Paliperidone
When ATH: N05AX13
Pharmacological action
Pharmacological action – antipsychotic (anxiolytic).
Paliperidone - D2-antagonist dopaminovыh retseptorov tsentralynogo actions, also has high antagonism against serotonin 5-HT2 receptors. Besides, paliperidone yavlyaetsya antagonistom α1- and α2-adrenergic and histamine H1 receptors. Paliperidone has no affinity for holinoretseptorami, muscarinic, and β1- и beta2-адренорецепторам. Pharmacological Activity (+)- and (-) -enantiomers of paliperidone is the same qualitatively and quantitatively.
Antipsychotic effect due to blockade of dopamine D2-receptors and the mesolimbic system Mesocortical. It causes minimal suppression of motor activity and to a lesser extent induces catalepsy, than classical antipsychotics (neuroleptics).
Balanced central serotonin antagonism and dopamine can reduce susceptibility to extrapyramidal side effects and enhance the therapeutic effects of the drug, including negative and positive symptoms of schizophrenia.
Paliperidone has an effect on sleep structure: reduces latency to sleep, reduces the number of awakenings after sleep, increases total sleep time, It increases during sleep and improves sleep quality index. It has antiemetic effect, It can cause an increase in the concentration of prolactin in plasma.
Pharmacokinetics
The pharmacokinetic characteristics of paliperidone after ingestion proportional to the dose in the recommended therapeutic range (3-12 Mg 1 time / day).
Absorption
After a single dose of the drug in the plasma paliperidone concentration steadily increased, and Cmax was achieved after 24 no. Features of release of drug substance from Invegi provides less fluctuation of maximum and minimum concentrations of paliperidone, than, observed with conventional dosage forms.
After receiving tablets paliperidone is a mutual transformation (+)- and (-)-enantiomers, and the ratio of AUC(+)/AUC(-) at steady state is about 1,6. The absolute bioavailability of paliperidone after oral administration of 28%. After a single dose 15 mg paliperidone in the form of sustained release tablets with high-calorie oily food Cmax and AUC increased, average, on 42-60% and 46-54% respectively, relative to the same parameters when taking the tablets on an empty stomach. Thus, the presence or absence of food in the stomach during reception can vary the concentration of paliperidone in plasma paliperidone.
Distribution
Most patients reached after paliperidone Css 4-5 day dosing 1 time / day.
Paliperidone is rapidly distributed in tissues and body fluids. Кажущийся CEO – 487 l. Plasma protein binding is 74%. Paliperidone binds preferentially to α1-acid glycoprotein and albumin.
Metabolism and excretion
There are four ways in vivo metabolism of paliperidone, none of which covers more than 6,5% dose: dealkylation, hydroxylation, dehydrogenation and benzisoxazole splitting. Studies in vitro have shown, that CYP2D6 and CYP3A4 isoenzymes may play a role in the metabolism of paliperidone, However, evidence, they play an important role in the metabolism of paliperidone in vivo, failed to obtain. Despite, that in the general population, the rate of metabolism of CYP2D6 substrates varies considerably, population pharmacokinetic studies did not reveal significant differences apparent clearance of paliperidone after administration between fast and slow metabolizers CYP2D6 substrates. Studies in vitro using microsomal preparations of heterologous systems demonstrated, that CYP1A2 isoenzymes, CYP2A6, CYP2C9, CYP2C19 and CYP3A5 are not involved in the metabolism of paliperidone. Through 1 one week after receiving the standard tablets, contained 1 mg paliperidone, 59% the dose is excreted in the urine as unchanged. This indicates that, that paliperidone is not subjected to intensive metabolism in the liver. About 80% the active substance was found in urine and about 11% – Calais. End T1 / 2 is about paliperidone 23 no.
Pharmacokinetics in special clinical situations
In patients with impaired hepatic function it is not necessary to reduce the dose of paliperidone, since the latter is not subjected to intensive metabolism in the liver. Research, which involved patients with moderate hepatic impairment (Class B for Child-Pugh), found, that these patients the concentration of free plasma paliperidone were similar to those in healthy individuals.
In patients with moderate and severe renal impairment the dose should be reduced paliperidone. Excretion of paliperidone was studied in patients with varying degrees of renal impairment. It was found, that the elimination of paliperidone decreased with decreasing QC. Total clearance of paliperidone was reduced by 32% in patients with mild renal impairment (KK from 50 to 80 ml / min), on 64% in patients with moderate renal impairment (KK from 30 to less 50 ml / min) and 71% in patients with severely impaired renal function (CC less than 30 ml / min). Average final T1 / 2 was paliperidone 24, 40 and 51 hours in patients with mild, moderate and severe renal impairment, respectively,. In people with normal kidney function (QC more 80 ml / min) the figure was 23 no.
It is not recommended to change the dose of paliperidone, depending on the age of the patient. The results of pharmacokinetic studies, which included elderly patients (age 65 and older, n=26) shown, that the apparent clearance of paliperidone in the steady state after receiving Invegi in this group was 20% below, than in adults (18-45 Years, n=28). At the same time, after adjusting for age-related decline QC, population analysis showed no effect of age on the pharmacokinetics of schizophrenia paliperidone.
There is no need to change the dose of paliperidone, depending on the patient's race. Population analysis showed no effect of race on the pharmacokinetics of paliperidone after administration.
The recommended dose of paliperidone are the same for men and women.
The apparent clearance of paliperidone after administration in women about 19% below, than men. This difference is mainly due to differences in lean body mass and CK between men and women, as population studies, after adjusting for lean body mass and QC, revealed no clinically relevant differences in the pharmacokinetics of paliperidone in men and women, taking the drug.
The pharmacokinetic characteristics of paliperidone after ingestion proportional to the dose in the recommended therapeutic range (3-12 Mg 1 time / day).
The recommended dose of paliperidone are the same for men and women.
It is not recommended to change the dose of paliperidone in smokers. In vitro studies using human liver enzymes showed, that paliperidone is not a substrate of CYP1A2, and therefore smoking should not affect the pharmacokinetics of paliperidone. In accordance with the results of in vitro studies, population studies found no differences in the pharmacokinetics of paliperidone between smokers and nonsmokers.
Indications
Schizophrenia (incl. exacerbation).
Prevention of exacerbations of schizophrenia.
Dosing and Administration
Paliperidone is intended for oral use.
The recommended dose is 6 mg 1 time / day, morning, regardless of the meal. The gradual increase of the initial dose is required. In some patients, the therapeutic effect causing lower or higher doses within the recommended range of 3-12 mg 1 time / day. The tablets should be swallowed whole, with some liquid, they can not chew, divided into pieces or grind.
For patients with mild renal impairment (QC more 50 ml / min, but less 80 ml / min)
The recommended dose is 6 mg 1 time / day. For patients with umerennymili severe renal impairment (CC less than 50 ml / min) The recommended dose is 3 mg 1 time / day. Change the dose when indicated follows the re-evaluation of the patient.
Patients with impaired hepatic function
Not required dose reduction.
For elderly patients with normal renal function (QC more 80 ml / min)
We recommend the same dose, as for adults with normal renal function. At the same time, elderly patients renal function may be reduced, in this case, the dose should be selected according to the function of kidneys in an individual patient.
It is not recommended to change the dose of paliperidone according to sex, age and smoking habit.
Application for violations of liver function
Patients with impaired hepatic function dose reduction is not required.
Application for violations of renal function
For patients with umerennymili severe renal impairment (CC less than 50 ml / min) The recommended dose is 3 mg 1 time / day.
Contraindications
Hypersensitivity to paliperidone.
Pregnancy and lactation
There is currently no data on the safety of paliperidone during pregnancy women and its impact on fetal development. The drug should not be administered during pregnancy except in cases of extreme necessity from a clinical point of view,. Influence of paliperidone on generic activities of women do not know.
The use of antipsychotic drugs in the III trimester of pregnancy is associated with reversible extrapyramidal symptoms in the newborn.
Paliperidone is excreted in breast milk, so the drug should not be prescribed during lactation.
Side effect
The most common side effects
Headache, tachycardia, akathisia, sinus tachycardia, extrapyramidal symptoms, drowsiness, dizziness, sedation, tremor, arterial hypertension, dystonia, orthostatic hypotension, dry mouth.
Dose-dependent side effects
Weight gain, headache, hyperptyalism, vomiting, dyskinesia, akathisia, dystonia, extrapyramidal symptoms, arterial hypertension, parkinsonizm.
The frequency of side effects listed below:
Often (more 10 %).
Often (more 1 % less 10 %).
Sometimes (more 0,1 % less 1 %).
Rarely (more 0,01 % less 0,1 %)
Rarely (less 0,01 %).
From the central and peripheral nervous system
Very often - headache.
Often – akathisia, dizziness, dystonia, extrapyramidal symptoms, arterial hypertension, parkinsonizm, sedation, drowsiness, tremor.
Sometimes - postural dizziness, dyskinesia, generalized epilepsy, fainting, nightmares.
On the part of the organ of vision
Sometimes - involuntary rotation of the eyeball.
Cardio-vascular system
Often - sinus tachycardia, tachycardia, AV block I degrees, bundle-branch block, orthostatic hypotension.
Inogda - bradycardia, heartbeat, sinus arrhythmia, gipotenziya, išemiâ, ECG changes.
From the digestive system
Often - pain in the upper abdomen, dry mouth, hyperptyalism, vomiting.
On the part of the musculoskeletal system
Sometimes - muscle rigidity.
Reproductive system
Sometimes - amenorrhea, galactorrhea, discharge from the nipple, erectile dysfunction, gynecomastia, changes in menstrual cycle.
Laboratory findings
Increased serum prolactin.
Allergic reactions
Sometimes - anaphylactic reaction.
Other
Often - asthenic disorders.
Sometimes - peripheral edema, weight gain.
Drug Interactions
Paliperidone, probably, not enter into a clinically significant pharmacokinetic interaction with drugs, are metabolized by cytochrome P450 isozymes. In vitro studies using human liver microsomes revealed, that paliperidone does not substantially oppression biotransformation of drugs, metabolized with participation of cytochrome P450 isoenzymes, including CYP1A4, CYP2А6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4 и CYP3A5. Therefore there is no reason to suppose, paliperidone that will inhibit clinically significant degree clearance of drugs, are metabolized by these enzymes. Besides, paliperidone, probably, It does not induce enzymes.
In therapeutic paliperidone concentrations did not inhibit P-glycoprotein, and therefore is able to inhibit in a clinically significant degree of transportation other preparations P-glycoprotein.
Given the fact, that paliperidone operates mainly on the CNS, it must be used with caution in combination with other centrally acting drugs and ethanol.
Paliperidone may neutralize the effect of levodopa and other dopamine agonists. Because of the ability of paliperidone to cause orthostatic hypotension may occur an additive effect when using the drug in conjunction with other drugs, cause orthostatic hypotension.
Paliperidone is not a substrate of CYP1A2 isoenzymes, CYP2А6, CYP2С9, CYP2C19 and CYP3A5. This indicates a low probability of its interaction with inhibitors or inducers of these enzymes. In in vitro studies revealed minimal participation of isoenzymes CYP2D6 and CYP3A4 in the metabolism of paliperidone, at the same time, there is no evidence, These isoenzymes play a significant role in the metabolism of paliperidone in vitro or in vivo.
Paliperidone, are cationic at physiological pH, excreted largely unchanged by the kidneys; with about half of excretion accounted for about half of the filter and - the share of active secretion. The use of paliperidone simultaneously with trimethoprim, which, as it is known, The inhibitory activity of renal cationic transport agents, It had no effect on the pharmacokinetics of paliperidone.
Simultaneous use of risperidone and paliperidone were not the subject of scientific research. Paliperidone is an active metabolite of risperidone, and therefore the simultaneous use of paliperidone and risperidone may increase the concentration of paliperidone in plasma.
Precautions
Neuroleptic malignant syndrome
Known, Antipsychotic drugs, including as paliperidone, can cause neuroleptic malignant syndrome (NMS), which is characterized by hyperthermia, muscle stiffness, instability of the autonomic nervous system function, depression of consciousness, as well as an increase in serum concentrations of creatine phosphokinase. Patients with NMS may also occur myoglobinuria (raʙdomioliz) and acute renal failure. If you have a patient objective or subjective symptoms of NMS should immediately cancel all antipsychotics, including as paliperidone.
Pozdnyaya dyskinesia
Preparations, having dopamine receptor antagonist properties, can cause tardive dyskinesia, which is characterized by rhythmical involuntary movements, mainly language and / or facial muscles. If you have a patient objective or subjective symptoms, indicating tardive dyskinesias, should consider the abolition of all antipsychotics, including as paliperidone.
Giperglikemiâ
In clinical studies of paliperidone occasionally observed undesirable effects, associated with glucose metabolism. It is recommended to carry out appropriate monitoring in patients with diabetes, and in patients, with risk factors for diabetes.
Orthostatic hypotension
Paliperidone has an activity of α-blockers, and thus may cause some patients orthostatic hypotension. Paliperidone must be used with caution in patients with cardiovascular disease (eg, heart failure, myocardial infarction or ischemia, conduction disorder of the heart muscle), cerebrovascular diseases, and to the states, contributing to hypotension (eg, dehydration and hypovolemia).
Convulsions
Like other antipsychotics, Paliperidone should be used with caution in patients, with a history of seizures or other diseases, lowering the seizure threshold.
Possibility of gastrointestinal obstruction
There are rare reports of obstructive symptoms of the gastrointestinal tract, associated with oral dosage forms nondeformable controlled release of the active substance. Paliperidone also refers to such dosage forms, and so it can be prescribed only to patients, that can swallow the tablets whole.
Elderly patients with dementia
Paliperidone is not studied in elderly patients with dementia. However, placebo-controlled trials, which involved elderly patients with dementia, showed increased incidence of cerebrovascular adverse effects (stroke and transient ischemic attack), incl. Fatal, patients, Get some atypical antipsychotics, vklyuchavshimi risperidone, aripiprazole, and olanzapine, compared to patients, who received placebo.
Parkinson's disease and dementia with Lewy bodies
It is necessary to carefully assess the potential risks and potential benefits in the appointment of antipsychotic drugs, including as paliperidone, patients, suffering from Parkinson's disease or dementia with Lewy bodies, since such patients may increase the risk of NMS, or increased sensitivity to antipsychotics, manifestations of which include, in addition to extrapyramidal symptoms, confusion, blunted reactions and postural hypotension with frequent falls.
Priapism
Preparations, capable of blocking the α-adrenergic effects, can cause priapism. In clinical trials of paliperidone were observed cases priapism, However paliperidone has said pharmacological activity, so the treatment can not completely exclude the risk of priapism.
The regulation of body temperature
Antipsychotics attributed this undesirable effect, as a violation of the body's ability to regulate temperature. Care should be taken when appointing paliperidone in patients with conditions, which can enhance the internal body temperature, which include intense exercise, the impact of high external temperatures, concurrent use of drugs with anticholinergic activity, or dehydration.
Antiemetic effect
In preclinical studies it was identified antiemetic effects of paliperidone. This effect, if it occurs in humans, may mask the objective and subjective symptoms of an overdose of some drugs, and such diseases, as a bowel obstruction, Reye's syndrome and brain tumor.
Translation patients on treatment with other antipsychotic drugs
There is currently no systematic data collected on the transfer of patients to the treatment for the treatment of paliperidone other antipsychotic drugs. Pharmacodynamics and pharmacokinetics in different antipsychotics are not the same, so doctors must carefully monitor patients during their transfer from one antipsychotic to another.
Effects on ability to drive vehicles and management mechanisms
Paliperidone may interfere with the ability of the activities, requiring quick mental reaction, therefore, patients should refrain from driving and using machinery until, until you have established their individual sensitivity to the drug.
