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The impracticality of surgically removing intramuscular long-acting injectable antipsychotic medication
YAJEM-56897; No of Pages 2 American Journal of Emergency Medicine xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
The impracticality of surgically removing intramuscular long-acting injectable antipsychotic medication
Keywords: Paliperidone palmitate Resection Plasma concentration
To the Editor, We at Janssen carefully reviewed the report by Omi et al. [1] regarding a patient in Japan with schizophrenia who developed acute circulatory failure and extrapyramidal symptoms following a second gluteal intramuscular injection of paliperidone palmitate and ultimately expired two months later. The authors noted that surgical resection of the subcutaneous and muscle tissue near the potential site of injection did not improve the patient's clinical symptoms. In addition, no paliperidone was found in the resected tissue. We wish to comment on several points made by the authors and to further clarify why resection of injection site tissue is unlikely to be an effective treatment to reduce the exposure to paliperidone and address potential side effects. The same case was reported to Janssen a year prior to publication of the article, and additional information relevant to the assessment of the case was provided. In particular, the patient had been hospitalized for several months for worsening of underlying schizophrenia. The reporter noted that the patient had been taking four oral antipsychotic medications, but due to a stuporous state that made it difficult for the patient to take oral medications, the patient was started on paliperidone palmitate. The patient was also reported to be diabetic and to have a poor nutritional status. The oral antipsychotics were discontinued and a dose of paliperidone palmitate 1-month formulation was administered. The patient was described as much improved afterward. The patient received a second dose, and approximately six days later the patient was transferred to a different hospital for the symptoms cited in the report. Paliperidone palmitate, like several other antipsychotic medications, can be associated with QT interval prolongation, postural hypotension due to alpha adrenergic receptor blockade, and extrapyramidal symptoms related to dopamine receptor blockade. In general, the risk of side effects can increase based on concomitant medications used at a given time and overall physical health. Other than the mention of vasopressors, it is not clear whether the patient received concomitant medications. Similarly, the role of the patient's underlying medical condition is also not clear. The authors cite a publication of fatalities in Japan among paliperidone palmitate treated patients between November 2013 and June 2014 during the early postmarketing phase vigilance (EPPV) period [2]. In the cited analysis and a subsequent publication on the same population [3], multiple underlying conditions, antipsychotic polypharmacy, and other risk factors that may have contributed to the
fatal outcomes were identified. Importantly, neither of these articles concluded that paliperidone palmitate was causally related to the deaths. The blood paliperidone concentrations cited were within the expected range for the dosage of 150 mg eq. administered, which does not support the hypothesis of paliperidone toxicity. After a 2nd dose of paliperidone palmitate 1-month injection, the median Cmax is 50.5 ng/mL, with range of 11.5–232 ng/mL [4]. The highest levels found in this patient were between 40 and 45 ng/mL. The timing of these levels aligns with the expected Tmax for paliperidone palmitate 1-month injections [4]. Notably, when the blood concentration levels decreased, QT interval and extrapyramidal symptoms improved but much of the patient's clinical status remained unchanged, suggesting that other factors may have contributed to the patient's deteriorated condition. Paliperidone palmitate is an aqueous suspension that is poorly soluble in water. When injected intramuscularly, the aqueous portion is rapidly absorbed leaving a small deposit (a few millimeters in diameter) of paliperidone palmitate that is slowly absorbed into systemic circulation which is rapidly hydrolyzed to free paliperidone. Should serious side effects emerge, it is recommended that paliperidone palmitate be discontinued followed by supportive care, including treatment of any concomitant medical conditions. The amount of medication that remains in the injection site tissue is so small in size (a few mm) and would be extremely difficult to locate, even if the site of injection was known. In addition, the tissue resection surgery itself could have potential adverse effects for the patient. As a company that conducts research, manufactures and distributes antipsychotics for the treatment of schizophrenia, including paliperidone palmitate, we at Janssen extend our sympathy to the late patient's family and loved ones. The safety and well-being of patients who use our products are of utmost importance to us, and we understand the difficult and chronic nature of schizophrenia. While we understand that the patient's medical team sought to improve his condition, we believe that resection of tissues to reduce the exposure to paliperidone would not be an effective intervention based on the way the drug is absorbed and metabolized. Edward Kim MD, MBA Janssen Scientific Affairs, LLC, United States Corresponding author at: 1125 Trenton-Harbourton Road, Titusville, NJ 08560, United States. E-mail address: [email protected]. Srihari Gopal MD, MHS Janssen Research and Development, LLC, United States E-mail address: [email protected]. Amy O'Donnell MD Global Medical Safety, Janssen Research and Development, LLC, United States E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ajem.2017.08.012 0735-6757/© 2017 Published by Elsevier Inc.
Please cite this article as: Kim E, et al, The impracticality of surgically removing intramuscular long-acting injectable antipsychotic medication, American Journal of Emergency Medicine (2017), http://dx.doi.org/10.1016/j.ajem.2017.08.012
2
The impracticality of surgically removing intramuscular long-acting injectable antipsychotic medication
Darmendra Ramcharran PhD Global Epidemiology, Janssen Research and Development, LLC, United States E-mail address: [email protected]. Maju Mathews MBBA Janssen Global Medical Affairs, United States E-mail address: [email protected]. Arun Singh MD Janssen Research and Development, LLC, United States E-mail address: [email protected].
References [1] Omi T, et al. The possibility of the treatment for long-acting injectable antipsychotics induced severe side effects. Am J Emerg Med 2017. http://dx.doi.org/10.1016/j.ajem. 2017.04.063. [2] Fujii Y. What lessons should we learn from the death of patients on Xeplion? Psychiatr Neurol Jpn (Seishin Shinkeigaky Zasshi) 2015;117(2):132–45. [3] Pierce P, Gopal S, Savitz A, et al. Paliperidone palmitate: Japanese postmarketing mortality results in patients with schizophrenia. Curr Med Res Opin Jun 05 2016:1–9. [4] Coppola D, Liu Y, Gopal S, et al. A one-year prospective study of the safety, tolerability, and pharmacokinetics of the highest available dose of paliperidone palmitate in patients with schizophrenia. BMC Psychiatry 2012;12:26. http://dx.doi.org/10.1186/ 1471-244X-12-26.
5 July 2017 Available online xxxx
Please cite this article as: Kim E, et al, The impracticality of surgically removing intramuscular long-acting injectable antipsychotic medication, American Journal of Emergency Medicine (2017), http://dx.doi.org/10.1016/j.ajem.2017.08.012
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
The impracticality of surgically removing intramuscular long-acting injectable antipsychotic medication
Keywords: Paliperidone palmitate Resection Plasma concentration
To the Editor, We at Janssen carefully reviewed the report by Omi et al. [1] regarding a patient in Japan with schizophrenia who developed acute circulatory failure and extrapyramidal symptoms following a second gluteal intramuscular injection of paliperidone palmitate and ultimately expired two months later. The authors noted that surgical resection of the subcutaneous and muscle tissue near the potential site of injection did not improve the patient's clinical symptoms. In addition, no paliperidone was found in the resected tissue. We wish to comment on several points made by the authors and to further clarify why resection of injection site tissue is unlikely to be an effective treatment to reduce the exposure to paliperidone and address potential side effects. The same case was reported to Janssen a year prior to publication of the article, and additional information relevant to the assessment of the case was provided. In particular, the patient had been hospitalized for several months for worsening of underlying schizophrenia. The reporter noted that the patient had been taking four oral antipsychotic medications, but due to a stuporous state that made it difficult for the patient to take oral medications, the patient was started on paliperidone palmitate. The patient was also reported to be diabetic and to have a poor nutritional status. The oral antipsychotics were discontinued and a dose of paliperidone palmitate 1-month formulation was administered. The patient was described as much improved afterward. The patient received a second dose, and approximately six days later the patient was transferred to a different hospital for the symptoms cited in the report. Paliperidone palmitate, like several other antipsychotic medications, can be associated with QT interval prolongation, postural hypotension due to alpha adrenergic receptor blockade, and extrapyramidal symptoms related to dopamine receptor blockade. In general, the risk of side effects can increase based on concomitant medications used at a given time and overall physical health. Other than the mention of vasopressors, it is not clear whether the patient received concomitant medications. Similarly, the role of the patient's underlying medical condition is also not clear. The authors cite a publication of fatalities in Japan among paliperidone palmitate treated patients between November 2013 and June 2014 during the early postmarketing phase vigilance (EPPV) period [2]. In the cited analysis and a subsequent publication on the same population [3], multiple underlying conditions, antipsychotic polypharmacy, and other risk factors that may have contributed to the
fatal outcomes were identified. Importantly, neither of these articles concluded that paliperidone palmitate was causally related to the deaths. The blood paliperidone concentrations cited were within the expected range for the dosage of 150 mg eq. administered, which does not support the hypothesis of paliperidone toxicity. After a 2nd dose of paliperidone palmitate 1-month injection, the median Cmax is 50.5 ng/mL, with range of 11.5–232 ng/mL [4]. The highest levels found in this patient were between 40 and 45 ng/mL. The timing of these levels aligns with the expected Tmax for paliperidone palmitate 1-month injections [4]. Notably, when the blood concentration levels decreased, QT interval and extrapyramidal symptoms improved but much of the patient's clinical status remained unchanged, suggesting that other factors may have contributed to the patient's deteriorated condition. Paliperidone palmitate is an aqueous suspension that is poorly soluble in water. When injected intramuscularly, the aqueous portion is rapidly absorbed leaving a small deposit (a few millimeters in diameter) of paliperidone palmitate that is slowly absorbed into systemic circulation which is rapidly hydrolyzed to free paliperidone. Should serious side effects emerge, it is recommended that paliperidone palmitate be discontinued followed by supportive care, including treatment of any concomitant medical conditions. The amount of medication that remains in the injection site tissue is so small in size (a few mm) and would be extremely difficult to locate, even if the site of injection was known. In addition, the tissue resection surgery itself could have potential adverse effects for the patient. As a company that conducts research, manufactures and distributes antipsychotics for the treatment of schizophrenia, including paliperidone palmitate, we at Janssen extend our sympathy to the late patient's family and loved ones. The safety and well-being of patients who use our products are of utmost importance to us, and we understand the difficult and chronic nature of schizophrenia. While we understand that the patient's medical team sought to improve his condition, we believe that resection of tissues to reduce the exposure to paliperidone would not be an effective intervention based on the way the drug is absorbed and metabolized. Edward Kim MD, MBA Janssen Scientific Affairs, LLC, United States Corresponding author at: 1125 Trenton-Harbourton Road, Titusville, NJ 08560, United States. E-mail address: [email protected]. Srihari Gopal MD, MHS Janssen Research and Development, LLC, United States E-mail address: [email protected]. Amy O'Donnell MD Global Medical Safety, Janssen Research and Development, LLC, United States E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ajem.2017.08.012 0735-6757/© 2017 Published by Elsevier Inc.
Please cite this article as: Kim E, et al, The impracticality of surgically removing intramuscular long-acting injectable antipsychotic medication, American Journal of Emergency Medicine (2017), http://dx.doi.org/10.1016/j.ajem.2017.08.012
2
The impracticality of surgically removing intramuscular long-acting injectable antipsychotic medication
Darmendra Ramcharran PhD Global Epidemiology, Janssen Research and Development, LLC, United States E-mail address: [email protected]. Maju Mathews MBBA Janssen Global Medical Affairs, United States E-mail address: [email protected]. Arun Singh MD Janssen Research and Development, LLC, United States E-mail address: [email protected].
References [1] Omi T, et al. The possibility of the treatment for long-acting injectable antipsychotics induced severe side effects. Am J Emerg Med 2017. http://dx.doi.org/10.1016/j.ajem. 2017.04.063. [2] Fujii Y. What lessons should we learn from the death of patients on Xeplion? Psychiatr Neurol Jpn (Seishin Shinkeigaky Zasshi) 2015;117(2):132–45. [3] Pierce P, Gopal S, Savitz A, et al. Paliperidone palmitate: Japanese postmarketing mortality results in patients with schizophrenia. Curr Med Res Opin Jun 05 2016:1–9. [4] Coppola D, Liu Y, Gopal S, et al. A one-year prospective study of the safety, tolerability, and pharmacokinetics of the highest available dose of paliperidone palmitate in patients with schizophrenia. BMC Psychiatry 2012;12:26. http://dx.doi.org/10.1186/ 1471-244X-12-26.
5 July 2017 Available online xxxx
Please cite this article as: Kim E, et al, The impracticality of surgically removing intramuscular long-acting injectable antipsychotic medication, American Journal of Emergency Medicine (2017), http://dx.doi.org/10.1016/j.ajem.2017.08.012