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Does Exforge (amlodipine and valsartan) cause side effects?
Calcium channel blockers block the transport of calcium into the smooth muscle cells lining the coronary arteries and other arteries of the body, which relaxes the muscles that surround arteries, dilating (enlarging) the arteries and lowering blood pressure.
Angiotensin is a chemical that attaches to angiotensin receptors found in primarily on smooth muscle cells surrounding blood vessels. Angiotensin's attachment to the receptors causes the blood vessels to narrow (constrict) which leads to an increase in blood pressure. Angiotensin receptor blockers block the angiotensin receptors, which dilates blood vessels and reduces blood pressure.
Common side effects of Exforge include:
Serious side effects of Exforge include:
- high blood potassium (hyperkalemia),
- reduced kidney function,
- allergic reactions, and rarely,
- angioedema (swelling of soft tissues including those of the throat and larynx).
Drug interactions of Exforge include potassium-sparing diuretics, potassium supplements, and salt substitutes containing potassium, which when combined with Exforge may lead to hyperkalemia (elevated potassium in the blood), and in heart failure patients, it increases serum creatinine, a test used for monitoring function of the kidneys.
When used in the second or third trimester of pregnancy valsartan may cause injury and even death to the fetus. Valsartan should not be used during pregnancy. When pregnancy is detected, Exforge should be stopped as soon as possible.
What are the important side effects of Exforge (amlodipine and valsartan)?
Side effects include:
- abdominal pain,
- diarrhea and
- reduced renal function, and
- allergic reactions.
Angioedema (swelling of soft tissues including those of the throat and larynx) is a rare but serious side effect of valsartan.
Exforge (amlodipine and valsartan) side effects list for healthcare professionals
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials 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.
Studies with Exforge
Exforge has been evaluated for safety in over 2600 patients with hypertension; over 1440 of these patients were treated for at least 6 months and over 540 of these patients were treated for at least 1 year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.
The hazards of valsartan are generally independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter.
The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race. In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the Exforgetreated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with Exforge were peripheral edema (0.4%), and vertigo (0.2%).
The adverse reactions that occurred in placebo-controlled clinical trials in at least 2% of patients treated with Exforge but at a higher incidence in amlodipine/valsartan patients (n=1437) than placebo (n=337) included peripheral edema (5.4% vs 3.0%), nasopharyngitis (4.3% vs 1.8%), upper respiratory tract infection (2.9% vs 2.1%) and dizziness (2.1% vs 0.9%).
Orthostatic events (orthostatic hypotension and postural dizziness) were seen in less than 1% of patients.
Other adverse reactions that occurred in placebo-controlled clinical trials with Exforge ( ≥ 0.2%) are listed below. It cannot be determined whether these events were causally related to Exforge.
Blood and Lymphatic System Disorders: Lymphadenopathy
Cardiac Disorders: Palpitations, tachycardia
Immune System Disorders: Seasonal allergies
Injury and Poisoning: Epicondylitis, joint sprain, limb injury
Reproductive System and Breast Disorders: Erectile dysfunction
Vascular Disorders: Flushing, hot flush Isolated cases of the following clinically notable adverse reactions were also observed in clinical trials: exanthema, syncope, visual disturbance, hypersensitivity, tinnitus, and hypotension.
Studies with Amlodipine
Norvasc has been evaluated for safety in more than 11000 patients in U.S. and foreign clinical trials. Other adverse events that have been reported < 1% but > 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain were:
Central and Peripheral Nervous System: neuropathy peripheral, tremor
Musculoskeletal System: arthrosis, muscle cramps
Psychiatric: sexual dysfunction (male and female), nervousness, abnormal dreams, depersonalization
Respiratory System: dyspnea
Urinary System: micturition frequency, micturition disorder, nocturia
Autonomic Nervous System: sweating increased
Hemopoietic: leukopenia, purpura, thrombocytopenia
Other events reported with amlodipine at a frequency of ≤ 0.1% of patients include:
- cardiac failure,
- pulse irregularity,
- skin discoloration,
- skin dryness,
- muscle weakness,
- cold and clammy skin,
- increased appetite,
- loose stools,
- taste perversion,
- abnormal visual accommodation, and
Adverse reactions reported for amlodipine for indications other than hypertension may be found in the prescribing information for Norvasc.
Studies with Valsartan
Diovan has been evaluated for safety in more than 4000 hypertensive patients in clinical trials. 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).
Other adverse reactions, not listed above, occurring in > 0.2% of patients in controlled clinical trials with valsartan are:
Body as a Whole: allergic reaction, asthenia
Musculoskeletal: muscle cramps
Neurologic and Psychiatric: paresthesia
Respiratory: sinusitis, pharyngitis
Other reported events seen less frequently in clinical trials were: angioedema. Adverse reactions reported for valsartan for indications other than hypertension may be found in the prescribing information for Diovan.
Clinical Lab Test Findings
Creatinine: In hypertensive patients, greater than 50% increases in creatinine occurred in 0.4% of patients receiving Exforge and 0.6% receiving placebo. In heart failure patients, greater than 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated 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.
Serum Potassium: In hypertensive patients, greater than 20% increases in serum potassium were observed in 2.8% of Exforge-treated patients compared to 3.4% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium were observed in 10% of valsartan-treated patients compared to 5.1% of placebo-treated patients.
Blood Urea Nitrogen (BUN): In hypertensive patients, greater than 50% increases in BUN were observed in 5.5% of Exforge-treated patients compared to 4.7% of placebo-treated patients. In heart failure patients, greater than 50% increases in BUN were observed in 16.6% of valsartan-treated patients compared to 6.3% of placebo-treated patients.
Neutropenia: Neutropenia was observed in 1.9% of patients treated with Diovan and 0.8% of patients treated with placebo.
Amlodipine: Gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
Valsartan: The following additional adverse reactions have been reported in postmarketing experience with valsartan:
Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Exforge should not be re-administered to patients who have had angioedema.
Renal: Impaired renal function, renal failure
Clinical Laboratory Tests: Hyperkalemia
Dermatologic: Alopecia, bullous dermatitis
What drugs interact with Exforge (amlodipine and valsartan)?
No drug interaction studies have been conducted with Exforge and other drugs, although studies have been conducted with the individual amlodipine and valsartan components.
Impact of Other Drugs on Amlodipine
Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment.
No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.
Impact of Amlodipine on Other Drugs
Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.
Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate.
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.
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 co-medication is considered necessary, monitoring of serum potassium is advisable.
CYP 450 Interactions: In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of 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.
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 Exforge and other agents that affect the RAS.
Do not coadminister aliskiren with Exforge in patients with diabetes. Avoid use of aliskiren with Exforge 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 valsartan. Monitor serum lithium levels during concomitant use.
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Related Disease Conditions
High Blood Pressure (Hypertension)
High blood pressure (hypertension) is a disease in which pressure within the arteries of the body is elevated. About 75 million people in the US have hypertension (1 in 3 adults), and only half of them are able to manage it. Many people do not know that they have high blood pressure because it often has no has no warning signs or symptoms. Systolic and diastolic are the two readings in which blood pressure is measured. The American College of Cardiology released new guidelines for high blood pressure in 2017. The guidelines now state that blood normal blood pressure is 120/80 mmHg. If either one of those numbers is higher, you have high blood pressure. The American Academy of Cardiology defines high blood pressure slightly differently. The AAC considers 130/80 mm Hg. or greater (either number) stage 1 hypertension. Stage 2 hypertension is considered 140/90 mm Hg. or greater. If you have high blood pressure you are at risk of developing life threatening diseases like stroke and heart attack.REFERENCE: CDC. High Blood Pressure. Updated: Nov 13, 2017.
Portal hypertension is most commonly caused by cirrhosis, a disease that results from scarring of the liver. Other causes of portal hypertension include blood clots in the portal vein, blockages of the veins that carry the blood from the liver to the heart, and a parasitic infection called schistosomiasis. Symptoms of portal hypertension include varices (enlarged veins), vomiting blood, blood in the stool, black and tarry stool, ascites (abnormal fluid collection within the peritoneum, the sac that contains the intestines within the abdominal cavity), confusion and lethargy, splenomegaly or enlargement of the spleen, and decreased white blood cell counts.
Pulmonary hypertension is elevated pressure in the pulmonary arteries that carry blood from the lungs to the heart. The most common symptoms are fatigue and difficulty breathing. If the condition goes undiagnosed, more severe symptoms may occur. As pulmonary hypertension worsens, some people with the condition have difficulty performing any activities that require physical exertion. While there is no cure for pulmonary hypertension, it can be managed and treated with medications and supplemental oxygen to increase blood oxygen levels.
Hypertension-Related Kidney Disease
Second Source WebMD Medical Reference
Treatment & Diagnosis
Medications & Supplements
- amlodipine/benazepril - oral, Lotrel
- valsartan - oral, Diovan
- amlodipine - oral, Norvasc
- amlodipine (Norvasc)
- valsartan, Diovan
- Losartan vs. Valsartan (Differences between Side Effects and Uses)
- Side Effects of Norvasc (amlodipine besylate)
- amlodipine and valsartan (Exforge)
- valsartan/hydrochlorothiazide (Diovan HCT)
- amlodipine/atorvastatin - oral, Caduet
- Entresto (sacubitril and valsartan)
- Lotrel (amlodipine and benazepril)
- Entresto (sacubitril and valsartan)
- Azor (amlodipine and olmesartan medoxomil)
- Tribenzor (olmesartan medoxomil, amlodipine, hydrochlorothiazide)
- Diovan HCT (valsartan/hydrochlorothiazide) Side Effects, Warnings, and Drug Interactions
- Consensi (amlodipine and celecoxib)
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.