Source: Health Products Regulatory Authority (IE) Revision Year: 2023 Publisher: Upjohn EESV, Rivium Westlaan 142, 2909 LD Capelle aan den IJssel, Netherlands
Pharmacotherapeutic group: Antipsychotic, indole derivatives
ATC code: NO5AE04
Ziprasidone has a high affinity for dopamine type 2 (D2) receptors and substantially higher affinity for serotonin type 2A (5HT2A) receptors. Receptor blockade, 12 hours after a single dose of 40 mg, was greater than 80% for serotonin type 2A and greater than 50% for D2 using positron emission tomography (PET). Ziprasidone also interacts with serotonin 5HT2C, 5HT1D and 5HT1A receptors where its affinities for these sites are equal to or greater than its affinity for the D2 receptor. Ziprasidone has moderate affinity for neuronal serotonin and norepinephrine transporters. Ziprasidone demonstrates moderate affinity for histamine H(1)- and alpha(1)-receptors. Ziprasidone demonstrates negligible affinity for muscarinic M(1)-receptors.
Ziprasidone has been shown to be an antagonist at both serotonin type 2A (5HT2A) and dopamine type 2 (D2) receptors. It is proposed that the therapeutic activity is mediated, in part, through this combination of antagonist activities. Ziprasidone is also a potent antagonist at 5HT2C and 5HT1D receptors, a potent agonist at the 5HT1A receptor and inhibits neuronal reuptake of norepinephrine and serotonin.
In a 52 week study, ziprasidone was effective in maintaining the clinical improvement during continuation therapy in patients who showed an initial treatment response: there was no clear evidence for a dose-response relationship amongst the ziprasidone groups. In this study, which included patients with both positive and negative symptoms, ziprasidone’s efficacy was demonstrated in both positive and negative symptoms.
The incidence of body weight gain, reported as an adverse event in short term (4-6 week) schizophrenia studies was low and identical in ziprasidone-treated and placebo-treated patients (both 0.4%). In a one-year placebo-controlled study a median weight loss of 1-3 kg was observed in ziprasidone-treated patients compared to a 3 kg median loss in placebo-treated patients.
In a double-blind comparative schizophrenia study, metabolic parameters including weight and fasting levels of insulin, total cholesterol and triglycerides and an insulin resistance (IR) index were measured. In patients receiving ziprasidone no significant changes from baseline were observed in any of these metabolic parameters.
A randomised post-approval study of 18,239 schizophrenic patients with observational follow-up for 1 year was conducted to determine whether ziprasidone´s effect on the QTc interval is associated with an increased risk of non-suicide mortality. This study, which was conducted in naturalistic clinical practice settings, showed no difference in the rate of over-all non-suicide mortality between ziprasidone and olanzapine treatments (primary end-point). The study also showed no difference in secondary end-points of all-cause mortality, mortality due to suicide, mortality due to sudden death, however, a non-significant numerically higher incidence of cardiovascular mortality was observed in the ziprasidone group. A statistically significantly higher incidence of all-cause hospitalisation, mainly due to differences in the number of psychiatric hospitalisations, was also observed in the ziprasidone group.
The efficacy of ziprasidone in adults with mania was established in two placebo controlled, double blind, 3 week studies which compared ziprasidone with placebo and one double blind, 12 week study which compared ziprasidone to haloperidol and placebo. These studies included approximately 850 patients meeting DSM-IV criteria for bipolar I disorder with an acute manic or mixed episode, with or without psychotic features. The baseline presence of psychotic features in the studies was 49.7%, 34.7% or 34.9%. Efficacy was assessed using the Mania Rating Scale (MRS). The Clinical Global Impression-Severity (CGI-S) scale was either a co-primary or key secondary efficacy variable in these studies. Ziprasidone treatment (40-80 mg BID, mean daily dose 120 mg) resulted in statistically significantly greater improvement in both MRS and CGI-S scores at Last Visit (3 weeks) compared with placebo. In the 12 week study, haloperidol treatment (mean daily dose 16 mg) produced significantly greater reductions in MRS scores compared with ziprasidone (mean daily dose 121 mg). Ziprasidone demonstrated comparable efficacy to haloperidol in terms of the proportion of patients maintaining a response to treatment from week 3 to week 12.
The efficacy of ziprasidone in the treatment of Bipolar I Disorder in paediatric patients (10 to 17 years of age) was evaluated in one four-week placebo-controlled trial (n=237) of inpatients or outpatients who met DSM-IV criteria for Bipolar I Disorder manic or mixed episodes with or without psychotic features and had a Y-MRS score ≥17 at baseline. This double-blind, placebo-controlled trial compared flexibly-dosed oral ziprasidone (80-160 mg/day (40-80 mg BID) in two divided doses for patients weighing ≥45 kg; 40-80 mg/day (20-40 mg BID) for patients weighing <45 kg) to placebo. Ziprasidone was administered as a single dose of 20 mg on the first day, then titrated over 1-2 weeks, in two daily doses, to a target range of 120-160 mg/day for patients weighing ≥45 kg, or 60-80 mg/day for patients weighing <45 kg. Asymmetric dosing, with morning doses 20 mg or 40 mg less than evening doses, was permitted. Ziprasidone was superior to placebo in change from baseline to week 4 on the Y-MRS total score. In this clinical trial, the mean daily doses administered were 119 mg and 69 mg in the patients weighing ≥45 kg and <45 kg, respectively.
There are no long-term clinical studies in adult patients investigating the efficacy of ziprasidone in the prevention of recurrence of manic/depressive symptoms.
Ziprasidone has been evaluated for safety in 237 paediatric patients (age 10 to 17 years) who participated in multiple-dose, clinical trials in bipolar mania; a total of 31 paediatric patients with Bipolar I Disorder were dosed with oral ziprasidone for at least 180 days.
In a 4-week trial in paediatric patients (10-17 years) with bipolar mania, there were no differences between ziprasidone and placebo patients in the mean change from baseline in body weight fasting glucose, total cholesterol, LDL cholesterol, or triglyceride levels.
The efficacy of ziprasidone in the treatment of Bipolar I Disorder was evaluated in a post marketing study in paediatric patients (n=171 [safety population]; n=168 [ITT population]) who met DSM-5 criteria for Bipolar I Disorder (manic or mixed) at baseline. The study compared flexibly-dosed oral ziprasidone (80‑160 mg/day [40-80 mg BID] for patients weighing ≥45 kg; 40-80 mg/day [20‑40 mg BID] for patients weighing <45 kg) to placebo over a 4‑week period. The study demonstrated that ziprasidone was superior to placebo in change from baseline to week 4 on the Y-MRS total score. The study did not observe any relevant differences between ziprasidone and placebo patients in the mean change from baseline in body weight fasting glucose, total cholesterol, LDL cholesterol, or triglyceride levels.
There are no long-term double-blind clinical studies investigating the efficacy and tolerability of ziprasidone in children and adolescents.
There are no long-term clinical studies in paediatric patients investigating the efficacy of ziprasidone in the prevention of recurrence of manic/depressive symptoms.
The paediatric schizophrenia program was a short-term, 6-week, placebo-controlled trial (A1281134), followed by a 26-week open-label extension study (A1281135) that was designed to provide information on the efficacy, safety and tolerability of oral ziprasidone (40-80 mg BID with meals) during its long-term administration in adolescent subjects aged 13 to 17 years (inclusive) with schizophrenia. The Geodon paediatric study in schizophrenia was terminated by Pfizer due to lack of efficacy (see section 4.2).
Following oral administration of multiple doses of ziprasidone with food, peak serum concentrations typically occur 6 to 8 hours post-dose. The absolute bioavailability of a 20 mg dose is 60% in the fed state. Pharmacokinetic studies have demonstrated that the bioavailability of ziprasidone is increased by up to 100% in the presence of food. It is therefore recommended that ziprasidone should be taken with food.
The volume of distribution is approximately 1.1 L/kg. Ziprasidone is more than 99% protein bound in serum.
The mean terminal half-life of ziprasidone after oral administration is 6.6 hours. Steady state is reached within 1-3 days. Mean clearance of ziprasidone administered intravenously is 5 ml/min/kg. Approximately 20% of the dose is excreted in urine, and approximately 66% is eliminated in faeces.
Ziprasidone demonstrates linear kinetics over the therapeutic dose range of 40 to 80 mg twice daily in fed subjects.
Ziprasidone is extensively metabolised after oral administration with only a small amount excreted in urine (<1%) or faeces (<4%) as unchanged ziprasidone. Ziprasidone is primarily cleared via three proposed metabolic routes to yield four major circulating metabolites, benzisothiazole piperazine (BITP) sulphoxide, BITP sulphone, ziprasidone sulphoxide and S-methyldihydroziprasidone. Unchanged ziprasidone represents about 44% of total drug-related material in serum.
Ziprasidone is primarily metabolised by two pathways: reduction and methylation to generate S-methyldihydroziprasidone which accounts for approximately two-thirds of the metabolism, and oxidative metabolism accounting for the other third. In vitro studies using human liver subcellular fractions indicate that S‑methyldihydroziprasidone is generated in two steps. These studies indicate that the first step is mediated primarily by chemical reduction by glutathione as well as by enzymatic reduction by aldehyde oxidase. The second step is methylation mediated by thiol methyltransferase. In vitro studies indicate that CYP3A4 is the major cytochrome P450 catalysing the oxidative metabolism of ziprasidone with a potential minor contribution of CYP1A2.
Ziprasidone, S-methyldihydroziprasidone, and ziprasidone sulphoxide, when tested in vitro, share properties which may predict a QTc-prolonging effect. S-methyldihydroziprasidone is mainly eliminated in faeces by biliary excretion with a minor contribution by CYP3A4 catalysed metabolism. Ziprasidone sulphoxide is eliminated through renal excretion and by secondary metabolism catalysed by CYP3A4.
Pharmacokinetic screening of patients has not revealed any significant pharmacokinetic differences between smokers and non-smokers.
No clinically significant age- or gender-differences in the pharmacokinetics of ziprasidone has been observed. The pharmacokinetics of ziprasidone in paediatric patients 10 to17 years of age were similar to those in adults after correcting for the differences in body weights.
Consistent with the fact that renal clearance contributes very little to its overall clearance, no progressive increases in ziprasidone exposure were noted when ziprasidone was administered to subjects with varying degrees of renal function. Exposures in subjects with mild (creatinine clearance 30-60 ml/min), moderate (creatinine clearance 10-29 ml/min) and severe impairment (requiring dialysis) were 146%, 87% and 75% those of healthy subjects (creatinine clearance >70 ml/min) following oral administration of 20 mg BID for seven days. It is unknown whether serum concentrations of the metabolites are increased in these patients.
In mild to moderate impairment of liver function (Child Pugh A or B) caused by cirrhoses, the serum concentrations after oral administration were 30% higher and the terminal half-life was about 2 hours longer than in normal patients. The effect of liver impairment on the serum concentrations of the metabolites is unknown.
Preclinical safety data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential. In reproductive studies in rats and rabbits, ziprasidone has shown no evidence of teratogenicity. Undesirable effects on fertility and decreased pup weights were observed at doses causing maternal toxicity such as decreased body weight gain. Increased perinatal mortality and delayed functional development of offspring occurred at maternal plasma concentrations extrapolated to be similar to the maximal concentrations in humans given therapeutic doses.
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