- Hydrochlorothiazide / valsartan Side Effects
- Hydrochlorothiazide and valsartan
- What is hydrochlorothiazide and valsartan?
- Important Information
- Before taking this medicine
- How should I take hydrochlorothiazide and valsartan?
- What happens if I miss a dose?
- What happens if I overdose?
- What should I avoid while taking hydrochlorothiazide and valsartan?
- Hydrochlorothiazide and valsartan side effects
- Hydrochlorothiazide and valsartan dosing information
- What other drugs will affect hydrochlorothiazide and valsartan?
- Further information
- More about hydrochlorothiazide / valsartan
- Diovan HCT
- CLINICAL PHARMACOLOGY
- valsartan/hydrochlorothiazide (Rx)
- Pregnancy Categories
- SIDE EFFECTS
- How does this medication work? What will it do for me?
- What form(s) does this medication come in?
- How should I use this medication?
- Who should NOT take this medication?
- What side effects are possible with this medication?
- Are there any other precautions or warnings for this medication?
- What other drugs could interact with this medication?
Hydrochlorothiazide / valsartan Side Effects
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Hydrochlorothiazide and valsartan
Generic Name: hydrochlorothiazide and valsartan (HYE droe klor oh THYE a zide and val SAR tan)
Brand Name: Diovan HCT
Medically reviewed by Drugs.com on Aug 30, 2019 – Written by Cerner Multum
- Side Effects
What is hydrochlorothiazide and valsartan?
Hydrochlorothiazide is a thiazide diuretic (water pill) that helps prevent your body from absorbing too much salt, which can cause fluid retention.
Valsartan is an angiotensin II receptor antagonist. Valsartan keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.
Hydrochlorothiazide and valsartan is a combination medicine used to treat high blood pressure (hypertension). Lowering blood pressure may lower your risk of a stroke or heart attack.
Hydrochlorothiazide and valsartan is usually given after other blood pressure medicines have been tried without success.
Hydrochlorothiazide and valsartan may also be used for purposes not listed in this medication guide.
Do not use if you are pregnant. Use effective birth control, and tell your doctor if you become pregnant during treatment.
If you have diabetes, do not use hydrochlorothiazide and valsartan together with any medication that contains aliskiren (a blood pressure medicine).
Before taking this medicine
You should not use hydrochlorothiazide and valsartan if you are allergic to it, or if you have:
decreased urination or are unable to urinate; or
an allergy to sulfa drugs.
If you have diabetes, do not use hydrochlorothiazide and valsartan together with any medication that contains aliskiren (a blood pressure medicine).
You may also need to avoid taking hydrochlorothiazide and valsartan with aliskiren if you have kidney disease.
Tell your doctor if you have ever had:
an electrolyte imbalance (such as low levels of potassium or magnesium, or high levels of calcium in your blood);
a heart attack;
angina (chest pain), congestive heart failure;
an allergy to penicillin;
a severe allergic reaction to another heart or blood pressure medicine;
lupus, gout, or high levels of uric acid in your blood;
if you are on a low-salt diet.
Do not use if you are pregnant. If you become pregnant, stop taking hydrochlorothiazide and valsartan and tell your doctor right away. Hydrochlorothiazide and valsartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.
You should not breastfeed while using hydrochlorothiazide and valsartan.
Hydrochlorothiazide and valsartan is not approved for use by anyone younger than 18 years old.
How should I take hydrochlorothiazide and valsartan?
Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed.
You may take this medication with or without food.
Your blood pressure will need to be checked often. Your kidney function may also need to be checked.
You may have very low blood pressure while taking this medication. Call your doctor if you are sick with vomiting or diarrhea, or if you are sweating more than usual.
If you need surgery, tell the surgeon ahead of time that you are using hydrochlorothiazide and valsartan.
It may take up to 4 weeks for this medication to control your blood pressure. Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.
Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or stop taking any of your medications without your doctor’s advice.
Store at room temperature away from moisture and heat.
What happens if I miss a dose?
Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.
What happens if I overdose?
Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.
What should I avoid while taking hydrochlorothiazide and valsartan?
Do not use potassium supplements or salt substitutes, unless your doctor has told you to.
Drinking alcohol can further lower your blood pressure and may cause side effects.
Avoid driving or hazardous activity until you know how hydrochlorothiazide and valsartan will affect you. Your reactions could be impaired. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy.
Hydrochlorothiazide and valsartan side effects
Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Call your doctor at once if you have:
a light-headed feeling, like you might pass out;
swelling in your hands or feet, rapid weight gain;
eye pain, vision problems;
an unusual skin rash;
pounding heartbeats or fluttering in your chest;
jaundice (yellowing of the skin or eyes); or
signs of an electrolyte imbalance–dry mouth, increased thirst, drowsiness, confusion, feeling restless, vomiting, muscle pain or weakness, lack of energy, fast heartbeats, little or no urine, or a seizure.
Common side effects include:
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Hydrochlorothiazide and valsartan dosing information
Usual Adult Dose for Hypertension:
Initial dose: 1 tablet (12.5 mg-160 mg) orally once a day
Maintenance dose: Titrate as necessary (every 1 to 2 weeks) up to a maximum of 25 mg-320 mg orally once a day
-Hydrochlorothiazide-valsartan may be substituted for the titrated components.
What other drugs will affect hydrochlorothiazide and valsartan?
Some medicines can make hydrochlorothiazide and valsartan much less effective when taken at the same time. If you also take cholestyramine or colestipol, take your hydrochlorothiazide and valsartan dose 4 hours before or 4 hours after you take the other medicine.
Tell your doctor about all your current medicines. Many drugs can affect hydrochlorothiazide and valsartan, especially:
cyclosporine, digoxin, digitalis, lithium, or ritonavir;
all your heart or blood pressure medicines;
insulin or oral diabetes medicine;
a diuretic or “water pill”;
opioid (narcotic) pain medicine;
a sleeping pill;
vitamin or mineral supplements that contain potassium;
an antibiotic–rifabutin, rifampin, rifapentine;
cancer medicine–cyclophosphamide, methotrexate; or
NSAIDs (nonsteroidal anti-inflammatory drugs)–aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.
This list is not complete and many other drugs may affect hydrochlorothiazide and valsartan. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible drug interactions are listed here.
Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.
Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.
Copyright 1996-2018 Cerner Multum, Inc. Version: 13.01.
More about hydrochlorothiazide / valsartan
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- Drug class: angiotensin II inhibitors with thiazides
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- Valsartan and Hydrochlorothiazide
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Other brands: Diovan HCT
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Mechanism Of Action
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). 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. Its action is therefore independent of the pathways for angiotensin II synthesis.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20000-fold) for the AT1 receptor than for the AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one 200th that of valsartan itself.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II) it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is unknown.
Valsartan: Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available.
Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed.
Hydrochlorothiazide: After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.
Skeletal muscle relaxants: Possible increased responsiveness to muscle relaxants such as curare derivatives.
Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may predispose the patient to digoxin toxicity.
Valsartan: Valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for the capsule formulation is about 25% (range 10% to 35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%. AUC and Cmax values of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.
Hydrochlorothiazide: The estimated absolute bioavailability of hydrochlorothiazide after oral administration is about 70%. Peak plasma hydrochlorothiazide concentrations (Cmax) are reached within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide.
Hydrochlorothiazide binds to albumin (40% to 70%) and distributes into erythrocytes. Following oral administration, plasma hydrochlorothiazide concentrations decline bi-exponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours.
Diovan HCT: Diovan HCT may be administered with or without food.
Valsartan: The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.
Valsartan: The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.
Hydrochlorothiazide: Is not metabolized.
Valsartan: Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites.
Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance).
Hydrochlorothiazide: About 70% of an orally administered dose of hydrochlorothiazide is eliminated in the urine as unchanged drug.
Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. A limited amount of data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
Pharmacokinetics of valsartan do not differ significantly between males and females.
Pharmacokinetic differences due to race have not been studied.
There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Valsartan has not been studied in patients with severe impairment of renal function (creatinine clearance < 10 mL/min). Valsartan is not removed from the plasma by hemodialysis.
In a study in individuals with impaired renal function, the mean elimination half-life of hydrochlorothiazide was doubled in individuals with mild/moderate renal impairment (30 < CrCl < 90 mL/min) and tripled in severe renal impairment (CrCl ≤ 30 mL/min), compared to individuals with normal renal function (CrCl > 90 mL/min) .
On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex, and weight) .
Drugs that alter gastrointestinal motility: The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g., atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, pro-kinetic drugs may decrease the bioavailability of thiazide diuretics.
Cholestyramine: In a dedicated drug interaction study, administration of cholestyramine 2 hours before hydrochlorothiazide resulted in a 70% reduction in exposure to hydrochlorothiazide. Further, administration of hydrochlorothiazide 2 hours before cholestyramine resulted in 35% reduction in exposure to hydrochlorothiazide.
Antineoplastic agents (e.g., cyclophosphamide, methotrexate): Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Developmental Toxicity Studies
Valsartan-Hydrochlorothiazide: There was no evidence of teratogenicity in mice, rats, or rabbits treated orally with valsartan at doses up to 600, 100, and 10 mg/kg/day, respectively, in combination with hydrochlorothiazide at doses up to 188, 31, and 3 mg/kg/day. These non-teratogenic doses in mice, rats and rabbits, respectively, represent 9, 3.5, and 0.5 times the MRHD of valsartan and 38, 13, and 2 times the MRHD of hydrochlorothiazide on a mg/m² basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)
Fetotoxicity was observed in association with maternal toxicity in rats and rabbits at valsartan doses of ≥ 200 and 10 mg/kg/day, respectively, in combination with hydrochlorothiazide doses of ≥ 63 and 3 mg/kg/day. Fetotoxicity in rats was considered to be related to decreased fetal weights and included fetal variations of sternebrae, vertebrae, ribs and/or renal papillae. Fetotoxicity in rabbits included increased numbers of late resorptions with resultant increases in total resorptions, postimplantation losses, and decreased number of live fetuses. The no observed adverse effect doses in mice, rats and rabbits for valsartan were 600, 100, and 3 mg/kg/day, respectively, in combination with hydrochlorothiazide doses of 188, 31, and 1 mg/kg/day. These no adverse effect doses in mice, rats, and rabbits, respectively, represent 9, 3, and 0.18 times the MRHD of valsartan and 38, 13, and 0.5 times the MRHD of hydrochlorothiazide on a mg/m² basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)
Valsartan: No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200, and 2 mg/kg/day in mice, rats, and rabbits represent 9, 6, and 0.1 times, respectively, the MRHD on a mg/m² basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)
Hydrochlorothiazide: Under the auspices of the National Toxicology Program, pregnant mice and rats that received hydrochlorothiazide via gavage at doses up to 3000 and 1000 mg/kg/day, respectively, on gestation days 6 through 15 showed no evidence of teratogenicity. These doses of hydrochlorothiazide in mice and rats represent 608 and 405 times, respectively, the MRHD on a mg/m² basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)
Valsartan-Hydrochlorothiazide: In controlled clinical trials including over 7600 patients, 4372 patients were exposed to valsartan (80, 160, and 320 mg) and concomitant hydrochlorothiazide (12.5 and 25 mg). Two factorial trials compared various combinations of 80/12.5 mg, 80/25 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg, and 320/25 mg with their respective components and placebo. The combination of valsartan and hydrochlorothiazide resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressure at trough of 14-21/8-11 mmHg at 80/12.5 mg to 320/25 mg, compared to 7-10/4-5 mmHg for valsartan 80 mg to 320 mg, and 5-11/2-5 mmHg for hydrochlorothiazide 12.5 mg to 25 mg alone.
Three other controlled trials investigated the addition of hydrochlorothiazide to patients who did not respond adequately to valsartan 80 mg to valsartan 320 mg, resulted in the additional lowering of systolic and diastolic blood pressure by approximately 4-12/2-5 mmHg.
The maximal antihypertensive effect was attained 4 weeks after the initiation of therapy, the first time point at which blood pressure was measured in these trials.
In long-term follow-up studies (without placebo control) the effect of the combination of valsartan and hydrochlorothiazide appeared to be maintained for up to 2 years. The antihypertensive effect is independent of age or gender. The overall response to the combination was similar for black and non-black patients.
There was essentially no change in heart rate in patients treated with the combination of valsartan and hydrochlorothiazide in controlled trials.
There are no trials of the Diovan HCT combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but the hydrochlorothiazide component and several ARBs, which are the same pharmacological class as the valsartan component, have demonstrated such benefits.
Valsartan: The antihypertensive effects of valsartan were demonstrated principally in 7 placebo-controlled, 4- to 12-week trials (1 in patients over 65 years) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95-115 mmHg. The studies allowed comparison of once-daily and twice-daily regimens of 160 mg/day; comparison of peak and trough effects; comparison (in pooled data) of response by gender, age, and race; and evaluation of incremental effects of hydrochlorothiazide.
Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160 mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long-term follow-up studies (without placebo control) the effect of valsartan appeared to be maintained for up to 2 years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in high-renin hypertensives (frequently whites). In pooled, randomized, controlled trials of Diovan that included a total of 140 blacks and 830 whites, valsartan and an ACE-inhibitor control were generally at least as effective in blacks as whites. The explanation for this difference from previous findings is unclear.
Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.
The 7 studies of valsartan monotherapy included over 2000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6-9/3-5 mmHg at 80 to 160 mg and 9/6 mmHg at 320 mg.
Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a comparable response in both groups.
In another 4-week study, 1876 patients randomized to valsartan 320 mg once daily had an incremental blood pressure reduction 3/1 mmHg lower than did 1900 patients randomized to valsartan 160 mg once daily.
In controlled trials, the antihypertensive effect of once daily valsartan 80 mg was similar to that of once daily enalapril 20 mg or once daily lisinopril 10 mg.
There was essentially no change in heart rate in valsartan-treated patients in controlled trials.
Initial Therapy – Hypertension
The safety and efficacy of Diovan HCT as initial therapy for patients with severe hypertension (defined as a sitting diastolic blood pressure ≥ 110 mmHg and systolic blood pressure ≥ 140 mmHg off all antihypertensive therapy) was studied in a 6-week multicenter, randomized, double-blind study. Patients were randomized to either Diovan HCT (valsartan and hydrochlorothiazide 160/12.5 mg once daily) or to valsartan (160 mg once daily) and followed for blood pressure response. Patients were force-titrated at 2-week intervals. Patients on combination therapy were subsequently titrated to 160/25 mg followed by 320/25 mg valsartan/hydrochlorothiazide. Patients on monotherapy were subsequently titrated to 320 mg valsartan followed by a titration to 320 mg valsartan to maintain the blind.
The study randomized 608 patients, including 261 (43%) females, 147 (24%) blacks, and 75 (12%) ≥ 65 years of age. The mean blood pressure at baseline for the total population was 168/112 mmHg. The mean age was 52 years. After 4 weeks of therapy, reductions in systolic and diastolic blood pressure were 9/5 mmHg greater in the group treated with Diovan HCT compared to valsartan. Similar trends were seen when the patients were grouped according to gender, race, or age.
Angiotensin system during second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death; 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; published reports include cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan; when pregnancy is detected discontinue therapy as soon as possible
Hypertension in pregnancy increases maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (eg, need for cesarean section, and post-partum hemorrhage); hypertension increases fetal risk for intrauterine growth restriction and intrauterine death; pregnant women with hypertension should be carefully monitored and managed accordingly
Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death
- Perform serial ultrasound examinations to assess intra-amniotic environment; fetal testing may be appropriate, based on week of gestation; however, oligohydramnios may not appear until after fetus has sustained irreversible injury; if oligohydramnios is observed, consider alternative drug treatment
- Closely observe neonates with histories of in utero exposure to drug for hypotension, oliguria, and hyperkalemia; in neonates with a history of in utero exposure to Diovan HCT, if oliguria or hypotension occurs, support blood pressure and renal perfusion; exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function
- Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma; hydrochlorothiazidecan cause placental hypoperfusion; accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma; use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia; since they do not prevent or alter course of EPH (edema, proteinuria, hypertension) gestosis (pre-eclampsia), these drugs should not be used to treat hypertension in pregnant women; use of hydrochlorothiazide for other indications (eg, heart disease) in pregnancy should be avoided
There is limited information regarding presence of drug in human milk, effects on breastfed infant, or on milk production; valsartan is present in rat milk; hydrochlorothiazide is present in human breast milk
Valsartan is present in rat milk. Hydrochlorothiazide is present in human breast milk
Because of potential for serious adverse reactions in breastfed infants, breastfeeding is not recommended during treatment with this drug combination
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reactions 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 practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Diovan HCT (valsartan and hydrochlorothiazide, USP) has been evaluated for safety in more than 5700 patients, including over 990 treated for over 6 months, and over 370 for over 1 year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with Diovan HCT was comparable to placebo.
The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race. In controlled clinical trials, discontinuation of therapy due to side effects was required in 2.3% of valsartan-hydrochlorothiazide patients and 3.1% of placebo patients. The most common reasons for discontinuation of therapy with Diovan HCT were headache and dizziness.
The only adverse reaction that occurred in controlled clinical trials in at least 2% of patients treated with Diovan HCT and at a higher incidence in valsartan-hydrochlorothiazide (n=4372) than placebo (n=262) patients was nasopharyngitis (2.4% vs. 1.9%).
Dose-related orthostatic effects were seen in fewer than 1% of patients. In individual trials, a doserelated increase in the incidence of dizziness was observed in patients treated with Diovan HCT.
Other adverse reactions that have been reported with valsartan-hydrochlorothiazide (>0.2% of valsartan-hydrochlorothiazide patients in controlled clinical trials) without regard to causality, are listed below:
Cardiovascular: Palpitations and tachycardia
Ear and Labyrinth: Tinnitus and vertigo
Gastrointestinal: Dyspepsia, diarrhea, flatulence, dry mouth, nausea, abdominal pain, abdominal pain upper, and vomiting
General and Administration Site Conditions: Asthenia, chest pain, fatigue, peripheral edema and pyrexia
Infections and Infestations: Bronchitis, bronchitis acute, influenza, gastroenteritis, sinusitis, upper respiratory tract infection, and urinary tract infection
Investigations: Blood urea increased
Musculoskeletal: Arthralgia, back pain, muscle cramps, myalgia, and pain in extremity
Nervous System: Dizziness postural, paresthesia, and somnolence
Psychiatric: Anxiety and insomnia
Renal and Urinary: Pollakiuria
Reproductive System: Erectile dysfunction
Respiratory, Thoracic and Mediastinal: Dyspnea, cough, nasal congestion, pharyngolaryngeal pain, and sinus congestion
Skin and Subcutaneous Tissue: Hyperhidrosis and rash
Other reported reactions seen less frequently in clinical trials included abnormal vision, anaphylaxis, bronchospasm, constipation, depression, dehydration, decreased libido, dysuria, epistaxis, flushing, gout, increased appetite, muscle weakness, pharyngitis, pruritus, sunburn, syncope, and viral infection.
In a clinical study in patients with severe hypertension (diastolic blood pressure ≥110 mmHg and systolic blood pressure ≥140 mmHg), the overall pattern of adverse reactions reported through 6 weeks of follow-up was similar in patients treated with Diovan HCT as initial therapy and in patients treated with valsartan as initial therapy. Comparing the groups treated with Diovan HCT (force-titrated to 320/25 mg) and valsartan (force-titrated to 320 mg), dizziness was observed in 6% and 2% of patients, respectively. Hypotension was observed in 1% of those patients receiving Diovan HCT and 0% of patients receiving valsartan. There were no reported cases of syncope in either treatment group. Laboratory changes with Diovan HCT as initial therapy in patients with severe hypertension were similar to those reported with Diovan HCT in patients with less severe hypertension .
Valsartan: 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 had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, hydrochlorothiazide, or lisinopril were 20%, 19%, 69% respectively (p <0.001).
Other reported reactions seen less frequently in clinical trials included chest pain, syncope, anorexia, vomiting, and angioedema.
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, leukopenia, hemolytic anemia, thrombocytopenia
Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions
Metabolic: hyperglycemia, glycosuria, hyperuricemia
Musculoskeletal: muscle spasm
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
In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Diovan HCT.
Creatinine/Blood Urea Nitrogen (BUN)
Minor elevations in creatinine and BUN occurred in 2% and 15% respectively, of patients taking Diovan HCT and 0.4% and 6% respectively, given placebo in controlled clinical trials
Hemoglobin And Hematocrit
Greater than 20% decreases in hemoglobin and hematocrit were observed in less than 0.1% of Diovan HCT patients, compared with 0% in placebo-treated patients
Liver Function Tests
Occasional elevations (greater than 150%) of liver chemistries occurred in Diovan HCT-treated patients
Neutropenia was observed in 0.1% of patients treated with Diovan HCT and 0.4% of patients treated with placebo
The following additional adverse reactions have been reported in valsartan or valsartan/hydrochlorothiazide 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.
There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Diovan HCT should not be re-administered to patients who have had angioedema.
Elevated liver enzymes and very rare reports of hepatitis
Impaired renal function
Clinical Laboratory Tests
Alopecia, bullous dermatitis
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
The following additional adverse reactions have been reported in postmarketing 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, and 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.
Read the entire FDA prescribing information for Diovan HCT (Valsartan and Hydrochlorothiazide)
How does this medication work? What will it do for me?
This is a combination product that contains 2 medications: valsartan and hydrochlorothiazide. This combination medication is used to treat high blood pressure.
Valsartan belongs to the class of medications called angiotensin II receptor blockers and helps to lower blood pressure by relaxing blood vessels. Hydrochlorothiazide belongs to the class of medications called diuretics or “water pills” and helps control blood pressure by getting rid of excess salt and water. The full effects of this combination product are usually seen within about 4 weeks.
This medication is most often used when a person has taken valsartan and hydrochlorothiazide as separate medications without any problems.
This medication may be available under multiple brand names and/or in several different forms. Any specific brand name of this medication may not be available in all of the forms or approved for all of the conditions discussed here. As well, some forms of this medication may not be used for all of the conditions discussed here.
Your doctor may have suggested this medication for conditions other than those listed in these drug information articles. If you have not discussed this with your doctor or are not sure why you are taking this medication, speak to your doctor. Do not stop taking this medication without consulting your doctor.
Do not give this medication to anyone else, even if they have the same symptoms as you do. It can be harmful for people to take this medication if their doctor has not prescribed it.
What form(s) does this medication come in?
80 mg/12.5 mg
Each light orange, ovaloid, film-coated tablet, imprinted with “HGH” on one side and “CG” on the other, contains valsartan 80 mg and hydrochlorothiazide 12.5 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose; coating: hydroxypropyl methylcellulose, polyethylene glycol, red iron oxide, talc, titanium dioxide, and yellow iron oxide.
160 mg/12.5 mg
Each dark red, ovaloid, film-coated tablet, imprinted with “HHH” on one side and “CG” on the other, contains valsartan 160 mg and hydrochlorothiazide 12.5 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose; coating: hydroxypropyl methylcellulose, polyethylene glycol, red iron oxide, talc, and titanium dioxide.
320 mg/12.5 mg
Each pink, ovaloid, film-coated tablet imprinted with “NVR” on one side and “HIL” on the other contains 320 mg of valsartan and 12.5 mg of hydrochlorothiazide as the active ingredients. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose; coating: hydroxypropyl methylcellulose, polyethylene glycol, red iron oxide, black iron oxide, talc, and titanium dioxide.
160 mg/25 mg
Each brown, ovaloid, film-coated tablet, imprinted with “HXH” on one side and “NVR” on the other, contains valsartan 160 mg and hydrochlorothiazide 25 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose; coating: black iron oxide, hydroxypropyl methylcellulose, polyethylene glycol, red iron oxide, talc, titanium dioxide, and yellow iron oxide.
320 mg/25 mg
Each yellow, ovaloid, film-coated tablet, imprinted with “NVR” on one side and “CTI” on the other, contains valsartan 320 mg and hydrochlorothiazide 25 mg. Nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose; coating: hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide, and yellow iron oxide.
How should I use this medication?
Once the dose of each component (valsartan and hydrochlorothiazide) has been determined by your doctor, the appropriate dose of the combination tablets can be taken once daily.The usual adult dose of valsartan ranges from 80 mg to 160 mg once daily, with a maximum of 320 mg, while the usual adult dose of hydrochlorothiazide ranges from 12.5 mg to 25 mg once daily, with a maximum of 25 mg.
This medication may be taken with or without food, but it should be taken in the same manner each day.
Many things can affect the dose of medication that a person needs, such as body weight, other medical conditions, and other medications. If your doctor has recommended a dose different from the ones listed here, do not change the way that you are taking the medication without consulting your doctor.
It is important to take this medication exactly as prescribed by your doctor. If you miss a dose, skip the missed dose and continue with your regular dosing schedule. Do not take a double dose to make up for a missed one. If you are not sure what to do after missing a dose, contact your doctor or pharmacist for advice.
Store this medication at room temperature, protect it from moisture, and keep it out of the reach of children.
Do not dispose of medications in wastewater (e.g. down the sink or in the toilet) or in household garbage. Ask your pharmacist how to dispose of medications that are no longer needed or have expired.
Who should NOT take this medication?
Do not use valsartan – hydrochlorothiazide if you:
- are allergic to valsartan, hydrochlorothiazide, or any ingredients of this medication
- are allergic to other sulfonamide-derived medications (sulfa drugs, e.g., sulfamethoxazole)
- are pregnant or breast-feeding
- have anuria (inability to pass urine)
- have severe kidney disease
- have diabetes or kidney disease and are taking aliskiren
- have symptoms of gout or unusually high uric acid levels
- have untreated or treatment-resistant electrolyte abnormalities
- have galactose intolerance (a rare hereditary condition)
What side effects are possible with this medication?
Many medications can cause side effects. A side effect is an unwanted response to a medication when it is taken in normal doses. Side effects can be mild or severe, temporary or permanent.
The side effects listed below are not experienced by everyone who takes this medication. If you are concerned about side effects, discuss the risks and benefits of this medication with your doctor.
The following side effects have been reported by at least 1% of people taking this medication. Many of these side effects can be managed, and some may go away on their own over time.
Contact your doctor if you experience these side effects and they are severe or bothersome. Your pharmacist may be able to advise you on managing side effects.
- back or leg pain
- decreased appetite
- decreased interest in sexual activity
- difficulty sleeping
- pins and needles sensation
- swollen glands (in mouth)
Although most of the side effects listed below don’t happen very often, they could lead to serious problems if you do not seek medical attention.
Check with your doctor as soon as possible if any of the following side effects occur:
- abdominal pain
- muscle pain or weakness
- pounding, rapid, or irregular heartbeat
- signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
- signs of bleeding (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
- signs of electrolyte changes (e.g., confusion, drowsiness, dry mouth, muscle fatigue, nausea, thirst, weakness)
- signs of gout (e.g., joint pain, swelling and warmth of joints)
- signs of infections (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
- signs of kidney problems (e.g., decreased urination, nausea, vomiting, swelling of the feet and ankles)
- signs of liver damage (yellowing of skin or whites of eyes, abdominal pain, loss of appetite, brown urine, light-coloured stools, tiredness, or weakness)
- signs of low blood pressure such as dizziness, lightheadedness, or fainting
- signs of pancreatitis (e.g., abdominal pain on the upper left side, back pain, nausea, fever, chills, rapid heartbeat, swollen abdomen)
- symptoms of high blood sugar (e.g., frequent urination, increased thirst, excessive eating, unexplained weight loss, poor wound healing, infections, fruity breath odour)
- unexplained muscle pain or weakness
Stop taking the medication and seek medical attention immediately if any of the following side effects occur:
- chest pain
- signs of a serious allergic reaction (swelling of face or throat, hives, difficulty breathing)
- severe skin rash, including skin blistering and peeling (possibly with headache, fever, coughing, or aching before the rash begins)
- symptoms of increased pressure in the eyes (e.g., decreased or blurred vision, eye pain, red eye, swelling of the eye)
Some people may experience side effects other than those listed. Check with your doctor if you notice any symptom that worries you while you are taking this medication.
Are there any other precautions or warnings for this medication?
Before you begin taking a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health. These factors may affect how you should take this medication.
HEALTH CANADA ADVISORY
January 31, 2019
Health Canada has issued new restrictions concerning the use of hydrochlorothiazide. To read the full Health Canada Advisory, visit Health Canada’s web site at www.hc-sc.gc.ca.
Allergic reaction: Some people who are allergic to sulfonamide medications also experience allergic reactions to hydrochlorothiazide. Before you take this medication, inform your doctor about any previous adverse reactions you have had to medications, especially to sulfonamide antibiotics or diabetes medications. Contact your doctor at once if you experience signs of an allergic reaction, such as skin rash, itching, difficulty breathing or swelling of the face and throat.
Cholesterol: Increases in cholesterol and triglyceride levels may occur when taking hydrochlorothiazide. At doses used in valsartan – hydrochlorothiazide, this rarely causes problems. However, if you have increased cholesterol or triglyceride levels, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
Diabetes: Hydrochlorothiazide may make it more difficult for people with diabetes to control their blood sugar levels. High blood sugar may occur, glucose tolerance may change, and diabetes may worsen. A dose adjustment of diabetes medications, including insulin, may be required. If you have diabetes, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
Electrolytes: The levels of electrolytes such as potassium, sodium, magnesium, and chloride can be reduced, and the levels of calcium can be increased by the use of hydrochlorothiazide. Your doctor will periodically check to see if these levels are in balance. Warning signs or symptoms of fluid and electrolyte imbalance include:
- decreased urination
- dryness of mouth
- low blood pressure
- muscle pains or cramps
- muscular fatigue
- nausea and vomiting
- racing heartbeat
Gout: Some people taking valsartan – hydrochlorothiazide may experience an acute gout attack as a result of high levels of uric acid in the blood. Symptoms of an acute gout attack include sudden pain, swelling, and stiffness in the affected joint, often the big toe. You may also experience a fever. If this is your first attack, seek medical attention as soon as possible. If you have had gout attacks before, follow your doctor’s instructions for dealing with the attack.
Kidney problems: Valsartan can cause changes to kidney function that may result in decreased kidney function, kidney failure, or possibly death. Certain people have experienced changes in kidney function (e.g., people with narrowed blood vessels in their kidneys, or those with severe congestive heart failure). The use of diuretics (water pills), nonsteroidal anti-inflammatory drugs (NSAIDs), or aliskiren may further increase risk of kidney problems for people already at risk for this problem. If you have reduced kidney function, renal artery stenosis (narrowing of blood vessels in the kidneys), or congestive heart failure, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed. If you have reduced kidney function, you may require lower doses of this medication.
Liver problems: Liver disease or reduced liver function may cause this medication to build up in the body, causing side effects. If you have reduced liver function or liver disease, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed. This medication is not recommended for people with severe liver impairment.
This medication may also cause a decrease in liver function. If you experience symptoms of liver problems such as fatigue, feeling unwell, loss of appetite, nausea, yellowing of the skin or whites of the eyes, dark urine, pale stools, abdominal pain or swelling, and itchy skin, contact your doctor immediately.
Low blood pressure: Occasionally, a greater-than-expected drop in blood pressure occurs after taking this medication. In some cases, this happens after the first dose. This is more likely to occur if you have a reduced salt intake, are on dialysis, are experiencing diarrhea or vomiting, or take diuretics (water pills) or the medication aliskiren. Your doctor may recommend that you have your blood pressure tested more often in these situations. If you have low blood pressure or are just starting to take this medication, move slowly from a reclined to an upright position to reduce the risk of dizziness.
Lupus: There have been reports of worsening or activation of lupus in people taking hydrochlorothiazide. If you have lupus, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
Pregnancy: Pregnant women should not take this medication. If you become pregnant while taking this medication, stop taking it immediately and call your doctor.
Breast-feeding: It is not known if valsartan passes into breast milk. Hydrochlorothiazide passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Do not breast-feed while you are taking this medication.
Children: The safety and effectiveness of using this medication have not been established for children. This medication is not recommended for children.
What other drugs could interact with this medication?
There may be an interaction between valsartan – hydrochlorothiazide and any of the following:
If you are taking any of these medications, speak with your doctor or pharmacist. Depending on your specific circumstances, your doctor may want you to:
- stop taking one of the medications,
- change one of the medications to another,
- change how you are taking one or both of the medications, or
- leave everything as is.
An interaction between two medications does not always mean that you must stop taking one of them. Speak to your doctor about how any drug interactions are being managed or should be managed.
Medications other than those listed above may interact with this medication. Tell your doctor or prescriber about all prescription, over-the-counter (non-prescription), and herbal medications that you are taking. Also tell them about any supplements you take. Since caffeine, alcohol, the nicotine from cigarettes, or street drugs can affect the action of many medications, you should let your prescriber know if you use them.
All material copyright MediResource Inc. 1996 – 2020. Terms and conditions of use. The contents herein are for informational purposes only. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Source: www.medbroadcast.com/drug/getdrug/Diovan-HCT