Deanxit PRAC Safety Review Pits Short-Term Benefit Against Persistent Neurologic Risk

PRAC Initiates Safety Review of Deanxit for Neurological Side Effects

The Pharmacovigilance Risk Assessment Committee (PRAC) has initiated a review of Deanxit, a fixed-dose combination medicine for treating depression and anxiety. This action follows reports of serious neurological and psychiatric side effects in patients, including movement disorders like tremors, stiffness, restlessness, and involuntary movements, as well as memory and thinking problems. Some patients experienced persistent symptoms even after discontinuing treatment. The PRAC will assess all available evidence to investigate the possible causes of these adverse events and determine if further risk reduction measures are necessary.

• PRAC Initiates Deanxit Safety Review: The Pharmacovigilance Risk Assessment Committee (PRAC) has commenced a safety review of Deanxit, a fixed-dose combination drug used for depression and anxiety. This referral was triggered by an increase in reported serious neurological and psychiatric adverse events associated with the medicine.
• Specific Neurological and Psychiatric Side Effects: The reported side effects include various movement disorders such as tremors, stiffness, restlessness, and involuntary movements. Additionally, patients experienced cognitive issues like memory and thinking problems, with some symptoms persisting even after treatment cessation, raising significant safety concerns.
• Investigation and Potential Measures: PRAC's review will involve requesting and assessing all relevant data from the marketing authorisation holders. The committee aims to thoroughly investigate the underlying causes of these reported side effects and evaluate the necessity of implementing further measures to mitigate risks associated with Deanxit.

Understanding Flupentixol/Melitracen's Safety Profile

In refractory chronic cough, short-term oral flupentixol-melitracen (flupentixol 0.5 mg + melitracen 10 mg), one tablet twice daily for two weeks followed by one week of off-treatment safety monitoring, showed a well-tolerated profile. Treatment-emergent adverse events occurred in 51.0% (15/49) of patients in the flupentixol-melitracen group and 34.0% (17/50) in the placebo group. No serious adverse events or treatment-related deaths were reported. All adverse events were mild and resolved after discontinuation. In chronic somatic disease with depression and anxiety, sertraline (75 mg/day) plus deanxit (one piece/day) for 2 weeks showed evidence for similar safety, with the overall safety profile of both groups favorable with no distinct differences. In somatoform pain disorder treated with deanxit, 1 tablet in every morning and lunchtime each day for 8 weeks, there were 3 cases as dizziness, trembling, dry mouth and constipation in the western medication group.

For flupentixol as an antipsychotic, sleep-related tolerability was favorable in a systematic review and network meta-analysis of 87 randomized clinical trials. According to the SUCRAs for insomnia, flupentixol (26 %) and perospirone (22.5%) were associated with a lower risk of somnolence, and the evidence shows that chlorpromazine, clozapine, flupentixol, perospirone, and amisulpride had favorable safety profiles. Extrapyramidal tolerability was less favorable, with EPS scores rather low and Parkinsonism improved in both groups in a randomized, double-blind comparison of flupentixol (4-12 mg/d) versus risperidone (2-6 mg/d), but anticholinergic drugs were prescribed significantly more frequently in the flupentixol group, which generally showed significantly more adverse events. Consistent with this, Second-generation antipsychotics showed a clear advantage over flupentixol concerning extrapyramidal symptoms co-medication.

Isolated neurologic and cardiac risk signals have been reported. Tardive dyskinesia are known to occur commonly among patients receiving neuroleptic drugs for prolonged periods, and a case report describes dyskinetic movements with a single low dose of oral Flupentixol presenting as acute-onset orofacial dyskinesia. With regard to corrected QT (QTc) prolongation propensity, flupentixol was categorized as (mild) among the most frequently redeemed antipsychotic drugs including zuclopenthixol (unknown/mild), flupentixol (mild), levomepromazine (moderate), and quetiapine (moderate/severe), in a Danish register-based cohort of patients co-treated with antipsychotic and diuretic drugs where hyperkalemia (>5.0 mmol/L, HR 2.82 [95% CI 2.25-3.54]), hypokalemia (<3.5 mmol/L, HR 1.59 [95% CI 1.29-1.95]), and high normal potassium levels were associated with increased risk of 6-month all-cause mortality independent of antipsychotic drugs (interaction: P = 0.06).

Challenges in Depression and Anxiety Treatment

Current pharmacologic and psychological interventions for depression, anxiety and related disorders produce meaningful results yet still fall short of being ideal due to limited response and remission rates and tolerability issues. A single course of treatment leaves between one-third and one-half of adolescent patients insufficiently improved and still depressed, with persistent residual symptoms and adherence challenges further limiting effectiveness.

• Incomplete response, remission and residual symptoms: Existing pharmacologic agents bear limited response and remission rates; persistent sleep problems are among the most difficult-to-treat residual symptoms of depression, and many currently available antidepressants have adverse effects on circadian processes, including sleep, and may actually worsen sleep problems.

• Tolerability and metabolic burden: SSRI and SNRI antidepressants are associated with central nervous system and gastrointestinal effects, sexual side effects and suicidality; long-term antidepressant use is associated with weight gain, affecting up to 55-65% of patients, contributing to treatment discontinuation, relapse, and worsened metabolic health outcomes, including increased risk for obesity and type 2 diabetes; tricyclic antidepressants, monoamine oxidase inhibitors, and mirtazapine are associated with the most substantial weight increases; metabolic syndrome is twice more frequent in schizophrenia as compared to the general population and is not correctly assessed and treated; akathisia has been found in 18% of subjects and has been associated with antipsychotic polytherapy.

• Adherence, persistence and treatment discontinuation: Medication is often insufficient, both in respect to dosage and length of time, with lack of adherence to treatment being the most important reason; patient beliefs about the disorder and about antidepressants, including lack of conviction that medication is needed and fear of dependence, have great influence on adherence; presence of sexual side effects may affect compliance and adherence to treatment and promote increased drop-out rates and poor adherence to treatment; adherence to treatment is diminished in subjects who report a subjective negative feeling after treatment intake independent of objective side effects.

• Access barriers to evidence-based psychotherapy: Youth with anxiety and obsessive-compulsive disorder rarely access exposure therapy; identified barriers include transportation, waitlists, and provider availability, cost, travel time, and burden placed on parents to find treatment with limited support; people with major depressive disorder and/or generalized anxiety disorder reported experiencing a large number of barriers that prevented them from finding effective psychotherapy in a timely manner.

Identifying Safety Signals in Depression and Anxiety Trials

Trials in major depressive disorder and generalized anxiety disorder consistently identify nausea as the most frequent treatment-emergent adverse event, with additional class-specific signals involving sexual dysfunction, blood pressure elevation, and discontinuation symptoms. Pregabalin trials in generalized anxiety disorder report transient dizziness and somnolence, while antidepressant trials report gastrointestinal, neuropsychiatric, and cardiovascular events.

• Selective serotonin reuptake inhibitors: Fluoxetine commonly produces nervousness, anxiety, insomnia and headache. Sexual dysfunction is more common with sertraline. Dry mouth can occur from paroxetine, and gastrointestinal effects (cramps, diarrhoea) from sertraline. The incidence of nausea appears to be no greater for any particular drug, especially after several weeks of treatment. Hyponatraemia and extrapyramidal side effects are rare events reported with all SSRIs.

• Escitalopram: Nausea was the only AE with an incidence greater than or equal to 10% and 5 percentage points greater than with placebo during short-term treatment. AEs related to sexual dysfunction were similarly frequent with escitalopram and citalopram, but were higher with paroxetine. The 8 week withdrawal rate due to AEs was higher with escitalopram than with placebo (7.3% vs 2.8%; p < 0.001) but lower than with paroxetine (6.6% vs 9.0%; p < 0.01) or venlafaxine (6.1% vs 13.2%; p < 0.01). Compared with paroxetine, escitalopram resulted in significantly fewer discontinuation symptoms (average increase in Discontinuation Emergent Signs and Symptoms Scale of 1.6 vs 3.9; p < 0.01). Mean weight change after 6 months of treatment with escitalopram (0.58 +/- 2.63 kg) was similar to that with placebo (0.15 +/- 2.33 kg). The incidence of cardiovascular events was similar to that with placebo.

• Duloxetine versus venlafaxine XR: Nausea was the most common treatment-emergent adverse event (TEAE) for both drugs, and was significantly higher with duloxetine 60 mg/day compared to venlafaxine 150 mg/day during the first 6 weeks of treatment (43.6% vs. 35.0%, P0.05). During the taper period, significantly more venlafaxine-treated patients reported discontinuation-emergent adverse events (DEAEs) than duloxetine-treated patients. Significantly more venlafaxine-treated patients (n = 4) than duloxetine-treated patients (n=0, P =.047) experienced sustained elevations of systolic blood pressure during the fixed dosing period.

• Venlafaxine versus placebo: Meta-analysis showed evidence of harm of venlafaxine versus placebo on serious adverse events (risk ratio: 2.66; 95% confidence interval: 1.67-4.25; p < 0.01; 22 trials), mainly due to a higher risk of sexual dysfunction and anorexia. Meta-analysis showed that venlafaxine also increased the risk of several non-serious adverse events: nausea, dry mouth, dizziness, sweating, somnolence, constipation, nervousness, insomnia, asthenia, tremor and decreased appetite.

• Bupropion: The most serious side effect of bupropion is the development of seizures. Additional adverse effects include agitation, dry mouth, insomnia, headaches, migraines, nausea, vomiting, constipation, and tremor. Insomnia has been reported quite frequently. Suspected adverse events reported to medical authorities in the UK or Germany indicate depression to be the most common psychiatric disorder associated with bupropion treatment. Switch to mania or hypomania is very rare, as are psychosis or organic mental disorders. Suicide attempts associated with bupropion use have been reported as possible adverse events.

• Pregabalin in generalized anxiety disorder: Safety and tolerability profiles are favorable, with transient dizziness and somnolence of mild-to-moderate severity being the most commonly reported adverse events. Withdrawal symptoms during a one-week taper phase were mild and were similar after both acute and chronic administration. One case report described a 38-year-old female patient who took up to 800 mg PRG per day, experienced euphoric feelings after PRG intake, increased the daily PRG dosage and consulted other physicians to receive additional PRG prescriptions, and developed a moderate withdrawal syndrome with vegetative symptoms during reduction.

• Other antidepressants: Levomilnacipran most common adverse events were nausea, headache, dry mouth, hyperhidrosis, and constipation, with discontinuation rates of 9% versus placebo (3%). Vortioxetine most common adverse effect is nausea followed by sexual dysfunction, constipation, and vomiting. Vilazodone most common adverse effects were diarrhea, nausea, vomiting, and insomnia. Mirtazapine most common side effect is increased sedation, with additional side effects including increased appetite and weight gain, dizziness, and transient elevations in cholesterol levels and liver function tests. Trazodone most common adverse reaction is drowsiness, followed by dizziness, dry mouth, and nervousness.

Deanxit Review: A Bellwether for Older Psychiatric Combinations

The initiation of a Pharmacovigilance Risk Assessment Committee (PRAC) review into Deanxit, a fixed-dose combination for depression and anxiety, marks a pivotal moment for the pharmaceutical industry and patient care in mental health. This action, triggered by reports of serious neurological and psychiatric side effects, brings into sharp focus the inherent challenges associated with older psychiatric medications, particularly those incorporating first-generation antipsychotics (FGAs).

Deanxit's inclusion of flupentixol, an FGA, is central to these concerns. Research indicates that FGAs are associated with a higher propensity for extrapyramidal symptoms (EPS), such as tremors and stiffness, and can lead to cognitive impairment, especially with prolonged use. Reports of acute-onset dyskinesia even with low doses of flupentixol further underscore these risks. The PRAC's investigation into persistent symptoms post-discontinuation is particularly alarming, suggesting potential long-term neurological sequelae that demand thorough evaluation.

This review carries several strategic implications. For the manufacturer, it signals potential regulatory actions ranging from updated safety warnings to market restrictions or even withdrawal, which could significantly impact revenue and brand reputation. More broadly, it could prompt increased scrutiny on other fixed-dose psychiatric combinations, pushing the industry towards a greater emphasis on robust post-market surveillance and real-world evidence generation. From a clinical perspective, this event may accelerate a shift towards newer antidepressants and anxiolytics with more favorable safety profiles, or even non-pharmacological alternatives, some of which have demonstrated comparable efficacy with fewer adverse events. Ultimately, the Deanxit review serves as a critical reminder of the delicate balance between therapeutic efficacy and patient safety, urging continuous re-evaluation of established treatments in light of evolving safety standards and available alternatives.