Manufacturer: Janssen Pharmaceuticals, Inc.
FDA Approval: March 5, 2019
Dosage Form: Nasal Spray
Dosage: 28mg/device, available as a 56mg kit or 84mg kit
Active Ingredient: esketamine hydrochloride
Inactive Ingredients: sodium hydroxide, edetate disodium, critic acid disodium, water
Treatment For: Major Depressive Disorder, Treatment-Resistant Depression
Therapeutic Areas: Psychiatry/Psychology, Neurology
Spravato (esketamine), manufactured by the Janssen Pharmaceutical Companies of Johnson & Johnson, was approved by the U.S. Food and Drug Administration (FDA) on March 5, 2019. In a 14-2 vote, an FDA panel determined that the benefits of esketamine outweigh the risks and recommended approval of the drug to the agency. The approval of Spravato is the first new depressant to be approved by the FDA in decades.
Spravato is a rapid-acting, nasal spray formulation of a non-competitive receptor antagonist N-methyl D-aspartate (NMDA). Esketamine is the s-enantiomer of the anesthetic ketamine, which was first approved by the FDA in 1970. This is the first time esketamine has been approved for any use. Ketamine is a variant of the hallucinogenic illicit drug Special K that has become a popular party drug because it causes sedation and out-of-body experiences. Psychiatrists have tried off-label use of ketamine as a last-ditch effort to treat individuals who do not respond to other antidepressants treatments or medications and found that it has the ability to relieve depressive symptoms within hours.
Esketamine was developed after years of preliminary research about the potential benefits of ketamine for depression. Spravato is designed to alleviate depressive symptoms much faster than other depressants with studies showing that patients may feel the effects within hours rather than weeks or months. Spravato should be used in conjunction with an oral antidepressant in adults struggling with major depressive disorder (MDD) or treatment-resistant depression (TRD). Individuals are considered to have TRD if they haven’t responded adequately to or haven’t seen any improvement in mood after trying at least two different antidepressants in the current depressive episode.
The main ingredient in Spravato is esketamine hydrochloride, which is a white crystalline powder that is soluble in ethanol or freely soluble in methanol and water. In the Spravato nasal spray, esketamine hydrochloride is contained as a solution in a vial within the device. The inactive ingredients are edetate disodium, critic acid disodium, and sodium hydroxide.
About Treatment-Resistant Depression
Studies show that about one-third of U.S. adults with MDD have TRD. This means that they have been treated with adequate doses of two or more different antidepressants for an adequate period of time but have not responded adequately to existing therapies. TRD is a serious and life-threatening condition that places an ongoing functional, economic, and emotional burden on the person and their loved ones. An individual suffering from depression is often unable to maintain social connections and manage life’s demands. This affects all aspects of a person’s life, including relationships, employment, school, and overall quality of life. TRD is associated with higher healthcare costs, greater morbidity, and various comorbid conditions. The impact is even greater for individuals who do not benefit from standard treatments.
Spravato Clinical Trials and Results
The FDA Approval of Spravato was based on 3 short-term clinical trials contacted for 4 weeks and 1 long-term maintenance-of-effect trial, which involved assessing the efficacy and safety of esketamine. The clinical trial program included more than 1,700 adults with treatment-resistance depression and generally has more severe symptoms than the patients who participated in other studies conducted for antidepressants drugs already available in the market. Spravato was also studied in 19 Phase 1 studies and four Phase 2 studies in patients with TRD and healthy volunteers.
In the 3 short-term studies, patients randomly received a placebo nasal spray or Spravato at the start of the treatment phase. All patients started a new oral antidepressant at the time they received a placebo nasal spray or Spravato and the new antidepressant was continued throughout the studies. The change from baseline on a scale used for the purpose of assessing the severity of depressive symptoms was the primary efficacy measure.
In one of the short-term studies, patients who took Spravato in conjunction with a newly initiated oral antidepressant experienced rapid, sustained, clinically meaningful, and statistically significant improvement in depression symptoms at four weeks compared to those who received an oral antidepressant and placebo nasal spray. Some effect was seen within 2 days. Patients who used Spravato experienced sustained improvement for treatment-resistant depression. In the long-term study, patients who continued treatment with Spravato plus an oral antidepressant and who were in stable remission were 51 percent less likely to relapse of depressive symptoms compared to those who maintained a regimen or an oral antidepressant and a placebo.
The other two short-term clinical trials failed to meet the specified statistical tests for showing the drug’s effectiveness. They did not show significant improvements over placebo. Members of the advisory committee expressed concern that because there was no significant difference in efficacy in patients receiving Spravato at 84 mg and those receiving 56mg, the studies do not sufficiently show that the higher 84 mg dose of Spravatoyieldsa therapeutic response in relation to its higher rate causing adverse side effects. In addition, the results did not confirm the response that has appeared in an earlier Phase 2 study and the dose administered.
Improvement of the condition among patients over 65 years wasn’t statistically significant. The report indicated this to mean that individuals who had depression later in life may not have responded significantly because the condition results in vascular changes. The drug may also not be the best for older adults since it tends to affect cognition and perception. The committee members also expressed concern about data integrity for the study that did not show the drug’s success when used by elderly patients. They pointed to discrepancies between an unusual response curve shift and lock data sets as well as protocol violations. One study showed significant treatment effects after 28 days and the other studies showed an effect 2 days following initiation of treatment.
Spravato Dosage and Administration
Each nasal spray device contains 28mg and delivers 2 sprays with a total of 32.3 mg of esketamine hydrochloride in 0.2 ml of a colorless solution with a pH of 4.5. Spravato is available as an 84 mg kit containing three 28mg nasal spray devices and a 56mg kit containing two 28mg nasal spray devices. Dosage may be adjusted based on tolerability and efficacy.
Induction phase (Weeks 1-4): Spravato should be administered twice per week during the first 4 weeks. The starting dose for the first is 56mg and subsequent dose may be 56mg or 84mg.
Maintenance phase (Weeks 5 and after): During the fifth to eighth week, 56mg or 84 mg of Spravato should be administered once weekly. From week nine and after, dosing frequency should be individualized to maintain response/remission. Spravato may be administered once or twice weekly.
Because of the risk for abuse and misuse, sedation, and dissociation, Spravato is only available through a program known as Spravato Risk Evaluation and Mitigation Strategy (REMS) Program. So, once a health care provider determines that Spravato is an appropriate treatment option, the patients will be treated in accordance with the REMS. This means that Spravato will be administered at a treatment center certified in the REMS program and by a healthcare provider trained to administer the medicine. Only patients enrolled in the program will be able to use the medicine. A session typically involves nasal administration and post-administration observation. The patient will self-administer the medicine under the direct observation of a healthcare provider and this means that patients cannot take the medicine home.
Prior to dosing with Spravato, the healthcare provider should assess the patient’s blood pressure. If baseline blood pressure is elevated, the benefits of Spravato treatment in patients with TRD and the risks of short term increases in blood pressure should be considered. Spravato should not be administered if an increase in intracranial pressure or blood pressure poses a serious risk.
Patients will be observed by the healthcare provider for at least 2 hours after administration. The observation is based on possible treatment-emergent dissociation, sedation, and blood pressure changes. Blood pressure should be reassessed at approximately 40 minutes after dosing with Spravato and subsequently until the value declines. More frequent and intensive blood pressure monitoring will be required for patients with a history of hypertensive encephalopathy because they may develop encephalopathy even with small increases in blood pressure. After the 2-hour observation period, the doctor will then determine if the patient is clinically stable and safe to be discharged at the end of the post-dose monitoring period. All patients will be enrolled in the program’s registry to characterize the risk of adverse outcomes and to support safe use of the drug.
Patients experiencing symptoms of a hypertensive encephalopathy (such as sudden severe focal neurological deficits, seizures, headache, diminished consciousness, or visual disturbances) or hypertensive crisis (such as shortness of breath, chest pain) should be referred immediately for emergency care.
Food and Liquid Intakes Prior to Administration
Because Spravato may cause nausea and vomiting after administration, patients should avoid drinking liquids at least 30 minutes before administration of Spravato and avoid food for at least 2 hours prior to administration.
Nasal Decongestant and Nasal Corticosteroid
Patients who require a nasal decongestant or nasal corticosteroid on a dosing day should use them at least 1 hour before administration of Spravato.
Driving and Operating Machinery
Two placebo-controlled studies were conducted to analyze patients’ ability to drive after Spravato administration. The effects of Spravato 84 mg on the ability to drive were comparable to placebo at 18 hours and 6 hours after administration. Some patients treated with Spravato could not drive for more than 8 hours post-dose because of the resultant adverse reactions to the medicine. Before Spravato is administered, patients should be instructed not to engage in potentially hazardous activities requiring motor coordination and mental alertness, such as operating machinery or driving a motor vehicle, until the next day after a restful sleep. Patients will also need to plan on how they go back home following treatment with Spravato.
SpravatoBlack Box Warning
Sedation and dissociation
Spravato may cause fainting, sleepiness (sedation), dizziness, anxiety, reduced sense of touch and sensation, spinning sensation, vomiting, feeling drunk, or feeling disconnected from yourself, feelings, thoughts, time, and space. If you feel like you’re going to pass out or feel like you cannot stay awake, tell your healthcare provider right away. Because of the possibility of prolonged or delayed sedation, the healthcare provider must closely monitor the patient for serious side effects for at least two hours, until the patient is safe to leave the healthcare setting. Also, because of the risks of dissociation, patients with psychosis must be carefully assessed before Spravato is administered and treatment should only be initiated if the benefits outweigh the risk.
Abuse and misuse
There’s a risk for abuse and psychological and physical dependence on esketamine. Just as with ketamine, abuse and misuse of Spravato can lead to bladder toxicity and cognitive problems. If you’ve ever abused or been dependent on prescription medicines, alcohol, or street drugs, it’s important to tell your healthcare provider about it. A healthcare provider should also be able to tell about the difference between addition and psychological and physical dependence. In addition, patients receiving Spravato should be monitored for abuse and misuse behavior and conditions such as drug-seeking behavior.
Increased risk of suicidal thoughts and behaviors
Depression is the most common cause of suicidal thoughts and behavior. Spravato may cause worsening of depression and increase the risk for suicidality in young adults aged ≤ 24 years and children. For this reason, esketamine should not be administered to pediatric patients. The risk of suicidal thoughts and actions also increases during the initial phase of treatment and in the event of a change in dosage. It is not known if the risk of suicidal thoughts in young adults, children or adolescents extends to long-term use (beyond 4 months). Healthcare providers are required to closely monitor patients treated with anti-depressants for the emergence or clinical worsening of suicidal thoughts and behavior.
To watch for and try to prevent suicidality, pay close attention to any changes you experience, especially sudden changes in behavior, mood, feelings, or thoughts. Also, if your depression is worsening, you have thoughts about suicide or dying or have made an attempt to commit suicide, tell your healthcare provider right away and keep all follow-up visits as scheduled. If you have concerns about symptoms, don’t hesitate to call your healthcare provider between scheduled visits.
Spravato Side Effects
Increased blood pressure: Your blood pressure may increase for about 40 minutes to 4 hours after Spravato administration. The healthcare provider is required to take your blood pressure before administering Spravato and 2 hours after. Tell your doctor if you have a sudden severe headache, seizures, chest pain, or change in vision after taking a dose. Spravato should not be used to treat depression in patients for whom an increase in intracranial pressure or blood pressure poses a serious risk such as arteriovenous malformation, aneurysmal vascular disease, and intracerebral hemorrhage.
Cognitive problems: Spravato can cause problems with thinking and remembering clearly.
Bladder Problems: Tell your doctor if you experience urgent or frequent need to urinate, urinate, frequently at night, or pain when urinating.
In essence, the most common side effects of Spravato when used in conjunction with an oral antidepressant include:
- dissociation and perceptual changes
- feeling drunk
- spinning sensation
- increased blood pressure
- reduced sense of touch and sensation
- lack of energy
Some patients may experience:
- nasal discomfort
- throat irritation
- dry mouth
- euphoric mood
- feeling abnormal
- oropharyngeal pain
- hyperhidrosis (excessive sweating)
- pollakiuria (abnormal and frequent urination)
Most of these side effects of Spravato usually occur right after taking the medicine and tend to go away the same day.
Before You Take Spravato
There are certain conditions that may be worsened by the use of Spravato. Before taking Spravato, tell your healthcare provider if you have any of the following medical conditions:
- Have heart brain problems, including:
- history of stroke
- history of heart attack
- high blood pressure (hypertension)
- heart failure or heart valve disease
- slow or fast heartbeats that cause chest pain, shortness of breath, fainting, or lightheadedness
- history of brain injury or any condition that causes increased pressure in the brain
- have ever had a condition known as “psychosis”, where you believe in things that are not true or hear, feel, or see things that are not there
- have liver problems
- are pregnant or plan to become pregnant. If you become pregnant during treatment with Spravato, tell your healthcare provider right away because the medicine may harm your baby.
- are breastfeeding or plan to breastfeed.
Spravato Use during Pregnancy
Spravato is not recommended during pregnancy and lactation. However, there are insufficient data to draw conclusions about any risks of miscarriage, major birth defects, or adverse fetal or maternal outcomes. Based on findings from pregnant given ketamine (a mixture of esketamine and arketamine), the drug may cause fetal harm and is therefore not recommended during pregnancy. Pregnant primates given N-methyl-D-aspartate (NMDA) receptors blockers during the period of peak fetal brain development showed a significant increase in neuronal apoptosis in the offspring’s developing brain. There are no data to show the effects of exposure before the third trimester in humans.
Pregnant rats were also treated with intranasal esketamine during pregnancy and lactation at exposures similar to the maximum recommended human dose (MRHD). The results showed that the administration of the drug resulted in a delay in the offspring’s sensorimotor development during the preweaning period. And during the postweaning period, the pups experienced decreased motor activity. Embryo-fetal reproduction studies in rabbits involved administration of esketamine at 0.3 times the exposure of the MRHD of 84mg/day. The studies showed skeletal malformation of the offspring at maternally toxic doses when the drug was administered with a No Observed Adverse Effect Level (NOAEL).
A study was done on 201 pregnant women with a depressive disorder who euthymic and pregnant while taking antidepressants. The women who discontinued treatment during pregnancy were more likely to experience a major relapse than those who continued antidepressants. Healthcare providers should consider the risk of untreated depression before changing or discontinuing treatment during pregnancy and postpartum.
When it comes to contraception, these animal reproduction studies show that embryo-fetal harm may occur when esketamine is administered to a pregnant woman. However, it’s not clear how the findings compare to females of reproductive potential. All pregnancies have a background risk of miscarriages, birth defects, or other adverse outcomes. But for women treated with Spravato, the estimated background risk is unknown. Esketamine is present in human milk but there are no data to show the effects on milk production or on the breastfed infant. Published animal studies report neurotoxicity and patients are advised not to breastfeed during treatment with esketamine.
Females of reproductive potential treated with Spravato should consider planning and prevention of pregnancy during treatment. There’s a pregnancy exposure registry for women exposed to antidepressants during pregnancy. Such patients should be registered with the National Pregnancy Registry for Antidepressants.
Taking Spravato with certain medicines may worsen some conditions or cause severe side effects. Tell your healthcare provider if you take the following medicines:
Central Nervous System Depressants: Use of Central Nervous System (CNS) Depressants such as alcohol, opioids, and benzodiazepines may increase sedation. Patients should, therefore, be closely monitored for sedation with concomitant use or CNS depressants and Spravato.
Psychostimulants: Use of Spravato with psychostimulants such as modafinil, amphetamines, armodafinil, and methylphenidate may increase blood pressure.
Monoamine Oxidase Inhibitors (MAOIs): There’s also the risk of increased blood pressure when Spravato is used concomitantly with monoamine oxidase inhibitors.
It’s therefore important to inform your healthcare provider about all the medicines that you take, including over-the-counter medicines, prescription drugs, herbal supplements, vitamins as well as illegal drugs or controlled substances.
Finding Help for a Spravato Lawsuit Near Me
If you or a loved one has been treated with Spravato and have suffered from adverse complications related to the medicine, contact Consumer Alert Now. We help connect individuals who’ve suffered injuries, damages, and adverse side effects of potentially harmful drugs with experienced mass tort attorneys across the United States. We can connect you with an attorney who’ll fight for your rights and ensure that you receive full compensation for the damages caused by the drug. For a free case review or consultation with our defective drug attorney, contact us today at 800-511-0747.