Pharmacology: Mechanism of Action: Risperidone, a benzisoxazole derivative, is a novel antipsychotic drug which binds with high affinity to serotonin type 2 (5-HT2), dopamine type 2 (D2), and α1-adrenergic receptors. Risperidone binds with a lower affinity to the α2-adrenergic and histamine H1 receptors.
Risperidone does not bind to dopamine D1 receptors and has no affinity (when tested at concentrations > 10-5 M) for muscarinic cholinergic receptors. Due to the lack of muscarinic receptor binding, risperidone is not expected to produce anticholinergic adverse effects.
Receptor occupancy was also demonstrated in vivo in humans. Using positron emission tomography, risperidone was shown to block both 5-HT2A and dopamine D2 receptors in three healthy volunteers. Although risperidone is a potent D2 antagonist, which is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy in animal models than classical antipsychotics. Risperidone has also been found to be one of the most potent known antagonists of 5-HT2A (cloned human receptor); 5-HT2A antagonism has been shown to reverse deficits in several in vivo animal models predictive of novel antipsychotic activity (PCP-induced social deficit, microdialysis assessment of dopamine output in prefrontal cortex, glutamate antagonist-induced hyperlocomotion). Balanced central serotonin and dopamine antagonism may reduce extrapyramidal side-effect liability.
Clinical Trials: Comparative Bioavailability Studies: Tablets: A Comparative Bioavailability Study of Pharmascience Inc. pms-RISPERIDONE 1 mg tablet was performed versus Janssen-Ortho Inc. RISPERDAL 1 mg tablet. Bioavailability data were measured, and the results are summarized in the following table: See Table 1.
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Oral Solution: A randomized, single-dose, crossover, comparative bioavailability study was performed on 31 healthy adult male volunteers (aged 19-39 years) under fasting conditions with two Risperidone Tartrate Oral Solutions, pms-RISPERIDONE 1 mg/mL Oral Solution and RISPERDAL 1 mg/mL Oral Solution, by Janssen-Ortho Inc. The pharmacokinetic data calculated for the pms-RISPERIDONE 1 mg/mL Oral Solution and RISPERDAL 1 mg/mL oral solution formulation are tabulated as follows: See Table 2.
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Schizophrenia: Short-Term Clinical Trials: The efficacy of risperidone in the management of the manifestations of schizophrenia was established in three well-controlled, short-term (6- to 8-week), double-blind, clinical trials of psychotic in patients who met the DSM-III-R criteria of schizophrenia.
Psychiatric signs and symptoms were assessed according to the following rating scales: PANSS (Positive and Negative Syndrome Scale) total score and positive and negative subscales, BPRS (Brief Psychiatric Rating Scale) total score and psychosis cluster (conceptual disorganization, hallucinatory behaviour, suspiciousness, and unusual thought content), CGI-S (Clinical Global Impression - Severity of Illness) and SANS (Scale for Assessing Negative Symptoms).
The results of the trials follow: A 6-week, double-blind, flexible-dose trial (N = 160) compared risperidone up to 10 mg per day with haloperidol up to 20 mg per day or placebo. The mean daily dose of risperidone was 7.8 mg at endpoint. Risperidone was statistically significantly superior to placebo on the BPRS total score and psychosis cluster, as well as on the SANS and CGI-S.
An 8-week, double-blind, fixed-dose trial (N = 1,356) compared 5 doses of risperidone (1, 4, 8, 12 and 16 mg per day) with haloperidol 10 mg per day or placebo. The higher doses generally produced better results than the 1 mg dose. On the PANSS total score and negative subscale, as well as on the BPRS total score, a bell-shaped dose response relationship was established with optimal therapeutic responses occurring at the 4 mg and 8 mg doses. On the PANSS positive subscale and BPRS psychosis cluster, the dose-response relationship was linear (i.e., increasing doses produced increasing efficacy).
An 8-week, double-blind, fixed-dose trial (N = 513) compared 4 doses of risperidone (2, 6, 10 or 16 mg per day) with haloperidol 20 mg per day or placebo. Risperidone was statistically significantly superior to placebo on all scales measured (PANSS total score and positive and negative subscales, BPRS total score and psychosis cluster and CGI-S), although the difference between the 2 mg daily dose and placebo did not reach statistical significance in each case. The most consistent response on all measures was seen with the 6 mg per day dose, and there was no indication that the larger doses provided greater benefits.
The efficacy and safety of once-daily risperidone were established in a 4-week, placebo-controlled trial. In patients (N = 246), who met the DSM-IV criteria of schizophrenia, received fixed doses of risperidone, 4 or 8 mg per day, or placebo. Both risperidone groups were superior to placebo on several measures, including 'clinical response' (≥ 20% reduction in PANSS total score), PANSS total score and the BPRS psychosis cluster (derived from PANSS). Patients receiving 8 mg per day risperidone did generally better than those receiving the 4 mg per day dose.
In all studies, parkinsonian adverse events were mild, but dose related. Risperidone elevated serum prolactin levels. Due to the α1-adrenergic blocking activity, orthostatic hypotension with compensatory tachycardia was also observed.
Long-Term Clinical Trials: Long-term efficacy and safety of risperidone were demonstrated in a double-blind, randomized, parallel-group trial (N = 365) (duration 1 to 2 years) which compared time to relapse during maintenance treatment with risperidone (1-8 mg/day, mean = 5 mg/day) and haloperidol (2.5-20 mg/day, mean = 8 mg/day) in chronic patients who met the DSM-IV criteria of schizophrenia or schizoaffective disorder and had been stable for at least one month. There was a statistically significant difference between the risperidone and the haloperidol treatment groups for distribution of time to relapse (mean = 452 days vs. 391 days).
The pattern of adverse events observed in patients receiving risperidone in long-term clinical trials is consistent with those observed in short-term trials.
Elderly Patients with Severe Dementia: The effect of risperidone upon the management of behavioural disturbances in geriatric patients with severe dementia was evaluated in two well-controlled clinical trials. The first study was a fixed-dose, dose-response study in which risperidone, at daily doses of 0.5, 1.0 and 2.0 mg per day, was compared to placebo (N = 617). The second study was a flexible-dose study in which risperidone was compared to haloperidol and placebo (N = 344). The duration of the studies was 12 weeks. In both studies, patients had to meet the DSM-IV criteria for Alzheimer's and/or vascular dementia. The scales used to assess symptomatic efficacy included the BEHAVE-AD (Behavioural Pathology in Alzheimer's Disease Rating Scale), the CMAI (Cohen-Mansfield Agitation Inventory) and the CGI-C (Clinical Global Impression-Change). Potential extrapyramidal adverse events were assessed by the ESRS (Extrapyramidal Symptom Rating Scale).
In the fixed-dose study, 73%, 16% and 12% of patients were diagnosed with Alzheimer's, vascular and mixed dementia, respectively. At baseline, the MMSE (Mini-Mental State Examination) scores ranged from 6.0 to 7.8, and more than 95% of patients were at least at stage 6 on the FAST (Functional Assessment Staging). The median ages of the patients treated with risperidone ranged from 82 to 84 years with an overall range of 60 to 105 years. Risperidone, 1.0 and 2.0 mg per day, given b.i.d., decreased significantly both verbal and physical aggression and psychotic behaviour. The differences between the 0.5 mg dose and placebo did not reach statistical significance. The incidence of extrapyramidal adverse events was significantly higher with risperidone, 2.0 mg per day, than with placebo. The difference between risperidone 0.5 mg and 1.0 mg per day and placebo was not significant.
In the flexible-dose study, 67%, 26% and 7% of patients were diagnosed with Alzheimer's, vascular and mixed dementia, respectively. At baseline, the MMSE scores ranged from 7.9 to 8.8, and 61% and 31% of patients were at stage 6 and stage 7 on the FAST, respectively. The median age of the patients treated with risperidone was 81 years (range 68 to 97 years).
Risperidone, at a mean endpoint dose of 1.1 mg per day, given b.i.d., decreased significantly aggressive behaviour but not psychosis. ESRS scores, assessing extrapyramidal symptoms, were similar in patients treated with risperidone and placebo.
Risperidone had no effect on any of the other behaviours assessed by the BEHAVE-AD, namely activity disturbances, anxieties and phobias, or affective disturbances. Furthermore, the drug had no effect on either the MMSE scores or the FAST.
Bipolar Disorder - Mania: The efficacy of risperidone in the acute treatment of manic episodes associated with Bipolar I disorder was demonstrated in 3 double-blind, placebo-controlled monotherapy trials. The trials included initially hospitalized patients who met the DSM-IV criteria for Bipolar I disorder with manic episodes (with or without psychotic features).
In all 3 trials, patients were randomized to placebo (n = 409) or risperidone (n = 434). One of the trials also included a group of patients treated with haloperidol (n = 144). All 3 studies were 3 weeks in duration.
Flexible dosages of 1 mg to 6 mg/day were studied in these trials. Patients received an initial dose of 2 or 3 mg risperidone on Day 1, after which the dosage could be increased or decreased by 1 mg/day, based on the patient's response and tolerability. The primary rating instrument for assessing manic symptoms was the Young Mania Rating Scale (YMRS) and the primary outcome was the change from baseline in total YMRS score at the Week 3 endpoint (LOCF).
At a flexible dosage range of 1-6 mg/day, the 3 trials demonstrated that risperidone was statistically significantly superior to placebo in reducing manic symptoms as measured by the primary outcome, mean change in total YMRS score from baseline to endpoint (LOCF) over 3 weeks (p < 0.001).
In general, secondary efficacy outcomes were consistent with the primary outcome. The percentage of patients with a decrease of ≥ 50% in total YMRS score from baseline to endpoint (3 weeks, LOCF) was significantly higher for risperidone than for placebo in all studies.
Bioequivalence of Oral Formulations: Risperidone oral solution is bioequivalent to risperidone tablets.
Detailed Pharmacology: Risperidone represents a new generation of neuroleptic drugs combining potent serotonin type 2 (5-HT2) and dopamine-D2 antagonism.
In in vitro receptor binding assays, risperidone exhibited high binding affinity for the following receptor sites (Ki nM): 5-HT2 (0.16), α1-adrenergic (0.81), dopamine-D2 (1.4), H1-histaminergic (2.1), and α2-adrenergic (7.5). Risperidone was inactive at muscarinic cholinergic receptor sites (Ki: > 10,000 nM). Affinity for dopamine-D2 binding sites in rat brain showed little regional variation and was comparable to the affinity for cloned human D2 receptors.
Serotonin Antagonism: In rats, risperidone dose-dependently inhibited tryptamine-, mescaline-, 5-HTP-, and DOM (2,5-dimethoxy-4-methylamphetamine)-induced behavioural effects (ED50: 0.014-0.049 mg/kg sc). Higher risperidone doses completely blocked the serotonin agonist-induced behavioural effects.
In drug discrimination studies, risperidone was a potent and selective antagonist of LSD and DOM (0.024-0.028 mg/kg sc), devoid of partial 5-HT2 agonist activity and LSD-like abuse and dependence liability. Low doses of risperidone (0.01-0.16 mg/kg ip) increased deep slow wave sleep and decreased paradoxical sleep in rats.
Peripheral 5-HT2 antagonism was reflected, at very low doses, in the antagonism of tryptamine-induced cyanosis in rats (ED50: 0.0011 mg/kg sc) and serotonin-induced bronchospasm in guinea pigs (ED50: 0.0027 mg/kg ip).
Dopamine-D2 Antagonism: Risperidone dose-dependently antagonized apomorphine- and amphetamine-induced behavioural effects, namely apomorphine-induced climbing behaviour in mice (ED50: 0.062 mg/kg ip), amphetamine-induced hyperactivity in rats (0.02-0.04 mg/kg), apomorphine-induced stereotypy in rats (ED50: 3.2 mg/kg ip), and apomorphine-induced rotational behaviour in unilaterally 6-hydroxy-dopamine-lesioned mice (0.1-1.0 mg/kg dose range). Risperidone also reduced spontaneous locomotion (ED50: 0.22 mg/kg sc) and conditioned avoidance responding (ED50: 0.48 mg/kg ip) in rats and induced catalepsy in the 0.59-3.0 mg/kg (sc) dose range.
Risperidone increased the levels of the dopamine metabolites (DOPAC and HVA) in a dose-dependent manner in various brain regions.
In common with other neuroleptics, risperidone also produced effects that are related to blockade of peripheral dopamine-D2 receptors. Risperidone was a potent antagonist of apomorphine-induced emesis in dogs (0.005-0.007 mg/kg following iv, sc, or po administration). After oral administration, the onset of action was rapid, and the duration was 24 hours. In vitro, risperidone reversed dopamine-suppressed prolactin release in primary culture of rat anterior pituitary cells. In vivo, risperidone dose-dependently increased serum prolactin levels in rodents after single and repeated administration.
Combined 5-HT2 and Dopamine-D2 Antagonism: The combined 5-HT2 and dopamine-D2 antagonism of risperidone resulted in differences from specific dopamine-D2 antagonists. Risperidone reduced both spontaneous and amphetamine-stimulated locomotor activity more gradually. Dopamine-D2 receptor occupation and the extent of dopamine turnover potentiation varied according to brain region. Low doses of risperidone completely blocked 5-HTP-induced head twitches and discrimination stimulus effects of the hallucinogenic serotonin agonists DOM and LSD. Disinhibitory effects in amphetamine-treated rats were seen over a much wider dose range. Risperidone increased social interaction time. A sequential tryptamine-apomorphine challenge was more readily controlled.
Interaction with Histamine-H1 and α-Adrenergic Receptors: Blockade of peripheral histamine-H1 receptors by risperidone was evidenced by protection from compound 48/80-induced lethality in rats (ED50: 0.014 mg/kg sc) although the very potent 5-HT2 antagonism of risperidone might have contributed to this activity. Risperidone antagonized histamine-induced bronchospasm in guinea pigs (ED50: 0.037 mg/kg ip).
Risperidone also blocked α1-adrenoceptors as indicated by protection from norepinephrine-induced lethality in rats (ED50: 0.074 mg/kg sc) and induction of palpebral ptosis (ED50: 0.19 mg/kg sc).
Blockade of central α2-adrenoceptors was found at 2.4 mg/kg in the xylazine test. Reversal of the antidiarrheal effect of clonidine at 0.67 mg/kg reflected blockade of peripheral α2-adrenoceptors.
Cardiovascular effects, such as hypotension and reflex tachycardia observed in dogs, are considered to be predominantly consequences of vascular α1-adrenoceptor blockade. These effects diminished or disappeared during chronic treatment, indicating the development of tachyphylaxis.
In anaesthetized mongrel dogs, risperidone produced dose-dependent vasodilation accompanied by an increase in cardiac contractility, aortic blood flow and cardiac output. The minimal effective dose (0.005 mg/kg) was similar to the antiemetic dose.
In conscious Labrador dogs, a single oral dose of 0.08 mg/kg (11 times the oral antiemetic dose) reduced systolic and diastolic pressure but did not affect heart rate. After a single oral dose of 0.31 mg/kg (44 times the oral antiemetic dose), the blood pressure lowering effect became more pronounced, heart rate increased and QTc interval became prolonged but PQ and QRS intervals remained essentially uninfluenced.
Drug Interactions: After repeated administration of oral doses up to 10 mg/kg/day, risperidone did not interact in vivo with liver drug-metabolizing enzymes (cytochrome P-450, glucuronosyltransferase, and cytochrome c-reductase) that are known to be generally involved in the metabolism of drugs.
Pharmacology of the 9-Hydroxy Metabolite: Risperidone is predominantly metabolized to its 9-hydroxy derivative. This metabolite and its 2 enantiomers were comparable in potency, onset and duration of action, oral activity and pharmacological profile to risperidone.
Pharmacokinetics: Absorption: Risperidone was well absorbed after oral administration, had high bioavailability, and showed dose-proportionality in the therapeutic dose range, although inter-individual plasma concentrations varied considerably. Mean peak plasma concentrations of risperidone and 9-hydroxyrisperidone were reached at about 1 hour and 3 hours, respectively, after drug administration. Food did not affect the extent of absorption; thus, risperidone can be given with or without meals.
Distribution: Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. Steady-state concentrations of risperidone and 9-hydroxyrisperidone were reached within 1-2 days and 5-6 days, respectively. In plasma, risperidone is bound to albumin and alpha1-acid glycoprotein (AGP). The plasma protein binding of risperidone is approximately 88%, that of the metabolite 77%.
Metabolism: Risperidone is extensively metabolized in the liver by CYP 2D6 to a major active metabolite, 9-hydroxyrisperidone, which appears approximately equi-effective with risperidone with respect to receptor-binding activity. (A second minor pathway is N-dealkylation.) Consequently, the clinical effect of the drug likely results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. The hydroxylation of risperidone is dependent upon debrisoquine 4-hydroxylase, i.e., the metabolism of risperidone is sensitive to the debrisoquine hydroxylation type genetic polymorphism. Consequently, the concentrations of parent drug and active metabolite differ substantially in extensive and poor metabolizers. However, the concentration of risperidone and 9-hydroxyrisperidone combined did not differ substantially between extensive and poor metabolizers, and elimination half-lives were similar in all subjects (approximately 20 to 24 hours).
Excretion: One week after administration, 70% of the dose is excreted in the urine and 14% in the faeces. In urine, risperidone plus 9-hydroxyrisperidone represents 35-45% of the dose. The remainder is inactive metabolites.
Special Populations and Conditions: Table 3 summarizes the pharmacokinetic parameters observed in various subpopulations: See Table 3.
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The results indicate that a 1 mg dose of risperidone produced modest pharmacokinetic changes in elderly subjects, including reduced clearance of the active antipsychotic fraction by about 30%. In patients with impaired liver function, the unbound fraction of risperidone was increased by about 35% due to diminished concentrations of both α1-AGP and albumin. In patients with impaired renal function, the changes were substantial; Cmax and AUC of risperidone and 9-hydroxyrisperidone combined were increased by about 40% and 160% respectively, half-life was prolonged by about 60% and clearance decreased by about 60%.
Plasma Levels in Patients with Severe Dementia: The plasma levels of risperidone and its major metabolite, 9-hydroxyrisperidone, were determined at steady state. Blood samples were obtained from 85% of all trial patients receiving risperidone. Blood samples were drawn prior to the morning dose. Thus, the plasma levels shown in Table 4 represent trough levels. (See Table 4.)
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The plasma concentration of risperidone and 9-hydroxyrisperidone combined was dose proportional over the dosing range of 0.5 to 2 mg daily dose (0.25 to 1 mg b.i.d.).
Toxicology: Acute Toxicity: See Table 5.
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Toxicity was manifested by symptoms such as palpebral ptosis, prostration, catalepsy, sedation, hypothermia, and hypotonia at all doses, and clonic convulsions and loss of righting reflex at near lethal and lethal doses.
Occasionally, signs of gastrointestinal disturbance were present. Autopsy occasionally revealed gastric lesions and bleeding in rodents. All survivors recovered within the 14-day observation period.
The acute oral toxicity of 9-hydroxyrisperidone in rats was similar to that of the parent drug.
Subacute Toxicity: Oral Toxicity Study in Wistar Rats (3 months): Groups of 20 male and 20 female Wistar rats were administered risperidone in the diet at doses of approximately 0, 0.63, 2.5 or 10 mg/100 g food/day. There was no drug-related mortality or effects on behaviour and physical appearance. There was an increase in body weight gain in females (low- and mid-dosed groups), a temporary and transient decrease in body weight gain in males (mid-dosed group), and a persistent decreased body weight gain in both high-dosed groups.
The following changes were observed in serum biochemistry: decreased aspartate aminotransferase in high-dosed males and mid- and high-dosed females; increased cholinesterase in high-dosed males.
In females the weight of the adrenals was decreased. In high-dosed males, the weight of the adrenals was increased, and the weight of the kidneys was decreased. The major histological findings at autopsy included stimulation of the mammary gland (mid- and high-dosed male and all treated female rats), decreased glandular development of the uterus with decreased vaginal cornification and epithelial thickness, and inflammatory cell infiltration in the prostate (mid and high doses).
Oral Toxicity in Wistar Rats (3 months + 1 month recovery): Groups of 10 male and 10 female Wistar rats (complemented with 5 male and 5 female rats in the control group and high-dosed group for a 1-month recovery period) were administered risperidone by gavage at 0 (vehicle), 0.16, 0.63, 2.5 and 10 mg/kg body weight/day. There was no drug-related mortality. The findings were qualitatively similar to those observed in the 3-month study using the dietary route of administration.
Laboratory examination revealed the following changes: a slight increase in hematocrit, hemoglobin and red blood cells (within the normal range); a slight increase, at the borderline of normal limits, in blood urea nitrogen in both males and females at 2.5 and 10 mg/kg body weight; a slight decrease in glucose (females at 10 mg/kg body weight), total protein (males and females at 10 mg/kg body weight), calcium, albumin and triglycerides (mostly within the normal range) at 10 mg/kg body weight in males. Urinalysis showed a slight decrease in specific gravity and creatinine in male and female rats dosed at 2.5 and 10 mg/kg body weight; a slightly increased pH (males and females dosed at 10 mg/kg body weight) and volume (males and females dosed at 2.5 and 10 mg/kg body weight); and increased appearance of bacteria at 10 mg/kg body weight (males and females).
Gross and histopathological examination displayed prolactin-dependent changes similar to those seen in the 3-month study, consisting of mammary gland stimulation, changes in the prostate, and uterine and vaginal changes.
After 1 month of recovery, most of the changes showed reversibility. Mammary gland stimulation was still present in the high-dosed animals.
Oral Toxicity in Beagle Dogs (3 months): Groups of 4 male and 4 female Beagle dogs were administered risperidone orally in gelatin capsules at 0 (untreated), 0.31, 1.25 and 5 mg/kg body weight/day. All animals survived the 3-month study. Adverse clinical signs included dose-related sedation, miosis, soft faeces and congested conjunctiva. There was a transient decrease of body weight gain in high-dosed dogs during the first half of the study.
Hematological and serum analysis revealed: dose-dependent decrease of hematocrit, hemoglobin and red blood cells (within normal range) in medium- and high-dosed dogs; a dose-related moderate increase in haptoglobin (within the normal range) at all doses; and an increase of cholesterol and phospholipids at the medium and high doses.
Testicular and prostate weights decreased in a dose-related manner. Gross and histopathological examination revealed: increased presence of red blood cells in the spleen red pulp of the high-dosed group; decreased glandular development of the uterus and reduced epithelial thickness of the vagina in all dosed females; an immature aspect of the prostate and incomplete spermatogenesis in mid- and high-dosed male dogs.
Oral Toxicity in Beagle Dogs (3 months + 2 months recovery): Groups of 6 male Beagle dogs were administered risperidone orally in capsules at 0 (untreated), 0.31, 1.25 and 5 mg/kg body weight/day. Four dogs/group were sacrificed after 3 months and the remaining 2 after 5 months. There was no drug-related mortality and findings were similar to those of the first 3-month study. A dose-related sedation and an initial body weight decrease at all doses were present.
Male dogs were studied in order to establish the effects of risperidone upon male genitalia and assess their reversibility.
Erythrocytic parameters decreased in a dose-related manner; the changes were reversible. Haptoglobin, cholesterol and phospholipid levels increased dose-dependently; the changes were reversible.
At the end of the treatment period only 2 low-dosed dogs ejaculated; at the end of the recovery period 2 low-dosed dogs were normal, 1 out of 2 medium-dosed dogs ejaculated normal sperm and 1 out of 2 high-dosed dogs ejaculated poor quality sperm (reduced sperm motility and concentration). At the end of the treatment period, testosterone levels were dose-dependently reduced. At the end of the recovery period, the levels were still reduced in the 2 high-dosed dogs.
Prostate and testicle weights were dose-dependently decreased and associated with immaturity. At the end of the recovery period, prostate weights remained slightly lower than in control animals. Dose-related increases in liver and spleen weights were reversible.
Chronic Toxicity: Oral Toxicity Study in Wistar Rats (12 months): Groups of 20 male and 20 female Wistar rats were administered risperidone in the diet at doses of approximately 0, 0.63, 2.5 and 10 mg/100 g food/day. Doses expressed as mg/kg were lower. There was no drug-related mortality. High-dose males and females exhibited decreased weight gain. At 2.5 mg/kg, serum analysis revealed slightly decreased potassium and blood urea nitrogen levels and a slight increase in cholinesterase (within normal limits) in males; and decreased alanine aminotransferase level in females.
In addition to the changed serum variables seen at 2.5 mg/kg, dosing at 10 mg/kg resulted in a markedly decreased body weight gain; and a marginally reduced number of white blood cells and thrombocytes, decreased glucose, decreased urine creatinine and increased urine volume (within normal limits) in males, and decreased glucose, total protein and albumin in females. Most changes were slight.
Histopathology indicated changes in the prostate and mammary glands of medium- and high-dosed males and in the uterus, ovaries and mammary glands of all treated females. Medium- and high-dosed males showed diffuse hyperplasia of the pituitary, and in high-dosed males, the zona fasciculata of the adrenals was increased.
Oral Toxicity Study in Beagle Dogs (12 months): Groups of 4 male and 4 female Beagle dogs were administered risperidone orally via gelatin capsules at doses of 0 (untreated), 0.31, 1.25 and 5 mg/kg body weight/day. All animals survived the 12-month study. At the low dose, the main effects were related to the expected pharmacological action of risperidone, i.e., sedation and an interaction with the endocrine system (male and female genital tract changes). Mid and high dosing produced a slight to moderate toxicity that is similar to that described in the 3-month studies.
Laboratory examination revealed slight anemia during the first 3 months (decreased hematocrit, hemoglobin and red blood cells); dose-dependent moderate increase of haptoglobin, cholesterol and phospholipids; and a slight decrease of potassium (high-dosed group).
Organ weight changes included increases in spleen and pituitary weight and decreases in the weight of testes and prostate. Histopathology examination showed changes in the male and female genital tract, namely prostatic changes (fibrosis and clear basal cells), degenerative changes in the testicles of some dogs, decreased glandular development of the uterus, and the absence of corpora lutea. In addition, an increased number of red blood cells were seen in the spleen.
Reproductive and Developmental Toxicology: Fertility and General Reproductive Performance in Wistar Rats: One hundred and ninety-two Wistar rats were divided into groups of 24 males and 24 females. Risperidone, at approximately 0, 0.31, 1.25 or 5 mg/kg body weight/day was administered orally through the diet to males for a minimum of 60 days prior to and during mating. Females were dosed for a minimum of 14 days prior to mating (with equivalently dosed males) and further during the first part of pregnancy up to Day 8. No drug- or dose-related mortalities occurred.
Paternal and maternal effects were responsible for dose-dependent decreased and delayed mating behaviour (all doses), manifested by lower copulation indices, which caused lower pregnancy rates in rats receiving risperidone. However, where copulation occurred, the pregnancy rates were normal.
Fertility Study in Male Wistar Rats: One hundred and ninety-two Wistar rats were divided into groups of 24 males and 24 females. Risperidone, 0 (vehicle), 0.16, 0.63 and 2.5 mg/kg body weight/day was administered by gavage to male rats 60 days prior to and during mating to untreated female rats. No drug-related mortality occurred.
Fertility, gestation and copulation indices and the cohabitation-mating interval were comparable between groups. Litter data were comparable between groups and no teratogenic effects were present. These findings indicate no adverse effects on male fertility.
Fertility Study in Female Wistar Rats: One hundred and forty-four Wistar rats were divided into groups of 12 males and 24 females. Risperidone, 0 (vehicle), 0.16, 0.63 or 2.5 mg/kg body weight/day was administered by gavage to female rats from 14 days prior to mating (with untreated male rats) up to Day 8 of pregnancy. All animals survived the study. A dose-related sedation was present in the medium- and high-dosed groups.
The cohabitation-mating interval was slightly increased in the low- and medium-dosed groups. The interval was clearly prolonged in the high-dosed group. However, the number of corpora lutea was not affected indicating a normal ovulation rate once ovulation occurred.
Fertility, copulation and pregnancy indices were comparable between groups, and in pregnant females, no adverse effects were observed in the offspring. No teratogenic effects were found.
Embryotoxicity and Teratogenicity Study in Sprague-Dawley Rats: Two Segment II studies were conducted in Sprague-Dawley rats. Groups of 24 female rats received risperidone 0 (vehicle), 0.63, 2.5 or 10 mg/kg body weight/day by gavage from Day 6 through Day 16 of pregnancy. There was no drug-related mortality.
The weights of the pups of the high-dosed group slightly decreased in one of the studies. Risperidone was not teratogenic at the doses studied.
Embryotoxicity and Teratogenicity Study in Wistar Rats: Groups of 36 female rats were administered risperidone 0 (vehicle), 0.63, 2.5 or 10 mg/kg body weight/day by gavage from Day 8 through Day 18 of pregnancy. Twelve females per group were allowed to deliver naturally, followed by an evaluation of the second generation, whereas the others were sacrificed at the end of the pregnancy period following a Caesarean section. There was no drug-related mortality. Dose-related sedation was present at all dosage levels.
In the low- and medium-dosage groups no adverse effects on the litter were present. In the high dosage group, there was maternal toxicity (decreased weight gain) associated with decreased pup weight and slightly delayed ossification (reduced number of visible metatarsal bones). During the lactation period, pup weights were slightly increased, and survival rates were normal. Risperidone was not teratogenic at the doses studied.
In the undosed second generation, physical and behavioural development was comparable between groups and no adverse effects on fertility or on other reproduction parameters were observed.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to risperidone therapy is unknown (see Pregnant Women: Teratogenic Effects under Use in Pregnancy & Lactation).
Embryotoxicity and Teratogenicity Study in New Zealand White Rabbits: Groups of 15 female rabbits were administered risperidone at 0 (vehicle), 0.31, 1.25 or 5 mg/kg/day by gavage from Day 6 through Day 18 of pregnancy. Maternal toxicity was evidenced in the high dosage group by the death of 3 dams and by reduced body weight gain. At the doses studied, no embryotoxicity or teratogenic effects were seen.
Perinatal and Postnatal Study in Wistar Rats: Groups of 24 female Wistar rats were administered risperidone orally through the diet, at approximately 0, 0.31, 1.25 or 5 mg/100 g food/day from Day 16 of pregnancy through a 3-week lactation period. There was no drug-related mortality. Both body weight and food consumption decreased at all dose levels during lactation in a dose-dependent way. Duration of gestation was normal in all groups.
The survival rate of pups was decreased in the high-dosed group with only 32% surviving. On day 4 of lactation, the body weight of pups in the high-dosed group was significantly less than that of controls.
Perinatal and Postnatal Study in Wistar Rats (with Second Generation Evaluation): Groups of 24 female Wistar rats were administered risperidone 0 (vehicle), 0.16, 0.63 or 2.5 mg/kg body weight/day by gavage from Day 18 of pregnancy through a 3-week lactation period. All females were allowed to deliver naturally. No drug-related mortality was noted. Maternal adverse effects were evidenced by a small but significant increase in duration of gestation and by decreased food consumption and weight gain during lactation in the high-dosed dams.
An increased number of stillborn pups was observed in the high-dosed group and survival was reduced at all doses probably due to decreased nursing.
In the non-dosed second generation (F1), 10 females/group were mated with males from the same group. Pups were delivered by Caesarean section. There were no adverse effects on fertility or on other reproductive parameters. Observation of pups of the F2 generation indicated no abnormalities.
Two-Generation Reproduction Study: One hundred and ninety-two Wistar rats were divided into groups of 24 males and 24 females. Risperidone, at approximately 0, 0.16, 0.63 or 2.5 mg/100 g food/day was administered orally through the diet to males for 60 days prior to and during mating. Females were dosed for 14 days prior to mating (with equivalently dosed males), during pregnancy and lactation until weaning of the first generation. There was no dosing of the second generation. No drug-related mortalities occurred.
The cohabitation-mating interval increased with increasing dose levels. However, the duration of gestation was comparable between groups. Pregnancy and copulation indices decreased significantly in the high-dosed rats, but all mated females became pregnant. During pregnancy, body weight gain decreased in the medium- and high-dosed females. Dosing during lactation resulted in a reduced body weight of the high-dosed dams. Teratogenic effects were not evidenced at any dose.
Litter data including litter size, weight at birth, weight gain, and survival rate were comparable between controls and low- and medium-dosed rats. In the high-dosed rats, birth weight and survival rate were slightly lowered. The latter was related to decreased nursing behaviour. After weaning, physical and behavioural development were unaffected.
In the non-dosed second generation, no relevant adverse effects on fertility or on other reproduction parameters were noted.
Juvenile Toxicity Studies in Rats and Dogs: In a toxicity study in juvenile rats treated with oral risperidone (0, 0.04, 0.16, 0.63 or 2.5/1.25 mg/kg/day), increased pup mortality and a delay in physical development was observed. In a 40-week study with juvenile dogs treated with oral risperidone (0, 0.31, 0.125 or 5 mg/kg/day), sexual maturation was delayed. Based on AUC, long bone growth was not affected in dogs at 3.6-times the maximum human oral exposure in adolescents (1.5 mg/day); while effects on long bones and sexual maturation were observed at 15 times the maximum human oral exposure in adolescents.
Mutagenicity: Risperidone had no mutagenic effects when tested by the DNA-repair test in rat hepatocytes, the Ames reverse mutation test in Salmonella typhimurium and Escherichia coli, the mammalian cell gene mutation test in mouse lymphoma cells, the sex-linked recessive lethal test in Drosophila melanogaster, the chromosome aberration test in human lymphocytes and Chinese hamster lung cells, and the micronucleus test in the mouse bone marrow cells.
Carcinogenicity: Carcinogenicity Study in Albino Swiss Mice (18 months): Four groups of 50 male and 50 female mice received risperidone orally through the diet, at doses of approximately 0, 0.63, 2.5 or 10 mg/kg body weight/day. A slightly increased mortality was present in medium- and high-dosed females. In female mice at all doses, body weight gain was increased.
Hematological (decreased erythrocytic parameters and an increase in platelets) and serum biochemical changes (decrease in glucose and increase in cholinesterase; and in females only increase in cholesterol, phospholipids, haptoglobin, total protein, calcium and albumin) were similar to those observed in rat chronic toxicity studies.
Organ weight changes included increases in liver, spleen and heart weight. The weight of gonads in both sexes and the weight of adrenals in females were decreased.
Gross and histopathological examination demonstrated an increased incidence of non-neoplastic, prolactin-dependent changes in the accessory sex glands (coagulating gland, seminal vesicle), pancreas, and pituitary gland in the medium- and high-dosed males. In females, at all doses, the changes involved increased (mammary gland, pituitary gland), or decreased (female genital tract) prolactin-dependent modifications.
Neoplastic changes: there was a positive trend for mammary adenocarcinomas and pituitary gland adenomas in females. Regarding prolactin-independent neoplasia, there was a positive trend for lung tumours in female animals (the incidence was within the range of historical controls).
Carcinogenicity Study in Wistar Rats (25 months): Four groups of 50 male and 50 female rats received risperidone orally through the diet at doses of approximately 0, 0.63, 2.5 or 10 mg/100 g food/day. Mortality was increased in medium- and high-dosed males, and high-dosed females. In males at all doses and in mid- and high-dosed females, toxicity was expressed by decreased body weight gain, deterioration in general condition (males) and some changes in hematological and biochemical parameters. Organ weight changes included increased adrenal and decreased gonad weights.
Macroscopically, changes were seen in the mammary and pituitary gland, testes and uterus. Histopathological examination revealed prolactin-mediated non-neoplastic changes in the mammary gland, the pituitary gland and in the male and female genital tract at all doses, as well as renal pathology.
Neoplastic changes included a dose-related increase in mammary gland adenocarcinoma in both males and females and an increase in pancreatic endocrine adenoma in males. Neoplasms of the female genital tract (vagina, cervix, uterus) were decreased.