Fluphenazine dosage

FLUPHENAZINE HYDROCHLORIDE Individualize dosage. The oral dose is approximately 2 to 3 times the parenteral dose. Institute treatment with a low initial dosage increase as necessary. Therapeutic effect is often achieved with doses... 

For psychotic patients stabilized on a fixed daily dosage of orally administered fluphenazine, conversion from oral therapy to the long-acting injectable fluphenazine decanoate may be indicated. 

This helps to determine the response to fluphenazine and to establish appropriate dosage. 

Once conversion to fluphenazine decanoate is made, careful clinical monitoring of the patient and appropriate dosage adjustment should be made at the time of each injection. 

Severely agitated patients - Initially treat with a rapid-acting phenothiazine. When acute symptoms subside, administer 25 mg of the fluphenazine decanoate adjust subsequent dosage as necessary. 

Poor risk patients - In poor risk patients (known phenothiazine hypersensitivity or with disorders predisposing to undue reactions), cautiously initiate oral or parenteral fluphenazine. When appropriate dosage is established, give equivalent dose of fluphenazine decanoate. 

A high risk of relapse is inherent to schizophrenic psychoses. A relapse is often triggered by emotional stress. It is very important to prevent a relapse by either maintaining low-dose oral medication or by switching to a depot antipsychotic. In some cases, this cannot be avoided. Especially when compliance is a problem, a depot medication may help to keep the patient free of psychotic symptoms. Frequently used depot antipsy-chotics are haloperidol-decanoate, fluphenazine-decanoate, and fluspirilene, which are given in relatively low dosages (see Table 41.4). In EOS, relapse prevention is more important than in adulthood, as the majority of patients have not yet finished school or started a professional career. 

Case Example Because of a patient s partial response to 5 months of clozapine therapy at 600 mg/day, risperidone was added for augmentation (started with 0.5 mg b.i.d. and increased to 1 mg b.i.d. after 1 week). Before this addition, the clozapine plasma level was 344 ng/mL, but after 2 weeks of risperidone augmentation, the level was elevated to 598 ng/mL with no adverse effects and substantial clinical benefit. In another report, there was an increase in the steady-state plasma levels of clozapine (675 mg/day) and its active metabolite norclozapine after the addition of risperidone 2 mg/day in a patient treated for 2 years. Before the addition of risperidone, her clozapine and norclozapine levels were 829 and 1,384 ng/mL, respectively. Two days after risperidone was added, these levels rose to 980 and 1,800 ng/mL. Clozapine dosage was reduced to 500 mg/day, and after 5 days of combined treatment with 4 mg/day of risperidone, the clozapine and norclozapine levels were 110 and 760 ng/mL, respectively. Aside from some mild oculogyric crises, she had no symptoms of clozapine toxicity or clinical changes during the period of cross-tapering. In another case, risperidone was added to clozapine because the patient had relapsed after discontinuation of fluphenazine and had not responded to clozapine. The addition of risperidone resulted in an acute remission of psychosis ( 100). 

Quitkin F, Rifkin A, Klein DF. Very high dosage vs. standard dosage fluphenazine in schizophrenia a double-blind study of nonchronic treatment-refractory patients. Arch Gen Psychiatry 1975 32 1276-1281. 

Kissling W, Moller HJ, Walter K, et al. Double-blind comparison of haloperidol decanoate and fluphenazine decanoate effectiveness, adverse effects, dosage and serum levels during a six months treatment for relapse prevention. Pharmacopsychiatry 1985 18 240-245. 

Because of increased responsiveness to all these drugs, dosage should usually be started at a fraction of that used in young adults. The half-lives of some phenothiazines are increased in the geriatric population. Thioridazine s half-life, for example, is more than doubled. Plasma protein binding of fluphenazine is reduced, which results in an increase of the free drug total drug ratio. 

Worsening parkinsonism was observed in two patients after treatment with olanzapine 5 mg/day (114). In contrast, coarse tremors induced by fluphenazine or haloper-idol disappeared in three patients within days of the start of treatment with olanzapine (10 mg/day), without discontinuation or reduction in the dosage of fluphenazine or haloperidol (115). Olanzapine is active at muscarinic cholinergic receptors, which may account for the observed suppression of neuroleptic drug-induced tremor however, two of the three patients had been taking ben-zatropine, an antagonist at muscarinic acetylcholine receptors, with little tremor relief, suggesting that olanzapine could suppress tremor by means of an action other than muscarinic blockade. 

The rate-determining step in the absorption of dmg esters such as fluphenazine decanoate (which has an aqueous solubility of about 1 part per million) is the hydrolysis of the dmg at the surface of the oil droplet. Hydrolysis of the fluphenazine decanoate to its soluble alcohol therefore depends on the state of dispersion and surface area of the droplets. Dispersing the droplets by mbbing the site of injection or by violent exercise can result in excessive dosage, with toxic effects. Exercise also causes increased blood flow and, as absorption is a dynamic process requiring the sweeping away of the dmg from the localised absorption site, this increased flow increases the rate of dmg dispersal. 

Of the numerous phenothiazines possessing piperazinylpropyl side-chains, fluphena-zine has been the most studied in terms of its pharmacokinetic properties. The apparent reason for the interest in fluphenazine is that it is available in both oral and depot injectable dosage forms. Oral fluphenazine experiences extensive first pass metabolism (419-422) to form numerous metabolites, all of which are less active than the parent drug (410, 420-426). A distribution study of orally administered fluphenazine using radioimmunoassay established that brain concentrations of fluphenazine exceeded plasma concentrations by 10 to 27 times (420). The inactive sulfoxide was the major metabolite found in brain, while brain levels of 7-hydroxy-fluphenazine and fluphenazine-N-oxide were very low (420). It was concluded that metabolites do not contribute to the pharmacology of fluphenazine and that only the plasma level of the parent drug needs be monitored for correlation to therapeutic response. 

A comparison of biotransformation patterns in patients receiving oral fluphenazine versus intramuscularly injected fluphenazine decanoate revealed a significant first pass effect (422,427). Thus, plasma ratios of fluphenazine sulfoxide and 7-hydroxy-fluphenazine to fluphenazine were much higher after oral administration compared with intramuscular administration of fluphenazine decanoate. The plasma ratios of fluphenazine-N-oxide to fluphenazine did not differ between the two dosage forms. In a study measuring fluphenazine serum levels during reduced dose fluphenazine decanoate maintenance therapy at two dose levels, it was determined that serum levels could be monitored at maintenance doses (429,430). 

I Drug-Drug Interactions. Carbamazepine induces the hepatic cytochrome P450 isoenzymes (1A2, 3A4, 2C9/10, and 2D6), which increases the metabolism of many medications, such as anticonvulsants (i.e., lamotrigine, topiramate, and valproate), antidepressants (i.e., tricyclics and bupropion), antipsychotics (i.e., clozapine, haloperi-dol, fluphenazine, olanzapine, and thiothixene), benzodiazepines, oral contraceptives, and protease inhibitors. " Women who receive carbamazepine require higher dosages of oral contraceptives or alternative contraceptive methods." ... 

For example, fluphenazine (No. 8) can be useful in daily doses as low as 2 mg. The derivatization of this compound as long-chain fatty acids, such as the decanoate and enan-thate, affords pro-drugs whose oleaginous solutions, on intramuscular injection of as little as 12.5 mg, can produce sustained clinical effects for as long as four weeks. Such a dosage form offers a distinct advantage for maintenance therapy for noncompliant patients. 

Except for the enanthate and decanoate forms of fluphenazine and haloperidol decanoate, dosage can be given intramuscularly up to every 6 hours for agitated patients. Haloperidol lactate has been given intravenously this is experimental. 

A schizophrenic patient failed to respond to fluphenazine, diazepam, clobazam and lormetazepam having taken the eombination for several weeks. The fluphenazine was stopped and clozapine started at a dose of 25 mg at noon and 100 mg at night. Toxic delirium and severe hypersalivation developed 3 hours later. The patient collapsed (systolic blood pressure 50 mmHg, diastolic blood pressure unrecordable) and stopped breathing. Resuscitation was started, and the patient remained unconscious for 30 minutes. After a few drug-free days clozapine 12.5 mg was successfully re-introduced, and very slowly titrated upwards a low benzodiazepine dosage was also given. ... 

When the occurrence of flip-flop kinetics is not recognised it may compromise the interpretation of results from studies on the pharmacokinetic behaviour of slow release dosage forms. Flip-flop pharmacokinetics may occur with any extravascularly administered parenteral slow release dosage form. Intramuscular depot injectimis of antipsychotics such as fluphenazine decanoate, haloperidol decanoate or flupenthixol decanoate show this behaviour. It also occurs after the administration of oral slow release products of active substances such as isoxuptine, carbamazepine, diclofenac, valproic acid, morphine and theophylline. 

---