Invega Sustenna

Serotonin-Dopamine Antagonist (SDA) Antipsychotics

Hazardous Drugs Classification
NIOSH 2016 List: Group 2
NIOSH reviewed data from studies provided by the manufacturer and determined it is unlikely that drug poses a carcinogenic, reproductive, or developmental hazard to workers in a healthcare setting and is no longer considered a hazardous drug by NIOSH.

Oral Administration Oral Solid Formulations

The patient should swallow extended-release (ER) tablets whole with plenty of liquid. Do not crush, chew, or divide the ER tablets.
May administer with or without food; however, the presence of food at the time of administration may increase paliperidone exposure.
The ER tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Intramuscular Administration

Once-monthly depot injection (Invega Sustenna)
For intramuscular (IM) use only. Do NOT administer by any other route. Each injection must be prepared and administered only by a health care professional. Avoid inadvertent injection into a blood vessel.
The first 2 initiation injections when patients are starting Invega Sustenna are administered 1 week apart. To avoid a missed second initiation dose, patients may be given the second dose 4 days before or after the 1-week time point. If the patient misses this second initiation dose, refer to the manufacturer's labeling and dosage for the management of the missed second initiation dose.
The third (3rd) and subsequent monthly injections are given at 1-month intervals. To avoid a missed monthly dose, patients may be administered the injection up to 7 days before or after the monthly due date.
The Invega Sustenna prefilled syringe is for single-use only. Do not administer the dose in divided injections.
When ready for use, shake the syringe vigorously for at least 10 seconds.
Select the appropriate needle from the Invega Sustenna injection kit. Only use the proper needle provided in the kit.
Deltoid injections: For patients weighing at least 90 kg (at least 200 pounds), use the 1.5-inch, 22-gauge needle (needle with grey colored hub). For those weighing less than 90 kg, use the 1-inch, 23-gauge needle (needle with blue colored hub).
Gluteal injections: The recommended needle size is 1.5-inch, 22-gauge needle (needle with grey colored hub). Administer into the upper-outer quadrant of the gluteal area.
While holding the syringe upright, twist the rubber tip cap clockwise to remove it. Peel the safety needle pouch halfway open. Grasp the needle sheath using the plastic peel pouch. Attach the safety needle to the luer connection of the syringe in a clockwise motion. Pull the needle sheath away from the needle with a straight pull. Do not twist the sheath. Bring the syringe with the attached needle into an upright position to de-aerate. De-aerate the syringe by moving the plunger rod carefully forward.
Inject the entire contents IM slowly and deeply into the selected muscle.
After the injection is complete, use thumb or flat surface to activate the needle protection system (see product labeling for visual aids). The protection system is fully activated when a "click" is heard. Appropriately discard the syringe with needle.
During treatment initiation, the initial 2 dosages should be administered into the deltoid muscle. Subsequent doses may be administered into the deltoid or gluteal muscle. Alternate injections between deltoid muscles if using the deltoid muscles for dosing sites. Alternate injections between the two gluteal muscles if using gluteal muscle sites.
Missed doses:
If it has been 4 to 6 weeks since the last injection: Resume the regular monthly dosing as soon as possible at the patient's previously stabilized dose, followed by injections at monthly intervals.
For missed doses of more than 6 weeks and up to 6 months: Resume the same dose the patient was previously stabilized on (unless the patient was stabilized on a dose of 234 mg, then the first 2 injections should each be 156 mg) as follows: administer a deltoid injection as soon as possible. Administer a second deltoid injection 1 week later at the same dose. Then, resume the previous stabilized dose in the deltoid or gluteal muscle 1 month after the second injection.
If more than 6 months have passed since the last monthly injection: Re-initiate using the treatment initiation regimen (e.g., 234 mg in deltoid on day 1, 156 mg in deltoid on day 8, then a monthly maintenance dose in the gluteal or deltoid muscle thereafter).
 
3-month depot injection (Invega Trinza)
For intramuscular (IM) use only. Do NOT administer by any other route. Each injection must be prepared and administered only by a health care professional.
Prepare exactly as directed. Do not mix with any other product or diluent or use any needles other than those included in the Invega Trinza injection kit.
Administer IM deep into the deltoid or gluteal muscle. Avoid inadvertent injection into a blood vessel.
Administer once every 3 months. If necessary, patients may be given the injection up to 2 weeks before or after the 3-month time point. Missed doses should be avoided.
Administer the dose as a single injection; do not divide the dose.
When administering a dose, ensure that the tab label is peeled off from the syringe and placed in patient record.
To avoid an incomplete administration, shake the syringe vigorously with a loose wrist and with the syringe tip pointing up for at least 15 seconds to ensure a homogeneous suspension.
After shaking the syringe for at least 15 seconds, check the liquid in the viewing window. The suspension should appear uniform and milky white. It is also normal to see small air bubbles.
If more than 5 minutes pass, shake vigorously again, with the syringe tip pointing up, for at least 15 seconds to re-suspend the medication.
Next, open needle pouch by peeling the cover back halfway. Place on a clean surface. Then, holding the syringe upright, twist and pull the rubber cap to remove.
Fold back needle cover and plastic tray. Then, firmly grasp the needle sheath through the pouch, as shown in the manufacturer's product information.
With your other hand, hold the syringe by the luer connection and attach it to the safety needle with a gentle clockwise twisting motion. Do not remove the pouch until the syringe and needle are securely attached.
Pull the needle sheath away from the needle in a straight motion. Do not twist the sheath, as this may loosen the needle from the syringe.
Hold the syringe upright and tap gently to make any air bubbles rise to the top. Remove air by pressing the plunger rod upward carefully until a drop of liquid comes out of the needle tip.
Inject contents within 5 minutes of shaking vigorously. Ensure the needle does not get clogged during the injection. Slowly inject the entire contents of the syringe, deep into the deltoid or gluteal muscle.
Administer using only the thin-wall needles that are provided in the manufacturer's pack. Do not use needles from the 1-month Invega Sustenna pack or other commercially available needles to reduce the risk of blockage. The dose pack contains one 1-inch, 22-gauge needle (pink hub) and one 1.5-inch, 22-gauge needle (yellow hub). The following are the needle size recommendations:
Invega Trinza Deltoid Injection
The recommended needle size for administration into the deltoid muscle is determined by the patient's weight.
For patients weighing less than 90 kg: The 1-inch, 22-gauge thin-wall needle (pink hub) is recommended.
For patients weighing at least 90 kg: The 1.5-inch, 22-gauge thin-wall needle (yellow hub) is recommended.
Administer into the center of the deltoid muscle. Deltoid injections should be alternated between the two deltoid muscles.
Invega Trinza Gluteal Injection
Regardless of patient weight, the recommended needle size for administration into the gluteal muscle is the 1.5-inch, 22-gauge thin-wall needle (yellow hub).
Administer into the upper-outer quadrant of the gluteal muscle. Gluteal injections should be alternated between the two gluteal muscles.
After the injection, use thumb or a flat surface to secure the needle in the safety device. The needle is secure when a "click" sound is heard. Dispose of the syringe and unused needle in an approved sharps container. Do not save the unused needle for future use.
If incomplete administration occurs, do not re-inject the dose remaining in the syringe and do not administer another dose. Closely monitor and treat the patient with oral supplementation as clinically indicated until the next scheduled 3-month injection.
Missed doses:
Missed dose 3.5 months and up to 4 months since last injection: If more than 3.5 months (up to but less than 4 months) have elapsed since the last injection, the previously administered dose should be administered as soon as possible, then continue with the 3-month injections following this dose.
Missed Dose 4 months and up to 9 months since last injection: Do not administer the next dose of Invega Trinza. Instead, use the re-initiation regimen shown in the manufacturer's labeling and dosage.
Missed Dose longer than 9 months since last injection: Re-initiate treatment with the 1-month depot injection (Invega Sustenna). Invega Trinza can then be resumed after adequate treatment with Invega Sustenna for at least 4 months.
 
6-month depot injection (Invega Hafyera)
For gluteal intramuscular (IM) injection only. Do NOT administer by any other route or at any other site. Each injection must be prepared and administered only by a health care professional. Avoid inadvertent injection into a blood vessel.
Prepare exactly as directed. Do not mix with any other product or diluent or use any needles other than those included in the Invega Hafyera injection kit. The injection kit contains a 1.5-inch, 20-gauge thin-wall safety needle.
Administer once every 6 months. If necessary, patients may be given the injection up to 2 weeks before or 3 weeks after the 6-month time point. Missed doses should be avoided.
Administer the dose as a single injection; do not divide the dose.
When administering a dose, ensure that the patient record includes information about the product given, the dose, site, and date of administration.
Inject slowly and deeply into the upper-outer quadrant of the gluteal muscle ONLY. Alternate sides with each subsequent injection.
To mix, hold the syringe with the syringe tip cap pointing up and shake VERY FAST for at least 15 seconds, rest briefly, then shake for an additional 15 seconds. To ensure complete mixing, use short, vigorous motions and a loose wrist.
After shaking, check the liquid in the viewing window. The suspension should appear uniform, thick, and milky white. It is also normal to see small air bubbles. If solid product is visible on sides or top or liquid is thin, repeat mixing process.
If more than 5 minutes pass, shake again VERY FAST, with the tip cap pointing up, for at least 30 seconds to resuspend the medication before administration.
To open the needle pouch, peel off the pouch cover and place pouch on a clean surface.
Hold the syringe with tip cap pointing up. Twist and pull off cap. Hold the syringe by the luer connection and twist it into the safety needle with a gentle clockwise twisting motion.
Pull back plunger gently to clear the syringe tip of any solid product (this will make pressing the plunger easier during the injection). Then, press the plunger carefully to remove air bubbles. Stop when a drop of liquid comes out of the needle tip.
Clean the selected gluteal injection site with an alcohol swab and allow it to dry. Do not touch, fan, or blow on the injection site after it is cleaned.
Pull the needle sheath away from the needle in a straight motion. Do not twist, as this may loosen the needle from the syringe.
Slowly inject IM into gluteal site using firm and consistent pressure on the plunger. Resistance on the plunger is normal. Administration may take approximately 30 seconds to complete. Ensure entire contents of the syringe have been injected prior to removal from the gluteal muscle.
After the injection, use thumb or a flat surface to secure the needle in the safety device. The needle is secure when a "click" sound is heard. Dispose of the syringe in an approved sharps container.
Bleeding or liquid at the injection site may be cleaned with cotton or a gauze pad. Gentle pressure may be applied until bleeding stops and the injection site can be covered with a bandage if needed. Do not rub injection site.
If incomplete administration occurs, do not re-inject the dose remaining in the syringe and do not administer another dose. Closely monitor and treat the patient with oral supplementation as clinically indicated until the next scheduled 6-month injection.
Missed doses:
Missed dose from 6 months and 3 weeks and up to and including 11 months: Do not administer the next dose of Invega Hafyera. Use the re-initiation regimens outlined in the manufacturer's prescribing information.
Missed dose longer than 11 months since last injection: Re-initiate treatment with the 1-month depot injection (Invega Sustenna). Invega Hafyera can then be resumed after adequate treatment with Invega Sustenna for at least 4 months.
Storage: Store an unopened Hafyera syringe carton in horizontal orientation to enhance ability to correctly mix the product prior to administration.

Severe

AV block / Early / 0-2.0
seizures / Delayed / 0-0.5
bradycardia / Rapid / Incidence not known
stroke / Early / Incidence not known
ileus / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
tardive dyskinesia / Delayed / Incidence not known
SIADH / Delayed / Incidence not known
water intoxication / Delayed / Incidence not known
neuroleptic malignant syndrome / Delayed / Incidence not known

Moderate

akathisia / Delayed / 3.0-17.0
pseudoparkinsonism / Delayed / 0-14.0
dystonic reaction / Delayed / 1.0-14.0
sinus tachycardia / Rapid / 0-14.0
hypertriglyceridemia / Delayed / 1.3-13.0
hyperglycemia / Delayed / 2.5-11.0
hypercholesterolemia / Delayed / 0-11.0
hyperlipidemia / Delayed / 0-11.0
dyskinesia / Delayed / 2.0-9.0
constipation / Delayed / 0-5.0
orthostatic hypotension / Delayed / 0-4.0
galactorrhea / Delayed / 3.1-4.0
bundle-branch block / Early / 0-3.0
blurred vision / Early / 0-3.0
cystitis / Delayed / 1.0-3.0
glossitis / Early / 0-3.0
hypertension / Early / 0-2.0
priapism / Early / 0.2-0.2
hyperprolactinemia / Delayed / 10.0
hypertonia / Delayed / Incidence not known
peripheral edema / Delayed / Incidence not known
palpitations / Early / Incidence not known
hypotension / Rapid / Incidence not known
QT prolongation / Rapid / Incidence not known
edema / Delayed / Incidence not known
diabetes mellitus / Delayed / Incidence not known
hyperinsulinemia / Early / Incidence not known
infertility / Delayed / Incidence not known
ejaculation dysfunction / Delayed / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
urinary retention / Early / Incidence not known
urinary incontinence / Early / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known
hyperthermia / Delayed / Incidence not known

Mild

weight gain / Delayed / 3.0-19.0
hyperkinesis / Delayed / 3.0-17.0
tremor / Early / 0-12.0
infection / Delayed / 1.0-12.0
vomiting / Early / 0-11.0
injection site reaction / Rapid / 3.0-10.0
nausea / Early / 2.0-8.0
libido decrease / Delayed / 0.9-7.1
hypersalivation / Early / 0-6.0
dyspepsia / Early / 0-6.0
menstrual irregularity / Delayed / 0-6.0
amenorrhea / Delayed / 4.7-6.0
pharyngitis / Delayed / 2.0-5.0
abdominal pain / Early / 0-4.0
myalgia / Early / 1.0-4.0
appetite stimulation / Delayed / 0-3.0
xerostomia / Early / 0-3.0
dental pain / Delayed / 1.0-3.0
diarrhea / Early / 1.0-3.0
gynecomastia / Delayed / 0-3.0
cough / Delayed / 0-3.0
rhinitis / Early / 1.0-3.0
back pain / Delayed / 1.0-3.0
musculoskeletal pain / Early / 1.0-3.0
epistaxis / Delayed / 0-2.0
arthralgia / Delayed / 0-2.0
syncope / Early / 0.8-0.8
flatulence / Early / Incidence not known
breast discharge / Delayed / Incidence not known
mastalgia / Delayed / Incidence not known
nasal congestion / Early / Incidence not known
fever / Early / Incidence not known
pruritus / Rapid / Incidence not known
urticaria / Rapid / Incidence not known
rash / Early / Incidence not known
muscle cramps / Delayed / Incidence not known
polydipsia / Early / Incidence not known
hypothermia / Delayed / Incidence not known

Dementia, geriatric

Clinical experience with paliperidone has not identified differences in responses between geriatric and younger adult patients. Because geriatric patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be more susceptible to side effects such as orthostasis and a prolonged QT interval. Use paliperidone with extreme caution in geriatric patients with cerebrovascular disease. Carefully titrate the dose to decrease the incidence of orthostatic hypotension. Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients because there is an increased risk of stroke and overall mortality. Patients with Dementia with Lewy Bodies are thought to experience increased sensitivity to antipsychotics manifesting as confusion, obtundation, postural instability with frequent falls, extrapyramidal effects, and symptoms resembling neuroleptic malignant syndrome. The Beers Criteria consider antipsychotics to be potentially inappropriate medications (PIMs) in elderly patients except for treating schizophrenia, bipolar disorder, and nausea/vomiting during chemotherapy. The Beers panel recommends avoiding antipsychotics in geriatric patients with delirium, dementia, or Parkinson's disease. Non-pharmacological strategies are first-line options for treating delirium- or dementia-related behavioral problems unless they have failed or are not possible and the patient is a substantial threat to self or others. If antipsychotic use is necessary in geriatrics with a history of falls or fractures, consider reducing the use of other CNS depressants and implement other fall risk strategies. Due to the potential for antipsychotic-induced hyponatremia and SIADH, sodium levels should be closely monitored when paliperidone is initiated and after dose changes. According to the federal Omnibus Budget Reconciliation Act (OBRA) regulations in residents of long-term care facilities, antipsychotic therapy should only be initiated in a patient with behavioral or psychological symptoms of dementia (BPSD) when the patient is a danger to self or others or has symptoms of mania or psychosis. For conditions persisting beyond 7 days, appropriate non-pharmacologic interventions must be attempted, unless clinically contraindicated and documented. OBRA provides general dosing guidance for the antipsychotic treatment of BPSD. Antipsychotics are subject to periodic review for effectiveness, medical necessity, gradual dose reduction, or rationale for continued use. Refer to the OBRA guidelines for complete information.  

Invega, INVEGA HAFYERA, Invega Sustenna, INVEGA TRINZA

Rx

Atypical antipsychotic that is the active metabolite of risperidone
Oral product used for schizophrenia / schizoaffective disorder in adults and schizophrenia in adolescents 12 years and older; the monthly (Invega Sustenna), 3-month (Invega Trinza), and 6-month (Invega Hafyera) depot injections are used for maintenance treatment of schizophrenia in adults; the 1-month injection also used for schizoaffective disorder as monotherapy or adjunct therapy to mood stabilizers or antidepressants in adults
As with all antipsychotics, increased mortality risk in elderly patients treated for dementia-related psychosis; lack of CYP450 activity reduces the potential for drug interactions

For the treatment of schizophrenia. Oral dosage (extended-release tablets) Adults

6 mg PO once daily, initially; 3 mg PO once daily may be effective for some patients. May increase by 3 mg/day, at intervals of more than 5 days, if needed. Use the lowest effective dose. Max: 12 mg/day PO. Maintenance treatment (to delay relapse) is recommended; paliperidone has been shown to delay relapse during long-term use. Periodically reassess the need for continued treatment. SUGGESTED CONVERSION TO EXTENDED-RELEASE TABLETS FROM INVEGA TRINZA 3-MONTH IM INJECTION: Start the daily dosing of the extended-release (ER) tablets at least 3 months after the last dose of Invega Trinza: If the last dose of Invega Trinza was 273 mg IM and it has been 3 months to 24 weeks or more since the dose: Initiate at 3 mg PO once daily. If the last dose of Invega Trinza was 410 mg IM and it has been 3 months to 24 weeks since the dose: Initiate at 3 mg PO once daily. If the last dose of Invega Trinza was 410 mg IM and it has been more than 24 weeks since the dose: Initiate at 6 mg PO once daily. If the last dose of Invega Trinza was 546 mg IM and it has been 3 months to 18 weeks since the dose: Initiate at 3 mg PO once daily. If the last dose of Invega Trinza was 546 mg and it has been more than 18 weeks and up to 24 weeks since the dose: Initiate at 6 mg PO once daily. If the last dose of Invega Trinza was 546 mg and it has been more than 24 weeks since the dose: Initiate at 9 mg PO once daily. If the last dose of Invega Trinza was 819 mg IM and it has been 3 months to 18 weeks since the dose: Initiate at 6 mg PO once daily. If the last dose of Invega Trinza was 819 mg and it has been more than 18 weeks and up to 24 weeks since the dose: Initiate at 9 mg PO once daily. If the last dose of Invega Trinza was 819 mg IM and it has been more than 24 weeks since the dose: Initiate at 12 mg PO once daily.

Children and Adolescents 12 years and older and weighing at least 51 kg

3 mg PO once daily, initially. May increase at increments of 3 mg/day at intervals of more than 5 days, if needed. Use lowest effective dose. Max: 12 mg/day PO. In clinical trials there was no clear benefit at higher doses (i.e., 12 mg/day), and adverse events were dose-related. Periodically reassess the need for continued treatment.

Children and Adolescents 12 years and older and weighing less than 51 kg

Initially, 3 mg PO once daily. May increase at increments of 3 mg/day at intervals of more than 5 days, if needed. Use lowest effective dose. Max: 6 mg/day PO. In clinical trials, there was no clear benefit at higher doses (i.e., 6 mg), and adverse events were dose-related. Periodically reassess the need for continued treatment.

Intramuscular dosage (i.e., Once-monthly extended-release injectable suspension; i.e., Invega Sustenna) Adults

THERAPY INITIATION: The initiation phase consists of 2 doses administered 1 week apart: 234 mg IM single dose into the deltoid muscle on Day 1, then 156 mg IM 1-week later (day 8) into the deltoid muscle. The second dose may be scheduled 4 days before or 4 days after the 1-week time point to help avoid a missed dose. MAINTENANCE DOSING: After the second dose, monthly IM maintenance dosing (either in the deltoid or gluteal muscle) is recommended. Administer the first maintenance dose 5 weeks after the first initiation dose, regardless of the timing of the second initiation dose. The recommended maintenance dose (third and subsequent doses) is 117 mg IM once per month; however, monthly dosing may range from 39 mg to 234 mg IM once per month according to clinical history, individual efficacy, and tolerability. The patient may receive the monthly dose up to 7 days before or after the monthly due date to help avoid a missed dose. Maintenance doses may be adjusted monthly; however, the full effect of a dose adjustment may not be evident for several months. Use the lowest effective dose. Periodically reassess the need for continued therapy. MISSED DOSES: Instructions for missed doses are specific and dependent on dose type (initiation or maintenance), and the duration since the last dose. FOR A MISSED SECOND INITIATION DOSE: If less than 4 weeks have elapsed since the first injection, give 156 mg IM into the deltoid muscle as soon as possible. A third injection of 117 mg IM (deltoid or gluteal) is recommended 5 weeks after the first injection, regardless of when the second injection is given. After that, follow the usual monthly cycle of injections. If 4 to 7 weeks have elapsed since the first injection, administer 156 mg IM into the deltoid muscle as soon as possible, followed by 156 mg IM into the deltoid muscle 1-week later. After that, follow the usual monthly cycle of injections. If more than 7 weeks have elapsed since the first injection, begin with the initial dosing regimen (i.e., 234 mg IM into the deltoid on day 1, then 156 mg IM into the deltoid 1-week later). Then, follow the usual monthly cycle of injections. FOR A MISSED MONTHLY DOSE: If a monthly maintenance dose is missed and less than 6 weeks have elapsed, give the missed dose as soon as possible, followed by injections at monthly intervals. If more than 6 weeks but not greater than 6 months have elapsed since the previous maintenance injection, give the previously established dose IM into the deltoid as soon as possible, followed by the same dose IM into the deltoid 1-week later, then resume monthly deltoid or gluteal dosing. If more than 6 weeks and not greater than 6 months have elapsed and the patient was receiving 234 mg/month, the first 2 injections should be 156 mg each, given 1 week apart into the deltoid. If more than 6 months have elapsed since the last maintenance injection, initiate the initial dosing titration regimen, then use monthly maintenance injections. CONVERSION FROM ORAL ANTIPSYCHOTICS TO PALIPERIDONE ONCE-MONTHLY INJECTION: For patients who have never taken paliperidone or risperidone, it is recommended to establish tolerability with oral paliperidone or risperidone before using paliperidone monthly injection. Use caution when injectable paliperidone is co-administered with risperidone or oral paliperidone. Safety data involving concurrent use of injectable paliperidone with other antipsychotics are limited. Oral therapy can be gradually discontinued at the time of initiating paliperidone injection. Patients previously stabilized on paliperidone ER tablets can attain similar paliperidone steady-state exposure during maintenance treatment with the following conversions: 3 mg/day PO converts to a long-acting injection dose of 39 mg to 78 mg/month IM; 6 mg/day PO converts to 117 mg/month IM; 9 mg/day PO converts to 156 mg/month IM; 12 mg/day PO converts to 234 mg/month IM. CONVERSION FROM OTHER LONG-ACTING INJECTABLE ANTIPSYCHOTICS TO PALIPERIDONE ONCE-MONTHLY INJECTION (INVEGA SUSTENNA): For patients who have never taken paliperidone or risperidone, establish tolerability with oral paliperidone or risperidone before using paliperidone monthly injection. For patients currently at steady-state on a long-acting injectable antipsychotic, initiate paliperidone therapy in place of the next scheduled injection of the previous antipsychotic. The usual first-week paliperidone initiation regimen is not required. The recommended paliperidone injection dose is 117 mg IM once monthly; however, the dose may range from 39 mg to 234 mg IM once monthly depending upon individual response and tolerability. CONVERSION FROM INVEGA TRINZA 3-MONTH INJECTION TO INVEGA SUSTENNA 1-MONTH INJECTION: Invega Sustenna should be started 3 months after the last dose of Invega Trinza using the equivalent 3.5-fold lower dose as follows: If the last dose of Invega Trinza was 273 mg IM: initiate Invega Sustenna 3 months later at 78 mg IM once monthly; continue monthly dosing thereafter. If the last dose of Invega Trinza was 410 mg IM: initiate Invega Sustenna 3 months later at 117 mg IM once monthly; continue monthly dosing thereafter. If the last dose of Invega Trinza was 546 mg IM: initiate Invega Sustenna 3 months later at 156 mg IM once monthly; continue monthly dosing thereafter. If the last dose of Invega Trinza was 819 mg IM: initiate Invega Sustenna 3 months later at 234 mg IM once monthly; continue monthly dosing thereafter.

Intramuscular dosage (3-month depot injectable suspension; i.e., Invega Trinza) Adults

Invega Trinza is only indicated after adequate treatment with the once-monthly extended-release maintenance injection (Invega Sustenna) for at least 4 months. In order to establish a consistent maintenance dose, it is recommended that the last two doses of Invega Sustenna be the same dosage strength before starting Invega Trinza. Since paliperidone is the major active metabolite of risperidone, caution should be exercised when Invega Trinza is co-administered with risperidone or oral paliperidone for extended periods of time. Safety data involving concomitant use of Invega Trinza with other antipsychotics are limited. CONVERSION FROM INVEGA SUSTENNA TO INVEGA TRINZA: Initiate Invega Trinza when the next 1-month injection (Invega Sustenna) is scheduled. Invega Trinza may be initiated up to 7 days before or after the monthly due date of the next scheduled Invega Sustenna dose to avoid missed appointments. Use the equivalent 3.5-fold higher dose to convert to Invega Trinza as follows: Patients stabilized on 39 mg IM monthly of Invega Sustenna: No conversion recommendations available. Patients stabilized on 78 mg IM monthly of Invega Sustenna: Initiate Invega Trinza at 273 mg IM every 3 months. Patients stabilized on 117 mg IM monthly of Invega Sustenna: Initiate Invega Trinza at 410 mg IM every 3 months. Patients stabilized on 156 mg IM monthly of Invega Sustenna: Initiate Invega Trinza at 546 mg IM every 3 months. Patients stabilized on 234 mg IM monthly of Invega Sustenna: Initiate Invega Trinza at 819 mg IM every 3 months. Following the initial Invega Trinza dose, the injection should be administered every 3 months thereafter. May adjust dose every 3 months in increments; the maintenance dose range is 273 mg to 819 mg IM once every 3 months based on individual efficacy and/or tolerability. Due to the long-acting nature of Invega Trinza, the response of a patient to an adjusted dose may not be apparent for several months. Max: 819 mg IM every 3 months. MISSED DOSES: Missed doses should be avoided. To avoid missed doses, patients can receive the Trinza injection up to 2 weeks before or after the date of their scheduled 3-month dose. Instructions if missed dose outside this time window: Missed dose from 3.5 months up to 4 months since the last injection: Administer needed dose as soon as possible, then continue with every 3 months schedule. Missed dose 4 to 9 months since the last injection: Do NOT administer the next dose. Instead, reinitiate as follows, first using Invega Sustenna, then following with Invega Trinza: If the last dose of Invega Trinza was 273 mg IM: Administer Invega Sustenna 78 mg IM on Day 1 into the deltoid muscle and administer another Invega Sustenna dose of 78 mg IM on Day 8 into the deltoid muscle. Then 1 month after the Day 8 injection, administer 273 mg IM of Invega Trinza (deltoid or gluteal muscle) and then every 3 months thereafter. If the last dose of Invega Trinza was 410 mg IM: Administer Invega Sustenna 117 mg IM on Day 1 into the deltoid muscle and administer another Invega Sustenna 117 mg IM on Day 8 into the deltoid muscle. Then 1 month after the Day 8 injection, administer 410 mg IM of Invega Trinza (deltoid or gluteal muscle) and then every 3 months thereafter. If the last dose of Invega Trinza was 546 mg IM: Administer Invega Sustenna 156 mg IM on Day 1 into the deltoid muscle and administer another Invega Sustenna 156 mg IM on Day 8 into the deltoid muscle. Then 1 month after the Day 8 injection, administer 546 mg IM of Invega Trinza (deltoid or gluteal muscle) and then every 3 months thereafter. If the last dose of Invega Trinza was 819 mg: Administer Invega Sustenna 156 mg on Day 1 into the deltoid muscle and administer another Invega Sustenna 156 mg IM on Day 8 into the deltoid muscle. Then, 1 month after the Day 8 injection, administer 819 mg IM of Invega Trinza (deltoid or gluteal muscle) and then every 3 months thereafter. Missed dose more than 9 months since last injection: Re-initiate treatment with the once-monthly injection (Invega Sustenna) as described in the prescribing information for that product. Invega Trinza can be resumed only after the patient has been adequately treated with Invega Sustenna for at least 4 months.

Intramuscular dosage (6-month depot injectable suspension, i.e. Invega Hafyera) Adults

Invega Hafyera is indicated after adequate treatment with once-monthly extended-release paliperidone injections (Invega Sustenna) for at least 4 months or every 3-month extended release paliperidone injections (Invega Trinza) for at least one 3-month cycle. DOSING: The recommended initial dose of Hafyera IM via gluteal injection every 6 months is determined by the dose of the prior paliperidone product. May adjust dosing every 6 months based on patient response and tolerability. Due to the long duration of action of Hafyera, patient response to dose adjustments may not be apparent for several months. Max Invega Hafyera dose: 1,560 mg IM via gluteal injection every 6 months. CONVERSION FROM INVEGA SUSTENNA TO INVEGA HAFYERA: When switching from monthly injections to the 6-month product, the two Invega Sustenna injections immediately prior to the switch should be the same strength to ensure the correct dose is selected and maintain adequate symptom control. Initiate Invega Hafyera when the next monthly injection of Invega Sustenna is due (up to 1 week before or 1 week after the due date). For patients maintained on 156 mg IM monthly, give Hafyera 1,092 mg IM as a gluteal injection every 6 months. For patients maintained on 234 mg IM monthly, give Hafyera 1,560 mg IM as gluteal injection every 6 months. Invega Sustenna doses of 39 mg, 78 mg, and 117 mg were not studied and do not have equivalent Hafyera doses. CONVERSION FROM INVEGA TRINZA TO INVEGA HAFYERA: Initiate Invega Hafyera when the next Invega Trinza dose is due (up to 2 weeks before or 2 weeks after the next scheduled 3-month dose). For patients maintained on 546 mg IM every 3 months, give Hafyera 1,092 mg IM as a gluteal injection every 6 months. For patients maintained on 819 mg IM every 3 months, give Hafyera 1,560 mg IM as a gluteal injection every 6 months. Invega Trinza doses of 273 mg and 410 mg were not studied and do not have equivalent Hafyera doses. MISSED DOSES: To avoid missed doses, patients can receive the Hafyera injection up to 2 weeks before or 3 weeks after the date of their scheduled 6-month dose. If a Hafyera dose is missed, re-initiate treatment with the once-monthly formulation (Invega Sustenna) given as deltoid injections. If more than 6 months and 3 weeks but less than 8 months have passed since the last dose of Hafyera, re-initate Sustenna as follows: For 1,092 mg doses, give Sustenna 156 mg IM into deltoid muscle on day 1, then give Hafyera 1,092 mg IM into gluteal muscle 1 month later. For 1,560 mg doses, give Sustenna 234 mg IM into deltoid muscle on day 1, then give Hafyera 1,560 mg IM into gluteal muscle 1 month later. If 8 to 11 months have passed since the last Hafyera dose, re-initiate as follows: For 1,092 mg dose, give Sustenna 156 mg IM into deltoid on day 1 and day 8, then administer Hafyera 1,092 mg IM into gluteal muscle 1 month after day 8. For 1,560 mg dose, give Sustenna 156 mg IM into deltoid on day 1 and 8, then Hafyera 1,560 mg IM into gluteal muscle 1 month after day 8. If more than 11 months have passed since the last dose of Invega Hafyera, re-initiate with once-monthly paliperidone injections (Invega Sustenna) as directed in the Sustenna product labeling. Hafyera may be resumed once the patient is maintained on once-monthly Sustenna injections for at least 4 months.

For the treatment of schizoaffective disorder as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. Oral dosage (extended-release tablets) Adults

6 mg PO once daily. Initial dose titration is not required. Dosages as low as 3 mg/day or as high as 12 mg/day may be beneficial for some patients. If necessary, may increase by 3 mg/day no more frequently than every 5 days. Max: 12 mg/day. A general trend toward greater efficacy was observed in clinical trials within the higher dosage range. Individualize dose since higher doses may be associated with an increase in adverse effects.

Intramuscular dosage (i.e., Invega Sustenna, once-monthly extended-release injectable suspension) Adults

THERAPY INITIATION: The initiation phase consists of 2 doses administered 1 week apart: 234 mg IM single dose into the deltoid muscle on Day 1, then 156 mg IM 1-week later (day 8) into the deltoid muscle. The second dose may be scheduled 4 days before or 4 days after the 1-week time point to help avoid a missed dose. MAINTENANCE DOSING: After the second dose, monthly IM maintenance dosing (either in the deltoid or gluteal muscle) is recommended. Administer the first maintenance dose 5 weeks after the first initiation dose, regardless of the timing of the second initiation dose. The recommended monthly maintenance dose range (third and subsequent doses) is 78 mg to 234 mg IM (deltoid or gluteal muscle) once monthly. The 39-mg dose was not studied for the long-term treatment of schizoaffective disorder. Max Invega Sustenna dose: 234 mg IM once monthly. To avoid a missed monthly dose, patients can receive their maintenance Invega Sustenna dose up to 7 days before or after the usual monthly due date. May adjust the maintenance dose monthly; however, the full effect of a dose adjustment may not be evident for several months. Use the lowest effective dose. Periodically reassess the need for treatment. MISSED DOSES: Instructions for missed doses are specific and dependent on dose type (initiation or maintenance), and the duration since the last dose. FOR A MISSED SECOND INITIATION DOSE: If less than 4 weeks have elapsed since the first injection, give 156 mg IM into the deltoid muscle as soon as possible. A third injection of 117 mg IM (deltoid or gluteal) is recommended 5 weeks after the first injection, regardless of when the second injection is given. After that, follow the usual monthly cycle of injections. If 4 to 7 weeks have elapsed since the first injection, administer 156 mg IM into the deltoid muscle as soon as possible, followed by 156 mg IM into the deltoid muscle 1-week later. After that, follow the usual monthly cycle of injections. If more than 7 weeks have elapsed since the first injection, begin with the initial dosing regimen (i.e., 234 mg IM into the deltoid on day 1, then 156 mg IM into the deltoid 1-week later). Then, follow the usual monthly cycle of injections. MISSED MONTHLY DOSES: If a monthly maintenance dose is missed and less than 6 weeks have elapsed, give the missed dose as soon as possible, followed by injections at monthly intervals. If more than 6 weeks but not greater than 6 months have elapsed since the previous maintenance injection, give the previously established dose IM into the deltoid as soon as possible, followed by the same dose IM into the deltoid 1-week later, then resume monthly deltoid or gluteal dosing. If more than 6 weeks and not more than 6 months have elapsed and the patient was receiving 234 mg/month, the first 2 injections should be 156 mg each, given 1 week apart into the deltoid. If more than 6 months have elapsed since the last maintenance injection, initiate the initial IM dosing titration regimen, then use monthly maintenance injections. CONVERSION FROM ORAL ANTIPYSCHOTIC TREATMENT TO EXTENDED-RELEASE PALIPERIDONE ONCE MONTHLY INJECTION (INVEGA SUSTENNA): For patients who have never taken oral paliperidone or oral or injectable risperidone, first establish tolerability with oral paliperidone or risperidone prior to initiating treatment with paliperidone extended-release injection. Previous oral therapy can be gradually discontinued at the time of initiating Sustenna injection. Patients previously stabilized on paliperidone ER tablets can attain similar parenteral paliperidone steady-state exposure with the following conversions: 3 mg/day PO converts to 39 mg/month to 78 mg/month IM; 6 mg/day PO converts to 117 mg/month IM; 9 mg/day PO converts to 156 mg/month IM; 12 mg/day PO converts to 234 mg/month IM. The 39-mg strength was not studied for schizoaffective disorder. CONVERSION FROM OTHER LONG-ACTING INJECTABLE ANTIPSYCHOTICS TO ONCE MONTHLY INJECTION (INVEGA SUSTENNA): For patients who have never taken oral paliperidone or oral or injectable risperidone, it is recommended to first establish tolerability with oral paliperidone or risperidone before initiating treatment with Invega Sustenna. For patients currently at steady-state on a long-acting injectable antipsychotic, initiate Sustenna in place of the next scheduled injection of the previous antipsychotic. The usual first-week initiation regimen is not required. Recommended monthly maintenance dose range: 78 mg IM to 234 mg IM based on efficacy and/or tolerability.

For the treatment of mania† associated with bipolar disorder†. Oral dosage Adults

6 mg PO once daily, initially. Adjust dose by 3 mg/day every 2 days or more based on clinical response and tolerability. Dose range: 3 to 12 mg/day.

For the treatment of severe behavioral or psychological symptoms of dementia† (BPSD)†. Oral dosage Geriatric Adults

Dosage not established. According to the Agency for Healthcare Research and Quality (AHRQ) atypical antipsychotic review in 2011, paliperidone had not been studied as an off-label treatment for behavioral disturbances associated with dementia. Antipsychotics are not FDA-approved for the treatment of behavioral problems associated with dementia and the labeling of all antipsychotics contains a boxed warning noting an increased risk of death in geriatric patients being treated for behavioral problems associated with dementia. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antipsychotics in long-term care facility (LTCF) residents with dementia-related behavioral symptoms. Specific criteria for treatment must be met, and adherence to daily dose thresholds for each antipsychotic is required, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. No OBRA dosing guidance is available for paliperidone due to a lack of studies or results available to assess the safety or efficacy of paliperidone in older adults with dementia. For all antipsychotics, the facility must attempt a gradual dose reduction (GDR) in 2 separate quarters, at least 1 month apart, within the first year of admission to the facility or after the facility has initiated an antipsychotic, unless clinically contraindicated. After the first year, a GDR must be attempted annually unless clinically contraindicated. The GDR may be considered clinically contraindicated if the target symptoms returned or worsened after the most recent GDR attempt within the facility and the physician has documented justification for why attempting additional dose reductions at that time would likely impair the resident's function or increase distressed behavior.

†Indicates off-label use

Hepatic Impairment

Oral paliperidone does not require dose adjustment in patients with mild or moderate hepatic impairment; paliperidone does not undergo extensive hepatic metabolism. Based on the oral information available, no dose adjustment to the patient's effective dose is recommended for patients with mild or moderate hepatic metabolism when Invega Sustenna injection is given monthly, when Invega Trinza is given every 3 months, or when Invega Hafyera is given every 6 months. Paliperidone products (all routes) have not been studied in patients with severe hepatic impairment.

Renal Impairment

Dosage adjustments are recommended in renal impairment and are dependent on CrCl estimates and the product chosen for use.
 
Oral extended-release tablets:
CrCl 80 mL/min or more: No dosage adjustments are necessary.
CrCl 50 to 79 mL/min: Recommended initial dose is 3 mg/day PO. Maximum: 6 mg/day PO.
CrCl 10 to 49 mL/min: Recommended initial dose is 1.5 mg/day PO. Maximum: 3 mg/day PO.
CrCl less than 10 mL/min: Use not recommended.
 
Extended-release once-monthly injection suspension (Invega Sustenna)
CrCl 80 mL/min or more: No dosage adjustments are necessary.
CrCl 50 to 79 mL/min: Initiate with 156 mg IM on day 1, and then administer 117 mg IM for the second dose on day 8, both given into the deltoid muscle. Follow with monthly injections of 78 mg IM once per month in either the deltoid or gluteal muscle. Dose may be adjusted as needed based on efficacy and tolerability to a maximum of 156 mg IM once per month.
CrCl less than 50 mL/min: Use not recommended.
 
Extended-release 3-month depot injection suspension (Invega Trinza)
CrCl 80 mL/min or more: No dosage adjustment is necessary.
CrCl 50 to 79 mL/min: Only for patients stabilized on Invega Sustenna once-monthly injections. Do not give to patients who have not been previously stabilized on Invega Sustenna injections monthly. Conversion dose is based on the stabilized previous dose of Invega Sustenna for the patient:
Last dose of Invega Sustenna 78 mg IM once monthly: Initiate with Invega Trinza 273 mg IM every 3 months.
Conversion from the Invega Sustenna 39 mg dose IM once monthly was not studied.
CrCl less than 50 mL/min: Use not recommended.
 
Extended-release 6-month depot injection suspension (Invega Hafyera)
CrCl less than 90 mL/min: Use is not recommended because dose adjustment is not possible with available product strengths.

Abarelix: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as abarelix. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Acarbose: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and diphenhydramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression during coadministration of paliperidone and dihydrocodeine and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and pyrilamine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acetaminophen; Chlorpheniramine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acetaminophen; Codeine: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and doxylamine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Drugs that can cause CNS depression, including dichloralphenazone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness if used concomitantly with atypical antipsychotics.
Acetaminophen; Diphenhydramine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and diphenhydramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acetaminophen; Hydrocodone: (Moderate) Concomitant use of drugs that can cause CNS depression, such as hydrocodone and paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Acetaminophen; Oxycodone: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression during coadministration of paliperidone and oxycodone and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and pyrilamine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Acrivastine; Pseudoephedrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and acrivastine, can increase both the frequency and the intensity of drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Adagrasib: (Major) Concomitant use of adagrasib and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Alfentanil: (Moderate) Drugs that can cause CNS depression such as alfentanil, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Alfuzosin: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as alfuzosin. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. If coadministration is considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, close monitoring is essential.
Alogliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Alogliptin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Alogliptin; Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Alpha-glucosidase Inhibitors: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Alprazolam: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Amifampridine: (Major) Carefully consider the need for concomitant treatment with atypical antipsychotics and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Atypical antipsychotics may increase the risk of seizures.
Amiodarone: (Major) Concomitant use of paliperidone and amiodarone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Avoid coadministration of amisulpride and paliperidone due to the potential for additive QT prolongation. Monitor ECG if coadministration is necessary. Amisulpride causes dose- and concentration- dependent QT prolongation. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose.
Amobarbital: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as a barbiturate is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug. It should be noted that clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates.
Amoxapine: (Moderate) Use caution during coadministration of amoxapine and paliperidone. Amoxapine exhibits some antipsychotic activity and may increase the risk of tardive dyskinesia or neuroleptic malignant syndrome (NMS) when antipsychotics, such as paliperidone, are given concurrently. Sedation, orthostatic hypotension, anticholinergic effects, and lowering of seizure threshold are potential problems with the combined use of amoxapine and antipsychotics.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as clarithromycin. However, if coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Anagrelide: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Do not use anagrelide with other drugs that prolong the QT interval. Torsade de pointes and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Angiotensin II receptor antagonists: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and angiotensin II receptor antagonists who are susceptible to hypotension.
Angiotensin-converting enzyme inhibitors: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and angiotensin-converting enzyme inhibitors who are susceptible to hypotension.
Apalutamide: (Major) Avoid using apalutamide if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of apalutamide is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Oral paliperidone may be used; however, a dosage increase may be necessary. Paliperidone is a P-glycoprotein (P-gp) substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. Apalutamide is a strong CYP3A4 inducer and a weak P-gp inducer. Coadministration with another strong CYP3A4/P-gp inducer decreased steady-state exposure of paliperidone by 37%.
Apomorphine: (Moderate) Coadministration of apomorphine and paliperidone may increase the risk for QT prolongation or sedation. Apomorphine and paliperidone may decrease the effectiveness of each other due to opposing effects on dopamine. Additive CNS effects are also possible. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. In general, atypical antipsychotics are less likely to interfere with Parkinson's disease treatments than traditional antipsychotics. Monitor for movement disorders, unusual changes in moods or behavior, sedation, fast, irregular heartbeat, and diminished effectiveness of either agent during coadministration.
Aripiprazole: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. In addition, the risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, tardive dyskinesia, or seizures may be increased during combined use of antipsychotics; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is necessary.
Arsenic Trioxide: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided with other agents also known to have this effect, such as arsenic trioxide. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Artemether; Lumefantrine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Artemether; lumefantrine is associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Consider ECG monitoring if paliperidone must be used with or after artemether; lumefantrine treatment.
Articaine; Epinephrine: (Major) The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of paliperidone. This blockade can cause an apparently paradoxical condition called 'epinephrine reversal'. The use of other agents for vascular support is recommended when needed.
Asenapine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as asenapine. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. In addition, the use of paliperidone with asenapine may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as a barbiturate is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug. It should be noted that clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Aspirin, ASA; Oxycodone: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression during coadministration of paliperidone and oxycodone and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Atomoxetine: (Major) Concomitant use of paliperidone and atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Azithromycin: (Major) Concomitant use of paliperidone and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bedaquiline: (Major) Concurrent use of paliperidone and bedaquiline should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Both drugs have been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of paliperidone overdose. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with paliperidone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with paliperidone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking paliperidone, reduce initial dosage and titrate to clinical response. If paliperidone is initiated a patient taking an opioid agonist, use a lower initial dose of paliperidone and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Benzodiazepines: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Beta-adrenergic blockers: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and beta-adrenergic blockers who are susceptible to hypotension.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Brexpiprazole: (Major) Caution is advisable during concurrent use of antipsychotics including brexpiprazole and paliperidone. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, tardive dyskinesia, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is necessary.
Bromocriptine: (Moderate) The effectiveness of bromocriptine may be reduced by most of the atypical antipsychotics, via their action as dopamine antagonists. Monitor the patient for reduced response to bromocriptine. The atypical antipsychotics elevate prolactin to various degrees. Atypical antipsychotics may also aggravate diabetes mellitus and cause metabolic changes including hyperglycemia; use caution if bromocriptine is taken for diabetes. If bromocriptine is taken for diabetes, monitor for worsening glycemic control.
Brompheniramine: (Moderate) Drugs that can cause CNS depression, such as brompheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when used with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Drugs that can cause CNS depression, such as brompheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when used with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Brompheniramine; Phenylephrine: (Moderate) Drugs that can cause CNS depression, such as brompheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when used with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Brompheniramine; Pseudoephedrine: (Moderate) Drugs that can cause CNS depression, such as brompheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when used with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Drugs that can cause CNS depression, such as brompheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when used with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Bupivacaine; Epinephrine: (Major) The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of paliperidone. This blockade can cause an apparently paradoxical condition called 'epinephrine reversal'. The use of other agents for vascular support is recommended when needed.
Buprenorphine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, coadministration of buprenorphine and paliperidone should be avoided. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Paliperidone also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of paliperidone and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during coadministration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation.
Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, coadministration of buprenorphine and paliperidone should be avoided. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Paliperidone also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of paliperidone and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during coadministration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation.
Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as paliperidone. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as paliperidone. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
Buspirone: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant atypical antipsychotic and buspirone use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Butabarbital: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as a barbiturate is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug. It should be noted that clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates.
Butalbital; Acetaminophen: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as a barbiturate is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug. It should be noted that clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as a barbiturate is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug. It should be noted that clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as a barbiturate is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug. It should be noted that clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates. (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as a barbiturate is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug. It should be noted that clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates. (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Butorphanol: (Moderate) Drugs that can cause CNS depression, including butorphanol, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when used with paliperidone, an antipsychotic with potential CNS depressant properties. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Cabergoline: (Moderate) Cabergoline should not be coadministered with paliperidone due to mutually antagonistic effects on dopaminergic function. The dopamine antagonist action of paliperidone may diminish the prolactin-lowering ability of cabergoline while the dopamine agonist effects of cabergoline may exacerbate a psychotic disorder, reducing the effectiveness of antipsychotics such as paliperidone.
Cabotegravir; Rilpivirine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Calcium-channel blockers: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and calcium-channel blockers who are susceptible to hypotension.
Canagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Canagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and paliperidone. Concurrent use may result in additive CNS depression.
Carbamazepine: (Major) It may be necessary to increase the dose of oral paliperidone during coadministration of a strong inducer of both CYP3A4 and P-gp, such as carbamazepine. Conversely, a reduction in oral paliperidone dose may be needed upon discontinuation of the inducer. Avoid using a strong inducer of CYP3A4 and/or P-gp if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong inducer is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. Coadministration of oral paliperidone (6 mg/day) and carbamazepine (200 mg twice daily) resulted in a 37% decrease in paliperidone Cmax and AUC during one study, primarily via an increase in paliperidone renal clearance. A minor decrease in the amount of unchanged paliperidone in the urine suggested only minimal effects from changes in CYP activity or paliperidone bioavailability.
Carbidopa; Levodopa: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
Carbidopa; Levodopa; Entacapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease. (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
Carbinoxamine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and carbinoxamine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Cariprazine: (Moderate) The risk of adverse effects may be increased during concurrent use of cariprazine with other antipsychotics, such as paliperidone. Similar to other antipsychotics, cariprazine administration has been associated with drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. The incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, but the risk appears to be increased.
Celecoxib; Tramadol: (Moderate) Concurrent use of tramadol and paliperidone should be administered with caution. Antipsychotics, such as paliperidone, may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and paliperidone.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and paliperidone. Concurrent use may result in additive CNS depression.
Central-acting adrenergic agents: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and central-acting adrenergic agents who are susceptible to hypotension.
Ceritinib: (Major) Avoid coadministration of paliperidone with ceritinib if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor electrolytes for QT prolongation and monitor electrolytes; close monitoring is essential if the patient has known risk factors for cardiac disease or arrhythmia. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Concentration-dependent QT prolongation has been reported with ceritinib therapy.
Cetirizine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and cetirizine due to the risk for additive CNS depression.
Cetirizine; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and cetirizine due to the risk for additive CNS depression.
Cetrorelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and dexchlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlorcyclizine: (Moderate) Coadministration of drugs that can cause CNS depression, including chlorcyclizine and paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlordiazepoxide: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlordiazepoxide; Amitriptyline: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlordiazepoxide; Clidinium: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chloroquine: (Major) Avoid coadministration of chloroquine with paliperidone due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose.
Chlorpheniramine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlorpheniramine; Codeine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them. (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlorpheniramine; Dextromethorphan: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them. (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression during coadministration of paliperidone and dihydrocodeine and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlorpheniramine; Hydrocodone: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them. (Moderate) Concomitant use of drugs that can cause CNS depression, such as hydrocodone and paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlorpheniramine; Phenylephrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlorpheniramine; Pseudoephedrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and chlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Chlorpromazine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as chlorpromazine. However, if coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. In addition, the risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use of antipsychotics; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is necessary. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Chlorthalidone; Clonidine: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and central-acting adrenergic agents who are susceptible to hypotension.
Ciprofloxacin: (Major) Concomitant use of paliperidone and ciprofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Because of the potential for TdP, use of cisapride with paliperidone is contraindicated.
Citalopram: (Major) Concomitant use of paliperidone and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clarithromycin: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as clarithromycin. However, if coadministration is considered necessary and the patient has known risk f

actors for cardiac disease or arrhythmias, close monitoring is essential.
Clemastine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and clemastine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Clobazam: (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Clofazimine: (Major) Concomitant use of clofazimine and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clonazepam: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Clonidine: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and central-acting adrenergic agents who are susceptible to hypotension.
Clorazepate: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Clozapine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as clozapine. However, if coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. In addition, coadministration of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.
Codeine: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Codeine; Guaifenesin: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Codeine; Phenylephrine; Promethazine: (Major) According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Promethazine, a phenothiazine antiemetic/antihistamine, has been associated with QT prolongation. Coadministration of promethazine and antipsychotics such as paliperidone may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from concurrent use of a phenothiazine and atypical antipsychotic has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone. (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Codeine; Promethazine: (Major) According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Promethazine, a phenothiazine antiemetic/antihistamine, has been associated with QT prolongation. Coadministration of promethazine and antipsychotics such as paliperidone may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from concurrent use of a phenothiazine and atypical antipsychotic has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone. (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
COMT inhibitors: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Crizotinib: (Major) Avoid coadministration of crizotinib with paliperidone if possible due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Paliperidone has also been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose.
Cyclizine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and cyclizine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Cyproheptadine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and cyproheptadine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Dapagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Dapagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Dapagliflozin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Dasatinib: (Major) Avoid coadministration of paliperidone and dasatinib if possible due to the potential for QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
Degarelix: (Major) Avoid coadministration of paliperidone with degarelix due to the potential for additive QT prolongation and risk of torsade de pointes (TdP); the efficacy of degarelix may also be reduced. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval. Additionally, paliperidone can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; degarelix is a GnRH analog.
Deutetrabenazine: (Major) Avoid coadministration of paliperidone with deutetrabenazine due to the potential for additive QT prolongation. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Monitor for signs and symptoms of neuroleptic malignant syndrome (NMS), restlessness, and agitation. If NMS is diagnosed, immediately discontinue deutetrabenazine, and provide intensive symptomatic treatment and medical monitoring. Recurrence of NMS has been reported with resumption of drug therapy. If akathisia or parkinsonism develops during treatment, the deutetrabenazine dose should be reduced; discontinuation may be required. Deutetrabenazine is a reversible, dopamine depleting drug and paliperidone is a dopamine antagonist. The risk for parkinsonism, NMS, or akathisia may be increased with concomitant administration. Monitor for excessive sedation and somnolence during coadministration of paliperidone and deutetrabenazine. Concurrent use may result in additive CNS depression.
Dexchlorpheniramine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and dexchlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and dexchlorpheniramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as paliperidone. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and diphenhydramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Dextromethorphan; Quinidine: (Major) Coadministration of paliperidone and quinidine should be avoided if possible due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinidine, a CYP2D6 inhibitor, is associated with QT prolongation and torsades de pointes (TdP). According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. While in vitro studies indicate that CYP2D6 is minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by CYP2D6 and it contributes to only a small fraction of total body clearance of paliperidone. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Diazepam: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Diazoxide: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and diazoxide who are susceptible to hypotension.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Dimenhydrinate: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and dimenhydrinate, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Diphenhydramine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and diphenhydramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Diphenhydramine; Ibuprofen: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and diphenhydramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Diphenhydramine; Naproxen: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and diphenhydramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Diphenhydramine; Phenylephrine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and diphenhydramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Disopyramide: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP). If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Dofetilide: (Major) Coadministration of dofetilide and paliperidone is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Dolasetron: (Major) Avoid coadministration of paliperidone and dolasetron if possible due to a possible increased risk for QT prolongation and torsade de pointes (TdP). If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose.
Dolutegravir; Rilpivirine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Donepezil: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Donepezil; Memantine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Dopamine: (Moderate) The vasoconstrictive properties and other effects of dopamine can be decreased by the alpha-adrenergic- and dopamine-blocking effects of paliperidone. Adjust dopamine therapy as clinically indicated to renal, heart rate, blood pressure, or other cardiovascular parameters.
Doxazosin: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and doxazosin who are susceptible to hypotension.
Doxylamine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and doxylamine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Doxylamine; Pyridoxine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and doxylamine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Dronabinol: (Moderate) Drugs that can cause CNS depression such as dronabinol, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Dronedarone: (Contraindicated) Concurrent use of dronedarone and paliperidone is contraindicated. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1,600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, including droperidol. However, if coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Dulaglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Eliglustat: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Empagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Empagliflozin; Linagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Empagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Encorafenib: (Major) Avoid coadministration of encorafenib and paliperidone if possible due to the potential for additive QT prolongation. If coadministration is necessary, close monitoring of ECGs and electrolytes essential, particularly in patients with known risk factors for cardiac disease or arrhythmias. Correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose.
Entacapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Entrectinib: (Major) Avoid coadministration of paliperidone with entrectinib due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Entrectinib has been associated with QT prolongation.
Enzalutamide: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as enzalutamide is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug.
Epinephrine: (Major) The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of paliperidone. This blockade can cause an apparently paradoxical condition called 'epinephrine reversal'. The use of other agents for vascular support is recommended when needed.
Eplerenone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and eplerenone who are susceptible to hypotension.
Eribulin: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, including eribulin. However, if coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. ECG monitoring is recommended during coadministration.
Ertugliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Ertugliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Ertugliflozin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Erythromycin: (Major) Concomitant use of paliperidone and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Escitalopram: (Major) Concomitant use of paliperidone and escitalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Esketamine: (Moderate) Closely monitor patients receiving esketamine and paliperidone for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Estazolam: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Eszopiclone: (Moderate) A reduction in the dose of eszopiclone should be considered during co-administration of other CNS depressants, such as antipsychotics, to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Antipsychotics with a higher incidence of sedation, such as olanzapine, clozapine, quetiapine, lurasidone, chlorpromazine, and thioridazine, are more likely to interact with eszopiclone. In one evaluation, concurrent use of eszopiclone and olanzapine reduced psychomotor function as measured by the Digit Symbol Substitution Test (DSST).
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Exenatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and paliperidone. Concurrent use may result in additive CNS depression.
Fenoldopam: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotenive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and fenoldopam who are susceptible to hypotension.
Fentanyl: (Major) Concomitant use of opiate agonists with paliperidone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with paliperidone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking paliperidone, use a lower initial dose of the opiate and titrate to clinical response. If paliperidone is prescribed for a patient taking an opiate agonist, use a lower initial dose of paliperidone and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Fingolimod: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, including fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. If coadministration is necessary, after the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Concomitant use of paliperidone and flecainide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluconazole: (Contraindicated) The concurrent use of fluconazole and paliperidone is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Fluconazole is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of paliperidone. These drugs used in combination may result in elevated paliperidone plasma concentrations, causing an increased risk for paliperidone-related adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as paliperidone.
Fluoxetine: (Major) Concomitant use of paliperidone and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluphenazine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Fluphenazine has a possible risk of QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. In addition, coadministration of two antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Flurazepam: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and paliperidone. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, use of the drug should be avoided with other agents known to prolong the QT interval. However, if concurrent use is necessary and the patient has risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as paliperidone. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Paliperidone has also been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fostemsavir: (Major) Avoid coadministration of paliperidone with fostemsavir due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gabapentin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of paliperidone and gabapentin. Concurrent use may result in additive CNS depression.
Ganirelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
Gemifloxacin: (Major) Concurrent use of paliperidone and gemifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If concurrent therapy is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is recommended. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab ozogamicin with paliperidone due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of and as needed during treatment. Close monitoring is particularly essential for patients with known risk factors for cardiac disease or arrhythmias. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose.
Gilteritinib: (Major) Avoid concomitant use of paliperidone with gilteritinib due to the potential for additive QT prolongation. If coadministration is necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Both paliperidone and gilteritinib have been associated with QT prolongation. Torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of paliperidone overdose.
Glasdegib: (Major) Avoid coadministration of glasdegib with paliperidone if possible due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Paliperidone has also been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose.
Glipizide; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Glyburide; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Goserelin: (Major) Avoid coadministration of goserelin with paliperidone due to the risk of reduced efficacy of goserelin and the risk of QT prolongation. Paliperidone can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; goserelin is a GnRH analog. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
Granisetron: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as granisetron. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Guaifenesin; Hydrocodone: (Moderate) Concomitant use of drugs that can cause CNS depression, such as hydrocodone and paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Guanfacine: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and central-acting adrenergic agents who are susceptible to hypotension.
Halogenated Anesthetics: (Major) Halogenated anesthetics can prolong the QT interval. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as halogenated anesthetics. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Haloperidol: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect, such as haloperidol. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. In addition, coadministration of two antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Histrelin: (Major) Avoid coadministration of histrelin with paliperidone due to the risk of reduced efficacy of histrelin and the risk of QT prolongation. Paliperidone can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Moderate) Concomitant use of drugs that can cause CNS depression, such as hydrocodone and paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Hydantoins: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of strong CYP3A4 inducers such as hydantions is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug.
Hydralazine: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and hydralazine who are susceptible to hypotension.
Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Paliperidone may cause orthostatic hypotension and enhance the orthostatic effects of nitrates. Orthostatic vital signs should be monitored in patients receiving paliperidone and nitrates who are susceptible to hypotension. (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and hydralazine who are susceptible to hypotension.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and central-acting adrenergic agents who are susceptible to hypotension.
Hydrocodone: (Moderate) Concomitant use of drugs that can cause CNS depression, such as hydrocodone and paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Hydrocodone; Ibuprofen: (Moderate) Concomitant use of drugs that can cause CNS depression, such as hydrocodone and paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of drugs that can cause CNS depression, such as hydrocodone and paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Hydromorphone: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression during concurrent use of paliperidone and hydromorphone and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Hydroxychloroquine: (Major) Concomitant use of paliperidone and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Avoid coadministration of hydroxyzine and paliperidone due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, because hydroxyzine causes pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including paliperidone. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose.
Ibuprofen; Oxycodone: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression during coadministration of paliperidone and oxycodone and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Ibutilide: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Ibutilide administration can cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Iloperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as iloperidone. In addition, coadministration of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Incretin Mimetics: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with paliperidone if possible due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Both inotuzumab and paliperidone have been associated with QT interval prolongation; TdP and ventricular fibrillation have been reported in the setting of paliperidone overdose. If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Close monitoring is essential for patients with known risk factors for cardiac disease or arrhythmias.
Insulin Degludec; Liraglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulin Glargine; Lixisenatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Insulins: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) It may be necessary to increase the dose of oral paliperidone during coadministration of a strong inducer of both CYP3A4 and P-gp, such as rifampin. Conversely, a reduction in oral paliperidone dose may be needed upon discontinuation of the inducer. Avoid using a strong inducer of CYP3A4 and/or P-gp if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong inducer is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6.
Isoniazid, INH; Rifampin: (Major) It may be necessary to increase the dose of oral paliperidone during coadministration of a strong inducer of both CYP3A4 and P-gp, such as rifampin. Conversely, a reduction in oral paliperidone dose may be needed upon discontinuation of the inducer. Avoid using a strong inducer of CYP3A4 and/or P-gp if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong inducer is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6.
Isosorbide Dinitrate, ISDN: (Moderate) Paliperidone may cause orthostatic hypotension and enhance the orthostatic effects of nitrates. Orthostatic vital signs should be monitored in patients receiving paliperidone and nitrates who are susceptible to hypotension.
Isosorbide Mononitrate: (Moderate) Paliperidone may cause orthostatic hypotension and enhance the orthostatic effects of nitrates. Orthostatic vital signs should be monitored in patients receiving paliperidone and nitrates who are susceptible to hypotension.
Itraconazole: (Major) Avoid coadministration of paliperidone and itraconazole if possible due to the potential for additive effects on the QT interval. Both paliperidone and itraconazole are associated with QT prolongation. Torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of paliperidone overdose. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with paliperidone if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as needed. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and paliperidone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as clarithromycin. However, if coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Lapatinib: (Major) Avoid coadministration of paliperidone with lapatinib if possible due to the risk of QT prolongation. If concomitant administration is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct electrolyte abnormalities prior to treatment. Paliperidone has been associated with QT prolongation. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and paliperidone. Concurrent use may result in additive CNS depression.
Lefamulin: (Major) Avoid coadministration of lefamulin with paliperidone as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and atypical antipsyhotics. Dosage adjustments of lemborexant and the atypical antipsychotic may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with paliperidone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of paliperidone overdose.
Leuprolide: (Major) Avoid coadministration of leuprolide with paliperidone due to the risk of reduced efficacy of leuprolide and the risk of QT prolongation. Paliperidone can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Avoid coadministration of leuprolide with paliperidone due to the risk of reduced efficacy of leuprolide and the risk of QT prolongation. Paliperidone can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Levocetirizine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and cetirizine due to the risk for additive CNS depression.
Levodopa: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
Levofloxacin: (Major) Concomitant use of paliperidone and levofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and paliperidone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Levorphanol: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression during coadministration of paliperidone and levorphanol and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Lidocaine; Epinephrine: (Major) The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of paliperidone. This blockade can cause an apparently paradoxical condition called 'epinephrine reversal'. The use of other agents for vascular support is recommended when needed.
Linagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Liraglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Lithium: (Major) Paliperidone and lithium are associated with QT prolongation. Torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of paliperidone overdose. Coadministration may increase the risk of QT prolongation and neurotoxicity and close monitoring is recommended. Neuroleptic malignant syndrome (NMS) has been observed occasionally during use of lithium and either atypical or conventional antipsychotics. Additive extrapyramidal effects have also been noted. Early case reports described an encephalopathic syndrome consisting of delirium, tremulousness, dyskinesia, seizures, leukocytosis, weakness, hyperpyrexia, confusion, extrapyramidal symptoms, elevations in laboratory values (e.g., liver function tests, blood urea nitrogen, fasting blood sugar) and, in some cases, irreversible brain damage, during use of lithium and conventional antipsychotics, particularly haloperidol. Subsequent rare reports of NMS or NMS-like reactions have been described during coadministration of lithium and atypical antipsychotics (e.g., risperidone, olanzapine, clozapine). Following resolution of NMS, there are isolated instances of re-emergence of symptoms following re-initiation of lithium as monotherapy. Lithium may be a risk factor for antipsychotic-induced NMS; however, this hypothesis has not been confirmed. In many reported cases, confounding factors have been present (e.g., previous history of NMS, high dose therapy). The ability of antipsychotics alone to precipitate NMS and the rarity of the condition further complicate assessment of lithium as a risk factor. A pharmacokinetic interaction between lithium and paliperidone is unlikely.
Lixisenatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Lofexidine: (Major) Avoid coadministration of lofexidine and paliperidone due to the potential for additive QT prolongation. Monitor ECG if coadministration is necessary. Additionally, monitor for excessive hypotension and sedation during coadministration since lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval; there are postmarketing reports of torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose.
Loop diuretics: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and loop diuretics who are susceptible to hypotension.
Loperamide: (Major) Loperamide should be avoided in combination with paliperidone. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to cause QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Loperamide; Simethicone: (Major) Loperamide should be avoided in combination with paliperidone. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to cause QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with paliperidone due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Lorazepam: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Loxapine: (Major) Avoid coadministration of antipsychotics, including loxapine and paliperidone, if possible. Coadministration may increase the risk of adverse events such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Lumacaftor; Ivacaftor: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as lumacaftor is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug.
Lumateperone: (Moderate) Coadministration of antipsychotics, such as lumateperone and paliperidone, may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from antipsychotic combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Lurasidone: (Major) Coadministration of antipsychotics, including paliperidone and lurasidone, should be avoided if possible. Coadministration of antipsychotics may increase the risk for drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, and seizures.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that may prolong the QT interval, such as paliperidone. Use of these drugs together may increase the risk of developing QT prolongation or torsade de pointes (TdP). Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose.
Maprotiline: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as maprotiline. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Mecamylamine: (Moderate) Paliperidone can cause orthostatic hypotension and therefore may have an additive effect with other drugs that can cause hypotension, such as mecamylamine. Lower initial doses of paliperidone may be necessary in patients receiving mecamylamine concomitantly.
Meclizine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and meclizine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Mefloquine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients who require drugs that prolong the QT interval. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Meglitinides: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Meperidine: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression during coadministration of paliperidone and meperidine and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including antipsychotics.
Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Metformin; Repaglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Metformin; Rosiglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Metformin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Metformin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Methadone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as methadone. The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is associated with an increased risk for QT prolongation and TdP, especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Also monitor patients for additive sedation during concurrent use.
Methohexital: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as a barbiturate is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug. It should be noted that clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates.
Methyldopa: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and central-acting adrenergic agents who are susceptible to hypotension.
Metoclopramide: (Contraindicated) Avoid metoclopramide in patients receiving atypical antipsychotics. There is a potential for additive effects, including increased frequency and severity of tardive dyskinesia (TD), other extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS). Some manufacturer labels for metoclopramide contraindicate the use of these drugs together, while others state avoidance is necessary. If these agents must be used together, monitor closely for movement disorders and additive CNS effects. There also may be additive sedation. Discontinue these medications at the first signs of dyskinesia.
Metronidazole: (Major) Concomitant use of metronidazole and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midazolam: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and paliperidone if possible; both drugs have been reported to increase the QT interval. If concomitant use is necessary, closely monitor for evidence of QT prolongation (e.g., electrocardiograms) during concurrent use. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to cause QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Mifepristone: (Major) Concomitant use of paliperidone and mifepristone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Miglitol: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Minoxidil: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and minoxidil who are susceptible to hypotension.
Mirtazapine: (Major) Concomitant use of paliperidone and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mitotane: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as mitotane is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since in vivo studies show this isoenzyme contributes to only a small fraction of total body clearance.
Mobocertinib: (Major) Concomitant use of mobocertinib and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Molindone: (Major) Coadministration of antipsychotics, including molindone and paliperidone, should be avoided if possible. Additive adverse effects including hypotension, drowsiness, anticholinergic effects (e.g., constipation, xerostomia), extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures may occur. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Monoamine oxidase inhibitors: (Moderate) Monitor blood pressure and for unusual drowsiness and sedation during coadministration of monoamine oxidase inhibitors (MAOIs) and paliperidone due to the risk for additive hypotension and CNS depression.
Morphine: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression during coadministration of paliperidone and morphine and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Morphine; Naltrexone: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression during coadministration of paliperidone and morphine and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Moxifloxacin: (Major) Concurrent use of paliperidone and moxifloxacin should be avoided if possible due to an increased risk for QT prolongation and torsade de pointes (TdP). If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Moxifloxacin has been associated with prolongation of the QT interval. Additionally, very rare cases of ventricular arrhythmias including TdP have been reported during postmarketing use, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded. Paliperidone has also been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose.
Nabilone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
Nafarelin: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Nalbuphine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and nalbuphine. Concurrent use may result in additive CNS depression.
Nateglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Nitrates: (Moderate) Paliperidone may cause orthostatic hypotension and enhance the orthostatic effects of nitrates. Orthostatic vital signs should be monitored in patients receiving paliperidone and nitrates who are susceptible to hypotension.
Nitroglycerin: (Moderate) Paliperidone may cause orthostatic hypotension and enhance the orthostatic effects of nitrates. Orthostatic vital signs should be monitored in patients receiving paliperidone and nitrates who are susceptible to hypotension.
Nitroprusside: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of nitrates. Orthostatic vital signs should be monitored in patients receiving paliperidone and sodium nitroprusside who are susceptible to hypotension.
Ofloxacin: (Major) Concomitant use of paliperidone and ofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as olanzapine. In addition, coadministration of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Olanzapine; Fluoxetine: (Major) Concomitant use of paliperidone and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as olanzapine. In addition, coadministration of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Olanzapine; Samidorphan: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as olanzapine. In addition, coadministration of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Oliceridine: (Moderate) Concomitant use of oliceridine with paliperidone may cause excessive sedation and somnolence. Limit the use of oliceridine with paliperidone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Ondansetron: (Major) Concomitant use of paliperidone and ondansetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Opicapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Osilodrostat: (Major) Avoid coadministration of osilodrostat and paliperidone due to the potential for additive QT prolongation. Monitor ECG if coadministration is necessary. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) According to the manufacturer of paliperidone, coadministration with other agents that prolong the QT interval, such as osimertinib, should be avoided. If concomitant use is unavoidable, closely monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Oxaliplatin: (Major) Avoid coadministration of paliperidone with oxaliplatin due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in postmarketing experience.
Oxazepam: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Oxycodone: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression during coadministration of paliperidone and oxycodone and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Oxymorphone: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression during coadministration of paliperidone and oxymorphone and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking paliperidone due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Pacritinib: (Major) Concomitant use of pacritinib and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Panobinostat: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. If coadministration is required, obtain an electrocardiogram (ECG) at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or more during therapy; permanently discontinue if QT prolongation does not resolve. Closely monitor patients with known risk factors for cardiac disease or arrhythmias.
Paroxetine: (Minor) Paroxetine is a potent inhibitor of CYP2D6, which may result in decreased clearance of partial CYP2D6 substrates such as paliperidone. Decreased metabolism of paliperidone may lead to clinically important adverse reactions such as extrapyramidal symptoms. In addition, paliperidone is associated with a risk for QT prolongation and torsade de pointes (TdP), and should be used cautiously with potent CYP2D6 inhibitors such as paroxetine. In one study of healthy subjects, paliperidone exposure was an average of 16% higher in extensive metabolizers of CYP2D6 who were receiving paroxetine 20 mg/day concurrently. The clinical significance of this interaction is unknown.
Pasireotide: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as pasireotide. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. If coadministration is necessary, closely monitor patients with known risk factors for cardiac disease or arrhythmias.
Pentamidine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Systemic pentamidine has been associated with QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Pentazocine: (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.
Pentazocine; Naloxone: (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.
Pentobarbital: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as a barbiturate is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug. It should be noted that clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates.
Perphenazine: (Major) Coadministration of antipsychotics, including paliperidone and perphenazine, should be avoided if possible. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, paliperidone should be avoided in combination with other drugs having an association with QT prolongation. In addition, coadministration of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Perphenazine; Amitriptyline: (Major) Coadministration of antipsychotics, including paliperidone and perphenazine, should be avoided if possible. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, paliperidone should be avoided in combination with other drugs having an association with QT prolongation. In addition, coadministration of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Phenobarbital: (Major) It may be necessary to increase the dose of oral paliperidone during coadministration of a strong inducer of both CYP3A4 and P-gp, such as phenobarbital. Conversely, a reduction in oral paliperidone dose may be needed upon discontinuation of the inducer. Avoid using a strong inducer of CYP3A4 and/or P-gp if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong inducer is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. Clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) It may be necessary to increase the dose of oral paliperidone during coadministration of a strong inducer of both CYP3A4 and P-gp, such as phenobarbital. Conversely, a reduction in oral paliperidone dose may be needed upon discontinuation of the inducer. Avoid using a strong inducer of CYP3A4 and/or P-gp if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong inducer is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. Clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates.
Pimavanserin: (Major) Coadministration of pimavanserin and paliperidone should be avoided if possible. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Pimavanserin may also cause QT prolongation. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Pimozide: (Contraindicated) Pimozide is an antipsychotic with a well-established risk of QT prolongation and torsade te pointes (TdP). Because of the potential for TdP, coadministration with paliperidone is contraindicated. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other drugs having an association with QT prolongation. Concurrent use of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Pioglitazone; Glimepiride: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states , and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Pioglitazone; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Pitolisant: (Major) Avoid coadministration of paliperidone with pitolisant due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Pitolisant prolongs the QT interval.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking paliperidone due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Posaconazole: (Contraindicated) The concurrent use of posaconazole and paliperidone is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, paliperidone should be avoided in combination with other drugs having an association with QT prolongation.
Potassium-sparing diuretics: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and potassium-sparing diuretics who are susceptible to hypotension.
Pramipexole: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or pramipexole during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and pramipexole may interfere with the effectiveness of each other. Additive CNS depressant effects are also possible. In general, atypical antipsychotics are less likely to interfere with pramipexole than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Pramlintide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Prazosin: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and prazosin who are susceptible to hypotension.
Pregabalin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of paliperidone and pregabalin. Concurrent use may result in additive CNS depression.
Prilocaine; Epinephrine: (Major) The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of paliperidone. This blockade can cause an apparently paradoxical condition called 'epinephrine reversal'. The use of other agents for vascular support is recommended when needed.
Primaquine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, including primaquine. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Primidone: (Major) It may be necessary to increase the dose of oral paliperidone during coadministration of a strong inducer of both CYP3A4 and P-gp, such as primidone. Conversely, a reduction in oral paliperidone dose may be needed upon discontinuation of the inducer. Avoid using a strong inducer of CYP3A4 and/or P-gp if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong inducer is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. Clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of primidone.
Procainamide: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Procainamide is associated with a well-established risk of QT prolongation and TdP. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Prochlorperazine: (Major) According to the manufacturer of paliperidone, the drug should be avoided in combination with other drugs having an association with QT prolongation. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Prochlorperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Coadministration of prochlorperazine and paliperidone may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Promethazine: (Major) According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Promethazine, a phenothiazine antiemetic/antihistamine, has been associated with QT prolongation. Coadministration of promethazine and antipsychotics such as paliperidone may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from concurrent use of a phenothiazine and atypical antipsychotic has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Promethazine; Dextromethorphan: (Major) According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Promethazine, a phenothiazine antiemetic/antihistamine, has been associated with QT prolongation. Coadministration of promethazine and antipsychotics such as paliperidone may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from concurrent use of a phenothiazine and atypical antipsychotic has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Promethazine; Phenylephrine: (Major) According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Promethazine, a phenothiazine antiemetic/antihistamine, has been associated with QT prolongation. Coadministration of promethazine and antipsychotics such as paliperidone may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from concurrent use of a phenothiazine and atypical antipsychotic has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Propafenone: (Major) Concomitant use of propafenone and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Pseudoephedrine; Triprolidine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and triprolidine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Pyrilamine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and pyrilamine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Quazepam: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Quetiapine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as quetiapine. In addition, coadministration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Quinidine: (Major) Coadministration of paliperidone and quinidine should be avoided if possible due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinidine, a CYP2D6 inhibitor, is associated with QT prolongation and torsades de pointes (TdP). According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. While in vitro studies indicate that CYP2D6 is minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by CYP2D6 and it contributes to only a small fraction of total body clearance of paliperidone. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Quinine: (Major) Concurrent use of quinine and paliperidone should be avoided if possible due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents that prolong the QT interval. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Quizartinib: (Major) Concomitant use of quizartinib and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ranolazine: (Major) According to the manufacturer of paliperidone, the drug should be avoided in combination with agents known to prolong the QT interval. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1,000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Rasagiline: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or rasagiline during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and rasagiline may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with rasagiline than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Relugolix: (Major) Avoid coadministration of paliperidone with relugolix due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of paliperidone with relugolix due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Remifentanil: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Advise patients to avoid driving or engaging in other activities requiring mental alertness as directed by their healthcare provider after administration of remifentanil.
Remimazolam: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Repaglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Ribociclib: (Major) Avoid coadministration of ribociclib with paliperidone due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents that prolong the QT interval. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with paliperidone due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents that prolong the QT interval. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Rifampin: (Major) It may be necessary to increase the dose of oral paliperidone during coadministration of a strong inducer of both CYP3A4 and P-gp, such as rifampin. Conversely, a reduction in oral paliperidone dose may be needed upon discontinuation of the inducer. Avoid using a strong inducer of CYP3A4 and/or P-gp if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong inducer is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6.
Rifapentine: (Major) Avoid using rifapentine if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of rifapentine is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Oral paliperidone may be used; however, a dosage increase may be necessary. Paliperidone is a P-glycoprotein (P-gp) substrate, with minor contributions in metabolism by CYP3A4. Rifapentine is a strong CYP3A4 inducer.
Rilpivirine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Risperidone: (Major) Because paliperidone is the major active metabolite of risperidone, excessive paliperidone exposure is possible during concurrent use of the two drugs and coadministration is generally avoided. In addition, paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as risperidone. Coadministration of antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures.
Romidepsin: (Major) Per the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Closely monitor patients with risk factors for cardiac disease or arrhythmias.
Ropinirole: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or ropinirole during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and ropinirole may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with ropinirole than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Rosiglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Rotigotine: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, excess sedation, and diminished effectiveness of the atypical antipsychotic or rotigotine during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and rotigotine may interfere with the effectiveness of each other. Additive CNS depressant effects are also possible. In general, atypical antipsychotics are less likely to interfere with rotigotine than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Safinamide: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or safinamide during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and safinamide may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with safinamide than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Saquinavir: (Major) Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, including paliperidone. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Closely monitor patients with known risk factors for cardiac disease or arrhythmias.
Saxagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Secobarbital: (Major) Avoid using a strong inducer of CYP3A4 if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong CYP3A4 inducer such as a barbiturate is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp. However, concurrent use of oral paliperidone with a strong CYP3A4 inducer alone may not be clinically relevant since this isoenzyme contributes to only a small fraction of total body clearance of the drug. It should be noted that clinically significant barbiturate enzyme-induction occurs after several days and may not be clinically significant with short-term use of barbiturates.
Selegiline: (Moderate) Monitor for loss of selegiline efficacy, signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, and unusual drowsiness and sedation during concomitant atypical antipsychotic and selegiline use. Dopamine antagonists, such as atypical antipsychotics, may diminish the effectiveness of selegiline. Concomitant use may increase the risk for serotonin syndrome or additive CNS depression. If serotonin syndrome occurs, discontinue therapy.
Selpercatinib: (Major) Avoid coadministration of paliperidone with selpercatinib due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Monitor ECGs more frequently for QT prolongation if coadministration is necessary. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
Semaglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Sertraline: (Major) Concomitant use of sertraline and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
SGLT2 Inhibitors: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Siponimod: (Major) Avoid coadministration of siponimod and paliperidone due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Sitagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Solifenacin: (Major) Concurrent use of paliperidone and solifenacin should be avoided if possible due to an increased risk for QT prolongation and torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. Solifenacin has also been associated with dose-dependent prolongation of the QT interval; TdP has been reported during postmarketing use, although causality has not been determined. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Sorafenib: (Major) Avoid coadministration of sorafenib with paliperidone due to the risk of additive QT prolongation. Sorafenib is associated with QTc prolongation. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Sotagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Sotalol: (Major) Concomitant use of sotalol and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
St. John's Wort, Hypericum perforatum: (Major) It may be necessary to increase the dose of oral paliperidone during coadministration of a strong inducer of both CYP3A4 and P-gp, such as St. John's Wort. Conversely, a reduction in oral paliperidone dose may be needed upon discontinuation of the inducer. Avoid using a strong inducer of CYP3A4 and/or P-gp if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong inducer is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and paliperidone. Drugs with CNS depressant properties, such as paliperidone, can potentiate the effects of stiripentol.
Sufentanil: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Advise patients to avoid driving or engaging in other activities requiring mental alertness as directed by their healthcare provider after administration of sufentanil.
Sulfonylureas: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Sunitinib: (Major) Avoid coadministration of paliperidone with sunitinib, if possible, due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor patients with known risk factors for cardiac disease or arrhythmias. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsade de pointes (TdP). Paliperidone has also been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose.
Suvorexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of suvorexant and atypical antipsyhotics. Dosage adjustments of suvorexant and the atypical antipsychotic may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if suvorexant is taken with other CNS depressants.
Tacrolimus: (Major) Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as tacrolimus. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Tamoxifen: (Major) Concomitant use of tamoxifen and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Telavancin: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as telavancin. However, if coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Temazepam: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Terazosin: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving terazosin who are susceptible to hypotension.
Tetrabenazine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as tetrabenazine. Tetrabenazine causes a small increase in the corrected QT interval (QTc). In addition, coadministration may increase the risk of adverse effects such as drowsiness, pseudoparkinsonism, neuroleptic malignant syndrome, akathisia, or orthostasis. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Thiazide diuretics: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and thiazide diuretics who are susceptible to hypotension.
Thioridazine: (Contraindicated) Thioridazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP) and is contraindicated for use with other drugs that are known to prolong the QT interval, including paliperidone. In addition, coadministration of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Thiothixene: (Major) Coadministration of antipsychotics, including paliperidone and thiothixene, should be avoided if possible. Coadministration may increase the risk of adverse events such as drowsiness, dizziness, hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Tipranavir: (Major) Avoid using a strong inducer of P-gp if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong P-gp inducer such as tipranavir is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6. A dosage increase of oral paliperidone may be required during coadministration of a strong inducer of both CYP3A4 and P-gp.
Tirzepatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Tolcapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Tolterodine: (Major) Concurrent use of paliperidone and tolterodine should be avoided if possible due to an increased risk for QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Paliperidone has also been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Toremifene: (Major) Avoid coadministration of paliperidone with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose.
Tramadol: (Moderate) Concurrent use of tramadol and paliperidone should be administered with caution. Antipsychotics, such as paliperidone, may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and paliperidone.
Tramadol; Acetaminophen: (Moderate) Concurrent use of tramadol and paliperidone should be administered with caution. Antipsychotics, such as paliperidone, may enhance the seizure risk of tramadol. Additive CNS depression may also be seen with the concomitant use of tramadol and paliperidone.
Trazodone: (Major) Avoid coadministration of trazodone and paliperidone if possible. Trazodone can prolong the QT/QTc interval at therapeutic doses and there are postmarketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Concurrent use can also result in additive adverse effects such as drowsiness and dizziness.
Triazolam: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Triclabendazole: (Major) Concomitant use of triclabendazole and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tricyclic antidepressants: (Moderate) Concurrent use of paliperidone and tricyclic antidepressants should be avoided if possible. Paliperidone has a risk for QT prolongation and torsade de pointes, and tricyclic antidepressants, primarily at elevated serum concentrations, may produce clinically significant prolongation of the QTc interval. In addition, there is a potential for other pharmacodynamic interactions, such as augmentation of CNS impairment.
Trifluoperazine: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Triprolidine: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and triprolidine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Triptorelin: (Major) Avoid coadministration of triptorelin with paliperidone due to the risk of reduced efficacy of triptorelin and the risk of QT prolongation. Paliperidone can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; triptorelin is a GnRH analog. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval.
Valproic Acid, Divalproex Sodium: (Moderate) Coadministration of a single 12 mg oral dose of paliperidone with divalproex sodium extended-release tablets (1,000 mg once daily) resulted in an increase in Cmax and AUC of paliperidone of about 50%. The clinical significance, if any, is unknown; however, a decrease in oral paliperidone dosage may be necessary in select patients after initiation of valproic acid, valproate, or divalproex sodium. A clinically meaningful pharmacokinetic interaction between injectable paliperidone (Invega Sustenna or Invega Trinza) and valproate, valproic acid, or divalproex sodium is not expected. Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment is needed for valproate or derivatives when coadministered with injectable forms of paliperidone.
Vandetanib: (Major) Avoid coadministration of vandetanib with paliperidone due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose.
Vardenafil: (Major) Concomitant use of vardenafil and paliperodone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vemurafenib: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, since the drug may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Vemurafenib has been associated with QT prolongation. If vemurafenib and paliperidone must be coadministered, ECG monitoring is recommended; closely monitor patients with known risk factors for cardiac disease or arrhythmias.
Venlafaxine: (Major) Concomitant use of venlafaxine and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Voclosporin: (Major) Avoid concomitant use of paliperidone with voclosporin due to the risk of additive QT prolongation and torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as clarithromycin. However, if coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Voriconazole: (Major) Avoid coadministration of paliperidone and voriconazole if possible due to the potential for additive effects on the QT interval. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. Voriconazole has been associated with QT prolongation and rare cases of TdP. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
Vorinostat: (Major) Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Vorinostat therapy is associated with a risk of QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Zaleplon: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zaleplon due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary.
Ziprasidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors. If concurrent use is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Coadministration may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures.
Zolpidem: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and zolpidem due to the risk for additive CNS depression and next-day psychomotor impairment; dose adjustments may be necessary. Limit the dose of Intermezzo sublingual tablets to 1.75 mg/day.
Zonisamide: (Moderate) Zonisamide may cause decreased sweating (oligohidrosis), elevated body temperature (hyperthermia), heat intolerance, or heat stroke. The manufacturer recommends caution in using concurrent drug therapies that may predispose patients to heat-related disorders such as antipsychotics. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if zonisamide is used with any of these agents.

INVEGA HAFYERA/Invega Sustenna/INVEGA TRINZA Intramuscular Inj Susp ER: 0.25mL, 0.5mL, 0.75mL, 0.88mL, 1mL, 1.32mL, 1.5mL, 1.75mL, 2.63mL, 3.5mL, 5mL, 39mg, 78mg, 117mg, 156mg, 234mg, 273mg, 410mg, 546mg, 819mg, 1092mg, 1560mg
Invega/Paliperidone Oral Tab ER: 1.5mg, 3mg, 6mg, 9mg

Adults

Oral ER tablet: 12 mg/day PO.
Invega Sustenna: 234 mg IM every 1 month of the extended-release monthly suspension injection.
Invega Trinza: 819 mg IM every 3 months of the extended-release depot suspension injection.
Invega Hafyera: 1,560 mg IM every 6 months of the extended-release depot suspension injection.

Geriatric

Oral ER tablet: 12 mg/day PO.
Invega Sustenna: 234 mg IM every 1 month of the extended-release monthly suspension injection.
Invega Trinza: 819 mg IM every 3 months of the extended-release depot suspension injection.
Invega Hafyera: 1,560 mg IM every 6 months of the extended-release depot suspension injection.

Adolescents

Adolescents weighing 51 kg or more: 12 mg/day PO for schizophrenia. The once-monthly, 3-month, and 6-month IM injections are not indicated.
Adolescents weighing less than 51 kg: 6 mg/day PO for schizophrenia. The once-monthly, 3-month, and 6-month IM injections are not indicated.

Children

Children 12 years of age and weighing 51 kg or more: 12 mg/day PO for schizophrenia. The once-monthly, 3-month, and 6-month IM injections are not indicated.
Children 12 years of age and weighing less than 51 kg: 6 mg/day PO for schizophrenia. The once-monthly, 3-month, and 6-month IM injections are not indicated.
Less than 12 years: Safety and efficacy have not been established.

Infants

Not indicated.

Neonates

Not indicated.

Paliperidone, also known as 9-hydroxyrisperidone, is the active metabolite of risperidone. Paliperidone has been shown to exhibit central dopamine (D2) and serotonin (5HT2A) receptor antagonism. Based on this receptor activity, paliperidone has been found effective in decreasing both positive and negative symptoms of schizophrenia. In general, atypical antipsychotics have a high serotonin to dopamine receptor affinity. They block dopamine receptors more specifically in the limbic area of the brain where it is thought that an excess of dopamine may contribute to positive symptoms of schizophrenia. Negative symptoms are thought to be caused by decreased dopamine activity in the mesocortical tracts of the brain. It has been hypothesized that antagonism of serotonin receptors in this area actually leads to an increase in dopamine release thereby reducing these symptoms. Dopamine blockade in the nigrostriatal pathway is thought to cause extrapyramidal effects. This adverse effect is generally decreased with atypical antipsychotics because of their reduced affinity for dopamine receptors in this area.
 
Paliperidone exhibits antagonist activity at alpha-1 and alpha-2 receptors, which likely contributes to its cardiovascular effects, such as orthostatic hypotension. The alpha-1 blocking effect is thought to be responsible for priapism, a potentially severe adverse reaction which has occurred during clinical use of the drug. Antagonism at histamine H1 receptors has also been demonstrated. There is no affinity for cholinergic or beta-adrenergic receptors. Animal studies indicate possible anti-emetic effects, but the relevance of this finding to humans is uncertain.

Paliperidone is administered orally as an extended-release tablet or intramuscularly as a once-monthly extended-release injectable suspension (Invega Sustenna), a 3-month extended-release injectable suspension (Invega Trinza), or a 6-month extended-release injectable suspension (Invega Hafyera). It is 74% bound to plasma proteins. Pathways including dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission account for up to 10% of the metabolism of paliperidone. Data from a small number of healthy volunteers indicate that between 51% to 67% of an oral dose is excreted unchanged in the urine, and 26% to 41% is eliminated as metabolites. Limited data suggest that about 80% of a dose is excreted in the urine, and 11% in the feces. The insoluble ingredients of the extended-release tablet, along with the tablet shell, are eliminated in the stool.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2D6, P-glycoprotein (P-gp)
In vitro data indicate that paliperidone is a P-gp substrate. While CYP3A4 and CYP2D6 may have a minor role in the metabolism of paliperidone, in vivo studies with inhibitors of these enzymes show no significant effect on the metabolism of paliperidone and they contribute to only a small fraction of total body clearance. No pharmacokinetic differences have been found between extensive metabolizers and slow metabolizers of CYP2D6. Results of a pharmacokinetic study between paliperidone and carbamazepine, a strong CYP3A4 and P-gp inducer, suggest that a dosage adjustment of oral paliperidone may be needed when used with a strong inducer of both CYP3A4 and P-gp. Concurrent use of injectable formulations of paliperidone with a strong inducer of either CYP3A4 and/or a P-gp inducer is not recommended; consider management with oral paliperidone in such cases.
 
Paliperidone is a weak inhibitor of P-gp at high concentrations in vitro, but the clinical relevance is unknown. Paliperidone is not a substrate of 1A2, 2A6, 2C9, or 2C19. In vitro studies indicate that paliperidone does not substantially inhibit the metabolism of 1A2, 2A6, 2C8/9/10, 2D6, 2E1, 3A4, or 3A5 substrates.

Oral Route

Administration of the oral extended-release tablets with a standard high fat meal increases the mean maximal concentration (Cmax) and AUC by 60% and 54%, respectively. Although administration with food may influence overall exposure to paliperidone, safety and efficacy trials indicate that the drug may be given without regard to meals. The absolute oral bioavailability is 28%. Peak plasma concentrations are attained about 24 hours after a single oral dose. Steady state concentrations are attained within approximately 4 to 5 days of oral dosing. The volume of distribution is 487 Liters. The elimination half-life is about 23 hours.

Intramuscular Route

Once-monthly depot, extended-release injection suspension (Invega Sustenna)
After an intramuscular (IM) injection, paliperidone palmitate dissolves slowly due to its extremely low water solubility. Paliperidone palmitate is hydrolyzed to paliperidone and then absorbed into the systemic circulation. Release of the IM formulation begins as early as day 1, and continues for as long as 126 days. After a single IM dose, the median time to maximum plasma concentration (Tmax) is 13 days. Results from single dose studies with therapeutic IM doses have shown that the average maximal concentration (Cmax) is 28% higher after a deltoid muscle injection than after a gluteal injection. The recommended regimen of administering the first two doses by deltoid injection was designed to quickly attain steady-state concentrations without using oral supplementation. Based on a population analysis, the apparent volume of distribution of paliperidone is 391 Liters. The median elimination half-life after single dose administration of 39 to 234 mg intramuscularly ranges from 25 days to 49 days. Because of the difference in median pharmacokinetic profiles among the three injection formulations, caution is recommended when making a direct comparison of their pharmacokinetic properties.
 
3-month depot, extended-release injection suspension (Invega Trinza)
After an intramuscular (IM) injection, paliperidone palmitate dissolves slowly due to its extremely low water solubility. Paliperidone palmitate is then hydrolyzed to paliperidone and absorbed into the systemic circulation. The release of the drug starts as early as day 1 and lasts for as long as 18 months. After a single IM dose, the plasma concentrations gradually reach maximum levels at a median Tmax of 30 to 33 days. Following IM deltoid injections at doses of 273 mg to 819 mg, the Cmax is an average of 11% to 12% higher than with the gluteal injection. The apparent volume of distribution is 1,960 Liters. The mean steady-state peak:trough ratios are similar between gluteal and deltoid injections. The median half-life over the therapeutic dose range is 84 to 95 days following deltoid injections, and the median half-life is 118 to 139 days following gluteal injections. The concentration of paliperidone remaining in the circulation 18 months after discontinuation of the 819 mg dose at steady-state is estimated to be 3% with deltoid injection and 7% with gluteal injection. When Invega Trinza is administered at doses that are 3.5-fold higher than the corresponding dose of the 1-month injection (Invega Sustenna), paliperidone exposures are similar to those obtained with corresponding monthly doses of Invega Sustenna and corresponding once daily doses of the extended-release tablets. The pharmacokinetic between-subject variability for Invega Trinza was similar to the variability for paliperidone extended-release tablets. Because of the difference in median pharmacokinetic profiles among the three injection formulations, caution is recommended when making a direct comparison of their pharmacokinetic properties.
 
6-month depot, extended-release injection suspension (Invega Hafyera)
After a gluteal intramuscular (IM) injection, paliperidone palmitate dissolves slowly due to extremely low water solubility. Paliperidone palmitate is then hydrolyzed to paliperidone and absorbed into the systemic circulation. The release of the drug starts as early as day 1 and is predicted to last longer than 18 months. After injection, plasma concentrations rise to reach maximum concentrations at a median Tmax of 29 to 32 days. Administration of the 6-month formulation resulted in paliperidone total exposure ranges that are within the exposure range of corresponding doses of oral, once-monthly, and every 3-month formulations. Mean trough concentrations at the end of the dosing interval were 20 to 25% lower when compared to corresponding doses of the 3-month depot injection, while the mean peak concentration was 1.4 to 1.5-fold higher for Invega Hafyera when compared to the 3-month formulation. The apparent volume of distribution is 1,960 Liters. The median steady state peak:trough ratios are 3.1 (for 1,092 mg dose) and 3 (for 1,560 mg dose). Because of the difference in median pharmacokinetic profiles among the three injection formulations, caution is recommended when making a direct comparison of their pharmacokinetic properties.

Pregnancy

When considering the use of paliperidone during pregnancy, the possibility of paliperidone-related adverse outcomes in the fetus or neonate should be weighed against the risks of an untreated maternal psychiatric condition, which may include hospitalization, relapse, suicide, and increased adverse perinatal outcomes (e.g., pre-term birth). A prospective observational study of women (n = 6) treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9,258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in major birth defects and cardiac malformations in a subgroup of 1,566 women exposed to risperidone during their first trimester of pregnancy; however, there is no mechanism of action to explain the increased malformation rate, and the overall available data from published epidemiologic studies of pregnant women exposed to atypical antipsychotics have not established a drug-associated risk of birth defects, miscarriages, or adverse maternal or fetal outcomes. Extrapyramidal symptoms and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates exposed to antipsychotics, including paliperidone, during the third trimester of pregnancy. These complications have varied in severity, with some neonates recovered within hours or days without specific treatment and others requiring prolonged hospitalization. Monitor neonates for extrapyramidal and withdrawal symptoms and manage symptoms appropriately. The knowledge about long-term neurobehavioral effects in offspring is limited for all antipsychotic agents and requires further investigation. According to the American Psychiatric Association treatment guidelines for schizophrenia, consider pregnancy testing in women of childbearing potential prior to initiation of an antipsychotic. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to paliperidone; information about the registry can be obtained at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by calling 1-866-961-2388.