Chemical formula: C₁₀₂H₁₇₂N₃₆O₃₂S₇ Molecular mass: 2,639.14 g/mol
Ziconotide interacts in the following cases:
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.
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.
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.
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.
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.
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.
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.
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.
There are no or limited amount of data from the use of ziconotide in pregnant women. Studies in animals have shown reproductive toxicity. 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.
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 list 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.
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.
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.
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