Uzedy

 Recommended Dosage

For patients who have never taken risperidone, establish tolerability with oral risperidone prior to initiating UZEDY.

UZEDY must be administered by a healthcare professional as an abdominal or upper arm subcutaneous injection. Do not administer UZEDY by any other route.

For detailed preparation and administration instructions, see Dosage and Administration .

To start UZEDY, switch from oral daily risperidone. Initiate UZEDY, as either a once monthly injection or a once every 2 month injection, the day after the last dose of oral therapy. See Table 1 to determine how to switch from oral risperidone to UZEDY once monthly (50 mg, 75 mg, 100 mg, or 125 mg) or once every 2 months (100 mg, 150 mg, 200 mg, or 250 mg) given via abdominal or upper arm subcutaneous injection. Neither a loading dose nor supplemental oral risperidone doses are recommended when switching. 

Patients can switch between doses of UZEDY once monthly and once every 2 months by administering the first dose of the new dosing regimen on the next scheduled date of administration in the original dosing regimen. Revise the dose administration schedule to reflect the change.

When a dose of UZEDY is missed, administer the next UZEDY injection as soon as possible. Do not administer more frequently than recommended.

 Dosage Modifications in Patients with Renal Impairment or Hepatic Impairment

Prior to initiating UZEDY in patients with renal or hepatic impairment, titrate with oral risperidone to at least 2 mg once daily. Following oral titration, and based on clinical response and tolerability, the recommended dosage of UZEDY is 50 mg once monthly [see Use in Specific Populations and Clinical Pharmacology ].

Dosage Modifications for Concomitant Use with Strong CYP2D6 Inhibitors and Strong CYP3A4 Inducers

Concomitant Use with Strong CYP2D6 Inhibitors

When initiation of fluoxetine or paroxetine is considered, place patients on a lower dose of UZEDY prior to the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone.

When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 50 mg once monthly or 100 mg once every 2 months of UZEDY, continue treatment with these doses unless clinical judgment necessitates interruption of UZEDY [see Drug Interactions ].

Concomitant Use with Strong CYP3A4 Inducers

At the initiation of therapy with strong CYP3A4 inducers (such as carbamazepine), patients should be closely monitored during the first 4 to 8 weeks since the dose of UZEDY may need to be adjusted. A dose increase, or additional oral risperidone, may be considered.

On discontinuation of a strong CYP3A4 inducer, re-evaluated the dosage of UZEDY or any additional oral risperidone therapy and, if necessary, decrease to adjust for the expected increase in plasma concentration of risperidone.

On discontinuation of a strong CYP3A4 inducer in a patient treated with UZEDY 50 mg once monthly or 100 mg once every 2 months, continue treatment with these doses unless clinical judgment necessitates interruption of UZEDY [see Drug Interactions ].

Preparation and Administration Instructions

• Read the instructions for preparation and administration below before administering UZEDY.
• For subcutaneous injection only. Do not inject by any other route.
• To be administered by a healthcare professional only.
• Allow UZEDY to come to room temperature for at least 30 minutes prior to administration.
• As a universal precaution, always wear gloves.

STEP 1

Check to make sure UZEDY kit contains:

• One sterile single-dose, prefilled glass syringe
• One sterile 21G x 5/8” needle

Do not substitute any components of the kit for administration.

STEP 2

Remove the kit from refrigerated storage and allow the package to sit at room temperature (20°C to 25°C [68°F to 77°F]) for at least 30 minutes.

Note: UZEDY is a solid at refrigerated temperatures and must reach room temperature prior to administration. Do not warm any other way and keep protected from light.

 STEP 3

Check that the drug in the syringe is white to off-white, opaque in color, and free from non-white particulate matter. Check that the pouch label states the needle size is 21G x 5/8”.

Do not use if any component of the kit is damaged or if the expiration date has passed.

 STEP 4

Expose the safety needle hub by peeling back the paper tab of the needle pouch. Set aside for use in Step 7.

STEP 5

Firmly hold the syringe by the white collar.

Flick Syringe Forcefully Three Times to Move the Bubble to the Cap

• Flick with a forceful downward whipping motion of your full arm to move the bubble to the cap of the syringe.
• Repeat this action 3 times to ensure that the bubble is at the cap of the syringe.

Note: Standing while you do this may help achieve required force.

Check that the Bubble is at the Cap of the Syringe

• The bubble will appear partially opaque.
• Holding the syringe up to light or against a dark backdrop may improve visibility.
• If the bubble is not at the cap, repeat Step 5 until it is.

STEP 6

Hold the syringe vertically by the white collar. Bend and snap off the cap.

Do not touch the syringe tip to avoid contamination.

STEP 7

Attach the Needle to the Syringe

• Hold the syringe vertically with the white collar at the top.
• Push the green hub of safety needle inside the white collar of syringe and rotate the safety needle while holding the white collar until secure and tight.

Inspect the needle connection to check that the hub is not damaged.

STEP 8

Select Injection Site from the Following Areas:

• Stomach area (abdomen) around the belly button
• Back and outer area of the upper arms

Do not inject UZEDY anywhere except in the areas specified above.

Do not inject UZEDY into an area that is tender, red, bruised, callused, tattooed, hard, or has scars or stretch marks.

 STEP 9

Clean the Injection Site with an alcohol wipe.

STEP 10

Remove the needle sheath by pulling the needle sheath away from the green hub to expose the needle.

Do not expel any visible air bubble.

 STEP 11

Pinch at least 1 inch of the area of cleaned skin with your free hand.

 STEP 12

Insert the needle into subcutaneous tissue (actual angle of injection will depend on the amount of subcutaneous tissue). Do not apply pressure to the plunger.

 STEP 13

Release the pinched skin once the needle is in the subcutaneous tissue.

 STEP 14

Inject the Medication

• Push on the plunger using a slow, firm, and steady push until the entire dose is delivered.
• Inject the entire dose at one time, without interruption.
• Check that the plunger stopper is at the White Collar.

IMPORTANT: UZEDY is viscous. Resistance will be experienced during dose delivery. Do not use excessive force in an attempt to deliver UZEDY faster.

STEP 15

Wait 2-3 seconds after the entire dose is delivered before removing the needle. Slowly pull the needle out from the injection site at the same angle as insertion.

 STEP 16

Activate (lock) the safety needle shield using one of the following methods:

• Surface Activation: Place the needle shield on a flat surface and pull the syringe backward until the needle shield covers the needle tip.
  

• Finger/Thumb Activation: Press either your thumb or finger on the needle shield and push it forward until the needle shield covers the needle tip.
  

There will be an audible click when the needle safety shield is locked.

Dispose of all syringe components in a suitable sharps container. 

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including UZEDY, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. 

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including UZEDY, during pregnancy (see Clinical Considerations).

Oral administration of risperidone to pregnant mice caused cleft palate at doses 3- to 4-times the oral maximum recommended human dose (MRHD) of 16 mg/day with maternal toxicity observed at 4-times MRHD based on mg/m2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the oral MRHD based on mg/m2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the oral MRHD based on mg/m2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the oral MRHD and offspring mortality increased at doses 0.1- to 3-times the oral MRHD based on mg/m2 body surface area.

The background risks of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR = 1.26, 95% CI = 1.02 to 1.56) and of cardiac malformations (RR = 1.26, 95% CI = 0.88 to 1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal data

No developmental toxicity studies were conducted with subcutaneous risperidone suspension.

Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3-times the oral MRHD of 16 mg/day based on mg/m2 body surface area; maternal toxicity occurred at 4-times the oral MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6-times the oral MRHD of 16 mg/day risperidone based on mg/m2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6-times the oral MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6- and 1.2-times the oral MRHD based on mg/m2 body surface area; postnatal development and growth of the offspring were also delayed.

Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1- to 3-times the oral MRHD of 16 mg/day based on mg/m2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5-times the oral MRHD based on mg/m2 body surface area.

In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3-times the oral MRHD based on mg/m2 and the only dose tested in the study.

 Lactation

Risk Summary

Limited data from published literature reports the presence of risperidone and its metabolite, 9-hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3 and 4.7% of the maternal weight-adjusted dosage. There are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to risperidone (see Clinical Considerations).

There is no information on the effects of risperidone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for UZEDY and any potential adverse effects on the breastfed child from UZEDY or from the mother’s underlying condition.

Clinical Considerations

Infants exposed to UZEDY through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

 Females and Males ofReproductive Potential

Infertility

Females

Based on the pharmacologic action of risperidone (D2 receptor antagonism), treatment with UZEDY may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions ].

Pediatric Use

The safety and effectiveness of UZEDY have not been established in pediatric patients.

Juvenile Animal Toxicity Data

No juvenile animal studies were conducted with subcutaneous risperidone suspension.

Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9-hydroxyrisperidone) that were similar to those in children and adolescents receiving the oral MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the oral MRHD of 6 mg/day for children, based on mg/m2 body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the oral MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the oral MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the oral MRHD of 6 mg/day for children.

Geriatric Use

Clinical studies of UZEDY in the treatment of schizophrenia did not include patients older than 65 years to determine whether or not they respond differently from younger patients.

In general, dose selection for geriatric patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

UZEDY is substantially excreted by the kidneys, and the risk of reactions may be greater in patients with impaired renal function. 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 [see Warnings and Precautions and Clinical Pharmacology ].

Elderly patients with dementia-related psychosis treated with UZEDY are at an increased risk of death compared to placebo. UZEDY is not approved for the treatment of patients with dementia‑related psychosis [see Boxed Warning and Warnings and Precautions ].

 Renal Impairment

In patients with renal impairment, titrate with oral risperidone (up to at least 2 mg daily) before initiating treatment with UZEDY [see Dosage and Administration and Clinical Pharmacology ].

UZEDY was not studied in patients with renal impairment.

 Hepatic Impairment

In patients with hepatic impairment, titrate with oral risperidone (up to at least 2 mg daily) before initiating treatment with UZEDY [see Dosage and Administration and Clinical Pharmacology ].

UZEDY has not been studied in patients with hepatic impairment; however, such effect has been investigated with oral risperidone.

Patients with Parkinson's Disease or Dementia with Lewy Bodies

Patients with Parkinson’s disease or dementia with Lewy bodies can experience increased sensitivity to UZEDY. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.