Amlodipine, hydrochlorothiazide, and valsartan

You should not use this medicine if you are allergic to amlodipine, hydrochlorothiazide, or valsartan, or:

• if you have ever had a severe allergic reaction to another blood pressure medicine;

• if you are allergic to any sulfa drug; or

• if you are unable to urinate.

If you have diabetes, do not use amlodipine, hydrochlorothiazide, and valsartan together with any medication that contains aliskiren (Amturnide, Tekturna, Tekamlo, Valturna).

You may also need to avoid taking this medicine with aliskiren if you have kidney disease.

To make sure amlodipine, hydrochlorothiazide, and valsartan is safe for you, tell your doctor if you have:

• kidney disease (or if you are on dialysis);

• liver disease;

• heart disease;

• an electrolyte imbalance (such as high levels of calcium, or low levels of potassium or magnesium in your blood);

• low blood pressure;

• glaucoma;

• lupus;

• a history of gallstones;

• gout;

• diabetes; or

• a penicillin allergy.

Do not use if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away. Valsartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

It is not known whether amlodipine, hydrochlorothiazide, and valsartan passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Usual Adult Dose for Hypertension:

Initial dose: 1 tablet orally once a day (The dosage may be increased after 2 weeks of therapy. The full blood pressure lowering effect was achieved 2 weeks after being on the maximal dose)

Maximum dose: Amlodipine/hydrochlorothiazide/valsartan 10 mg/25 mg/320 mg orally once a day

Comment:
-Indicated for patients whose blood pressure is adequately controlled on amlodipine, valsartan, and hydrochlorothiazide (as single component formulations or a dual component formulation with a single component formulation). Individual dose titration with each component is recommended before administering the fixed dose combination.

Applies to amlodipine / hydrochlorothiazide / valsartan: oral tablet

Along with its needed effects, amlodipine / hydrochlorothiazide / valsartan may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking amlodipine / hydrochlorothiazide / valsartan:

• Dizziness
• swelling

• Bladder pain
• bloody or cloudy urine
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain
• chills
• cold sweats
• coma
• confusion
• convulsions
• cough
• decreased urination
• diarrhea
• difficult or labored breathing
• difficult, burning, or painful urination
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• fast, pounding, or irregular heartbeat or pulse
• fever
• flushed, dry skin
• frequent urge to urinate
• fruit-like breath odor
• head congestion
• hoarseness or other voice changes
• increased hunger
• increased sweating
• increased thirst
• lightheadedness
• loss of appetite
• loss of consciousness
• lower back or side pain
• muscle aches and pains
• nausea or vomiting
• numbness or tingling in the hands, feet, or lips
• shivering
• sneezing
• sore throat
• stuffy or runny nose
• sweating
• tightness in the chest
• trouble sleeping
• unexplained weight loss
• unusual tiredness or weakness

Some side effects of amlodipine / hydrochlorothiazide / valsartan may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• back pain
• belching
• heartburn
• indigestion
• muscle spasms
• stomach discomfort, upset, or pain

• Bleeding after defecation
• body aches or pain
• burning feeling in the chest or stomach
• change in taste
• continuing ringing or buzzing or other unexplained noise in the ears
• decreased interest in sexual intercourse
• decreased weight
• depression
• difficulty having a bowel movement (stool)
• difficulty moving
• fear or nervousness
• feeling of constant movement of self or surroundings
• hearing loss
• inability to have or keep an erection
• increased appetite
• itching skin
• lack or loss of strength
• loss in sexual ability, desire, drive, or performance
• loss of taste
• muscle weakness
• neck pain
• pain in the arms or legs
• pain, swelling, or redness in the joints
• rash
• sensation of spinning
• shakiness in the legs, arms, hands, or feet
• sleeplessness
• sneezing
• swelling of the joints
• tender, swollen glands in the neck
• tenderness in the stomach area
• toothache
• trouble swallowing
• uncomfortable swelling around the anus
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• upper abdominal or stomach pain
• voice changes
• weight loss

Applies to amlodipine / hydrochlorothiazide / valsartan: oral tablet

Cardiovascular

Rare (less than 0.1%): Palpitations, chest pain, angioedema
Uncommon (0.1% to 1%): Orthostatic hypotension, postural dizziness
Frequency not reported: Cardiac arrhythmias (including ventricular ectopy and complete AV heart block)
-Amlodipine component: Arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, postural hypotension, vasculitis
-Hydrochlorothiazide component: Cardiac arrhythmias (including ventricular ectopy and complete AV heart block associated with hypokalemia and hyponatremia)
-Valsartan component: Dizziness related to orthostatic hypotension, palpitations, chest pain[Ref]

Dermatologic

Frequency not reported: Erythema annular centrifugum, acute eczematous dermatitis, morbilliform, leukocytoclastic vasculitis, phototoxic dermatitis, subacute cutaneous lupus erythematosus-like condition, pruritus, rash, hyperhidrosis
-Amlodipine component: Angioedema, erythema multiforme, rash erythematosus, rash maculopapular
-Hydrochlorothiazide component: Erythema annular centrifugum, acute eczematous dermatitis, morbilliform, leukocytoclastic vasculitis, phototoxic dermatitis, a rare subacute lupus erythematosus-like reaction[Ref]

Gastrointestinal

Uncommon (0.1% to 1%): Diarrhea, constipation, appetite changes, dry mouth, dyspepsia, nausea, vomiting, flatulence, pancreatitis, cholecystitis, abdominal pain, toothache, gastritis, anorexia, dehydration, hemorrhoids
-Amlodipine component: Frequency not reported Anorexia, dysphagia, pancreatitis, gingival hyperplasia
-Hydrochlorothiazide component: Rare (less than 0.1%): Pancreatitis, nausea, acute cholecystitis
-Valsartan component: Rare (less than 0.1%): Diarrhea, constipation, dry mouth, dyspepsia, anorexia, nausea, vomiting, taste disturbance, flatulence[Ref]

Hematologic

Common (1% to 10%): Neutropenia
Uncommon (0.1% to 1%): Hematocrit decreased, hemoglobin decreased
Rare (0.01% to 0.1%): Immune complex hemolytic anemia
Postmarketing reports: Thrombocytopenia
-Amlodipine component: Frequency not reported: Leucopenia, purpura, thrombocytopenia
-Hydrochlorothiazide component Frequency not reported: Aplastic anemia, agranulocytosis, hemolytic anemia
-Valsartan component: Frequency not reported: Decreases in hematocrit or hemoglobin, neutropenia, thrombocytopenia[Ref]

Hepatic

Uncommon (0.1% to 1%): Increases in hepatic enzymes (usually reversible)
Frequency not reported: Blood creatine phosphokinase increased
-Amlodipine component: Very rare (less than 0.01%): Hepatitis; Frequency not reported: Hepatic enzyme elevations, jaundice
-Hydrochlorothiazide component: Rare (less than 0.1%): Intrahepatic cholestasis, jaundice.
-Valsartan component: Very rare (less than 0.01%): Hepatitis; Frequency not reported: Elevated liver enzymes[Ref]

Hypersensitivity

Rare (less than 0.1%): Nausea, diarrhea, rash, acute pulmonary edema, interstitial nephritis or cystitis, anaphylaxis, erythema multiforme, vasculitis, serum sickness
-Hydrochlorothiazide component: Frequency not reported: Photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions[Ref]

Immunologic

Common (1% to 10%): nasopharyngitis (2.1%), Respiratory tract infection, bronchitis, influenza, viral infection, tooth abscess, viral gastritis, rhinitis
Rare (0.01% to 0.1%): Allergic vasculitis, hemolytic anemia
-Amlodipine component: Uncommon (0.1% to 1%): Angioedema, erythema multiforme
-Hydrochlorothiazide component: Very rare (less than 0.01%): Necrotizing vasculitis
-Valsartan component: Frequency not reported: Angioedema[Ref]

Metabolic

Common (1% to 10%): Edema
Rare (0.01% to 0.1%): Hypokalemia, hyperkalemia, metabolic alkalosis, hyponatremia, hypomagnesemia, hypercalcemia, hyperglycemia, elevated serum uric acid levels, elevated serum cholesterol
Frequency not reported: Weight loss, blood uric acid increased, blood creatine phosphokinase increased, hypokalemia, diabetes mellitus, hyperlipidemia, hyponatremia, night sweats
-Amlodipine component: Frequency not reported: Hot flushes, malaise, rigors, hyperglycemia, thirst, weight gain
-Hydrochlorothiazide component: Frequency not reported: Glycosuria, hyperuricemia
-Valsartan component: Common (1% to 10%): Hyperkalemia[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, muscle cramps
Frequency not reported: Myalgia, asthenia, noncardiac chest pain, pain in extremity, arthralgia, muscular weakness, musculoskeletal pain weakness, musculoskeletal stiffness, joint swelling, neck pain, osteoarthritis, tendonitis
-Amlodipine component: Frequency not reported: Arthrosis, muscle cramps, muscle cramps, muscle weakness, ataxia, hypertonia
-Hydrochlorothiazide component: Frequency not reported: Myalgia, chills
-Valsartan component: Rare (less than 0.1%): Rhabdomyolysis; Frequency not reported: Back pain, muscle cramps[Ref]

Nervous system

Common (1% to 10%): Headache, fatigue, dizziness, chills, malaise
Rare (less than 0.1%): Vertigo, tinnitus
Frequency not reported: Vertigo, paresthesia, somnolence, syncope, carpal tunnel syndrome, disturbance in attention, dysgeusia, head discomfort, lethargy, sinus headache, tremor
-Amlodipine component: Frequency not reported: Peripheral neuropathy, tremor, increased sweating
-Hydrochlorothiazide component; Frequency not reported: Restlessness
-Valsartan component: Frequency not reported: Headache, orthostatic effects, (including dizziness), vertigo[Ref]

Ocular

Rare (less than 0.1%): Abnormal vision, blurred vision
-Amlodipine component: Rare (less than 0.1%): Xerophthalmia; Frequency not reported: Abnormal vision, conjunctivitis, diplopia, eye pain
-Hydrochlorothiazide component: Frequency not reported: Transient blurred vision, xanthopsia, idiosyncratic reactions resulting in acute transient myopia and acute angle-closure glaucoma[Ref]

Psychiatric

Rare (less than 0.1%): Anxiety, depression, decreased libido, insomnia, paresthesias, somnolence
-Amlodipine component: Uncommon (0.1% to 1%): Insomnia, nervousness, depression, abnormal dreams, depersonalization, parosmia, mood changes, apathy, agitation, amnesia;
-Hydrochlorothiazide component: Rare (less than 0.1%): Sleep disturbances, depression
-Valsartan component: Frequency not reported: Insomnia[Ref]

Renal

Rare (less than 0.1%): Renal insufficiency, azotemia
-Amlodipine component: Rare (less than 0.1%): Interstitial nephritis
-Hydrochlorothiazide component: Rare (less than 0.1%): Interstitial nephritis; Frequency not reported: Increase in serum creatinine and BUN (which may be due to hydrochlorothiazide-induced intravascular volume depletion)
-Valsartan component: Frequency not reported: Impaired renal function, serum creatinine increased, blood urea nitrogen increased, potassium increased[Ref]

Respiratory

Uncommon (0.1% to 1%): Dyspnea, acute pulmonary edema
-Amlodipine component: Frequency not reported: Pulmonary edema, nasal congestion, cough, pharyngolaryngeal pain
Hydrochlorothiazide component: Rare (less than 0.1%): Acute noncardiogenic pulmonary edema
-Valsartan component: Common (1% to 10%): Cough; Frequency not reported: Sinusitis, pharyngitis[Ref]

Genitourinary

Rare (less than 0.1%): Dysuria, urinary tract infection, erectile dysfunction, pollakiuria.
-Amlodipine component: Frequency not reported: Micturition frequency, micturition disorder, nocturia, gynecomastia
-Hydrochlorothiazide component: Common (1% to 10%): Dysuria
-Valsartan component: Rare (0.01% to 0.1%): impotence[Ref]

Endocrine

Frequency not reported: Glucose intolerance, altered lipid profile

Other

Frequency not reported: Ear and labyrinth disorders, tinnitus[Ref]

Some side effects of amlodipine / hydrochlorothiazide / valsartan may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Initial dose: 1 tablet orally once a day (The dosage may be increased after 2 weeks of therapy. The full blood pressure lowering effect was achieved 2 weeks after being on the maximal dose)

Maximum dose: Amlodipine/hydrochlorothiazide/valsartan 10 mg/25 mg/320 mg orally once a day

Comment:
-Indicated for patients whose blood pressure is adequately controlled on amlodipine, valsartan, and hydrochlorothiazide (as single component formulations or a dual component formulation with a single component formulation). Individual dose titration with each component is recommended before administering the fixed dose combination.

Amlodipine:
-Exposure to amlodipine is increased in patients with hepatic insufficiency. Lower doses of amlodipine/hydrochlorothiazide/valsartan should be considered.

Valsartan:
-Mild-to-moderate liver disease: No dose adjustment is necessary
-Severe liver disease: Data not available

Hydrochlorothiazide:
-Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

Amlodipine/hydrochlorothiazide/valsartan: Not recommended for initial therapy
-Severe hepatic impairment: Amlodipine/hydrochlorothiazide/valsartan should be avoided in patients with severe hepatic impairment or progressive liver disease, because minor alterations of fluid and electrolyte balance, such as those resulting from diuretic use, may precipitate hepatic coma.

CrCl 30 mL/min or less: Not recommended
CrCl 30 mL/min or more: No adjustment recommended

Limited data suggest amlodipine/hydrochlorothiazide/valsartan is only minimally removed by hemodialysis, if at all.