Side Effects of Diovan (valsartan)

Diovan (valsartan) is an angiotensin receptor blocker (ARB) used to treat high blood pressure and congestive heart failure. 

• Diovan is also prescribed after heart attacks since it may reduce deaths in patients who developed congestive heart failure after a heart attack. 
• Diovan also may reduce hospitalizations in patients with 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 of blood vessels. 
• Angiotensin’s attachment to the receptors causes the blood vessels to narrow (vasoconstrict) which leads to an increase in blood pressure (hypertension). Diovan blocks the angiotensin receptor. 
• By blocking the action of angiotensin, Diovan dilates blood vessels and reduces blood pressure. 

Common side effects of Diovan include:

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

Serious side effects of Diovan 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 include potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium which when taken with Diovan may lead to hyperkalemia (elevated potassium in the blood) and in heart failure patients, it increases serum creatinine, a blood test used for monitoring function of the kidneys.

Combining Diovan with nonsteroidal anti-inflammatory drugs (NSAIDs) in patients who are elderly, fluid-depleted, or with poor kidney function may result in reduced kidney function, including kidney failure.

Aspirin and other NSAIDs may reduce the effects of ARBs such as Diovan.

When used in the second or third trimester of pregnancy, Diovan can cause injury and even death to the fetus. Diovan should not be used during pregnancy. When pregnancy is detected, Diovan should be stopped as soon as possible.

It is unknown if Diovan is secreted into human milk. Consult your doctor before breastfeeding. 

Valsartan is generally well-tolerated. The most common side effects are:

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

Other important side effects are:

• hyperkalemia,
• impotence,
• reduced renal function, and
• allergic reactions.

Rhabdomyolysis (inflammation and destruction of muscle) and angioedema (swelling of soft tissues including those of the throat and larynx) are rare but serious side effects of valsartan.

Clinical Studies Experience

• Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adult Hypertension

• Diovan (valsartan) has been evaluated for safety in more than 4,000 patients, including over 400 treated for over 6 months, and more than 160 for over 1 year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with Diovan was similar to placebo.
• The overall frequency of adverse reactions was neither dose-related nor related to gender, age, race, or regimen. Discontinuation of therapy due to side effects was required in 2.3% of valsartan patients and 2.0% of placebo patients. The most common reasons for discontinuation of therapy with Diovan were headache and dizziness.
• The adverse reactions that occurred in placebo-controlled clinical trials in at least 1% of patients treated with Diovan and at a higher incidence in valsartan (n=2,316) than placebo (n=888) patients included
  • viral infection (3% vs. 2%),
  • fatigue (2% vs. 1%), and
  • abdominal pain (2% vs. 1%).
  • Headache, dizziness, upper respiratory infection, cough, diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema, and arthralgia occurred at a more than 1% rate but at about the same incidence in placebo and valsartan patients.
• 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, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p <0.001).
• Dose-related orthostatic effects were seen in less than 1% of patients. An increase in the incidence of dizziness was observed in patients treated with Diovan 320 mg (8%) compared to 10 to 160 mg (2% to 4%).
• Diovan has been used concomitantly with hydrochlorothiazide without evidence of clinically important adverse interactions.
• Other adverse reactions that occurred in controlled clinical trials of patients treated with Diovan (>0.2% of valsartan patients) are listed below. It cannot be determined whether these events were causally related to Diovan.

Body as a Whole: Allergic reaction and asthenia

Cardiovascular: Palpitations

Dermatologic: Pruritus and rash

Digestive: Constipation, dry mouth, dyspepsia, and flatulence

Musculoskeletal: Back pain, muscle cramps, and myalgia

Neurologic and Psychiatric: Anxiety, insomnia, paresthesia, and somnolence

Respiratory: Dyspnea

Special Senses: Vertigo

Urogenital: Impotence

• Other reported events seen less frequently in clinical trials included chest pain, syncope, anorexia, vomiting, and angioedema.

Pediatric Hypertension

• Diovan has been evaluated for safety in over 400 pediatric patients aged 6 to 17 years and more than 160 pediatric patients aged 6 months to 5 years.
• No relevant differences were identified between the adverse experience profile for pediatric patients aged 6 to 16 years and that previously reported for adult patients.
• Headache and hyperkalemia were the most common adverse events suspected to be study drug-related in older children (6 to 17 years old) and younger children (6 months to 5 years old), respectively.
• Hyperkalemia was mainly observed in children with underlying renal disease.
• Neurocognitive and developmental assessment of pediatric patients aged 6 to 16 years revealed no overall clinically relevant adverse impact after treatment with Diovan for up to 1 year.
• Diovan is not recommended for pediatric patients under 6 years of age. In a study (n=90) of pediatric patients (1 to 5 years), two deaths and three cases of on-treatment transaminase elevations were seen in the one-year open-label extension phase.
• These 5 events occurred in a study population in which patients frequently had significant co-morbidities.
• A causal relationship to Diovan has not been established. In a second study in which 75 children aged 1 to 6 years were randomized, no deaths and one case of marked liver transaminase elevations occurred during a 1 year open-label extension.

Heart Failure

• The adverse experience profile of Diovan in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients.
• In the Valsartan Heart Failure Trial, comparing valsartan in total daily doses up to 320 mg (n=2,506) to placebo (n=2,494), 10% of valsartan patients discontinued for adverse reactions vs. 7% of placebo patients.
• The table shows adverse reactions in double-blind short-term heart failure trials, including the first 4 months of the Valsartan Heart Failure Trial, with an incidence of at least 2% that were more frequent in valsartan-treated patients than in placebo-treated patients.
• All patients received standard drug therapy for heart failure, frequently as multiple medications, which could include diuretics, digitalis, beta-blockers.
• About 93% of patients received concomitant ACE inhibitors.

• Discontinuations occurred in 0.5% of valsartan-treated patients and 0.1% of placebo patients for each of the following:
  • elevations in creatinine and
  • elevations in potassium.
• Other adverse reactions with an incidence greater than 1% and greater than placebo included
  • headache NOS,
  • nausea,
  • renal impairment NOS,
  • syncope,
  • blurred vision,
  • upper abdominal pain and
  • vertigo.
• (NOS = not otherwise specified).
• From the long-term data in the Valsartan Heart Failure Trial, there did not appear to be any significant adverse reactions not previously identified.

Post-Myocardial Infarction

• The safety profile of Diovan was consistent with the pharmacology of the drug and the background diseases, cardiovascular risk factors, and clinical course of patients treated in the post-myocardial infarction setting.
• The table shows the percentage of patients discontinued in the valsartan and captopriltreated groups in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) with a rate of at least 0.5% in either of the treatment groups.
• Discontinuations due to renal dysfunction occurred in 1.1% of valsartan-treated patients and 0.8% of captopril-treated patients.

Postmarketing Experience

The following additional adverse reactions have been reported in postmarketing experience:

Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Diovan 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, renal failure

Clinical Laboratory Tests: Hyperkalemia

Dermatologic: Alopecia, bullous dermatitis

Blood and Lymphatic: There are very rare reports of thrombocytopenia

Vascular: Vasculitis

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

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.

No clinically significant pharmacokinetic interactions were observed when Diovan (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.

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.

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.

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 and other agents that affect the RAS.

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

Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including Diovan. Monitor serum lithium levels during concomitant use.

Clinical Laboratory Test Findings

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Diovan.

Creatinine

Minor elevations in creatinine occurred in 0.8% of patients taking Diovan and 0.6% given placebo in controlled clinical trials of hypertensive patients. In heart failure trials, greater than 50% increases in creatinine were observed in 3.9% of Diovan-treated patients compared to 0.9% of placebotreated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients.

Hemoglobin And Hematocrit

Greater than 20% decreases in hemoglobin and hematocrit were observed in 0.4% and 0.8%, respectively, of Diovan patients, compared with 0.1% and 0.1% in placebo-treated patients. One valsartan patient discontinued treatment for microcytic anemia.

Liver Function Tests

Occasional elevations (greater than 150%) of liver chemistries occurred in Diovan-treated patients. Three patients (<0.1%) treated with valsartan discontinued treatment for elevated liver chemistries.

Neutropenia

Neutropenia was observed in 1.9% of patients treated with Diovan and 0.8% of patients treated with placebo.

Serum Potassium

In hypertensive patients, greater than 20% increases in serum potassium were observed in 4.4% of Diovan-treated patients compared to 2.9% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium were observed in 10.0% of Diovantreated patients compared to 5.1% of placebo-treated patients.

Blood Urea Nitrogen (BUN)

In heart failure trials, greater than 50% increases in BUN were observed in 16.6% of Diovan-treated patients compared to 6.3% of placebo-treated patients.