Preparat: Abilify, ABILIFY MAINTENA, Abilify Maintena Kit, Aripiprazol Ebb, Aripiprazol Krka, Aripiprazol STADA, Aripiprazole Accord, Aripiprazole Accord Healthcare, Aripiprazole Aristo, Aripiprazole Medical Valley, Aripiprazole Sandoz, Aripiprazole Teva, Aripiprazole Zentiva
ATC kod: N05AX12
Substanser: aripiprazol, aripiprazolmonohydrat
Exponeringen för aripiprazol kan i genomsnitt förväntas bli något högre hos kvinnor än hos män efter administrering av lika stora doser. Detta beror sannolikt främst på könsassocierade viktskillnader. Det saknas hittills belägg för att skillnaden medför terapeutiska konsekvenser vid behandling av schizofreni. Dock har bättre behandlingseffekter indikerats vid affektiva tillstånd med vissa symtom hos kvinnor. Emellertid gäller det endast enstaka studier med tveksamt bevisvärde.
Män förefaller i högre utsträckning än kvinnor utveckla låga prolaktinnivåer vid aripiprazolbehandling, sannolikt till följd av könshormonella skillnader.
En högre frekvens av rapporterade hemodynamiska och gastrointestinala biverkningar har rapporterats för kvinnor, men kontrollerade långtidsstudier som belyser den eventuella kliniska relevansen av detta har inte identifierats.
A higher exposure of aripiprazole and its active metabolite dehydro-aripiprazole was noted in female versus male subjects after similar oral doses according to data presented by the manufacturer . Approximately 30-40% higher mean values of Cmax and AUC were reported respectively, for both the parent compound and the metabolite . A large part of this difference might have been attributable to sex-related differences in weight, which was also indicated by pharmacokinetic analyses from six bioequivalence studies comprising 148 healthy volunteers (85 men, 63 women) . Of note, the differences in mean exposure (AUC, Cmax) between male and female subjects in the bioequivalence studies were small (<15 % difference in unadjusted Cmax and AUC, and ≈ 7 % difference after adjusting for weight) and arguably clinically insignificant .
No dosage adjustment based on patient’s sex is recommended in the drug label information [1, 3]. Interestingly, no dosage adjustment based on weight is recommended either, which may result in higher exposures in women as a consequence of lower average body weights. The magnitude and clinical significance of differences in exposure should be regarded as uncertain and may be influenced by several other factors. Interindividual variability in cytochrome P450 2D6 and 3A4 activity may be more important than sex differences regarding aripiprazole pharmacokinetics . In light of these different sources of pharmacokinetic variability, the potential value of therapeutic drug monitoring should be considered.
No sex-related differences in therapeutic response were evident from subgroup analyses based on the pivotal clinical trials of aripiprazole for the treatment of schizophrenia and bipolar mania, respectively, according to the pharmaceutical company .
In a very short-term (24 hour), open-label trial including acutely agitated patients (112 men, 89 women) with schizophrenia or a manic/mixed episode of type 1 bipolar disorder, a slightly higher reduction of excitatory symptoms specifically (PANSS-EC total score and selected individual components) was noted in women than in men receiving similar doses of aripiprazole . The difference between the sexes was statistically significant but small (71% vs. 67% reduction in PANSS-EC total score, respectively) and should arguably be interpreted with caution.
According to the U.S. drug label information, a smaller mean reduction in MADRS total score was noted in men than in women treated with adjunctive aripiprazole for major depressive disorder . This appears to be based on a subgroup analysis from a short-term (6-week) double-blind, multicenter RCT (133 men, 225 women) . However, no sex-related efficacy difference was demonstrated in a later, similar trial (127 men, 254 women) . It should be noted that major depressive disorder is not an approved indication for aripiprazole in Europe.
In relation to other antipsychotic agents, aripiprazole is generally accepted to be less prone to cause hyperprolactinemia , a well-characterized antidopaminergic side effect. On account of its partially D2-agonistic properties, aripiprazole use has in fact frequently been associated with decreased prolactin levels, especially when switching from other antipsychotic agents in the setting of established hyperprolactinemia [7, 8]. This propensity to decrease prolactin levels appears to be more pronounced in men than in women treated with aripiprazole, conceivably due to stimulatory effects on prolactin secretion exerted by estrogens [8, 9]. The same relationship has been indicated in adolescents (10-17 years of age), where the incidence of hypoprolactinemia was higher in boys than in girls receiving aripiprazole in the context of clinical trials, according to the European product information .
It has been suggested that women might be disproportionately affected by hemodynamic (decreases in blood pressure, increases in heart rate)  and gastrointestinal (nausea/vomiting)  side effects of aripiprazole. The proposed cause would be a higher mean exposure of aripiprazole in women after similar doses (refer to “Pharmacokinetics and dosing” above) [2, 10]. However, these claims are based on reviews of pharmacovigilance reports  prone to several forms of bias, and single-dose observations in healthy volunteers , respectively. Thus, a cautious interpretation is warranted.
No clear evidence of sex-related differences in the incidence of adverse reactions were revealed in subgroup analyses of pivotal clinical trial data, according to the pharmaceutical company .
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Fler kvinnor än män hämtade ut läkemedel innehållande aripiprazol (ATC-kod N05AX12) på recept i Sverige år 2019, totalt 11 938 kvinnor och 10 506 män. Det motsvarar 2,4 respektive 2,0 personer per tusen invånare. Andelen som hämtat ut läkemedel var högst i åldersgruppen 30-44 år hos kvinnor och i åldersgruppen 25-39 år hos män. I genomsnitt var läkemedel innehållande aripiprazol 1,4 gånger vanligare hos kvinnor .
Faktagranskat av: Diana Rydberg, Carl-Olav Stiller
Godkänt av: Karin Schenck-Gustafsson