ATACAND HCT Candesartan Cilexetil and Hydrochlorothiazide 16 mg; 12.5 mg Tablet, 90-count

WARNINGS Fetal Toxicity 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 ATACAND HCT 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 ATACAND HCT, 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 ATACAND HCT for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use ). There was no evidence of teratogenicity or other adverse effects on embryo-fetal development when pregnant mice, rats or rabbits were treated orally with candesartan cilexetil alone or in combination with hydrochlorothiazide. For mice, the maximum dose of candesartan cilexetil was 1000 mg/kg/day (about 150 times the maximum recommended daily human dose [MRHD] Doses compared on the basis of body surface area.

MRHD considered to be 32 mg for candesartan cilexetil and 12.5 mg for hydrochlorothiazide. ). For rats, the maximum dose of candesartan cilexetil was 100 mg/kg/day (about 31 times the MRHD 1 ). For rabbits, the maximum dose of candesartan cilexetil was 1 mg/kg/day (a maternally toxic dose that is about half the MRHD 1 ).

In each of these studies, hydrochlorothiazide was tested at the same dose level (10 mg/kg/day, about 4, 8, and 15 times the MRHD 1 in mouse, rats, and rabbit, respectively). There was no evidence of harm to the rat or mouse fetus or embryo in studies in which hydrochlorothiazide was administered alone to the pregnant rat or mouse at doses of up to 1000 and 3000 mg/kg/day, respectively. Thiazides cross the placental barrier and appear in cord blood.

There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. Hypotension ATACAND HCT can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.

Patients with symptomatic hypotension may require temporarily reducing the dose of ATACAND HCT or volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with ATACAND HCT. In patients with heart failure, ATACAND HCT may cause excessive hypotension, which may lead to oliguria, azotemia, and (rarely) with acute renal failure and death (see WARNINGS, Impaired Renal Function ).

In such patients, ATACAND HCT therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of candesartan or diuretic is increased. Impaired Renal Function Monitor renal function periodically in patient…

ADVERSE REACTIONS Candesartan Cilexetil-Hydrochlorothiazide ATACAND HCT has been evaluated for safety in more than 2800 patients treated for hypertension. More than 750 of these patients were studied for at least six months and more than 500 patients were treated for at least one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.

The overall incidence of adverse events reported with ATACAND HCT was comparable to placebo. The overall frequency of adverse experiences was not related to dose, age, gender, or race. In placebo-controlled trials that included 1089 patients treated with various combinations of candesartan cilexetil (doses of 2-32 mg) and hydrochlorothiazide (doses of 6.25-25 mg) and 592 patients treated with placebo, adverse events, whether or not attributed to treatment, occurring in greater than 2% of patients treated with ATACAND HCT and that were more frequent for ATACAND HCT than placebo were: Respiratory System Disorder: upper respiratory tract infection (3.6% vs 3.0%); Body as a Whole: back pain (3.3% vs 2.4%); influenza-like symptoms (2.5% vs 1.9%); Central/Peripheral Nervous System: dizziness (2.9% vs 1.2%).

Post-Marketing Experience The following have been very rarely reported in post-marketing experience with candesartan cilexetil: Digestive: Abnormal hepatic function and hepatitis. Hematologic: Neutropenia, leukopenia, and agranulocytosis. Immunologic: Angioedema Metabolic and Nutritional Disorders: Hyperkalemia, hyponatremia.

Respiratory System Disorders: Cough Skin and Appendages Disorders: Pruritus, rash and urticaria. Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. Hydrochlorothiazide Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed below: Gastrointestinal: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, constipation, gastric irritation, 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, urticaria, purpura Musculoskeletal: muscle spasm 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. Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia Special Senses: transient blurred vision, xanthopsia Urogenital: impotence 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.

Drug Interactions Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected. Interactions common to both Candesartan Cilexetil and Hydrochlorothiazide 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 angiotensin II receptor antagonists, including candesartan, may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible. Monitor renal function periodically in patients receiving candesartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including candesartan may be attenuated by NSAIDs including selective COX-2 inhibitors.

Lithium Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists or hydrochlorothiazide. Monitor serum lithium levels during concomitant use. Interactions with Candesartan Cilexetil 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.

Closely monitor blood pressure, renal function and electrolytes in patients on ATACAND HCT and other agents that affect the RAS. Co-administration of ATACAND HCT with potassium sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.

Do not co-administer aliskiren with ATACAND HCT in patients with diabetes. Avoid use of aliskiren with ATACAND HCT in patients with renal impairment (GFR <60 mL/min) (see CONTRAINDICATIONS ). Interactions with Hydrochlorothiazide 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. Diazoxide − the hyperglycemic effect of diazoxide may be enhanced by thiazides. Ion 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.

Stagger the dosage of hydrochlorothiazide and ion exchange resins such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) − Possible increased responsiveness to muscle relaxants such as curare derivatives. Digitalis − Thiazide-induced hypokalemia or hypomagnesemia may predispose to digoxin toxicity.

Noradrenaline – Thiazides may decrease arterial responsiveness to noradrenaline, but not enough to preclude effectiveness of the pressor agent for therapeutic use. Steroids or Adrenocorticotropic Hormone – Hypokalemia may develop during concomitant use of steroids or adrenocorticotropic hormone (ACTH). Cytotoxic products – Thiazides may reduce the renal excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Cyclosporine − Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.