Diovan HCT (valsartan/hydrochlorothiazide) Side Effects, Warnings, and Drug Interactions

Diovan HCT (valsartan/hydrochlorothiazide) is a combination of an angiotensin receptor blocker (ARB) and a diuretic (water pill) used to treat high blood pressure (hypertension) and congestive heart failure. 

Angiotensin, formed in the blood by the action of angiotensin converting enzyme (ACE), is a powerful chemical that attaches to angiotensin receptors found in many tissues but primarily on smooth muscle cells surrounding blood vessels. Angiotensin’s attachment to the receptors causes the muscles to contract and the blood vessels to narrow (vasoconstrict) which leads to an increase in blood pressure (hypertension). 

Valsartan blocks the angiotensin receptor. By blocking the action of angiotensin, valsartan dilates (widens) blood vessels and reduces blood pressure. Hydrochlorothiazide is a diuretic (water pill) used to treat high blood pressure and accumulation of fluid (edema). 

It works by blocking salt and water reabsorption in the kidneys, thus causing increased output of urine containing increased amounts of water and salt (diuresis). The mechanism of its action in lowering high blood pressure is not well understood. The combination of valsartan and hydrochlorothiazide reduces blood pressure more that either drug alone.

Common side effects of Diovan HCT include:

• headache,
• dizziness,
• fatigue,
• abdominal pain,
• cough,
• diarrhea, and
• nausea.

Serious side effects of Diovan HCT include:

• high blood potassium (hyperkalemia),
• impotence,
• reduced renal function,
• allergic reactions, and
• rarely, rhabdomyolysis (inflammation and destruction of muscle) and
• angioedema (swelling of soft tissues including those of the throat and larynx).

Drug interactions of Diovan HCT include lithium. 

Combining Diovan HCT and lithium increases lithium levels in the body and increases side effects of lithium like:

• increased thirst,
• decreased heart rate,
• weakness,
• blurred vision,
• decreased concentration, and
• ringing in the ears. 

Diovan HCT should be used with caution with nonsteroidal anti-inflammatory drugs (NSAIDs) because they can worsen kidney function and lower water removing effects of Diovan HCT. 

Diovan HCT is not recommended for pregnant females. It may cause injury and even death to the developing fetus. Diovan HCT is not recommended for females who are breastfeeding because it may enter breast milk.

Side effect of valsartan/hydrochlorothiazide are the same as its individual components.

Valsartan is generally well-tolerated. The most common side effects of valsartan include:

• Headache
• Dizziness
• Fatigue
• Abdominal pain
• Cough
• Diarrhea
• Nausea

Patients also may experience:

• Hyperkalemia (high blood potassium)
• Impotence
• Reduced renal function
• Allergic reactions

Rare but serious side effects of valsartan are:

• rhabdomyolysis (inflammation and destruction of muscle), and
• angioedema (swelling of soft tissues including those of the throat and larynx).

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.

Hypertension

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

Vascular: Hypotension

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.

Initial Therapy - Hypertension

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

Neutropenia was observed in 0.1% of patients treated with Diovan HCT and 0.4% of patients treated with placebo

Postmarketing Experience

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.

Hypersensitivity

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.

Digestive

Elevated liver enzymes and very rare reports of hepatitis

Renal

Impaired renal function

Clinical Laboratory Tests

Hyperkalemia

Dermatologic

Alopecia, bullous dermatitis

Vascular

Vasculitis

Nervous System

Syncope

Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Hydrochlorothiazide

The following additional adverse reactions have been reported in 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.

Valsartan-Hydrochlorothiazide

Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists or thiazides. Monitor lithium levels in patients taking Diovan HCT.

Valsartan

No clinically significant pharmacokinetic interactions were observed when valsartan was coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.

Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the timecourse of the anticoagulant properties of warfarin.

CYP 450 Interactions

In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.

Transporters

The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.

Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

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, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) 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 Blockade Of The Renin-Angiotensin System (RAS)

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. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on Diovan HCT and other agents that affect the RAS.

Do not coadminister aliskiren with Diovan HCT in patients with diabetes. Avoid use of aliskiren with Diovan HCT in patients with renal impairment (GFR <60 mL/min).

Hydrochlorothiazide

When administered concurrently, the following drugs may interact with thiazide diuretics:

Antidiabetic Drugs (oral agents and insulin)

Dosage adjustment of the antidiabetic drug may be required.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs And COX-2 Selective Inhibitors)

When Diovan HCT and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Carbamazepine

May lead to symptomatic hyponatremia.

Ion Exchange Resins

Staggering the dosage of hydrochlorothiazide and ion exchange resins (e.g., cholestyramine, colestipol) such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of resins would potentially minimize the interaction.

Cyclosporine

Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gouttype complications.