Valsartan/Hydrochlorothiazide

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[edit] BRAND NAMES

[edit] STRUCTURE

[edit] MECHANISM OF ACTION

Valsartan is a member of a family of drugs called angiotensin receptor blockers (ARBs).

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium.

Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland.


Hydrochlorothiazide is a thiazide diuretic, it acts on the distal convoluted tubule by inhibiting the sodium-chloride symporter. thus, it reduces NaCl reabsorption, leading to a retention of water in the urine.

This symporter reabsorbs about 5% of filtered sodium. Hydrochlorothiazide is less efficacious than loop diuretics in producing diuresis. Nevertheless, it is sufficiently powerful to satisfy most therapeutic needs requiring a diuretic, making it one of the mostly used diuretics.

Hydrochlorothiazide enhance also Ca++ reabsorption in the distal convoluted tubule by inhibiting Na+ entry and thus enhancing the activity of Na+-Ca++ exchanger in the basolateral membrane of epithelial cells.

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours

[edit] INDICATIONS

Valsartan/Hydrochlorothiazide is indicated for the treatment of hypertension.

  • Valsartan/Hydrochlorothiazide may be used in patients whose blood pressure is not adequately controlled on monotherapy.
  • Valsartan/Hydrochlorothiazide may be used as initial therapy in patients who are likely to need multiple drugs to achieve blood pressure goals.
  • The choice of Valsartan/Hydrochlorothiazide as initial therapy for hypertension should be based on an assessment of potential benefits and risks.

Patients with stage 2 hypertension are at a relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk.

[edit] DOSAGE

The recommended dose of Valsartan/Hydrochlorothiazide is 1 coated tablet per day. When clinically appropriate either 80 mg valsartan and 12.5 mg hydrochlorothiazide or 160 mg valsartan and 12.5 mg hydrochlorothiazide may be used, when necessary 160 mg valsartan and 25 mg hydrochlorothiazide. Maximum dose is 320/25mg. The maximum antihypertensive effect is seen within 2 to 4 weeks.

Renal impairment No dosage adjustment is required for patients with mild to moderate renal impairment (Glomerular Filtration Rate (GFR) ≥30 mL/min). Due to the hydrochlorothiazide component, Valsartan/Hydrochlorothiazide is contraindicated in patients with anuriaand should be used with caution in patients with severe renal impairment (GFR <30 mL/min). Thiazide diuretics are ineffective as monotherapy in severe renal impairment (GFR <30 mL/min) but may be useful in these patients, when used with due caution in combination with a loop diuretic even in patients with GFR <30 mL/min.

Hepatic impairment No dosage adjustment is required in patients with mild to moderate hepatic impairment. Due to the hydrochlorothiazide component, Valsartan/Hydrochlorothiazide should be used with particular caution in patients with severe hepatic impairment. Due to the valsartan component, Valsartan/Hydrochlorothiazide should be used with particular caution in patients with biliary obstructive disorders.

[edit] CONTRAINDICATIONS

  • Hypersensitivity to any of the components (valsartan and hydrochlorothiazide) and to other sulfonamide-derived drugs.
  • Pregnancy
  • Severe hepatic impairment
  • Biliary cirrhosis and cholestasis
  • Anuria; severe renal impairment (creatinine clearance < 30 mL/min)
  • Refractory Hypokalaemia, hyponatremia, hypercalcemia, and symptomatic hyperuricemia.

[edit] WARNINGS AND PRECAUTIONS

Fetal/Neonatal Morbidity and Mortality
Valsartan/Hydrochlorothiazide can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Drugs that act on the renin-angiotensin system can cause fetal and neonatal morbidity and mortality when used in pregnancy. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

Hypotension in Volume- and/or Salt-Depleted Patients
Excessive reduction of blood pressure was rarely seen (0.7%) in patients with uncomplicated hypertension treated with (valsartan and hydrochlorothiazide) in controlled trials. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of (valsartan and hydrochlorothiazide), or the treatment should start under close medical supervision.

If hypotension occurs, the patient should be placed in the 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.

Impaired Hepatic Function
Hydrochlorothiazide: Thiazide diuretics should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Valsartan: As the majority of valsartan is eliminated in the bile, patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, showed lower valsartan clearance (higher AUCs). Care should be exercised in administering valsartan to these patients.

Hypersensitivity Reaction
Hydrochlorothiazide: 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.

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

Lithium Interaction
Hydrochlorothiazide: Lithium generally should not be given with thiazides.

Serum Electrolytes
Valsartan – Hydrochlorothiazide: In the controlled trials of various doses of the combination of valsartan and hydrochlorothiazide the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 3.0%; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4%.

Hydrochlorothiazide: All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Impaired Renal Function
Valsartan: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with valsartan.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. In a 4-day trial of valsartan in 12 patients with unilateral renal artery stenosis, no significant increases in serum creatinine or blood urea nitrogen were observed. There has been no long-term use of valsartan in patients with unilateral or bilateral renal artery stenosis, but an effect similar to that seen with ACE inhibitors should be anticipated.

Hydrochlorothiazide: Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

[edit] INTERACTIONS

  • Antidiabetic drugs: Dosage adjustment of antidiabetic may be required
  • Cholestyramine and colestipol: Reduced absorption of thiazides (12.3)
  • Lithium: Increased risk of lithium toxicity. Monitor serum lithium concentrations during concurrent use.
  • Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including valsartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
  • Potassium: Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If comedication is considered necessary, monitoring of serum potassium is advisable.
  • Dual inhibition of the renin-angiotensin system: 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 Valsartan/Hydrochlorothiazide and other agents that affect the RAS. Do not coadminister aliskiren with Valsartan/Hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with Valsartan/Hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min).

[edit] PREGNANCY AND LACTATION

Pregnancy Category D (US) : When pregnancy is detected, discontinue as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus.

Nursing Mothers : It is not known whether valsartan is excreted in human milk. Valsartan was excreted into the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Hydrochlorothiazide is excreted in human breast milk. Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from Valsartan/Hydrochlorothiazide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

[edit] SIDE EFFECTS

The most common reasons for discontinuation of therapy were headache and dizziness. The only adverse experience that occurred in >2% of patients treated with Valsartan/Hydrochlorothiazide and at a higher incidence than placebo was nasopharyngitis.

Adverse drug reactions are ranked by frequency, the most frequent first, using the following convention: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Frequency of adverse drug reactions with valsartan/hydrochlorothiazide
Metabolism and nutrition disorders
Uncommon:        Dehydration
Nervous system disorders
Very rare:        Dizziness
Uncommon:        Paraesthesia
Not known:        Syncope
Eye disorders
Uncommon:        Vision blurred
Ear and labyrinth disorders
Uncommon:        Tinnitus
Vascular disorders
Uncommon:        Hypotension
Respiratory, thoracic and mediastinal disorders
Uncommon:        Cough
Not known:        Non cardiogenic pulmonary edema
Gastrointestinal disorders
Very rare:        Diarrhea
Musculoskeletal and connective tissue disorders
Uncommon:        Myalgia
Very rare:        Arthralgia
Renal and urinary disorders
Not known:        impaired renal function
General disorders and administration site conditions
Uncommon:        Fatigue
Investigations
Not known:        Serum uric acid increased, Serum bilirubin and Serum creatinine Increased, Hypokalemia, Hyponatremia, Elevation of Blood Urea Nitrogen, Neutropenia.

[edit] RELATED LINKS

[edit] BIBLIOGRAPHY

[edit] REFERENCES

Antihypertensives
ACE inhibitors Benazepril (Lotensin)   Captopril (Capoten)   Cilazapril   Delapril   Enalapril (Renitec, Vasotec)   Fosinopril (Monopril)  Lisinopril (Prinivil, Zestril)   Moexipril (Univasc)  Perindopril (Aceon)  Quinapril (Accupril)  Ramipril (Altace, Triatec)   Trandolapril (Mavik)  Zofenopril (Bifril, Zopranol)
Angiotensin II receptor antagonist Azilsartan (Edarbi)   Candesartan (Atacand)   Eprosartan (Teveten)   Irbesartan (Aprovel, Avapro, Karvea)   Losartan (Cozaar)   Olmesartan (Benicar, Olmetec)   Telmisartan (Micadis)   Valsartan (Diovan, Tareg)
Renin inhibitors Aliskiren (Rasilez, Tekturna)
Alpha-1 blockers Doxazosin (Cardura)   Prazosin (Minipress)   Terazosin (Hytrin)
Alpha-2 agonists (centrally acting) Clonidine (Oral route)   Clonidine (Transdermal) (Catapresan)   Guanfacine (Tenex)   Methyldopa (Aldomet)
Calcium channel blockers Dihydropyridines‎ Amlodipine (Norvasc)   Barnidipine (Vasexten)   Felodipine (Plendil)   Isradipine (Dynacirc)   Lacidipine (Lacipil, Motens)   Lercanidipine (Zanidip)   Manidipine   Nicardipine   Nifedipine (Adalat)   Nisoldipine   Nitrendipine
Benzothiazepine‎ Diltiazem (Cardizem, Taztia XT, Tiazac, Tildiem)
Phenylalkylamine‎ Gallopamil   Verapamil (Calan)
Beta blockers Beta1 selective (cardioselective) Acebutolol (Sectral)   Atenolol (Tenormin)   Betaxolol (Kerlon)   Bisoprolol (Concor)   Celiprolol (Cordiax)   Metoprolol (Betaloc, Lopressor, Toprol-XL)   Nebivolol (Bystolic, Lobivon, Nebilox)
Nonselective (Beta1 and Beta2 blockers) Oxprenolol (Trasitensin)   Propranolol (Inderal)   Timolol (Blocadren)
Nonselective (Beta1, Beta2 and Alpha1 blockers) Carvedilol (Dilatrend)   Labetalol (Trandate)
Beta blocker with intrinsic sympathomimetic activity (ISA) Acebutolol (Sectral)   Celiprolol (Cordiax)
Lipophilic Beta blockers Propranolol (Inderal)   Metoprolol (Betaloc, Lopressor, Toprol-XL)   Oxprenolol (Trasitensin)
Diuretics Carbonic anhydrase inhibitors Acetazolamide (Diamox)
Loop diuretics Bumetanide   Etacrynic acid   Furosemide (Lasix)   Piretanide   Torasemide (Demadex)
Thiazide diuretics Chlorothiazide (Diuril)   Hydrochlorothiazide (Esidrex)
Thiazide-like diuretics Chlortalidone (Hygroton)   Indapamide (Lozol, Lozide)   Metolazone
Potassium-sparing diuretics Epithelial sodium channel blockers: Amiloride (Midamor)   Triamterene (Dyrenium)
Aldosterone receptor antagonists: Potassium canrenoate   Eplerenone (Inspra)   Spironolactone (Aldactone)
Osmotic diuretics Mannitol
Combination therapy Amiloride/Hydrochlorothiazide (Moduretic)   Spironolactone/Hydrochlorothiazide (Aldactazide)