[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] {"ENALAPRIL MALEATE"}

[Assistant] {'contraindications': '{"Contraindications Enalapril maleate is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema. Do not coadminister aliskiren with enalapril maleate in patients with diabetes (see PRECAUTIONS, Drug Interactions)."}', 'adverse_reactions': '{"Adverse Reactions Enalapril maleate has been evaluated for safety in more than 10,000 patients, including over 1000 patients treated for one year or more. Enalapril maleate has been found to be generally well tolerated in controlled clinical trials involving 2987 patients. For the most part, adverse experiences were mild and transient in nature. In clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 3.3 percent of patients with hypertension and in 5.7 percent of patients with heart failure. The frequency of adverse experiences was not related to total daily dosage within the usual dosage ranges. In patients with hypertension the overall percentage of patients treated with enalapril maleate reporting adverse experiences was comparable to placebo. HYPERTENSION Adverse experiences occurring in greater than one percent of patients with hypertension treated with enalapril maleate in controlled clinical trials are shown below. In patients treated with enalapril maleate, the maximum duration of therapy was three years; in placebo treated patients the maximum duration of therapy was 12 weeks. Enalapril Maleate (n=2314) Incidence (discontinuation) Placebo (n=230) Incidence Body As A Whole Fatigue 3.0 (<0.1) 2.6 Orthostatic Effects 1.2 (<0.1) 0.0 Asthenia 1.1 (0.1) 0.9 Digestive Diarrhea 1.4 (<0.1) 1.7 Nausea 1.4 (0.2) 1.7 Nervous/Psychiatric Headache 5.2 (0.3) 9.1 Dizziness 4.3 (0.4) 4.3 Respiratory Cough 1.3 (0.1) 0.9 Skin Rash 1.4 (0.4) 0.4 HEART FAILURE Adverse experiences occurring in greater than one percent of patients with heart failure treated with enalapril maleate are shown below. The incidences represent the experiences from both controlled and uncontrolled clinical trials (maximum duration of therapy was approximately one year). In the placebo treated patients, the incidences reported are from the controlled trials (maximum duration of therapy is 12 weeks). The percentage of patients with severe heart failure (NYHA Class IV) was 29 percent and 43 percent for patients treated with enalapril maleate and placebo, respectively. Enalapril Maleate (n=673) Incidence (discontinuation) Placebo (n=339) Incidence Body As A Whole Orthostatic Effects 2.2 (0.1) 0.3 Syncope 2.2 (0.1) 0.9 Chest Pain 2.1 (0.0) 2.1 Fatigue 1.8 (0.0) 1.8 Abdominal Pain 1.6 (0.4) 2.1 Asthenia 1.6 (0.1) 0.3 Cardiovascular Hypotension 6.7 (1.9) 0.6 Orthostatic Hypotension 1.6 (0.1) 0.3 Angina Pectoris 1.5 (0.1) 1.8 Myocardial Infarction 1.2 (0.3) 1.8 Digestive Diarrhea 2.1 (0.1) 1.2 Nausea 1.3 (0.1) 0.6 Vomiting 1.3 (0.0) 0.9 Nervous/Psychiatric Dizziness 7.9 (0.6) 0.6 Headache 1.8 (0.1) 0.9 Vertigo 1.6 (0.1) 1.2 Respiratory Cough 2.2 (0.0) 0.6 Bronchitis 1.3 (0.0) 0.9 Dyspnea 1.3 (0.1) 0.4 Pneumonia 1.0 (0.0) 2.4 Skin Rash 1.3 (0.0) 2.4 Urogenital Urinary Tract Infection 1.3 (0.0) 2.4 Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0 percent of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in order of decreasing severity. Body As A Whole: Anaphylactoid reactions (see WARNINGS, Anaphylactoid and Possibly Related Reactions). Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see WARNINGS, Hypotension); pulmonary embolism and infarction; pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; palpitation, Raynaud\'s phenomenon. Digestive: Ileus, pancreatitis, hepatic failure, hepatitis (hepatocellular [proven on rechallenge] or cholestatic jaundice) (see WARNINGS, Hepatic Failure), melena, anorexia, dyspepsia, constipation, glossitis, stomatitis, dry mouth. Hematologic: Rare cases of neutropenia, thrombocytopenia and bone marrow depression. Musculoskeletal: Muscle cramps. Nervous/Psychiatric: Depression, confusion, ataxia, somnolence, insomnia, nervousness, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream abnormality. Respiratory: Bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection, pulmonary infiltrates, eosinophilic pneumonitis. Skin: Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity. Special Senses: Blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing. Urogenital: Renal failure, oliguria, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), flank pain, gynecomastia, impotence. Miscellaneous: A symptom complex has been reported which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Angioedema: Angioedema has been reported in patients receiving enalapril maleate with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalapril maleate should be discontinued and appropriate therapy instituted immediately (see WARNINGS). Hypotension: In the hypertensive patients, hypotension occurred in 0.9 percent and syncope occurred in 0.5 percent of patients following the initial dose or during extended therapy. Hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent of hypertensive patients. In heart failure patients, hypotension occurred in 6.7 percent and syncope occurred in 2.2 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 1.9 percent of patients with heart failure (see WARNINGS). Cough: See PRECAUTIONS, Cough. Pediatric Patients The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients. Clinical Laboratory Test Findings Serum Electrolytes: Hyperkalemia (see PRECAUTIONS), hyponatremia. Creatinine, Blood Urea Nitrogen: In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with enalapril maleate alone. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis (see PRECAUTIONS). In patients with heart failure who were also receiving diuretics with or without digitalis, increases in blood urea nitrogen or serum creatinine, usually reversible upon discontinuation of enalapril maleate and/or other concomitant diuretic therapy, were observed in about 11 percent of patients. Increases in blood urea nitrogen or creatinine were a cause for discontinuation in 1.2 percent of patients. Hematology: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in either hypertension or congestive heart failure patients treated with enalapril maleate but are rarely of clinical importance unless another cause of anemia coexists. In clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded. Liver Function Tests Elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic Failure). to report suspected adverse reactions call 1-800-332-10881 1 - to report suspected adverse reactions call 1-800-332-1088"}', 'drug_interactions': None, 'indications_and_usage': '{"Indications and Usage Hypertension Enalapril maleate is indicated for the treatment of hypertension. Enalapril maleate is effective alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of enalapril maleate and thiazides are approximately additive. Heart Failure Enalapril maleate is indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis. In these patients enalapril maleate improves symptoms, increases survival, and decreases the frequency of hospitalization (see CLINICAL PHARMACOLOGY, Heart Failure, Mortality Trials for details and limitations of survival trials). Asymptomatic Left Ventricular Dysfunction In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction ≤35 percent), enalapril maleate decreases the rate of development of overt heart failure and decreases the incidence of hospitalization for heart failure (see CLINICAL PHARMACOLOGY, Heart Failure, Mortality Trials for details and limitations of survival trials). In using enalapril maleate consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that enalapril maleate does not have a similar risk (see WARNINGS). In considering use of enalapril maleate it should be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks (see WARNINGS, Head and Neck Angioedema)."}', 'warnings_and_cautions': None, 'overdosage': '{"Overdosage Limited data are available in regard to overdosage in humans. Single oral doses of enalapril above 1,000 mg/kg and ≥1,775 mg/kg were associated with lethality in mice and rats, respectively. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis (see WARNINGS, Anaphylactoid reactions during membrane exposure)."}', 'active_flag': 'Y', 'generic_name': '{"ENALAPRIL MALEATE"}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': '{"Warnings Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including enalapril maleate) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril maleate. This may occur at any time during treatment. In such cases enalapril maleate should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided (see ADVERSE REACTIONS). Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS). Anaphylactoid reactions during desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid reactions during membrane exposure Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Hypotension Excessive hypotension is rare in uncomplicated hypertensive patients treated with enalapril maleate alone. Patients with heart failure given enalapril maleate commonly have some reduction in blood pressure, especially with the first dose, but discontinuation of therapy for continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy (see DOSAGE AND ADMINISTRATION). Patients at risk for excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with enalapril maleate in patients at risk for excessive hypotension who are able to tolerate such adjustments (see PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS). In patients at risk for excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of enalapril maleate, which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of enalapril maleate or concomitant diuretic may be necessary. Neutropenia/Agranulocytosis Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. Marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered. Hepatic Failure Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Fetal toxicity Pregnancy category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue enalapril maleate tablets as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue enalapril maleate tablets, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to enalapril maleate tablets for hypotension, oliguria, and hyperkalemia [see PRECAUTIONS, Pediatric use]. No teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. On a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (MRHDD)."}', 'precautions': '{"Precautions General Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, enalapril should be given with caution to patients with obstruction in the outflow tract of the left ventricle. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including enalapril maleate, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death [see PRECAUTIONS, Drug Interaction]. In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy. Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when enalapril maleate has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or enalapril maleate may be required. Evaluation of patients with hypertension or heart failure should always include assessment of renal function (see DOSAGE AND ADMINISTRATION). Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately one percent of hypertensive patients in clinical trials. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive patients. In clinical trials in heart failure, hyperkalemia was observed in 3.8 percent of patients but was not a cause for discontinuation. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with enalapril maleate (see Drug Interactions). Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. Information for Patients Angioedema: Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin converting enzyme inhibitors, including enalapril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician. Hypotension: Patients should be cautioned to report light headedness, especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician. Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician. Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia. Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to enalapril maleate tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. NOTE: As with many other drugs, certain advice to patients being treated with enalapril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Drug Interactions Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on enalapril maleate tablets and other agents that affect the RAS. Do not coadminister aliskiren with enalapril maleate in patients with diabetes. Avoid use of aliskiren with enalapril maleate in patients with renal impairment (GFR <60 mL/min). Hypotension - Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGS and DOSAGE AND ADMINISTRATION). Agents Causing Renin Release: The antihypertensive effect of enalapril maleate is augmented by antihypertensive agents that cause renin release (e.g., diuretics). Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including enalapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving enalapril and NSAID therapy. In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate. In this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. Other Cardiovascular Agents: Enalapril maleate has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine, prazosin and digoxin without evidence of clinically significant adverse interactions. Agents Increasing Serum Potassium: Enalapril maleate attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium sparing agents should generally not be used in patients with heart failure receiving enalapril maleate. Lithium: Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant enalapril maleate and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium. Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril maleate. Carcinogenesis, Mutagenesis, Impairment of Fertility There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis. Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow. There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis). Pregnancy Nursing Mothers Enalapril and enalaprilat have been detected in human breast milk. Because of the potential for serious adverse reactions in nursing infants from enalapril, a decision should be made whether to discontinue nursing or to discontinue enalapril maleate, taking into account the importance of the drug to the mother. Pediatric Use Neonates with a history of in utero exposure to enalapril Maleate: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure. Antihypertensive effects of enalapril maleate have been established in hypertensive pediatric patients age 1 month to 16 years. Use of enalapril maleate in these age groups is supported by evidence from adequate and well-controlled studies of enalapril maleate in pediatric and adult patients as well as by published literature in pediatric patients (see CLINICAL PHARMACOLOGY, Clinical Pharmacology in Pediatric Patients and DOSAGE AND ADMINISTRATION). Enalapril maleate is not recommended in neonates and in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m2, as no data are available."}', '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] {PREGABALIN}

[Assistant] {'contraindications': '{"4. Contraindications Pregabalin is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy [SEE WARNINGS AND PRECAUTIONS (5.2)]."}', 'adverse_reactions': '{"6. Adverse Reactions The following serious adverse reactions are described elsewhere in the labeling: Angioedema [see WARNINGS AND PRECAUTIONS (5.1)] Hypersensitivity [see WARNINGS AND PRECAUTIONS (5.2)] Suicidal Behavior and Ideation [seeWARNINGS AND PRECAUTIONS (5.3)] Respiratory Depression [see WARNINGS AND PRECAUTIONS (5.4)] Dizziness and Somnolence [seeWARNINGS AND PRECAUTIONS (5.5)] Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation [see WARNINGS AND PRECAUTIONS (5.6)] Peripheral Edema [see WARNINGS AND PRECAUTIONS (5.7)] Weight Gain [see WARNINGS AND PRECAUTIONS (5.8)] Tumorigenic Potential [see WARNINGS AND PRECAUTIONS (5.9)] Ophthalmological Effects [see WARNINGS AND PRECAUTIONS (5.10)] Creatine Kinase Elevations [see WARNINGS AND PRECAUTIONS (5.11)] Decreased Platelet Count [see WARNINGS AND PRECAUTIONS (5.12)] PR Interval Prolongation [see WARNINGS AND PRECAUTIONS (5.13)] 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. In all controlled and uncontrolled trials across various patient populations during the premarketing development of pregabalin, more than 10,000 patients have received pregabalin. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years. Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all adult populations combined, 14% of patients treated with pregabalin and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and less than 1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the pregabalin group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each). Most Common Adverse Reactions in All Controlled Clinical Studies in Adults In premarketing controlled trials of all adult patient populations combined (including DPN, PHN, and adult patients with partial-onset seizures), dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and \\"thinking abnormal\\" (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with pregabalin than by subjects treated with placebo (greater than or equal to 5% and twice the rate of that seen in placebo). Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Adverse Reactions Leading to Discontinuation In clinical trials in adults with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with pregabalin and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients. Most Common Adverse Reactions Table 4 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with neuropathic pain associated with diabetic neuropathy in the combined pregabalin group for which the incidence was greater in this combined pregabalin group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of \\"mild\\" or \\"moderate”. Table 4. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Body system Preferred term 75 mg/day [N=77] % 150 mg/day [N=212] % 300 mg/day [N=321] % 600 mg/day [N=369] % All PGB* [N=979] % Placebo [N=459] % Body as a whole Asthenia 4 2 4 7 5 2 Accidental injury 5 2 2 6 4 3 Back pain 0 2 1 2 2 0 Chest pain 4 1 1 2 2 1 Face edema 0 1 1 2 1 0 Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1 Metabolic and nutritional disorders Peripheral edema 4 6 9 12 9 2 Weight gain 0 4 4 6 4 0 Edema 0 2 4 2 2 0 Hypoglycemia 1 3 2 1 2 1 Nervous system Dizziness 8 9 23 29 21 5 Somnolence 4 6 13 16 12 3 Neuropathy 9 2 2 5 4 3 Ataxia 6 1 2 4 3 1 Vertigo 1 2 2 4 3 1 Confusion 0 1 2 3 2 1 Euphoria 0 0 3 2 2 0 Incoordination 1 0 2 2 2 0 Thinking abnormal† 1 0 1 3 2 0 Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses Blurry vision‡ 3 1 3 6 4 2 Abnormal vision 1 0 1 1 1 0 * PGB: pregabalin †Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. ‡Investigator term; summary level term is amblyopia Controlled Studies in Postherpetic Neuralgia Adverse Reactions Leading to Discontinuation In clinical trials in adults with postherpetic neuralgia, 14% of patients treated with pregabalin and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (4%) and somnolence (3%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring in greater frequency in the pregabalin group than in the placebo group, were confusion (2%), as well as peripheral edema, asthenia, ataxia, and abnormal gait (1% each). Most Common Adverse Reactions Table 5 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with neuropathic pain associated with postherpetic neuralgia in the combined pregabalin group for which the incidence was greater in this combined pregabalin group than in the placebo group. In addition, an event is included, even if the incidence in the all pregabalin group is not greater than in the placebo group, if the incidence of the event in the 600 mg/day group is more than twice that in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of \\"mild\\" or \\"moderate”. Overall, 12.4% of all pregabalin-treated patients and 9% of all placebo-treated patients had at least one severe event while 8% of pregabalin-treated patients and 4.3% of placebo-treated patients had at least one severe treatment-related adverse event. Table 5. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia Body system Preferred term 75 mg/d [N=84] % 150 mg/d [N=302] % 300 mg/d [N=312] % 600 mg/d [N=154] % All PGB* [N=852] % Placebo [N=398] % Body as a whole Infection 14 8 6 3 7 4 Headache 5 9 5 8 7 5 Pain 5 4 5 5 5 4 Accidental injury 4 3 3 5 3 2 Flu syndrome 1 2 2 1 2 1 Face edema 0 2 1 3 2 1 Digestive system Dry mouth 7 7 6 15 8 3 Constipation 4 5 5 5 5 2 Flatulence 2 1 2 3 2 1 Vomiting 1 1 3 3 2 1 Metabolic and nutritional disorders Peripheral edema 0 8 16 16 12 4 Weight gain 1 2 5 7 4 0 Edema 0 1 2 6 2 1 Musculoskeletal system Myasthenia 1 1 1 1 1 0 Nervous system Dizziness 11 18 31 37 26 9 Somnolence 8 12 18 25 16 5 Ataxia 1 2 5 9 5 1 Abnormal gait 0 2 4 8 4 1 Confusion 1 2 3 7 3 0 Thinking abnormal† 0 2 1 6 2 2 Incoordination 2 2 1 3 2 0 Amnesia 0 1 1 4 2 0 Speech disorder 0 0 1 3 1 0 Respiratory system Bronchitis 0 1 1 3 1 1 Special senses Blurry vision‡ 1 5 5 9 5 3 Diplopia 0 2 2 4 2 0 Abnormal vision 0 1 2 5 2 0 Eye Disorder 0 1 1 2 1 0 Urogenital System Urinary Incontinence 0 1 1 2 1 0 * PGB: pregabalin †Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. ‡ Investigator term; summary level term is amblyopia Controlled Studies of Adjunctive Therapy for Partial-Onset Seizures in Adult Patients Adverse Reactions Leading to Discontinuation Approximately 15% of patients receiving pregabalin and 6% of patients receiving placebo in trials of adjunctive therapy for partial-onset seizures discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, less than 1% of patients in the placebo group withdrew due to each of these events. Other adverse reactions that led to discontinuation of at least 1% of patients in the pregabalin group and at least twice as frequently compared to the placebo group were asthenia, diplopia, blurred vision, thinking abnormal, nausea, tremor, vertigo, headache, and confusion (which each led to withdrawal in 2% or less of patients). Most Common Adverse Reactions Table 6 lists all dose-related adverse reactions occurring in at least 2% of all pregabalin-treated patients. Dose-relatedness was defined as the incidence of the adverse event in the 600 mg/day group was at least 2% greater than the rate in both the placebo and 150 mg/day groups. In these studies, 758 patients received pregabalin and 294 patients received placebo for up to 12 weeks. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of \\"mild\\" or \\"moderate”. Table 6. Dose-related Adverse Reaction Incidence in Controlled Trials in Adjunctive Therapy for Partial-Onset Seizures in Adult Patients Body System Preferred Term 150 mg/d [N = 185] % 300 mg/d [N = 90] % 600 mg/d [N = 395] % All PGB* [N = 670]† % Placebo [N = 294] % Body as a Whole Accidental Injury 7 11 10 9 5 Pain 3 2 5 4 3 Digestive System Increased Appetite 2 3 6 5 1 Dry Mouth 1 2 6 4 1 Constipation 1 1 7 4 2 Metabolic and Nutritional Disorders Weight Gain 5 7 16 12 1 Peripheral Edema 3 3 6 5 2 Nervous System Dizziness 18 31 38 32 11 Somnolence 11 18 28 22 11 Ataxia 6 10 20 15 4 Tremor 3 7 11 8 4 Thinking Abnormal‡ 4 8 9 8 2 Amnesia 3 2 6 5 2 Speech Disorder 1 2 7 5 1 Incoordination 1 3 6 4 1 Abnormal Gait 1 3 5 4 0 Twitching 0 4 5 4 1 Confusion 1 2 5 4 2 Myoclonus 1 0 4 2 0 Special Senses Blurred Vision§ 5 8 12 10 4 Diplopia 5 7 12 9 4 Abnormal Vision 3 1 5 4 1 * PGB: pregabalin † Excludes patients who received the 50 mg dose in Study E1. ‡ Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. § Investigator term; summary level term is amblyopia Controlled Studies with Fibromyalgia Adverse Reactions Leading to Discontinuation In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150 to 600 mg/day) and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (6%) and somnolence (3%). In comparison, less than 1% of placebo-treated patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue, headache, balance disorder, and weight increased. Each of these adverse reactions led to withdrawal in approximately 1% of patients. Most Common Adverse Reactions Table 9 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of patients with fibromyalgia in the ‘all pregabalin’ treatment group for which the incidence was greater than in the placebo treatment group. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of \\"mild\\" or \\"moderate\\". Table 9. Adverse Reaction Incidence in Controlled Trials in Fibromyalgia System Organ Class Preferred term 150 mg/d [N=132] % 300 mg/d [N=502] % 450 mg/d [N=505] % 600 mg/d [N=378] % All PGB* [N=1517] % Placebo [N=505] % Ear and Labyrinth Disorders Vertigo 2 2 2 1 2 0 Eye Disorders Vision blurred 8 7 7 12 8 1 Gastrointestinal Disorders Dry mouth 7 6 9 9 8 2 Constipation 4 4 7 10 7 2 Vomiting 2 3 3 2 3 2 Flatulence 1 1 2 2 2 1 Abdominal distension 2 2 2 2 2 1 General Disorders and Administrative Site Conditions Fatigue 5 7 6 8 7 4 Edema peripheral 5 5 6 9 6 2 Chest pain 2 1 1 2 2 1 Feeling abnormal 1 3 2 2 2 0 Edema 1 2 1 2 2 1 Feeling drunk 1 2 1 2 2 0 Infections and Infestations Sinusitis 4 5 7 5 5 4 Investigations Weight increased 8 10 10 14 11 2 Metabolism and Nutrition Disorders Increased appetite 4 3 5 7 5 1 Fluid retention 2 3 3 2 2 1 Musculoskeletal and Connective Tissue Disorders Arthralgia 4 3 3 6 4 2 Muscle spasms 2 4 4 4 4 2 Back pain 2 3 4 3 3 3 Nervous System Disorders Dizziness 23 31 43 45 38 9 Somnolence 13 18 22 22 20 4 Headache 11 12 14 10 12 12 Disturbance in attention 4 4 6 6 5 1 Balance disorder 2 3 6 9 5 0 Memory impairment 1 3 4 4 3 0 Coordination abnormal 2 1 2 2 2 1 Hypoesthesia 2 2 3 2 2 1 Lethargy 2 2 1 2 2 0 Tremor 0 1 3 2 2 0 Psychiatric Disorders Euphoric Mood 2 5 6 7 6 1 Confusional state 0 2 3 4 3 0 Anxiety 2 2 2 2 2 1 Disorientation 1 0 2 1 2 0 Depression 2 2 2 2 2 2 Respiratory, Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 2 1 3 3 2 2 * PGB: pregabalin Controlled Studies in Neuropathic Pain Associated with Spinal Cord Injury Adverse Reactions Leading to Discontinuation In clinical trials of adults with neuropathic pain associated with spinal cord injury, 13% of patients treated with pregabalin and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were somnolence (3%) and edema (2%). In comparison, none of the placebo-treated patients withdrew due to somnolence and edema. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue and balance disorder. Each of these adverse reactions led to withdrawal in less than 2% of patients. Most Common Adverse Reactions Table 10 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of patients for which the incidence was greater than in the placebo treatment group with neuropathic pain associated with spinal cord injury in the controlled trials. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of \\"mild\\" or \\"moderate\\". Table 10. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Spinal Cord Injury System Organ Class Preferred term PGB* (N=182) Placebo (N=174) % % Ear and labryrinth disorders Vertigo 2.7 1.1 Eye disorders Vision blurred 6.6 1.1 Gastrointestinal disorders Dry mouth 11.0 2.9 Constipation 8.2 5.7 Nausea 4.9 4.0 Vomiting 2.7 1.1 General disorders and administration site conditions Fatigue 11.0 4.0 Edema peripheral 10.4 5.2 Edema 8.2 1.1 Pain 3.3 1.1 Infections and infestations Nasopharyngitis 8.2 4.6 Investigations Weight increased 3.3 1.1 Blood creatine phosphokinase increased 2.7 0 Musculoskeletal and connective tissue disorders Muscular weakness 4.9 1.7 Pain in extremity 3.3 2.3 Neck pain 2.7 1.1 Back pain 2.2 1.7 Joint swelling 2.2 0 Nervous system disorders Somnolence 35.7 11.5 Dizziness 20.9 6.9 Disturbance in attention 3.8 0 Memory impairment 3.3 1.1 Paresthesia 2.2 0.6 Psychiatric disorders Insomnia 3.8 2.9 Euphoric mood 2.2 0.6 Renal and urinary disorders Urinary incontinence 2.7 1.1 Skin and subcutaneous tissue disorders Decubitus ulcer 2.7 1.1 Vascular disorders Hypertension 2.2 1.1 Hypotension 2.2 0 * PGB: Pregabalin Other Adverse Reactions Observed During the Clinical Studies of Pregabalin Following is a list of treatment-emergent adverse reactions reported by patients treated with pregabalin during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the WARNINGS AND PRECAUTIONS SECTION (5). Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever, Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction, Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia, Alanine aminotransferase increased, Aspartate aminotransferase increased Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypoesthesia, Libido decreased, Nystagmus, Paresthesia, Sedation, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia, Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn Skin and Appendages – Frequent: Pruritus, Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race. Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of pregabalin. 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. Nervous System Disorders – Headache Gastrointestinal Disorders – Nausea, Diarrhea Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement Skin and subcutaneous tissue disorders – Bullous pemphigoid There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking pregabalin with opioids or other CNS depressants, or in the setting of underlying respiratory impairment. In addition, there are postmarketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when pregabalin was co\xad administered with medications that have the potential to produce constipation, such as opioid analgesics."}', 'drug_interactions': '{"7. Drug Interactions Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (less than 2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that pregabalin capsule is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between pregabalin and commonly used antiepileptic drugs [see CLINICAL PHARMACOLOGY (12)]. Pharmacodynamics Multiple oral doses of pregabalin were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when pregabalin was co-administered with these drugs. No clinically important effects on respiration were seen."}', 'indications_and_usage': '{"1.Indications and Usage Section 1 INDICATIONS AND USAGE Pregabalin capsule is indicated for: Management of neuropathic pain associated with diabetic peripheral neuropathy Management of postherpetic neuralgia Adjunctive therapy for the treatment of partial onset seizures in patients 17 years of age and older Management of fibromyalgia Management of neuropathic pain associated with spinal cord injury Pediatric use information is approved for Pfizer\'s LYRICA (pregabalin) Capsules and Oral Solution products. However, due to Pfizer\'s marketing exclusivity rights, this drug product is not labeled with that pediatric information."}', 'warnings_and_cautions': '{"5. Warnings and Precautions 5.1 Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with pregabalin. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue pregabalin immediately in patients with these symptoms. Exercise caution when prescribing pregabalin to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema. 5.2 Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with pregabalin. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue pregabalin immediately in patients with these symptoms. 5.3 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including pregabalin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono-and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing pregabalin capsules or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.4 Respiratory Depression There is evidence from case reports, human studies, and animal studies associating pregabalin with serious, life-threatening, or fatal respiratory depression when co-administered with central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe pregabalin with another CNS depressant, particularly an opioid, or to prescribe pregabalin to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating pregabalin at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including pregabalin). There is more limited evidence from case reports, animal studies, and human studies associating pregabalin with serious respiratory depression, without co-administered CNS depressants or without underlying respiratory impairment. 5.5 Dizziness and Somnolence Pregabalin may cause dizziness and somnolence. Inform patients that pregabalin-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery [SEE PATIENT COUNSELING INFORMATION (17)]. In the pregabalin controlled trials in adult patients, dizziness was experienced by 30% of pregabalin-treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of pregabalin-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of pregabalin therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In pregabalin-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients [SEE DRUG INTERACTIONS (7)]. Pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 5.6 Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation As with all antiepileptic drugs (AEDs), withdraw pregabalin gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. Following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea. If pregabalin is discontinued, taper the drug gradually over a minimum of 1 week rather than discontinue the drug abruptly. 5.7 Peripheral Edema Pregabalin treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials in adult patients, the incidence of peripheral edema was 6% in the pregabalin group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of pregabalin patients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in patients taking both pregabalin and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with pregabalin only, and 19% (23/120) of patients who were on both pregabalin and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on pregabalin only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when co-administering pregabalin and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using pregabalin in these patients. 5.8 Weight Gain Pregabalin treatment may cause weight gain. In pregabalin controlled clinical trials in adult patients of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of pregabalin-treated patients and 2% of placebo-treated patients. Few patients treated with pregabalin (0.3%) withdrew from controlled trials due to weight gain. Pregabalin associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see WARNINGS AND PRECAUTIONS (5.7)]. Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of pregabalin-associated weight gain are unknown. Among diabetic patients, pregabalin-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received Pregabalin for at least 2 years, the average weight gain was 5.2 kg. While the effects of pregabalin-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, Pregabalin treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C). 5.9 Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of pregabalin, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see NONCLINICAL TOXICOLOGY (13.1)]. The clinical significance of this finding is unknown. Clinical experience during pregabalin\'s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients greater than 12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with pregabalin, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment. 5.10 Ophthalmological Effects In controlled studies in adult patients, a higher proportion of patients treated with pregabalin reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued pregabalin treatment due to vision- related events (primarily blurred vision). Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with pregabalin and 5% of placebo- treated patients. Visual field changes were detected in 13% of pregabalin-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of pregabalin-treated and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions [SEE PATIENT COUNSELING INFORMATION (17)]. 5.11 Creatine Kinase Elevations Pregabalin treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for pregabalin-treated patients and 28 U/L for the placebo patients. In all controlled trials in adult patients across multiple patient populations, 1.5% of patients on pregabalin and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three pregabalin-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and pregabalin is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with pregabalin if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. 5.12 Decreased Platelet Count Pregabalin treatment was associated with a decrease in platelet count. Pregabalin-treated subjects experienced a mean maximal decrease in platelet count of 20 × 103/μL, compared to 11 × 103/μL in placebo patients. In the overall database of controlled trials in adult patients, 2% of placebo patients and 3% of Pregabalin patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and less than 150 × 103/μL. A single Pregabalin-treated subject developed severe thrombocytopenia with a platelet count less than 20 × 103/ μL. In randomized controlled trials, Pregabalin was not associated with an increase in bleeding-related adverse reactions. 5.13 PR Interval Prolongation Pregabalin treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data in adult patients, the mean PR interval increase was 3-6 msec at pregabalin doses greater than or equal to 300 mg/day. This mean change difference was not associated with an increased risk of PR increase greater than or equal to 25% from baseline, an increased percentage of subjects with on-treatment PR greater than 200 msec, or an increased risk of adverse reactions of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories."}', 'overdosage': '{"10. Overdosage Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans In the postmarketing experience, the most commonly reported adverse events observed with pregabalin when taken in overdose include reduced consciousness, depression/anxiety, confusional state, agitation, and restlessness. Seizures and heart block have also been reported. Deaths have been reported in the setting of lone Pregabalin overdose and in combination with other CNS depressants. Treatment or Management of Overdose There is no specific antidote for overdose with pregabalin. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up\xad-to-date information on the management of overdose with pregabalin. Pregabalin can be removed by hemodialysis. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours)."}', 'active_flag': 'Y', 'generic_name': '{PREGABALIN}', 'route': '{ORAL}', 'product_type': '{"HUMAN PRESCRIPTION DRUG"}', 'stop_use': None, 'do_not_use': None, 'when_using': None, 'warnings': None, '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] {"CONESTAT ALFA"}

[Assistant] {'contraindications': '{"4 CONTRAINDICATIONS RUCONEST is contraindicated in patients with a history of allergy to rabbits or rabbit-derived products. RUCONEST is contraindicated in patients with a history of life-threatening immediate hypersensitivity reactions to C1 esterase inhibitor preparations, including anaphylaxis. Known or suspected allergy to rabbits and rabbit-derived products. History of immediate hypersensitivity reactions, including anaphylaxis, to C1 esterase inhibitor preparations. ( 4 )"}', 'adverse_reactions': '{"6 ADVERSE REACTIONS The serious adverse reaction in clinical studies of RUCONEST was anaphylaxis. The most common adverse reactions (≥ 2%) reported in all clinical trials were headache, nausea, and diarrhea. The serious adverse reaction reported in clinical trials was anaphylactic reaction. ( 6 ) The common adverse reactions (≥ 2%) reported in clinical trials were headache, nausea, and diarrhea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals, Inc. at 1-800-508-0024 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, the 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 clinical practice. The RUCONEST clinical development program evaluated a combined total of 940 administrations in 236 subjects (symptomatic and non-symptomatic). In clinical studies, a total of 205 symptomatic HAE patients received treatment with RUCONEST for a combined total of 650 acute angioedema attacks. Among these HAE patients, 83 were treated for a single HAE attack and 122 were treated for multiple attacks. Three randomized, placebo-controlled clinical trials (RCTs) were conducted in which 137 patients experiencing acute HAE attacks received RUCONEST (either an initial 50 U/kg or 100 U/kg body weight dose) or placebo (saline solution). Table 2 shows all adverse reactions (ARs) in the RCTs, compared with the placebo group. Table 2. Adverse reactions occurring in ≥ 2% of subjects in the three RCT studies * Includes 5 patients who received an additional 50 U/kg dose MedDRA: Medical Dictionary for Regulatory Activities, version 15.0. ** Events only occurring in placebo patients are not listed MedDRA Preferred Term RUCONEST 100 U/kg (N=29) n(%) RUCONEST 50 U/kg* (N=66) n(%) Placebo** (N=47) n(%) Total number of patients with adverse reactions 4 (14%) 6 (9%) 13 (28%) Headache 3 (10%) 0 2 (4%) Sneezing 0 1 (2%) 0 Angioedema 1 (3%) 0 0 Erythema marginatum 0 1 (2%) 0 Skin burning sensation 0 1 (2%) 0 Back pain 0 2 (3%) 0 C-reactive protein increased 0 1 (2%) 0 Fibrin D-dimer increased 0 1 (2%) 0 Vertigo 1 (3%) 0 0 Procedural headache 0 1 (2%) 0 Lipoma 0 1 (2%) 0 Integrated RCT and Open-Label Extension (OLE) Studies In a total of seven RCT and OLE studies, 205 patients experiencing acute HAE attacks were treated with RUCONEST for a total of 650 HAE attacks. Included in this population were 124 patients who were treated at the 50 U/kg dosage strength for one or more attacks. Table 3 shows adverse reactions in ≥ 2% of patients in any RUCONEST group for the integrated dataset combining all seven RCT and OLE studies in patients experiencing acute HAE attacks. Table 3. Adverse reactions in the seven RCT and OLE studies occurring ≥ 2% of RUCONEST-treated patients (all doses), irrespective of causality * RUCONEST doses: doses up to 100 U/kg MedDRA: Medical Dictionary for Regulatory Activities, version 15.0. MedDRA Preferred Term All RUCONEST doses * N=205 n(%) Headache 19 (9%) Nausea 5 (2%) Diarrhea 5 (2%) Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Pre- and post-exposure samples from 205 HAE patients treated for 650 acute attacks with RUCONEST were tested for the antibodies against plasma-derived C1INH or rhC1INH and for antibodies against host-related impurities (HRI). Testing was performed prior to and after treatment of a first attack and subsequent repeated attacks at 7, 22 or 28, and 90 days after RUCONEST treatment. Prior to the first exposure to RUCONEST, the frequency of anti-C1INH antibodies varied from 1.2% to 1.6% of samples. After the first exposure, the frequency of anti-C1INH antibodies varied from 0.6% to 1.0% of samples tested. After repeated exposures, the frequency of anti-C1INH antibodies varied from 0.5 to 2.2% of samples tested. The frequency of anti-HRI antibodies was 1.0% in pre-exposure samples, and after the first exposure varied from 3.5% to 4.6%. After repeated exposure, the frequency of anti-HRI antibodies varied from 5.7% to 17% of samples. At least 10% of subjects formed a specific antibody response to RUCONEST after five treated HAE attacks. No anti-C1INH neutralizing antibodies were detected. Observed anti-C1INH and anti-HRI antibodies were not associated with adverse clinical findings. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to RUCONEST with the incidence of antibodies to other products may be misleading. Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure. Adverse reactions in HAE patients receiving RUCONEST include abdominal pain and rash."}', 'drug_interactions': None, 'indications_and_usage': '{"1 INDICATIONS AND USAGE RUCONEST is a C1 esterase inhibitor [recombinant] indicated for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema (HAE). Limitation of Use: Effectiveness was not established in HAE patients with laryngeal attacks. RUCONEST is a C1 esterase inhibitor [recombinant] indicated for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema (HAE). ( 1 ) Limitation of Use: Effectiveness was not established in HAE patients with laryngeal attacks."}', 'warnings_and_cautions': '{"5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions, including anaphylaxis may occur. Should symptoms occur, discontinue RUCONEST and administer appropriate treatment. ( 5.1 ) Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of plasma derived C1 esterase inhibitor products in patients with risk factors. Monitor patients with known risk factors for TE events during and after RUCONEST administration. ( 5.2 ) 5.1 Hypersensitivity Severe hypersensitivity reactions may occur [see Patient Counseling Information (17) ]. The signs and symptoms of hypersensitivity reactions may include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and/or anaphylaxis during or after injection of RUCONEST. Should symptoms occur, discontinue RUCONEST and institute appropriate treatment. Because hypersensitivity reactions may have symptoms similar to HAE attacks, treatment methods should be carefully considered. 5.2 Thromboembolic Events Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of plasma derived C1 esterase inhibitor products in patients with risk factors. Risk factors may include the presence of an indwelling venous catheter/access device, prior history of thrombosis, underlying atherosclerosis, use of oral contraceptives or certain androgens, morbid obesity, and immobility. Monitor patients with known risk factors for TE events during and after RUCONEST administration."}', 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"C1 ESTERASE INHIBITOR RECOMBINANT"}', 'route': '{INTRAVENOUS}', '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 (Product Information and Instructions for Use). Patients being treated with RUCONEST should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of RUCONEST. •Advise female patients to notify their physician if they are pregnant or intend to become pregnant during the treatment of acute attacks of HAE with RUCONEST.•Advise patients to notify their physician if they are breastfeeding or plan to breastfeed.•Inform patients of the risks and benefits of RUCONEST before prescribing or administering it to the patient. Advise patients to immediately report : •Signs and symptoms of allergic hypersensitivity reactions, such as hives, urticaria, tightness of the chest, wheezing, hypotension and/or anaphylaxis experienced during or after injection of RUCONEST ( see WARNINGS AND PRECAUTIONS/Hypersensitivity [ 5 ] ). Manufactured by: Pharming Technologies B.V. Darwinweg 24 NL-2333 CR Leiden The Netherlands RUCONEST ® is a registered trademark of Pharming Group N.V. Distributed by: Santarus, Inc., a wholly owned subsidiary of Salix Pharmaceuticals, Inc. Raleigh, NC 27615 Product protected by the following U.S patent Nos. 7,067,713. Please see www.salix.com for patent information. US License No. 2012 REV FEB 2015 VENART-307-1 60002124-02 Santarus Logo Salix Logo"}', 'pregnancy': '{"8.1 Pregnancy Pregnancy Category B. Studies performed in rats and rabbits at doses up to 12.5 times the human dose of 50 U/kg could not exclude an effect on embryofetal development. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, RUCONEST should only be used during pregnancy if clearly needed."}', 'pediatric_use': '{"8.4 Pediatric Use The safety and efficacy of RUCONEST were evaluated in 17 adolescent patients (13-17 years of age) treated for 52 HAE attacks. Eight out of 17 (47%) adolescent patients experienced adverse reactions. No serious adverse reactions were reported in these patients. The most common reactions (occurring in at least 2 patients) were: abdominal pain, headache, and oropharyngeal pain."}', 'geriatric_use': '{"8.5 Geriatric Use The clinical studies of RUCONEST included seven patients older than 65 years. The clinical studies included an insufficient number of patients in this age group to determine if they respond differently from younger patients."}'}


[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] {"MICONAZOLE NITRATE"}

[Assistant] {'contraindications': None, 'adverse_reactions': None, 'drug_interactions': None, 'indications_and_usage': '{"Uses • treats vaginal yeast infections • relieves external itching and irritation due to a vaginal yeast infection"}', 'warnings_and_cautions': None, 'overdosage': None, 'active_flag': 'Y', 'generic_name': '{"MICONAZOLE NITRATE"}', 'route': '{VAGINAL}', 'product_type': '{"HUMAN OTC DRUG"}', 'stop_use': '{"Stop use and ask a doctor if • symptoms do not get better in 3 days • symptoms last more than 7 days • you get a rash or hives, abdominal pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge"}', 'do_not_use': '{"Do not use if you have never had a vaginal yeast infection diagnosed by a doctor"}', 'when_using': '{"When using this product • do not use tampons, douches, spermicides or other vaginal products. Condoms and diaphragms may be damaged and fail to prevent pregnancy or sexually transmitted diseases (STDs). • do not have vaginal intercourse • mild increase in vaginal burning, itching or irritation may occur • if you do not get complete relief ask a doctor before using another product"}', 'warnings': '{"Warnings For vaginal use only Do not use if you have never had a vaginal yeast infection diagnosed by a doctor Ask a doctor before use if you have • vaginal itching and discomfort for the first time • lower abdominal, back or shoulder pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge. You may have a more serious condition. • vaginal yeast infections often (such as once a month or 3 in 6 months). You could be pregnant or have a serious underlying medical cause for your symptoms, including diabetes or a weakened immune system. • been exposed to the human immunodeficiency virus (HIV) that causes AIDS Ask a doctor or pharmacist before use if you are taking the prescription blood thinning medicine warfarin, because bleeding or bruising may occur When using this product • do not use tampons, douches, spermicides or other vaginal products. Condoms and diaphragms may be damaged and fail to prevent pregnancy or sexually transmitted diseases (STDs). • do not have vaginal intercourse • mild increase in vaginal burning, itching or irritation may occur • if you do not get complete relief ask a doctor before using another product Stop use and ask a doctor if • symptoms do not get better in 3 days • symptoms last more than 7 days • you get a rash or hives, abdominal pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. If swallowed, 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}