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UZEDY (risperidone) extended-release injectable

Explore what’s possible for adult patients with schizophrenia or bipolar I disorder

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WELTRUZA (olanzapine) for extended release injectable suspension

The power of olanzapine in a once-monthly subcutaneous injection for adults living with schizophrenia

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INDICATIONS & IMPORTANT SAFETY INFORMATION

 

INDICATIONS AND USAGE

UZEDY® (risperidone) extended-release injectable suspension for subcutaneous use is indicated in adults for the treatment of schizophrenia and as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder.

IMPORTANT SAFETY INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. UZEDY is not approved for use in patients with dementia-related psychosis and has not been studied in this patient population.

CONTRAINDICATIONS: UZEDY is contraindicated in patients with a known hypersensitivity to risperidone, its metabolite, paliperidone, or to any of its components. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone or paliperidone.

WARNINGS AND PRECAUTIONS

Cerebrovascular Adverse Reactions: In trials of elderly patients with dementia-related psychosis, there was a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in patients treated with oral risperidone compared to placebo. UZEDY is not approved for use in patients with dementia-related psychosis.
Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue UZEDY and provide symptomatic treatment and monitoring.
Tardive Dyskinesia (TD): TD, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause TD is unknown.

The risk of developing TD and the likelihood that it will become irreversible are believed to increase with the duration of treatment and the cumulative dose. The syndrome can develop, after relatively brief treatment periods, even at low doses. It may also occur after discontinuation. TD may remit partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however,
may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has on the long-term course of the syndrome is unknown.

If signs and symptoms of TD appear in a patient treated with UZEDY, drug discontinuation should be considered. However, some patients may require treatment with UZEDY despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.
Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and diabetes mellitus (DM), in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics, including risperidone. Patients with an established diagnosis of DM who are started on atypical antipsychotics, including UZEDY, should be monitored regularly for worsening of glucose control. Patients with risk factors for DM (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including UZEDY, should undergo fasting blood glucose (FBG) testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including UZEDY, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including UZEDY, should undergo FBG testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of risperidone.

Dyslipidemia has been observed in patients treated with atypical antipsychotics.

Weight gain has been observed with atypical antipsychotic use. Monitoring weight is recommended.


Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.
Orthostatic Hypotension and Syncope: UZEDY may induce orthostatic hypotension associated with dizziness, tachycardia, and in some
patients, syncope. UZEDY should be used with particular caution in patients with known cardiovascular disease, cerebrovascular disease, and conditions which would predispose patients to hypotension and in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral risperidone and antihypertensive medication.
Falls: Antipsychotics, including UZEDY, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other fall-related injuries. Somnolence, postural hypotension, motor and sensory instability have been reported with the use of risperidone. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Leukopenia, Neutropenia, and Agranulocytosis have been reported with antipsychotic agents, including risperidone. In patients with a pre-existing history of a clinically significant low white blood cell count (WBC) or absolute neutrophil count (ANC) or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of UZEDY at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue UZEDY in patients with ANC < 1000/mm3) and follow their WBC until recovery.
Potential for Cognitive and Motor Impairment: UZEDY, like other antipsychotics, may cause somnolence and has the potential to impair judgement, thinking, and motor skills. Somnolence was a commonly reported adverse reaction associated with oral risperidone treatment. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that treatment with UZEDY does not affect them adversely.
Seizures: During premarketing studies of oral risperidone in adult patients with schizophrenia, seizures occurred in 0.3% of patients (9 out of 2,607 patients), two in association with hyponatremia. Use UZEDY cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including UZEDY, should be used cautiously in patients at risk for aspiration.
Priapism has been reported during postmarketing surveillance for other risperidone products. A case of priapism was reported in premarket studies of UZEDY. Severe priapism may require surgical intervention.
Body temperature regulation. Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use UZEDY with caution in patients who experience these conditions.

ADVERSE REACTIONS

The most common adverse reactions with risperidone in patients with schizophrenia (≥5% and greater than placebo) were parkinsonism,
akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.

The most common adverse reactions with risperidone in patients with bipolar disorder were weight increased (5% in monotherapy trial) and tremor and parkinsonism (≥10% in adjunctive therapy trial).

The most common injection site reactions with UZEDY (≥5% and greater than placebo) were pruritus and nodule.

DRUG INTERACTIONS

  • Carbamazepine and other strong CYP3A4 inducers decrease plasma concentrations of risperidone.
  • Fluoxetine, paroxetine, and other strong CYP2D6 inhibitors increase risperidone plasma concentration.
  • Due to additive pharmacologic effects, the concomitant use of centrally-acting drugs, including alcohol, may increase nervous system disorders.
  • UZEDY may enhance the hypotensive effects of other therapeutic agents with this potential.
  • UZEDY may antagonize the pharmacologic effects of dopamine agonists.
  • Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS)


USE IN SPECIFIC POPULATIONS
Pregnancy: May cause EPS and/or withdrawal symptoms in neonates with third trimester exposure. 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/clinicaland-research-programs/pregnancyregistry/.
Lactation: Infants exposed to risperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and EPS.
Fertility: UZEDY may cause a reversible reduction in fertility in females.
Pediatric Use: Safety and effectiveness of UZEDY have not been established in pediatric patients.
Renal or Hepatic Impairment: Carefully titrate on oral risperidone up to at least 2 mg daily before initiating treatment with UZEDY.
Patients with Parkinson’s disease or dementia with Lewy bodies can experience increased sensitivity to UZEDY. Manifestations and features are consistent with NMS.

Please see the full Prescribing Information for UZEDY, including Boxed WARNING.

INDICATION AND USAGE

WELTRUZATM (olanzapine) for extended-release injectable suspension is indicated for the treatment of schizophrenia in adults.

IMPORTANT SAFETY INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. WELTRUZA is not approved for use in patients with dementia-related psychosis.

WARNINGS AND PRECAUTIONS

Post-Injection Delirium/Sedation Syndrome (PDSS) has been reported in <0.1% of intramuscular injections of another extended-release olanzapine product. PDSS presented with signs and symptoms consistent with olanzapine overdose (eg, agitation, dysarthria, tachycardia, extrapyramidal symptoms, and sedation or coma). The majority of patients were hospitalized and some required supportive care, including intubation. The majority of cases occurred within the first 3 hours after injection. The risk of an event is the same at each injection, so the risk per patient is cumulative (i.e., increases with the number of injections).


Healthcare professionals should consider PDSS in the differential diagnosis in the event a patient experiences the signs and symptoms of olanzapine overdose. In pre-marketing trials with WELTRUZA, there were no reported cases of PDSS. However, the risk of PDSS with WELTRUZA is currently unknown.

Cerebrovascular Adverse Reactions: In placebo-controlled trials in elderly patients with dementia-related psychosis treated with oral risperidone, aripiprazole, or olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke compared to those treated with placebo. WELTRUZA is not approved for the treatment of patients with dementia-related psychosis.


Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue WELTRUZA and provide intensive symptomatic treatment and monitoring.


Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS has been reported with exposure to olanzapine. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue WELTRUZA if DRESS is suspected.

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Weight gain and changes in metabolic laboratory parameters were consistent with those expected with long-term olanzapine treatment. Olanzapine’s specific metabolic profile, based on data from oral olanzapine, is presented below.

  • Hyperglycemia and Diabetes Mellitus (DM): in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, have been reported in patients treated with atypical antipsychotics (AAP), including olanzapine. While relative risk estimates are inconsistent, the association between AAP and increase in glucose levels appears to fall on a continuum, and olanzapine appears to have a greater association compared with some other AAPs. Physicians should consider the risks and benefits when prescribing WELTRUZA to patients with an established diagnosis of DM or with a borderline increase in blood glucose levels. Patients taking WELTRUZA should be monitored regularly for worsening of glucose control. Patients starting treatment with WELTRUZA should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. In some cases, hyperglycemia resolved when the AAP was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of olanzapine.
  • Dyslipidemia: Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using WELTRUZA, is recommended. Clinically significant, and sometimes very high (≥500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use.
  • Weight Gain: Potential consequences of weight gain should be considered prior to starting WELTRUZA. Patients receiving WELTRUZA should receive regular monitoring of weight.

Tardive Dyskinesia (TD): TD, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs, including WELTRUZA. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients are likely to develop TD. Whether antipsychotic drug products differ in their potential to cause TD is unknown.

The risk of developing TD and the likelihood that it will become irreversible are believed to increase with the duration of treatment and the cumulative dose. The syndrome can develop, after relatively brief treatment periods, even at low dosasges. It may also occur after discontinuation. TD may remit partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has on the long-term course of the syndrome is unknown.

If signs and symptoms of TD appear in a patient treated on olanzapine, drug discontinuation should be considered. However, some patients may require treatment with olanzapine despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

Orthostatic Hypotension and Syncope: WELTRUZA may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia, and in some patients, syncope. Olanzapine should be used with particular caution in patients with known cardiovascular disease, cerebrovascular disease, and conditions that would predispose patients to hypotension.

Falls: Antipsychotics, including WELTRUZA, may cause somnolence, postural hypotension, motor and sensory instability which may lead to falls and, consequently, fractures or other injuries. If patients have a condition or take concomitant drugs that could exacerbate these effects, complete fall risk assessments when initiating treatment with WELTRUZA and recurrently for patients on long-term treatment.

Leukopenia, Neutropenia, and Agranulocytosis: have been reported with antipsychotics, including olanzapine. Patients with a history of a clinically significant low white blood cell (WBC) count or drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy, and discontinuation of WELTRUZA should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000 mm3) should discontinue WELTRUZA and have their WBC followed until recovery.

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.

Seizures: Like other antipsychotic drugs, WELTRUZA may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold and WELTRUZA should be used cautiously. Conditions that lower the seizure threshold may be more prevalent in older patients.

Potential for Cognitive and Motor Impairment: WELTRUZA, like other antipsychotics, may cause somnolence and has the potential to impair judgement, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that WELTRUZA does not affect them adversely.

Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing WELTRUZA for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Anticholinergic Effects: Olanzapine exhibits in vitro muscarinic receptor affinity. In premarketing clinical trials, oral olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. WELTRUZA should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions. In postmarketing experience, the risk for severe adverse reactions (including fatalities) was increased with concomitant use of anticholinergic medications.

Hyperprolactinemia: As with other drugs that antagonize dopamine receptors, olanzapine elevates prolactin levels, and the elevation persists during chronic administration. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.

ADVERSE EVENTS

Most common adverse reactions (≥5% in at least one of the treatment groups and greater than placebo) associated with WELTRUZA treatment: weight increased, somnolence, headache, constipation, and injection site reactions (induration, pain, erythema, pruritus, swelling).

DRUG INTERACTIONS

  • Strong CYP1A2 or Glucuronyl Transferase Inducers: Concomitant use may decrease olanzapine exposure; monitor for lack of symptom control and consider dosage increase of WELTRUZA
  • Strong CYP1A2 Inhibitors: Consider dosage reduction of WELTRUZA when administered concomitantly with strong CYP1A2 Inhibitors
  • Centrally-Acting Drugs and Alcohol: May potentiate orthostatic hypotension.
  • CNS Acting Drugs: Caution should be used when used in combination with other centrally acting drugs and alcohol.
  • Antihypertensive Agents: Enhanced antihypertensive effect.
  • Levodopa and Dopamine Agonists: May antagonize levodopa/dopamine agonists.
  • Anticholinergic Drugs: Can increase the risk for severe gastrointestinal adverse reactions related to hypomotility

USE IN SPECIFIC POPULATIONS

Pregnancy: Use only if the potential benefit justifies the potential risk to the fetus. WELTRUZA may cause extrapyramidal symptoms (EPS) and/or withdrawal symptoms in neonates with third-trimester exposure. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including WELTRUZA, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for AAPs at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Lactation: WELTRUZA is present in human milk. Infants should be monitored for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).

Fertility: WELTRUZA may cause a reversible reduction in fertility in females.

Pediatric Use: Safety and effectiveness of WELTRUZA in pediatric patients have not been established  

Please see the full Prescribing Information for WELTRUZA, including Boxed WARNING.