Trevicta (Suspension) Instructions for Use

Marketing Authorization Holder

Johnson & Johnson, LLC (Russia)

Manufactured By

Janssen Pharmaceutica, NV (Belgium)

Contact Information

JANSSEN, pharmaceutical division of Johnson & Johnson LLC

ATC Code

N05AX13 (Paliperidone)

Active Substance

Paliperidone (Rec.INN WHO registered)

Dosage Form

Trevicta

Prolonged-release intramuscular suspension 200 mg/1 ml: 0.875 ml (175 mg), 1.315 ml (263 mg), 1.75 ml (350 mg), or 2.625 ml (525 mg) syringes with injection needles

Dosage Form, Packaging, and Composition

Prolonged-release suspension for intramuscular administration white or almost white, free from foreign particles.

Excipients: polysorbate 20 – 10 mg, macrogol 4000 (polyethylene glycol 4000) – 75 mg, citric acid monohydrate – 7.5 mg, sodium dihydrogen phosphate monohydrate – 6.0 mg, sodium hydroxide – 5.4 mg, water for injections – up to 1 ml.

0.875 ml (175 mg) – syringes (1) complete with needles for intramuscular injection (2 pcs. – for deltoid and gluteal muscle) – carton packs.
1.315 ml (263 mg) – syringes (1) complete with needles for intramuscular injection (2 pcs. – for deltoid and gluteal muscle) – carton packs.
1.75 ml (350 mg) – syringes (1) complete with needles for intramuscular injection (2 pcs. – for deltoid and gluteal muscle) – carton packs.
2.625 ml (525 mg) – syringes (1) complete with needles for intramuscular injection (2 pcs. – for deltoid and gluteal muscle) – carton packs.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Psycholeptics; antipsychotics; other antipsychotics

Pharmacological Action

Mechanism of action

Paliperidone belongs to the chemical class of benzisoxazole derivatives and is an atypical antipsychotic agent. Paliperidone palmitate is hydrolyzed to paliperidone. The latter is a centrally acting antagonist primarily of serotonin 5-HT_2A receptors, as well as dopamine D₂ receptors, adrenergic α₁ and α₂ receptors, and H₁ histamine receptors. Paliperidone does not bind to cholinergic muscarinic receptors or adrenergic β₁ and β₂ receptors. The pharmacological activity of the (+) and (-) enantiomers of paliperidone is quantitatively and qualitatively similar.

The therapeutic efficacy of the drug in schizophrenia is presumed to be mediated through a combined antagonism of D₂ and 5-HT_2A receptors.

Pharmacokinetics

Absorption and distribution

Due to its extremely low water solubility, paliperidone palmitate dissolves slowly after intramuscular injection, is hydrolyzed to paliperidone, and absorbed into the systemic circulation. Release of the substance begins on the first day and continues for up to 18 months. After a single intramuscular injection, the plasma concentration of paliperidone gradually increases, reaching a maximum after 30-33 days (median T_max). After intramuscular injection of Trevicta in doses of 175-525 mg into the deltoid muscles, the C_max value is on average 11-12% higher than the corresponding value after injection into the gluteal muscles. The release characteristics of the active ingredient and the dosing regimen of Trevicta ensure prolonged maintenance of therapeutic concentration. The AUC (area under the concentration-time curve) of paliperidone after administration of Trevicta is dose-proportional in the range of 175-525 mg, and the C_max dynamics approach dose proportionality. The mean peak-to-trough ratio was 1.6 after administration of Trevicta into the gluteal muscles and 1.7 after administration into the deltoid muscles. The apparent volume of distribution of paliperidone after administration of Trevicta is 1960 L. Paliperidone is 74% bound to plasma proteins.

After administration of the drug, the (-) and (+)-enantiomers of paliperidone interconvert, reaching an AUC ratio of (+)- to (-)-enantiomers of about 1.7 – 1.8.

Metabolism and excretion

Within one week after a single oral dose of 1 mg of ¹⁴C-paliperidone with immediate release of the active ingredient, 59% of the administered dose is excreted unchanged in the urine; this indicates the absence of significant metabolism of the drug in the liver. Approximately 80% of the administered radioactivity was found in the urine and 11% in the feces. Four metabolic pathways of the drug are known in vivo, but none of them accounts for more than 10% of the administered dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole cleavage. Although in vitro studies suggest a role for CYP2D6 and CYP3A4 isoenzymes in the metabolism of paliperidone, there is no evidence of a significant role for these isoenzymes in the metabolism of paliperidone in vivo. A population pharmacokinetic analysis revealed no noticeable difference in the clearance of paliperidone after oral administration between people with active and poor CYP2D6 metabolism. In vitro studies using human liver microsomes showed that Paliperidone does not significantly inhibit the metabolism of drugs by CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 isoenzymes.

In in vitro studies, Paliperidone exhibited properties of a P-glycoprotein substrate, and at high concentrations, properties of a weak P-glycoprotein inhibitor. There are no corresponding in vivo data, and the clinical significance of this information is unclear. According to the results of a population pharmacokinetic analysis, the median apparent half-life of paliperidone after administration of Trevicta in doses of 175-525 mg ranged from 84-95 days for injections into the deltoid muscles to 118-139 days for injections into the gluteal muscles. The residual concentration of paliperidone in the blood 18 months after the last injection of Trevicta at a dose of 525 mg is 3% and 7% of the mean steady-state concentration for injection into the deltoid and gluteal muscle, respectively.

Comparison of Trevicta and other paliperidone drugs

The frequency of administration of Trevicta is once every 3 months, unlike Xeplion (paliperidone palmitate in the dosage form of prolonged-release suspension for intramuscular injection, intended for monthly administration). When Trevicta was administered at doses 3.5 times the corresponding dose of Xeplion, Trevicta achieved systemic levels of paliperidone similar to those achieved with monthly administration of the corresponding doses of Xeplion, as well as with oral administration of the corresponding doses of paliperidone in prolonged-release tablets.

The variability in paliperidone pharmacokinetics between patients is similar to that of paliperidone in extended-release tablets. Caution should be exercised when comparing the pharmacokinetic properties of different forms of paliperidone due to their different pharmacokinetic profiles.

Special patient categories

Elderly patients (65 years and older)

Age is not a factor requiring dose adjustment. However, such adjustment may be required due to age-related decline in creatinine clearance.

Renal impairment

Trevicta has not been systematically studied in patients with renal impairment. The distribution of paliperidone after a single oral dose of 3 mg extended-release tablets was studied in patients with varying degrees of renal function. As creatinine clearance (CrCl) decreased, the excretion of paliperidone decreased: in mild renal impairment (CrCl 50-80 ml/min) – by 32%, in moderate renal impairment (CrCl 30-50 ml/min) – by 64%, in severe renal impairment (CrCl 10-30 ml/min) – by 71%, resulting in an AUC_0-∞ increase compared to healthy volunteers by 1.5, 2.6, and 4.8 times, respectively. Based on limited data on the use of Trevicta in patients with mild renal impairment and the results of pharmacokinetic modeling, both the initial and maintenance doses of Xeplion should be reduced in patients with mild renal impairment. Patients can be switched to Trevicta therapy by increasing the corresponding doses intended for patients with mild renal impairment by 3.5 times. No additional dose adjustment is required after starting Trevicta therapy.

Hepatic impairment

Paliperidone is not significantly metabolized in the liver. Although the use of Trevicta in patients with hepatic impairment has not been studied, no dose adjustment is required for mild to moderate hepatic impairment. In a study of oral paliperidone in patients with moderate hepatic impairment (Child-Pugh class B), the plasma concentration of free paliperidone was the same as in healthy volunteers. The use of paliperidone in patients with severe hepatic impairment has not been studied.

Race

A population pharmacokinetic analysis of the results of a study of oral paliperidone revealed no difference in the pharmacokinetics of paliperidone after administration of the drug among people of different races.

Gender

No clinically significant differences in the pharmacokinetics of paliperidone between men and women were found.

Effect of smoking on drug pharmacokinetics

According to in vitro studies using human liver microsomes, Paliperidone is not a substrate for CYP1A2, so smoking should not affect the pharmacokinetics of paliperidone. According to the results of a population pharmacokinetic analysis based on data from Xeplion studies, no differences were found between smokers and non-smokers, which is consistent with the aforementioned in vitro experimental results.

Body mass index

Dose adjustment based on body mass index is not required. A decrease in C_max was observed in overweight and obese individuals. The minimum residual concentrations under apparent steady-state conditions were similar in individuals with normal weight, overweight, and obesity.

Indications

• Treatment of schizophrenia in adult patients previously treated with maintenance therapy with Xeplion for at least 4 months.

ICD codes

Dosage Regimen

Method of administration

Trevicta should be administered once every 3 months.

Before administration, parenteral medicinal products should be inspected for foreign particles and discoloration. No more than 5 minutes before administration, the syringe must be shaken vigorously for at least 15 seconds to obtain a homogeneous suspension.

The drug is intended for intramuscular use only. Subcutaneous or intravascular administration is not permitted. Avoid accidental entry into a blood vessel. The drug should be administered by healthcare professionals. The drug must be administered as a single injection; it is prohibited to divide the dose into several injections. The drug should be administered slowly, deep into the gluteal or deltoid muscle.

Only the thin-walled safety needles included in the kit can be used for the administration of Trevicta. Needles from the Xeplion package or other commercially available needles must not be used.

The recommended needle size for administration of Trevicta into the deltoid muscle is determined by the patient’s body weight. For patients weighing less than 90 kg, a 25 mm needle is recommended. For patients weighing ≥90 kg, a 51 mm needle is recommended. The drug should be administered into the center of the deltoid muscle. Injection sites should be alternated between the two deltoid muscles.

For administration of Trevicta into the gluteal muscle, a 51 mm needle is recommended regardless of body weight. The drug is administered into the upper outer quadrant of the gluteal muscle. Injection sites should be alternated between the two gluteal muscles.

Since Paliperidone is an active metabolite of risperidone, caution should be exercised when Trevicta and risperidone or an oral form of paliperidone are used concomitantly for a prolonged period. Data on the safety of concomitant use of Trevicta and other antipsychotics are limited.

Incomplete dose administration

To avoid administration of an incomplete dose of Trevicta, the syringe with the drug must be shaken vigorously for at least 15 seconds no more than 5 minutes before administration to obtain a homogeneous suspension. Nevertheless, in case of incomplete dose administration, it is prohibited to administer the drug remaining in the syringe, and it is also prohibited to administer another dose. The patient must be carefully monitored and provided with appropriate therapy until the next scheduled Trevicta injection in 3 months.

Dosage

Trevicta can only be used after treatment with Xeplion for at least 4 months. To correctly determine the maintenance dose before starting Trevicta, it is recommended to administer the last 2 monthly injections at the same dosage.

Treatment with Trevicta should be started on the day corresponding to the next scheduled injection of Xeplion, using the dose of Trevicta calculated based on the previous dose of Xeplion, according to Table 1. Trevicta can be administered 7 days earlier or later than the day of the next scheduled Xeplion injection.

Table 1. Scheme for switching from Xeplion to Trevicta (conversion using a factor of 3.5).

Instructions for use and handling of the drug

Administer once every 3 months.

Shake the syringe vigorously for at least 15 seconds before injection.

For intramuscular use only. No other routes of administration are permitted.

The drug must be administered as a single injection; it is prohibited to divide the dose into several injections. The drug should be administered by healthcare professionals.

Trevicta is for intramuscular use only. The drug should be administered slowly into the deep muscle layer, taking precautions to avoid entering a blood vessel.

The drug should be administered once every 3 months.

Read the instructions completely before use.

The information label should be torn off the syringe and placed in the patient’s medical record. Before using Trevicta, longer and more vigorous shaking is required compared to Xeplion. The syringe must be shaken vigorously, with the syringe tip pointing upwards, for at least 15 seconds no more than 5 minutes before administration.

Thin-walled safety needles are specifically designed for Trevicta injections; only the needles included in the kit should be used.

1. Needle selection

Needle selection is determined by the injection site and the patient’s weight.

Injections into the deltoid muscle: for a patient weighing less than 90 kg, use a needle with a pink hub, 25 mm for a patient weighing 90 kg or more, use a needle with a yellow hub, 51 mm

Injections into the gluteal muscle regardless of patient weight, use a needle with a yellow hub, 51 mm.

2. Preparation for injection

Holding the syringe tip upwards, shake the syringe vigorously with a relaxed wrist for at least 15 seconds to obtain a homogeneous suspension.

Attention: before use, Trevicta requires longer and more vigorous shaking compared to Xeplion.

Proceed to the next step immediately after shaking. If more than 5 minutes have passed before the injection, shake the upward-pointing syringe vigorously again for at least 15 seconds to re-suspend the suspension.

Inspection of the suspension: after shaking the syringe for 15 seconds, inspect the liquid through the product viewing window. The suspension should be homogeneous, milky white in color. The suspension may contain small air bubbles.

Open the needle package and remove the cap: open the needle pouch by tearing the back side of the packaging halfway. Place the pouch on a clean surface. Then, holding the syringe vertically, twist, pull off and remove the rubber cap.

Pick up the needle package: push back the plastic syringe holder and the back of the packaging. Then firmly squeeze the needle protective cap through its packaging.

Attach the needle: with the other hand, holding the syringe by the Luer cone (needle attachment site), attach it to the safety needle by gently turning the syringe clockwise. Do not remove the needle from its packaging until it is securely attached to the syringe.

Remove the needle protective cap: remove the needle protective cap with a straight pull. Do not twist the protective cap, as this may loosen the needle attachment to the syringe.

Remove air bubbles: holding the syringe vertically, gently tap it to allow air bubbles to rise to the top. Expel the air by gently pressing the syringe plunger until a drop of liquid appears at the tip of the needle.

3. Injection

Administer the drug: slowly inject the entire contents of the syringe intramuscularly, into the deep layers of the deltoid or gluteal muscle. No other routes of administration are permitted.

4. After injection

Secure the needle: after completing the injection, use your thumb or a flat object to bring the needle protection into the working position. The needle is considered secured after a “click” is heard.

Proper disposal: the syringe and unused needles must be disposed of in a sharps container.

The thin-walled safety needles are specifically designed for use with Trevicta. Unused needles should be disposed of; their future use is not permitted.

Adverse Reactions

This section provides information on adverse reactions. Adverse reactions are undesirable events that, based on a comprehensive assessment of available information, are considered to be reasonably likely to be associated with the use of paliperidone palmitate. In some cases, it is impossible to reliably establish a causal relationship with paliperidone palmitate. Furthermore, since clinical studies are conducted under varying conditions, the incidence of adverse reactions observed in clinical studies cannot be directly compared to the incidence in clinical studies of other drugs and may not reflect the incidence observed in real-world clinical practice.

Clinical trial data

The information described in this section includes data from three clinical trials.

One study is a long-term randomized relapse prevention study involving 506 patients with schizophrenia who received Xeplion therapy in the open-label phase; of these, 379 patients subsequently received one injection of Trevicta in the open-label phase. In the double-blind, placebo-controlled phase, 160 patients were randomized to receive at least one injection of Trevicta, and 145 patients were randomized to the placebo group. The mean duration of drug use in the double-blind phase was 150 (standard deviation 79) days in the placebo group and 175 (standard deviation 90) days in the Trevicta group.

In a second long-term double-blind active-controlled non-inferiority study involving 1429 patients with acute illness, patients were randomized to continue receiving Xeplion or to switch to Trevicta for 48 weeks. The mean duration of drug use in the double-blind therapy phase was 295 (standard deviation 88) days in the Trevicta group and 287 (standard deviation 96) days in the Xeplion group.

Additionally, a Phase 1 study was conducted in which 308 patients with schizophrenia or schizoaffective disorder received a single injection of Trevicta in combination with other oral antipsychotic drugs.

The majority of adverse reactions were mild or moderate in severity.

Adverse reactions observed in the long-term relapse prevention study are presented in Table 5. The most common adverse reactions reported in this study were injection site reactions, increased weight, headache, upper respiratory tract infections, akathisia, and parkinsonism.

5.1% of patients discontinued therapy in the open-label phase due to adverse events. In the double-blind phase, 1 patient receiving placebo discontinued therapy due to adverse events; no patients receiving Trevicta discontinued therapy. The safety profile of Trevicta was similar to that of Xeplion.

Table 5. Adverse reactions identified with the use of Trevicta in a long-term relapse prevention study in patients with schizophrenia.

^ain the open-label phase, patients received multiple doses of Xeplion followed by a single administration of Trevicta before randomization to receive placebo or Trevicta in the subsequent double-blind phase.

^bthe term “tachycardia” includes tachycardia, sinus tachycardia.
The term “injection site reactions” includes injection site reaction, injection site erythema, injection site extravasation, injection site induration, injection site inflammation, injection site mass, injection site nodule, injection site pain, injection site swelling.
The term “increased weight” includes increased weight, increased waist circumference.
The term “upper respiratory tract infections” includes upper respiratory tract infection, nasopharyngitis, pharyngitis, rhinitis.
The term “somnolence” includes somnolence, sedation.
The term “akathisia” includes akathisia, restlessness.
The term “parkinsonism” includes parkinsonism, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, muscle tightness, musculoskeletal stiffness, hypersalivation.
The term “dystonia” includes dystonia, blepharospasm.

^cFrequency is based on the number of patients with at least one adverse event, not the number of events.

Data from other clinical studies

Paliperidone palmitate is hydrolyzed to paliperidone. Paliperidone is the active metabolite of risperidone; thus, the adverse reaction profiles of risperidone and paliperidone (including both oral and injectable formulations) are related. This subsection includes additional adverse reactions that have been reported in clinical studies of paliperidone and/or risperidone.

The following are adverse reactions identified in clinical studies of Trevicta not included in Table 5.

Infections and infestations acarodermatitis, bronchitis, cellulitis, cystitis, ear infection, eye infection, influenza, onychomycosis, pneumonia, respiratory tract infection, sinusitis, subcutaneous abscess, tonsillitis.

Blood and lymphatic system disorders anemia, neutropenia, decreased white blood cell count.

Immune system disorders hypersensitivity.

Endocrine disorders: glucosuria, hyperprolactinemia.

Metabolism and nutrition disorders: increased blood cholesterol, increased blood triglycerides, decreased appetite, increased appetite, polydipsia, decreased weight^a.

Psychiatric disorders: agitation^a, anorgasmia, blunted affect, depression^a, insomnia^a, decreased libido, nervousness, nightmares, sleep disorder.

Nervous system disorders: cerebral ischemia, attention disturbance, dizziness, postural dizziness, dysarthria, hypoesthesia, paresthesia, psychomotor hyperactivity, syncope, tardive dyskinesia, tremor^a.

Eye disorders conjunctivitis, dry eye, glaucoma, increased lacrimation, blurred vision.

Ear and labyrinth disorders ear pain, tinnitus, vertigo.

Cardiac disorders atrioventricular block, bradycardia, conduction disorder, electrocardiogram abnormal, electrocardiogram QT prolonged, palpitations, postural orthostatic tachycardia syndrome, hypertension^a, hypotension.

Respiratory, thoracic and mediastinal disorders cough, dyspnea, epistaxis, nasal congestion, oropharyngeal pain, respiratory tract congestion.

Gastrointestinal disorders abdominal discomfort, abdominal pain, cheilitis, constipation^a, diarrhea^a, dry mouth, dyspepsia, dysphagia, flatulence, gastroenteritis, toothache^a.

Hepatobiliary disorders increased gamma-glutamyltransferase, increased hepatic enzymes, increased transaminases.

Skin and subcutaneous tissue disorders : acne, drug eruption, dry skin, eczema, erythema, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders arthralgia, back pain^a, increased blood creatine phosphokinase, joint stiffness, joint swelling, muscle spasms, muscle weakness, musculoskeletal pain^a, neck pain.

Renal and urinary disorders dysuria, pollakiuria, urinary incontinence.

Reproductive system and breast disorders breast discomfort, breast enlargement, breast pain, ejaculation disorder, erectile dysfunction, gynecomastia, menstrual disorder^b, sexual dysfunction.

General disorders and administration site conditions asthenia, body temperature increased, chest discomfort, chest pain, chills, withdrawal syndrome, face edema, fatigue^a, gait disturbance, malaise, edema^b, pyrexia.

Injury, poisoning and procedural complications fall.

^areported in > 2% of patients receiving Trevicta or Xeplion.

^bthe term “edema” includes generalized edema, peripheral edema, pitting edema. The term “menstrual disorders” includes irregular menstruation, oligomenorrhea.

The following are other adverse reactions observed in clinical studies of paliperidone (Xeplion and oral paliperidone) and risperidone, and not observed in clinical studies of Trevicta.

Blood and lymphatic system disorders eosinophil count increased.

Immune system disorders anaphylactic reactions.

Metabolism and nutrition disorders : anorexia.

Nervous system disorders balance disorder, convulsions^a, coordination abnormal, decreased level of consciousness, diabetic coma, head titubation, loss of consciousness, neuroleptic malignant syndrome, unresponsiveness to stimuli, bradykinesia, stroke, hypertonia, lethargy, oromandibular dystonia, parkinsonian gait, transient ischemic attack.

Eye disorders eye movement disorder, eye rolling, eye hyperemia, photophobia, oculogyric crisis.

Cardiac disorders bundle branch block, sinus arrhythmia, flushing, ischemia.

Respiratory, thoracic and mediastinal disorders dysphonia, hyperventilation, aspiration pneumonia, pulmonary congestion, rales, wheezing.

Gastrointestinal disorders fecal incontinence, fecaloma, intestinal obstruction, tongue edema, upper abdominal pain, small intestinal obstruction.

Skin and subcutaneous tissue disorders : dandruff, hyperkeratosis, seborrheic dermatitis, skin discoloration, generalized pruritus, papular rash.

Musculoskeletal and connective tissue disorders posture abnormal, rhabdomyolysis, myalgia, pain in extremity, muscle twitching, nuchal rigidity, torticollis, trismus.

Reproductive system and breast disorders breast engorgement, vaginal discharge, breast discharge, delayed menstruation, irregular menstruation, breast tenderness, retrograde ejaculation.

General disorders and administration site conditions body temperature decreased, induration, thirst, peripheral edema.

^aThe term “convulsions” includes grand mal convulsions.

Events of special interest for this drug class

Extrapyramidal symptoms (EPS). Results from the double-blind, placebo-controlled phase of the long-term relapse prevention study indicate that the Trevicta group had a higher incidence of adverse events related to extrapyramidal symptoms compared to the placebo group (13 patients [8.1%] and 5 patients [3.4%], respectively). Several methods were used to assess EPS: (1) the Simpson-Angus Scale (SAS) for parkinsonism, (2) the Barnes Akathisia Rating Scale (BAS), (3) the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia, (4) the use of anticholinergic medications for EPS treatment, (5) the frequency of spontaneous reports of EPS. The assessment of extrapyramidal symptoms included a pooled analysis of the following symptom groups: dyskinesia, dystonia, hyperkinesia, parkinsonism, and tremor.

Assessment of extrapyramidal symptom frequency using rating scales and for anticholinergic medication use

Adverse reactions related to EPS

Following the injection of Trevicta in the open-label phase, 12 patients (3.2%) experienced extrapyramidal symptoms that were new or worsened in severity, with events from the hyperkinesia group (1.6%) and parkinsonism group (1.3%) being the most frequent. One patient discontinued therapy in the open-label phase due to restlessness. An assessment of the time to onset of EPS during the double-blind phase did not show clustering of these events; such clustering would be expected to be associated with the peak plasma concentration of paliperidone in the placebo group.

Dystonia. Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonia symptoms include spasm of the neck muscles, sometimes progressing to tightness in the throat, difficulty swallowing, difficulty breathing, and protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity at higher doses of first-generation antipsychotics. A higher risk of acute dystonia is observed in males and younger patients.

Pain and injection site reactions. Redness and swelling were reported in no more than 2% of patients in either group during the double-blind phase of the long-term relapse prevention study and were classified as mild (on a 4-point scale where 0 = none, 1 = mild, 2 = moderate, 3 = severe). No induration at the injection site was reported in either group during the double-blind phase, and no patient discontinued therapy due to the administration of Trevicta.

Assessment of injection site pain by patients was similar in the placebo and Trevicta groups during the double-blind phase.

Assessment of injection site pain by patients during a Phase I clinical study with a single dose of Xeplion allowed for the evaluation of changes in injection site pain over time. Residual pain peaked at 1 or 6 hours after administration, then decreased over 3 days. Injections into the deltoid muscle were more painful compared to injections into the gluteal muscle, although all pain scores were below 10 points on a 100-point scale.

Weight gain. In the double-blind, placebo-controlled phase of the long-term relapse prevention study, clinically significant weight gain ≥ 7% from the baseline of the double-blind phase to its end was reported in 15 patients (10%) in the Trevicta group and 1 patient (1%) in the placebo group. Conversely, clinically significant weight loss ≥ 7% from the baseline of the double-blind phase to its end was reported in 2 patients (1%) in the Trevicta group and 12 patients (8%) in the placebo group. The mean change in body weight from the baseline of the double-blind phase to its end was +0.94 kg and -1.28 kg for Trevicta and placebo, respectively.

Laboratory parameters: serum prolactin. During the double-blind, placebo-controlled phase of the long-term relapse prevention study, an increase in prolactin concentrations above reference values (> 13.13 ng/mL in men and > 26.72 ng/mL in women) was noted more frequently in men and women taking Trevicta compared to the placebo group (9% vs 3% and 5% vs 3%, respectively). In the Trevicta group, the mean change from the baseline of the double-blind phase to its end was +2.90 ng/mL for men (versus 10.26 ng/mL in the placebo group) and +7.48 ng/mL for women (versus – 32.93 ng/mL in the placebo group). One woman (2.4%) in the Trevicta group experienced amenorrhea, while no adverse events potentially related to prolactin concentration were noted in the placebo group. Among men in both groups, no adverse events potentially related to prolactin concentration were observed.

Post-marketing data

In addition to adverse reactions reported during clinical studies and listed above, the following adverse reactions have been observed during the post-marketing use of paliperidone and/or risperidone.

The frequency of adverse reactions was classified as follows: very common (≥ 10%), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and < 0.1%), and very rare (< 0.01%, including isolated cases).

Table 6 presents adverse reactions observed during post-marketing surveillance of paliperidone and/or risperidone. The provided frequencies are based on the frequency of spontaneous reports for paliperidone and on clinical studies using injectable formulations of paliperidone.

Table 6. Adverse reactions observed during post-marketing surveillance of paliperidone and/or risperidone.

In addition to those listed above, thrombotic thrombocytopenic purpura has been noted during the post-marketing use of paliperidone and/or risperidone.

In very rare cases during post-marketing use, cases of anaphylactic reactions have been reported in patients previously treated with oral risperidone or paliperidone following the administration of Xeplion.

Contraindications

• Hypersensitivity to paliperidone or any component of the drug;
• Since Paliperidone is an active metabolite of risperidone, Trevicta is contraindicated in patients with known hypersensitivity to risperidone;

In patients treated with risperidone or paliperidone, hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported.

With caution

Trevicta should be used with caution in the following cases (see more detailed information in the “Special Precautions” section)

• In patients with cardiovascular diseases (e.g., heart failure, myocardial infarction or ischemia, conduction disorders), cerebrovascular disorders, or conditions predisposing to hypotension (e.g., dehydration, hypovolemia, use of antihypertensive drugs);
• In patients with a history of seizures or other conditions that may lower the seizure threshold;
• In patients who may be exposed to factors that increase body temperature, such as strenuous exercise, high ambient temperature, exposure to drugs with anticholinergic activity, and dehydration;
• In patients with a history of arrhythmia or congenital long QT syndrome, or taking drugs that prolong the QT interval;
• When used in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and dopamine agonists;
• In patients with dementia, patients with Parkinson’s disease or dementia with Lewy bodies;
• In patients with possible prolactin-dependent tumors;
• In patients with impaired liver or kidney function.

Use in Pregnancy and Lactation

Pregnancy

The safety of intramuscular paliperidone palmitate or oral paliperidone during human pregnancy has not been established. A teratogenic effect was not noted in animal studies. At high doses of oral paliperidone, a slight increase in fetal mortality was observed in animals. Xeplion did not affect the course of pregnancy in rats, but its high doses were toxic to pregnant females. Doses of oral paliperidone and intramuscular Xeplion, which produce exposures exceeding the maximum therapeutic human doses by 20-22 times and 6 times, respectively, did not affect the offspring of laboratory animals.

If a woman has taken antipsychotic drugs (including Paliperidone) in the third trimester of pregnancy, newborns are at risk of extrapyramidal disorders and/or withdrawal syndrome of varying severity. These symptoms may include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. Newborns should be monitored for the occurrence of extrapyramidal disorders and/or withdrawal syndrome and provided with appropriate medical care. In some newborns, the symptoms resolve within a few days or hours without specific treatment, while others may require prolonged hospitalization. Since Paliperidone was detected in plasma for up to 18 months after a single injection of Trevicta, the long duration of action of the drug should be taken into account, as newborns may be at risk of exposure to Trevicta taken before pregnancy or in the first or second trimester.

Trevicta should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. The effect of Trevicta on labor and delivery in humans is unknown.

Pregnant women should be informed of the potential risks to the fetus. The effect of Trevicta on the risk of major birth defects and miscarriage is unknown.

Breastfeeding

Studies of paliperidone in animals and risperidone in humans have found excretion of paliperidone in breast milk, therefore women receiving Trevicta should not breastfeed. Since Paliperidone was detected in plasma for up to 18 months after a single injection of Trevicta, the long duration of action of the drug should be taken into account, as breastfed infants may be at risk of exposure to Trevicta taken long before the start of breastfeeding.

Use in Hepatic Impairment

Trevicta should be used with caution in patients with impaired liver function.

Use in Renal Impairment

Trevicta should be used with caution in patients with impaired renal function.

Pediatric Use

The safety and efficacy of Trevicta in patients under 18 years of age have not been studied. The use of TREVICTA is not recommended in patients under 18 years of age due to the potentially longer duration of adverse effects compared to shorter-acting drugs. In clinical studies of oral paliperidone, no increase in the frequency of dystonia, hyperkinesia, tremor, and parkinsonism was observed in adolescents compared to adult patients.

Geriatric Use

Insufficient numbers of patients aged 65 years and older were included in clinical studies to determine whether their response to therapy differs from that of younger patients. Available clinical experience has not revealed differences in response between elderly and younger patients.

Paliperidone is substantially excreted by the kidneys, and the clearance of paliperidone is reduced in patients with impaired renal function. For elderly patients with normal renal function, the same dose of Trevicta is recommended as for younger patients with normal renal function. Renal function may be impaired in elderly patients, and such patients are subject to the recommendations for patients with impaired renal function provided below.

Special Precautions

Increased mortality in elderly patients with dementia-related psychosis

Trevicta has not been studied in elderly patients with dementia.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. A cross-analysis of study results showed increased mortality in elderly patients with dementia receiving atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine, compared with placebo. Among patients receiving risperidone and placebo, mortality was 4% and 3.1%, respectively. An analysis of 17 placebo-controlled clinical studies revealed a 1.6-1.7-fold increase in the risk of death in patients taking atypical antipsychotics compared with patients taking placebo. Over a typical 10-week controlled study, mortality among patients taking the drug and placebo was 4.5% and 2.6%, respectively. Although the causes of death were varied, most were cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that conventional antipsychotics, like atypical antipsychotics, may increase mortality. It is unclear to what extent the increased mortality in observational studies is related to antipsychotic drug use versus other patient characteristics. Trevicta is not indicated for the treatment of dementia-related psychosis.

Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis

Placebo-controlled studies have found an increased incidence of cerebrovascular adverse events (transient ischemic attacks and stroke), including fatal cases, in elderly patients with dementia receiving some atypical antipsychotics, including risperidone, aripiprazole, and olanzapine, compared with placebo. Studies of oral paliperidone, Xeplion, and Trevicta in elderly patients with dementia have not been conducted; these drugs are not indicated for the treatment of dementia-related psychosis.

Neuroleptic malignant syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported with the use of antipsychotic drugs, including paliperidone. It is characterized by hyperthermia, muscle rigidity, autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, cardiac arrhythmia), and altered consciousness. In addition, elevated serum creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure may occur.

Diagnostic evaluation of patients with this syndrome is complicated. It is important to identify cases where the clinical presentation includes serious medical conditions (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

If NMS develops:
(1) immediately discontinue antipsychotics and other drugs not essential for concomitant therapy;
(2) provide intensive symptomatic treatment and medical monitoring of the patient;
(3) treat any concomitant medical conditions for which specific treatment is available. There is no unanimous opinion on specific pharmacological treatment for uncomplicated cases of NMS.

If antipsychotic treatment is required after recovery from NMS, careful monitoring should be resumed, as cases of recurrent NMS have been reported.

QT interval

Paliperidone causes a small increase in the corrected QT interval (QTc). Concomitant use of paliperidone and drugs known to prolong the QTc interval, such as Class 1A (quinidine, procainamide) or Class III (amiodarone, sotalol) antiarrhythmics, antipsychotics (chlorpromazine, thioridazine), antibiotics (gatifloxacin, moxifloxacin), and others, should be avoided. Caution is advised when using Trevicta in patients with a history of cardiac arrhythmias or congenital long QT syndrome.

Certain conditions, particularly bradycardia, hypokalemia, hypomagnesemia, concomitant use of other drugs that may prolong the QTc interval, and congenital long QT syndrome, may increase the risk of torsades de pointes and/or sudden death when used concomitantly with drugs that may prolong the QTc interval.

The effect of paliperidone on the QT interval was evaluated in a double-blind, active-controlled (moxifloxacin, single 400 mg dose) multicenter study of oral paliperidone in adult patients, in 4 efficacy studies, and in one maintenance study with Xeplion.

In the first study (n=141), administration of 8 mg of immediate-release oral paliperidone (n=50) resulted in a QTcLD (QT interval corrected for heart rate using a population-specific linear method) increase of 12.3 msec on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration after 8 mg of immediate-release oral paliperidone (C_max = 113 ng/mL) was approximately 2 times higher than the plasma concentration after the maximum dose of 525 mg Trevicta administered into the deltoid muscle (median C_max= 56 ng/mL). In the same study, administration of 4 mg of immediate-release oral paliperidone resulted in a steady-state C_max of 35 ng/mL, with a QTcLD increase of 6.8 msec on day 2 at 1.5 hours post-dose.

In four efficacy studies of the drug Xeplion, no patient exhibited a QTcLD change of more than 60 msec, and no patient had a QTcLD exceeding 500 msec at any time. In the maintenance therapy study, no patient exhibited a QTcLD change of more than 60 msec; one patient had a QTcLD of 507 msec (the QT interval corrected using Bazett’s formula (QTcB) was 483 msec); this same patient had a heart rate of 45 beats per minute.

In the long-term study of Trevicta for the maintenance treatment of schizophrenia, one patient (< 1%) had a QTcLD increase of more than 60 msec during the open-label phase; no patients exhibited a QTcLD change of more than 60 msec after Trevicta administration during the double-blind phase, and no patient had a QTcLD exceeding 480 msec at any time.

Tardive Dyskinesia

Use of drugs with dopamine receptor antagonist properties is associated with the development of tardive dyskinesia, characterized by rhythmic, involuntary movements, primarily of the tongue and/or facial muscles.

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop during treatment with antipsychotic drugs. Although the prevalence of the syndrome is higher in elderly patients, particularly elderly women, it is impossible to predict which patients will develop the syndrome. It is not known whether antipsychotic drugs differ in their potential to cause tardive dyskinesia.

Although the risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase with increasing duration of treatment and cumulative dose of the antipsychotic drug, the syndrome can develop after a relatively short treatment period at low doses, although such cases are uncommon.

There is no known treatment for tardive dyskinesia; however, if the antipsychotic drug is discontinued, the syndrome may partially or completely remit. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of tardive dyskinesia and thus potentially mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.

Trevicta should be prescribed in a manner that minimizes the likelihood of tardive dyskinesia occurring. Long-term antipsychotic therapy should generally be reserved for patients with other chronic conditions that respond to antipsychotic drugs. In patients requiring chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be used. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear, discontinuation of all antipsychotics, including Trevicta, should be considered. The long duration of action of Trevicta should be taken into account. Some patients may require treatment with Trevicta despite the emergence of the syndrome.

Metabolic Changes

Hyperglycemia and Diabetes Mellitus. Hyperglycemia and diabetes mellitus, in some cases leading to ketoacidosis, hyperosmolar coma, or death, have been observed during treatment with antipsychotics. Most such cases were reported from post-marketing and epidemiological studies. Cases of hyperglycemia and diabetes mellitus have also been reported with the use of Trevicta. Establishing a causal relationship between the use of atypical antipsychotic drugs and impaired glucose metabolism is complicated by the increased risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these factors, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with atypical antipsychotics.

Patients with an established diagnosis of diabetes mellitus who are starting treatment with atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. All patients should be monitored clinically for symptoms of hyperglycemia and diabetes mellitus, such as polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia resolved upon discontinuation of the atypical antipsychotic; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the antipsychotic drug.

Data from a long-term clinical study of Trevicta for the maintenance treatment of schizophrenia are presented below.

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Data from a long-term clinical study of Trevicta for the maintenance treatment of schizophrenia are presented below.

Weight Gain

Significant weight gain has been observed with atypical antipsychotic treatment. Patient weight should be monitored.

Data from a long-term clinical study of Trevicta for the maintenance treatment of schizophrenia on mean weight changes and the proportion of patients with weight gain greater than 7% are presented below.

Orthostatic Hypotension and Syncope

Due to its alpha-adrenergic blocking activity, Paliperidone may cause orthostatic hypotension and syncope in some patients. In the long-term maintenance therapy clinical study, syncope was reported in < 1% (1/506) of patients treated with Xeplion during the open-label phase; during the double-blind phase, no cases of syncope were reported in either group. In the long-term maintenance therapy clinical study, orthostatic hypotension was reported in < 1% (1/506) of patients treated with Xeplion and in < 1% (1/379) of patients after a single dose of Trevicta during the open-label phase; during the double-blind phase, no cases of arterial hypotension were reported in either group.

Trevicta should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose to hypotension (e.g., dehydration, hypovolemia, concomitant use of antihypertensive medications). Orthostatic vital signs should be monitored in patients who are prone to hypotension.

Leukopenia, Neutropenia, Agranulocytosis

Cases of leukopenia and neutropenia have been reported during clinical trials and post-marketing use with antipsychotic agents, including Trevicta. Agranulocytosis has also been reported.

Possible risk factors for developing leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and a history of drug-induced leukopenia/neutropenia. It is advisable to perform frequent complete blood counts during the first few months of therapy in such patients; discontinuation of Trevicta should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur.

Patients with severe neutropenia (absolute neutrophil count < 1 × 10⁹/L) should discontinue Trevicta until their WBC recovers.

The long duration of action of Trevicta should be taken into account.

Hyperprolactinemia

Paliperidone, like other drugs that are dopamine D₂ receptor antagonists, elevates prolactin levels, and the elevation persists during chronic administration. The prolactin elevation with paliperidone is similar to that seen with risperidone, which is associated with higher prolactin elevations than other antipsychotics.

Regardless of etiology, hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone (GnRH), resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

Long-standing hyperprolactinemia associated with hypogonadism can lead to decreased bone mineral density in both female and male patients.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. In carcinogenicity studies of risperidone conducted in mice and rats, increases in pituitary, mammary, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary adenomas, and pancreatic adenomas) were observed. To date, clinical and epidemiological studies have not shown an association between chronic administration of antipsychotic drugs and tumorigenesis; however, the available evidence is considered too limited to be conclusive. Caution should be exercised when prescribing paliperidone to patients with potentially prolactin-dependent tumors.

In the long-term study of Trevicta for maintenance treatment, shifts in prolactin levels to above the reference range (> 13.13 ng/mL for men and > 26.72 ng/mL for women) from double-blind baseline occurred more frequently in men and women treated with Trevicta compared with the placebo group (46% vs. 25% and 32% vs. 15%, respectively). One woman (2.4%) in the Trevicta group experienced amenorrhea, while no adverse events potentially associated with prolactin levels were reported in the placebo group. Among men in both groups, no adverse events potentially associated with prolactin levels were observed.

Prior to the double-blind phase (during the 29-week open-label phase of the long-term maintenance study), the mean prolactin concentration was 17.1 ng/mL in men (N = 368) and 51.6 ng/mL in women (N = 122). At 12 weeks after a single injection of Trevicta at the end of the open-label phase, the mean prolactin concentration was 25.8 ng/mL in men (N = 322) and 70.6 ng/mL in women (N = 107). During the open-label phase, 27% of women and 42% of men had a shift in prolactin levels to above the reference range from baseline; the incidence of prolactin-related adverse reactions was higher in women than in men (7.9% and 3.7%, respectively). The most common (≥ 3%) potentially prolactin-dependent adverse reactions in women were amenorrhea (4.7%) and galactorrhea (3.1%). In men during the open-label phase, no potentially prolactin-dependent adverse reactions occurred with a frequency greater than 3%.

Seizures

In the long-term maintenance therapy clinical study, there were no reports of seizures or convulsions. In the pivotal clinical study of Xeplion, a double-blind, placebo-controlled clinical trial in patients with schizophrenia, < 1% of patients (1/1293) treated with Xeplion experienced convulsions, and < 1% of patients (1/510) treated with placebo experienced grand mal type seizures.

As with other antipsychotics, Trevicta should be used with caution in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years of age or older.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Trevicta and other antipsychotic drugs should be used with caution in patients at risk for aspiration pneumonia.

Priapism

Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. No cases of priapism were reported in clinical trials of Trevicta; however, priapism has been reported during post-marketing surveillance of oral paliperidone. Severe priapism may require surgical intervention.

Effect on Body Temperature Regulation

Antipsychotics have been associated with disruption of the body’s ability to reduce core body temperature. Caution is advised when prescribing Trevicta for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., strenuous exercise, exposure to extreme heat, concomitant medication with anticholinergic activity, or dehydration.

Hypersensitivity Reactions

Very rare cases of anaphylactic reactions have been reported during post-marketing use of Xeplion in patients who have previously tolerated oral forms of paliperidone or risperidone.

If a hypersensitivity reaction occurs, Trevicta should be discontinued, appropriate supportive clinical measures should be instituted, and the patient should be monitored until symptoms resolve.

Venous Thromboembolism

Cases of venous thromboembolism have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for venous thromboembolism, all possible risk factors should be identified before and during treatment with Trevicta, and preventive measures undertaken.

Parkinson’s Disease and Dementia with Lewy Bodies

The physician should weigh the risks versus the benefits when prescribing antipsychotics, including Trevicta, to patients with Parkinson’s disease or Dementia with Lewy Bodies, as both of these patient groups may be at increased risk for Neuroleptic Malignant Syndrome (NMS) and may be at increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, and extrapyramidal symptoms.

Antiemetic Effect

An antiemetic effect was observed in preclinical studies with paliperidone. This effect in patients may mask signs and symptoms of overdose with certain drugs or conditions such as intestinal obstruction, Reye’s syndrome, or brain tumor.

Introduction

During intramuscular injection, caution should be exercised to avoid accidental entry of the drug into a blood vessel.

Intraoperative Floppy Iris Syndrome (IFIS)

IFIS has been observed during cataract surgery in patients treated with α₁-adrenergic receptor antagonists, such as the drug Trevicta.

IFIS increases the risk of eye-related complications during and after surgery. The surgeon performing such an operation should be informed in advance that the patient has taken or is currently taking drugs with α₁-adrenergic receptor antagonist activity. The potential benefit of discontinuing therapy with α₁-adrenergic receptor antagonists before surgery has not been established and should be weighed against the risks associated with discontinuing antipsychotic therapy.

Renal Impairment

The plasma concentration of paliperidone is increased in patients with impaired renal function. Dose adjustment is recommended in patients with mild renal impairment. The use of Trevicta is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min).

Hepatic Impairment

The use of Trevicta in patients with severe hepatic impairment (Child-Pugh class C) has not been studied. Caution should be exercised when using paliperidone in such patients.

Effect on Ability to Drive and Operate Machinery

Somnolence, sedation, and dizziness have been reported with the use of Trevicta. Trevicta may impair the performance of activities requiring concentration and speed of psychomotor reactions and may also affect vision. Therefore, patients should be advised not to drive vehicles or operate moving machinery until their individual sensitivity is established.

Overdose

Since Trevicta is intended for administration by healthcare professionals, the likelihood of overdose by patients is low.

Symptoms. A limited number of cases of paliperidone overdose are known. Among the few cases reported in pre-registration studies of oral paliperidone, the maximum estimated intake was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and unsteady gait. Other expected signs and symptoms correspond to an enhancement of the known pharmacological effects of paliperidone, i.e., drowsiness, lethargy, tachycardia, hypotension, QT interval prolongation. Polymorphic ventricular tachycardia of the ‘torsades de pointes’ type and ventricular fibrillation have been noted with overdose of oral paliperidone. In cases of acute overdose, the possibility of the patient having taken multiple drugs should be considered.

Treatment. The prolonged release of the active substance and the long half-life of paliperidone should be considered when assessing the need for treatment and patient recovery. There is no specific antidote for paliperidone. General supportive measures should be implemented, ensuring and maintaining a patent airway, adequate pulmonary ventilation, and oxygen saturation. Cardiovascular function should be monitored immediately, including continuous ECG monitoring to detect possible arrhythmias. In case of hypotension and circulatory collapse, appropriate measures should be taken, such as intravenous administration of fluids and/or sympathomimetics. Anticholinergic drugs should be used if severe extrapyramidal symptoms develop. The patient should be carefully monitored until recovery.

Drug Interactions

Like other antipsychotics, Paliperidone may prolong the QT interval, therefore Trevicta should be used with caution in combination with other drugs that prolong the QT interval, such as antiarrhythmic drugs (including quinidine, disopyramide, procainamide, amiodarone, sotalol), antihistamines, antipsychotic drugs (chlorpromazine, thioridazine); antibiotics (including gatifloxacin, moxifloxacin), some antimalarial drugs (including mefloquine).

Since paliperidone palmitate is hydrolyzed to paliperidone, the results of studies with oral paliperidone should be considered when assessing the potential for drug interactions.

Ability of Trevicta to affect other drugs

Paliperidone is not expected to exhibit clinically significant pharmacokinetic interactions with drugs metabolized by cytochrome P450 isoenzymes. In vitro studies using human liver microsomes showed that Paliperidone does not substantially inhibit the metabolism of substances by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, Paliperidone is not expected to clinically significantly decrease the clearance of drugs metabolized by these isoenzymes. Paliperidone is also not expected to exhibit inducing properties on these isoenzymes.

Paliperidone at high concentrations is a weak inhibitor of P-glycoprotein. However, there are no in vivo data in this regard, and the clinical significance of this is unknown.

Given the effect of paliperidone on the CNS, Trevicta should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and dopamine receptor agonists. The patient’s condition should be monitored during concomitant use.

Due to the ability of Trevicta to cause orthostatic hypotension, an additive enhancement of this effect may be observed when the drug is used concomitantly with other drugs possessing this ability. In patients prone to hypotension, orthostatic physiological parameters should be monitored.

Paliperidone should be used with caution in combination with drugs that lower the seizure threshold, such as phenothiazines, butyrophenones, tricyclic derivatives, selective serotonin reuptake inhibitors, tramadol, mefloquine, etc.

Concomitant administration of oral paliperidone 12 mg once daily and divalproex sodium extended-release tablets (at a dose of 500-2000 mg once daily) did not affect the pharmacokinetics of valproate. No dose adjustment of paliperidone or valproate is required when used concomitantly.

Pharmacokinetic interaction between Trevicta and lithium is unlikely.

Ability of other drugs to affect Trevicta

Clinically important interactions between paliperidone and drugs metabolized by the cytochrome P450 system isoenzymes are not expected. Paliperidone is not a substrate for CYP1A2, CYP2A6, CYP2C9, CYP2C19, and CYP3A5 isoenzymes. This suggests a low likelihood of interaction with inhibitors and inducers of these isoenzymes. Although in vitro studies indicate a minimal potential involvement of CYP2D6 and CYP3A4 isoenzymes in the metabolism of paliperidone, there are currently no data indicating that these enzymes play a significant role in the metabolism of paliperidone in vivo. In vitro studies indicate that Paliperidone is a substrate for P-glycoprotein.

Paliperidone is metabolized to a limited extent by the CYP2D6 isoenzyme. In a drug interaction study of oral paliperidone with the potent CYP2D6 inhibitor paroxetine in healthy volunteers, no clinically significant change in the pharmacokinetics of paliperidone was found.

Concomitant use of paliperidone and potent inducers of CYP3A4 and P-glycoprotein may lead to a decrease in plasma concentrations of paliperidone. Concomitant use of paliperidone and potent inducers of CYP3A4 and P-glycoprotein should be avoided if possible. If the use of a potent inducer is necessary, consideration should be given to switching the patient to paliperidone extended-release tablets. Concomitant administration of oral once-daily extended-release paliperidone with carbamazepine (200 mg twice daily) resulted in an average decrease in C_max and AUC of paliperidone of approximately 37%. This decrease is largely due to a 35% increase in the renal clearance of paliperidone, likely due to the activation of renal P-glycoprotein by carbamazepine. A very small decrease in the amount of drug excreted unchanged in the urine suggests that carbamazepine has only a weak effect on the hepatic metabolism or bioavailability of paliperidone. When carbamazepine is initiated, the dose of Trevicta should be re-evaluated and, if necessary, increased. Conversely, upon discontinuation of carbamazepine, the dose of Trevicta should be re-evaluated and, if necessary, decreased. The long duration of action of Trevicta should be taken into account.

Paliperidone is a cation at physiological pH and is primarily excreted unchanged by the kidneys – half by filtration and half by active secretion. Concomitant use of trimethoprim, which inhibits the renal cationic active transport system, did not affect the pharmacokinetics of paliperidone.

Concomitant administration of extended-release oral paliperidone 12 mg once daily and divalproex sodium extended-release tablets (2 tablets of 500 mg once daily) resulted in an increase in C_max and AUC of paliperidone of approximately 50%, likely as a result of increased oral absorption of the drug. Since no significant effect on total clearance was observed, no clinically significant interaction is expected between divalproex sodium extended-release tablets and Trevicta. This interaction has not been studied with Trevicta.

Use of Trevicta with risperidone or with the oral form of paliperidone

Since Paliperidone is an active metabolite of risperidone, caution should be exercised during long-term concomitant use of Trevicta and risperidone or the oral form of paliperidone. Data on the safety of concomitant use of Trevicta and other antipsychotics are limited.

Pharmacokinetic interaction between lithium and paliperidone is unlikely.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.