英文药名: Prialt(Ziconotide Acetate)

中文药名: 齐可诺肽鞘内输注液

生产厂家: Eisai Inc.
药品介绍
药品分类：止痛,解痉新药
适应症
本品用于适合鞘内注射并且对其他治疗(如全身镇痛药、辅助治疗或鞘内注射吗啡)不能耐受或无效的严重慢性疼痛患者。
用法用量
鞘内滴注，初始剂量根据患者情况而定，最高初始剂量为2．4mg/天(0．1mg/h)，以后剂量可提高但每周不超过2～3倍，直到第21天时达到最高推荐剂量19．2mg/天(0．8mg/h)。通过调整给药泵的滴速达到确定的给药剂量。剂量的调整应根据患者的疼痛程度及不良事件的发生情况而定，在临床试验中，21天时的平均药物剂量为6．9～19．2mg/天(0．29～0．8mg/h)。
本品可采用剂量可调的植入式自动定时给药泵或外置式微量输液泵及导管鞘内滴注。可使用未稀释的原药液(25mg/ml，每支20m1)或稀释液(100mg/ml，每支1ml、2ml或5ml，用0．9%氯化钠注射液稀释)。
齐考诺肽是一种内注射型用于治疗全身镇痛药等不能耐受或无效的严重慢性疼痛患者的新药
Prialt solution for infusion
1. Name of the medicinal product
Prialt 100 micrograms/ml solution for infusion
2. Qualitative and quantitative composition
 One ml solution contains 100 μg ziconotide (as acetate).
1 ml vial: Each vial contains 100 μg ziconotide (as acetate).
5 ml vial: Each vial contains 500 μg ziconotide (as acetate).
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Solution for infusion. Clear, colourless solution, free of visible particles.
4. Clinical particulars
4.1 Therapeutic indications
Ziconotide is indicated for the treatment of severe, chronic pain in adults who require intrathecal (IT) analgesia.
4.2 Posology and method of administration
Treatment with ziconotide should only be undertaken by physicians experienced in intrathecal (IT) administration of medicinal products.
Posology
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).
Hepatic Impairment
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.
Renal Impairment
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.
Paediatric population
The safety and efficacy of ziconotide in children aged 0-≤ 18 years has not been established.
No data are available.
Method of administration
Intrathecal use.
For instructions on dilution of the medicinal product before administration, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
Combination with IT chemotherapy (see section 4.5).
4.4 Special warnings and precautions for use
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.
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, aggressiveness, 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. It is recommended that patients 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 in the general population. Ziconotide may cause or worsen depression with the risk of suicide in susceptible patients.
Depression of Central Nervous System (CNS)
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 CNS depressant medicinal products should also be considered as they may contribute to the reduced level of arousal.
4.5 Interaction with other medicinal products and other forms of interaction
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).
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.
4.6 Fertility pregnancy and lactation
Pregnancy
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 using contraception.
Breast-feeding
It is unknown whether ziconotide/metabolites are excreted in human milk.
A risk to the newborns/infants cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ziconotide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
No specific studies with ziconotide in humans have been conducted to evaluate effects on fertility. In a study 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).
4.7 Effects on ability to drive and use machines
Ziconotide has moderate influence on the ability to drive and use machines.
Ziconotide may cause confusion, somnolence and other neurological adverse reactions, therefore patients must be advised not to drive or operate machines if affected.
4.8 Undesirable effects
Summary of the safety profile
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%), and vomiting (11%) and somnolence (10%). Most ADRs were mild to moderate in severity and resolved over time.
Tabulated list of adverse reactions
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
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, aggressiveness.
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
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
Description of selected adverse reactions
Meningitis
Administration of medicinal products by the intrathecal route carries the risk of potential serious infections, such as meningitis, which may be life threatening. Patients and physicians must be vigilant for typical symptoms and signs of meningitis (see section 4.4).
Elevations of creatine phosphokinase
Elevations in creatine phosphokinase were usually asymptomatic. Monitoring of creatine phosphokinase is recommended. Discontinuation of ziconotide should be considered in the event of progressive or significant elevation of creatine phosphokinase in association with clinical features of myopathy 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 psychiatric disturbances, such as hallucinations, paranoid reactions, hostility, aggressiveness, 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. It is recommended that patients undergo a neuropsychiatric evaluation before and after starting intrathecal ziconotide (see section 4.4).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
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.
Symptoms
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.
Management
General medical supportive measures should be administered to patients who receive an overdose until the exaggerated pharmacological effects of the medicinal product have resolved.
5. Pharmacological properties
5.1 Pharmacodynamic properties
 Pharmacotherapeutic group: Analgesics, other analgesics and antipyretics, ATC code: N02BG08
Mechanism of action
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.
Pharmacodynamic effects
Though statistically significant relationships and reasonable correlation between cerebrospinal fluid (CSF) exposure (AUC, Cmax) 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.
Alternative dosing regimens including initiation of dosing with lower doses of ziconotide and bolus administration 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 with fewer adverse events.
Bolus administration studies suggest that bolus dosing may be useful in identifying patients who may benefit from long term use of ziconotide, however, may result in more adverse events than administration by continuous infusion.
These studies suggest that these alternative methods of administration of ziconotide may be possible however, due to the limited numbers of patients, these results are inconclusive and there is currently insufficient evidence available to make definitive recommendations for such alternative dosing regimens.
Clinical efficacy and safety
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.
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
Respondera n (%)	34 (47.9%)	7 (17.5%)	0.001
Dose at end of titration (μg/hr) Mean Median Range	0.91 0.60 0.074 - 9.36

aResponders 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.
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
Respondera n (%)	57 (33.7%)	11 (12.8%)	< 0.001
Dose at end of titration (μg/hr) Mean Median Range	1.02 0.50 0.019 - 9.60

aResponders 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.
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) 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 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
Respondera 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

aResponders 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)	t½ (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 (Cmax; range: 16.4 – 132 ng/ml) values were variable and dose-dependent, but appeared only approximately dose-proportional. Plasma concentrations 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 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 IT administration due to both the low IT infusion rate and relatively rapid plasma clearance. The mean plasma 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 the filtered active substance is rapidly endocytosed and ultimately transported back to the systemic circulation.
Renal and hepatic impairment
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.
Other special 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.
5.3 Preclinical safety data
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to 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 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.
Environmental Risk Assessment (ERA)
The environmental exposure assessment that has been made on ziconotide concludes that ziconotide will not represent a risk to the environment.
6. Pharmaceutical particulars
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
Unopened vials
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 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.
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 or 5 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 37°C 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. Marketing authorisation holder
Eisai Ltd.,
European Knowledge Centre
Mosquito Way
Hatfield
Herts
AL10 9SN
United Kingdom
8. Marketing authorisation number(s)
EU/1/04/302/001 – 1ml solution for infusion.
EU/1/04/302/003 – 5ml solution for infusion.
9. Date of first authorisation/renewal of the authorisation
 Date of first authorisation: 21 February 2005
Date of latest renewal: 21 February 2010
10. Date of revision of the text
17 January 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
11. Legal category
POM - Medicinal product subject to medical prescription
FDA批准齐可诺肽鞘内输注液(ziconotide,Prialt)上市
美国FDA批准伊兰（Elan）公司的齐考诺肽（ziconotide）鞘内输注液（Prialt）上市，用于鞘内输注治疗用其他治疗方法耐受或无效（如全身性镇痛、辅助治疗或鞘内输注吗啡）病人的慢性严重疼痛。
本品是以海蜗牛肽阻滞疼痛信号新颖的非麻醉药品。仅获准以Medtronic SynchroMed EL、SynchroMed II 输注系统和Simms Deltec Cadd Micro外微输注器和导管给药。
FDA批准本品是基于三项治疗1200多例患者的III期临床研究，评价了对无论全身性给药方法和（或）鞘内输注镇痛药和其他药物治疗无效的严重慢性疼痛病人Prialt鞘内输注的有效性和安全性。
Prialt用药系一新颖的治疗方法，对患有严重慢性疼痛尤为重要。首个鞘内输注的镇痛药已批准20余年，而Prialt基于现有最大和最广泛鞘内输注镇痛药安全性数据之一，为医生和病人提供了重要的治疗新观念。伊兰公司科学家开发的Prialt系一类称为N型钙通道阻滞剂的非阿片类镇痛药。本品新颖的作用机制是通过对常规传递疼痛信号的神经靶向和阻断N型钙通道发挥的。
在美国39个中心对220例耐阿片类镇痛药严重慢性疼痛成人患者的随机双盲安慰剂对照III期临床研究中，大多数患者有神经痛。所有病人采用鞘内输注：随机接受Prialt（112例）或安慰剂（108例）。治疗的初始剂量是一日2.4μg（0.1μg/h），剂量增加小于或等于一日2.4μg（小于或等于0.1μg/h），一周2～3次用药3周。3周时，测定主要疗效VASPI计分平均值改变，结果显示用药组较安慰剂组具有统计意义上的改善（P=0.036）。早在1周时即可观测到VASPI计分改善，第3周的平均剂量是一日6.9μg（0.29μg/h）。大多数次要终点也显示Prialt组患者具有统计意义上的改善。主要不良反应是轻至中度的眩晕、运动失调(行走不稳)、意识模糊和步态异常(行走困难)。