[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] {GLIPIZIDE,"METFORMIN HYDROCHLORIDE"}

[Assistant] {'contraindications': '{"CONTRAINDICATIONS Glipizide and Metformin HCl Tablets are contraindicated in patients with: 1. Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 )(see WARNINGS and PRECAUTIONS ). 2. Known hypersensitivity to glipizide or metformin hydrochloride. 3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin."}', 'adverse_reactions': '{"ADVERSE REACTIONS Glipizide and Metformin HCl Tablets In a double-blind 24-week clinical trial involving Glipizide and Metformin HCl Tablets as initial therapy, a total of 172 patients received Glipizide and Metformin HCl Tablets 2.5 mg/250 mg, 173 received Glipizide and Metformin HCl Tablets 2.5 mg/500 mg, 170 received glipizide, and 177 received metformin. The most common clinical adverse events in these treatment groups are listed in Table 4 . Table 4: Clinical Adverse Events >5% in any Treatment Group, by Primary Term, in Initial Therapy Study Adverse Event Number (%) of Patients Glipizide5 mgtabletsN=170 Metformin500 mgtabletsN=177 Glipizide and Metformin HCl2.5 mg/250 mg tabletsN=172 Glipizide and Metformin HCl2.5 mg/500 mg tabletsN=173 Upper respiratory infection 12 (7.1) 15 (8.5) 17 (9.9) 14 (8.1) Diarrhea 8 (4.7) 15 (8.5) 4 (2.3) 9 (5.2) Dizziness 9 (5.3) 2 (1.1) 3 (1.7) 9 (5.2) Hypertension 17 (10.0) 10 (5.6) 5 (2.9) 6 (3.5) Nausea/vomiting 6 (3.5) 9 (5.1) 1 (0.6) 3 (1.7) In a double-blind 18-week clinical trial involving Glipizide and Metformin HCl Tablets as second-line therapy, a total of 87 patients received Glipizide and Metformin HCl Tablets, 84 received glipizide, and 75 received metformin. The most common clinical adverse events in this clinical trial are listed in Table 5 . Table 5: Clinical Adverse Events >5% in any Treatment Group, by Primary Term, in Second-Line Therapy Study Adverse Event Number (%) of Patients Glipizide 5 mg tablets a N=84 Metformin 500 mg tablets a N=75 Glipizide and Metformin HCl5 mg/500 mg tablets a N=87 Diarrhea 11 (13.1) 13 (17.3) 16 (18.4) Headache 5 (6.0) 4 (5.3) 11 (12.6) Upper respiratory infection 11 (13.1) 8 (10.7) 9 (10.3) Musculoskeletal pain 6 (7.1) 5 (6.7) 7 (8.0) Nausea/vomiting 5 (6.0) 6 (8.0) 7 (8.0) Abdominal pain 7 (8.3) 5 (6.7) 5 (5.7) UTI 4 (4.8) 6 (8.0) 1 (1.1) Hypoglycemia In a controlled initial therapy trial of Glipizide and Metformin HCl Tablets 2.5 mg/250 mg and 2.5 mg/500 mg the numbers of patients with hypoglycemia documented by symptoms (such as dizziness, shakiness, sweating, and hunger) and a fingerstick blood glucose measurement ≤50 mg/dL were 5 (2.9%) for glipizide, 0 (0%) for metformin, 13 (7.6%) for Glipizide and Metformin HCl Tablets 2.5 mg/250 mg, and 16 (9.3%) for Glipizide and Metformin HCl Tablets 2.5 mg/500 mg. Among patients taking either Glipizide and Metformin HCl Tablets 2.5 mg/250 mg or Glipizide and Metformin HCl Tablets 2.5 mg/500 mg, 9 (2.6%) patients discontinued Glipizide and Metformin HCl Tablets due to hypoglycemic symptoms and 1 required medical intervention due to hypoglycemia. In a controlled second-line therapy trial of Glipizide and Metformin HCl Tablets 5 mg/500 mg, the numbers of patients with hypoglycemia documented by symptoms and a fingerstick blood glucose measurement ≤50 mg/dL were 0 (0%) for glipizide, 1 (1.3%) for metformin, and 11 (12.6%) for Glipizide and Metformin HCl Tablets. One (1.1%) patient discontinued Glipizide and Metformin HCl Tablets therapy due to hypoglycemic symptoms and none required medical intervention due to hypoglycemia. (See PRECAUTIONS ) Gastrointestinal Reactions Among the most common clinical adverse events in the initial therapy trial were diarrhea and nausea/vomiting; the incidences of these events were lower with both Glipizide and Metformin HCl Tablets dosage strengths than with metformin therapy. There were 4 (1.2%) patients in the initial therapy trial who discontinued Glipizide and Metformin HCl Tablets therapy due to gastrointestinal (GI) adverse events. Gastrointestinal symptoms of diarrhea, nausea/vomiting, and abdominal pain were comparable among Glipizide and Metformin HCl Tablets, glipizide and metformin in the second-line therapy trial. There were 4 (4.6%) patients in the second-line therapy trial who discontinued Glipizide and Metformin HCl Tablets therapy due to GI adverse events. Glipizide Gastrointestinal Reactions Cholestatic and hepatocellular forms of liver injury accompanied by jaundice have been reported rarely in association with glipizide; Glipizide and Metformin HCl Tablets should be discontinued if this occurs."}', 'drug_interactions': None, 'indications_and_usage': '{"INDICATIONS AND USAGE Glipizide and Metformin HCl Tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE Glipizide Overdosage of sulfonylureas, including glipizide, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery. Clearance of glipizide from plasma would be prolonged in persons with liver disease. Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit. Metformin Hydrochloride Overdose of metformin hydrochloride has occurred, including ingestion of amounts >50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS ). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected."}', 'active_flag': 'Y', 'generic_name': '{"GLIPIZIDE AND METFORMIN HCL"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS WARNING: LACTIC ACIDOSIS Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [ see PRECAUTIONS ] Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see PRECAUTIONS ] . If metformin-associated lactic acidosis is suspected, immediately discontinue Glipizide and Metformin HCl Tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see PRECAUTIONS ]. SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to 1 of 4 treatment groups (Diabetes 19 (Suppl. 2):747-830, 1970). UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glipizide and of alternative modes of therapy. Although only 1 drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure."}', 'precautions': '{"PRECAUTIONS General Glipizide and Metformin HCl Tablets Lactic Acidosis —There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increases lactate: pyruvate ratio; metformin plasma levels were generally > 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of Glipizide and Metformin HCl Tablets. In Glipizide and Metformin HCl Tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue Glipizide and Metformin HCl Tablets and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: • Renal Impairment —The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patients renal function include (see Dosage and Administration , Clinical Pharmacology ): o Before initiating Glipizide and Metformin HCl Tablets, obtain an estimated glomerular filtration rate (eGFR) o Glipizide and Metformin HCl Tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 . Initiation of Glipizide and Metformin HCl Tablets are not recommended in patients with eGFR between 30-45 mL/min/1.73 m 2 (See Contraindications ). o Obtain an eGFR at least annually in all patients taking Glipizide and Metformin HCl Tablets. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. o In patients taking Glipizide and Metformin HCl Tablets whose eGFR falls below 45 mL/min/1.73 m 2 , assess the benefit and risk of continuing therapy. • Drug interactions —The concomitant use of Glipizide and Metformin HCl Tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients. • Age 65 or Greater —The risk of metformin-associated lactic acidosis increases with the patient\'s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients. • Radiologic studies with contrast —Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and lactic acidosis. Stop Glipizide and Metformin HCl Tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism or heart failure, or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart Glipizide and Metformin HCl Tablets if renal function is stable. • Surgery and other procedures —Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Glipizide and Metformin HCl Tablets should be temporarily discontinued while patients have restricted food and fluid intake. • Hypoxic states —Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue Glipizide and Metformin HCl Tablets. • Excessive Alcohol intake —Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Glipizide and Metformin HCl Tablets. • Hepatic impairment—Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of Glipizide and Metformin HCl Tablets in patients with clinical or laboratory evidence of hepatic disease. Hypoglycemia Glipizide and Metformin HCl Tablets are capable of producing hypoglycemia; therefore, proper patient selection, dosing, and instructions are important to avoid potential hypoglycemic episodes. The risk of hypoglycemia is increased when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents or ethanol. Renal insufficiency may cause elevated drug levels of both glipizide and metformin hydrochloride. Hepatic insufficiency may increase drug levels of glipizide and may also diminish gluconeogenic capacity, both of which increase the risk of hypoglycemic reactions. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and people who are taking beta-adrenergic blocking drugs. Glipizide Renal and hepatic disease The metabolism and excretion of glipizide may be slowed in patients with impaired renal and/or hepatic function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted. Hemolytic anemia Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Glipizide and Metformin HCl Tablets belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency. Vitamin B12 levels In controlled clinical trials with metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B 12 , without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on metformin and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests ). Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. In these patients, routine serum vitamin B 12 measurements at 2- to 3-year intervals may be useful. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glipizide and Metformin HCl Tablets or any other antidiabetic drug. Information for Patients Glipizide and Metformin HCl Tablets Patients should be informed of the potential risks and benefits of Glipizide and Metformin HCl Tablets and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions; a regular exercise program; and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters. The risks of lactic acidosis associated with metformin therapy, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue Glipizide and Metformin HCl Tablets immediately and promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Glipizide and Metformin HCl Tablets, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving Glipizide and Metformin HCl Tablets. (See Patient Information printed below.) Laboratory Tests Periodic fasting blood glucose (FBG) and HbA 1c measurements should be performed to monitor therapeutic response. Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, vitamin B12 deficiency should be excluded. Instruct patients to inform their doctor that they are taking glipizide and metformin tablets prior to any surgical or radiological procedure, as temporary discontinuation of glipizide and metformin tablets may be required until renal function has been confirmed to be normal (see Precautions ). Drug Interactions Glipizide and Metformin HCl Tablets Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Glipizide and Metformin HCl Tablets, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Glipizide and Metformin HCl Tablets, the patient should be observed closely for hypoglycemia. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid as compared to sulfonylureas, which are extensively bound to serum proteins. Glipizide The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory agents, some azoles, and other drugs that are highly protein-bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving Glipizide and Metformin HCl Tablets, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Glipizide and Metformin HCl Tablets, the patient should be observed closely for loss of blood glucose control. In vitro binding studies with human serum proteins indicate that glipizide binds differently than tolbutamide and does not interact with salicylate or dicumarol. However, caution must be exercised in extrapolating these findings to the clinical situation and in the use of Glipizide and Metformin HCl Tablets with these drugs. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known. The effect of concomitant administration of fluconazole and glipizide has been demonstrated in a placebo-controlled crossover study in normal volunteers. All subjects received glipizide alone and following treatment with 100 mg of fluconazole as a single oral daily dose for 7 days, the mean percent increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35% - 81%). In studies assessing the effect of colesevelam on the pharmacokinetics of glipizide ER in healthy volunteers, reductions in glipizide AUC0-∞ and Cmax of 12% and 13%, respectively, were observed when colesevelam was coadministered with glipizide ER. When glipizide ER was administered 4 hours prior to colesevelam, there was no significant change in glipizide AUC0-∞ or Cmax, -4% and 0%, respectively. Therefore, Glipizide and Metformin HCl Tablets should be administered at least 4 hours prior to colesevelam to ensure that colesevelam does not reduce the absorption of glipizide. Metformin Hydrochloride Furosemide A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood C max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C max and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically. Nifedipine A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine. Drugs that reduce metformin clearance Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins. Other Carbonic Anhydrase Inhibitors Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Glipizide and Metformin HCl Tablets may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients. Alcohol Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving Glipizide and Metformin HCl Tablets. Carcinogenesis, Mutagenesis, Impairment of Fertility No animal studies have been conducted with the combined products in Glipizide and Metformin HCl Tablets. The following data are based on findings in studies performed with the individual products. Glipizide A 20-month study in rats and an 18-month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility. Metformin Hydrochloride Long-term carcinogenicity studies were performed with metformin alone in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily (MRHD) dose of 2000 mg of the metformin component of Glipizide and Metformin HCl Tablets based on body surface area comparisons. No evidence of carcinogenicity with metformin alone was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin alone in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day of metformin alone. There was no evidence of a mutagenic potential of metformin alone in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes).Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin alone when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the MRHD dose of the metformin component of Glipizide and Metformin HCl Tablets based on body surface area comparisons. Pregnancy Teratogenic Effects: Pregnancy Category C Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible. Because animal reproduction studies are not always predictive of human response, Glipizide and Metformin HCl Tablets should not be used during pregnancy unless clearly needed. (See below.) There are no adequate and well-controlled studies in pregnant women with Glipizide and Metformin HCl Tablets or its individual components. No animal studies have been conducted with the combined products in Glipizide and Metformin HCl Tablets. The following data are based on findings in studies performed with the individual products. Glipizide Glipizide was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5-50 mg/kg). This fetotoxicity has been similarly noted with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and believed to be directly related to the pharmacologic (hypoglycemic) action of glipizide. In studies in rats and rabbits, no teratogenic effects were found. Metformin Hydrochloride Metformin alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the MRHD dose of 2000 mg of the metformin component of Glipizide and Metformin HCl Tablets based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. Nonteratogenic Effects Prolonged severe hypoglycemia (4-10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. It is not recommended that Glipizide and Metformin HCl Tablets be used during pregnancy. However, if it is used, Glipizide and Metformin HCl Tablets should be discontinued at least 1 month before the expected delivery date. ( See Pregnancy: Teratogenic Effects: Pregnancy Category C .) Nursing Mothers Although it is not known whether glipizide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue Glipizide and Metformin HCl Tablets, taking into account the importance of the drug to the mother. If Glipizide and Metformin HCl Tablets are discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. Pediatric Use Safety and effectiveness of Glipizide and Metformin HCl Tablets in pediatric patients have not been established. Geriatric Use Of the 345 patients who received Glipizide and Metformin HCl Tablets 2.5 mg/250 mg and 2.5 mg/500 mg in the initial therapy trial, 67 (19.4%) were aged 65 and older while 5 (1.4%) were aged 75 and older. Of the 87 patients who received Glipizide and Metformin HCl Tablets in the second-line therapy trial, 17 (19.5%) were aged 65 and older while 1 (1.1%) was at least aged 75. No overall differences in effectiveness or safety were observed between these patients and younger patients in either the initial therapy trial or the second-line therapy trial, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients (see also WARNINGS , PRECAUTIONS and DOSAGE AND ADMINISTRATION )."}', 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}


[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] {"BENZALKONIUM CHLORIDE"}

[Assistant] {'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses for hand washing to decrease bacteria on the skin."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"BENZALKONIUM CHLORIDE"}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if: irritation and redness develops."}', 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings For external use only. When using this product: avoid contact with eyes. In case of eye contact, flush with water."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}


[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] {MENTHOL}

[Assistant] {'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses: For the temporary relief of minor aches and pains of muscles and joints."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{MENTHOL}', 'route': '{TOPICAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings: For external use only Flammable. Keep away from flame. Keep out of reach of children- if swallowed get medical help or contact a poison center right away. Avoid contact with eyes Do not apply to open wounds or damaged skin Do not bandage tightly Consult a doctor if excessive skin irritation occurs, or if you are prone to allergic reactions to salicylates, including aspirin. If condition worsens, if symptoms persist for more than 7 days or clear up and recur again within a few days, discontinue use of this product and consult a doctor."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}


[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] {GUAIFENESIN}

[Assistant] {'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses helps loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passageways of bothersome mucus and makes coughs more productive"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"GUAIFENESIN 400 MG"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings Do not use: for children under 12 years of age"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}


[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] {DOXYCYCLINE}

[Assistant] {'contraindications': '{"CONTRAINDICATIONS This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines."}', 'adverse_reactions': '{"ADVERSE REACTIONS Due to oral doxycycline’s virtually complete absorption, side effects to the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines. Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline class. Most of these patients took medications immediately before going to bed. (See DOSAGE AND ADMINISTRATION .) Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above. (See WARNINGS .) Renal Toxicity: Rise in BUN has been reported and is apparently dose related. (See WARNINGS .) Hypersensitivity Reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus. Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported with tetracyclines. Other: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines. (See PRECAUTIONS-General .) When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of the thyroid gland. No abnormalities of thyroid function are known to occur."}', 'drug_interactions': '{"Drug Interactions: Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations. Absorption of tetracyclines is impaired by bismuth subsalicylate. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracycline may render oral contraceptives less effective."}', 'indications_and_usage': '{"INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline capsules, USP and other antibacterial drugs, doxycycline capsules, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Doxycycline capsules, USP are indicated for the treatment of the following infections: Rocky mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. Respiratory tract infections caused by Mycoplasma pneumoniae . Lymphogranuloma venereum caused by Chlamydia trachomatis . Psittacosis (ornithosis) caused by Chlamydophila psittaci . Trachoma caused by Chlamydia trachomatis , although the infectious agent is not always eliminated as judged by immunofluorescence. Inclusion conjunctivitis caused by Chlamydia trachomatis . Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis . Nongonococcal urethritis caused by Ureaplasma urealyticum . Relapsing fever due to Borrelia recurrentis . Doxycycline capsules, USP are also indicated for the treatment of infections caused by the following gram-negative microorganisms: Chancroid caused by Haemophilus ducreyi . Plague due to Yersinia pestis . Tularemia due to Francisella tularensis . Cholera caused by Vibrio cholerae . Campylobacter fetus infections caused by Campylobacter fetus . Brucellosis due to Brucella species (in conjunction with streptomycin). Bartonellosis due to Bartonella bacilliformis . Granuloma inguinale caused by Klebsiella granulomatis. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline capsules, USP are indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriologic testing indicates appropriate susceptibility to the drug: Escherichia coli Enterobacter aerogenes Shigella species Acinetobacter species Respiratory tract infections caused by Haemophilus influenzae . Respiratory tract and urinary tract infections caused by Klebsiella species . Doxycycline capsules, USP are indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: Upper respiratory infections caused by Streptococcus pneumoniae . Anthrax due to Bacillus anthracis , including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis . When penicillin is contraindicated, doxycycline capsules, USP are an alternative drug in the treatment of the following infections: Uncomplicated gonorrhea caused by Neisseria gonorrhoeae . Syphilis caused by Treponema pallidum . Yaws caused by Treponema pallidum subspecies pertenue. Listeriosis due to Listeria monocytogenes . Vincent’s infection caused by Fusobacterium fusiforme . Actinomycosis caused by Actinomyces israelii . Infections caused by Clostridium species . In acute intestinal amebiasis, doxycycline capsules, USP may be a useful adjunct to amebicides. In severe acne, doxycycline capsules, USP may be useful adjunctive therapy."}', 'warnings_and_cautions': None, 'overdosage': '{"OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life, and it would not be of benefit in treating cases of overdosage."}', 'active_flag': 'Y', 'generic_name': '{DOXYCYCLINE}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"WARNINGS The use of drugs of the tetracycline class, including doxycycline, during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use of doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g. anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and doxycycline should be avoided because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every six hours. This reaction was shown to be reversible when the drug was discontinued. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryo toxicity has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus. The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function. Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema."}', 'precautions': '{"PRECAUTIONS General: As with other antibacterial preparations, use of this drug may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, doxycycline should be discontinued, and appropriate therapy instituted. Incision and drainage or other surgical procedures should be performed in conjunction with antibacterial therapy when indicated. Prescribing doxycycline in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients: All patients taking doxycycline should be advised: – to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruptions, etc.) occurs. Sunscreen or sunblock should be considered. (See WARNINGS .) – to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS .) – that the absorption of tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. (See Drug Interactions .) – that the absorption of tetracyclines is reduced when taking bismuth subsalicylate. (See Drug Interactions .) – not to use outdated or poorly stored doxycycline. – that the use of doxycycline might increase the incidence of vaginal candidiasis. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including doxycycline should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by doxycycline or other antibacterial drugs in the future. Laboratory Tests: In venereal disease when coexistent syphilis is suspected, a dark-field examination should be done before treatment is started and the blood serology repeated monthly for at least four months. In long-term therapy, periodic laboratory evaluations of organ systems, including hematopoietic, renal, and hepatic studies should be performed. Drug Interactions: Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations. Absorption of tetracyclines is impaired by bismuth subsalicylate. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracycline may render oral contraceptives less effective. Drug/Laboratory Test Interactions: False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals to evaluate the carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with related antibacterial, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibacterial (tetracycline, oxytetracycline). Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied. Pregnancy: Teratogenic Effects. Pregnancy Category D: There are no adequate and well-controlled studies on the use of doxycycline in pregnant short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS - the Teratogen Information System-concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk. 1 A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. (Sixty-three [0.19%] of the controls and 56 [0.30%] of the cases were treated with doxycycline.) This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases. 2 A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age. 3 Labor and Delivery: The effect of tetracyclines on labor and delivery is unknown. Nursing Mothers: Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines, including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated; however, the effects of prolonged exposure to doxycycline in breast milk are unknown. 4 Because of the potential for adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. (See WARNINGS .) Pediatric Use: Because of the effects of drugs of the tetracycline –class, on tooth development and growth, use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g. anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. (see WARNINGS and DOSAGE AND ADMINISTRATION)."}', 'information_for_patients': '{"Information for Patients: All patients taking doxycycline should be advised: – to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruptions, etc.) occurs. Sunscreen or sunblock should be considered. (See WARNINGS .) – to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS .) – that the absorption of tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. (See Drug Interactions .) – that the absorption of tetracyclines is reduced when taking bismuth subsalicylate. (See Drug Interactions .) – not to use outdated or poorly stored doxycycline. – that the use of doxycycline might increase the incidence of vaginal candidiasis. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including doxycycline should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by doxycycline or other antibacterial drugs in the future."}', 'pregnancy': '{"Pregnancy: Teratogenic Effects. Pregnancy Category D: There are no adequate and well-controlled studies on the use of doxycycline in pregnant short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS - the Teratogen Information System-concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk. 1 A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. (Sixty-three [0.19%] of the controls and 56 [0.30%] of the cases were treated with doxycycline.) This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases. 2 A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age. 3"}', 'pediatric_use': '{"Pediatric Use: Because of the effects of drugs of the tetracycline –class, on tooth development and growth, use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g. anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. (see WARNINGS and DOSAGE AND ADMINISTRATION)."}', 'geriatric_use': None}


[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] {"CETIRIZINE HYDROCHLORIDE","PSEUDOEPHEDRINE HYDROCHLORIDE"}

[Assistant] {'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: runny nose sneezing itchy, watery eyes itching of nose or throat nasal congestion reduces swelling of nasal passages temporarily relieves sinus congestion and pressure temporarily restores freer breathing through the nose"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"CETIRIZINE HYDROCHLORIDE AND PSEUDOEPHEDRINE HYDROCHLORIDE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. you get nervous, dizzy, or sleepless symptoms do not improve within 7 days or are accompanied by fever"}', 'do_not_use': '{"Do not use if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson\'s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product."}', 'when_using': '{"When using this product do not use more than directed drowsiness may occur avoid alcoholic drinks alcohol, sedatives, and tranquilizers may increase drowsiness be careful when driving a motor vehicle or operating machinery"}', 'warnings': '{"Warnings Do not use if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson\'s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product. Ask a doctor before use if you have heart disease thyroid disease diabetes glaucoma high blood pressure trouble urinating due to an enlarged prostate gland liver or kidney disease. Your doctor should determine if you need a different dose. Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. When using this product do not use more than directed drowsiness may occur avoid alcoholic drinks alcohol, sedatives, and tranquilizers may increase drowsiness be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if an allergic reaction to this product occurs. Seek medical help right away. you get nervous, dizzy, or sleepless symptoms do not improve within 7 days or are accompanied by fever If pregnant or breast-feeding if breast-feeding: not recommended if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away at 1-800-222-1222."}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}


[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] {"DIPHENHYDRAMINE HYDROCHLORIDE"}

[Assistant] {'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Use for relief of occasional sleeplessness."}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"DIPHENHYDRAMINE HCL"}', 'route': '{ORAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if sleeplessness persists continuously for more than 2 weeks. Insomnia may be a symptom of a serious underlying medical illness."}', 'do_not_use': '{"Do not use for children under 12 years of age with any other product containing diphenhydramine, even one used on skin"}', 'when_using': '{"When using this product avoid alcoholic drinks."}', 'warnings': '{"Warnings Do not use for children under 12 years of age with any other product containing diphenhydramine, even one used on skin Ask a doctor before use if you have a breathing problem such as emphysema or chronic bronchitis glaucoma trouble urinating due to an enlarged prostate gland Ask a doctor or pharmacist before use if you are taking sedatives or tranquilizers. When using this product avoid alcoholic drinks. Stop use and ask a doctor if sleeplessness persists continuously for more than 2 weeks. Insomnia may be a symptom of a serious underlying medical illness. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222)"}', 'precautions': None, 'information_for_patients': None, 'pregnancy': None, 'pediatric_use': None, 'geriatric_use': None}