Prialt · 4.8 Undesirable effects · 1

HOS-093834 · has-adverse-reaction-information · PDF-Seite 22

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 reactions. The most common adverse reactions 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%), 22 headache (12%), asthenia (13%), vomiting (11%), and somnolence (10%). Most adverse reactions were mild to moderate in severity and resolved over time. Tabulated list of adverse reactions Unless otherwise noted the table shows the incidence rates of adverse reactions reported in the intrathecal clinical trials with ziconotide (short- and long-term exposure). Within each frequency grouping 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, meningitis infestations Immune system anaphylactic disorders reactiona Metabolism and appetite decreased, nutrition anorexia disorders Psychiatric confusional anxiety, auditory delirium, psychotic disorders state hallucination, disorder, suicidal insomnia, agitation, ideation, suicide disorientation, attempt, thought hallucination, visual blocking, abnormal hallucination, dreams, depression, paranoia,

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HOS-093828 · has-adverse-reaction-information · PDF-Seite 6

6 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 reactions. The most common adverse reactions 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 adverse reactions were mild to moderate in severity and resolved over time. Tabulated list of adverse reactions Unless otherwise noted the table shows the incidence rates of adverse reactions reported in the intrathecal clinical trials with ziconotide (short- and long-term exposure). Within each frequency grouping 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, meningitis infestations Immune system anaphylactic disorders reactiona Metabolism and appetite decreased, nutrition anorexia disorders Psychiatric confusional anxiety, auditory delirium, psychotic disorders state hallucination, disorder, suicidal insomnia, agitation, ideation, suicide disorientation, attempt, thought hallucination, visual blocking, abnormal hallucination, dreams, depression, paranoia, aggressiveness

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HOS-093824 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Combination with IT chemotherapy (see section 4.5). 3 Pre-existing history of psychosis with ziconotide. History of suicidal attempt or suicidal ideation with ziconotide.(see Section 4.2, 4.4 and 4.8). Infection at the microinfusion injection site, uncontrolled bleeding diathesis, and spinal canal obstruction that impairs circulation of cerebrospinal fluid (CSF).

HOS-093830 · has-contraindication-information · PDF-Seite 19

19 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Combination with IT chemotherapy (see section 4.5). Pre-existing history of psychosis with ziconotide. History of suicidal attempt or suicidal ideation with ziconotide (see Section 4.2, 4.4 and 4.8). Infection at the microinfusion injection site, uncontrolled bleeding diathesis, and spinal canal obstruction that impairs circulation of cerebrospinal fluid (CSF).

HOS-093829 · has-indication-information · PDF-Seite 18

Prialt is indicated for the treatment of severe, chronic pain in adults who require intrathecal (IT) analgesia.

HOS-093823 · has-indication-information · PDF-Seite 2

Prialt is indicated for the treatment of severe, chronic pain in adults who require intrathecal (IT) analgesia.

HOS-093826 · has-interaction-information · PDF-Seite 5

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 5 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 (pruritus 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.

HOS-093832 · has-interaction-information · PDF-Seite 21

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. 21 The addition of IT morphine to stable doses of IT ziconotide is better tolerated (pruritus 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.

HOS-093833 · has-pregnancy-information · PDF-Seite 22

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 newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Prialt 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).

HOS-093827 · has-pregnancy-information · PDF-Seite 6

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 newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Prialt 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).

HOS-093831 · has-warning-information · PDF-Seite 20

Patients should undergo a neuropsychiatric evaluation before, after starting and during intrathecal ziconotide, and immediately when any depressive signs or symptoms appear (see Sections 4.3, 4.4 and 4.8). Caregivers should contact a physician immediately if the patient experiences symptoms of potentially life-threatening adverse event. 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. Risk of infection 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 zic

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HOS-093825 · has-warning-information · PDF-Seite 4

Patients should undergo a neuropsychiatric evaluation before, after starting and during intrathecal ziconotide, and immediately when any depressive signs or symptoms appear (see Sections 4.3, 4.4 and 4.8). Caregivers should contact a physician immediately if the patient experiences symptoms of potentially life-threatening adverse event. 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. Risk of infection 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). 4 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 o

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