英文药名: Artane(Trihexyphenidyl Tablets)

中文药名: 苯海索片

药品名称

通用名称：盐酸苯海索片
常用名称: 苯海索，盐酸三己芬迪 , 盐酸苯海索 , 乙醇-苯海索
英文名称: Tremin ，Benzhexol ，Benzhexol Hydrochloride ，Benzhexolum ，Cyclodol
商品名称：安坦 ，Artane
成份: 盐酸苯海索
性状: 本品为白色片。
药理毒理

本品为中枢抗胆碱抗帕金森病药，作用在于选择性阻断纹状体的胆碱能神经通路，而对外周作用较小，从而有利于恢复帕金森病患者脑内多巴胺和乙酰胆碱的平衡，改善患者的帕金森病症状。
药代动力学

口服后吸收快而完全，可透过血脑屏障，口服1小时起效，作用持续6～12小时。服用量的56%随尿排出，肾功能不全时排泄减慢，有蓄积作用，并可从乳汁分泌。
适应症

用于帕金森病、帕金森综合征。也可用于药物引起的锥体外系疾患。
规格

2mg，5mg/每片
用法用量

口服。帕金森病、帕金森综合征，开始一日1～2mg，以后每3～5日增加2mg，至疗效最好而又不出现副反应为止，一般一日不超过10mg，分3～4次服用，须长期服用。极量一日20mg。药物诱发的锥体外系疾患，第一日2～4mg，分2～3次服用，以后视需要及耐受情况逐渐增加至5～10mg。
老年患者应酌情减量。
任何疑问，请遵医嘱！
不良反应

常见口干、视物模糊等，偶见心动过速、恶心、呕吐、尿潴留、便秘等。长期应用可出现嗜睡、抑郁、记忆力下降、幻觉、意识混浊。
禁忌

青光眼、尿潴留、前列腺肥大患者。
孕妇及哺乳期妇女用药

慎用。
儿童用药

慎用。
老年患者用药

老年人长期应用容易促发青光眼。伴有动脉硬化者，对常用量的抗帕金森病药容易出现精神错乱、定向障碍、焦虑、幻觉及精神病样症状，应慎用。
药物相互作用

1．本品与乙醇或其他中枢神经系统抑制药合用时，可使中枢抑制作用加强。
2．本品与金刚烷胺、抗胆碱药、单胺氧化酶抑制药帕吉林及丙卡巴肼合用时，可加强抗胆碱作用，并可发生麻痹性肠梗阻。
3．本品与单胺氧化酶抑制剂合用，可导致高血压。
4．本品与制酸药或吸附性止泻剂合用时，可减弱本品的效应。
5．本品与氯丙嗪合用时，后者代谢加快，可使其血药浓度降低。
6．本品与强心苷类合用可使后者在胃肠道停留时间延长，吸收增加，易于中毒。
药物过量

中毒症状： 超剂量时，可见瞳孔散大、眼压增高、心悸、心动过速、排尿困难、无力、头痛、面红、发热或腹胀。有时伴有精神错乱、谵妄、妄想、幻觉等中毒性精神病症状。严重者可出现昏迷、惊厥、循环衰竭。
处理：催吐或洗胃，采取增加排泄措施，并依病情进行相应对症治疗和支持疗法。
Trihexyphenidyl Oral Solution
Generic Name: trihexyphenidyl hydrochloride
Dosage Form: oral solution
Trihexyphenidyl Hydrochloride
Oral Solution USP
2 mg per 5 mL
Rx ONLY

Trihexyphenidyl Oral Solution Description
Trihexyphenidyl Hydrochloride Oral Solution USP is a synthetic antispasmodic drug. It is designated chemically as α-Cyclohexylα-phenyl-1-piperidinepropanol hydrochloride and its structural formula is as follows:

C20H31NO•HCl   M.W. 337.93

Trihexyphenidyl hydrochloride occurs as a white or creamy-white, almost odorless, crystalline powder. It is very slightly soluble in ether and benzene, slightly soluble in water and soluble in methanol.

Each 5 mL (teaspoonful) for oral administration contains 2 mg trihexyphenidyl hydrochloride and alcohol 5% in a clear, colorless, lime-mint flavored preparation. In addition, it contains the following inactive ingredients: citric acid, flavoring, methylparaben, propylparaben, purified water, sodium chloride and sorbitol solution.

Trihexyphenidyl Oral Solution - Clinical Pharmacology

Trihexyphenidyl exerts a direct inhibitory effect upon the parasympathetic nervous system. It also has a relaxing effect on smooth musculature; exerted both directly upon the muscle tissue itself and indirectly through an inhibitory effect upon the parasympathetic nervous system. Its therapeutic properties are similar to those of atropine although undesirable side effects are ordinarily less frequent and severe than with the latter.

Indications and Usage for Trihexyphenidyl Oral Solution

Trihexyphenidyl is indicated as an adjunct in the treatment of all forms of parkinsonism (postencephalitic, arteriosclerotic, and idiopathic). It is often useful as adjuvant therapy when treating these forms of parkinsonism with levodopa. Additionally, it is indicated for the control of extrapyramidal disorders caused by central nervous system drugs such as the dibenzoxazepines, phenothiazines, thioxanthenes, and butyrophenones.

Contraindications

Trihexyphenidyl is contraindicated in patients with hypersensitivity to trihexyphenidyl or to any of the other ingredients. Trihexyphenidyl is also contraindicated in patients with narrow angle glaucoma. Blindness after long-term use due to narrow angle glaucoma has been reported.

Warnings

Patients to be treated with trihexyphenidyl should have a gonioscope evaluation prior to initiation of therapy and close monitoring of intraocular pressures. The use of anticholinergic drugs may precipitate angle closure with an increase in intraocular pressure. If blurring of vision occurs during therapy, the possibility of narrow angle glaucoma should be considered. Blindness has been reported due to aggravation of narrow angle glaucoma. (See CONTRAINDICATIONS and ADVERSE REACTIONS).

Trihexyphenidyl should be administered with caution in hot weather, especially when given concomitantly with other atropine-like drugs to the chronically ill, alcoholics, those who have central nervous system disease, or those who do manual labor in a hot environment. Anhidrosis may occur more readily when some disturbance of sweating already exists. If there is evidence of anhidrosis, the possibility of hyperthermia should be considered. Dosage should be decreased so that the ability to maintain body heat equilibrium via perspiration is not impaired. Severe anhidrosis and fatal hyperthermia have occurred with the use of anticholinergics under the conditions described above.

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with dose reduction or discontinuation of trihexyphenidyl. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

Precautions

General

Patients with cardiac, liver, or kidney disorders, or with hypertension, should be closely monitored.

Since trihexyphenidyl has atropine-like properties, patients on long-term treatment should be carefully monitored for untoward reactions.

Since trihexyphenidyl has parasympatholytic activity, it should be used with caution in patients with glaucoma, obstructive disease of the gastrointestinal or genitourinary tracts, and in elderly males with possible prostatic hypertrophy. Incipient glaucoma may be precipitated by parasympatholytic drugs such as trihexyphenidyl.

Tardive dyskinesia may appear in some patients on long-term therapy with antipsychotic drugs or may occur after therapy with these drugs has been discontinued. Antiparkinsonism agents do not alleviate the symptoms of tardive dyskinesia, and in some instances may aggravate them.

However, parkinsonism and tardive dyskinesia often coexist in patients receiving chronic neuroleptic treatment, and anticholinergic therapy with trihexyphenidyl may relieve some of these parkinsonism symptoms. Trihexyphenidyl is not recommended for use in patients with tardive dyskinesia unless they have concomitant Parkinson's disease.

Patients with arteriosclerosis or with a history of idiosyncrasy to other drugs may exhibit reactions of mental confusion, agitation, disturbed behavior, or nausea and vomiting. Such patients should be allowed to develop a tolerance through the initial administration of a small dose and gradual increase in dose until an effective level is reached. If a severe reaction should occur, administration of the drug should be discontinued for a few days and then resumed at a lower dosage. Psychiatric disturbances can result from indiscriminate use (leading to overdosage) to sustain continued euphoria. (See DRUG ABUSE AND DEPENDENCE).

Abrupt withdrawal of treatment for parkinsonism may result in acute exacerbation of parkinsonism symptoms; therefore, abrupt withdrawal should be avoided (See DOSAGE AND ADMINISTRATION).

Information for Patients

Trihexyphenidyl may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. Patients should be cautioned about operating machinery, including automobiles, until they are reasonably certain that trihexyphenidyl therapy does not adversely affect their ability to engage in such activities.

Because of increased sedative effects, patients should be cautioned to avoid the use of alcohol or other CNS depressants while taking trihexyphenidyl.

Since this medication may increase the susceptibility to heat stroke (gastrointestinal (GI) problems, fever, heat intolerance), use with caution during hot weather. (See WARNINGS).

Patients should be advised to report the occurrence of GI problems, fever, or heat intolerance promptly since paralytic ileus, hyperthermia, or heat stroke may occur.

If GI upset occurs, trihexyphenidyl may be taken with food.

Patients should have close monitoring of intraocular pressure. (See WARNINGS).

Drug Interactions

Cannabinoids, barbiturates, opiates, and alcohol may have additive effects with trihexyphenidyl, and thus, an abuse potential exists.

Concurrent use of alcohol or other CNS depressants with trihexyphenidyl may cause increased sedative effects.

Monoamine oxidase inhibitors and tricyclic antidepressants possessing significant anticholinergic activity may intensify the anticholinergic effects of antidyskinetic agents because of the secondary anticholinergic activities of these medications.

Prophylactic administration of anticholinergic agents, such as trihexyphenidyl, as a prevention of drug-induced parkinsonism during neuroleptic therapy is not recommended. There may be an increased risk for the development of tardive dyskinesia during concomitant administration of anticholinergics and neuroleptics (See PRECAUTIONS, General).

The usual dose of either trihexyphenidyl or levodopa may need to be reduced during concomitant therapy, since concomitant administration may increase drug-induced involuntary movements (See DOSAGE AND ADMINISTRATION).

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies or adequate genotoxicity or fertility studies have been conducted for trihexyphenidyl.

Pregnancy

TERATOGENIC EFFECTS

PREGNANCY CATEGORY C

Animal reproduction studies to evaluate teratogenic and embryotoxic potential have not been conducted with trihexyphenidyl. It is also not known whether trihexyphenidyl can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Trihexyphenidyl should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when trihexyphenidyl is administered to a nursing woman.

As with other anticholinergics, trihexyphenidyl may cause suppression of lactation. Therefore, trihexyphenidyl should only be used if the expected benefit to the mother outweighs the potential risk to the infant.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. (See also ADVERSE REACTIONS).

Geriatric Use

Sensitivity to the actions of parasympatholytic drugs may increase with age, particularly over the age of 60; therefore, elderly patients generally should be started on low doses of trihexyphenidyl and observed closely. Trihexyphenidyl has been shown to cause some cognitive dysfunctions in the elderly, including confusion and memory impairment. (See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Adverse Reactions

Minor side effects, such as dryness of the mouth, blurred vision, dizziness, mild nausea or nervousness, will be experienced by 30 to 50 percent of all patients. These sensations, however, are much less troublesome with trihexyphenidyl than with belladonna alkaloids and are usually less disturbing than unalleviated parkinsonism. Such reactions tend to become less pronounced, and even to disappear, as treatment continues. Even before these reactions have remitted spontaneously, they may often be controlled by careful adjustment of dosage form, amount of drug, or interval between doses.

Isolated instances of suppurative parotitis secondary to excessive dryness of the mouth, skin rashes, dilatation of the colon, paralytic ileus, and certain psychiatric manifestations such as delusions, hallucinations, and paranoia, all of which may occur with any of the atropine-like drugs, have been reported rarely with trihexyphenidyl.

Potential side effects associated with the use of any atropine-like drugs, including trihexyphenidyl, include cognitive dysfunctions, including confusion and memory impairment; constipation, drowsiness, urinary hesitancy or retention, tachycardia, dilation of the pupil, increased intraocular pressure, choreiform movements, weakness, vomiting, and headache. Exacerbation of parkinsonism with abrupt treatment withdrawal has been reported. Neuroleptic malignant syndrome with abrupt treatment withdrawal has been reported (See WARNINGS, Neuroleptic Malignant Syndrome).

The occurrence of angle-closure glaucoma in patients receiving trihexyphenidyl has been reported (blindness has been reported in some cases). Paradoxical sinus bradycardia, dry skin, and cycloplegia have been reported.

In addition to adverse events seen in adults, the following adverse events have been reported in the literature in pediatric patients: hyperkinesia, psychosis, forgetfulness, weight loss, restlessness, chorea, and sleep alterations.

Drug Abuse and Dependence

Although trihexyphenidyl is not classified as a controlled substance, the possibility of abuse should be borne in mind due to its stimulant and euphoriant properties.

Overdosage

The mean oral LD50 of trihexyphenidyl has been reported to be 365 mg/kg (range, 325 to 410 mg/kg) in mice and 1660 mg/kg (1420 to 1940 mg/kg) in rats. At a dose of 40 mg/kg, dogs have exhibited emesis, restlessness followed by drowsiness, equilibrium disturbances, and mydriasis.

In humans, doses up to 300 mg (5 mg/kg) have been ingested without fatalities or sequelae. However, rare cases of death associated with trihexyphenidyl overdosages taken in conjunction with other CNS-depressant agents have been reported or in patients with a compromised respiratory condition. Trihexyphenidyl blood concentrations associated with the fatalities ranged from 0.03 to 0.80 mg/l.

Signs and Symptoms

Overdosage with trihexyphenidyl produces typical central symptoms of atropine intoxication (the central anticholinergic syndrome). Correct diagnosis depends upon recognition of the peripheral signs of parasympathetic blockade, including dilated and sluggish pupils; warm, dry skin; facial flushing; decreased secretions of the mouth, pharynx, nose, and bronchi; foul-smelling breath; elevated temperature; tachycardia, cardiac arrhythmias; decreased bowel sounds; and urinary retention. Neuropsychiatric signs such as delirium, disorientation, anxiety, hallucinations, illusions, confusion, incoherence, agitation, hyperactivity, ataxia, lip smacking and tasting movements, loss of memory, paranoia, combativeness, and seizures may be present. The condition can progress to stupor, coma, paralysis, cardiac and respiratory arrest, and death.

Treatment

Treatment of acute overdose involves symptomatic and supportive therapy. Gastric lavage or other methods to limit absorption should be instituted. A small dose of diazepam or a short-acting barbiturate may be administered if CNS excitation is observed. Phenothiazines are contraindicated because the toxicity may be intensified due to their antimuscarinic action, causing coma. Respiratory support, artificial respiration or vasopressor agents may be necessary. Hyperpyrexia must be reversed, fluid volume replaced and acid-balance maintained. Urinary catheterization may be necessary. It is not known if trihexyphenidyl is dialyzable.

Trihexyphenidyl Oral Solution Dosage and Administration

Dosage should be individualized. The initial dose should be low and then increased gradually, especially in patients over 60 years of age. Whether trihexyphenidyl may best be given before or after meals should be determined by the way the patient reacts. Postencephalitic patients, who are usually more prone to excessive salivation, may prefer to take it after meals and may, in addition, require small amounts of atropine which, under such circumstances, is sometimes an effective adjuvant. If trihexyphenidyl tends to dry the mouth excessively, it may be better to take it before meals, unless it causes nausea. If taken after meals, the thirst sometimes induced can be allayed by mint candies, chewing gum or water.

Abrupt withdrawal of treatment for parkinsonism may result in acute exacerbation of parkinsonism symptoms; therefore, abrupt withdrawal should be avoided.

Abrupt withdrawal of treatment may result in neuroleptic malignant syndrome (NMS) (See WARNINGS).

Idiopathic Parkinsonism

As initial therapy for parkinsonism, 1 mg of trihexyphenidyl hydrochloride oral solution USP may be administered the first day. The dose may then be increased by 2 mg increments at intervals of three to five days, until a total of 6 to 10 mg is given daily. The total daily dose will depend upon what is found to be the optimal level. Many patients derive maximum benefit from this daily total of 6 to 10 mg, but some patients, chiefly those in the postencephalitic group, may require a total daily dose of 12 to 15 mg.

Drug-Induced Parkinsonism

The size and frequency of the trihexyphenidyl dose needed to control extrapyramidal reactions to commonly employed tranquilizers, notably the phenothiazines, thioxanthenes, and butyrophenones, must be determined empirically. The total daily dosage usually ranges between 5 and 15 mg although, in some cases, these reactions have been satisfactorily controlled with as little as 1 mg daily. It may be advisable to commence therapy with a single 1 mg dose. If the extrapyramidal manifestations are not controlled in a few hours, the subsequent doses may be progressively increased until satisfactory control is achieved. Satisfactory control may sometimes be more rapidly achieved by temporarily reducing the dosage of the tranquilizer when instituting trihexyphenidyl therapy and then adjusting the dosage of both drugs until the desired ataractic effect is retained without onset of extrapyramidal reactions.

It is sometimes possible to maintain the patient on a reduced trihexyphenidyl dosage after the reactions have remained under control for several days. Instances have been reported in which these reactions have remained in remission for long periods after trihexyphenidyl therapy was discontinued.

Concomitant Use with Levodopa

When trihexyphenidyl is used concomitantly with levodopa, the usual dose of each may need to be reduced. Careful adjustment is necessary, depending on side effects and degree of symptom control. A trihexyphenidyl dosage of 3 to 6 mg daily, in divided doses, is usually adequate.

Concomitant Use with Other Parasympathetic Inhibitors

Trihexyphenidyl may be substituted, in whole or in part, for other parasympathetic inhibitors. The usual technique is partial substitution initially, with progressive reduction in the other medication as the dose of trihexyphenidyl is increased.

The total daily intake of trihexyphenidyl hydrochloride oral solution USP is tolerated best if divided into 3 doses and taken at mealtimes. High doses (>10 mg daily) may be divided into 4 parts, with 3 doses administered at mealtimes and the fourth at bedtime.

How is Trihexyphenidyl Oral Solution Supplied

Trihexyphenidyl Hydrochloride Oral Solution USP, a clear, colorless, lime-mint flavored preparation is supplied in the following oral dosage form:

NDC 0121-0658-16 - Bottles of 473 mL

Dispense in a tight, light-resistant container with a child-resistant closure.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].