Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: RIEMSER Pharma GmbH, An der Wiek 7, 17493, Greifswald-Insel Riems, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Combination with IT chemotherapy (see section 4.5).
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.
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, 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, 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 and spontaneous reports of anaphylactic reactions have been received.
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.
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.
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.
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.
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 ziconotide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
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).
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.
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.
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).
Uncommon: sepsis, meningitis
Not Known: anaphylactic reactiona
Common: appetite decreased, anorexia
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
Very common: dizziness, nystagmus, memory impairment, headache, somnolence
Common: dysarthria, amnesia, dysgeusia, tremor, balance impaired, ataxia, aphasia, burning sensation, sedation, paraesthesia, hypoaesthesia, disturbance in attenti on, speech disorder, areflexia, coordination abnorm al, 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
Very common: vision blurred
Common: diplopia, visual disturbance, photophobia
Common: vertigo, tinnitus
Uncommon: atrial fibrillation
Common: orthostatic hypotension, hypotension
Common: dyspnoea
Uncommon: respiratory distress
Very common: nausea, vomiting
Common: diarrhoea, dry mouth, constipation, nausea aggravated, upper abdominal pain
Uncommon: dyspepsia
Common: pruritus, sweating increased
Uncommon: rash
Common: pain in limb, myalgia, muscle spasms, muscle cramp, muscle weakness, arthralgia, peripheral swelling
Uncommon: rhabdomyolysis, myositis, back pain, muscle twitching, neck pain
Common: urinary retention, urinary hesitation, dysuria, urinary incontinence
Uncommon: acute renal failure
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
Common: blood creatine phosphokina se increased, weight decreased
Uncommon: electrocardiogram abnormal, aspartate aminotransferase increased, blood creatine phosphokinase MM increased, body temperature increased
a From spontaneous reporting
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 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).
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 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 the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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