İHALE DÜNYASI
İHALE DÜNYASI
AVALIDE (irbesartan-hydrochlorothiazide) Tablets is a combination of an angiotensin II receptor antagonist (AT 1 subtype), irbesartan, and a thiazide diuretic, hydrochlorothiazide (HCTZ). Irbesartan is a non-peptide compound, chemically described as a 2-butyl-3-[ p -( o -1 H -tetrazol-5-ylphenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one. Its empirical formula is C 25 H 28 N 6 O, and its structural formula is: Irbesartan is a white to off-white crystalline powder with a molecular weight of 428.5. It is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4. Irbesartan is slightly soluble in alcohol and methylene chloride and practically insoluble in water. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 and its structural formula is: Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.7. Hydrochlorothiazide is slightly soluble in water and freely soluble in sodium hydroxide solution. AVALIDE is available for oral administration in tablets containing either 150 mg or 300 mg of irbesartan combined with 12.5 mg of hydrochlorothiazide or 300 mg of irbesartan combined with 25 mg hydrochlorothiazide. Inactive ingredients include: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, ferric oxide red, ferric oxide yellow, silicon dioxide, and magnesium stearate. In addition, the 300/25 mg pink film-coated tablet contains ferric oxide black, hypromellose-2910, PEG-3350, titanium dioxide, and carnauba wax. image of Irbesartan chemical structure image of Hydrochlorothiazide chemical structure
AVALIDE (R) (irbesartan-hydrochlorothiazide) Tablets is indicated for the treatment of hypertension. AVALIDE may be used in patients whose blood pressure is not adequately controlled on monotherapy. AVALIDE may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. The choice of AVALIDE as initial therapy for hypertension should be based on an assessment of potential benefits and risks. Patients with stage 2 (moderate or severe) hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and may be shaped by considerations such as the baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy. Data from Studies V and VI [see Clinical Studies (14.2) ] provide estimates of the probability of reaching a blood pressure goal with AVALIDE compared to irbesartan or HCTZ monotherapy. The relationship between baseline blood pressure and achievement of a SeSBP less than 140 or less than 130 mmHg or SeDBP less than 90 or less than 80 mmHg in patients treated with AVALIDE compared to patients treated with irbesartan or HCTZ monotherapy are shown in Figures 1a through 2b. Figure 1a: Probability of Achieving SBP less than 140 mmHg in Patients from Initial Therapy Studies V (Week 8) and VI (Week 7)* Figure 1b: Probability of Achieving SBP less than 130 mmHg in Patients from Initial Therapy Studies V (Week 8) and VI (Week 7)* Figure 2a: Probability of Achieving DBP less than 90 mmHg in Patients from Initial Therapy Studies V (Week 8) and VI (Week 7)* Figure 2b: Probability of Achieving DBP less than 80 mmHg in Patients from Initial Therapy Studies V (Week 8) and VI (Week 7)* *For all probability curves, patients without blood pressure measurements at Week 7 (Study VI) and Week 8 (Study V) were counted as not reaching goal (intent-to-treat analysis). The above graphs provide a rough approximation of the likelihood of reaching a targeted blood pressure goal (eg, Week 8 sitting systolic blood pressure less than or equal to 140 mmHg) for the treatment groups. The curve of each treatment group in each study was estimated by logistic regression modeling from all available data of that treatment group. The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures. For example, a patient with a blood pressure of 180/105 mmHg has about a 25% likelihood of achieving a goal of less than 140 mmHg (systolic) and 50% likelihood of achieving less than 90 mmHg (diastolic) on irbesartan alone (and lower still likelihoods on HCTZ alone). The likelihood of achieving these goals on AVALIDE rises to about 40% (systolic) or 70% (diastolic). AVALIDE is a combination of irbesartan, an angiotensin II receptor antagonist, and hydrochlorothiazide, a thiazide diuretic, indicated for hypertension: In patients not adequately controlled with monotherapy (1) As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals (1) . image of figure 1a image of figure 1b image of figure 2a image of figure 2b
Enter section text here General Considerations Maximum effects within 2 to 4 weeks after dose change (2.1) . Renal impairment: Not recommended for patients with severe renal impairment (creatinine clearance less than 30 mL/min) (2.1 , 5.8) . Hypertension Not controlled on monotherapy: Initiate with 150/12.5 mg. Titrate to 300/12.5 mg then 300/25 mg if needed. One tablet daily (2.2) . Replacement therapy: May be substituted for titrated components (2.3) . Initial therapy: Initiate with 150/12.5 mg once daily for 1 to 2 weeks and titrate as needed up to maximum of 300/25 mg once daily (2.4) . 2.1 General Considerations The side effects of irbesartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent phenomena (eg, pancreatitis), the former much more common than the latter. [See Adverse Reactions (6) .] Maximum antihypertensive effects are attained within 2 to 4 weeks after a change in dose. AVALIDE may be administered with or without food. AVALIDE may be administered with other antihypertensive agents. Renal impairment. The usual regimens of therapy with AVALIDE may be followed as long as the patient's creatinine clearance is greater than 30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so AVALIDE is not recommended. Hepatic impairment. No dosage adjustment is necessary in patients with hepatic impairment. 2.2 Add-On Therapy In patients not controlled on monotherapy with irbesartan or hydrochlorothiazide, the recommended doses of AVALIDE, in order of increasing mean effect, are (irbesartan-hydrochlorothiazide) 150/12.5 mg, 300/12.5 mg, and 300/25 mg. The largest incremental effect will likely be in the transition from monotherapy to 150/12.5 mg. [See Clinical Studies (14.2) .] 2.3 Replacement Therapy AVALIDE may be substituted for the titrated components. 2.4 Initial Therapy The usual starting dose is AVALIDE 150/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 300/25 mg tablet once daily as needed to control blood pressure [see Clinical Studies (14.2) ]. AVALIDE is not recommended as initial therapy in patients with intravascular volume depletion [see Warnings and Precautions (5.2) ].
AVALIDE is contraindicated in patients who are hypersensitive to any component of this product. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Hypersensitivity to any component of this product (4) Anuria (4) Hypersensitivity to sulfonamide-derived drugs (4)
Enter section text here Most common adverse events (?5% on AVALIDE and more often than on placebo) are dizziness, fatigue, and musculoskeletal pain (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Irbesartan-Hydrochlorothiazide AVALIDE (irbesartan-hydrochlorothiazide) Tablets has been evaluated for safety in 1694 patients treated for essential hypertension in 6 clinical trials. In Studies I through IV with AVALIDE, no adverse events peculiar to this combination drug product have been observed. Adverse events have been limited to those that were reported previously with irbesartan or hydrochlorothiazide (HCTZ). The overall incidence of adverse events was similar with the combination and placebo. In general, treatment with AVALIDE was well tolerated. For the most part, adverse events have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of AVALIDE therapy due to clinical adverse events was required in only 3.6%. This incidence was significantly less (p=0.023) than the 6.8% of patients treated with placebo who discontinued therapy. In these double-blind controlled clinical trials, the following adverse events reported with AVALIDE occurred in ?1% of patients, and more often on the irbesartan-hydrochlorothiazide combination than on placebo, regardless of drug relationship: Irbesartan/HCTZ (n=898) (%) Placebo (n=236) (%) Irbesartan (n=400) (%) HCTZ (n=380) (%) Body as a Whole Chest Pain 2 1 2 2 Fatigue 7 3 4 3 Influenza 3 1 2 2 Cardiovascular Edema 3 3 2 2 Tachycardia 1 0 1 1 Gastrointestinal Abdominal Pain 2 1 2 2 Dyspepsia/heartburn 2 1 0 2 Nausea/vomiting 3 0 2 0 Immunology Allergy 1 0 1 1 Musculoskeletal Musculoskeletal Pain 7 5 6 10 Nervous System Dizziness 8 4 6 5 Dizziness Orthostatic 1 0 1 1 Renal/Genitourinary Abnormality Urination 2 1 1 ct2 The following adverse events were also reported at a rate of 1% or greater, but were as, or more, common in the placebo group: headache, sinus abnormality, cough, URI, pharyngitis, diarrhea, rhinitis, urinary tract infection, rash, anxiety/nervousness, and muscle cramp. Adverse events occurred at about the same rates in men and women, older and younger patients, and black and non-black patients. Adverse events in Studies V and VI were similar to those described above in Studies I through IV. Irbesartan Other adverse events that have been reported with irbesartan, without regard to causality, are listed below: Body as a Whole: fever, chills, orthostatic effects, facial edema, upper extremity edema Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, hypotension, syncope, arrhythmic/conduction disorder, cardiorespiratory arrest, heart failure, hypertensive crisis Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout Gastrointestinal: diarrhea, constipation, gastroenteritis, flatulence, abdominal distention Musculoskeletal/Connective Tissue: musculoskeletal trauma, extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, joint stiffness, bursitis, muscle weakness Nervous System: anxiety/nervousness, sleep disturbance, numbness, somnolence, vertigo, emotional disturbance, depression, paresthesia, tremor, transient ischemic attack, cerebrovascular accident Renal/Genitourinary: prostate disorder Respiratory: cough, upper respiratory infection, epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea, wheezing Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain, conjunctivitis Hydrochlorothiazide Other adverse events that have been reported with hydrochlorothiazide, without regard to causality, are listed below: Body as a Whole: weakness Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions Metabolic: hyperglycemia, glycosuria, hyperuricemia Musculoskeletal: muscle spasm Nervous System/Psychiatric: restlessness Renal: renal failure, renal dysfunction, interstitial nephritis Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis Special Senses: transient blurred vision, xanthopsia Initial Therapy In the moderate hypertension Study V (mean SeDBP between 90 and 110 mmHg), the types and incidences of adverse events reported for patients treated with AVALIDE were similar to the adverse event profile in patients on initial irbesartan or HCTZ monotherapy. There were no reported events of syncope in the AVALIDE treatment group and there was one reported event in the HCTZ treatment group. The incidences of pre-specified adverse events on AVALIDE, irbesartan, and HCTZ, respectively, were: 0.9%, 0%, and 0% for hypotension; 3.0%, 3.8%, and 1.0% for dizziness; 5.5%, 3.8%, and 4.8% for headache; 1.2%, 0%, and 1.0% for hyperkalemia; and 0.9%, 0%, and 0% for hypokalemia. The rates of discontinuation due to adverse events on AVALIDE, irbesartan alone, and HCTZ alone were 6.7%, 3.8%, and 4.8%. In the severe hypertension (SeDBP ?110 mmHg) Study VI, the overall pattern of adverse events reported through 7 weeks of follow-up was similar in patients treated with AVALIDE as initial therapy and in patients treated with irbesartan as initial therapy. The incidences of the pre-specified adverse events on AVALIDE and irbesartan, respectively, were: 0% and 0% for syncope; 0.6% and 0% for hypotension; 3.6% and 4.0% for dizziness; 4.3% and 6.6% for headache; 0.2% and 0% for hyperkalemia; and 0.6% and 0.4% for hypokalemia. The rates of discontinuation due to adverse events were 2.1% and 2.2%. [See Clinical Studies (14.2) .] 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of AVALIDE. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to AVALIDE. The following have been very rarely reported: urticaria; angioedema (involving swelling of the face, lips, pharynx, and/or tongue); and hepatitis. Hyperkalemia has been rarely reported. Very rare cases of jaundice have been reported with irbesartan. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. 6.3 Laboratory Abnormalities In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of AVALIDE. Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in 2.3% and 1.1%, respectively, of patients with essential hypertension treated with AVALIDE alone. No patient discontinued taking AVALIDE due to increased BUN. One patient discontinued taking AVALIDE due to a minor increase in serum creatinine. Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with AVALIDE alone, one patient was discontinued due to elevated liver enzymes. Serum Electrolytes: [See Warnings and Precautions (5.2 , 5.6) .]
Enter section text here Symptomatic hypotension with intravascular volume- or sodium-depletion. Correct volume-depletion prior to administration. Not recommended as initial therapy in volume-depleted patients (2.4 , 5.2) . Impaired hepatic function: Thiazides should be used with caution as minor fluid and electrolyte imbalances may precipitate hepatic coma (5.7) . Impaired renal function: Use with caution. Oliguria or azotemia with acute renal failure and/or death has been reported in medications affecting the renin-angiotensin-aldosterone system (5.8) . Thiazide diuretics may cause an exacerbation or activation of systemic lupus erythematosus (5.4) . 5.1 Fetal/Neonatal Morbidity and Mortality AVALIDE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1) ]. In several dozen published cases, angiotensin converting enzyme (ACE) inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Similar renal findings occur in reproductive toxicology studies in rats. Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. 5.2 Hypotension in Volume- or Salt-Depleted Patients Excessive reduction of blood pressure was rarely seen in patients with uncomplicated hypertension treated with irbesartan alone (less than 0.1%) or with irbesartan-hydrochlorothiazide (approximately 1%). Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with intravascular volume- or sodium-depletion, eg, in patients treated vigorously with diuretics or in patients on dialysis. Such volume depletion should be corrected prior to administration of antihypertensive therapy. If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. 5.3 Hypersensitivity Reaction Hydrochlorothiazide Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. 5.4 Systemic Lupus Erythematosus Hydrochlorothiazide Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. 5.5 Lithium Interaction Hydrochlorothiazide Lithium generally should not be given with thiazides. [See Drug Interactions (7) .] 5.6 Electrolyte and Metabolic Imbalances Irbesartan-Hydrochlorothiazide In double-blind clinical trials of various doses of irbesartan and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium less than 3.5 mEq/L) was 7.5% versus 6.0% for placebo; the incidence of hyperkalemia (serum potassium greater than 5.7 mEq/L) was less than 1.0% versus 1.7% for placebo. No patient discontinued due to increases or decreases in serum potassium. On average, the combination of irbesartan and hydrochlorothiazide had no effect on serum potassium. Higher doses of irbesartan ameliorated the hypokalemic response to hydrochlorothiazide. Hydrochlorothiazide Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (eg, increased ventricular irritability). Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice. Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus, latent diabetes mellitus may become manifest during thiazide therapy. The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient. If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy. 5.7 Hepatic Impairment Hydrochlorothiazide Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. 5.8 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 whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Irbesartan would be expected to behave similarly. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or BUN have been reported. There has been no known use of irbesartan in patients with unilateral or bilateral renal artery stenosis, but a similar effect should be anticipated. Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. --- BOXED WARNING: WARNING: USE IN PREGNANCY When pregnancy is detected, discontinue AVALIDE as soon as possible. When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. [See Warnings and Precautions (5.1) .] WARNING: USE IN PREGNANCY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue AVALIDE as soon as possible. When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. (5.1)
Irbesartan No significant drug-drug interactions have been reported with irbesartan. [See Clinical Pharmacology (12.3) .] Hydrochlorothiazide When administered concurrently the following drugs may interact with thiazide diuretics: Alcohol, Barbiturates, or Narcotics: potentiation of orthostatic hypotension may occur. Antidiabetic Drugs (oral agents and insulin): dosage adjustment of the antidiabetic drug may be required. Other Antihypertensive Drugs: additive effect or potentiation. Cholestyramine and Colestipol Resins: absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. Corticosteroids, ACTH: intensified electrolyte depletion, particularly hypokalemia. Pressor Amines (eg, Norepinephrine): possible decreased response to pressor amines but not sufficient to preclude their use. Skeletal Muscle Relaxants, Nondepolarizing (eg, Tubocurarine): possible increased responsiveness to the muscle relaxant. Lithium: should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with AVALIDE. [See Warnings and Precautions (5.5) .] Non-steroidal Anti-inflammatory Drugs: in some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when AVALIDE (irbesartan-hydrochlorothiazide) Tablets and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Hydrochlorothiazide (7) : Alcohol, Barbiturates, Narcotics: Potentiation of orthostatic hypotension Antidiabetic Drugs: Dosage adjustment of antidiabetic may be required Cholestyramine and colestipol: Reduced absorption of thiazides Corticosteroids, ACTH: Hypokalemia, electrolyte depletion Lithium: Reduced renal clearance and high risk of lithium toxicity when used with diuretics. Should not be given with diuretics. NSAIDs: Can reduce diuretic, natriuretic, and antihypertensive effects of diuretics. Observe patient closely.