[System]
You are a highly knowledgeable and precise medical assistant specializing in pharmacology. Your role is to assist doctors by providing detailed and accurate information on the combined effects of multiple pharmaceutical compounds when used together. Specifically, you will analyze and report on the following aspects: "contraindications", "adverse_reactions", "drug_interactions", "indications_and_usage", "warnings_and_cautions", "overdosage", "active_flag", "generic_name", "route", "product_type", "stop_use", "do_not_use", "when_using", "warnings", "precautions", "information_for_patients", "pregnancy", "pediatric_use", and "geriatric_use".

When a list of compounds is provided as input, your response must be structured, reliable, and formatted as a single JSON object. This object should represent the collective effects and interactions of the compounds together, including the following keys:

- "contraindications": A detailed list of conditions or factors that would make the combined use of the compounds inadvisable.
- "adverse_reactions": Information about potential negative side effects that may occur when the compounds are used together.
- "drug_interactions": Details on how the compounds may interact with each other and with other medications or substances.
- "indications_and_usage": The medical conditions for which the combined use of the compounds may be prescribed or used.
- "warnings_and_cautions": Important warnings and precautions that need to be taken into account when using the compounds together.
- "overdosage": Guidance on what to do in case of overdose and the potential consequences of overdosing on the combination of compounds.
- "active_flag": An indication of whether the combined use of the compounds is currently active or approved for use.
- "generic_name": The generic names of the compounds used together.
- "route": The method by which the compounds are administered (e.g., oral, intravenous) and how these routes may interact.
- "product_type": The types of pharmaceutical products and how their combination may affect efficacy or safety.
- "stop_use": Conditions under which the combined use of the compounds should be discontinued.
- "do_not_use": Specific scenarios or conditions in which the compounds should not be used together.
- "when_using": Instructions or advice on what to do or avoid while using the compounds together.
- "warnings": General warnings associated with the combined use of the compounds.
- "precautions": Precautionary measures to take before or while using the compounds together.
- "information_for_patients": Information that should be conveyed to patients regarding the use of the compounds together.
- "pregnancy": Guidelines on the use of the compounds together during pregnancy.
- "pediatric_use": Guidelines on the use of the compounds together in pediatric patients.
- "geriatric_use": Guidelines on the use of the compounds together in elderly patients.

Ensure that the JSON object is comprehensive, clear, and contains all necessary information about the combined effects. Your responses should be as thorough and accurate as possible to aid doctors in making informed decisions for their patients.

[User] {"OLOPATADINE HYDROCHLORIDE"}

[Assistant] {'contraindications': '{"4 CONTRAINDICATIONS None. None ( 4 )."}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The most clinically significant adverse reactions described in other sections of labeling include: Epistaxis, Nasal Ulceration, and Nasal Septal Perforation [see Warnings and Precautions ( 5.1 )] Somnolence and Impaired Mental Alertness [see Warnings and Precautions (5.2)] The most common (> 1%) adverse reactions, included bitter taste, headache, epistaxis, pharyngolaryngeal pain, post-nasal drip, cough, and urinary tract infection in patients 12 years of age and older and epistaxis, headache, upper respiratory tract infection, bitter taste, pyrexia, and rash in patients 6 to 11 years of age ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflect exposure to olopatadine hydrochloride nasal solution in 2,770 patients with seasonal or perennial allergic rhinitis in 10 controlled clinical trials of 2 weeks to 12 months duration. Olopatadine hydrochloride nasal solution is not indicated for use in patients with perennial allergic rhinitis. The safety data from adults and adolescents are based upon 6 placebo-controlled clinical trials (3.7 pH vehicle nasal spray or 7 pH vehicle nasal spray) in which 1,834 patients with seasonal or perennial allergic rhinitis (652 males and 1,182 females) 12 years of age and older were treated with olopatadine hydrochloride nasal solution two sprays per nostril twice daily. There were 1,180 patients (olopatadine hydrochloride nasal solution, 587; vehicle nasal spray, 593) that participated in 3 efficacy and safety trials of 2 weeks duration. There were 2,840 patients (olopatadine hydrochloride nasal solution, 1,247; 3.7 pH vehicle nasal spray, 1,251; 7 pH vehicle nasal spray, 342) that participated in 3 long-term clinical trials of 1-year duration. The racial distribution of adult and adolescent patients receiving olopatadine hydrochloride nasal solution was 77% white, 9% black, and 14% other. The incidence of discontinuation due to adverse reactions in these controlled clinical trials was comparable for olopatadine hydrochloride nasal solution and vehicle nasal spray. Overall, 4.7% of the 1,834 adult and adolescent patients across all 6 studies treated with olopatadine hydrochloride nasal solution, 3.5% of the 1,844 patients treated with 3.7 pH vehicle nasal spray discontinued due to adverse reactions, and 2.9% of the 342 patients treated with 7 pH vehicle nasal spray discontinued due to adverse reactions. The safety data from pediatric patients 6 to 11 years of age are based upon 3 clinical trials in which 870 children with seasonal allergic rhinitis (376 females and 494 males) were treated with olopatadine hydrochloride nasal solution one or two sprays per nostril twice daily for 2 weeks. The racial distribution of pediatric patients receiving olopatadine hydrochloride nasal solution was 68.6% white, 16.6% black, and 14.8% other. The incidence of discontinuation due to adverse reactions in these controlled clinical trials was comparable for olopatadine hydrochloride nasal solution and vehicle nasal spray. Overall, 1.4% of the 870 pediatric patients across all 3 studies treated with olopatadine hydrochloride nasal solution and 1.3% of the 872 pediatric patients treated with vehicle nasal spray discontinued due to adverse reactions. Adults and Adolescents 12 Years of Age and Older in Short-Term (2 week) Trials There were 1,180 patients 12 years of age and older (olopatadine hydrochloride nasal solution, 587; vehicle nasal spray, 593) that participated in 3 efficacy and safety trials of 2 weeks duration. Table 1 presents the most common adverse reactions (0.9% or greater in patients treated with olopatadine hydrochloride nasal solution that occurred more frequently in patients treated with olopatadine hydrochloride nasal solution compared with vehicle nasal spray in the 3 clinical trials of 2 weeks duration. Table 1: Adverse Reactions Occurring at an Incidence of 0.9% or Greater in Controlled Clinical Trials of 2 Weeks Duration with Olopatadine Hydrochloride Nasal Solution (Nasal Spray) in Adolescent and Adult Patients 12 Years of Age and Older with Seasonal Allergic Rhinitis Adult and Adolescent Patients 12 Years and Older Adverse Reaction Olopatadine Hydrochloride Nasal Solution (Nasal Spray) N = 587 Vehicle Nasal Spray N = 593 Bitter taste 75 (12.8%) 5 (0.8%) Headache 26 (4.4%) 24 (4%) Epistaxis 19 (3.2%) 10 (1.7%) Pharyngolaryngeal Pain 13 (2.2%) 8 (1.3%) Post-nasal drip 9 (1.5%) 5 (0.8%) Cough 8 (1.4%) 3 (0.5%) Urinary tract infection 7 (1.2%) 3 (0.5%) CPK elevation 5 (0.9%) 2 (0.3%) Dry mouth 5 (0.9%) 1 (0.2%) Fatigue 5 (0.9%) 4 (0.7%) Influenza 5 (0.9%) 1 (0.2%) Nasopharyngitis 5 (0.9%) 4 (0.7%) Somnolence 5 (0.9%) 2 (0.3%) Throat irritation 5 (0.9%) 0 (0%) There were no differences in the incidence of adverse reactions based on gender or race. Clinical trials did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger subjects. Pediatric Patients 6 to 11 Years of Age There were 1,742 pediatric patients 6 to 11 years of age (olopatadine nasal spray, 870; vehicle nasal spray, 872) with seasonal allergic rhinitis that participated in 3 clinical trials of 2 weeks duration. Two of the studies used the investigational formulation of olopatadine nasal spray, and one of the studies used olopatadine hydrochloride nasal solution. One study evaluated the safety of olopatadine hydrochloride nasal solution at doses of one and two sprays per nostril twice daily in 1188 patients, in which 298 were exposed to olopatadine hydrochloride nasal solution1 spray, 296 were exposed to olopatadine hydrochloride nasal solution (nasal spray) 2 sprays, 297 were exposed to vehicle 1 spray, and 297 were exposed to vehicle 2 sprays twice daily for 2 weeks. Table 2 presents the most common adverse reactions (greater than 1% in pediatric patients 6 to 11 years of age treated with olopatadine hydrochloride nasal solution one spray per nostril) that occurred more frequently with olopatadine hydrochloride nasal solution compared with vehicle nasal spray. Table 2. Adverse Reactions Occurring at an Incidence of Greater Than 1% in a Controlled Clinical Trial of 2 Weeks Duration With Olopatadine Hydrochloride Nasal Solution (Nasal Spray) in Pediatric Patients 6 to 11 Years of Age With Seasonal Allergic Rhinitis Pediatric Patients 6 to 11 Years of Age Adverse Reaction Olopatadine Hydrochloride Nasal Solution One Spray per Nostril N = 298 Vehicle Nasal Spray One Spray per Nostril N = 297 Epistaxis 17 (5.7%) 11 (3.7%) Headache 13 (4.4%) 11 (3.7%) Upper respiratory tract infection 8 (2.6%) 0 Bitter taste 3 (1%) 0 Pyrexia 4 (1.3%) 3 (1%) Rash 4 (1.3%) 0 There were no differences in the incidence of adverse reactions based on gender, race, or ethnicity. Long-Term (12 month) Safety Trials In a 12-month, placebo-controlled, safety trial (vehicle nasal spray), 890 patients 12 years of age and older with perennial allergic rhinitis were randomized to treatment with olopatadine hydrochloride nasal solution two sprays per nostril twice daily (445 patients) or vehicle nasal spray (445 patients). In the olopatadine hydrochloride nasal solution and vehicle nasal spray groups, 72% and 74% of patients, respectively, completed the trial. Overall, 7% and 5%, respectively, discontinued study participation due to an adverse reaction. The most frequently reported adverse reaction was epistaxis, which occurred in 25% of patients treated with olopatadine hydrochloride nasal solution and 28% in patients treated with vehicle nasal spray. Epistaxis resulted in discontinuation of 0.9% of patients treated with olopatadine hydrochloride nasal solution and 0.2% of patients treated with vehicle nasal spray. Nasal ulcerations occurred in 10% of patients treated with olopatadine hydrochloride nasal solution and 9% of patients treated with vehicle nasal spray. Nasal ulcerations resulted in discontinuation of 0.4% of patients treated with olopatadine hydrochloride nasal solution and 0.2% patients treated with vehicle nasal spray. There were no patients with nasal septal perforation in either treatment group. Somnolence was reported in 1 patient treated with olopatadine hydrochloride nasal solution and 1 patient treated with vehicle nasal spray. Weight increase was reported in 6 patients treated with olopatadine hydrochloride nasal solution and 1 patient treated with vehicle nasal spray. Depression or worsening of depression occurred in 9 patients treated with olopatadine hydrochloride nasal solution and in 5 patients treated with vehicle nasal spray. Three patients, 2 of whom had preexisting histories of depression, who received olopatadine hydrochloride nasal solution were hospitalized for depression compared to none who received vehicle nasal spray. In a second 12-month placebo-controlled, safety trial (vehicle nasal spray), 459 patients 12 years of age and older with perennial allergic rhinitis were treated with two sprays per nostril of an investigational formulation of olopatadine hydrochloride nasal solution containing povidone (not the commercially marketed formulation) and 465 patients were treated with 2 sprays of a vehicle nasal spray containing povidone. Nasal septal perforations were reported in one patient treated with the investigational formulation of olopatadine hydrochloride nasal solution and 2 patients treated with the vehicle nasal spray. Epistaxis was reported in 19% of patients treated with the investigational formulation of olopatadine hydrochloride nasal solution and 12% of patients treated with vehicle nasal spray. Somnolence was reported in 3 patients treated with the investigational formulation of olopatadine hydrochloride nasal solution compared to 1 patient treated with vehicle nasal spray. Fatigue was reported in 5 patients treated with the investigational formulation of olopatadine hydrochloride nasal solution compared to 1 patient treated with vehicle nasal spray. In a third 3-arm, 12-month, placebo-controlled, safety trial (vehicle nasal spray), conducted post approval, 1,026 patients 12 years of age and older with perennial allergic rhinitis were randomized to treatment with olopatadine hydrochloride nasal solution (343 patients), a 3.7 pH vehicle nasal spray (341 patients), or a 7 pH vehicle nasal spray (342 patients). All treatments were administered as two sprays per nostril, twice daily. Overall, 5% of olopatadine hydrochloride nasal solution patients, 2% of 3.7 pH vehicle patients and 3% of 7 pH vehicle patients discontinued due to adverse reactions. The most frequently reported adverse event was epistaxis, which occurred in 24% of patients treated with olopatadine hydrochloride nasal solution, 20% of patients treated with 3.7 pH vehicle nasal spray, and 23% of patients treated with 7 pH vehicle nasal spray. Epistaxis resulted in the discontinuation of 2 patients treated with olopatadine hydrochloride nasal solution and 1 patient treated with 7 pH vehicle nasal spray. Nasal septal perforation was reported for one patient treated with the 3.7 pH vehicle nasal spray. Nasal ulcerations occurred in 9% of patients treated with olopatadine hydrochloride nasal solution, 8% of patients treated with 3.7 pH vehicle nasal spray, and 9% of patients treated with 7 pH vehicle nasal spray. Nasal ulceration resulted in the discontinuation of 1 patient treated with olopatadine hydrochloride nasal solution. Hyposmia and anosmia were each reported by one patient treated with olopatadine hydrochloride nasal solution. Neither somnolence nor weight loss was reported. Depression occurred in 3 patients treated with olopatadine hydrochloride nasal solution, 2 patients treated with 3.7 pH vehicle nasal spray, and 3 patients treated with 7 pH vehicle nasal spray. There were no long-term clinical trials in children below 12 years of age. 6.2 Postmarketing Experience During the post approval use of olopatadine hydrochloride nasal solution, the following adverse reactions have been identified. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most common adverse reactions reported include dizziness, dysgeusia, epistaxis, headache, nasal discomfort, oropharyngeal pain, and somnolence. Additionally, hyposmia and anosmia have been reported with the use of olopatadine hydrochloride nasal solution."}', 'drug_interactions': '{"7 DRUG INTERACTIONS Formal drug-drug interaction studies were not conducted for olopatadine hydrochloride nasal solution. Drug interactions with inhibitors of liver enzymes are not anticipated because olopatadine is eliminated predominantly by renal excretion. Drug interactions involving P450 inhibition and plasma protein binding are also not expected [see Clinical Pharmacology ( 12.3 )]."}', 'indications_and_usage': '{"1 INDICATIONS AND USAGE Olopatadine hydrochloride nasal solution is indicated for the relief of the symptoms of seasonal allergic rhinitis in adults and pediatric patients 6 years of age and older. Olopatadine hydrochloride nasal solution is an H 1 receptor antagonist indicated for the relief of the symptoms of seasonal allergic rhinitis in adults and pediatric patients 6 years of age and older ( 1 )."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Epistaxis, Nasal Ulceration, and Nasal Septal Perforation: Monitor patients periodically for signs of adverse effects on the nasal mucosa. Discontinue if ulcerations or perforations occur. Avoid use in patients with nasal disease other than allergic rhinitis ( 5.1 ). Avoid engaging in hazardous occupations requiring complete mental alertness and coordination, such as driving or operating machinery when taking olopatadine hydrochloride nasal solution ( 5.2 ). Avoid concurrent use of alcohol or other central nervous system depressants with olopatadine hydrochloride nasal solution ( 5.2 ). 5.1 Local Nasal Effects Epistaxis and Nasal Ulceration In placebo-controlled clinical trials (vehicle nasal spray) of 2 weeks to 12 months duration, epistaxis and nasal ulcerations were reported [see Adverse Reactions ( 6.1 )] . Nasal Septal Perforation Three placebo-controlled long term (12 months) safety trials (vehicle nasal spray) were conducted. In the first safety trial, patients were treated with an investigational formulation of olopatadine hydrochloride nasal solution containing povidone (not the commercially marketed formulation) or a vehicle nasal spray containing povidone. Nasal septal perforations were reported in one patient treated with the investigational formulation of olopatadine hydrochloride nasal solution and 2 patients treated with the vehicle nasal spray. In the second safety trial with olopatadine hydrochloride nasal solution, which does not contain povidone, there were no reports of nasal septal perforation. In the third safety trial, one patient exposed to the 3.7 pH vehicle nasal spray (containing no povidone) reported a nasal septal perforation [see Adverse Reactions ( 6.1 )]. Before starting olopatadine hydrochloride nasal solution, conduct a nasal examination to ensure that patients are free of nasal disease other than allergic rhinitis. Perform nasal examinations periodically for signs of adverse effects on the nasal mucosa and consider stopping olopatadine hydrochloride nasal solution if patients develop nasal ulcerations. 5.2 Somnolence and Impaired Mental Alertness In clinical trials, the occurrence of somnolence has been reported in some patients taking olopatadine hydrochloride nasal solution [see Adverse Reactions ( 6.1 )] . Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination, such as driving or operating machinery after administration of olopatadine hydrochloride nasal solution. Concurrent use of olopatadine hydrochloride nasal solution with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur."}', 'overdosage': '{"10 OVERDOSAGE Symptoms of antihistamine overdose may include drowsiness in both adults and children. Agitation and restlessness followed by drowsiness may also occur in children. There is no known specific antidote to olopatadine hydrochloride nasal solution. Should overdose occur, symptomatic or supportive treatment is recommended, taking into account any concomitantly ingested medications. For additional information about overdose treatment, call a poison control center (1-800-222-1222)."}', 'active_flag': 'Y', 'generic_name': '{"OLOPATADINE HYDROCHLORIDE"}', 'route': '{NASAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, 'precautions': None, 'information_for_patients': '{"17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Local Nasal Effects and Other Common Adverse Reactions Inform patients that treatment with olopatadine hydrochloride nasal solution may lead to adverse reactions, which include epistaxis and nasal ulcerations [see Warnings and Precautions ( 5.1 )] . Other common adverse reactions reported with use of olopatadine hydrochloride nasal solution include bitter taste, headache, and pharyngolaryngeal pain [see Adverse Reactions ( 6 )]. Somnolence and Impaired Mental Alertness Somnolence has been reported in some patients taking olopatadine hydrochloride nasal solution. Caution patients against engaging in hazardous occupations requiring complete mental alertness and motor coordination, such as driving or operating machinery after administration of olopatadine hydrochloride nasal solution [see Warnings and Precautions ( 5.2 )]. Concurrent Use of Alcohol and Other Central Nervous System Depressants Advise patients that concurrent use of olopatadine hydrochloride nasal solution with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur [see Warnings and Precautions ( 5.2 )]. Keep Spray Out of Eyes Inform patients to avoid spraying olopatadine hydrochloride nasal solution in their eyes [see Dosage and Administration (2.3)]. APOTEX INC. OLOPATADINE HYDROCHLORIDE NASAL SOLUTION Manufactured by Manufactured for Apotex Inc. Apotex Corp. Toronto, Ontario Weston, FL Canada M9L 1T9 33326 April 2021"}', 'pregnancy': '{"8.1 Pregnancy Risk Summary Published data from postmarketing experience with antihistamines, with similar mechanism of action to olopatadine hydrochloride nasal solution, have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, there are no published human data specific to olopatadine hydrochloride nasal solution. In animal reproductive studies, oral administration of olopatadine hydrochloride to pregnant rats and rabbits caused a decrease in the number of live fetuses at maternal doses approximately 110 and 1460 times the maximum recommended human daily intranasal dose (MRHDID) on a mg/m 2 basis, respectively (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4%, and 15% to 20%, respectively. Data Animal Data In an oral embryo-fetal development study, pregnant rabbits were dosed throughout the period of organogenesis at doses up to 400 mg/kg/day. A decrease in the number of live fetuses was observed at 400 mg/kg/day (1460 times the MRHDID, on a mg/m 2 basis). In an oral embryo-fetal development study, pregnant rats were dosed throughout the period of organogenesis at doses up to 600 mg/kg/day. Maternal toxicity, producing death and reduced maternal body weight gain was observed at 600 mg/kg/day (approximately 1100 times the MRHDID on a mg/m 2 basis). Olopatadine produced cleft palate at 60 mg/kg/day (approximately 110 times the MRHDID on a mg/m 2 basis) and decreased embryo-fetal viability and reduced fetal weight in rats at 600 mg/kg/day (approximately 1100 times the MRHDID on a mg/m 2 basis). In peri-/postnatal toxicity studies, pregnant rats received oral doses of olopatadine up to 600 mg/kg/day during late gestation and throughout the lactation period. Olopatadine produced decreased neonatal survival at 60 mg/kg/day (approximately 110 times the MRHDID on a mg/m 2 basis) and reduced body weight gain in pups at 4 mg/kg/day (approximately 7 times the MRHDID on a mg/m 2 basis). These effects appeared attributable to exposure of pups via the milk as demonstrated in a cross-fostered study in which pups of untreated dams cross-fostered to dams treated with 60 mg/kg/day olopatadine orally during the lactation period exhibited decreased body weight gain."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and effectiveness of olopatadine hydrochloride nasal solution for the relief of symptoms of seasonal allergic rhinitis have been established in pediatric patients aged 6 years and older. The safety and effectiveness of olopatadine in pediatric patients 6 to 11 years of age are supported by 3 vehicle-controlled 2-week studies in 870 patients [see Adverse Reactions (6.1)] . Doses studied included one and two sprays per nostril twice daily. One of these studies evaluated the safety of olopatadine hydrochloride nasal solution at doses of one and two sprays per nostril twice daily in 1,188 patients, of which 298 patients were exposed to olopatadine hydrochloride nasal solution 1 spray, and 297 patients were exposed to vehicle 1 spray. In this study, the incidence of epistaxis with olopatadine hydrochloride nasal solution use was 5.7% [see Adverse Reactions (6.1), Clinical Studies (14)]. The safety and effectiveness of olopatadine hydrochloride nasal solution in pediatric patients aged 12 years and older are supported by 3 randomized, double blind, parallel group, multicenter, placebo-controlled clinical trials of 2 weeks duration in adult and adolescent patients [see Clinical Studies (14)]. In these studies, the incidence of epistaxis with olopatadine hydrochloride nasal solution use in 587 patients was 3.2% [see Adverse Reactions (6.1)]. The safety and effectiveness of olopatadine hydrochloride nasal solution have not been established in pediatric patients under 6 years of age. The safety of olopatadine hydrochloride nasal solution at a dose of one spray per nostril twice daily was evaluated in one 2-week vehicle-controlled study in 132 pediatric patients 2 to 5 years of age with allergic rhinitis. In this trial, 66 patients were exposed to olopatadine hydrochloride nasal solution. The most common (greater than 1%) adverse events reported were diarrhea (9.1%), epistaxis (6.1%), rhinorrhea (4.5%), bitter taste (3%) and wheezing (3%). Diarrhea was reported more frequently (9.1%) in patients 2 to 5 years of age than 6 to 11 year old age group (< 1%)."}', 'geriatric_use': '{"8.5 Geriatric Use Clinical studies of olopatadine hydrochloride nasal solution did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy."}'}


[System]
You are a highly knowledgeable and precise medical assistant specializing in pharmacology. Your role is to assist doctors by providing detailed and accurate information on the combined effects of multiple pharmaceutical compounds when used together. Specifically, you will analyze and report on the following aspects: "contraindications", "adverse_reactions", "drug_interactions", "indications_and_usage", "warnings_and_cautions", "overdosage", "active_flag", "generic_name", "route", "product_type", "stop_use", "do_not_use", "when_using", "warnings", "precautions", "information_for_patients", "pregnancy", "pediatric_use", and "geriatric_use".

When a list of compounds is provided as input, your response must be structured, reliable, and formatted as a single JSON object. This object should represent the collective effects and interactions of the compounds together, including the following keys:

- "contraindications": A detailed list of conditions or factors that would make the combined use of the compounds inadvisable.
- "adverse_reactions": Information about potential negative side effects that may occur when the compounds are used together.
- "drug_interactions": Details on how the compounds may interact with each other and with other medications or substances.
- "indications_and_usage": The medical conditions for which the combined use of the compounds may be prescribed or used.
- "warnings_and_cautions": Important warnings and precautions that need to be taken into account when using the compounds together.
- "overdosage": Guidance on what to do in case of overdose and the potential consequences of overdosing on the combination of compounds.
- "active_flag": An indication of whether the combined use of the compounds is currently active or approved for use.
- "generic_name": The generic names of the compounds used together.
- "route": The method by which the compounds are administered (e.g., oral, intravenous) and how these routes may interact.
- "product_type": The types of pharmaceutical products and how their combination may affect efficacy or safety.
- "stop_use": Conditions under which the combined use of the compounds should be discontinued.
- "do_not_use": Specific scenarios or conditions in which the compounds should not be used together.
- "when_using": Instructions or advice on what to do or avoid while using the compounds together.
- "warnings": General warnings associated with the combined use of the compounds.
- "precautions": Precautionary measures to take before or while using the compounds together.
- "information_for_patients": Information that should be conveyed to patients regarding the use of the compounds together.
- "pregnancy": Guidelines on the use of the compounds together during pregnancy.
- "pediatric_use": Guidelines on the use of the compounds together in pediatric patients.
- "geriatric_use": Guidelines on the use of the compounds together in elderly patients.

Ensure that the JSON object is comprehensive, clear, and contains all necessary information about the combined effects. Your responses should be as thorough and accurate as possible to aid doctors in making informed decisions for their patients.

[User] {ALPRAZOLAM}

[Assistant] {'contraindications': '{"CONTRAINDICATIONS Alprazolam extended-release tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines. Alprazolam extended-release tablets may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in patients with acute narrow angle glaucoma. Alprazolam extended-release tablets are contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) (see CLINICAL PHARMACOLOGY , WARNINGS and PRECAUTIONS–Drug Interactions )."}', 'adverse_reactions': '{"ADVERSE REACTIONS The information included in the subsection on Adverse Events Observed in Short-Term, Placebo-Controlled Trials with alprazolam extended-release tablets is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder. Adverse event reports were elicited either by general inquiry or by checklist, and were recorded by clinical investigators using terminology of their own choosing. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened during therapy following baseline evaluation. In the tables and tabulations that follow, standard MedDRA terminology (version 4.0) was used to classify reported adverse events. Adverse Events Observed in Short-Term, Placebo-Controlled Trials of Alprazolam Extended-Release Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials Approximately 17% of the 531 patients who received alprazolam extended-release in placebo-controlled clinical trials for panic disorder had at least one adverse event that led to discontinuation compared to 8% of 349 placebo-treated patients. The most common events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of the patients treated with alprazolam extended-release at a rate at least twice that of placebo) are shown in the following table. Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials System Organ Class/ Adverse Event Percentage of Patients Discontinuing Due to Adverse Events Alprazolam Extended-Release (n=531) Placebo (n=349) Nervous system disorders Sedation Somnolence Dysarthria Coordination abnormal Memory impairment 7.5 3.2 2.1 1.9 1.5 0.6 0.3 0 0.3 0.3 General disorders/administration site conditions Fatigue 1.7 0.6 Psychiatric disorders Depression 2.5 1.2 Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam Extended-Release The prescriber should be aware that adverse event incidence cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with event incidence obtained from other clinical investigations involving different treatments, uses, and investigators. The cited values, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. The following table shows the incidence of treatment-emergent adverse events that occurred during 6- to 8-week placebo-controlled trials in 1% or more of patients treated with alprazolam extended-release where the incidence in patients treated with alprazolam extended-release was greater than the incidence in placebo-treated patients. The most commonly observed adverse events in panic disorder patients treated with alprazolam extended-release (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased (see table). Treatment-Emergent Adverse Events: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Alprazolam Extended-Release System Organ Class/Adverse Event Percentage of Patients Reporting Adverse Event Alprazolam Extended Release (n=531) Placebo (n=349) Nervous system disorders Sedation Somnolence Memory impairment Dysarthria Coordination abnormal Mental impairment Ataxia Disturbance in attention Balance impaired Paresthesia Dyskinesia Hypoesthesia Hypersomnia 45.2 23 15.4 10.9 9.4 7.2 7.2 3.2 3.2 2.4 1.7 1.3 1.3 22.6 6 6.9 2.6 0.9 5.7 3.2 0.6 0.6 1.7 1.4 0.3 0 General disorders/administration site conditions Fatigue Lethargy 13.9 1.7 9.2 0.6 Infections and infestations Influenza Upper respiratory tract infections 2.4 1.9 2.3 1.7 Psychiatric disorders Depression Libido decreased Disorientation Confusion Depressed mood Anxiety 12.1 6 1.5 1.5 1.3 1.1 9.2 2.3 0 0.9 0.3 0.6 Metabolism and nutrition disorders Appetite decreased Appetite increased Anorexia 7.3 7 1.5 7.2 6 0 Gastrointestinal disorders Dry mouth Constipation Nausea Pharyngolaryngeal pain 10.2 8.1 6 3.2 9.7 4.3 3.2 2.6 Investigations Weight increased Weight decreased 5.1 4.3 4.3 3.7 Injury, poisoning, and procedural complications Road traffic accident 1.5 0 Reproductive system and breast disorders Dysmenorrhea Sexual dysfunction Premenstrual syndrome 3.6 2.4 1.7 2.9 1.1 0.6 Musculoskeletal and connective tissue disorders Arthralgia Myalgia Pain in limb 2.4 1.5 1.1 0.6 1.1 0.3 Vascular disorders Hot flushes 1.5 1.4 Respiratory, thoracic, and mediastinal disorders Dyspnea Rhinitis allergic 1.5 1.1 0.3 0.6 Skin and subcutaneous tissue disorders Pruritus 1.1 0.9 Other Adverse Events Observed During the Premarketing Evaluation of Alprazolam Extended-Release Tablets Following is a list of MedDRA terms that reflect treatment-emergent adverse events reported by 531 patients with panic disorder treated with alprazolam extended-release. All potentially important reported events are included except those already listed in the above table or elsewhere in labeling, those events for which a drug cause was remote, those event terms that were so general as to be uninformative, and those events that occurred at rates similar to background rates in the general population. It is important to emphasize that, although the events reported occurred during treatment with alprazolam extended-release, they were not necessarily caused by the drug. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least l/l00 patients; infrequent adverse events are those occurring in less than l/100 patients but at least l/1000 patients; rare events are those occurring in fewer than l/1000 patients. Cardiac disorders: Frequent: palpitation; Infrequent: sinus tachycardia Ear and Labyrinth disorders: Frequent: Vertigo; Infrequent: tinnitus, ear pain Eye disorders: Frequent: blurred vision; Infrequent: mydriasis, photophobia Gastrointestinal disorders: Frequent: diarrhea, vomiting, dyspepsia, abdominal pain; Infrequent: dysphagia, salivary hypersecretion General disorders and administration site conditions: Frequent: malaise, weakness, chest pains; Infrequent: fall, pyrexia, thirst, feeling hot and cold, edema, feeling jittery, sluggishness, asthenia, feeling drunk, chest tightness, increased energy, feeling of relaxation, hangover, loss of control of legs, rigors Musculoskeletal and connective tissue disorders: Frequent: back pain, muscle cramps, muscle twitching Nervous system disorders: Frequent: headache, dizziness, tremor; Infrequent: amnesia, clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea syndrome, sleep talking, stupor Psychiatric system disorders: Frequent: irritability, insomnia, nervousness, derealization, libido increased, restlessness, agitation, depersonalization, nightmare; Infrequent: abnormal dreams, apathy, aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings, dysphonia, hallucination, homicidal ideation, mania, hypomania, impulse control, psychomotor retardation, suicidal ideation Renal and urinary disorders: Frequent: difficulty in micturition; Infrequent: urinary frequency, urinary incontinence Respiratory, thoracic, and mediastinal disorders: Frequent: nasal congestion, hyperventilation; Infrequent: choking sensation, epistaxis, rhinorrhea Skin and subcutaneous tissue disorders: Frequent: sweating increased; Infrequent: clamminess, rash, urticaria Vascular disorders: Infrequent: hypotension The categories of adverse events reported in the clinical development program for alprazolam tablets in the treatment of panic disorder differ somewhat from those reported for alprazolam extended-release tablets because the clinical trials with alprazolam tablets and alprazolam extended-release tablets used different standard medical nomenclature for reporting the adverse events. Nevertheless, the types of adverse events reported in the clinical trials with alprazolam tablets were generally the same as those reported in the clinical trials with alprazolam extended-release tablets. Discontinuation-Emergent Adverse Events Occurring at an Incidence of 5% or More Among Patients Treated with Alprazolam Extended-Release The following table shows the incidence of discontinuation-emergent adverse events that occurred during short-term, placebo-controlled trials in 5% or more of patients treated with alprazolam extended-release where the incidence in patients treated with alprazolam extended-release was two times greater than the incidence in placebo-treated patients. Discontinuation-Emergent Symptoms: Incidence in Short-Term, Placebo-Controlled Trials with Alprazolam Extended-Release System Organ Class/ Adverse Event Percentage of Patients Reporting Adverse Event Alprazolam Extended Release (n=422) Placebo (n=261) Nervous system disorders Tremor Headache Hypoesthesia Paresthesia 28.2 26.5 7.8 7.1 10.7 12.6 2.3 2.7 Psychiatric disorders Insomnia Nervousness Depression Derealization Anxiety Depersonalization 24.2 21.8 10.9 8 7.8 5.7 9.6 8.8 5 3.8 2.7 1.9 Gastrointestinal disorders Diarrhea 12.1 3.1 Respiratory, thoracic and mediastinal disorders Hyperventilation 8.5 2.7 Metabolism and nutrition disorders Appetite decreased 9.5 3.8 Musculoskeletal and connective tissue disorders Muscle twitching 7.4 2.7 Vascular disorders Hot flushes 5.9 2.7 There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam (see WARNINGS ). To discontinue treatment in patients taking alprazolam extended-release tablets, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam extended-release tablets be decreased by no more than 0.5 mg every three days (see DOSAGE AND ADMINISTRATION ). Some patients may benefit from an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder. Post Introduction Reports Various adverse drug reactions have been reported in association with the use of alprazolam tablets since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam tablets cannot be readily determined. Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, angioedema, peripheral edema, hyperprolactinemia, gynecomastia, and galactorrhea (see PRECAUTIONS )."}', 'drug_interactions': '{"Drug Interactions Use with Other CNS Depressants If alprazolam extended-release tablets are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression. Use with Imipramine and Desipramine The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown. Drugs that inhibit alprazolam metabolism via cytochrome P450 3A The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs of this type). Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam (caution is recommended during coadministration with alprazolam) Fluoxetine — Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance. Propoxyphene — Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%. Oral Contraceptives — Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%. Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines (caution is recommended during coadministration with alprazolam) Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of alprazolam 1 mg and steady state doses of sertraline (50 to 150 mg/day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with alprazolam (see WARNINGS ). Drugs demonstrated to be inducers of CYP3A Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam."}', 'indications_and_usage': '{"INDICATIONS AND USAGE Alprazolam extended-release tablets USP are indicated for the treatment of panic disorder, with or without agoraphobia. This claim is supported on the basis of two positive studies with alprazolam extended-release tablets USP conducted in patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic disorder (see CLINICAL EFFICACY TRIALS ). Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. The longer-term efficacy of alprazolam extended-release tablets USP has not been systematically evaluated. Thus, the physician who elects to use this drug for periods longer than 8 weeks should periodically reassess the usefulness of the drug for the individual patient."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Clinical Experience Overdosage reports with alprazolam tablets are limited. Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes, and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality. Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage. General Treatment of Overdose As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. If hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited value. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested. Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use."}', 'active_flag': 'Y', 'generic_name': '{ALPRAZOLAM}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS Dependence and Withdrawal Reactions, Including Seizures Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam. These include a spectrum of withdrawal symptoms; the most important is seizure (see DRUG ABUSE AND DEPENDENCE ). Even after relatively short-term use at doses of ≤ 4 mg/day, there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients who received alprazolam tablets, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of alprazolam tablets greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day. Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency, or more severe in intensity than seen at baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline. The rate of relapse, rebound, and withdrawal in patients with panic disorder who received alprazolam extended-release tablets has not been systematically studied. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder who received alprazolam tablets showed a high rate of rebound and withdrawal symptoms compared to placebo treated patients. In a controlled clinical trial in which 63 patients were randomized to alprazolam tablets and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal. In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 71% to 93% of patients treated with alprazolam tablets tapered completely off therapy compared to 89% to 96% of placebo treated patients. In a controlled postmarketing discontinuation study of panic disorder patients treated with alprazolam tablets, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. Seizures were reported for three patients in panic disorder clinical trials with alprazolam extended-release. In two cases, the patients had completed 6 weeks of treatment with alprazolam extended-release 6 mg/day before experiencing a single seizure. In one case, the patient abruptly discontinued alprazolam extended-release, and in both cases, alcohol intake was implicated. The third case involved multiple seizures after the patient completed treatment with alprazolam extended-release 4 mg/day and missed taking the medication on the first day of taper. All three patients recovered without sequelae. Seizures have also been observed in association with dose reduction or discontinuation of alprazolam tablets, the immediate release form of alprazolam. Seizures attributable to alprazolam were seen after drug discontinuance or dose reduction in 8 of 1980 patients with panic disorder or in patients participating in clinical trials where doses of alprazolam greater than 4 mg/day for over 3 months were permitted. Five of these cases clearly occurred during abrupt dose reduction, or discontinuation from daily doses of 2 to 10 mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from a single dose of 1 mg after tapering at a rate of 1 mg every three days from 6 mg daily. In two other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from alprazolam. The risk of seizure seems to be greatest 24 to 72 hours after discontinuation (see DOSAGE AND ADMINISTRATION for recommended tapering and discontinuation schedule). Status Epilepticus The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam tablets. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well. Interdose Symptoms Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam tablets have been reported in patients with panic disorder taking prescribed maintenance doses. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound, or withdrawal symptoms over the entire course of the interdosing interval. Risk of Dose Reduction Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose (e.g., the patient forgets, the patient is admitted to a hospital). Therefore, the dosage of alprazolam extended-release should be reduced or discontinued gradually (see DOSAGE AND ADMINISTRATION ). CNS Depression and Impaired Performance Because of its CNS depressant effects, patients receiving alprazolam extended-release should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with alprazolam extended-release. Risk of Fetal Harm Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If alprazolam is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Because of experience with other members of the benzodiazepine class, alprazolam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug. Alprazolam Interaction With Drugs That Inhibit Metabolism Via Cytochrome P450 3A The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant degree, alprazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with alprazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class. The following are examples of drugs known to inhibit the metabolism of alprazolam and/or related benzodiazepines, presumably through inhibition of CYP3A. Potent CYP3A Inhibitors Azole antifungal agents — Ketoconazole and itraconazole are potent CYP3A inhibitors and have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.7 fold, respectively. The coadministration of alprazolam with these agents is not recommended. Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the coadministration of alprazolam with them is not recommended (see CONTRAINDICATIONS ). Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam (caution and consideration of appropriate alprazolam dose reduction are recommended during coadministration with the following drugs) Nefazodone — Coadministration of nefazodone increased alprazolam concentration two-fold. Fluvoxamine — Coadministration of fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%, and decreased measured psychomotor performance. Cimetidine — Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%. Other Drugs Possibly Affecting Alprazolam Metabolism Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed in the PRECAUTIONS section (see PRECAUTIONS–Drug Interactions )."}', 'precautions': '{"PRECAUTIONS General Suicide As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Mania Episodes of hypomania and mania have been reported in association with the use of alprazolam tablets in patients with depression. Uricosuric Effect Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam. Use in Patients with Concomitant Illness It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in elderly or debilitated patients (see DOSAGE AND ADMINISTRATION ). The usual precautions in treating patients with impaired renal, hepatic, or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam tablets. A decreased systemic alprazolam elimination rate (e.g., increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving alprazolam tablets (see CLINICAL PHARMACOLOGY ). Information for Patients To assure safe and effective use of alprazolam extended-release, the physician should provide the patient with the following guidance. • Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines. • Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication. • Inform your physician if you are nursing. • Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc. • Do not increase the dose even if you think the medication “does not work anymore” without consulting your physician. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence. • Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur. • Some patients may find it very difficult to discontinue treatment with alprazolam extended-release due to severe emotional and physical dependence. Discontinuation symptoms, including possible seizures, may occur following discontinuation from any dose, but the risk may be increased with extended use at doses greater than 4 mg/day, especially if discontinuation is too abrupt. It is important that you seek advice from your physician to discontinue treatment in a careful and safe manner. Proper discontinuation will help to decrease the possibility of withdrawal reactions that can range from mild reactions to severe reactions such as seizure. Laboratory Tests Laboratory tests are not ordinarily required in otherwise healthy patients. However, when treatment is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable in keeping with good medical practice. Drug Interactions Use with Other CNS Depressants If alprazolam extended-release tablets are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression. Use with Imipramine and Desipramine The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown. Drugs that inhibit alprazolam metabolism via cytochrome P450 3A The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs of this type). Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam (caution is recommended during coadministration with alprazolam) Fluoxetine — Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance. Propoxyphene — Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%. Oral Contraceptives — Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%. Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines (caution is recommended during coadministration with alprazolam) Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of alprazolam 1 mg and steady state doses of sertraline (50 to 150 mg/day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with alprazolam (see WARNINGS ). Drugs demonstrated to be inducers of CYP3A Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam. Drug/Laboratory Test Interactions Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose). Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay. Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day. Pregnancy Teratogenic Effects Pregnancy Category D (see WARNINGS section). Nonteratogenic Effects It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines. Labor and Delivery Alprazolam has no established use in labor or delivery. Nursing Mothers Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use alprazolam. Pediatric Use Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established. Geriatric Use The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of alprazolam should be used in the elderly to preclude the development of ataxia and oversedation (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION )."}', 'information_for_patients': '{"Information for Patients To assure safe and effective use of alprazolam extended-release, the physician should provide the patient with the following guidance. • Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines. • Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication. • Inform your physician if you are nursing. • Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc. • Do not increase the dose even if you think the medication “does not work anymore” without consulting your physician. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence. • Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur. • Some patients may find it very difficult to discontinue treatment with alprazolam extended-release due to severe emotional and physical dependence. Discontinuation symptoms, including possible seizures, may occur following discontinuation from any dose, but the risk may be increased with extended use at doses greater than 4 mg/day, especially if discontinuation is too abrupt. It is important that you seek advice from your physician to discontinue treatment in a careful and safe manner. Proper discontinuation will help to decrease the possibility of withdrawal reactions that can range from mild reactions to severe reactions such as seizure."}', 'pregnancy': '{"Pregnancy Teratogenic Effects Pregnancy Category D (see WARNINGS section). Nonteratogenic Effects It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines."}', 'pediatric_use': '{"Pediatric Use Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established."}', 'geriatric_use': '{"Geriatric Use The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of alprazolam should be used in the elderly to preclude the development of ataxia and oversedation (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION )."}'}


[System]
You are a highly knowledgeable and precise medical assistant specializing in pharmacology. Your role is to assist doctors by providing detailed and accurate information on the combined effects of multiple pharmaceutical compounds when used together. Specifically, you will analyze and report on the following aspects: "contraindications", "adverse_reactions", "drug_interactions", "indications_and_usage", "warnings_and_cautions", "overdosage", "active_flag", "generic_name", "route", "product_type", "stop_use", "do_not_use", "when_using", "warnings", "precautions", "information_for_patients", "pregnancy", "pediatric_use", and "geriatric_use".

When a list of compounds is provided as input, your response must be structured, reliable, and formatted as a single JSON object. This object should represent the collective effects and interactions of the compounds together, including the following keys:

- "contraindications": A detailed list of conditions or factors that would make the combined use of the compounds inadvisable.
- "adverse_reactions": Information about potential negative side effects that may occur when the compounds are used together.
- "drug_interactions": Details on how the compounds may interact with each other and with other medications or substances.
- "indications_and_usage": The medical conditions for which the combined use of the compounds may be prescribed or used.
- "warnings_and_cautions": Important warnings and precautions that need to be taken into account when using the compounds together.
- "overdosage": Guidance on what to do in case of overdose and the potential consequences of overdosing on the combination of compounds.
- "active_flag": An indication of whether the combined use of the compounds is currently active or approved for use.
- "generic_name": The generic names of the compounds used together.
- "route": The method by which the compounds are administered (e.g., oral, intravenous) and how these routes may interact.
- "product_type": The types of pharmaceutical products and how their combination may affect efficacy or safety.
- "stop_use": Conditions under which the combined use of the compounds should be discontinued.
- "do_not_use": Specific scenarios or conditions in which the compounds should not be used together.
- "when_using": Instructions or advice on what to do or avoid while using the compounds together.
- "warnings": General warnings associated with the combined use of the compounds.
- "precautions": Precautionary measures to take before or while using the compounds together.
- "information_for_patients": Information that should be conveyed to patients regarding the use of the compounds together.
- "pregnancy": Guidelines on the use of the compounds together during pregnancy.
- "pediatric_use": Guidelines on the use of the compounds together in pediatric patients.
- "geriatric_use": Guidelines on the use of the compounds together in elderly patients.

Ensure that the JSON object is comprehensive, clear, and contains all necessary information about the combined effects. Your responses should be as thorough and accurate as possible to aid doctors in making informed decisions for their patients.

[User] {BENZOCAINE}

[Assistant] {'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use For oral mucosal use only, as directed by dentist. For the temporary relief of pain due to minor dental procedures."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{BENZOCAINE}', 'route': '{DENTAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings Methemoglobinemia warning: Use of this product may cause methemoglobinemia, a serious condition that must be treated promptly because it reduces the amount of oxygen carried in the blood. This can occur even if you have used this product before. Stop use and seek immediate medical attention if you or a child in your care develops: pale, gray or blue colored skin (cyanosis) headache rapid heart rate shortness of breath dizziness or lightheadedness fatigue or lack of energy \u200bAllergy alert: \u200bDo not use on patients with a history of allergies to local anesthetics such as procaine, butacaine, benzocaine or other \\"caine\\" anesthetics. \u200bDo not use \u200bfor more than 7 days unless directed by a physician. If sore mouth symptoms do not improve in 7 days; irritation, pain, or redness persists or worsens; or if swelling, rash or fever develops, see your physician promptly. for teething in children under 2 years of age \u200bWhen using this product \u200bavoid contact with eyes. If contact occurs, flush with water. \u200bDo not exceed recommended dosage. \u200bIf more than used for pain is accidentally swallowed, get medical help or contact a Poison Control Center right away. \u200bIf pregnant or breastfeeding, \u200bask a health professional before use."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}