Isofredil
Isofredil Uses, Dosage, Side Effects, Food Interaction and all others data.
Isofredil binds selectively to the human dopaminergic D2 and D3 receptor subtypes without any affinity for D1, D4 and D5 receptor subtypes. Unlike classical and atypical neuroleptics, amisulpride displays low affinity for serotonin, α- adrenergic, histamine receptor subtypes, muscarinic receptors and sigma sites. In the rodent, it preferentially blocks post synaptic D2 receptors located in the limbic structures as compared to those in the striatum as indicated by its reversal of d-amphetamineinduced hyperactivity without affecting stereotypies. In addition, it does not induce catalepsy and it does not produce D2 hypersensitivity after repeated treatment.Moreover, it preferentially blocks pre-synaptic D2/D3 dopamine receptors, producing dopamine release responsible for its disinhibitory effects. This atypical pharmacological profile may explain amisulpride’s antipsychotic effect at higher doses through post-synaptic dopamine receptor blockade located in the limbic areas and its efficacy against negative symptoms, at lower doses, through presynaptic dopamine receptor blockade. In addition, the reduced tendency of amisulpride to produce extrapyramidal side effects may be related to its preferential limbic activity.
Isofredil is a selective dopamine D2 and D3 receptor antagonist with no affinity towards other dopamine receptor subtypes. Isofredil is an atypical antipsychotic agent that works as an antagonist at dopamine receptors in the limbic system. Since it works preferentially in the limbic system, amisulpride is less likely to be associated with extrapyramidal adverse effects than other atypical antipsychotic agents. Isofredil has no affinity for serotonin, alpha-adrenergic, H1-histamine, cholinergic, and sigma receptors. In clinical trials, amisulpride improved reduced secondary negative symptoms, affective symptoms, and psychomotor retardation in patients with acute exacerbation of schizophrenia. Notably, amisulpride has a differential target binding profile at different doses: at low doses, amisulpride selectively binds to presynaptic dopamine autoreceptors. At high doses, it preferentially binds to post-synaptic dopamine receptors. This explains how amisulpride reduces negative symptoms at low doses and mediates antipsychotic effects at high doses. One study alluded that the antinociceptive effects of amisulpride are mediated through opioid receptor acvitation and D2 receptor antagonism. The actions of amisulpride at opioid receptors may explain its pro-convulsant properties.
Isofredil is also an antiemetic agent that prevents and alleviates postoperative nausea and vomiting. It primarily works by blocking dopamine signalling in the chemoreceptor trigger zone, which is a brain area that relays stimuli to the vomiting center.
In clinical trials comprising Caucasian and Japanese subjects, amisulpride caused dose- and concentration-dependent prolongation of the QT interval; thus, intravenous infusion under a strict dosing regimen and close monitoring of patients with pre-existing cardiovascular conditions are recommended. Isofredil increases plasma prolactin levels, leading to an association with benign pituitary tumours such as prolactinoma.
| Trade Name | Isofredil |
| Availability | Prescription only |
| Generic | Amisulpride |
| Amisulpride Other Names | Aminosultopride, Amisulprida, Amisulpride, Amisulpridum |
| Related Drugs | amitriptyline, ondansetron, quetiapine, Abilify, Seroquel, Zofran, aripiprazole, olanzapine, risperidone, metoclopramide |
| Type | |
| Formula | C17H27N3O4S |
| Weight | Average: 369.479 Monoisotopic: 369.172227057 |
| Protein binding | Plasma protein binding ranges from 25% to 30% in the concentration range from 37 to 1850 ng/mL. Amisulpride distributes into erythrocytes. |
| Groups | Approved, Investigational |
| Therapeutic Class | Atypical neuroleptic drugs |
| Manufacturer | |
| Available Country | Greece |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Isofredil is used for the treatment of acute and chronic schizophrenic disorders, in which positive symptoms (such as delusions, hallucinations, thought disorders) and/or negative symptoms (such as blunted affect, emotional and social withdrawal) are prominent, including patients characterized by predominant negative symptoms.
Elderly: Isofredil should be used with particular caution because of a possible risk of hypotension or sedation.
Children: The efficacy and safety of amisulpride from puberty to the age of 18 years have not been established: there are limited data available on the use of amisulpride in adolescents in schizophrenia. Therefore, the use of amisulpride from puberty to the age of 18 years is not recommended. In children up to puberty, the use of amisulpride is contraused
Use in hepatic impairment: The impact of hepatic impairment on hepatic metabolism and hepato-biliary excretion of amisulpride has not been studied. Isofredil should be used with caution in patients with moderate or severe hepatic impairment.
Use in renal impairment: Isofredil is eliminated by the renal route. In cases of renal insufficiency, the dose should be decreased and intermittent treatment should be considered
Isofredil is also used to associated treatment for these conditions: Acute Schizophrenia, Chronic Schizophrenia, Negative Symptom, Post Operative Nausea and Vomiting (PONV)
How Isofredil works
Dopamine is an essential and critical neurotransmitter produced in the substantia nigra and ventral tegmental regions of the brain. Dopaminergic projection function in the nigrostriatal, mesolimbic, and mesocortical systems. Hyperactive dopamine transmission in the mesolimbic areas, or dopamine dysregulation in various major brain regions, is understood as the key driver of positive and negative symptoms of schizophrenia. Many antipsychotic agents act as D2 receptor antagonists, as with amisulpride. Isofredil is a selective dopamine D2 and D3 receptor antagonist. It has high preferential activity towards dopamine receptors in the limbic system rather than the striatum, leading to a lower risk of extrapyramidal side effects than other atypical antipsychotic agents. At low doses, amisulpride reduces negative symptoms of schizophrenia by blocking pre-synaptic dopamine D2 and D3 receptors, increasing the levels of dopamine in the synaptic cleft and facilitating dopaminergic transmission. At higher doses, amisulpride blocks postsynaptic receptors, inhibiting dopaminergic hyperactivity: this explains the drug improving positive symptoms. Isofredil also works as an antagonist at 5-HT7A receptors and 5-HT2A receptors, which may be related to its antidepressant effects.
The chemoreceptor trigger zone (CTZ), also commonly known as the area postrema (AP), is an important brain region located within the dorsal surface of the medulla oblongata. CTZ is involved in emesis: it contains receptors, such as dopamine receptors, that are activated in response to emetic agents in the blood and relay information to the vomiting center, which is responsible for inducing the vomiting reflex. Isofredil is an antiemetic agent that works to limit signals that promote nausea and vomiting. Isofredil binds to D2 and D3 receptors in the CTZ, leading to reduced dopaminergic signalling into the vomiting center.
Dosage
Isofredil dosage
For acute psychotic episodes, oral doses between 400 mg/d and 800 mg/d are recommended. In individual cases, the daily dose may be increased up to 1200 mg/d. Doses above 1200 mg/d have not been extensively evaluated for safety and therefore should not be used. Doses above 800 mg/d have not been shown to be superior to lower doses and may increase the incidence of adverse events. No specific titration is required when initiating the treatment with amisulpride.
Doses should be adjusted according to individual response. Doses should preferably be administered before meals. Isofredil should be administered twice daily for doses above 400 mg. For patients with mixed positive and negative symptoms, doses should be adjusted to obtain optimal control of positive symptoms. Maintenance treatment should be established individually with the minimally effective dose. For patients characterized by predominant negative symptoms, oral doses between 50 mg/d and 300 mg/d are recommended. Doses should be adjusted individually.
Toxicity
In mice, oral LD50 is 1024 mg/kg, intraperitoneal LD50 is 175 mg/kg, and subcutaneous LD50 is 224 mg/kg. The Lowest published toxic dose (TDLo) following subcutaneous administration is 0.24 mg/kg in rats. The oral TDLo in men is 4.3 mg/kg.
Oral doses of amisulpride above 1200 mg/day are associated with adverse effects related to dopamine-2 (D2) antagonism. Cardiovascular adverse reactions include prolongation of the QT interval, torsades de pointes, bradycardia, and hypotension. Neuropsychiatric adverse reactions include sedation, coma, seizures, and dystonic and extrapyramidal reactions. As there is no specific antidote for amisulpride overdosage, management includes cardiac monitoring and treatment of severe extrapyramidal symptoms. Drug elimination with the use of hemodialysis is effective. Severe extrapyramidal effects may be managed with anticholinergic drugs.
Precaution
Neuroleptic Malignant Syndrome (NMS) is a potentially fatal syndrome that has been reported in association with anti psychotic medicines, including amisulpride. Neuroleptic malignant syndrome is characterised by hyperthermia, muscle rigidity, autonomic instability, and elevated CPK, may occur. In the event of any symptoms which could suggest NMS, in particular hyperthermia, particularly with high daily doses, all antipsychotic medicines including amisulpride should be discontinued. Isofredil can lower the seizure threshold. Therefore patients with a history of seizures should be closely monitored during amisulpride therapy.
Food Interaction
- Avoid alcohol. Isofredil may enhance the effects of alcohol.
- Take with or without food. A high fat meal does not significantly affect drug pharmacokinetics, although a carbohydrate rich meal decreases drug absorption and levels.
Isofredil Drug Interaction
Major: venlafaxine, fluoxetineModerate: aripiprazole, glycerin, albuterol, olanzapineUnknown: aspirin, charcoal, amoxicillin / clavulanate, ubiquinone, copper gluconate, ginkgo, sodium iodide, levocarnitine, pregabalin, acetaminophen, diazepam, cyanocobalamin, cholecalciferol, alprazolam
Volume of Distribution
Following oral administration, the volume of distribution is 5.8 L/kg. Following intravenous infusion, the mean volume of distribution of amisulpride is estimated to be 127 to 144 L in surgical patients and 171 L in healthy subjects.
Elimination Route
Following oral administration, amisulpride is rapidly absorbed with absolute bioavailability of 48%. Isofredil has two absorption peaks, with one rapidly achieved within one hour post-dose and a second peak occurring between three to four hours post-dose. Following oral administration of a 50 mg dose, two peak plasma concentrations were 39 ± 3 and 54 ± 4 ng/mL.
Following intravenous administration, the peak plasma concentration of amisulpride is achieved at the end of the infusion period and the plasma concentration decreases by 50% within approximately 15 minutes. The AUC(0-∞) increases dose-proportionally in the dose range from 5 mg to 40 mg, which is about four times the maximum recommended dose. In healthy patients receiving intravenous amisulpride, the mean (SD) Cmax was 200 (139) ng/mL at the dose of 5 mg and 451 (230) ng/mL at the dose of 10 mg. The AUC ranged from 136 to 154 ng x h/mL in the dose range of 5 mg to 10 mg. In patients undergoing surgery, the mean (SD) Cmax ranged from 127 (62) to 161 (58) ng/mL at the dose of 5 mg. At the dose of 10 mg, it was 285 (446) ng/mL. The AUC ranged from 204 to 401 ng x h/mL.
Half Life
Elimination is biphasic. The elimination half-life of amisulpride is approximately 12 hours after an oral dose. The mean elimination half-life is approximately four to five hours in both healthy subjects and patients undergoing surgery receiving intravenous amisulpride.
Clearance
The plasma clearance of amisulpride is 20.6 L/h in surgical patients and 24.1 L/h in healthy subjects following intravenous administration. Renal clearance was estimated to be 20.5 L/hr (342 mL/min) in healthy subjects.
Elimination Route
Following intravenous administration, about 74% of amisulpride is excreted in urine, where 58% of the recovered dose was excreted as unchanged amisulpride. About 23% of the dose is excreted in feces, with 20% of the excreted dose as unchanged parent drug. Following intravenous administration, about four metabolites were identified in urine and feces, accounting for less than 7% of the total dose administered. About 22 to 25% of orally administered amisulpride is excreted in urine, mostly as the unchanged parent drug.
Pregnancy & Breastfeeding use
pregnancy Category C. The safety of amisulpride during human pregnancy has not been established, and therefore use of amisulpride is not recommended during pregnancy and in women of child bearing potential not using effective contraception, unless the benefits justify the potential risks and the administered dose and duration of treatment should be as low and as short as possible. Isofredil has been found in the breast milk of treated women. Breast-feeding is contraindicated.
Contraindication
Hypersensitivity to the active ingredient or to other ingredients of the product. Concomitant prolactin-dependent tumours e.g. pituitary gland prolactinomas and breast
cancer. Phaeochromocytoma. Children up to puberty. Lactation.
Storage Condition
Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.
Innovators Monograph
You find simplified version here Isofredil
Isofredil contains Amisulpride see full prescribing information from innovator Isofredil Monograph, Isofredil MSDS, Isofredil FDA label
FAQ
What is Isofredil used for?
Isofredil is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes.
How safe is Isofredil?
Isofredil demonstrated a satisfactory global safety profile in the range of doses usually prescribed.
How does Isofredil work?
Isofredil works by blocking the receptors in the brain that dopamine acts on. This prevents the excessive activity of dopamine and helps to control psychotic illness.
What are the common side effects of Isofredil?
Common side effects of Isofredil are include:
- Difficulty sleeping (insomnia) or feeling anxious or agitated
- Feeling drowsy or sleepy
- Constipation, feeling or being sick, dry mouth
- Putting on weight
- Unusual production of breast milk in women and men, breast pain
- Menstrual period stops
- Breast enlargement in men
- Difficulty in getting or maintaining an erection, or in ejaculating
- Feeling dizzy (which can be due to low blood pressure)
- Blurred vision
Is Isofredil safe during pregnancy?
Isofredil is not recommended during pregnancy and in women of childbearing potential not using effective contraception. If you use Isofredil during the last three months of pregnancy, your baby may suffer from agitation, increased muscle tension, involuntary trembling of the body, sleepiness, breathing problems or difficulty in feeding. Talk to your doctor, if your baby develops any of these symptoms.
Is Isofredil safe during breastfeeding?
You should not breast-feed during therapy with Isofredil. Talk to your doctor about the best way to feed your baby if you are taking Isofredil.
Can I drive after taking Isofredil?
You may feel less alert, drowsy or sleepy and have blurred vision while taking this medicine. If this happens, do not drive or use any tools or machines.
Can I drink alcohol with Isofredil?
Do not drink alcohol while you are taking Isofredil. This is because Isofredil can change the way the alcohol affects you.
Can Isofredil used for children?
This Isofredil is not recommended in people under 18 years old.
What happen If I take more does on Isofredil?
If you take more tablets than you should, tell a doctor or go to a hospital casualty department straight away. Take the medicine pack with you. This is so the doctor knows what you have taken. The following effects may happen: feeling restless or shaky, rigid muscles, feeling drowsy or sleepy which could lead to a loss of consciousness.
What happen If I forget to take Isofredil?
If you forget to take a dose at the right time, take it as soon as you remember, then go on as before. However, do not take a double dose to make up for a forgotten tablet.
What happen If I stop taking Isofredil ?
Keep taking Isofredil until your doctor tells you to stop. Do not stop taking your medicine just because you feel better as your illness may get worse or come back. Unless your doctor tells you otherwise, Isofredil should not be stopped suddenly as this may cause withdrawal effects such as muscle stiffness or unusual body movements.
When should be taken of Isofredil?
You can take Isofredil once a day (lower doses) or twice a day, in the morning and evening (for higher doses). Take your Isofredil dose at the same times each day. It is best to take your Isofredil dose before food.
How quickly does Isofredil work?
To begin with, most people find that this medication will help them feel more relaxed and calm. Later, after one or two weeks, other symptoms should begin to improve. Unfortunately, you might get some side effects before you start to feel any better. Most side effects should go away after a few weeks.
How long does Isofredil stay in my system?
The elimination half-life of Isofredil is approximately 12 hours after an oral dose. Isofredil is eliminated unchanged in the urine. Fifty percent of an intravenous dose is excreted via the urine, of which 90% is eliminated in the first 24 hours.
Can I take Isofredil for a long time?
Treatment with Isofredil is usually long-term unless you experience an adverse effect.
Does Isofredil lower blood pressure?
Isofredil does not affect blood pressure to the same extent as other antipsychotic drugs and so blood pressure monitoring is not mandatory for this drug.
Can Isofredil affects my heart ?
Electrocardiogram showed that all antipsychotics except for Isofredil tended to prolong mean QTc times, prolongation of which increases the risk of ventricular tachycardia.
Can Isofredil affect my kidneys?
Isofredil are known to cause acute kidney injury (AKI). Such outcomes include hypotension, acute urinary retention, and the neuroleptic malignant syndrome or rhabdomyolysis.
Can Isofredil affects my liver?
Severe liver problems have been reported with Isofredil.
Does Isofredil make I sleepy?
Elderly people may be prescribed a lower dose. This is because Isofredil may make you feel sleepy or lower your blood pressure which could make you feel dizzy, light headed or faint.
