[Date of Approval
Date of revision
Fenaminophen Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
Warnings
Increased mortality in elderly patients with dementia-related psychosis
There is an increased risk of death when atypical antipsychotics are used to treat elderly patients with dementia-related psychosis compared to placebo. An analysis of 17 placebo-controlled clinical trials (mean plural treatment duration of 10 weeks) in older patients with dementia-related psychosis found that the risk of death was 1.6-1.7 times greater in the drug-treated group than in the placebo-controlled group. In a 10-week controlled clinical trial, the mortality rate was 4.5% in the drug-treated group and 2.6% in the placebo-controlled group. Although the causes of death varied, most deaths were due to cardiovascular disease (e.g., heart failure, sudden death) or infection (e.g., infectious pneumonia). Observational studies have shown that, similar to atypical antipsychotics, treatment with typical antipsychotics may increase mortality. Whether the increased mortality in observational studies is attributable to the antipsychotic or to some characteristic of the patients themselves is unclear. Fenaza is not approved for the treatment of patients with dementia-related psychosis (see [Precautions]).
Drug Name
Generic name: Perphenazine Tablets
English name: Perphenazine Tablets
Hanyu Pinyin: Fennaijing Pian
Ingredients
The main ingredient of this product is Fennactine, whose chemical name is: 4-[3-(2-chlorophenothiazin-10-yl)propyl]-1-piperazineethanol.
Chemical structure formula.
Molecular formula: C21H26ClN3OS
Molecular weight: 403.97
Properties】This product is a film-coated tablet, which appears white to off-white after removing the film coating.
Indications
1.Schizophrenia; 2.Severe nausea and vomiting.
Specification】2mg
Dosage
Oral For the treatment of schizophrenia, start with a small dose of 2~4mg (1~2 tablets) 2~3 times a day. Increase by 6mg (3 tablets) every 1-2 days, gradually increasing to the usual therapeutic dose of 20-60mg (10-30 tablets) a day. Maintenance dose is 10~20mg (5~10 tablets) a day. For anti-vomiting, 2~4mg (1~2 tablets) once, 2~3 times a day.
【Adverse reactions】.
1. Although all of the following adverse reactions were not reported during the use of this drug; however, they all need to be considered because of the pharmacological similarity between various phenothiazine derivatives. Extrapyramidal symptoms are more common for compounds with a piperazine moiety (of which Fenaza is one), while others (e.g., sedation, jaundice, and hematologic malignancy) are less common.
2. Central nervous system (CNS) effects.
① Extrapyramidal reactions.
Angular recoil, teeth clenching, oblique neck, posterior cervical tilt, limb aches and paresthesia, motor restlessness, ocular rotation crisis, hyperreflexia, dystonia (including tongue protrusion, discoloration, soreness and atrophy, tonic spasm of masticatory muscles, tightness of the throat, slurred speech, dysphagia), inability to sit still, dyskinesia, Parkinson’s disease, and ataxia. Their incidence and severity usually increase accordingly to the dose, however, there is considerable individual variation in the tendency to develop these symptoms. Extrapyramidal symptoms can usually be controlled by co-administration of an effective antiparkinsonian drug (e.g., benztropine mesylate) and/or by dose reduction. However, in some cases, these extrapyramidal reactions may persist after discontinuation of treatment with Endrin.
② Dystonia.
Class effects.
Symptoms of dystonia and prolonged abnormal contractions of muscle groups may occur in susceptible individuals during the first few days of treatment. Symptoms of dystonia include: muscle spasms in the neck, sometimes progressing to throat tightness, dysphagia, dyspnea, and/or tongue protrusion. These symptoms occur once on low doses of typical antipsychotics and are more frequent and more likely to be more severe at higher doses. An elevated risk of acute dystonia has been observed in men and in younger patient groups.
(iii) Persistent delayed-onset dyskinesia.
As with all antipsychotic medications, some patients on long-term treatment may develop delayed-onset dyskinesia, or it may occur after medication is discontinued. Although the risk is greater in older patients receiving high doses, particularly in women, it may occur in both men and women and in children. These symptoms can persist and may be irreversible in some patients. The syndrome is characterized by rhythmic involuntary movements of the tongue, face, mouth, or jaw (e.g., tongue protrusion, cheek swelling, mouth wrinkling, chewing movements). Sometimes, these may also be accompanied by involuntary movements of the extremities. There is no effective treatment for delayed-onset dyskinesia; anti-Parkinsonian medications usually do not relieve the symptoms of this syndrome. If these symptoms occur, it is recommended that all antipsychotic medications be discontinued. The syndrome may be masked if treatment needs to be restarted, or if the dose of the medication is increased, or if a different antipsychotic is switched. It has been reported that subtle tongue wriggling may be an early sign of the syndrome and may not occur if the medication is discontinued at this time.
3. Other CNS side effects.
These include cerebral edema; abnormal cerebrospinal fluid proteins; convulsive seizures, especially in patients with abnormal EEGs or a history of such; and headaches.
Neuroblocker malignant syndrome has been reported in patients treated with antipsychotics (see [Precautions]).
Drowsiness may occur, especially during the first or second week, and usually resolves thereafter. If it causes distress, the dose may be reduced. Hypnotic effects are minimal, especially in patients who are allowed to remain active.
Adverse behavioral effects include paradoxical exacerbation of psychotic symptoms, catatonic mental states, psychomotor agitation, lethargy, paradoxical excitement, fidgeting, hyperactivity, nocturnal confusion, abnormal dreams, and insomnia.
Hyperreflexia has been reported in newborns when phenothiazine is used during pregnancy.
4. Autonomic reactions.
Dry or salivating mouth, nausea, vomiting, diarrhea, anorexia, constipation, intractable constipation, fecal impaction, urinary retention, urinary frequency or incontinence, bladder paralysis, polyuria, nasal congestion, pallor, muscle weakness, dilated pupils, foggy vision, glaucoma, sweating, hypertension, hypotension, and sometimes pulse changes may occur. Significant autonomic effects rarely occur in patients on daily doses of phenothiazine below 24 mg.
Paralytic intestinal obstruction occasionally occurs with phenothiazine treatment and can lead to complications and death in severe cases. This is of particular concern in psychiatric patients, who may not seek treatment for the condition.
5. Allergic reactions.
Urticaria, erythema, eczema, exfoliative dermatitis, pruritus, photosensitivity, asthma, fever, anaphylactic-like reactions, laryngeal edema, and angioneurotic edema; contact dermatitis among caregivers responsible for administration; in very rare cases, individual specificity or hypersensitivity to phenothiazines can lead to cerebral edema, circulatory collapse, and death.
6. Endocrine effects.
Lactation, breast overflow, moderate breast enlargement in women treated with high doses as well as male female-pattern breasts, menstrual cycle disorders, amenorrhea, changes in libido, ejaculation suppression, abnormal anti-diuretic hormone (ADH) secretion syndrome, false-positive pregnancy test, hyperglycemia, hypoglycemia, glycosuria.
7. Cardiovascular effects.
Postural hypotension, tachycardia (especially sudden large increase in dose), bradycardia, cardiac arrest, dizziness and lightheadedness. Occasionally, hypotensive effects may produce shock-like conditions. Nonspecific (quinidine-like effects) and usually reversible electrocardiographic (ECG) changes have been observed in some patients receiving phenothiazine antipsychotics.
Sudden death has occasionally been reported in patients receiving phenothiazines. In some cases, death was apparently due to cardiac arrest; in others, it may have been due to asphyxia due to failure of the cough reflex. In some patients, the etiology could not be determined and the death could not be attributed to phenothiazine.
8. Hematological effects.
Granulocyte deficiency, eosinophilia, leukopenia, hemolytic anemia, thrombocytopenic purpura, and allohemocytopenia. Most cases of granulocyte deficiency occur during the 4th to 10th week of treatment. Patients should be closely monitored for sudden onset of sore throat or signs of infection, especially during this phase. If white blood cell and sorted cell counts show significant cytosuppression, discontinue the product and initiate appropriate therapy. However, a slight decrease in white blood cell count does not in itself indicate that the product should be discontinued.
9. Other effects.
Special considerations during long-term treatment include skin pigmentation, which occurs primarily in exposed areas; ocular changes, including deposition of fine particulate matter in the cornea and lens, which may progress to astrocytic lens opacification in more severe cases; corneal epithelial lesions; and pigmentary retinopathy. Also of note: peripheral edema, reversal of adrenergic effects, increased protein-bound iodine (PBI) not attributable to increased thyroxine, parotid enlargement (rare), hyperthermia, systemic lupus erythematosus-like syndrome, increased appetite and weight, bulimia, photophobia, and muscle weakness.
Liver damage (cholestasis) may occur. Jaundice may occur, usually during the second to fourth week of treatment, and is considered to be a hypersensitivity reaction. The incidence is very low. Clinical presentation is similar to that of infectious hepatitis, but with laboratory features of obstructive jaundice. Usually reversible; however, chronic jaundice has been reported.
[Contraindicated
Contraindicated in basal ganglion lesions, Parkinson’s disease, Parkinson’s syndrome, myelosuppression, glaucoma, coma, and hypersensitivity to phenothiazines.
Contraindicated in patients who are comatose or highly unresponsive; in patients receiving high doses of central nervous system depressants (barbiturates, alcohol, narcotics, analgesics, or antihistamines); in patients with the presence of hematologic malignancy, bone marrow suppression, or hepatic impairment; and in patients with known hypersensitivity reactions to Endorphin products, ingredients in products, or related compounds.
The use of Endrin product is also contraindicated in patients with suspected or established subcortical brain injury with/without hypothalamic injury, as hyperthermia exceeding 40°C (104°F) may occur in these patients, sometimes not until 14 to 16 hours after dosing. Systemic icing is recommended when such reactions occur; antipyretics may also be effective.
[Caution].
1. Increased mortality in elderly patients with dementia-related psychosis: Compared to placebo, elderly patients with dementia-related psychosis taking antipsychotic drugs have an increased risk of death. Endrin is not approved for the treatment of patients with dementia-related psychosis (see cautionary statement).
2. Delayed dyskinesia: Patients treated with antipsychotic medications may develop a potentially irreversible involuntary dyskinesia syndrome. As the duration of treatment and the total cumulative dose of antipsychotic medication used by the patient increases, the risk of developing delayed dyskinesia and its potential to become irreversible increases. However, the syndrome may also occur after relatively short periods of treatment at low doses, although this is less common.
There is no known treatment for diagnosed cases of tardive dyskinesia, but the syndrome may remit partially or completely if antipsychotic medication is discontinued. However, antipsychotic medication itself may suppress (or partially suppress) the signs and symptoms of the syndrome, which may obscure the pathogenesis of the underlying movement disorder syndrome. The impact of symptom suppression on the long-term course of the movement disorder syndrome is unknown.
Given these considerations, endorphin should be prescribed in a manner that is most likely to reduce the risk of developing movement disorder syndrome. Chronic antipsychotic treatment is usually indicated for patients with chronic disease who (1) are known to respond to antipsychotic medications and (2) have no available alternative, equivocal, low-risk treatment options. In patients requiring long-term treatment, the minimum dose and shortest duration of treatment required for the desired clinical outcome should be sought. The need for continued treatment should be reassessed periodically.
Consider discontinuing the drug if patients treated with fenadine develop signs and symptoms of delayed dyskinesia. However, some patients may still require treatment with fenofibrate despite the presence of the syndrome.
Neuroblocker Malignant Syndrome (NMS): The use of antipsychotic medications, including fenbutrazine, can cause Neuroblocker Malignant Syndrome (NMS), whose clinical manifestations include hyperthermia, myoclonus, altered mental status, and autonomic dysregulation (irregular pulse or blood pressure, tachycardia, sweating, and arrhythmias). Other symptoms may include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnostic evaluation of patients with this syndrome is complex. It is important to distinguish between the following conditions in the differential diagnosis, including cases of severe medical disease (e.g., pneumonia, systemic infections, etc.) and untreated or inadequately treated extra-pyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary CNS pathology.
Treatment of NMS should include (1) immediate discontinuation of antipsychotic medications and other unnecessary comorbidities, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of any serious complications with a specific treatment regimen. There is no consensus on specific pharmacologic treatment options for NMS without comorbidities.
If a patient requires antipsychotic medication after recovery from NMS, the potential problems with medication should be carefully considered. Patients should be monitored closely, as relapse of NMS has been reported.
4. Leukopenia, neutropenia and granulocyte deficiency
Leukopenia/neutropenia events associated with antipsychotics have been reported in clinical trials and/or post-marketing experience. Granulocyte deficiency has also been reported.
Possible risk factors for leukopenia/neutropenia include a preexisting reduced white blood cell count (WBC) and a history of drug-induced leukopenia/neutropenia. Patients with a history of clinically significant leukopenia or drug-induced leukopenia/neutropenia should be closely monitored for a complete blood count (CBC) during the first few months of therapy and should discontinue the product when a clinically significant decrease in leukocytes without other predisposing factors is first detected.
Patients with clinically significant neutropenia should be carefully monitored for fever or signs and symptoms associated with infection and should be treated promptly if these signs or symptoms develop. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue the product and then monitor the white blood cell count until recovery.
5. Antipsychotics can elevate prolactin levels; and this elevated effect persists during long-term administration. Tissue culture experiments have shown that approximately 1/3 of human breast cancers are prolactin-dependent in vitro and may be a potentially important risk factor if these drugs are prescribed to patients with previously detected breast cancer. The clinical significance of elevated serum prolactin levels is unclear in most patients, although a number of disorders have been reported, such as breast overflow, amenorrhea, male gynecomastia, and impotence. Increased mammary tumors have been observed in rodents after long-term administration of antipsychotic drugs. However, none of the clinical studies and epidemiological studies conducted to date have shown a correlation between long-term administration of these drugs and mammary tumor formation; the available evidence is too limited to allow definitive conclusions to be drawn.
6. If hypotension is present, epinephrine should not be given because its effects can be blocked and partially reversed by endometrium. If a vasopressor is required, norepinephrine may be used. In patients with mitral valve insufficiency or pheochromocytoma, the use of phenothiazines is more likely to trigger severe acute hypotension. Patients with pheochromocytoma may experience rebound hypertension.
7. Endorphin products may lower the convulsive threshold in susceptible individuals; they should be used with caution in patients who are abstinent from alcohol and in patients with convulsive disorders. If the patient is receiving anticonvulsant medication, it may be necessary to increase the dose of this medication when combined with Endorphin products.
8. This product should be used with caution in patients with psychotic depression. The possibility of suicide during treatment in depressed patients persists until there is significant remission of symptoms. Such patients should not be exposed to large amounts of this drug.
9. Endrin may impair the mental and/or physical ability required to perform risky tasks (e.g., driving a car or operating machinery); therefore, patients should be warned accordingly.
10. The antiemetic effect of endorphin may mask signs of toxicity from other drug overdoses or make the diagnosis of conditions such as brain tumors or intestinal obstruction more difficult.
11. A significant increase in body temperature (but not otherwise indicated) may indicate that the individual is intolerant to Endrin, in which case the drug should be discontinued.
12, For patients undergoing surgery and on high doses of phenothiazines, careful observation should be made for possible hypotension. In addition, it may be necessary to reduce the dosage of anesthetics or central nervous system depressants.
13. As with all phenothiazines, endothiazine should not be used indiscriminately. Patients who have experienced severe adverse reactions during treatment with other phenothiazines should be observed carefully when administering the drug. There is also a tendency to increase the incidence of some adverse effects of endothiazide when higher doses are used. Whenever possible, as with other phenothiazines, patients receiving any dose of Endorphin products should be closely supervised.
Because phenothiazines and CNS depressants (opioids, analgesics, antihistamines, barbiturates) can potentiate each other, it is recommended that when other drugs are added, the dose used should be lower than the regular dose of the added drug and that caution be exercised when combining them.
15. Because it can enhance the anticholinergic effect, caution should be exercised in patients who are receiving atropine or related drugs; in addition, caution should be exercised in patients who may be exposed to extreme heat or phosphorus-containing insecticides.
16. Blood cell counts and liver and kidney functions should be checked regularly. The drug needs to be discontinued and appropriate treatment taken when signs of blood malignancy appear. Phenothiazine treatment should be discontinued if liver tests reveal abnormalities. Patients on long-term treatment should be monitored for their renal function; if the blood urea nitrogen (BUN) is abnormal, drug therapy should be stopped.
17.Caution should be exercised when using phenothiazine derivatives for treatment of patients with reduced renal function.
18.The drug should be used with caution in patients suffering from obstructed breathing due to acute lung infection or chronic respiratory diseases (such as severe asthma or emphysema).
19.Usually, phenothiazines (including Fenaza) do not produce psychiatric dependence. Gastritis, nausea and vomiting, dizziness and tremor have been reported after abrupt cessation of high-dose therapy. These symptoms have been reported to be alleviated by continued treatment with antiparkinsonian drugs for several weeks after phenothiazine withdrawal.
20, When patients receive long-term treatment, the possibility of liver damage, corneal and lenticular deposits, and irreversible movement disorders should be kept in mind.
21.Since photosensitivity has been reported, excessive exposure to sunlight should be avoided during phenothiazine treatment.
22. Alcohol should be avoided when using this product. The patient’s response to alcohol may be enhanced, and drug potentiation and hypotension may occur. The risk of suicide and drug overdose may be enhanced due to the enhanced effect on the drug when the patient drinks alcohol in excess.
23, Should be used with caution in patients with cardiovascular disease (e.g., heart failure, myocardial infarction, conduction abnormalities).
24.The appearance of allergic rash and malignant syndrome should be immediately discontinued and treated accordingly.
25.Patients with epilepsy should be used with caution.
Pregnant women and nursing mothers
Fetuses exposed to antipsychotic drugs at the end of pregnancy are at risk of developing extrapyramidal or withdrawal symptoms after birth, which may vary in severity. These symptoms include agitation, hypertonia, hypotonia, tremor, drowsiness, respiratory distress, and feeding disorders. In some cases, symptoms are self-limiting, in other cases, neonates require intensive care unit support and long-term hospitalization.
The safety of using Endrin during pregnancy and lactation has not been established. Therefore, when administered to pregnant women, nursing mothers, or women who may become pregnant, the potential benefit of treatment must be weighed against the potential harm that treatment may cause to the mother and child.
Use with caution in pregnant women. Consider discontinuing breast-feeding during the use of this product in nursing mothers.
For Children】The dosage for children under 12 years of age has not been determined.
Geriatric Use】Dosage should be reduced as appropriate, start with a small dose and increase slowly.
Drug Interactions
1, this product and ethanol or central nervous system depressants, especially when combined with inhalation general anesthetics or barbiturates and other intravenous general anesthetics, can increase each other’s effectiveness.
2.When this product is combined with amphetamines, the effect of the latter can be weakened because phenothiazines have alpha-adrenergic receptor blocking effect.
3.The combination of this product and acid control drugs or antidiarrheal drugs can reduce the oral absorption.
4.The combination of this product and anticonvulsant drugs can not make anticonvulsant drugs more effective.
5.The combination of this product and anticholinergic drugs, the effect of each other to strengthen.
6.The combination of this product and epinephrine, the alpha receptor effect of epinephrine is blocked, only the beta receptor effect is shown, which can lead to obvious hypotension and tachycardia.
7.When this product is combined with guanethidine drugs, the antihypertensive effect of the latter can be offset.
8.When this product is combined with levodopa, the latter can inhibit the antitremor paralysis effect of the former.
9.When combined with monoamine oxidase inhibitors or tricyclic antidepressants, the anticholinergic effect of the two can be mutually enhanced and prolonged.
Drug overdose]
Toxic symptoms.
1. Central nervous system: Exciting symptoms such as irritability and insomnia. Special attention should be paid to those with a history of convulsions, especially children, who are prone to tremors of the limbs, jaw twitching, slurred speech, etc.
2. Cardiovascular system: palpitations, chills in the extremities, drop in blood pressure, upright hypotension, persistent hypotensive shock, and can lead to atrioventricular block and ventricular premature beats, which can cause cardiac arrest.
Treatment.
1. If large amounts of this product are taken, symptomatic treatment and supportive therapy should be administered. Emesis is not recommended because of the possibility of seizures, central nervous system depression, or head/neck dystonic reactions and subsequent aspiration. Gastric lavage (after tracheal intubation, if the patient is unconscious) should be considered, and activated charcoal should be given along with a light laxative. There is no specific antidote available.
2. Standard measures (oxygen, intravenous fluids, corticosteroids) should be used to manage circulatory shock or metabolic acidosis. Airway patency and adequate fluid intake should be maintained. However, fluid infusion should not be excessive to prevent heart failure and pulmonary edema. Body temperature should be regulated. Hypothermia is expected, but severe hypothermia may occur and must be treated aggressively. (See Contraindications.)
3. If any abnormal signs are present, an electrocardiogram should be performed and cardiac function should be closely monitored. Close monitoring of cardiac function for not less than five days is recommended. Vasopressants such as norepinephrine may be used to treat hypotension, but epinephrine should not be used.
4, Hemodialysis and peritoneal dialysis are not practical because of the low plasma concentration of the drug.
5.Since overdose administration is often intentional, patients may try to commit suicide by other means during the recovery phase.
6. Symptomatic treatment and supportive therapy are given according to the condition.
Pharmacology and Toxicology
It is a piperazine derivative of phenothiazine, and its pharmacological effect is similar to that of chlorpromazine. The antipsychotic effect is mainly related to its blocking of dopamine receptors (DA2) in the midbrain limbic system and midbrain-cortical pathway associated with emotional thinking, while the blocking of a-adrenergic receptors in the reticular upstream activation system is related to the sedative and tranquilizing effect. It has a strong antiemetic effect and a weak sedative effect.
Pharmacokinetics]
After oral administration, peak mean blood concentrations of fenbutrazine were observed between 1 and 3 hours after administration. The half-life of the blood concentration of fenbutrazine was not dose dependent and ranged from 9 to 12 hours. A 5-day study was conducted in normal volunteers (n = 12) in which subjects received 4 mg of fenofibrate every 8 hours and reached steady-state concentrations of fenofibrate within 72 hours of dosing. The mean (%CV) Cmax and Cmin values of endorphin and 7-hydroxyendorphin at steady state are shown in the following table.
Parameters Endorphin 7-hydroxyendorphin Cmax (pg/mL) 984 (43) 509 (25) Cmin (pg/mL) 442 (76) 350 (56) Peak concentrations of 7-hydroxypiperazine were observed 2 to 4 hours after administration, with terminal phase half-lives of 9.9 to 18.8 hours. Fenazaquinone is extensively metabolized in the liver to a variety of metabolites via sulfation, hydroxylation, dealkylation, and glucuronidation. The pharmacokinetics of Endrin co-varies with cytochrome P450 2D6 (CYP 2D6)-mediated isoquinone hydroxylation and is therefore affected by genetic polymorphisms – i.e., very low or no activity of this enzyme in 7% to 10% of Caucasians and, to a lesser extent, Asians, a population also known as “weak metabolizers”. Compared to normal or “fast” metabolizers, Endrin is metabolized more slowly in CYP 2D6 “weak” metabolizers, and the concentration of Endrin is higher.
Storage】Store under shade and seal.
Package】High density polyethylene bottle for oral solid medicine, 100 tablets/bottle/box.
Expiration date】24 months
Execution Standard
Approval number】State Drug Administration H31021083
[Drug Marketing License Holder
Name: Shanghai Chaohui Pharmaceutical Co.
Registered Address: No. 2151 Fuyuan Road, Baoshan District, Shanghai
Postal Code: 201908
Telephone number: 021-66866679
Fax number: 021-66866679
Web address: http://www.zhpharma.com
Manufacturer
Company name: Shanghai Chaohui Pharmaceutical Co.
Address: No. 2151, Fuyuan Road, Baoshan District, Shanghai
Postal Code: 201908
Telephone number: 021-66866679
Fax number: 021-66866679
Web address: http://www.zhpharma.com