FDA label 43bcd98f-da5a-18d5-e054-00144ff88e88

BOXED WARNING When pregnancy is detected, discontinue Exforge HCT as soon as possible. (5.1) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)

WARNINGS AND PRECAUTIONS Hypotension: Correct volume depletion prior to initiation ( 5.2 ) Increased angina and/or myocardial infarction ( 5.3 ) Monitor renal function and potassium in susceptible patients ( 5.4 , 5.5 ) Exacerbation or activation of systemic lupus erythematosus ( 5.7 ) Observe for signs of fluid or electrolyte imbalance ( 5.9 ) Acute angle-closure glaucoma ( 5.10 ) 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 Exforge HCT as soon as possible [see Use in Specific Populations (8.1)]. Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated with the maximum dose of Exforge HCT (10/320/25 mg) compared to 1.8% of valsartan/HCTZ (320/25 mg) patients, 0.4% of amlodipine/valsartan (10/320 mg) patients, and 0.2% of HCTZ/amlodipine (25/10 mg) patients in a controlled trial in patients with moderate to severe uncomplicated hypertension. In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. Correct this condition prior to administration of Exforge HCT. Exforge HCT has not been studied in patients with heart failure, recent myocardial infarction, or in patients undergoing surgery or dialysis. Patients with heart failure or post-myocardial infarction patients given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients. Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Do not initiate treatment with Exforge HCT in patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy. If excessive hypotension occurs with Exforge HCT, the patient should be placed in a 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. Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on Exforge HCT. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Exforge HCT [see Drug Interactions (7)] . In the controlled trial of Exforge HCT in moderate to severe hypertensive patients, the incidence of hypokalemia (serum potassium <3.5 mEq/L) at any time post-baseline with the maximum dose of Exforge HCT (10/320/25 mg) was 10% compared to 25% with HCTZ/amlodipine (25/10 mg), 7% with valsartan/HCTZ (320/25 mg), and 3% with amlodipine/valsartan (10/320 mg). One patient (0.2%) discontinued therapy due to an adverse event of hypokalemia in each of the Exforge HCT and HCTZ/amlodipine groups. The incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4% with Exforge HCT compared to 0.2% to 0.7% with the dual therapies. Some patients with heart failure have developed increases in potassium on valsartan. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or valsartan may be required. Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically. If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis, or ECG alterations), Exforge HCT should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides. 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. Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of valsartan or thiazide diuretics. Monitor lithium levels in patients receiving Exforge HCT and lithium [see Drug Interactions (7)] . Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hydrochlorothiazide 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. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Exforge HCT. Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. 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 can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

ADVERSE REACTIONS Most common adverse events (≥2% incidence) are dizziness, peripheral edema, headache, dyspepsia, fatigue, muscle spasms, back pain, nausea and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. In the controlled trial of Exforge HCT, where only the maximum dose (10/320/25 mg) was evaluated, safety data were obtained in 582 patients with hypertension. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall frequency of adverse reactions was similar between men and women, younger (<65 years) and older ( > 65 years) patients, and black and white patients. In the active controlled clinical trial, discontinuation because of adverse events occurred in 4.0% of patients treated with Exforge HCT 10/320/25 mg compared to 2.9% of patients treated with valsartan/HCTZ 320/25 mg, 1.6% of patients treated with amlodipine/valsartan 10/320 mg, and 3.4% of patients treated with HCTZ/amlodipine 25/10 mg. The most common reasons for discontinuation of therapy with Exforge HCT were dizziness (1.0%) and hypotension (0.7%). The most frequent adverse events that occurred in the active controlled clinical trial in at least 2% of patients treated with Exforge HCT are presented in the following table. Preferred Term Aml/Val/HCTZ 10/320/25 mg N=582 n (%) Val/HCTZ 320/25 mg N=559 n (%) Aml/Val 10/320 mg N=566 n (%) HCTZ/Aml 25/10 mg N=561 n (%) Dizziness 48 (8.2) 40 (7.2) 14 (2.5) 23 (4.1) Edema 38 (6.5) 8 (1.4) 65 (11.5 ) 63 (11.2) Headache 30 (5.2) 31 (5.5) 30 (5.3) 40 (7.1) Dyspepsia 13 (2.2) 5 (0.9) 6 (1.1) 2 (0.4) Fatigue 13 (2.2) 15 (2.7) 12 (2.1) 8 (1.4) Muscle spasms 13 (2.2) 7 (1.3) 7 (1.2) 5 (0.9) Back pain 12 (2.1) 13 (2.3) 5 (0.9) 12 (2.1) Nausea 12 (2.1) 7 (1.3) 10 (1.8) 12 (2.1) Nasopharyngitis 12 (2.1) 13 (2.3) 13 (2.3) 12 (2.1) Orthostatic events (orthostatic hypotension and postural dizziness) were seen in 0.5% of patients. Other adverse reactions that occurred in clinical trials with Exforge HCT (>0.2%) are listed below. It cannot be determined whether these events were causally related to Exforge HCT. Cardiac Disorders: tachycardia Ear and Labyrinth Disorders: vertigo, tinnitus Eye Disorders: vision blurred Gastrointestinal Disorders: diarrhea, abdominal pain upper, vomiting, abdominal pain, toothache, dry mouth, gastritis, hemorrhoids General Disorders and Administration Site Conditions: asthenia, noncardiac chest pain, chills, malaise Infections and Infestations: upper respiratory tract infection, bronchitis, influenza, pharyngitis, tooth abscess, gastroenteritis viral, respiratory tract infection, rhinitis, urinary tract infection Injury, Poisoning and Procedural Complications: back injury, contusion, joint sprain, procedural pain Investigations: blood uric acid increased, blood creatine phosphokinase increased, weight decreased Metabolism and Nutrition Disorders: hypokalemia, diabetes mellitus, hyperlipidemia, hyponatremia Musculoskeletal and Connective Tissue Disorders: pain in extremity, arthralgia, musculoskeletal pain, muscular weakness, musculoskeletal weakness, musculoskeletal stiffness, joint swelling, neck pain, osteoarthritis, tendonitis Nervous System Disorders: paresthesia, somnolence, syncope, carpal tunnel syndrome, disturbance in attention, dizziness postural, dysgeusia, head discomfort, lethargy, sinus headache, tremor Psychiatric Disorders: anxiety, depression, insomnia Renal and Urinary Disorders: pollakiuria Reproductive System and Breast Disorders: erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: dyspnea, nasal congestion, cough, pharyngolaryngeal pain Skin and Subcutaneous Tissue Disorders: pruritus, hyperhidrosis, night sweats, rash Vascular Disorders: hypotension Isolated cases of the following clinically notable adverse reactions were also observed in clinical trials: anorexia, constipation, dehydration, dysuria, increased appetite, viral infection. Amlodipine Amlodipine has been evaluated for safety in more than 11000 patients in US and foreign clinical trials. Other adverse reactions not listed above that have been reported in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain were: Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, postural hypotension, vasculitis Central and Peripheral Nervous System: neuropathy peripheral, tremor Gastrointestinal: anorexia, dysphagia, pancreatitis, gingival hyperplasia General: allergic reaction, hot flushes, malaise, rigors, weight gain Musculoskeletal System: arthrosis, muscle cramps Psychiatric: sexual dysfunction (male and female), nervousness, abnormal dreams, depersonalization Skin and Appendages: angioedema, erythema multiforme, rash erythematous, rash maculopapular Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus Urinary System: micturition frequency, micturition disorder, nocturia Autonomic Nervous System: sweating increased Metabolic and Nutritional: hyperglycemia, thirst Hemopoietic: leukopenia, purpura, thrombocytopenia Other adverse reactions reported with amlodipine at a frequency of ≤0.1% of patients include: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia. Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina. Adverse reactions reported for amlodipine for indications other than hypertension may be found in its full prescribing information. Valsartan Valsartan has been evaluated for safety in more than 4000 hypertensive patients in clinical trials. In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p <0.001). Other adverse reactions, not listed above, occurring in >0.2% of patients in controlled clinical trials with valsartan are: Digestive: flatulence Respiratory: sinusitis, pharyngitis Urogenital: impotence Adverse reactions reported for valsartan for indications other than hypertension may be found in the prescribing information for Diovan. Hydrochlorothiazide Other adverse reactions not listed above 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, hemolytic anemia Hypersensitivity: photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions Metabolic: glycosuria, hyperuricemia 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. Clinical Laboratory Test Findings Clinical laboratory test findings for Exforge HCT were obtained in a controlled trial of Exforge HCT administered at the maximal dose of 10/320/25 mg compared to maximal doses of dual therapies, i.e., valsartan/HCTZ 320/25 mg, amlodipine/valsartan 10/320 mg, and HCTZ/amlodipine 25/10 mg. Findings for the components of Exforge HCT were obtained from other trials. Creatinine: In hypertensive patients, greater than 50% increases in creatinine occurred in 2.1% of Exforge HCT patients compared to 2.4% of valsartan/HCTZ patients, 0.7% of amlodipine/valsartan patients, and 1.8% of HCTZ/amlodipine patients. In heart failure patients, greater than 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients. Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in Exforge HCT-treated patients. Blood Urea Nitrogen (BUN): In hypertensive patients, greater than 50% increases in BUN were observed in 30% of Exforge HCT-treated patients compared to 29% of valsartan/HCTZ patients, 15.8% of amlodipine/valsartan patients, and 18.5% of HCTZ/amlodipine patients. The majority of BUN values remained within normal limits. In heart failure patients, greater than 50% increases in BUN were observed in 17% of valsartan-treated patients compared to 6% of placebo-treated patients. Serum Electrolytes (Potassium): In hypertensive patients, greater than 20% decreases in serum potassium were observed in 6.5% of Exforge HCT-treated patients compared to 3.3% of valsartan/HCTZ patients, 0.4% of amlodipine/valsartan patients, and 19.3% of HCTZ/amlodipine patients. Greater than 20% increases in potassium were observed in 3.5% of Exforge HCT-treated patients compared to 2.4% of valsartan/HCTZ patients, 6.2% of amlodipine/valsartan patients, and 2.2% of HCTZ/amlodipine patients. In heart failure patients, greater than 20% increases in serum potassium were observed in 10% of valsartan-treated patients compared to 5.1% of placebo-treated patients [see Warnings and Precautions (5.5)] . Neutropenia: Neutropenia (<1500/L) was observed in 1.9% of patients treated with valsartan and 0.8% of patients treated with placebo. The following additional adverse reactions have been reported in postmarketing experience. 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. Amlodipine With amlodipine, gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine. Valsartan The following additional adverse reactions have been reported in postmarketing experience with valsartan or valsartan/hydrochlorothiazide: Blood and Lymphatic: Decrease in hemoglobin, decrease in hematocrit, neutropenia Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Exforge HCT should not be re-administered to patients who have had angioedema. Digestive: Elevated liver enzymes and very rare reports of hepatitis Renal: Impaired renal function, renal failure Clinical Laboratory Tests: Hyperkalemia Dermatologic: Alopecia, bullous dermatitis Vascular: Vasculitis Nervous System: Syncope Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. Hydrochlorothiazide The following additional adverse reactions have been reported in post-marketing experience with hydrochlorothiazide: Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, impotence, visual impairment. Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic evaluation is necessary.

<table> <col span="1" width="108"/> <col span="1" width="94"/> <col span="1" width="72"/> <col span="1" width="72"/> <col span="1" width="72"/> <tbody> <tr> <td> <content styleCode="bold">Preferred Term</content> </td> <td> <content styleCode="bold">Aml/Val/HCTZ</content> <content styleCode="bold"> 10/320/25 mg </content> <content styleCode="bold"> N=582 </content> <content styleCode="bold"> n (%) </content> </td> <td> <content styleCode="bold">Val/HCTZ</content> <content styleCode="bold"> 320/25 mg </content> <content styleCode="bold"> N=559 </content> <content styleCode="bold"> n (%) </content> </td> <td> <content styleCode="bold">Aml/Val</content> <content styleCode="bold"> 10/320 mg </content> <content styleCode="bold"> N=566 </content> <content styleCode="bold"> n (%) </content> </td> <td> <content styleCode="bold">HCTZ/Aml</content> <content styleCode="bold"> 25/10 mg </content> <content styleCode="bold"> N=561 </content> <content styleCode="bold"> n (%) </content> </td> </tr> <tr> <td> <content styleCode="bold">Dizziness</content> </td> <td> <content styleCode="bold">48 (8.2)</content> </td> <td> <content styleCode="bold">40 (7.2)</content> </td> <td> <content styleCode="bold">14 (2.5)</content> </td> <td> <content styleCode="bold">23 (4.1)</content> </td> </tr> <tr> <td> <content styleCode="bold">Edema </content> </td> <td> <content styleCode="bold">38 (6.5)</content> </td> <td> <content styleCode="bold"> 8 (1.4)</content> </td> <td> <content styleCode="bold"> 65 (11.5</content> <content styleCode="bold">)</content> </td> <td> <content styleCode="bold"> 63 (11.2)</content> </td> </tr> <tr> <td> <content styleCode="bold">Headache</content> </td> <td> <content styleCode="bold">30 (5.2)</content> </td> <td> <content styleCode="bold">31 (5.5)</content> </td> <td> <content styleCode="bold">30 (5.3)</content> </td> <td> <content styleCode="bold">40 (7.1)</content> </td> </tr> <tr> <td> <content styleCode="bold">Dyspepsia</content> </td> <td> <content styleCode="bold">13 (2.2)</content> </td> <td> <content styleCode="bold"> 5 (0.9)</content> </td> <td> <content styleCode="bold"> 6 (1.1)</content> </td> <td> <content styleCode="bold"> 2 (0.4)</content> </td> </tr> <tr> <td> <content styleCode="bold">Fatigue</content> </td> <td> <content styleCode="bold">13 (2.2)</content> </td> <td> <content styleCode="bold">15 (2.7)</content> </td> <td> <content styleCode="bold">12 (2.1)</content> </td> <td> <content styleCode="bold"> 8 (1.4)</content> </td> </tr> <tr> <td> <content styleCode="bold">Muscle spasms</content> </td> <td> <content styleCode="bold">13 (2.2)</content> </td> <td> <content styleCode="bold"> 7 (1.3)</content> </td> <td> <content styleCode="bold"> 7 (1.2)</content> </td> <td> <content styleCode="bold"> 5 (0.9)</content> </td> </tr> <tr> <td> <content styleCode="bold">Back pain</content> </td> <td> <content styleCode="bold">12 (2.1)</content> </td> <td> <content styleCode="bold">13 (2.3)</content> </td> <td> <content styleCode="bold"> 5 (0.9)</content> </td> <td> <content styleCode="bold">12 (2.1)</content> </td> </tr> <tr> <td> <content styleCode="bold">Nausea</content> </td> <td> <content styleCode="bold">12 (2.1)</content> </td> <td> <content styleCode="bold"> 7 (1.3)</content> </td> <td> <content styleCode="bold">10 (1.8)</content> </td> <td> <content styleCode="bold">12 (2.1)</content> </td> </tr> <tr> <td> <content styleCode="bold">Nasopharyngitis</content> </td> <td> <content styleCode="bold">12 (2.1)</content> </td> <td> <content styleCode="bold">13 (2.3)</content> </td> <td> <content styleCode="bold">13 (2.3)</content> </td> <td> <content styleCode="bold">12 (2.1)</content> </td> </tr> </tbody> </table>