Amlodipine, valsartan, and hydrochlorothiazide

Name: Amlodipine, valsartan, and hydrochlorothiazide

Commonly used brand name(s)

In the U.S.

  • Exforge HCT

Available Dosage Forms:

  • Tablet

Therapeutic Class: Antihypertensive

Pharmacologic Class: Amlodipine

Chemical Class: Amlodipine

Before Using amlodipine, valsartan, and hydrochlorothiazide

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For amlodipine, valsartan, and hydrochlorothiazide, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to amlodipine, valsartan, and hydrochlorothiazide or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of amlodipine, valsartan, and hydrochlorothiazide combination in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of amlodipine, valsartan, and hydrochlorothiazide combination in the elderly. However, elderly patients are more likely to have unwanted effects which may require an adjustment in the dose for patients receiving amlodipine, valsartan, and hydrochlorothiazide.

Pregnancy

Pregnancy Category Explanation
All Trimesters D Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking amlodipine, valsartan, and hydrochlorothiazide, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using amlodipine, valsartan, and hydrochlorothiazide with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

  • Aliskiren
  • Dofetilide

Using amlodipine, valsartan, and hydrochlorothiazide with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Aceclofenac
  • Acemetacin
  • Acetyldigoxin
  • Amiodarone
  • Amphetamine
  • Amtolmetin Guacil
  • Arsenic Trioxide
  • Aspirin
  • Atazanavir
  • Benazepril
  • Benzphetamine
  • Bromfenac
  • Bufexamac
  • Captopril
  • Celecoxib
  • Ceritinib
  • Choline Salicylate
  • Clarithromycin
  • Clonixin
  • Clopidogrel
  • Conivaptan
  • Cyclophosphamide
  • Cyclosporine
  • Dantrolene
  • Deslanoside
  • Dexibuprofen
  • Dexketoprofen
  • Dextroamphetamine
  • Diclofenac
  • Diflunisal
  • Digitalis
  • Digitoxin
  • Digoxin
  • Dipyrone
  • Domperidone
  • Droperidol
  • Droxicam
  • Eliglustat
  • Enalapril
  • Enalaprilat
  • Etodolac
  • Etofenamate
  • Etoricoxib
  • Felbinac
  • Fenoprofen
  • Fepradinol
  • Feprazone
  • Flecainide
  • Floctafenine
  • Flufenamic Acid
  • Flurbiprofen
  • Fosinopril
  • Ibuprofen
  • Idelalisib
  • Indomethacin
  • Ketanserin
  • Ketoprofen
  • Ketorolac
  • Lacosamide
  • Levomethadyl
  • Lisdexamfetamine
  • Lisinopril
  • Lithium
  • Lornoxicam
  • Loxoprofen
  • Lumiracoxib
  • Meclofenamate
  • Mefenamic Acid
  • Meloxicam
  • Methamphetamine
  • Methotrexate
  • Metildigoxin
  • Moexipril
  • Morniflumate
  • Nabumetone
  • Naproxen
  • Nepafenac
  • Netupitant
  • Niflumic Acid
  • Nimesulide
  • Nimesulide Beta Cyclodextrin
  • Ouabain
  • Oxaprozin
  • Oxyphenbutazone
  • Parecoxib
  • Perindopril
  • Phenylbutazone
  • Piketoprofen
  • Piperaquine
  • Piroxicam
  • Proglumetacin
  • Propyphenazone
  • Proquazone
  • Proscillaridin
  • Quinapril
  • Ramipril
  • Rofecoxib
  • Salicylic Acid
  • Salsalate
  • Simeprevir
  • Simvastatin
  • Sodium Salicylate
  • Sotalol
  • Sulindac
  • Tacrolimus
  • Tegafur
  • Telaprevir
  • Tenoxicam
  • Tiaprofenic Acid
  • Tolfenamic Acid
  • Tolmetin
  • Trandolapril
  • Trimethoprim
  • Valdecoxib

Using amlodipine, valsartan, and hydrochlorothiazide with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Aceclofenac
  • Acemetacin
  • Aminolevulinic Acid
  • Amtolmetin Guacil
  • Bepridil
  • Bromfenac
  • Bufexamac
  • Carbamazepine
  • Celecoxib
  • Cholestyramine
  • Choline Salicylate
  • Clonixin
  • Dexibuprofen
  • Dexketoprofen
  • Diclofenac
  • Diflunisal
  • Dipyrone
  • Droxicam
  • Etodolac
  • Etofenamate
  • Etoricoxib
  • Felbinac
  • Fenoprofen
  • Fepradinol
  • Feprazone
  • Floctafenine
  • Flufenamic Acid
  • Flurbiprofen
  • Ginkgo
  • Gossypol
  • Ibuprofen
  • Indinavir
  • Indomethacin
  • Ketoprofen
  • Ketorolac
  • Licorice
  • Lornoxicam
  • Loxoprofen
  • Lumiracoxib
  • Meclofenamate
  • Mefenamic Acid
  • Meloxicam
  • Morniflumate
  • Nabumetone
  • Naproxen
  • Nepafenac
  • Niflumic Acid
  • Nimesulide
  • Nimesulide Beta Cyclodextrin
  • Oxaprozin
  • Oxyphenbutazone
  • Parecoxib
  • Phenylbutazone
  • Piketoprofen
  • Piroxicam
  • Proglumetacin
  • Propionic Acid
  • Propyphenazone
  • Proquazone
  • Rofecoxib
  • Salicylic Acid
  • Salsalate
  • Sodium Salicylate
  • Sulindac
  • Tenoxicam
  • Tiaprofenic Acid
  • Tolfenamic Acid
  • Tolmetin
  • Topiramate
  • Valdecoxib

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of amlodipine, valsartan, and hydrochlorothiazide. Make sure you tell your doctor if you have any other medical problems, especially:

  • Angina (severe chest pain) or
  • Diabetes or
  • Electrolyte imbalances (e.g., low levels of salt or sodium in the body) or
  • Fluid imbalances (caused by dehydration, vomiting, or diarrhea) or
  • Gallstones, or history of or
  • Glaucoma, acute angle-closure or
  • Gout, history of or
  • Heart attack, history of or
  • Heart or blood vessel disease (e.g., severe obstructive coronary artery disease) or
  • Hypercalcemia (high calcium in the blood) or
  • Hypercholesterolemia (high cholesterol in the blood) or
  • Hypertriglyceridemia (high triglycerides or fats in the blood) or
  • Systemic lupus erythematosus (an autoimmune disorder)—Use with caution. May make these conditions worse.
  • Angioedema (an allergic reaction) with other blood pressure medicines (e.g., benazepril, enalapril, lisinopril, Lotrel®, Vasotec®, Zestoretic®, Zestril®), history of, or
  • Anuria (not able to pass urine) or
  • Diabetes patients who are also taking aliskiren (Tekturna®) or
  • Sulfa drug allergy (antibiotic or stomach medicines, e.g., sulfamethoxazole, sulfasalazine, sulfisoxazole, Azulfidine®, Bactrim®, Septra®)—Should not be used in patients with these conditions.
  • Aortic or mitral stenosis (problem with heart valve), severe—May cause side effects to become worse.
  • Asthma, history of—May increase likelihood of having an allergic reaction.
  • Congestive heart failure, severe—Use may lead to kidney problems.
  • Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

How is this medicine (Amlodipine, Valsartan, and Hydrochlorothiazide) best taken?

Use amlodipine, valsartan, and hydrochlorothiazide as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Take with or without food.
  • To gain the most benefit, do not miss doses.
  • Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
  • Take amlodipine, valsartan, and hydrochlorothiazide at the same time of day.
  • This medicine may cause you to pass urine more often. To keep from having sleep problems, try to take before 6 pm.
  • Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.

What do I do if I miss a dose?

  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about amlodipine, valsartan, and hydrochlorothiazide, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about amlodipine, valsartan, and hydrochlorothiazide. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using amlodipine, valsartan, and hydrochlorothiazide.

Review Date: October 4, 2017

Drug Interactions

No drug interaction studies have been conducted with amlodipine/valsartan/hydrochlorothiazide and other drugs, although studies have been conducted with the individual components. A pharmacokinetic drug-drug interaction study has been conducted to address the potential for pharmacokinetic interaction between the triple combination, amlodipine/valsartan/hydrochlorothiazide, and the corresponding three double combinations. No clinically relevant interaction was observed.

Amlodipine

Impact of other Drugs on Amlodipine

CYP3A Inhibitors

Coadministration 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 coadministered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology (12.3)].

CYP3A Inducers

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.

Sildenafil

Monitor for hypotension when sildenafil is coadministered with amlodipine [see Clinical Pharmacology (12.2)].

Impact of Amlodipine on other Drugs

Simvastatin

Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12.3)].

Immunosuppressants

Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when coadministered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3)].

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.

In vitro metabolism studies have indicated that CYP450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism [see Pharmacokinetics - Valsartan, (12.3)].

Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.

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.

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, co-administration 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 amlodipine/valsartan/hydrochlorothiazide and other agents that affect the RAS.

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

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 amlodipine, valsartan and hydrochlorothiazide.

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.

Non-steroidal anti-inflammatory drugs (NSAIDs and COX-2 selective inhibitors): When amlodipine/valsartan/hydrochlorothiazide and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of 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 [see Clinical Pharmacology (12.3)].

Cyclosporine: Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.

Clinical Studies

Amlodipine/valsartan/hydrochlorothiazide was studied in a double-blind, active controlled study in hypertensive patients. A total of 2,271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressure was 170/107 mmHg) received treatments of amlodipine/valsartan/HCTZ 10/320/25 mg, valsartan/HCTZ 320/25 mg, amlodipine/valsartan 10/320 mg, or HCTZ/amlodipine 25/10 mg. At study initiation patients assigned to the two-component arms received lower doses of their treatment combination while patients assigned to the amlodipine/valsartan/hydrochlorothiazide arm received 160/12.5 mg valsartan/hydrochlorothiazide. After one week, amlodipine/valsartan/hydrochlorothiazide patients were titrated to 5/160/12.5 mg amlodipine/valsartan/hydrochlorothiazide, while all other patients continued receiving their initial doses. After two weeks, all patients were titrated to their full treatment dose. A total of 55% of patients were male, 14% were 65 years or older, 72% were Caucasian, and 17% were black.

At week 8, the triple combination therapy produced greater reductions in blood pressure than each of the three dual combination treatments (p<0.0001 for both diastolic and systolic blood pressures reductions). The reductions in systolic/diastolic blood pressure with amlodipine/valsartan/ Hydrochlorothiazide were 7.6/5.0 mmHg greater than with valsartan/HCTZ, 6.2/3.3 mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater than with amlodipine/HCTZ (see Figure 1). The full blood pressure lowering effect was achieved 2 weeks after being on the maximal dose of amlodipine/valsartan/hydrochlorothiazide(see Figure 2 and Figure 3). As the pivotal study was an active controlled trial, the treatment effects shown in Figures 1, 2, and 3 include a placebo effect of unknown size.

A subgroup of 283 patients was studied with ambulatory blood pressure monitoring. The blood pressure lowering effect in the triple therapy group was maintained throughout the 24-hour period (see Figure 4 and Figure 5).

There are no trials of the amlodipine/valsartan/hydrochlorothiazide combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but both the amlodipine and hydrochlorothiazide components and several ARBs, which are the same pharmacological class as the valsartan component, have demonstrated such benefits.

How is Amlodipine, Valsartan, and Hydrochlorothiazide Supplied

Amlodipine/valsartan/hydrochlorothiazide is available as film-coated tablets containing amlodipine besylate equivalent to 5 mg or 10 mg of amlodipine free-base with valsartan 160 mg or 320 mg and hydrochlorothiazide 12.5 mg or 25 mg providing for the following available combinations: 5/160/12.5 mg, 10/160/12.5 mg, 5/160/25 mg, 10/160/25 mg or 10/320/25 mg. All strengths are packaged in bottles of 30, 90 and 500 tablets.

5 mg amlodipine /160 mg valsartan /12.5 mg hydrochlorothiazide Tablets - White to off-white, film coated, oval shaped biconvex tablets, debossed with "P" on one side of the tablet and "172" on the other

 

Bottles of 30

 

NDC 49884-172-11

 

Bottles of 90

 

NDC 49884-172-09

 

Bottles of 500

 

NDC 49884-172-05

10 mg amlodipine /160 mg valsartan /12.5 mg hydrochlorothiazide Tablets – Peach to light brown, film coated, oval shaped biconvex tablets, debossed with "P" on one side of the tablet and "174" on the other.

 

Bottles of 30

 

NDC 49884-174-11

 

Bottles of 90

 

NDC 49884-174-09

 

Bottles of 500

 

NDC 49884-174-05

5 mg amlodipine /160 mg valsartan /25 mg hydrochlorothiazide Tablets – Yellow, film-coated, oval shaped biconvex tablets debossed with “P” on one side of the tablet and “173” on the other.

 

Bottles of 30

 

NDC 49884-173-11

 

Bottles of 90

 

NDC 49884-173-09

 

Bottles of 500

 

NDC 49884-173-05

10 mg amlodipine /160 mg valsartan /25 mg hydrochlorothiazide Tablets – Bright yellow, film-coated oval shaped, biconvex tablets debossed with “P” on one side of the tablet and “185” on the other.

 

Bottles of 30

 

NDC 49884-185-11

 

Bottles of 90

 

NDC 49884-185-09

 

Bottles of 500

 

NDC 49884-185-05

10 mg amlodipine /320 mg valsartan /25 mg hydrochlorothiazide Tablets – White to off white, film coated, oval shaped biconvex tablets, debossed with "P" on one side of the tablet and "175" on the other

 

Bottles of 30

 

NDC 49884-175-11

 

Bottles of 90

 

NDC 49884-175-09

 

Bottles of 500

 

NDC 49884-175-05

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15º to 30°C (59º to 86°F).

[See USP Controlled Room Temperature.]

Protect from moisture.

Dispense in tight container (USP).

PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to amlodipine/valsartan/hydrochlorothiazide during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physician as soon as possible.

Symptomatic Hypotension: A patient receiving amlodipine/valsartan/hydrochlorothiazide should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patients should be told that if syncope occurs, amlodipine/valsartan/hydrochlorothiazide should be discontinued until the physician has been consulted.

All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

Potassium Supplements: A patient receiving amlodipine/valsartan/hydrochlorothiazide should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.

Test Interactions

See individual agents.

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