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The Benefits of Long-Acting Injectables for the Treatment of Schizophrenia
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DR. ALVA: With all this in mind, let’s talk about another class of medications: long-acting injectables, or LAIs.
LAI antipsychotic therapies are administered by a trained healthcare professional via injection. They work by continuously delivering a set therapeutic concentration over many weeks. While LAIs offer another option, I’m sure we often hear similar questions and concerns from adult patients such as a fear of needles, not wanting to go into their doctor’s office or uncertainty about the amount of medication. As providers, it’s important that we adequately educate them and take the time to answer their questions so we, as a team, can have a discussion and land on the right treatment for them.
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 non-adherence. In addition, some adult patients may simply prefer the ease of an injection every month or every couple of months rather than worrying about taking a pill for their schizophrenia every day.
There can be many factors for why someone wouldn’t take medicine, from stigma to forgetting, which can happen to anyone, but adults living with schizophrenia are often non-adherent due to the nature of the condition or a lack of social support.
MATTHEWS: Yeah absolutely. So, we mentioned that anybody could easily forget to take medication.
And in my clinical experience working with adults with schizophrenia, oftentimes, when I’ve talked about long-acting injectables, it’s almost like a sigh of relief because patients do not need to struggle every day with that decision, “Do I take this pill for my schizophrenia?” And oftentimes they prefer the ease of the injection, rather than taking that oral pill and not having to be reminded that they have schizophrenia every single morning when they take their medication.
DR. ALVA: I completely concur. You know sometimes, if somebody were to ask you, “Hey, what are those pills for? I see that you’re taking them on a regular basis.” And there’s still that stigma, that reluctance, about sharing one’s diagnosis. Obviously, that’s a grim reminder that, you know, they could be outed as having something that makes them a bit peculiar, or odd.
As mentioned before, because LAIs are administered by healthcare professionals, treatment teams have greater insight into when an adult patient has missed a dose and can therefore provide additional support to get that patient back on therapy. Additionally, market research found that out of 200 patients surveyed, less than half, or 45%, were aware of 1-month medication options and only 18% were aware that a 6-month dosing option exists.
We’re here today to help raise awareness of LAIs so both our fellow providers and their adult patients are more informed about other treatment options out there. By equipping healthcare professionals and their adult patients with information on the various schizophrenia treatment options and less-frequent dosing options, they can help these patients and their family members make more-informed treatment decisions, ideally early on in their treatment journeys.
On that note, that market research also showed there is a gap between adult patients’ desired treatment options and what they actually get prescribed. In the survey, nearly 90%, or 44 of 49 adult schizophrenia patients currently on a long-acting injectable, agreed that after knowing what living with schizophrenia is like, they wish they would have started on an LAI sooner.
Additionally, about 90%, or 172 of 192 adult schizophrenia patients who were surveyed, wanted their providers to recommend LAIs, if they felt it was the right treatment option, even if they were stable on a current treatment according to market research. Despite these findings, in my experience many providers may fall into a pattern and primarily prescribe oral antipsychotics and only consider LAIs once an adult patient is later on in the disease course.
MATTHEWS: Now, I want to take a moment to acknowledge that administration of an injection, particularly in a crisis setting, can be associated with negative experiences for our adult patients and can result in fear and distrust in their provider and care plan.
Of course, it is important to note here that LAIs are not the same injections patients receive in these emergency situations, but it is a critical piece of context we, as providers, should consider when having discussions with our adult patients about a treatment plan. This all reinforces how important it is that we, as providers, educate our adult patients about all options and approach these conversations as a dialogue to figure out what will work best for the particular person and build a trusting relationship early on.
DR. ALVA: That is a great point, Desiree, and as providers we should keep in mind how trust can be broken if the patient is fearful or is not understanding the full picture when it comes to a treatment plan.
Speaking of raising awareness on early LAI initiation, several clinical guidelines recommend use of LAIs for a first relapse after diagnosis. As an example, I’ll describe the Florida Medicaid Program guidelines.
For an initial schizophrenia episode, these 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. To enable this transition, the antipsychotic chosen for treatment would need to be available as both oral and LAI formulations.
An example of an LAI that meets these standards is INVEGA SUSTENNA® or paliperidone palmitate from Johnson & Johnson, a once-monthly option for adults with schizophrenia that is administered by an HCP once a month after 2 starter doses. This LAI is part of the Johnson & Johnson, or J&J, LAI portfolio, which includes a 3-month option, INVEGA TRINZA® (which is paliperidone palmitate every 3-months), and a 6-month option, INVEGA HAFYERA® (which is paliperidone palmitate every 6-months). Adult patients can transition to INVEGA HAFYERA®, the 6-month option, once tolerability has been established with INVEGA SUSTENNA® at an appropriate dose for at least four months, with the last two doses being the same, and enjoy the flexibility of more or less frequent dosing options. Your thoughts, Desiree?
MATTHEWS: Yeah so, I’m thinking about many of my young adults living with schizophrenia, and the flexibility with less frequent doses is something that many of my patients wish that was available sooner, or that a healthcare provider actually talked to them about. So, I’m thinking about my patients that have gone off to college and they see me virtually via telemedicine, but then receive their medication, actually, by a pharmacist in North Carolina only twice a year. So that flexibility to have them engaged in their daily activity, school, work, without needing them to be seen necessarily in the office every single time has been really great for those patients just wanting to get back to their usual life.
DR. ALVA: What an excellent point. And I would totally concur with that because I think that a life less defined by having to remember to take your medicine on a daily basis is one that, oftentimes, feels fuller for that patient.
And 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.
It’s important to note that it 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. With that said Desiree, let’s talk more about how INVEGA SUSTENNA® compares with daily orals. Can you talk about the PRIDE trial?
MATTHEWS: The comparative safety and efficacy trial was a randomized, open-label, 15-month clinical trial that investigated the efficacy and safety of INVEGA SUSTENNA® as compared to a group of commonly prescribed daily oral antipsychotics for the treatment of schizophrenia.
Notably, INVEGA SUSTENNA® was found to be 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.
The primary endpoint was time to first treatment failure, which was determined by an independent review board. 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.
In the intent-to-treat population, 226 adult patients received INVEGA SUSTENNA® and 218 adult patients received a daily oral.Findings from this study demonstrated that the rate of treatment failure was considerably lower in the INVEGA SUSTENNA® group, experienced by 39.8% of these patients versus 53.7% of adult patients in the daily oral group.
INVEGA SUSTENNA® was associated with a statistically significant greater ability to delay first treatment failure than daily orals, with the P value equal to .011. Specifically, the median time to first treatment failure was 416 days for the INVEGA SUSTENNA® group versus 226 days for the daily oral group.
Across both groups, the most common reasons for first treatment failure were arrest, incarceration, and a psychiatric-related hospitalization.
At month 15, adult patients in the INVEGA SUSTENNA® group had a 30% lower risk of a relapse than those in the daily oral group. Notably, in the trial, adherence to treatment was considerably higher in the INVEGA SUSTENNA® group, in which 95.2% had a medication possession ratio, or MPR, greater than 80% when assessed using injection records. This is in contrast to the daily oral group, in which 24.3% had a MPR greater than 80% when assessed using pharmacy-based prescription refill records.
DR. ALVA: Thank you for that review of efficacy data. Now let’s look at safety and dosing. 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. Additionally, in the pivotal, placebo-controlled clinical trials, the percentages of adult patients who discontinued treatment due to adverse events were similar between patients who received INVEGA SUSTENNA® and placebo.
The most common adverse events of 5% or greater observed in these trials were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder.
In terms of dosing, we noted earlier that some adult patients receiving once-monthly INVEGA SUSTENNA® injections may be eligible for and interested in further reducing the number of treatments they receive over the course of a year, including as few as two times per year.
For the 3-month dosing option, INVEGA TRINZA®, adult patients must have been adequately treated with
INVEGA SUSTENNA® for at least 4 months with the last 2 doses being the same prior to the transition. For the 6-month dosing option, INVEGA HAFYERA®, adult patients must have been adequately treated either with
INVEGA SUSTENNA® for at least 4 months with the last 2 doses being the same or for one 3-month injection cycle with INVEGA TRINZA®, at an appropriate dose.
MATTHEWS: As we wrap up this discussion about INVEGA SUSTENNA®, one final point that bears mentioning here is that these J&J LAIs are among the latest paliperidone palmitate treatment options for adults living with schizophrenia.
It is very important for providers to maintain awareness and consistently ensure that our adult patients are also aware of their treatment options. Providers need to educate patients on modern schizophrenia treatment plans that include less-frequent dosing options to support informed decision-making and to help adults living with schizophrenia find the best option for them.
The ability to receive a long-term treatment like INVEGA SUSTENNA® that is professionally administered rather than a daily dose of schizophrenia medication can free up time for our adult patients, so they can focus on activities they enjoy while still keeping their schizophrenia symptoms under control.
By providing long-acting symptom control in each dose and removing the daily reminder of their schizophrenia treatment, J&J LAIs can allow adults living with schizophrenia to both simplify their treatment regimen and focus more on the things that are important to them, avoid the burden of a daily schizophrenia pill, and potentially lead a more stable day-to-day life with their schizophrenia symptoms controlled.
DR. ALVA: In closing, thank you, Desiree, for having this discussion with me today on schizophrenia, the challenges associated with nonadherence and relapse, and the benefits offered by J&J LAIs, specifically INVEGA SUSTENNA®.
MATTHEWS: My pleasure.
DR. ALVA: And thank you to all who joined us today.
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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 a typical 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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