Professional Information

Phenothiazines (Systemic)

This monograph includes information on the following:

1) Chlorpromazine
2) Fluphenazine
3) Mesoridazine
4) Methotrimeprazine ^*
5) Pericyazine ^*
6) Perphenazine
7) Pipotiazine ^*
8) Prochlorperazine
9) Promazine ^*
10) Thioproperazine ^*
11) Thioridazine
12) Trifluoperazine
13) Triflupromazine ^†

INN:
Methotrimeprazine— Levomepromazine
Pericyazine—Periciazine

BAN:
Pipotiazine—Pipothiazine
Triflupromazine—Fluopromazine

JAN:
Methotrimeprazine—Levomepromazine
Pericyazine—Propericiazine

VA CLASSIFICATION
Chlorpromazine
Primary: CN701
Secondary: GA609; AU305; CN309; CN206

Fluphenazine
Primary: CN701
Secondary: CN103

Mesoridazine
Primary: CN701

Methotrimeprazine
Primary: CN701
Secondary: CN103; CN309; GA609; CN206

Pericyazine
Primary: CN701

Perphenazine
Primary: CN701
Secondary: GA609

Pipotiazine
Primary: CN701

Prochlorperazine
Primary: CN701
Secondary: GA609

Promazine
Primary: CN701

Thioproperazine
Primary: CN701

Thioridazine
Primary: CN701
Secondary: AU305; CN309

Trifluoperazine
Primary: CN701
Secondary: GA609

Triflupromazine
Primary: CN701
Secondary: GA609

Commonly used brand name(s): Apo-Fluphenazine²; Apo-Perphenazine⁶; Apo-Thioridazine¹¹; Apo-Trifluoperazine¹²; Chlorpromanyl-20¹; Chlorpromanyl-40¹; Chlorpromazine Hydrochloride Intensol¹; Compazine⁸; Compazine Spansule⁸; Largactil¹; Largactil Liquid¹; Largactil Oral Drops¹; Majeptil¹⁰; Mellaril¹¹; Mellaril Concentrate¹¹; Mellaril-S¹¹; Modecate²; Modecate Concentrate²; Moditen Enanthate²; Moditen HCl²; Neuleptil⁵; Novo-Chlorpromazine¹; Novo-Ridazine¹¹; Novo-Trifluzine¹²; Nozinan⁴; Nozinan Liquid⁴; Nozinan Oral Drops⁴; Nu-Prochlor⁸; PMS Fluphenazine²; PMS Perphenazine⁶; PMS Prochlorperazine⁸; PMS Thioridazine¹¹; PMS Trifluoperazine¹²; Permitil²; Permitil Concentrate²; Piportil L⁷; Prolixin²; Prolixin Concentrate²; Prolixin Decanoate²; Prolixin Enanthate²; Serentil³; Serentil Concentrate³; Stelazine¹²; Stelazine Concentrate¹²; Stemetil⁸; Stemetil Liquid⁸; Thorazine¹; Thorazine Spansule¹; Trilafon⁶; Trilafon Concentrate⁶; Vesprin¹³.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^*Not commercially available in the U.S.

^†Not commercially available in Canada.

Category:

Antipsychotic—Chlorpromazine ; Fluphenazine; Mesoridazine; Methotrimeprazine; Perphenazine; Pipotiazine ; Prochlorperazine; Promazine; Thioproperazine; Thioridazine; Trifluoperazine ; Triflupromazine;

Antipsychotic adjunct— Pericyazine;

Antiemetic—Chlorpromazine ; Methotrimeprazine; Perphenazine; Prochlorperazine ; Trifluoperazine; Triflupromazine;

Analgesic—Methotrimeprazine ;

Sedative—Chlorpromazine ; Methotrimeprazine; Thioridazine;

Antidyskinetic (Huntington's chorea) —Chlorpromazine; Thioridazine;

Antineuralgia adjunct— Fluphenazine;

Anesthetic adjunct— Chlorpromazine; Methotrimeprazine (intravenous) ;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Psychotic disorders (treatment)—Chlorpromazine ^{08} ^{42}, fluphenazine ^{78} ^{86}, mesoridazine ^{10} ^{63}, methotrimeprazine ^{58}, perphenazine ^{38} ^{83}, pipotiazine ^{61}, prochlorperazine ^{68} ^{84}, promazine ^{53}, thioproperazine ^{70}, thioridazine ^{06}, trifluoperazine ^{07} ^{75}, and triflupromazine ^{36} are indicated in the management of manifestations of psychotic conditions. They are clearly effective in schizophrenia , and produce a quieting effect in hyperactive or excited psychotic patients.

Note: Thioridazine and mesoridazine are indicated for the management of schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs. Due to the risk of significant, potentially life-threatening, proarrhythmic effects with thioridazine and mesoridazine treatment, it is strongly recommended that a patient be given at least 2 trials, each with a different antipsychotic drug product, at an adequate dose, and for an adequate duration^{109}^{110}.

Note: Mesoridazine has not been proven to be effective in the treatment of refractory schizophrenic patients, as it has not been evaluated in clinical trials.^{110}

—Methotrimeprazine is used in elderly patients for the management of psychosis associated with dementia ^{58}.
—Chlorpromazine ^{22} ^{42}, methotrimeprazine ^{58}, and thioproperazine ^{70} are indicated in the management of manifestations of the manic phase of manic-depressive illness.
—[Chlorpromazine], [fluphenazine ] ^{86}, mesoridazine ^{10}, [ thioridazine] , and [trifluoperazine] ^{75} are used in the treatment of adults with severe behavior problems associated with psychotic disorders who show combativeness and/or explosive, hyperexcitable behavior that is out of proportion to the immediate provocation. Chlorpromazine ^{08} ^{22}, [ mesoridazine] , thioridazine ^{06}, and [ trifluoperazine] ^{75} also are used in the treatment of children with severe behavior problems associated with psychotic disorders who show combativeness and/or explosive, hyperexcitable behavior that is out of proportion to the immediate provocation and in whom other approaches to management have failed ^{89}.
—Long-acting parenteral forms, fluphenazine decanoate ^{50} and enanthate ^{44} ^{60} and pipotiazine palmitate ^{61}, are indicated for the maintenance treatment of nonagitated patients with chronic schizophrenia who are stabilized with shorter-acting neuroleptics and who may benefit from transfer to a longer-acting drug.

Psychotic disorders (treatment adjunct)—Pericyazine is indicated as an adjunctive medication for the control of residual prevailing hostility, impulsivity, and aggressiveness in patients with psychoses ^{59}.

Nausea and vomiting (treatment)—Prochlorperazine ^{68} ^{84}, chlorpromazine ^{08} ^{22} ^{42}, methotrimeprazine ^{58}, perphenazine ^{38} ^{83}, [trifluoperazine ] ^{75}, and triflupromazine ^{36} are indicated in the control of severe nausea and vomiting in selected patients, with prochlorperazine being superior to other phenothiazines.

Pain (treatment)—Methotrimeprazine is indicated for the relief of moderate to severe pain in nonambulatory patients, and for the production of obstetrical analgesia when respiratory depression should be avoided ^{58}.

Sedation—Methotrimeprazine is indicated as a presurgical or obstetrical medication to produce sedation and somnolence ^{58}.
—Chlorpromazine is indicated for relief of apprehension and restlessness before surgery ^{08} ^{22} ^{42}.

Anesthesia, general, adjunct—[Chlorpromazine ] ^{42} and intravenously-administered methotrimeprazine ^{58} are indicated as adjuncts to anesthesia, to increase the effects of anesthetics. The dose of a barbiturate or narcotic should be reduced by at least one half when used with chlorpromazine or methotrimeprazine during surgery or labor ^{42} ^{58}.

Tetanus (treatment adjunct)¹—Chlorpromazine is indicated, usually in conjunction with a barbiturate, for the treatment of tetanus ^{08}.

Porphyria, acute, intermittent (treatment)¹—Chlorpromazine is indicated in the treatment of acute intermittent porphyria ^{08} ^{22}.

Hiccups, intractable (treatment)—Chlorpromazine is indicated for the relief of intractable hiccups ^{08} ^{22} ^{42}.

[Pain, neurogenic (treatment adjunct) ]¹—Fluphenazine has been used as an adjunct to tricyclic antidepressant therapy for some chronic pain states, such as in patients trying to withdraw from narcotics, and in treatment of symptoms of diabetic neuropathy ^{93}.

[Huntington's disease, choreiform movement of (treatment)]¹—Chlorpromazine and thioridazine are effective in reducing choreiform movement in Huntington's disease ^{35} ^{41}, and have been used as alternatives to haloperidol.

Behavior problems, severe (treatment)—[ Chlorpromazine], [fluphenazine] ^{86}, mesoridazine ^{10}, [thioridazine ] , and [trifluoperazine] ^{75} may be used in the treatment of adults with severe behavior problems associated with neurologic disease other than Pretension's disease who show combativeness and/or explosive, hyperexcitable behavior that is out of proportion to the immediate provocation and in whom other approaches to management have failed ^{89}.
—Chlorpromazine ^{08} ^{22}, [ mesoridazine] , thioridazine ^{06}, and [ trifluoperazine] ^{75} also may be used when other approaches to management have failed in the treatment of children with severe behavior problems associated with neurologic disease other than juvenile Pretension's disease and in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders such as impulsivity, mood lability, aggressiveness, short attention span, and poor frustration tolerance. Their use is acceptable only in children who are displaying combative, dangerous, or destructive behaviors ^{89}.

—In exceptional cases, thioridazine ^{06} may be used in the short-term treatment of geriatric patients with multiple symptoms, such as anxiety, agitation, depressed mood, tension, sleep disturbances, and fears. However, because of the anticholinergic effects of thioridazine and the availability of safer antipsychotic medications, its use should be restricted to those patients in whom several other approaches to management have been tried and have failed ^{89}.

—Although prochlorperazine and trifluoperazine have been used in the treatment of nonpsychotic anxiety ^{02} ^{68}, they generally have been replaced by less potentially harmful agents. Their use for this indication may be acceptable only in unusual cases after several non-antipsychotic approaches to treatment have been tried and have failed and the potential benefit outweighs the risks associated with these drugs ^{89}.

—Thioridazine ^{06} has been used in the short-term treatment of adult patients with moderate to severe mental depression with varying degrees of anxiety. However, this medication generally has been replaced by less potentially harmful agents and its use for this indication may be acceptable only in unusual cases after several other approaches to treatment have been tried and have failed ^{89}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Aliphatic: Chlorpromazine ^{13}; methotrimeprazine ^{58}; promazine ^{13} ^{53}; triflupromazine ^{13}
    Piperazine: Fluphenazine ^{13} ^{34}; perphenazine ^{13} ^{38}; prochlorperazine ^{13}; thioproperazine ^{70}; trifluoperazine ^{13} ^{75}
    Piperidine: Mesoridazine ^{10} ^{13}; pericyazine ^{59}; pipotiazine ^{61}; thioridazine ^{13}
Molecular weight—
    Chlorpromazine: 318.87 ^{62}
    Chlorpromazine hydrochloride: 355.33 ^{62}
    Fluphenazine decanoate: 591.8 ^{41}
    Fluphenazine enanthate: 549.70 ^{62}
    Fluphenazine hydrochloride: 510.45 ^{62}
    Mesoridazine besylate: 544.77 ^{62}
    Methotrimeprazine: 328.48 ^{62}
    Pericyazine: 365.50 ^{62}
    Perphenazine: 403.98 ^{62}
    Pipotiazine palmitate: 714.10 ^{62}
    Prochlorperazine: 373.95 ^{62}
    Prochlorperazine edisylate: 564.15 ^{62}
    Prochlorperazine maleate: 606.10 ^{62}
    Prochlorperazine mesylate: 566.2 ^{41}
    Promazine hydrochloride: 320.89 ^{62}
    Thioproperazine mesylate: 638.84 ^{70}
    Thioridazine: 370.59 ^{62}
    Thioridazine hydrochloride: 407.05 ^{62}
    Trifluoperazine hydrochloride: 480.43 ^{62}
    Triflupromazine: 352.43 ^{62}
    Triflupromazine hydrochloride: 388.89 ^{62}

Mechanism of action/Effect:

Antipsychotic—Thought to improve psychotic conditions by blocking postsynaptic ^{18} dopamine D ₂ receptors ^{13} in the mesolimbic area of the brain ^{31} and by producing alpha-adrenergic blockade ^{22} ^{68}.

Antiemetic—Phenothiazines act centrally to inhibit or block the dopamine D ₂ receptors in the medullary chemoreceptor trigger zone (CTZ) and peripherally by blocking the vagus nerve in the gastrointestinal tract. The antiemetic effects of phenothiazines may be augmented by their anticholinergic, sedative, and antihistaminic effects. ^{16}

Analgesic; sedative—Methotrimeprazine raises pain threshold and produces amnesia by suppression of sensory impulses. The alpha-adrenergic blocking effects of phenothiazines may produce sedation and tranquilization ^{70}.

Other actions/effects:

Drug	Action ^*
	Legend: I=Antiemetic II=Anticholinergic III=Extrapyramidal IV=Hypotensive V=Sedative
	I	II	III	IV	V
Aliphatic
Chlorpromazine	S ^{42}	S ^{13} ^{18}	W ^{13} ^{18}–M ^{41}	S ^{13} ^{18}	S ^{13} ^{42}
Methotrimeprazine	S ^{31}	M–S ^{41}	W ^{31}–M ^{41}	S ^{31}	S ^{41} ^{58}
Promazine	M	S ^{41}	W	S	S ^{41}
Triflupromazine	S	S	M ^{13} ^{18}	M ^{18}	M ^{18}–S ^{13}
Piperazine
Fluphenazine	W ^{31}	W ^{13} ^{31}	S ^{13} ^{86}	W ^{13} ^{78}	W ^{78} ^{86}
Perphenazine	S	W ^{13} ^{18}–M	S ^{13} ^{18}	W ^{13} ^{18}	W ^{13} ^{18}–M
Prochlorperazine	S	W ^{41}	S ^{41} ^{84}	W ^{41} ^{84}	W ^{41} ^{84}–M
Thioproperazine	W	W ^{41}	S ^{41} ^{70}	W ^{41} ^{70}	W ^{41} ^{70}
Trifluoperazine	S ^{75}	W ^{13} ^{75}	S ^{13} ^{75}	W ^{13} ^{41}	W ^{41} ^{75}
Piperidine
Mesoridazine	W	M	W ^{18} ^{41}	M ^{13}–S ^{18} ^{47}	S ^{18} ^{41}
Pericyazine	S ^{59}	S ^{41} ^{59}	M	M	S ^{41} ^{59}
Pipotiazine	W	W ^{61}	S ^{61}	W ^{61}	W ^{61}
Thioridazine	W ^{06}	M–S ^{01}	W ^{06} ^{13}	M–S ^{13} ^{18}	M–S

^* S=strong; M=moderate; W=weak

Blockade of dopaminergic ^{18} ^{21} and alpha-adrenergic ^{21} receptors in the tuberoinfundibular system ^{18} by phenothiazines alters the release of hypothalamic and pituitary (hypophyseal) hormones ^{21}, leading to increases in prolactin concentrations that persist throughout treatment ^{06} ^{10} ^{68}.

Electrocardiogram (ECG) changes that reflect abnormal cardiac repolarization, including prolongation of the QT _c interval, have been observed in patients taking phenothiazines ^{94}. Sudden and unexpected deaths due to cardiac arrest have occurred in patients taking phenothiazines who previously had been found to have these ECG changes ^{06} ^{10}. Thioridazine is the phenothiazine most frequently involved in cases of sudden cardiac death ^{94}.

The cough reflex–suppressant effect of phenothiazines may increase the risk of aspiration ^{22} or asphyxia ^{68} ^{83}.

Phenothiazines lower the seizure threshold ^{07}.

Absorption:

Absorption may be erratic and peak plasma concentrations show large interindividual differences ^{96} ^{100}, possibly due to large interindividual differences in extent of first-pass metabolism ^{96}.

Distribution:

Phenothiazines have a large volume of distribution ^{06} ^{84}, readily cross the placenta ^{75} ^{81}, and are distributed into breast milk ^{07} ^{68} ^{81}.

Protein binding:

Very high ^{75} (90% or more) ^{95}.

Biotransformation:

Hepatic ^{13} ^{75} to active and inactive metabolites ^{100}. Because parenteral administration bypasses first-pass metabolism, the proportions of parent drug and metabolites present in the circulation may differ with different routes of administration ^{100}. Depending on the contributions of the parent drug and each metabolite to efficacy and/or adverse effects, these differences in proportion can result in differences in effects, leading the patient to experience the oral and parenteral dosage forms of the same medication differently ^{100}.

Cytochrome P450 2D6 (CYP2D6) has been shown to be involved in the metabolism of perphenazine ^{96} and thioridazine ^{97}.

Mesoridazine is an active metabolite of thioridazine ^{100}.

Onset of action:

Antipsychotic effect:

Gradual (up to several weeks ^{13} ^{22}) and variable between patients ^{61}.

Long-acting parenteral dosage forms:

Fluphenazine decanoate injection: Antipsychotic effects usually begin between 24 and 72 hours after administration and become significant within 48 to 96 hours ^{51}.

Pipotiazine palmitate injection: Antipsychotic effects usually begin within the first 48 to 72 hours after administration and become significant within 1 week ^{61}.

Time to peak effect:

Antipsychotic effect—Approximately 4 to 7 days to achieve steady-state plasma concentrations with oral dosage forms ^{95}, and 4 to 6 weeks with depot dosage forms ^{101}; peak therapeutic effects may take from 6 weeks to 6 months ^{13}.

Antipsychotic and antiemetic effects (perphenazine)—1 to 2 hours after intramuscular injection, maintained for an average of 6 hours ^{83}.

Analgesic effect (methotrimeprazine)—Within 20 to 40 minutes after intramuscular injection, maintained for about 4 hours ^{57}.

Elimination:
    Renal and biliary ^{10} ^{50} ^{63}, with some enterohepatic recycling ^{100}.
    In dialysis—Phenothiazines are not successfully dialyzed ^{08} ^{10} because of their high protein binding and large volume of distribution ^{06}.

Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one phenothiazine may be sensitive to other phenothiazines also ^{06} ^{08} ^{36}.

Tumorigenicity

Phenothiazines produce an elevation in prolactin concentrations, which persists throughout administration. Tissue culture experiments indicate that approximately one third of human breast cancers are prolactin-dependent in vitro , a factor of potential importance if the prescription of these medications is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin concentrations is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic medications. However, neither clinical studies nor epidemiologic studies conducted to date have shown an association between long-term administration of these medications and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time. ^{06} ^{08} ^{10}

Pregnancy/Reproduction
Fertility—
Animal studies with several phenothiazines have shown a decrease in fertility ^{50} ^{57} ^{59}.

Pregnancy—
Phenothiazines are not recommended for use during pregnancy ^{08} ^{68}. Phenothiazines cross the placenta ^{75} ^{81} ^{101}. Although adequate and well-controlled studies in humans have not been done, there have been reports of prolonged jaundice, hyporeflexia or hyperreflexia, and extrapyramidal effects in the neonates of mothers who received phenothiazines during pregnancy ^{07} ^{08} ^{68} ^{101}.

Chlorpromazine: Reproductive studies in rodents have shown a potential for embryotoxicity, increased neonatal mortality, and decreased performance of the offspring in administered tests ^{08} ^{22}. The possibility of permanent neurological damage in offspring of rodent mothers cannot be excluded ^{08}.

Fluphenazine: Withdrawal effects, including severe rhinorrhea, vomiting, respiratory distress, and extrapyramidal effects, have been reported in neonates following in utero exposure to fluphenazine throughout gestation ^{102}. Single injections of the decanoate dosage form during gestation in rabbits and rats revealed no teratogenic effects ^{50}. However, in rabbits, a dose of 5.6 mg per kg of body weight (mg/kg) may have interfered with implantation and also may have contributed to delayed ossification in the fetuses ^{50}.

Mesoridazine: Intrauterine resorptions were increased in rats and rabbits given 70 mg/kg and 125 mg/kg of mesoridazine, respectively ^{10}. However, no drug-related teratology was seen ^{10}.

Methotrimeprazine: Reproductive studies in animals and clinical experience have failed to show a teratogenic effect. However, a possible antifertility effect has been suggested since successive generations of animals administered methotrimeprazine have shown smaller litter sizes than those of controls. ^{57}

Pericyazine: Reproductive studies in rats and rabbits failed to show a teratogenic effect ^{59}. However, in the rats, which were administered pericyazine from 33 days precoitus throughout pregnancy and lactation, the average pairing-to-birth interval was lengthened, indicating a possible antifertility effect ^{59}. In mice administered 5 to 15 mg/kg of pericyazine from 8 to 14 days postcoitus, increased fetal death and delayed ossification were seen ^{59}.

Pipotiazine: No teratogenic effects were seen in reproductive studies in mice, rats, and rabbits ^{61}. However, when pipotiazine was administered to rats (5 mg/kg and 15 mg/kg) and rabbits (10 mg/kg and 20 mg/kg) throughout pregnancy, fetal toxicity, increased fetal resorption, and inhibited intrauterine fetal growth were seen ^{61}.

Thioridazine: Reproductive studies in animals and clinical experience have failed to show a teratogenic effect ^{06}.

Trifluoperazine: Reproductive studies in rats given more than 600 times the human dose showed an increased incidence of malformations and reduced weight and litter size linked to maternal toxicity ^{07}.

All phenothiazines—FDA pregnancy categories are not included in product labeling presently.

Breast-feeding

Phenothiazines are distributed into breast milk ^{08} ^{68} and may cause drowsiness or movement disorders in the nursing infant ^{88}. Breast-feeding while receiving phenothiazines is not recommended ^{81}.

Pediatrics

Children are prone to develop neuromuscular or extrapyramidal reactions ^{68}, especially dystonias, and should be closely monitored while receiving therapeutic doses of phenothiazines. Children with acute illnesses, such as chickenpox, central nervous system (CNS) infections, measles, gastroenteritis, and dehydration, are especially at risk ^{68}.

Geriatrics

Geriatric patients tend to develop higher plasma concentrations of phenothiazines ^{15}. Therefore, these patients usually require lower initial dosage and a more gradual titration of dosage ^{08} ^{13}.

Elderly patients appear to be more prone to orthostatic hypotension ^{08} ^{68} and exhibit an increased sensitivity to the anticholinergic and sedative effects of phenothiazines. In addition, they are more prone to develop extrapyramidal side effects ^{68}, such as tardive dyskinesia ^{08} and parkinsonism ^{06}.

It has been suggested that elderly patients receive half the usual adult dose. Patients with organic mental disorders or acute confusional states should initially receive one third to one half the usual adult dose ^{25}, with the dose being increased no more frequently than every 2 or 3 days, preferably at intervals of 7 to 10 days, if possible. After clinical improvement occurs, periodic attempts should be made to discontinue medication ^{06} ^{15}.

Pharmacogenetics

Cytochrome P450 2D6 (CYP2D6) has been shown to be involved in the metabolism of perphenazine ^{96} ^{99} and thioridazine ^{97}. Approximately 7% of the white population are poor metabolizers of CYP2D6 substrates due to genotype and have reduced clearance and higher plasma concentrations of these medications ^{96} ^{98} ^{99}. Single-dose studies have shown plasma concentrations of perphenazine and thioridazine to be about four times higher in poor metabolizers than in extensive metabolizers ^{96}. However, one study of perphenazine serum concentrations corrected for dose (C/dose) at steady-state showed less variation in perphenazine C/dose between poor metabolizers and extensive metabolizers (twofold) than between individual subjects (thirtyfold) ^{96}.

Dental

The peripheral anticholinergic effects of phenothiazines may decrease or inhibit salivary flow, especially in middle-aged or elderly patients, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort ^{59}.

Extrapyramidal reactions induced by phenothiazines will result in increased motor activity of the head, face, and neck. Occlusal adjustments, bite registrations, and treatment for bruxism may be made less reliable. ^{03}

The leukopenic and thrombocytopenic effects of phenothiazines may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal, and patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Surgical

Patients receiving phenothiazines who must undergo surgery should be closely monitored for hypotension ^{36} ^{61}. Also, dosage reductions of anesthetics and other CNS depressants are recommended ^{36} ^{42} ^{61}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: The isoenzyme cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of perphenazine ^{96} ^{99}, thioridazine ^{97}^{109}, and possibly other phenothiazines ^{104}. Concurrent use of inhibitors of CYP2D6 and phenothiazines may lead to increased phenothiazine plasma concentrations and increased risk of developing adverse effects ^{103}, including changes in cardiac rhythm ^{104}^{109}. Also, phenothiazine use may inhibit the metabolism of other medications that are metabolized by CYP2D6 ^{104}. Therefore, possible interactions between phenothiazines and medications that inhibit CYP2D6 or that are substrates of CYP2D6, other than those listed below, should be considered ^{104}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol or
» CNS depression–producing medications, other (see Appendix II )    (prolonged and intensified CNS ^{06} ^{08} ^{10} and respiratory depression ^{06} ^{10} and increased hypotensive effects ^{08} may occur during concurrent or sequential use ^{07}; dosage reductions may be necessary, except that dosage of anticonvulsant medications should not be decreased ^{22} ^{42})

    (use of a high dose of barbiturate with mesoridazine has resulted in respiratory arrest ^{10})

    (dosage of CNS depressants such as anesthetics, barbiturates, and narcotics should be reduced by 50 to 75% when used with a phenothiazine ^{08} ^{42} ^{58}, except in the case of anticonvulsant use of a barbiturate ^{22})

    (barbiturates ^{81} and carbamazepine ^{47} increase the metabolism of phenothiazines by induction of hepatic microsomal enzymes, thus decreasing plasma concentrations, and possibly the therapeutic effect, of the phenothiazine)

    (alcohol may increase the risk of heatstroke in patients receiving phenothiazines ^{71} ^{74})

Amantadine or
Anticholinergics or other medications with anticholinergic action (see Appendix II )    (anticholinergic side effects of these medications and/or phenothiazines may be intensified ^{81} ^{84}; the hyperpyretic effect of phenothiazines may be potentiated by the loss of sweating as a cooling mechanism ^{71}, possibly leading to heatstroke ^{31}, especially when environmental temperatures are high ^{28}; because of increased risk of paralytic ileus due to decreased intestinal motility, patients should be advised to report occurrence of gastrointestinal problems ^{31} ^{59} ^{84})

    (parenteral methotrimeprazine, used as preanesthetic medication, may be administered concurrently, but with caution, with lowered doses of atropine or scopolamine; tachycardia and a fall in blood pressure may occur, and CNS reactions, such as stimulation, delirium, and extrapyramidal reactions, may be aggravated ^{57})

Amphetamines    (stimulant effects may be decreased when amphetamines are used concurrently with phenothiazines since phenothiazines produce dopamine D ₂ receptor blockade; also, the antipsychotic effectiveness of phenothiazines may be reduced)

Antacids, aluminum- or magnesium-containing or
Antidiarrheals, adsorbent    (ingestion of these medications within 2 hours of a phenothiazine may inhibit the absorption of an orally administered phenothiazine ^{13})

Anticoagulants, oral    (effects may be decreased by phenothiazines ^{22} ^{68})

Anticonvulsants, including barbiturates    (phenothiazines may lower the seizure threshold; dosage adjustment of anticonvulsant medications may be necessary ^{08} ^{68})

    (phenothiazines may inhibit phenytoin metabolism, leading to phenytoin toxicity ^{08} ^{22} ^{68})

» Antidepressants, tricyclic or
» Fluoxetine or
» Fluvoxamine or
» Paroxetine or
» Maprotiline    (concurrent use may prolong and intensify the sedative and anticholinergic effects of either these medications or phenothiazines ^{13}; plasma concentrations of antidepressants and/or phenothiazines may be increased by mutual inhibition of metabolism ^{13} ^{31}^{109}; the risk of neuroleptic malignant syndrome [NMS] may be increased ^{31}; QT interval–prolonging effects of these medications and phenothiazines increase the risk of developing cardiac arrhythmias ^{13}^{109})

» Antithyroid agents    (concurrent use with phenothiazines may increase the risk of agranulocytosis ^{31})

Apomorphine    (prior ingestion of phenothiazine antiemetics may decrease the emetic response to apomorphine ^{59}; also, the CNS depressant effects of phenothiazine antiemetics are additive to those of apomorphine and may induce dangerous respiratory depression, circulatory system effects, or prolonged sleep)

Appetite suppressants    (concurrent use with phenothiazines may antagonize the anorectic effect of appetite suppressants)

Beta-adrenergic blocking agents    (concurrent use of beta-blocking agents, possibly including ophthalmics, with phenothiazines may result in increased plasma concentrations of both medications ^{08} ^{68}^{109} because of inhibition of metabolism; this may result in additive hypotensive effects ^{81}, irreversible retinopathy, cardiac arrhythmias, and tardive dyskinesia ^{20})

    (increases in plasma levels of thioridazine and its metabolites of 50 to 400% and 80 to 300%, respectively, have been reported with concurrent propranolol use ^{06})

Bromocriptine    (increased serum prolactin concentrations induced by phenothiazines may interfere with effects of bromocriptine; dosage adjustments may be necessary )

Diuretics, thiazide    (concurrent use may potentiate orthostatic hypotension ^{08} ^{68}, hyponatremia ^{30}, and water intoxication ^{30}; alternate methods of hypertension control should be considered ^{30})

» Extrapyramidal reaction–causing medications, other (see Appendix II )    (concurrent use with phenothiazines may increase the severity and frequency of extrapyramidal effects)

Hepatotoxic medications, other (see Appendix II )    (concurrent use of phenothiazines with medications known to alter hepatic microsomal enzyme activity may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or with a history of liver disease, should be carefully monitored)

» Hypotension-producing medications, other (see Appendix II )    (concurrent use with phenothiazines may produce severe hypotension ^{19} ^{79} with postural syncope ^{19})

    (the antihypertensive effect of guanethidine may be antagonized by phenothiazines ^{81})

» Levodopa    (antiparkinsonian effects of levodopa may be inhibited when it is used concurrently with phenothiazines ^{81} because of blockade of dopamine receptors in the brain)

» Lithium    (an encephalopathic syndrome has been reported in a few patients receiving lithium concurrently with antipsychotic medications ^{08} ^{68}; symptoms have included weakness, lethargy, fever, tremulousness, confusion, extrapyramidal symptoms, and, in some cases, irreversible brain damage ^{07} ^{08} ^{68}; patients receiving this combination should be monitored closely for evidence of neurological toxicity ^{08} ^{68})

    (concurrent use with chlorpromazine and possibly other phenothiazines may reduce gastrointestinal absorption of the phenothiazine, thereby decreasing its serum concentrations ^{13} by as much as 40%; concurrent use may increase rate of renal excretion of lithium ^{41}; extrapyramidal symptoms may be increased ^{18}; also, nausea and vomiting, early indications of lithium toxicity, may be masked by the antiemetic effect of some phenothiazines)

» Metrizamide    (risk of having seizures is increased with intrathecal metrizamide administration; phenothiazines should be discontinued at least 48 hours before, and not resumed for at least 24 hours following, myelography ^{08})

Opioid (narcotic) analgesics    (in addition to increased CNS and respiratory depression, concurrent use with phenothiazines increases orthostatic hypotension and increases the risk of severe constipation, which may lead to paralytic ileus and/or urinary retention ^{39})

Ototoxic medications, especially ototoxic antibiotics (see Appendix II )    (phenothiazines may mask some symptoms of ototoxicity such as tinnitus, dizziness, or vertigo)

Paroxetine    (the CNS effects of perphenazine were shown to be increased in five subjects when paroxetine was added to perphenazine treatment ^{103}; paroxetine may interfere with the metabolism of phenothiazines through inhibition of CYP2D6 ^{103})

Photosensitizing medications, other    (concurrent use with phenothiazines may cause additive photosensitizing effects)

    (in addition, concurrent use of systemic methoxsalen, trioxsalen, or tetracyclines with phenothiazines may potentiate intraocular photochemical damage to the choroid, retina, or lens ^{12} ^{43})

» QT interval–prolonging medications, other, including:
Astemizole or
Cisapride or
Disopyramide or
Erythromycin or
Pimozide or
Probucol or
Procainamide or
Quinidine    (additive QT interval prolongation may increase the risk of developing cardiac arrhythmias ^{09} ^{13})

Succinylcholine    (concurrent use with methotrimeprazine may cause tachycardia and a fall in blood pressure, CNS stimulation and delirium, and an aggravation of extrapyramidal effects ^{57})

Sympathomimetic agents for cardiovascular use, especially:
» Epinephrine    (the alpha-adrenergic blocking action of phenothiazines may reduce the pressor response to these medications and reduce their duration of action ^{06} ^{27})

    (sympathomimetics that stimulate both alpha- and beta-adrenergic receptors, such as epinephrine, may lead to hypotension and tachycardia when used with a phenothiazine, due to unopposed beta-adrenergic stimulation ^{06} ^{27} ^{53})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Bilirubin tests, urine    (phenothiazine use may produce false-positive results ^{13} ^{81} due to the presence of metabolites in urine ^{81})

» Electrocardiogram (ECG) readings    (prolonged QT _c intervals ^{94}, lowered and inverted T waves, and the appearance of waves that may be bifid T or U waves have been reported ^{06} ^{10} ^{86}; ECG changes seem to be caused by altered repolarization ^{94} and not by myocardial damage ^{06} ^{10} ^{86}; however, deaths, presumably due to cardiac arrest, have occurred in patients who previously had shown these ECG changes during phenothiazine treatment ^{06} ^{10}; ECG changes and sudden death have been seen more frequently with thioridazine use than with use of other phenothiazines ^{94} ^{105}; the predictive utility of monitoring ECGs in patients taking phenothiazines is questionable ^{06} ^{10})

Gonadorelin test for hypothalamic-pituitary gonadotropic function     (phenothiazines may blunt the response to gonadorelin by increasing serum prolactin concentrations ^{48})

Metyrapone test of hypothalamic-pituitary complex    (interference may be caused by reduction of adrenocorticotropic hormone [ACTH] secretion due to phenothiazine use ^{81})

Phenylketonuria (PKU) test    (phenothiazines may produce false-positive results ^{07} ^{08} ^{68})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medicine should not be used when the following medical problems exist:
» Cardiovascular disease, severe hypertension or hypotension ^{06}^{109} or
» CNS depression, severe ^{06} ^{08} ^{10} or
» Comatose states or^{06} ^{08} ^{10}
» Congenital long QT syndrome or^{109}
» History of cardiac arrhythmias or^{109}
» Known genetic defect leading to reduced levels of activity of P450 2D6 isozyme activity ^{109}    (may be exacerbated)

Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active    (CNS depression ^{42} and hypotension ^{38} ^{53} may be potentiated; risk of heatstroke may be increased ^{71} ^{74}; chronic alcohol abusers may be predisposed to hepatotoxic reactions during phenothiazine therapy ^{67}; dosage reduction may be necessary ^{53})

Angina pectoris    (pain may be increased if phenothiazine treatment leads to an increase in physical activity ^{07} ^{75} ^{79})

» Blood dyscrasias    (may be exacerbated ^{42}; treatment may have to be discontinued ^{61})

» Brain damage, subcortical or
» Cerebral atherosclerosis, marked    (a severe hyperthermic reaction may occur, sometimes 14 to 16 hours after phenothiazine administration ^{50} ^{81} ^{86})

Breast cancer    (potentially higher risk of disease progression and possible increased resistance to endocrine and cytotoxic treatment, due to phenothiazine-induced prolactin secretion ^{04} ^{05})

» Cardiac reserve deficiency, such as mitral insufficiency, severe or
» Cerebrovascular insufficiency or
» Pheochromocytoma or
» Renal insufficiency    (severe hypotension is more likely to occur ^{61} ^{68} ^{75} ^{78})

Cardiovascular disease ^{08}    (increased risk of hypotension ^{61} and/or exacerbation of condition by phenothiazine-induced hypotension ^{42} ^{53}; ECG changes related to repolarization have been seen in some patients without cardiovascular disease who were taking phenothiazines ^{38}; myocardial depression, cardiomegaly, congestive heart failure [CHF], and arrhythmias may be induced)

Conditions for which vomiting is a sign, such as:
Brain tumor
Drug overdose
Intestinal obstruction
» Reye's syndrome    (diagnosis may be obscured by the antiemetic effect of phenothiazines ^{08} ^{42} ^{68}; less likely with thioridazine ^{06})

    (increased risk of hepatotoxicity in children and adolescents with Reye's syndrome ^{36})

Glaucoma, or predisposition to    (may be potentiated by anticholinergic effects of phenothiazines ^{08} ^{58} ^{59})

» Hepatic function impairment    (phenothiazines can cause hepatic dysfunction ^{08} ^{58} ^{67})

    (metabolism may be decreased; higher serum phenothiazine concentrations may increase CNS effects ^{03})

    (patients with a history of hepatic encephalopathy due to cirrhosis have increased sensitivity to the CNS effects of phenothiazines ^{08})

Parkinson's disease    (potentiation of extrapyramidal effects ^{70})

Peptic ulcer or
Urinary retention    (may be exacerbated ^{86}; phenothiazines have caused bladder paralysis in some patients ^{78})

Prostatic hypertrophy, symptomatic    (increased risk of urinary retention ^{42} ^{58})

Respiratory disorders, chronic, especially in children    (may be potentiated due to CNS depressant effect of phenothiazines ^{08} ^{22} ^{53}; also, cough-suppressant effects of phenothiazines may be especially problematic in these patients ^{22})

Seizure disorders, or history of    (seizures may be precipitated ^{06} ^{08} ^{70})

» Sensitivity to any phenothiazine, or history of    (may be potentiated upon re-exposure to any phenothiazine in patients with a history of phenothiazine-induced blood dyscrasias, jaundice, or skin reactions ^{06} ^{08} ^{59})

Sensitivity to parabens, sulfites, or tartrazine    (some dosage forms of phenothiazines contain parabens ^{08}, sulfites ^{07} ^{22} ^{83}, or tartrazine [FD&C Yellow No. 5] ^{78})

Caution should also be used in geriatric, emaciated, and debilitated patients, who usually require a lower initial dose ^{08} , and in patients who will be exposed to organophosphate or carbamate pesticides ^{06} ^{10} , extreme heat ^{07} ^{22} ^{68} , or extreme cold ^{81} .

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Abnormal-movement determinations and
» Careful observation for early signs of tardive dyskinesia     (recommended at periodic intervals, especially in the elderly and in patients on high-dose or long-term maintenance therapy; reduction of the phenothiazine dosage, if clinically feasible, will aid in the detection of tardive dyskinesia since the medication may mask the syndrome ^{06} ^{10} ^{78}; since there is no known effective treatment, the phenothiazine should be discontinued, if possible, or the dosage should be reduced at earliest signs, usually fine, worm-like movements of the tongue, to stop further development ^{06} ^{10} ^{59})

    (for institutionalized patients, recommended every 2 ^{54} to 3 ^{90} months during therapy using the abnormal involuntary movement scale [AIMS], and again at 8 to 12 weeks after therapy has been discontinued ^{03})

Blood cell counts and differential in patients with sore throat and fever or infections    (may be required during high-dose or prolonged therapy when symptoms of infection develop; agranulocytosis is most likely to occur between the 4th and 10th weeks of therapy; if significant cellular depression occurs, medication should be discontinued and appropriate therapy initiated; rechallenge in recovered patients will usually cause a recurrence of agranulocytosis; use of alternate neuroleptics, such as haloperidol or thioxanthenes, is recommended ^{24})

Blood pressure measurements    (recommended periodically to detect hypotension; fatal hypotension has occurred with phenothiazine use ^{07})

ECG, baseline measurement    (Patients being considered for treatment with thioridazine should have a baseline ECG performed. Patients with a QTc interval greater than 450 msec should not receive thioridazine. Periodic ECG's during thioridazine treatment may be useful and it should be discontinued in patients who are found to have a QTc interval over 500 msec ^{01})

Hepatic function determinations and
Urine tests for bilirubin and bile    (may be required at periodic intervals during prolonged therapy ^{07} ^{58}, or if jaundice or influenza-like symptoms occur ^{08}, to detect liver function impairment; jaundice is most likely to occur between the 2nd and 4th weeks of therapy and is thought to be a sensitivity reaction ^{08} ^{81}; phenothiazine should be discontinued if bilirubinemia, bilirubinuria, or jaundice occurs ^{08})

Ophthalmologic examinations    (recommended, if possible, prior to initiation of phenothiazine therapy as a baseline; initial screening should include measurement of visual acuity with and without refraction, a color vision test to detect possible central defects, and, if feasible, a slit-lamp microscopy study of the fundus and examination of the visual fields ^{76}. Tests may be required at periodic intervals [usually every 6 to 12 months] ^{03} during high-dose or prolonged therapy, since deposition of particulate matter in the lens and cornea has occurred with some phenothiazines ^{08} ^{38}, especially thioridazine ^{106}; therapy should be discontinued if corneal, retinal, or lens changes are noticed ^{03}; blurred vision, defective color vision, and night blindness are early symptoms of pigmentary retinopathy and may be reversible if the phenothiazine is discontinued in the early stages ^{69})

Phenothiazine concentrations, serum    (although generally not useful in determining dosage ^{18}, determinations may be useful when toxicity ^{13} or poor response ^{13} ^{18} occurs, or when noncompliance is suspected ^{13} ^{18})

» Potassium levels, serum    (patients being considered for thioridazine treatment should have a baseline serum potassium level measurement. Serum potassium should be normalized before starting treatment. Periodic serum potassium levels during thioridazine treatment may be useful ^{109})

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Akathisia ^{06} ^{08} ^{10} (restlessness or need to keep moving)

blurred vision associated with anticholinergic effect ^{10} ^{42}

dystonic extrapyramidal effects ^{08} ^{10} (muscle spasms of face, neck, body, arms, or legs, causing unusual postures or expressions on face; sticking out of tongue; tic-like or twitching movements; trouble in breathing, speaking, or swallowing; twisting movements of body; inability to move eyes)

hypotension ^{08} ^{10} ( fainting)— less common with the piperazine phenothiazines ^{38} ^{75}

ocular changes ^{08}
including deposition of opaque material in lens and cornea ^{06} ^{08} ^{10}
epithelial keratopathy ^{08}
or pigmentary retinopathy ^{06} ^{08} ^{69}( blurred vision; defective color vision ; difficulty seeing at night)

parkinsonian extrapyramidal effects ^{06} ^{08} ^{10} (difficulty in speaking or swallowing; loss of balance control; mask-like face; shuffling walk; stiffness of arms or legs; trembling and shaking of hands and fingers)

tardive dyskinesia ^{08} ^{10} (lip smacking or puckering; puffing of cheeks; rapid or worm-like movements of tongue; uncontrolled chewing movements; uncontrolled movements of arms or legs), or tardive dystonia ^{90} (unusual facial expressions or body positions ; increased blinking or spasms of eyelid ; uncontrolled twisting movements of neck, trunk, arms, or legs)

Note: Hypotension is more frequent in the elderly and at the beginning of treatment, especially if high doses are used ^{59}. Acute hypotensive crisis ^{59} leading to cardiac arrest has occurred rarely ^{06} ^{78}.
Parkinsonian effects occur more frequently in the elderly ^{15}, whereas dystonias occur more often in younger patients ^{15} ^{32} ^{33}. Symptoms may be seen in the first few days of treatment or after prolonged treatment, and can recur after even a single dose ^{23}. Extrapyramidal effects may be dose-related and may decrease with a decrease in dosage ^{61}. The effects are more common with the piperazine phenothiazines ^{38}.
Ocular changes occur more frequently with high-dose or long-term use of phenothiazines ^{06} ^{08}, which are absorbed by melanin in the uveal tract of the eye ^{106}. The deposition of a phenothiazine in the eye eventually can lead to damage of the rods and cones ^{106} and to blindness ^{104}. These ocular changes occur more frequently with thioridazine than with other phenothiazines ^{104} ^{106}. Although the greatest risk occurs with thioridazine doses above 800 mg per day, there have been cases reported with use of lower doses of thioridazine ^{106}.
Tardive dyskinesia is seen more frequently in elderly patients ^{06} ^{10}, patients with brain damage ^{13}, and patients who have received long-term treatment with antipsychotic medications ^{06} ^{08}. However, it can occur in any patient after as few as 3 months of antipsychotic therapy ^{06} ^{08} ^{64}. Tardive dyskinesia can be masked by antipsychotic medication and may become evident after discontinuation of the medication ^{06} ^{08}. The syndrome may be irreversible ^{06} ^{08}.

Incidence less frequent

Difficulty in urinating ^{06} ^{08}

photosensitivity ^{08} (skin rash; severe sunburn)

skin rash ^{06} ^{10} —associated with contact dermatitis (with liquid products) ^{08} , other allergic reaction ^{08} ^{53} , or cholestatic jaundice

Incidence rare

Blood dyscrasias ^{59}
including agranulocytosis ^{06} ^{10} ^{68}
leukocytopenia ^{06} ^{53}
or thrombocytopenia ^{06} ^{53} (sore throat; fever; unusual bleeding or bruising; unusual tiredness or weakness )—more frequent with aliphatic phenothiazines, less frequent with piperazine phenothiazines ^{38} ^{75}

cholestatic jaundice ^{08} ^{58} ^{67} (abdominal or stomach pains ; aching muscles and joints; fever and chills; severe skin itching; yellow eyes or skin ; fatigue; nausea, vomiting, or diarrhea)

dark urine ^{81}

fever, significant ^{38}

melanosis ^{06} ^{08} (tanning or blue-gray discoloration of skin)—more common in females ^{08} and with long-term, high-dose chlorpromazine or thioridazine therapy ^{73} ^{76}

neuroleptic malignant syndrome (NMS) ^{06} ^{10} ^{11} ( difficult or fast breathing; drooling ; fast heartbeat; fever; high or low [irregular] blood pressure; impaired consciousness, ranging from confusion to coma; increased sweating ; loss of bladder control; severe muscle stiffness; trembling or shaking; trouble in speaking or swallowing)

obstipation or paralytic ileus ^{06} (severe constipation)

paradoxical effects ^{38} ^{53}
including aggravation of psychosis ^{38} ^{53} ^{75}
agitation ^{38} ^{75}
bizarre dreams ^{75}
excitement ^{38} ^{75}
and insomnia ^{38} ^{75} (trouble in sleeping)

pneumonia ^{36} (chest pain; shortness of breath)— may be asymptomatic ^{63}

priapism ^{06} ^{08} ^{26} (prolonged, painful, inappropriate penile erection)

QT prolongation and torsades de pointes^{109} (irregular or slow heart rate; recurrent fainting; sudden death)—appears to be dose related

seizures ^{59} ^{68} —more common in patients with a family history of seizures or febrile convulsions ^{53} ^{61}

systemic lupus erythematosus–like syndrome ^{07} ^{51} ^{53} (fever; hair loss; headaches; increased sensitivity of skin to sunlight; joint pain; redness of hands; skin rash; sores in mouth; unusual tiredness or weakness)

temperature regulation dysfunction ^{38} ^{59} ^{68}
including heatstroke ^{06} ^{10} (hot dry skin; inability to sweat; muscle weakness; confusion), or hypothermia ^{50} ( clumsiness; confusion; drowsiness; muscle weakness; shivering)

Note: Agranulocytosis can develop within the first 3 months of treatment, with recovery within 1 to 2 weeks after medication is discontinued; may recur upon rechallenge in recovered patients ^{24}.
Dark urine usually is caused by the presence of phenothiazine metabolites in the urine ^{81}; however, because hepatic dysfunction has been associated with phenothiazines ^{67}, this effect should be reported to the physician.
Significant fever not attributable to any other cause may represent an idiosyncratic reaction to the phenothiazine ^{38} ^{83}. Discontinuing the phenothiazine may be necessary ^{38} ^{83}.
Liver function tests may be abnormal without overt jaundice ^{67}. Jaundice may appear about 2 weeks after severe pruritus and may progress to chronic active hepatitis ^{67}. Discontinuing medication may be necessary ^{67} ^{68}.
Heatstroke, caused by phenothiazine-induced suppression of temperature regulation in the hypothalamus ^{11}, may occur in environmental conditions of high heat and high humidity. The effectiveness of sweating as a cooling mechanism may be reduced by humid conditions and by the anticholinergic effects of phenothiazines or their combination with other anticholinergic medications, such as nonprescription cold medications or antihistamines. Adequate interior environmental temperature control (air-conditioning) must be maintained for institutionalized patients during hot weather because of the increased risk of heatstroke and neuroleptic malignant syndrome (NMS). ^{54} Patients should be advised to stay in cool areas, to avoid exertion and dehydration, and not to take other anticholinergic medications. Phenothiazines may also cause hypothermia ^{50} in cold weather, since the disruption of the thermoregulatory mechanisms results in a poikilothermic state ^{41} ^{71}.
Skin pigmentation changes in melanosis occur on exposed areas of the body ^{08} ^{53} and may fade after discontinuation of the phenothiazine ^{08}.
NMS may occur at any time during neuroleptic therapy and is potentially fatal ^{64}. It is most commonly seen within the first month of therapy ^{91}, after the patient has switched from one neuroleptic to another ^{92}, or after a dosage increase ^{92}. Along with the overt signs of skeletal muscle rigidity, hyperthermia, autonomic dysfunction, and altered consciousness, differential diagnosis may reveal leukocytosis ^{64} ^{92} (9500 to 26,000 cells per cubic millimeter), elevated liver enzyme tests ^{92}, and elevated creatine kinase (CK) ^{64} ^{92}.

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Anticholinergic effects ^{06} ^{08} (constipation; decreased sweating; dizziness [orthostatic hypotension]; drowsiness ^{10}; dry mouth)—less frequent with piperazine phenothiazines ^{75}

nasal congestion ^{06} ^{08}

Note: Drowsiness usually diminishes during the first few weeks of treatment ^{53} ^{58} ^{59} or with a reduction in dosage ^{53} ^{58}.

Incidence less frequent

Changes in menstrual period ^{06} ^{08} ^{10}

decreased sexual ability ^{10} ^{61}

fever, mild, after intramuscular injection of a phenothiazine ^{53} ^{68}

hypertrophic papillae of the tongue ^{86} (rough or “fuzzy” tongue)

increased salivation ^{61} (watering of mouth)

photophobia ^{10} (increased sensitivity of eyes to light)

secretion of milk, unusual ^{06} ^{08} ^{10}

swelling or pain in breasts ^{06} ^{08} ^{10}

weight gain, unusual ^{06} ^{10} ^{42}

Those indicating need for medical attention if they occur after the medication is discontinued
Incidence more frequent

Tardive dyskinesia, persistent ^{06} ^{08} ^{10} ( lip smacking or puckering; puffing of cheeks; rapid or worm-like movements of tongue; uncontrolled chewing movements ; uncontrolled movements of arms or legs ), or tardive dystonia, persistent ^{90} ( muscle spasms of face, neck, body, arms, or legs causing unusual postures or expressions on face; sticking out of tongue; tic-like or twitching movements ; trouble in breathing, speaking, or swallowing; twisting movements of body ; inability to move eyes)

Incidence less frequent

Dizziness ^{08} ^{68}

nausea and vomiting ^{08} ^{68}

stomach pain ^{08}

trembling of fingers and hands ^{08} ^{68}

Overdose
For specific information on the agents used in the management of phenothiazine overdose, see:
   • Benztropine in Antidyskinetics (Systemic) monograph;
   • Charcoal, Activated (Oral-Local) monograph;
   • Diazepam in Benzodiazepines (Systemic) monograph;
   • Digitalis Glycosides (Systemic) monograph;
   • Diphenhydramine in Antihistamines (Systemic) monograph;
   • Norepinephrine and/or Phenylephrine in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph; and/or
   • Phenytoin in Anticonvulsants, Hydantoin (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose

Note: Toxic blood concentration ranges have not been established for the phenothiazines ^{06}. However, for thioridazine, toxicity may begin at a blood concentration of 1 mg/dL and the lethal concentration range is thought to be 2 to 8 mg/dL ^{06}.

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute

Areflexia or hyperreflexia ^{06} ^{10} (loss of or increase in reflexes )

blurred vision ^{10}

cardiac toxicity ^{06} ^{08} ^{10}
including cardiac arrhythmia ^{06} ^{08} ^{10}
cardiac arrest ^{08}
congestive heart failure ^{10}
hypotension ^{06} ^{08} ^{10}
shock ^{06}
tachycardia ^{06} ^{10}
QRS changes ^{06} ^{10}
or ventricular fibrillation ^{06} ^{10} (fainting; fast, slow, or irregular heartbeat; shortness of breath; unusual tiredness or weakness)

CNS toxicity ^{10}
including agitation ^{06} ^{08} ^{10}
confusion ^{06} ^{10}
convulsions ^{06} ^{08} ^{10} —may be followed by respiratory depression ^{10}
disorientation ^{10}
drowsiness, stupor, or coma ^{06} ^{08} ^{10}

dilated pupils ^{06} ^{10}

dryness of mouth ^{06} ^{08} ^{10}

hyperpyrexia ^{08} ^{10} (fever), or hypothermia ^{59} (clumsiness; confusion; drowsiness ; muscle weakness; shivering)

muscle rigidity ^{10}

pulmonary edema or respiratory depression ^{06} ( trouble in breathing)

vomiting ^{10}

Treatment of overdose
Treatment is essentially symptomatic and supportive ^{06} ^{42}.

To decrease absorption:
Attempting early gastric lavage ^{08} ^{10}; avoiding induction of vomiting because potential phenothiazine-induced impaired consciousness or dystonic reactions of the head and neck may result in aspiration of vomitus ^{06} ^{08} ^{68}.

Administering activated charcoal slurry repeatedly ^{06}.

Administering saline cathartic, especially if extended-release dosage form has been ingested ^{08} ^{68}.

Specific treatment:
Controlling cardiac arrhythmias with intravenous phenytoin, 9 to 11 mg per kg of body weight (mg/kg).

Digitalizing for cardiac failure ^{10} ^{83}.

Treating hypotension with intravenous fluids ^{06} ^{58} and a vasopressor such as norepinephrine or phenylephrine (not using a vasopressor with mixed alpha and beta agonist activity, such as epinephrine, because it may cause paradoxical hypotension due to alpha blockade by phenothiazine) ^{06} ^{08} ^{58}.

Controlling convulsions with diazepam ^{10} ^{75} followed by phenytoin while monitoring ECG; avoiding barbiturates since they may potentiate respiratory ^{06} and CNS ^{83} depression.

Administering benztropine or diphenhydramine to manage acute parkinsonian effects that may occur ^{06} ^{08} ^{83}.

Monitoring:
Monitoring CNS function ^{06}.

Monitoring cardiovascular function for not less than 5 days ^{83}.

Supportive care:
Maintaining respiratory function ^{08} ^{10}, including pharyngeal and tracheal suction to remove excess mucus, if necessary ^{75}.

Maintaining body temperature.

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Note: Dialysis of phenothiazines has not been successful ^{08} ^{10} ^{68}.
If extended-release dosage form has been ingested, treatment should continue for as long as overdose signs and symptoms remain ^{08} ^{68}.
Patient may not show arousal for up to 48 hours even when supportive and counteractive measures are employed ^{81}.
Phenothiazines are radiopaque and ingested tablets may be seen on roentgenogram ^{75}.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Phenothiazines (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to any phenothiazine

Pregnancy—Not recommended for use during pregnancy because of reports of jaundice, hyporeflexia or hyperreflexia, and extrapyramidal symptoms in neonates

Breast-feeding—Distributed into breast milk; may cause drowsiness or movement disorders in the infant

Use in children—Children, especially those with acute illnesses, are more prone to extrapyramidal symptoms

Use in the elderly—Elderly patients are more likely to develop extrapyramidal, anticholinergic, hypotensive, and sedative effects; reduced dosage recommended

Dental—Phenothiazine-induced blood dyscrasias may result in infections, delayed healing, and bleeding; dry mouth may cause caries and candidiasis; increased motor activity of face, head, and neck may interfere with some dental procedures
Other medications, especially alcohol, antithyroid agents, other CNS depression-producing medications, epinephrine, other extrapyramidal reaction–causing medications, other hypotension-producing medications, levodopa, lithium, maprotiline, metrizamide, other QT interval–prolonging medications, or antidepressants, tricyclic or the following: fluoxetine, fluvoxamine, or paraoxetine
Other medical problems, especially active alcoholism, blood dyscrasias, brain damage, cardiovascular disease, severe CNS depression, cerebrovascular disease, congenital long QT syndrome, hepatic function impairment, history of cardiac arrhythmias, known genetic defect leading to reduced levels of activity of P450 2D6 isoenzyme activity, pheochromocytoma, renal insufficiency, or Reye's syndrome

Proper use of this medication
»
Proper administration of this medication

For oral dosage forms
Taking with food, milk, or water to reduce stomach irritation

Diluting each dose of medication that comes in dropper bottle with a recommended beverage immediately prior to use

Swallowing the extended-release dosage form whole

For rectal dosage forms
Chilling suppository if too soft to insert

How to insert suppository
» Compliance with therapy; not taking more or less medication than prescribed

» Several weeks of therapy may be required to produce desired effects in treatment of mental or emotional conditions

» Proper dosing
Missed dose when dosing schedule is:

• One dose a day—Taking as soon as possible if remembered the same day; skipping missed dose if not remembered until the next day; going back to regular dosing schedule; not doubling doses

• More than one dose a day—Taking as soon as possible if within an hour or so of missed dose; skipping missed dose if not remembered until later; going back to regular dosing schedule; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress of therapy

» Checking with physician before discontinuing medication; gradual dosage reduction may be needed

Avoiding use of antacids or antidiarrheal

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