This review critically examines the clinical utility, efficacy, and tolerability of fluphenazine long-acting injectable (LAI) relative to contemporary alternatives. It further evaluates whether fluphenazine LAI confers substantive advantages over other available formulations for the management of schizophrenia, particularly in light of its long-standing use.

Nicolau syndrome is a rare condition characterized by severe pain at the site of injection, leading to ulceration and necrosis of the local tissues. Its presentation is usually acute. Nicolau syndrome is commonly seen in patients after intramuscular, intra-articular, or subcutaneous injections of non-steroidal anti-inflammatory drugs, antiepileptics, antipsychotics, antibiotics, antihistamines, and corticosteroids. Immediate diagnosis and management of this syndrome are of great importance. We herein report a rare presentation of Nicolau syndrome in a 36-year-old married male who suffered from paranoid schizophrenia for the past 3 years. The patient presented with dull pain, mild swelling, and necrotic ulceration over the injection site after receiving intramuscular fluphenazine. The patient underwent wound debridement and was given prophylactic antibiotics. Despite a wide range of therapeutic options for the management of Nicolau syndrome described in the literature, there exist limited guidelines for its management.

Schizophrenia is a severe chronic mental illness characterised by impaired emotional and cognitive functioning. To treat this condition, antipsychotics are available in limited dosage forms, mainly oral and injectable formulations. Although injectable antipsychotics were designed to enhance adherence, they are invasive, painful and require a healthcare professional to be administered. To overcome such administration issues, extensive research has been focused on developing transdermal antipsychotic formulations. In this work, three microneedle (MN) systems were developed to deliver fluphenazine (FLU) systemically. A decanoic prodrug of FLU called fluphenazine decanoate (FLUD) was used in two of the MN formulations due to its high lipophilicity. FLU-D was loaded into dissolving MNs and nanoemulsion (NE)-loaded MNs. The parent drug FLU was loaded into poly(lactic-co-glycolic acid) (PLGA)-tipped MNs. All MN systems were characterised and evaluated in vitro and in vivo. The in vivo evaluation of the three developed MN systems showed their ability to deliver FLU into the systemic circulation, as the Cmax of FLU-D dissolving MNs was 36.11 ± 12.37 ng/ml. However, the Cmax of FLU-D NE loaded dissolving MNs was 12.92 ± 6.3 ng/ml and for FLU-PLGA tipped MNs was 21.57 ± 2.45 ng/ml. Compared to an intramuscular (IM) injection of FLU-D in sesame oil, the relative bioavailabilities were 26.96 %, 21.73 % and 42.45 % for FLU-D dissolving MNs, FLU-D NE dissolving MNs and FLU-PLGA tipped MNs, respectively. FLU plasma levels were maintained above the minimum human therapeutic limits for a week. Consequently, these various MN formulations are considered to be a viable options for the transdermal delivery of fluphenazine and its prodrug. The three MN systems developed offer patients a user-friendly, painless, and convenient long-acting delivery method for FLU. Reducing dosing frequency and using less invasive drug administration methods can enhance adherence and foster positive therapeutic outcomes. This study demonstrates the capability and adaptability of MNs technology to transport hydrophobic molecules from the skin to the systemic circulation.

Fluphenazine (FPZ) decanoate, an ester-type prodrug formulated as a long-acting injection (LAI), is used in the treatment of schizophrenia. FPZ enanthate was also developed as an LAI formulation, but is no longer in use clinically because of the short elimination half-life of FPZ, the parent drug, after intramuscular injection. In the present study, the hydrolysis of FPZ prodrugs was evaluated in human plasma and liver to clarify the reason for this difference in elimination half-lives. FPZ prodrugs were hydrolyzed in human plasma and liver microsomes. The rate of hydrolysis of FPZ enanthate in human plasma and liver microsomes was 15-fold and 6-fold, respectively, faster than that of FPZ decanoate. Butyrylcholinesterase (BChE) and human serum albumin (HSA) present in human plasma, and two carboxylesterase (CES) isozymes, hCE1 and hCE2, expressed in ubiquitous organs including liver, were mainly responsible for the hydrolysis of FPZ prodrugs. FPZ prodrugs may not be bioconverted in human skeletal muscle at the injection site because of lack of expression of BChE and CESs in muscle. Interestingly, although FPZ was a poor substrate for human P-glycoprotein, FPZ caproate was a good substrate. In conclusion, it is suggested that the shorter elimination half-life of FPZ following administration of FPZ enanthate compared with FPZ decanoate can be attributed to the more rapid hydrolysis of FPZ enanthate by BChE, HSA and CESs.

Sinus tachycardia and orthostatic hypotension have been so far reported among the negative cardiovascular complications of antipsychotic agents. This study aimed to report a case with bradycardia induced by fluphenazine decanoate administration. The patient was a 29-year-old man, admitted to the general teaching hospital in Sari, Iran, with a complaint of abdominal and gastric pain as well as weight loss following 7 months of fasting based on religious delusions. The patient developed bradycardia, 36 hours after fluphenazine decanoate administration. His pulse rate was also 46 beats per min (bpm). The antipsychotic medication was thus held and the patient did not take any drugs. On the 21st day after discontinuing this agent, the pulse rate reached 70 bpm. This case report notifies that much more attention should be paid to all patients before starting fluphenazine decanoate administration, and close cardiac monitoring must be done.

Artificial insemination, performed to maximize genetic diversity in populations of zoo-housed animals, requires intensive management and has been associated with low success rates in fractious species. In these species, stressors, such as frequent handling, may impact fertility. Long-acting neuroleptic pharmaceuticals (LANs) can attenuate the stress response to handling, but may also disrupt ovulation in some species, compromising their use for artificial insemination. Therefore, the goal of this study was to determine whether LANs may be used to mitigate stress during reproductive management in wild equids without inhibiting ovulation. Six female Persian onagers (Equus hemionus onager) were treated with fluphenazine decanoate (FD; 0.1 mg/kg IM) or saline control in a random crossover design study. Urinary cortisol, progesterone, estrogen metabolites and behavior were monitored, and follicular dynamics were examined using ultrasonography until ovulation. Onagers demonstrated significantly lower cortisol concentrations (P = 0.03) when treated with FD (6.61 ± 3.26 ng/mg creatinine) compared to saline (9.73 ± 3.19 ng/mg creatinine). Overall, there were no differences in peak estrogen (P = 0.51) or progesterone (P = 0.38) concentrations between the two groups, and all animals ovulated within the expected time frame following FD treatment. However, some onagers exhibited only minor reductions in cortisol secretion and one treated female demonstrated a suppressed luteal progesterone peak, indicating a possible reproductive cost to FD administration. While FD may be useful for highly fractious equids for which the stress of handling delays or inhibits ovulation, these results warrant further investigation of dosing.

Fluphenazine decanoate is a long-acting phenothiazine neuroleptic that attenuates the stress response and may be useful during intensive handling for reproductive procedures in non-domestic ungulates. However, phenothiazines are also associated with elevated serum prolactin, which can suppress fertility in some species. For this study, 10 female domestic goats were used as a model for non-domestic caprids to test effects of fluphenazine decanoate on serum cortisol and reproductive cyclicity following estrus synchronization. Two identical trials were conducted during the breeding season, employing a random crossover design. First, females underwent estrus synchronization using a 14-day treatment with progesterone (330 mg; CIDR). After 7 days of CIDR exposure, the treatment group (n = 5) received fluphenazine decanoate (1.0 mg/kg IM) and controls (n = 5) received an equivalent volume of 0.9% saline IM. At CIDR withdrawal (Day 14), animals received 125 mg cloprostenol sodium to lyse any luteal tissue and synchronize estrus. Blood was collected every 2 hr from 36 hr after CIDR withdrawal until 24 hr after standing estrus, or up to 5 days to monitor stress and reproductive hormones. Serum cortisol, prolactin, luteinizing hormone (LH) and progesterone concentrations were determined by enzyme immunoassay. While treatment with fluphenazine was associated with lower cortisol concentrations compared to controls (P = 0.001), 4 of the 10 treated animals experienced elevated serum prolactin, suppression of the LH surge and inhibition of ovulation. These findings suggest that long-acting neuroleptic drugs reduce the adrenal stress response, but may interfere with reproductive responses and negatively influence breeding success.

Fluphenazine, a potent antipsychotic used to treat schizophrenia in humans, is used in racehorses as a performance-enhancing drug, and for that reason it has been banned by the Association of Racing Commissioners International. A liquid chromatography-tandem mass spectrometry method for detecting and quantitating fluphenazine in equine serum was developed and validated. The method was then employed to quantitate fluphenazine in serum samples collected from three study horses after intramuscular injection of fluphenazine decanoate. Stability testing showed that fluphenazine is stable in unextracted and processed samples as well as samples that have been subjected to up to three freeze-thaw cycles. The limit of detection and lower limit of quantitation of fluphenazine were determined to be 0.05 and 0.1 ng/mL, respectively. Precision was evaluated based on one-way analysis of variance of replicate quality control samples and was determined to be 27.2% at the 0.2 ng/mL level and 18.1% at the 2 ng/mL level. Bias was determined to be 0.55% at the 0.2 ng/mL level and 3.66% at the 2 ng/mL level. In two of three horses, fluphenazine was detected in serum up to 14 days post-administration. The highest detected concentration of fluphenazine in serum was 1.4 ng/mL.

Long-term follow-up data of patients with schizophrenia on depot antipsychotics have been few and the longest follow-up period has been up to 7 years. We carried out a systematic chart review to examine 10-year outcomes for outpatients with schizophrenia who were receiving a conventional depot antipsychotic. Maintenance of outpatient status for 10 years was considered as a favorable outcome. From the initial sample of 1587 outpatients, 90 patients who were receiving a depot antipsychotic were included in this study (mean±SD, age 44.0±13.0 years; men, N=54). Haloperidol decanoate, fluphenazine decanoate, fluphenazine enanthate, and haloperidol decanoate plus fluphenazine enanthate were used in 53 (58.9%), 29 (32.2%), seven (7.8%), and one (1.1%) patients, respectively. These depot antipsychotics accounted for 36.9% of the total antipsychotic dosage on average. Seventeen patients (18.9%) successfully maintained outpatient status for 10 years. The most frequent reason for dropout was 'hospitalization' (N=49, 54.4%), followed by 'referral to another clinic/hospital' (N=9, 10.0%) and 'side effects' (N=7, 7.8%). As only 36.9% of the chlorpromazine equivalents were administered through depot antipsychotics, it is difficult to draw any firm conclusion. Still, the data suggest that even depot antipsychotics may not sufficiently prevent relapse in the treatment of schizophrenia.