Summary

• A potentially fatal symptom complex, sometimes referred to as Neuroleptic Malignant Syndrome (NMS), has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (unstable blood pressure, diaphoresis, and cardiac arrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.¹
• The management of NMS should be started immediately once the syndrome is suspected and includes patient admittance to a well-equipped intensive care unit with circulatory and ventilator support, prompt discontinuation of the offending agent, and symptomatic treatment of the complications, not the syndrome itself.¹
• Based on a review of Janssen Pharmaceuticals’ safety databases for INVEGA SUSTENNA and INVEGA TRINZA through April 30, 2018, NMS was estimated at an incidence rate of 0.044% per year. During the review, one case of NMS was identified among 5008 patients with >1 injection of INVEGA SUSTENNA or INVEGA TRINZA followed for 2271.6 patient-years. This case is summarized below.²
• In addition, four additional cases of NMS in patients receiving INVEGA SUSTENNA are described below.^3-6
• A recent literature search did not identify any relevant citations pertaining to NMS and INVEGA TRINZA or INVEGA HAFYERA.

DOSAGE STRENGTH INFORMATION

Doses of INVEGA SUSTENNA may be expressed in milligram equivalents of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to mg of paliperidone palmitate to reflect the commercially available dosage strengths in the United States. The conversion factor from mg eq to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal 25, 50, 75, 100, and 150 mg eq of paliperidone, respectively.

CASE REPORTS

Netcheva et al (2021)⁶ presented the case of a 54-year-old male patient diagnosed with schizoaffective disorder who was hospitalized after a fall from his bed at home. Initially, the patient’s Glasgow Coma Scale score was 15, temperature was 38.5°C, heart rate was 104, and blood pressure was 100/69 mmHg. While in the emergency department, the patient remained febrile (38.6°C), experienced rigidity with bradykinesia and severe dysarthria, and had an elevated creatine kinase level of 18,000 U/L and nontoxic lithium level of 0.44 mmol/L. He had been treated with INVEGA SUSTENNA for 1 year, at a dose of 234 mg intramuscularly (IM) every 28 days. Due to extrapyramidal symptoms (EPS) of bradykinesia and cogwheel rigidity in the upper extremities and dysarthria, this dose was lowered to 156 mg IM every 28 days 2 months before hospitalization. His most recent dose of INVEGA SUSTENNA, administered 2 weeks before hospitalization, was 156 mg IM. During this time, the patient’s vital signs and creatinine kinase level (50 U/L) were normal. The patient was also treated with lithium for the 2 years before hospitalization, with a dose decrease from 1200 mg daily to 900 mg daily approximately 2 months before hospitalization for renal protection (elevated creatinine level of 105 μmol/L and high normal lithium level of 1.07 mmol/L). The patient experienced improvement 2 weeks before the fall, with a decrease in rigidity and dysarthria and a decrease in creatinine level to 88 μmol/L. The diagnosis of NMS was made during hospitalization, based on the patient’s exposure to antipsychotic medication, fever, rigidity, elevated creatinine kinase level, autonomic instability, and lack of any other explanation for all symptoms. Infection, substance intoxication or withdrawal, structural central nervous system abnormalities, and rheumatological causes were ruled out. The patient was treated with fluid resuscitation, creatinine kinase monitoring, and lithium discontinuation. The creatinine kinase level, dysarthria, and rigidity all subsequently improved. Lithium retrial worsened the patient's dysarthria, increased stiffness, and increased temperature, with subsequent discontinuation again resulting in improvement. During hospitalization, the patient's psychiatric symptoms remained in remission and it was decided to not administer the next scheduled dose of INVEGA SUSTENNA.

The authors concluded that the specific trigger for development of NMS in this patient was unclear. It is possible that the EPS and dysarthria that the patient experienced for 2 months before the onset of NMS may have been subclinical NMS. The fall and time on the floor led to reduced oral intake and mild dehydration, which may have been the trigger for definitive NMS.

Garcia et al (2019)⁵ presented a case of NMS in a 43-year-old incarcerated male with a past medical history of acquired immune deficiency syndrome, polysubstance use disorder, and schizoaffective disorder who was found collapsed in prison with “abnormal muscle movements” 36 hours after he received a dose of INVEGA SUSTENNA to replace his prior therapy of olanzapine. The patient initially had normal vital signs, however he displayed rigidity in his extremities and a Glasgow Coma score of 8. He was given etomidate and succinylcholine, intubated, and transferred to the ICU where he became hyperthermic, hypertensive, tachycardic, and rigid. The patient was treated with bromocriptine and dantrolene and showed an improvement in symptoms during the next 12 hours. However, his symptoms returned sporadically over the next 5 days requiring repeated paralysis and dose escalation of bromocriptine and dantrolene. Throughout the next 9 days, peak paliperidone blood concentrations as measured using liquid chromatography-mass spectroscopy were 37 ng/mL (therapeutic range 20-60 ng/mL) and his olanzapine concentrations declined to an undetectable level. On hospital day 10, the patient returned to baseline mental and physical health. He was tapered from the dantrolene therapy over 7 days, followed by bromocriptine over 14 days. Two months after discharge, the patient exhibited no signs of returned symptoms.

The authors’ concluded that continued exposure to INVEGA SUSTENNA caused NMS with a duration as observed in previous reports and disease manifestations more severe than usual.

Kane et al (2019)² presented one case of NMS in a 55-year-old male patient diagnosed with paranoid schizophrenia who participated in a randomized, double-blind, parallel-group study of flexibly dosed INVEGA SUSTENNA versus risperidone long-acting injection. The patient was taking flupenthixol decanoate 15 mg IM every 2 weeks for 6 years which was discontinued 22 days before study randomization. Following oral tolerability testing with paliperidone ER 3 mg daily from day -6 to day -3 of the screening period, the patient received gluteal injections of INVEGA SUSTENNA 78 mg on day 1 and day 8 of the double-blind treatment period. On day 15, the patient was hospitalized with symptoms of confusion and pyrexia and had “trouble relaxing” his muscles; NMS was suspected.  Laboratory results revealed an elevated creatine phosphokinase (5824 U/L [normal range: 55-197 U/L]) and elevated hepatic enzymes (AST 128 U/L [normal range: 12-45 U/L]; ALT 91 U/L [normal range: 7-40 U/L]). Blood pressure and pulse rate were normal. Treatment with INVEGA SUSTENNA was discontinued on day 19 and muscle rigidity was managed with benztropine 1-2 mg/day (days 19-26). Pyrexia was treated with acetaminophen as needed. The patient was withdrawn from the study and flupenthixol decanoate was reinitiated on day 23. On day 28, the patient left the hospital on a ”leave-of-absence” but returned following symptoms of “not feeling well”, disorientation, and fever.  The patient left the hospital again from days 36 to 46 after all evaluations were normal. On day 46 he was discharged from the hospital following complete recovery.  

The investigators concluded that this case of NMS was possibly related to INVEGA SUSTENNA but noted that discontinuation of flupenthixol decanoate 22 days before INVEGA SUSTENNA initiation and oral tolerability testing with paliperidone ER may also be contributory factors.  

Kaur et al (2016)³ presented the case of a 35-year-old male who experienced symptoms of inappropriate antidiuretic hormone (SIADH), NMS, and rhabdomyolysis following treatment with INVEGA SUSTENNA 234 mg IM for an acute exacerbation of his schizoaffective disorder. Two days after injection, the patient was transferred to the ICU following a 5-minute hyponatremic, tonic-clonic seizure that spontaneously resolved. An EEG showed diffuse cerebral dysfunction possibly secondary to the medication effect. Pertinent lab values included: serum sodium 108 mg/dL (normal range: 136-146); serum osmolality 242 mosm/L (normal range: 275-295), urine osmolality 438 mosm/L (range: 50-1200) and anion gap metabolic acidosis pH 7.32 (PCO₂ 30/PO₂ 78/AG 16). A diagnosis of euvolemic hyponatremia and hypo-osmolality secondary to SIADH was made and treated with 3% hypertonic saline at a rate of 50 mL/hour.

On the third day of hospitalization, the patient was observed to have muscle rigidity and fever (additional lab values in Table: Lab Values During Hospitalization). He was intubated and treated with IV normal saline and sodium bicarbonate at a rate of 75 mL/hour which improved sodium levels. The patient was diagnosed with paliperidone-induced SIADH, NMS, and rhabdomyolysis. He was treated with IV dantrolene 100 mg twice daily for two days, bromocriptine 2.5 mg via nasogastric tube three times daily for five days, then once daily for an additional five days, and lorazepam 2 mg IV as needed.  Following two weeks of treatment, the patient’s labs normalized, and he was transferred out of the ICU (see Table: Lab Values During Hospitalization).

The authors concluded that the patient’s history of schizoaffective disorder, use of depot neuroleptics, and catatonia may have predisposed him to NMS.

Langley-DeGroot et al (2016)⁴ described the case of a 61-year-old man who presented with an atypical case of NMS following treatment with INVEGA SUSTENNA for chronic schizophrenia. The patient presented to the hospital following noncompliance with oral risperidone 4 mg/day resulting in a 2-week period of worsening paranoid delusions and auditory hallucinations. Risperidone 4 mg/day was resumed on hospital day 1 (HD1) and his symptoms began to improve. The patient was switched to INVEGA SUSTENNA to improve adherence and prevent future relapses. INVEGA SUSTENNA 234 mg was initiated via gluteal injection on HD5 following discontinuation of oral risperidone on HD4. On the morning of HD6, the patient experienced a presyncopal episode, had a fever of 102°F, and was tachycardic (125 beats/min) with intermittent rigors on exam. All other vitals were normal, and the patient was alert and oriented. Laboratory results revealed leukocytosis (13,700 cells/mm³) and an elevated erythrocyte sedimentation rate (31 mm/h). From HD6 to HD8 temperatures remained elevated, surpassing 104°F despite around-the-clock maximum dosing of acetaminophen and cooling blankets. Creatine kinase (CK) increased to 645 IU/L on HD7. Bromocriptine 2.5 mg every 4 hours was initiated on HD8 for suspected NMS. On HD10 the patient's fever remitted and CK decreased to 78 IU/L; therefore, bromocriptine and acetaminophen were discontinued. While no occult infection was identified, leukocytosis continued, reaching up to 26,100 cells/mm³. On HD15, the patient's leukocyte count decreased to 22,600 cells/mm³ and he was rechallenged with oral risperidone 2 mg/day. Since oral risperidone was tolerated, the dose was increased to 4 mg/day on HD18 and the patient was discharged on HD19.

The authors noted that while the patient did show signs of hyperthermia and autonomic instability throughout his hospital stay, he did not experience some of the typical NMS symptoms such as muscle rigidity, altered mental status, and CK levels >1000 IU/L. However, the authors believe that the high persistent fever coupled with a negative work-up for alternative etiologies (i.e. infection and catatonia) support the NMS diagnosis. They caution that due to the long-acting nature of the drug, a protracted course of NMS may be observed.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 18 April 2024.