathy or rhabdomyolysis,discontinuation of ziconotide should be considered.

Hypersensitivity reactions, including anaphylaxis, have not been observed during clinical trials and theimmunogenicity of ziconotide administered by the IT route appears to be low. However, the potentialfor severe allergic reactions cannot be excluded and spontaneous reports of anaphylactic reactionshave been received.

Cognitive and neuropsychiatric adverse reactions

Cognitive and neuropsychiatric adverse reactions, particularly confusion, are common in patientstreated with ziconotide. Cognitive impairment typically appears after several weeks of treatment.

Episodes of acute psychiatric disturbances, such as hallucinations, paranoid reactions, hostility,aggressiveness, delirium, psychosis and manic reactions have been reported in patients treated withziconotide. The ziconotide dose should be reduced or discontinued if signs or symptoms of cognitiveimpairment or neuropsychiatric adverse reactions develop, but other contributing causes should also beconsidered. The cognitive effects of ziconotide are typically reversible within 1 - 4 weeks afterdiscontinuation of the medicinal product, but may persist in some cases. It is recommended thatpatients undergo a neuropsychiatric evaluation before and after starting intrathecal ziconotide.

In patients with severe chronic pain there is a higher incidence of suicide and suicide attempts than inthe general population. Ziconotide may cause or worsen depression with the risk of suicide insusceptible patients.

Depression of Central Nervous System (CNS)

Patients have experienced depressed levels of consciousness while receiving ziconotide. The patientusually remains conscious and breathing is not depressed. The event may be self-limited, butziconotide should be discontinued until the event resolves. The re-introduction of ziconotide is notrecommended in these patients. Withdrawal of concomitant CNS depressant medicinal productsshould 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 relativelylow plasma protein binding (see section 5.2) make metabolic-based interactions or plasma proteindisplacement 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. Cautionshould be exercised when ziconotide is administered to patients who are receiving systemicchemotherapy (see section 4.4).

Medicinal products that affect specific peptidases/proteases would not be expected to impact uponziconotide plasma exposure. Based on very limited clinical investigations, both angiotensinconverting 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 ziconotidetherapy, opiate withdrawal should be gradual. For patients being withdrawn from IT opiates, the ITopiate infusion dose should be gradually tapered over a few weeks and replaced with apharmacologically equivalent dose of oral opiates. Adding IT ziconotide to stable doses of ITmorphine (see section 5.1), is possible but requires special attention, as a high rate of neuropsychiatricadverse reactions (confusion/thinking abnormal, paranoid reactions and hallucinations, and abnormalgait), some of them serious, was observed in Study 202 despite a low dose of ziconotide. Vomiting andanorexia, 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 beenreported) (see section 5.1).

An increased incidence of somnolence has been observed when ziconotide is administeredconcomitantly with systemic baclofen, clonidine, bupivacaine or propofol thus for the time being theirsimultaneous use is discouraged.

No data are available regarding the concomitant use of partial opioid agonists (e.g. buprenorphine)with ziconotide.

There are no or limited amount of data from the use of ziconotide in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Ziconotide is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

It is unknown whether ziconotide/metabolites are excreted in human milk.

A risk to newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain fromziconotide therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

No specific studies with ziconotide in humans have been conducted to evaluate effects on fertility. In astudy on male and female fertility in rats no effects in males while reductions in corpora lutea;implantation sites and number of live embryos were observed in females (see section 5.3).

Ziconotide has moderate influence on the ability to drive and use machines.

Ziconotide may cause confusion, somnolence and other neurological adverse reactions, thereforepatients 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 morethan 1,400 patients participating in acute and chronic pain clinical trials. The duration of treatment hasranged from one-hour bolus infusion to continuous use for more than 6 years. The median exposuretime was 43 days. The infusion dose rate ranged from 0.03 - 912 μg/day, with a median final dose rateof 7.2 μg/day.

In clinical trials, 88% of patients experienced adverse reactions. The most common adverse reactionsreported 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 adverse reactionswere mild to moderate in severity and resolved over time.

Unless otherwise noted the table shows the incidence rates of adverse reactions reported in theintrathecal clinical trials with ziconotide (short- and long-term exposure). Within each frequencygrouping undesirable effects are presented in order of decreasing frequency.

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1,000 to < 1/100)

Rare (≥ 1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

System Organ Very common Common Uncommon Not Known

Class

Infections and sepsis, meningitisinfestations

Immune system Anaphylacticdisorders reactiona

Metabolism and appetite decreased,nutrition anorexiadisorders

Psychiatric confusional anxiety, auditory delirium, psychoticdisorders state hallucination, disorder, suicidalinsomnia, agitation, ideation, suicidedisorientation, attempt, thoughthallucination, visual blocking, abnormalhallucination, dreams,depression, paranoia, aggressivenessirritability,depressionaggravated,nervousness, affectlability, mental statuschanges, anxietyaggravated,confusion aggravated

System Organ Very common Common Uncommon Not Known

Class

Nervous system dizziness, dysarthria, amnesia, incoherence, loss ofdisorders nystagmus, dysgeusia, tremor, consciousness,memory balance impaired, coma, stupor,impairment, ataxia, aphasia, convulsions,headache, burning sensation, cerebrovascularsomnolence sedation, accident,paraesthesia, encephalopathyhypoaesthesia,disturbance in attention, speech disorder,areflexia,coordination abnormal, dizziness postural,cognitive disorder,hyperaesthesia,hyporeflexia,ageusia, depressedlevel ofconsciousness,dysaesthesia,parosmia, mentalimpairment

Eye disorders vision blurred diplopia,visual disturbance,photophobia

Ear and vertigo, tinnituslabyrinthdisorders

Cardiac atrial fibrillationdisorders

Vascular orthostatic hypotensidisorders on, hypotension

Respiratory, dyspnoea respiratory distressthoracic andmediastinaldisorders

Gastrointestinal nausea, diarrhoea, dry mouth, dyspepsiadisorders vomiting constipation, nauseaaggravated, upperabdominal pain

Skin and pruritus, sweating rashsubcutaneous increasedtissue disorders

Musculoskeletal pain in limb, rhabdomyolysis,and connective myalgia, muscle myositis, back pain,tissue disorders spasms, muscle muscle twitching,cramp, muscle neck painweakness, arthralgia,peripheral swelling

System Organ Very common Common Uncommon Not Known

Class

Renal and urinary retention, acute renal failureurinary urinary hesitation,disorders dysuria, urinaryincontinence

General gait abnormal, fatigue, pyrexia, difficulty indisorders and asthenia lethargy, walkingadministration oedema peripheral,site conditions rigors, fall,chest pain, feelingcold, pain, feelingjittery, painexacerbated

Investigations blood electrocardiogramcreatine phosphokina abnormal, aspartatese increased, weight aminotransferasedecreased increased, bloodcreatinephosphokinase MMincreased, bodytemperatureincreased

a. From spontaneous reporting

Meningitis

Administration of medicinal products by the intrathecal route carries the risk of potential seriousinfections, such as meningitis, which may be life threatening. Patients and physicians must be vigilantfor typical symptoms and signs of meningitis (see section 4.4).

Elevations of creatine phosphokinase

Elevations in creatine phosphokinase were usually asymptomatic. Monitoring of creatinephosphokinase is recommended. Discontinuation of ziconotide should be considered in the event ofprogressive or significant elevation of creatine phosphokinase in association with clinical features ofmyopathy or rhabdomyolysis (see section 4.4).

CNS adverse reactions

Cognitive and neuropsychiatric adverse reactions are common in patients treated with ziconotide.

Cognitive impairment typically appears after several weeks of treatment. Episodes of acute psychiatricdisturbances, such as hallucinations, paranoid reactions, hostility, aggressiveness, delirium, psychosisand manic reactions have been reported in patients treated with ziconotide. The ziconotide dose shouldbe reduced or discontinued if signs or symptoms of cognitive impairment or neuropsychiatric adversereactions develop, but other contributing causes should also be considered. The cognitive effects ofziconotide are typically reversible within 1 - 4 weeks after discontinuation of the medicinal product,but may persist in some cases. It is recommended that patients undergo a neuropsychiatric evaluationbefore and after starting intrathecal ziconotide (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In intravenous infusion studies, healthy male volunteers received ziconotide at doses of upto70,000 μg/day or 3,200 times the maximum recommended daily intrathecal infusion dose. Posturalhypotension 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 doseof 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 μgover a 24-hour period (31 μg/hour) and resumed treatment at the intended dose after experiencing areduction in Visual Analog Scale of Pain Intensity (VASPI) from 82 to 2.5 mm. In some patients whoreceived intrathecal doses greater than the maximum recommended dose, exaggeratedpharmacological effects, e.g., ataxia, nystagmus, dizziness, stupor, depressed level of consciousness,muscle spasms, confusional state, sedation, hypotension, aphasia, speech disorder, nausea andvomiting were observed. There was no indication of respiratory depression. Most patients underobservation recovered within 24 hours of withdrawal of the medicinal product.

General medical supportive measures should be administered to patients who receive an overdose untilthe exaggerated pharmacological effects of the medicinal product have resolved.

Pharmacotherapeutic group: Analgesics, other analgesics and antipyretics, ATC code: N02BG08

Ziconotide is a synthetic analogue of a ω-conopeptide, MVIIA, found in the venom of the Conusmagus marine snail. It is an N-type calcium channel blocker (NCCB). NCCs regulateneurotransmitter 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 intoprimary 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 spinalsignalling of pain.

Though statistically significant relationships and reasonable correlation between cerebrospinal fluid(CSF) exposure (AUC, Cmax) and clinical response measures have been observed following 1 hour ITadministration, 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 anappropriate dose. However, maximal effects may be delayed for approximately 24 hours in somepatients. Given the occurrence of analgesia and adverse reactions at similar doses, the recommendedinterval between dose increases is 48 hours or more. If necessary the dose can be decreased by anyamount (including stopping the infusion) for the management of adverse reactions.

Nervous system adverse reactions, particularly dizziness, nausea and abnormal gait appear to becorrelated 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 andrelatively rapid plasma clearance (see section 5.2). Therefore, pharmacological effects related tosystemic exposure should be minimal.

The median dose at response is approximately 6.0 μg/day and approximately 75% of responsivepatients require ≤ 9.6 μg/day. To limit the occurrence of serious adverse reactions, a maximum doseof 21.6 μg/day is recommended. However, in clinical trials it has been observed that patients whotolerate doses of 21.6 μg/day following slow titration over a 3 to 4-week period, generally toleratehigher 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 ofthe patency of the intrathecal catheter should be considered if the required ziconotide dose continuallyincreases and there is no benefit or increase in adverse reactions.

Alternative dosing regimens including initiation of dosing with lower doses of ziconotide and bolusadministration have been explored in a limited number of studies available in the literature.

The use of lower doses through continuous administration was demonstrated to achieve efficacy withfewer adverse reactions.

Bolus administration studies suggest that bolus dosing may be useful in identifying patients who maybenefit from long term use of ziconotide, however, may result in more adverse reactions thanadministration by continuous infusion.

These studies suggest that these alternative methods of administration of ziconotide may be possiblehowever, due to the limited numbers of patients, these results are inconclusive and there is currentlyinsufficient evidence available to make definitive recommendations for such alternative dosingregimens.

There were three placebo-controlled clinical trials of IT ziconotide.

Two short-term studies, 95-001 (malignant pain) and 96-002 (non malignant pain), involving366 patients, demonstrated the efficacy of IT ziconotide in severe chronic pain using the percentchange in Visual Analog Scale of Pain Intensity (VASPI) as the primary efficacy measure. Thesestudies were of short duration, 5 and 6 days respectively, and used a more rapid dose escalation andhigher doses than recommended in Section 4.2.

Efficacy results from study 95-001

Initial treatment assignment

Parameter Ziconotide (n = 71) Placebo (n = 40) p-value

Mean VASPI score at 74.1 (± 13.82) 77.9 (± 13.60) _baseline in mm (SD)

Mean VASPI score at end of 35.7 (± 33.27) 61.0 (± 22.91) _initial titration in mm (SD)% improvement in VASPI 51.4 (± 43.63) 18.1 (± 28.28) < 0.001score at end of initial titration(SD)

Respondera n (%) 34 (47.9%) 7 (17.5%) 0.001

Dose at end of titration(μg/hr)

Mean 0.91

Median 0.60

Range 0.074 - 9.36aResponders were defined as those patients who 1) experienced a ≥ 30% drop in VASPI scorecompared to baseline; 2) had stable or decreased concomitant opioid analgesics; and 3) had opiate typeunchanged from preinfusion if receiving opiates.

SD - Standard Deviation.

Efficacy results from study 96-002

Initial treatment assignment

Parameter Ziconotide (n = 169)b Placebo (n = 86) p-value

Mean VASPI score at 80.1 (± 15.10) 76.9 (± 14.58) _baseline in mm (SD)

Mean VASPI score at end of 54.4 (± 29.30) 71.9 (± 30.93) _initial titration in mm (SD)% improvement in VASPI 31.2 (± 38.69) 6.0 (± 42.84) < 0.001score at end of initial titration(SD)

Respondera n (%) 57 (33.7%) 11 (12.8%) < 0.001

Dose at end of titration(μg/hr)

Mean 1.02

Median 0.50

Range 0.019 - 9.60aResponders were defined as those patients who 1) experienced a ≥ 30% drop in VASPI scorecompared to baseline; 2) had stable or decreased concomitant opioid analgesics; and 3) had opiate typeunchanged from preinfusion if receiving opiates.b164 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) werevaried 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 allgroups.

Study 301 (n = 220) was of longer duration (21 days), involved more cautious up-titration and lowerdoses of IT ziconotide, and enrolled the most refractory population of patients studied in the threestudies. All patients in the 301 study had failed IT therapy with combinations of analgesics and theirphysicians considered that 97% of the patients were refractory to currently available treatments. Themajority had spinal pain (n = 134), especially failed back surgery (n = 110); a lower proportion hadneuropathy (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 reactions 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 80.7 (± 14.98) 80.7 (± 14.91) -in mm (SD)

Mean VASPI score at end of 67.9 (± 22.89) 74.1 (± 21.28) _initial titration in mm (SD)% improvement in VASPI score 14.7 (± 27.71) 7.2 (± 24.98) 0.0360at end of initial titration (SD)

Respondera n (%) 18 (16.1%) 13 (12.0%) 0.390

Dose at end of titration (μg/hr)

Mean 0.29

Median 0.25

Range 0.0 - 0.80aResponders were defined as those who experienced a ≥ 30% drop in VASPI score compared tobaseline.

SD - Standard Deviation.

Combination studies with IT Morphine

Clinical studies 201 and 202 indicate that the combination of IT ziconotide and IT morphine mayeffectively reduce pain and decrease systemic opioid use over a sustained period of time for patientswhose pain was inadequately controlled with their maximum tolerated dose of IT ziconotide (median8.7 μg/day, mean 25.7 μg/day - study 201) or with IT morphine (study 202) alone. When adding ITziconotide to stable doses of IT morphine, as with the initiation of IT ziconotide monotherapy, theappearance of psychotic adverse reactions. (e.g., hallucinations, paranoid reactions) or discontinuationdue to increased adverse reactions may occur. (see section 4.5).

The CSF pharmacokinetics of ziconotide have been studied following one-hour IT infusions of1 - 10 μg of ziconotide in patients with chronic pain. The plasma pharmacokinetics followingintravenous doses (0.3 - 10 μg/kg/24 hr) were also studied. IT and intravenous pharmacokinetics dataare summarised below.

CSF and Plasma Pharmacokinetics of Ziconotide [mean ± SD (median)]

Route of Fluid Number CL (ml/min) Vd (ml) t½ (hr)administration matrix ofpatients

Intrathecal CSF 23 0.38 ± 0.56 155 ± 263 4.6 ± 0.9(0.26) (99) (4.5)

Intravenous Plasma 21 270 ± 44 30,460 ± 6,366 1.3 ± 0.3(260) (29,320) (1.3)

CL = clearance; Vd = distribution volume; t½ = half life

Following one-hour IT administration (1 - 10 μg), both cumulative exposure (AUC; range: 83.6 -608 ng/h/ml) and peak exposure (Cmax; range: 16.4 - 132 ng/ml) values were variable anddose-dependent, but appeared only approximately dose-proportional. Plasma concentrations followingcontinuous (≥ 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 medicinalproduct; < 0.04 ng/ml). No accumulation of ziconotide in plasma following long-term ITadministration (up to 9 months) has been observed.

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 distributemainly within the CSF until transferred to the systemic circulation. Upon reaching the systemiccirculation, ziconotide appears to be more extensively distributed, based on a plasma distributionvolume of approximately 30 l and is only about 53% bound (non-specifically) to human plasmaproteins.

Ziconotide is a peptide consisting of 25 naturally-occurring amino acids of the L-configuration, anddoes not appear to be appreciably metabolised in the CSF. Following passage into the systemiccirculation, ziconotide is expected to be primarily susceptible to proteolytic cleavage by variousubiquitous peptidases/proteases present in most organs (e.g., kidney, liver, lung, muscle, etc.), and thusdegraded to peptide fragments and its individual constituent free amino acids. The generated freeamino acids are expected to be taken up by cellular carrier systems and either subjected to normalintermediary metabolism or used as substrates for constitutive biosynthetic processes. Due to the widedistribution of these peptidases it is not expected that hepatic or renal impairment would affect thesystemic clearance of ziconotide. The biological activity of the various expected proteolyticdegradation products has not been assessed. It is unlikely that the degradation products of ziconotidewill have significant biological activity, as peptides consisting of the individual peptide loop structureshave been found to have binding affinities for N-type voltage sensitive calcium channels that areseveral orders of magnitude lower than that of the parent (ziconotide) compound.

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 t½ = 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 ITadministration due to both the low IT infusion rate and relatively rapid plasma clearance. The meanplasma elimination half-life (t½) 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 thefiltered active substance is rapidly endocytosed and ultimately transported back to the systemiccirculation.

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 hepaticdysfunction will significantly impact systemic exposure of ziconotide.

Although only limited data are available, there is no obvious effect of race, height, weight, gender orage on CSF ziconotide exposure after IT administration.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of themaximum human exposure indicating little relevance to clinical use.

In subchronic continuous intrathecal infusion studies in rats and dogs, behavioural effects were seen atdoses ≥ 8-fold the maximum recommended clinical intrathecal infusion dose of 21.6 μg/day (on amg/kg basis). These effects were defined by exaggerated pharmacological actions of ziconotide andnot by neurotoxic lesions or target organ toxicity. Observations included transient and reversibleneurological effects consisting of tremors, uncoordinated movements and hyper- and hypoactivity.

The long-term consequences to neuronal function of continuous N-type calcium-channel block havenot been demonstrated in experimental animals. Changes in neurological signalling have not beenstudied in experimental animals. Ziconotide did not induce bacterial gene mutation and was notgenotoxic. Chronic animal studies have not been performed to assess the carcinogenic potential ofziconotide. However, ziconotide did not induce cell transformation in the in vitro Syrian hamsterembryo (SHE) assay and did not increase cell proliferation (pre-neoplastic lesion formation) orapoptosis after subchronic intrathecal exposure in dogs.

In rat fertility studies, there were no effects in males while reductions in corpora lutea; implantationsites and number of live embryos were observed in females. No adverse effects on femalereproduction and post-natal development in rats were seen at systemic exposures up to 2,300 timeshuman 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 exposuresneeded to elicit these effects in rats and rabbits.

Methionine

Sodium chloride

Water for injections

Hydrochloric acid (pH adjuster)

Sodium hydroxide (pH adjuster)

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

4 years

In-use shelf-life (diluted product)

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 infusionpump immediately. If not used immediately, in-use storage times and conditions prior to use are theresponsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C, unless dilutionhas taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vial in the outer carton in order to protectfrom light.

For storage conditions after dilution of the medicinal product, see section 6.3.

Type I glass vials with butyl rubber stoppers coated with fluorinated polymer.

Each vial contains 20 ml solution for infusion.

One vial per carton.

If dilution is required, Prialt must be diluted aseptically with preservative-free sodium chloride9 mg/ml (0.9%) solution for injection before use. The concentration of the solution used in theinfusion pump must be no lower than 5 μg/ml ziconotide in an external pump and 25 μg/ml in aninternal pump.

Strict aseptic procedures must be used during the preparation and handling of the solution for infusionand refilling of the pump. The patient and health-care providers must be familiar with the handling ofthe external or internal infusion system and be aware of the need to guard against infection.

Specific instructions for using the pumps must be obtained from the manufacturer.

Prialt has been shown to be chemically and physically compatible with the implantable Synchromedpump and the external CADD-Micro pump at the concentration levels indicated above. Chemical andphysical in-use stability has been demonstrated for 14 days at 37ºC in the Synchromed pump when thepump has not previously been exposed to the medicinal product. The initial fill must therefore bereplaced after 14 days.

Prialt was stable for 60 days at 37°C in the Synchromed pump previously exposed to the medicinalproduct. Stability has been demonstrated for 21 days at room temperature in the CADD-Micro pump.

The technical data are given only for information and should not limit health-care providers’ choice.

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 withsodium 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 candegrade ziconotide.

Prior to initiation of therapy, an internal pump must be rinsed three times with 2 ml of Prialt at25 μg/ml. The concentration of Prialt in a naïve pump may be reduced due to adsorption onto thesurfaces of the device, and/or dilution by the residual space of the device. Because of this, after thefirst use of Prialt, the reservoir should be emptied and refilled after 14 days. Subsequently the pumpshould be emptied and refilled every 60 days.

Prialt 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 medicinal product or waste material should be disposed of inaccordance with local requirements.

Esteve Pharmaceuticals GmbH

Hohenzollerndamm 150-15114199 Berlin

Germany

EU/1/04/302/004 - 20 ml solution for infusion

Date of first authorisation: 21 February 2005

Date of latest renewal: 18 September 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu