Approval date: 07/19/2007
Revision date: 01 October 2012
July 30, 2014
December 01, 2015
Amitriptyline hydrochloride tablets instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
Antidepressants and Suicidal Tendencies
Results of short-term clinical trials of depression (MDD) and other psychiatric disorders have shown that antidepressants increase the risk of suicidal ideation (suicidal thoughts and committing suicidal acts) in children, adolescents, and young adults (≤ 24 years of age) compared to placebo. Anyone considering the use of this or other antidepressants in children, adolescents, or young adults (≤24 years of age) must weigh the clinical need against the risks. Short-term clinical trials have not shown an increased risk of suicidal ideation in adult patients aged >24 years using antidepressants compared with the placebo group; in adult patients aged 65 years and older using antidepressants, the risk of suicidal ideation was reduced compared with the placebo group. Depression and certain psychiatric disorders are inherently associated with an increased risk of suicide, and the worsening of clinical symptoms, suicidal ideation, and abnormal changes in behavior after initiation of antidepressant treatment in patients of all ages must be closely observed and reasonably monitored. Families and caregivers should be advised that patients must be closely observed and communicated with their physicians. This product is not approved for use in pediatric patients (see [Warnings], [Precautions] and [Pediatric Use]).
Drug Name]
Generic Name: Amitriptyline Hydrochloride Tablets
Hanyu Pinyin: Yansuan Amitilin Pian
English name: Amitriptyline Hydrochloride Tablets
Ingredients
The active ingredient of this product is amitriptyline hydrochloride.
Chemical name: N,N-dimethyl-3-[10,11-dihydro-5H-dibenzo[a,d]cycloheptatriene-5-ylidene]-1-propanamine hydrochloride.
Chemical structure formula.
Molecular formula: C20H23N-HCl
Molecular weight: 313.87
Excipient name: corn starch, dextrin, pregelatinized starch, calcium hydrogen phosphate, sucrose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium stearate, sodium carboxymethyl starch, pharmaceutical film-coated premixed excipient (gastric soluble type).
Properties
This product is film-coated tablets, white after removing the coating.
Indications
It is used for the treatment of various depressions. It has strong sedative effect and is mainly used for the treatment of anxious or agitated depression.
Specification
25mg
Dosage and Administration
Take orally. The usual dosage for adults is 25mg once, 2~3 times a day, then gradually increase to 150~250mg 3 times a day according to the condition and tolerance, the high dosage is not more than 300mg a day, the maintenance dosage is 50~150mg a day.
[Adverse Reactions].
In each category, the following adverse reactions are listed in order of decreasing severity. Listed are some of the adverse reactions reported for the non-specific drug. However, pharmacological similarities between tricyclic antidepressants require that each reaction should be considered when amitriptyline is given.
1, Cardiovascular system: myocardial infarction; stroke; nonspecific ECG changes and AV conduction changes; heart conduction block; arrhythmias; hypotension, especially upright hypotension; syncope; hypertension; tachycardia; palpitations.
2. CNS and neuromuscular: coma; seizures; hallucinations; delusions; confusional states; disorientation; movement disorders; ataxia; tremor; peripheral neuropathy; extremity paralysis, tingling, and sensory abnormalities; extrapyramidal symptoms, including abnormal involuntary movements and delayed dyskinesia; dysarthria; inattention; agitation; anxiety; insomnia; restlessness; nightmares; sleepiness; dizziness weakness; fatigue; headache; ADH (antidiuretic hormone) dyssecretion syndrome; tinnitus; EEG map changes.
3, Anticholinergic: paralytic intestinal obstruction, hyperthermia; urinary retention, urethral dilatation; constipation; blurred vision, dysregulation, increased intraocular pressure, dilated pupils; dry mouth.
4. Allergic reactions: rash; urticaria; photosensitization; facial and tongue edema.
5. Hematology: bone marrow suppression, including granulocyte deficiency, leukopenia, thrombocytopenia; purpura; eosinophilia.
6, digestive system: rare hepatitis (including changes in liver function and jaundice); nausea; epigastric discomfort; vomiting; anorexia; stomatitis; abnormal taste; diarrhea; swollen parotid glands; black tongue.
7.Endocrine: swollen testicles and female-type breasts in men; enlarged breasts and breast overflow in women; increased or decreased libido; impotence; increased and decreased blood sugar levels.
8.Other: hair loss; edema; weight gain or loss; frequent urination; increased sweating.
9.Withdrawal symptoms
After long-term use, sudden cessation of treatment may produce nausea, headache and discomfort. Gradual dose reduction has been reported to produce transient symptoms within two weeks, including irritability, restlessness, dreaming, and sleep disturbances.
These symptoms do not indicate addiction. Mania or mild mania has been reported within 2 to 7 days after discontinuation of chronic treatment with tricyclic antidepressants.
10. Adverse reactions of unknown causality
Other reactions reported in cases where a causal relationship could not be established are listed as cautionary information for physicians.
10.1 Systemic: Lupus-like syndrome (mobile arthritis, positive ANA and rheumatoid factor). Digestive: liver failure, loss of taste.
10.2 Post-marketing adverse events
Very rare reports of syndromes similar to neuroblocker malignant syndrome (NMS) have been reported after initiation of amitriptyline hydrochloride or dose increases, with or without co-administration of drugs known to cause NMS. Symptoms include muscle stiffness, fever, mental status changes, sweating, tachycardia, and tremor.
Cases of SS have been reported very rarely when amitriptyline hydrochloride is combined with other drugs that have been thought to be associated with serotonin syndrome (SS).
Contraindications
Amitriptyline hydrochloride is contraindicated in patients who have shown a history of allergic reactions to the drug.
It should not be used in combination with monoamine oxidase inhibitors. Risk of hyperthermia, severe convulsions and death have occurred in patients treated with both tricyclic antidepressants and monoamine oxidase inhibitors. When replacement of monoamine oxidase inhibitors with amitriptyline hydrochloride is desired, an interval of at least 14 days is required after discontinuation of monoamine oxidase inhibitors. Treatment with amitriptyline hydrochloride should then be started cautiously and the dose increased gradually until an optimal response is achieved.
Amitriptyline hydrochloride should not be combined with cisapride because of the risk of increased QT interval and increased risk of arrhythmias.
This drug is not recommended for acute recovery after myocardial infarction.
【Caution】.
1, Suicidal ideation and suicidal behavior in children, adolescents and young adults
Patients with depression, both adults and children, with or without antidepressants, are at risk of worsening depression and/or developing suicidal ideation or behavior (suicidal ideation) or behavioral abnormalities, and this risk may persist until the treated disorder is in significant remission. Suicide is a known risk for depression and certain other psychiatric disorders, which are themselves the strongest predictors of suicide. However, there is a long-standing concern that antidepressants early in treatment may induce increased depression and suicidal ideation in some patients. Pooled analyses of short-term placebo-controlled trials of antidepressants (SSRIs and others) have shown that these medications can increase the risk of suicidal ideation and behavior (suicidal ideation) in children, adolescents, and young adults (aged 18-24 years) with depression and other psychiatric disorders. In adults older than 24 years, short-term trials did not show an increased risk of suicide compared with placebo; in adults 65 years and older, this risk was reduced with antidepressant use compared with placebo.
A pooled analysis of placebo-controlled trials in children and adolescents with depression, obsessive-compulsive disorder, or other psychiatric disorders included a total of 24 short-term trials of nine antidepressants in 4,400 patients. A pooled analysis of placebo-controlled trials in adults with depression or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressants in more than 77,000 patients. There was considerable variability in the risk of suicidal ideation among the different drugs, but for almost all drugs studied, the risk tended to increase in younger patients. The absolute risk of suicidal ideation varied between indications, with the highest incidence in depression. However, within the same age group and across indications, the risk differences (drug versus placebo) were relatively stable. These risk differences (differences in the number of cases of suicidal ideation per 1000 patients treated with drugs versus placebo) are shown in Table 1.
Table 1: Suicidal ideation per 1000 treated patients
Age range Difference in number of cases of suicidal ideation per 1000 patients treated with drugs versus placebo Increase relative to placebo-treated patients <18 14 more cases 18-24 5 more cases Decrease relative to placebo-treated patients 25-64 1 less case ≥65 6 less cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trial, but the numbers were too small to draw conclusions about the effect of the drug on suicide.
It is not clear whether long-term use (i.e., longer than a few months) also poses a risk of suicide. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants delays the recurrence of depression.
All patients treated with antidepressants for any indication should be monitored appropriately and closely for clinical exacerbations, suicidal ideation, and behavioral abnormalities, especially during the first few months of medication, or when medication doses are adjusted, either by increase or decrease.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, impulsivity, inability to sit still (psychomotor restlessness), hypomania, and mania have been previously reported in adult and pediatric patients treated with antidepressants for depression as well as other psychiatric and nonpsychiatric indications. Although a causal link between the presence of such symptoms and the exacerbation of depression and/or the development of suicidal impulses has not been established, there is concern that such symptoms may be a precursor to the development of suicidal ideation that accompanies treatment.
Changes in treatment regimen, including the possibility of discontinuing medication, should be considered in patients with persistent exacerbation of depression or sudden onset of suicidality, or in patients presenting with symptoms that may be precursors to exacerbation of depression or suicidality, especially if these symptoms are severe, appear suddenly, or are not part of the patient’s presenting symptoms.
If a patient is receiving antidepressant medication for depression or other indications including psychosis or nonpsychosis, family members and caregivers should be informed of the need to monitor the patient for agitation, irritability, abnormal behavior and other symptoms described above, as well as suicidal ideation, and to report such symptoms immediately to the health care provider. Such monitoring should include daily observation by family members or caregivers. Amitriptyline hydrochloride should be prescribed at the lowest dose of the drug that will control the condition in order to reduce the risk of overdose.
2. Screening of patients with bipolar disorder
Depressive episodes can be the initial manifestation of bipolar disorder. It is generally believed (although not proven in controlled trials) that treatment of such episodes with antidepressants alone may increase the likelihood of mixed/manic episodes in patients at risk for bipolar disorder. It is unclear whether some of the symptoms described by clinical exacerbation and suicide risk represent such a conversion. However, before initiating treatment with antidepressants, patients with depressive symptoms should be adequately screened to determine whether they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that amitriptyline hydrochloride has not been approved for the treatment of depressive episodes associated with bipolar I disorder.
3. Closed-angle glaucoma
Pupil dilation occurs in patients with anatomically narrow atrial angles who have not undergone open iridectomy with a variety of antidepressants (including amitriptyline hydrochloride), which may induce closed-angle glaucoma.
4. Use in patients with concomitant disease
Use with caution in patients with a history of seizures (because of the atropine-like effects of this drug) and in patients with a history of urinary retention or closed-angle glaucoma. In patients with closed-angle glaucoma, even average doses may cause seizures.
Patients with cardiovascular disease should be closely monitored. Tricyclic antidepressants, including amitriptyline hydrochloride, have been reported to cause arrhythmias, sinus tachycardia, and prolonged conduction times, especially when administered at high doses. Myocardial infarction and stroke have been reported in this class of drugs.
Amitriptyline hydrochloride must be strictly regulated when used to treat patients with hyperthyroidism or patients receiving thyroid medication.
5. Other
Amitriptyline hydrochloride may block the antihypertensive effects of guanethidine or similarly acting compounds.
Amitriptyline may potentiate the response to alcohol and the effects of barbiturates and other CNS inhibitors. In patients in whom alcohol consumption may be excessive, it should be kept in mind that this potentiation may increase the inherent risk of any suicide attempt or drug overdose. Delirium has been reported with concomitant use of amitriptyline and disulfiram.
Enhanced psychotic symptoms may occur in patients with schizophrenia; this may be exaggerated in patients with paranoid symptoms. In depressed patients, especially those known to have bipolar disorder, there may be a shift to mania or mild mania. In these cases, the dose of amitriptyline may need to be lowered, or a strong sedative such as fenadine may be given concurrently.
Concomitant administration of amitriptyline hydrochloride and electroshock therapy may increase the harms associated with such treatment. Therefore, the use of amitriptyline hydrochloride should be limited in patients who must receive such therapy.
If possible, the drug should be discontinued a few days before elective surgery.
Elevated and decreased blood glucose levels have been reported.
Amitriptyline hydrochloride should be used with caution in patients with impaired hepatic function.
[For pregnant and lactating women].
Pregnancy Classification Category C
Studies have shown that amitriptyline can cross the placenta. Although a causal relationship has not been established, a number of adverse events, including CNS effects, limb deformities, or developmental delays, have been reported in infants whose mothers have taken amitriptyline during pregnancy.
Appropriate and well-controlled studies have not been implemented in pregnant women. Amitriptyline hydrochloride should be administered to pregnant women during pregnancy only if, on balance, the potential benefits to the pregnant woman outweigh the potential risks to the fetus.
Nursing Mothers
Amitriptyline can be distributed in breast milk. In one report, a patient treated with amitriptyline 100 mg/day while breastfeeding her infant resulted in drug levels of 83 to 141 ng/mL being detected in the mother’s serum. Drug levels of 135 to 151 ng/mL were detected in breast milk, but no traces of the drug were detected in the infant’s serum.
Because of the potential for serious adverse reactions to amitriptyline in nursing infants, the decision to discontinue nursing or discontinue the drug needs to be considered in light of the importance of the drug to the mother.
Pediatric Dosage]
Not to be used in children under 6 years of age; reduce dosage as appropriate in children over 6 years of age.
For Elderly]
Start with a small dose and reduce the dosage according to the condition.
Drug Interactions
Topiramate
In the presence of topiramate, some patients may experience a substantial increase in amitriptyline concentration and any adjustment of amitriptyline dose should be based on the patient’s clinical response and not on plasma levels.
Drugs metabolized by P450 2D6
The biochemical activity of the drug-metabolizing isoenzyme cytochrome P450 2D6 (isoquinuclidinium hydroxylase) is decreased in a subgroup of Caucasian populations (approximately 7 to 10% of Caucasians called “weak metabolizers”); reliable estimates of decreased P450 2D6 isoenzyme activity have not been obtained in Asians, Africans, and other populations. Plasma concentrations of tricyclic antidepressants (TCA) in weak metabolizers were higher than expected when given at conventional doses. The increase in plasma concentrations may be small or considerable (8-fold increase in TCA plasma AUC) for the portion of the drug that depends on being metabolized by P450 2D6.
In addition, certain drugs inhibit the activity of this isoenzyme and cause normal metabolizers to resemble weak metabolizers. In individuals on stable TCA doses, sudden toxicity may occur when one of these inhibitory drugs is given as combination therapy. Some of the drugs that inhibit cytochrome P450 2D6 are not metabolized by the enzyme (quinidine, cimetidine) and many are substrates of P450 2D6 (many other antidepressants, phenothiazines, and the type Ic antiarrhythmics propafenone and flecainide). Although all selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the degree of inhibition.The extent to which SSRI-TCA interactions may cause clinical problems depends on the degree of inhibition and pharmacokinetics of the SSRI involved. However, caution should be exercised in the combination of TCA with any SSRI and in switching from one class of drug to another. It is particularly important to take into account the long half-life of the parent compound and active metabolite before starting TCA therapy in patients withdrawing from fluoxetine, and therefore adequate time must be allowed (at least 5 weeks is required).
When tricyclic antidepressants are combined with drugs that inhibit cytochrome P450 2D6, the dose may require a lower dose than that usually prescribed for tricyclic antidepressants or other drugs. In addition, when one of these other drugs is withdrawn from the combined therapy, an increased dose of tricyclic antidepressants may be required. TCA plasma levels need to be monitored whenever TCA is given in combination with another drug known to be a P450 2D6 inhibitor.
Monoamine oxidase inhibitors (see [Contraindications]). Guanethidine or similar acting compounds; thyroid medications; alcohol, barbiturates and other CNS inhibitors; disulfiram (
See [Precautions]).
When amitriptyline is combined with cholinergic blocking agents or sympathomimetic drugs (including epinephrine combined with local anesthetics), close monitoring and careful dose adjustment is required.
Hyperthermia has been reported when amitriptyline is administered with anticholinergic drugs or with tranquilizers, especially during hot weather.
Paralytic intestinal obstruction may occur in patients on tricyclic antidepressants and anticholinergics in combination.
Cimetidine has been reported to decrease the hepatic metabolism of certain tricyclic antidepressants, thereby delaying the elimination and increasing the steady-state concentration of these drugs. Clinically significant effects of tricyclic antidepressants have been reported when used in conjunction with cimetidine. Increased plasma levels of tricyclic antidepressants (particularly anticholinergics) and increased incidence and severity of side effects have been reported when cimetidine is added to tricyclic antidepressant regimens. In well-controlled patients receiving a combination of tricyclic antidepressants and cimetidine, discontinuation of cimetidine may decrease the plasma levels and efficacy of the antidepressant.
Caution is advised if patients are also receiving high doses of etravironol. Transient delirium has been reported in patients treated with etravironol 1 g and amitriptyline hydrochloride 75-150 mg.
Drug overdose]
Death may occur with overdose of these drugs. Polypharmacy intake (including alcohol) is common in intentional tricyclic antidepressant overdoses. Because the management of drug overdoses is complex and variable, physicians are advised to contact a poison control center for the latest information on treatment. Tricyclic antidepressant overdose rapidly progresses to signs and symptoms of toxicity and therefore requires hospital monitoring as soon as possible.
1. Manifestations
Important manifestations of drug overdose include cardiac rhythm disturbances, severe hypotension, convulsions, and CNS depression, including coma. ECG changes, especially in the QRS axis or width, are clinically important indications of tricyclic antidepressant toxicity. In addition, terminal QRS complex wave right axis shift with prolonged QT interval and sinus tachycardia are specific and sensitive indications of first generation tricyclic drug overdose. The absence of these findings does not exclude drug overdose. Prolonged PR intervals, ST-T wave changes, ventricular tachycardia, and fibrillation may also occur.
Other signs of overdose may include: decreased myocardial contractility, confusion, inattention, transient visual hallucinations, pupillary dilation, ocular motility disorders, agitation, polyneurogenic neuropathy, xerosis, lethargy, muscle rigidity, vomiting, hypothermia, hyperthermia, or any of the symptoms listed in [ADVERSE REACTIONS].
2.Administration
2.1 General management
Monitor electrocardiogram and start cardiac monitoring immediately. Protect the patient’s airway, establish an intravenous line, and initiate gastric lavage. Monitor cardiac monitoring for at least 6 hours and observe for signs of CNS or respiratory depression, hypotension, cardiac rhythm disturbances and/or conduction block, and seizures as needed. If signs of toxicity occur at any time during this period, extended monitoring is required. Several cases have been reported of patients dying from fatal arrhythmias following drug overdose; all of these patients exhibited clinical evidence of significant toxicity prior to death, and most received inadequate bowel cleansing. Monitoring of plasma drug levels should not be used to guide the management of patients.
2.2 Gastrointestinal cleansing
All patients suspected of tricyclic antidepressant overdose should receive gastrointestinal cleansing. This should include extensive gastric lavage followed by treatment with activated charcoal. If the patient’s consciousness is impaired, ensure a clear airway before gastric lavage. Emetics are prohibited.
2.3 Cardiovascular
A maximal limb lead QRS time frame of ≥0.10 seconds is probably the best indication of drug overdose severity. Serum pH should be maintained in the range of 7.45 to 7.55 using intravenous sodium bicarbonate. Hyperventilation may also be used if the pH response is not adequate. The use of both hyperventilation and sodium bicarbonate should be used with extreme caution and frequent monitoring of pH. pH should not exceed 7.60 or pCO2 should not be less than 20 mm Hg. Rhythm disorders that do not respond well to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bromobendazole, or phenytoin sodium. Type Ia and Ic antiarrhythmic agents (e.g., quinidine, propiamine, and procainamide) are usually contraindicated.
In rare cases, hemoperfusion may be beneficial in acutely poisoned patients with acute refractory cardiovascular instability. However, hemodialysis, peritoneal dialysis, blood exchange therapy, and forced diuresis have usually been reported to be ineffective in the treatment of tricyclic antidepressant poisoning.
2.4 CNS
In patients with CNS suppression, early intubation is recommended because of the potential for sudden deterioration. Seizures should be controlled with benzodiazepines or, if these are ineffective, other anticonvulsants (e.g., phenobarbital or phenytoin) may be used.
Treatment with toxic lentil is not recommended unless life-threatening symptoms are present and have failed to respond to other treatments, and only in consultation with a poison control center.
3. Psychiatric follow-up
Because drug overdoses are often well thought out, patients may attempt suicide by other means during the recovery phase. A referral to psychiatry may therefore be appropriate.
4. Management of children
Management principles for children are similar to those for adult drug overdoses. And for specific treatment of children, it is strongly recommended that the physician consult with the local poison control center.
Pharmacology and toxicology]
Amitriptyline hydrochloride is an antidepressant with sedative effect. The mechanism of action in humans is not clear. It is not a monoamine oxidase inhibitor and does not act primarily by stimulating the central nervous system.
Amitriptyline inhibits the membrane pump mechanism responsible for the uptake of norepinephrine and serotonin in adrenergic and serotonin neurons. Pharmacologically, this action enhances or prolongs neuronal activity because of the physiological importance of the reuptake of these biogenic amines in terminating transmission activity. Some believe that this interference with the reuptake of norepinephrine and/or serotonin forms the basis of the antidepressant activity of amitriptyline.
[Pharmacokinetics].
Studies conducted in humans following oral administration of 14C-labeled drugs have shown that amitriptyline is rapidly absorbed and metabolized. Plasma radioactivity was practically negligible, although significant radioactivity was detected in urine for 4 to 6 hours and 1/3 to 1/2 of the drug dose was excreted within 24 hours.
Amitriptyline is metabolized by N-demethylation and bridge hydroxylation in humans, rabbits and rats. Virtually the entire dose is excreted as a glucuronide conjugate or sulfate conjugate of the metabolite, with only a small amount of the prototype drug in the urine. Other metabolic pathways may be involved.
Storage]
Store under shade and seal.
Packaging
High density polyethylene bottle for oral solid medicine, 100 tablets/bottle.
Expiration date
24 months
Execution Standard
Approval number】
State Drug Certificate H43020561
[Drug Marketing Licensee
Name: Hunan Dongting Pharmaceutical Co.
Registered Address: No. 16, Dongyan Road, Chenjiagang Community, Deshan Street Office, Changde Economic and Technological Development Zone, Hunan Province (No. 16, Dongyan Road, Deshan, Changde)
【Manufacturer
Company name: Hunan Dongting Pharmaceutical Co.
Production Address: No. 375 Deshan Avenue, Changde Economic and Technological Development Zone, Hunan Province
Postal code: 415001
Contact：（0736）7313298 7315683
Fax
Fax: (0736) 7317385
Web
Address: http://www.dtpharm.com