Multiple drugs interaction

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An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

• * Drug interaction

A case eport described two patients, of whom, a 66-year-old man developed serotonin syndrome (SS) following concomitant administration of duloxetine, lithium, haloperidol and off-label lopinavir/ritonavir, and a 78-year-old man developed serotonin syndrome following concomitant administration of off-label lopinavir/ritonavir, risperidone and morphine [routes not stated].

Case 1: A 66-year-old man, who had a history of cervical spinal stenosis, hypertension and bipolar disorder, was hospitalised with bilateral pneumonia because of coronavirus disease-19 (COVID-19). He was initiated on off-label treatment with hydroxychloroquine 200mg and lopinavir/ritonavir 400mg/100mg, both two times a day, while continuing his previous duloxetine 120 mg/day and lithium 800 mg/day treatment for bipolar disorder. By day 3, he developed delirium, and haloperidol 1mg two times a day was added to his therapy. For the following 4 days, his level of consciousness declined progressively, in association with urinary retention, high BP, tachycardia and diaphoresis. A neurological examination showed obtundation, with the patient only capable of obeying single orders and emitting unintelligible sounds; multifocal axial, facial and appendicular myoclonus; and generalised hyperreflexia with ankle clonus. His blood creatine kinase and creatinine levels increased from previously normal values, but his lithium level was normal. An electroencephalogram showed diffuse encephalopathy, while brain MRI did not show any remarkable findings. Owing to a suspicion of SS, haloperidol, duloxetine, lopinavir/ritonavir and lithium were stopped. He was treated with cyproheptadine, leading to an improvement of the myoclonus; however, it had to be discontinued because of excessive somnolence. Over the following 10 days, the myoclonus disappeared with steady improvement in his neurological status. A subsequent diagnosis of SS was made, which was thought to be related to pharmacokinetic interaction between duloxetine, lithium, haloperidol and lopinavir/ritonavir.

Case 2: A 78-year-old man, who had a history of diabetic chronic kidney disease, prior colorectal cancer and hypertension, was hospitalised with mild respiratory symptoms secondary to COVID-19. Oxygen and off-label treatment with hydroxychloroquine 200mg plus lopinavir/ritonavir 400mg/100mg, both two times a day, was started. Additionally, he received off-label treatment with 2 doses of interferon β-1b on days 3 and 4, and a single dose of tocilizumab on day 9 because of a sustained fever, progressive dyspnoea, which necessitated a higher oxygen flow with a reservoir, and radiologic deterioration congruous with bilateral pneumonia. By day 10, he developed acute delirium, which necessitated risperidone 1mg two times a day for the following 48 hours and a single administration of morphine 3mg for dyspnoea control. Subsequently, his level of consciousness deteriorated, and he developed hyperthermia, tachycardia and diaphoresis, which was non-responsive to unspecified antipyretics. A neurological examination showed hyperreflexia, confusion, multifocal limb myoclonus of moderate amplitude, ocular clonus and mild cogwheel rigidity of all four limbs. His blood creatine kinase and creatinine level increased from previously normal levels. An electroencephalogram showed diffuse encephalopathy, and his brain CT scan was insignificant. As SS was suspected, risperidone and lopinavir/ritonavir were immediately stopped. He was treated with clonazepam, fluid therapy and active cooling. His symptoms rapidly ameliorated and resolved within the following several days. A subsequent diagnosis of SS was made, which was thought to be related to pharmacokinetic interaction between lopinavir/ritonavir, risperidone and morphine.