Hydrochlorothiazide

INZIRQO™ (hydrochlorothiazide) is a thiazide diuretic indicated for: The treatment of hypertension in adult and pediatric patients alone or in combination with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarction (1.1). The treatment of edema associated with congestive heart failure, hepatic cirrhosis and renal disease including the nephrotic syndrome in adult and pediatric patients. (1.2).

1.1 Hypertension INZIRQO is indicated for the treatment of hypertension in adult and pediatric patients, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes., including the class to which this drug principally belongs. Control of high blood pressure should be part of comprehensive cardiovascular risk management including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. INZIRQO can be used alone or in combination with other antihypertensive agents.

1.2 Edema Treatment of edema associated with congestive heart failure, hepatic cirrhosis, and renal disease including the nephrotic syndrome in adult and pediatric patients.

For Oral Suspension: When reconstituted as directed, INZIRQO is an off-white to light brown colored suspension with caramel, peppermint flavor containing 10 mg/mL of hydrochlorothiazide, USP. For oral suspension: 10 mg/mL (3)

INZIRQO is contraindicated: In patients with anuria. In patients with hypersensitivity to hydrochlorothiazide or any ingredient in INZIRQO. In patients with hypersensitivity to sulfonamide-derived drugs. Anuria (4) Hypersensitivity to hydrochlorothiazide or any ingredient in INZIRQO (4) Hypersensitivity to sulfonamide-derived drugs (4)

Monitor kidney function periodically (5.1) Monitor and correct serum electrolytes prior to use and monitor periodically (5.2). Monitor blood sugar, lipid levels, uric acid and calcium levels periodically. (5.3) Exacerbation or activation of systemic lupus erythematosus (5.4) Acute angle-closure glaucoma and acute myopia (5.5)

5.1 Impaired Renal Function Monitor kidney function periodically. Diuretics can cause hypovolemia which may precipitate acute kidney injury. Patients with chronic kidney disease, heart failure, or volume depletion may be at particular risk of developing acute renal failure on INZIRQO. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in kidney function while on INZIRQO.

5.2 Electrolyte Abnormalities INZIRQO can cause potentially symptomatic hypokalemia, hyponatremia, hypomagnesemia, and hypochloremic alkalosis. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Hypokalemia is dose dependent. Monitor and correct serum electrolytes prior to use and monitor periodically. Discontinue INZIRQO if hypokalemia is associated with clinical symptoms (e.g., ECG changes, muscular weakness).

5.3 Metabolic Disturbances INZIRQO may increase blood sugar levels, affect diabetes control, and cause changes in the need for diabetes medication. INZIRQO may raise serum levels of cholesterol and triglycerides. Monitor blood sugar and lipid levels. INZIRQO may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Increases in serum uric acid are dose related. INZIRQO decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving INZIRQO. Discontinue thiazides before carrying out tests for parathyroid function.

5.4 Systemic Lupus Erythematosus Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

5.5 Acute Angle-Closure Glaucoma and Acute Myopia Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction resulting in acute angle closure glaucoma and elevated intraocular pressure with or without a noticeable acute myopic shift and/or choroidal effusions. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma may result in permanent vision loss. Discontinue drug intake. Consider prompt medical or surgical treatments if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

The following adverse reactions with INZIRQO are described elsewhere: Impaired Renal Function [see Warnings and Precautions (5.1)] Electrolyte Abnormalities [see Warnings and Precautions (5.2)] Metabolic Disturbances [see Warnings and Precautions (5.3)] Systemic Lupus Erythematosus [see Warnings and Precautions (5.4)] Acute Angle-Closure Glaucoma and Acute Myopia [see Warnings and Precautions (5.5)] Adverse reactions include hypokalemia, hyponatremia, hypomagnesemia, hyperglycemia, hyperuricemia, hyperlipidemia and hypotension. See Adverse Reactions (6) To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity. Body as a Whole: Weakness. Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics or antihypertensive drugs). Gastrointestinal: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia. Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia. Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura. Metabolic: Electrolyte imbalance, hyperglycemia, glycosuria, hyperuricemia. Musculoskeletal: Muscle spasm. Nervous System: Vertigo, paresthesia, dizziness, headache, restlessness. Renal: Renal failure, renal dysfunction, interstitial nephritis. Skin and Appendages: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia. Special Senses: Transient blurred vision, xanthopsia. Urogenital System: Impotence.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of hydrochlorothiazide. Non-melanoma Skin Cancer Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥ 50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

NSAID: May lead to increased risk of renal impairment and loss of diuretic and antihypertensive effect (7.1). Cholestyramine and colestipol: Reduced absorption of thiazides (7.1) Lithium: Increased lithium concentrations and lithium toxicity (7.2) Antidiabetic drugs: Dosage adjustment of antidiabetic may be required (7.2)

7.1 Potential for Other Drugs to Affect INZIRQO Non-Steroidal Anti-Inflammatory Agents: Administration of a nonsteroidal anti-inflammatory agent, including a selective COX-2 inhibitor can reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics. Therefore, when INZIRQO and nonsteroidal anti-inflammatory agents are used concomitantly, check to determine if the desired effect of the diuretic is obtained. Cholestyramine and Colestipol : Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Stagger the dosage of INZIRQO and the resin such that INZIRQO is administered at least 4 hours before or 4 to 6 hours after the administration of the resin.

7.2 Potential for INZIRQO to Affect Other Drugs Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of hydrochlorothiazide. Monitor serum lithium levels during concomitant use and adjust the lithium dose during concomitant administration or discontinuation of hydrochlorothiazide. Antidiabetic Drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required when coadministered with hydrochlorothiazide.

8.1 Pregnancy Risk Summary Untreated hypertension during pregnancy can lead to adverse outcomes for the mother and the fetus (see Clinical Considerations). Available data from published observational studies have not demonstrated a drug-associated risk of major birth defects, miscarriage or adverse maternal outcomes with hydrochlorothiazide use during pregnancy. However, there have been rare reports of jaundice, thrombocytopenia, and electrolyte imbalances in infants exposed to thiazide medications during pregnancy. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Monitor pregnant women with hypertension. Data Animal Data Teratogenic effects: Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide /kg (approximately 146-fold and 97-fold the maximum recommended human dose based on body surface area), respectively, provided no evidence of harm to the fetus.

8.2 Lactation Risk Summary Available data from published literature indicate hydrochlorothiazide is present in human milk (see Data) . There are no reports of adverse effects on breastfed infants exposed to hydrochlorothiazide during lactation. Doses of hydrochlorothiazide associated with clinically significant diuresis have been associated with impaired milk production. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for INZIRQO and any potential adverse effects on the breastfed infant from INZIRQO or from the underlying maternal condition. Data A single study involving one woman and her infant showed a peak concentration of 275 mcg/L at 3 hours following 50 mg dose. No drug was detected (<20 mcg/L) in the infant’s plasma at 2 and 11 hours following the mother’s dose.

8.4 Pediatric Use INZIRQO is approved for use in pediatric patients for the following: Treatment of hypertension to lower blood pressure Treatment of edema associated with congestive heart failure, hepatic cirrhosis, and renal disease, including the nephrotic syndrome

8.5 Hepatic Impairment Monitor for mental status changes when using INZIRQO in patients with hepatic impairment because fluid shifts may precipitate hepatic coma.

Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The mechanism of the antihypertensive effect of thiazides is not fully understood.