Amlodipine, Valsartan and Hydrochlorothiazide (Page 2 of 9)

5.3 Increased Angina and/or Myocardial Infarction

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.

5.4 Impaired Renal Function

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 amlodipine, valsartan and hydrochlorothiazide. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on amlodipine, valsartan and hydrochlorothiazide [see DRUG INTERACTIONS (7) ].

5.5 Potassium Abnormalities

In the controlled trial of amlodipine, valsartan and hydrochlorothiazide 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 amlodipine, valsartan and hydrochlorothiazide (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 amlodipine, valsartan and hydrochlorothiazide and HCTZ/amlodipine groups. The incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4% with amlodipine, valsartan and hydrochlorothiazide 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), amlodipine, valsartan and hydrochlorothiazide should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides.

5.6 Hypersensitivity Reaction

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.

5.7 Systemic Lupus Erythematosus

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

5.8 Lithium Interaction

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 amlodipine, valsartan and hydrochlorothiazide; and lithium [see DRUG INTERACTIONS (7) ].

5.9 Metabolic Imbalances

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 amlodipine, valsartan and hydrochlorothiazide.

5.10 Acute Myopia and Secondary Angle-Closure Glaucoma

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.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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 amlodipine, valsartan and hydrochlorothiazide, 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% of patients treated with amlodipine, valsartan and hydrochlorothiazide 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 amlodipine, valsartan and hydrochlorothiazide were dizziness (1%) 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 amlodipine, valsartan and hydrochlorothiazide 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 amlodipine, valsartan and hydrochlorothiazide (>0.2%) are listed below. It cannot be determined whether these events were causally related to amlodipine, valsartan and hydrochlorothiazide.

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 valsartan tablets.

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 amlodipine, valsartan and hydrochlorothiazide were obtained in a controlled trial of amlodipine, valsartan and hydrochlorothiazide 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 amlodipine, valsartan and hydrochlorothiazide tablets were obtained from other trials.

Creatinine:

In hypertensive patients, greater than 50% increases in creatinine occurred in 2.1% of amlodipine, valsartan and hydrochlorothiazide 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 amlodipine, valsartan and hydrochlorothiazide-treated patients.

Blood Urea Nitrogen (BUN):

In hypertensive patients, greater than 50% increases in BUN were observed in 30% of amlodipine, valsartan and hydrochlorothiazide-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 amlodipine, valsartan and hydrochlorothiazide-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 amlodipine, valsartan and hydrochlorothiazide-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.