Addressing Challenges of Nonadherence Among Adults With Schizophrenia

Sponsored by Johnson & Johnson

In a new Psychiatric Times® Expert Perspectives video series sponsored by Johnson & Johnson, Gus Alva, MD, Medical Director of ATP Clinical Research in Costa Mesa, California, and Desiree Matthews, PMHNP, Owner and Clinical Director at Different Mental Health Program, reviewed common challenges associated with the treatment of schizophrenia, such as treatment nonadherence and relapse. They also reviewed long-acting injectables (LAIs), and specifically once-monthly INVEGA SUSTENNA® (paliperidone palmitate), as options for adults that can help address these challenges.

According to Dr. Alva, schizophrenia requires consistent, long-term treatment regardless of whether symptoms are present.^1,2 The key goals of treatment include delaying time to relapse and improving overall functioning.¹ Delaying relapse is of particular importance, as relapses may include symptoms such as psychosis, hallucinations, or other disruptive behaviors. Each relapse can cause further functional deterioration for patients, reduced treatment response, and poorer outcomes overall.³ Studies have even shown that some adult patients may never regain their original level of functioning following relapse.¹ “It is critical for providers to initiate treatment earlier in the disease course to delay risk of relapse,” said Dr. Alva.⁴

Ideally, treatment should be initiated during the first 5 years following diagnosis, which is considered the “critical period” during which the disease can progress rapidly.⁵ Ms. Matthews elaborated, “While healthcare providers (HCPs) can work to treat the condition at various stages, initiating treatment during this critical period may positively influence short- and long-term outcomes.”⁶

Standard treatments for schizophrenia are oral antipsychotic therapies, which may offer efficacy in up to 80% of adult patients with schizophrenia.^1,7 However, Dr. Alva noted that this efficacy rate could be considerably lower in the real world. “These results are often hindered by a high rate of nonadherence, with approximately half of adult patients not taking their [oral] medication as prescribed,” he said.^1,8

Nonadherence is important to highlight, shared Ms. Matthews, because it is one of the main predictors of a future relapse. Risk factors for nonadherence can include a fear of side effects, perceptions about treatment, financial difficulties, education level, stigma, poor social support systems, and certain psychopathological symptoms associated with schizophrenia, such as delusions and impaired insight.¹ How a treatment is administered also affects adherence.^1,9 Since LAIs are administered professionally, providers are aware of when patients are nonadherent.¹⁰

LAIs work by continuously delivering a consistent therapeutic concentration over the weeks or months following an injection.¹⁰ They are administered by a trained HCP; therefore, treatment teams have greater insight into when an adult patient has missed a dose and can provide additional support to help the patient reinitiate therapy.¹⁰ “I see LAIs as a good option for adult patients who have a history of poor or uncertain adherence to orals, specifically those who experience frequent relapse due to nonadherence,” said Dr. Alva.¹¹ “In addition, some adult patients may simply prefer the ease of an injection every month or even less frequently rather than worrying about taking a pill for their schizophrenia every day.”^1,2

Dr. Alva shared that many providers may primarily prescribe oral antipsychotics, and they consider LAIs only once an adult patient is later in the disease course; however, some clinical guidelines recommend use of LAIs after diagnosis.⁷ For example, with an initial schizophrenia episode, the Florida Medicaid Program guidelines recommend administering a second-generation antipsychotic, either as oral-only, or as oral, and then, after establishing efficacy and tolerability, switching to the LAI of the same antipsychotic.⁷

To enable this transition from oral to LAI, the antipsychotic chosen for treatment would need to be available as both oral and LAI formulations, said Dr. Alva.² For example, the oral formulation of paliperidone is also available as the LAI INVEGA SUSTENNA® from Johnson & Johnson, a once-monthly option for adults with schizophrenia that is administered by an HCP monthly after 2 starter doses.¹² Once tolerability has been established at an appropriate dose for at least 4 months, adult patients have the option to transition to the 3-month option, INVEGA TRINZA® (paliperidone palmitate 3-month), or the 6-month option, INVEGA HAFYERA® (paliperidone palmitate 6-month).^12-14 “This is why we like to recommend INVEGA SUSTENNA®—because there is a possibility of moving to a 3-month option or a 6-month option in the future,” said Dr. Alva. Importantly, INVEGA SUSTENNA® “is the only LAI treatment that is proven to be superior to a group of oral antipsychotics in a trial with real-world design elements,” he shared.^10,12

Ms. Matthews reviewed details of the trial, which was a randomized, open-label, 15-month study that investigated the efficacy and safety of INVEGA SUSTENNA® (n = 226) compared to a group of commonly prescribed daily oral antipsychotics (n = 218) for the treatment of schizophrenia.¹⁰ Results from the trial showed that “INVEGA SUSTENNA® [was] superior in delaying the time to treatment failure compared to a group of seven of the most prescribed daily orals: aripiprazole, haloperidol, olanzapine, paliperidone, perphenazine, quetiapine, and risperidone,” noted Ms. Matthews.¹⁰ “The delay to first treatment failure was statistically significant (mean time to first treatment failure, 416 days for INVEGA SUSTENNA® vs 226 days for orals, P = .011).”¹⁰ In addition, the rate of treatment failure overall was considerably lower with INVEGA SUSTENNA® versus oral therapy (39.8% versus 53.7%, respectively).¹⁰ Treatment failure was defined as either incarceration, a psychiatric-related hospitalization, suicide, treatment supplementation due to lack of efficacy, treatment discontinuation due to lack of efficacy or safety, or an increase in psychiatric services needed to prevent psychiatric-related hospitalization.¹⁰

“Notably, in the trial, adherence to treatment was considerably higher in the INVEGA SUSTENNA® group, in which 95.2% had a medication possession ratio (MPR) greater than 80% when assessed using injection records,” said Ms. Matthews. “This is in contrast to the daily oral group, in which 24.3% had an MPR greater than 80% when assessed using pharmacy-based prescription refill records.”¹⁰ At month 15, patients in the INVEGA SUSTENNA® group had a 30% lower risk of relapse than those in the daily oral group.^10,12 In the Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study, the 5 most common adverse events in the INVEGA SUSTENNA® group were injection-site pain (18.6%), insomnia (16.8%), weight increase (11.9%), akathisia (11.1%), and anxiety (10.6%).¹⁰

Regarding safety, Dr. Alva noted, “INVEGA SUSTENNA® has a long-term tolerability profile, which makes it a good option for providers looking to recommend an LAI to their adult patients.”^10,12 In pivotal, placebo-controlled trials, discontinuation rates due to adverse events were similar between patients who received INVEGA SUSTENNA® and placebo.¹² The most common adverse events of 5% or greater observed in these trials were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder.¹²

In closing, the experts emphasized the importance of patient education and shared decision-making during treatment selection. Adult patients may not be aware of these LAIs from Johnson & Johnson as less frequent dosing options, or the clinical-related and potential convenience offered by this treatment type. Ms. Matthews summarized, “By providing long-acting symptom control in each dose and removing the daily reminder of their schizophrenia treatment, LAIs from Johnson & Johnson can allow adults living with schizophrenia to simplify their treatment regimen, avoid the burden of a daily schizophrenia pill, and potentially lead a more stable day-to-day life with their schizophrenia symptoms controlled.”

INDICATION

INVEGA HAFYERA®, an every-six-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in adults after they have been adequately treated with:

• A once-a-month paliperidone palmitate extended release injectable suspension (e.g., INVEGA SUSTENNA®) for at least four months or
• An every-three-month paliperidone palmitate extended release injectable suspension (e.g., INVEGA TRINZA®) for at least one three-month cycle.

INVEGA TRINZA® is an atypical antipsychotic indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA® for at least four months.

INVEGA SUSTENNA® is an atypical antipsychotic indicated for the treatment of schizophrenia in adults.

IMPORTANT SAFETY INFORMATION

Contraindications: INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA® are contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of their formulation

Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported at a higher incidence in elderly patients with dementia-related psychosis taking risperidone, aripiprazole, and olanzapine compared to placebo. No studies have been conducted with oral paliperidone, INVEGA HAFYERA®, INVEGA TRINZA® or INVEGA SUSTENNA® in elderly patients with dementia. These medications are 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 paliperidone.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse of 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 INVEGA HAFYERA®, INVEGA TRINZA® or INVEGA SUSTENNA® and provide symptomatic treatment and monitoring.

QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QTc interval and in patients with risk factors for prolonged QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

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 tardive dyskinesia is unknown.

The risk of developing TD and the likelihood that it will become irreversible appear 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 upon the long-term course of the syndrome is unknown.

If signs and symptoms of TD appear in a patient on INVEGA HAFYERA®, INVEGA TRINZA® or INVEGA SUSTENNA®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA HAFYERA®, INVEGA TRINZA® or INVEGA SUSTENNA® 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: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia during treatment should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug.

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

Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Orthostatic Hypotension and Syncope: INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA® may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA®, which may lead to falls and, consequently, fractures or other fall-related injuries. 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 antipsychotics, including INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA®. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or drug-induced leukopenia/neutropenia, perform a complete blood count frequently during the first few months of therapy. Consider discontinuing INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA® 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 INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA® in patients with severe neutropenia (absolute neutrophil count <1000/mm³) and follow their WBC until recovery.

Hyperprolactinemia: As with other drugs that antagonize dopamine D₂ receptors, INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA® elevate prolactin levels, and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.

Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA®. INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA® have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA® do not adversely affect them.

Seizures: INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.

Administration: For intramuscular injection only by a healthcare professional using only the needles provided in the INVEGA HAFYERA®, INVEGA TRINZA® or INVEGA SUSTENNA® kits. Care should be taken to avoid inadvertent injection into a blood vessel.

Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s Wort) during a dosing interval for INVEGA HAFYERA®, INVEGA TRINZA® or INVEGA SUSTENNA®. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

Pregnancy/Nursing: INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with INVEGA HAFYERA®, INVEGA TRINZA® or INVEGA SUSTENNA®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA HAFYERA®, INVEGA TRINZA® or INVEGA SUSTENNA® during pregnancy. INVEGA HAFYERA®, INVEGA TRINZA® and INVEGA SUSTENNA® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA HAFYERA®, INVEGA TRINZA® or INVEGA SUSTENNA® and any potential adverse effect on the breastfed infant from INVEGA HAFYERA®, INVEGA TRINZA® or INVEGA SUSTENNA® or the mother’s underlying condition.

Commonly Observed Adverse Reactions for INVEGA HAFYERA®: The most common adverse reactions (incidence at least 5% in the double-blind phase) in the INVEGA HAFYERA® clinical trial were upper respiratory tract infection, injection site reaction, weight increased, headache and parkinsonism.

Commonly Observed Adverse Reactions for INVEGA TRINZA®: The most common adverse reactions (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia and parkinsonism.

Commonly Observed Adverse Reactions for INVEGA SUSTENNA®: The most common adverse reactions in clinical trials in patients with schizophrenia (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia and extrapyramidal disorder.

Please click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA HAFYERA®, click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA TRINZA® and click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA SUSTENNA®.

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References

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12. INVEGA SUSTENNA® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.
13. INVEGA TRINZA® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.
14. INVEGA HAFYERA® [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.