Tribenzor

Serious side effects have been reported with Tribenzor. See the “Tribenzor Precautions” section.

Common side effects include:

• dizziness
• swelling (edema) of the ankles, feet, and hands
• headache
• tiredness
• stuffy or runny nose and sore throat
• muscle twitching (spasms)
• nausea
• upper respiratory tract infection
• diarrhea
• urinary tract infection
• swelling (edema) of the joints

This is not a complete list of Tribenzor side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• water pills (diuretics) such as chlorthalidone (Hygrotron, Thalitone) or hydrochlorothiazide (Microzide, Hydrodiuril)
• potassium-sparing diuretics such as:
  • spironolactone (Aldactone)
  • triamterene (Dyrenium)
  • amiloride (Midamor)
• aliskiren (Tekturna)
• angiotensin-converting enzyme (ACE) inhibitors such as:
  • benazepril (Lotensin, Lotensin HCT)
  • captopril (Capoten, Capozide)
  • enalapril (Vasotec, Vaseretic)
  • fosinopril (Monopril, Monopril HCT)
  • lisinopril (Prinivil, Prinzide, Zestril, Zestoretic)
  • moexipril (Univasc, Uniretic)
  • quinapril (Accupril, Accuretic, Quinaretic)
  • ramipril (Altace)
  • trandolapril (Mavik, Tarka)
• other angiotensin receptor II blockers such as:
  • azilsartan (Edarbi)
  • candesartan (Atacand)
  • irbesartan (Avapro)
  • losartan (Cozaar)
  • olmesartan (Benicar)
  • telmisartan (Micardis, Twynsta)
  • valsartan (Diovan)
• aspirin and other NSAIDs (non-steroidal anti-inflammatory drugs) such as:
  • celecoxib (Celebrex)
  • diclofenac (Cambia, Cataflam, Flector, Voltaren, Zipsor and others)
  • etodolac (Lodine)
  • ibuprofen (Advil, Motrin, Nuprin)
  • indomethacin (Indocin, Indocin SR)
  • ketoprofen (Orudis, Actron, Oruvail)
  • ketorolac (Toradol)
  • meloxicam (Mobic)
  • nabumetone (Relafen)
  • naproxen (Naprosyn)
  • naproxen sodium (Aleve, Anaprox, Naprelan)
  • oxaprozin (Daypro)
  • piroxicam (Feldene)
• any type of medicine for diabetes
• narcotic pain medications such as morphine (MS Contin, Kadian), hydrocodone (Norco, Vicodin), oxymorphone (Opana, Percocet, Roxicet)
• sleeping pills and anti-seizure medicines called barbiturates
• lithium (Eskalith, Lithobid)
• steroids such as hydrocortisone (Cortef, Hydrocortone) and methylprednisolone (Medrol)
• cholesterol lowering medicines such as statins (atorvastatin, simvastatin, or rosuvastatin) and fibrates (fenofibrate, gemfibrozil)
• alcohol
• colesevelam (WelChol)

This is not a complete of Tribenzor drug interactions. Ask your doctor or pharmacist for more information.

• Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.
• Your doctor may start you on the 20/5/12.5 mg once daily dose of Tribenzor and may increase your dose as necessary to achieve the desired blood pressure response.
• The maximum recommended dose for this medication is 40 /10 /25 mg once daily.

• Store this medication at room temperature.
• Keep this and all medications out of the reach of children.

You should not use this medicine if you are allergic to amlodipine, hydrochlorothiazide, or olmesartan, or:

• if you are allergic to any sulfa drug; or

• if you are unable to urinate.

If you have diabetes, do not use amlodipine, hydrochlorothiazide, and olmesartan together with any medication that contains aliskiren (Amturnide, Tekturna, Tekamlo).

You may also need to avoid taking this medicine with aliskiren if you have kidney disease.

To make sure amlodipine, hydrochlorothiazide, and olmesartan is safe for you, tell your doctor if you have:

• kidney disease;

• liver disease;

• heart disease;

• an electrolyte imbalance (such as high levels of calcium, or low levels of potassium or magnesium in your blood);

• low blood pressure;

• glaucoma;

• lupus;

• gout;

• diabetes; or

• a penicillin allergy.

Do not use if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away. Olmesartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

It is not known whether amlodipine, hydrochlorothiazide, and olmesartan passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Keep taking Tribenzor (olmesartan, amlodipine, and hydrochlorothiazide) as you have been told by your doctor or other health care provider, even if you feel well.
• Take this medicine at the same time of day.
• To gain the most benefit, do not miss doses.
• 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.

• 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 this medicine, 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 Tribenzor 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 this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Tribenzor. 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 this medicine.

Review Date: October 4, 2017

Tribenzor tablets are available in the following strength combinations:

Clinical Trials 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.

Tribenzor
In the controlled trial of Tribenzor, patients were randomized to Tribenzor (olmesartan medoxomil/amlodipine/hydrochlorothiazide 40/10/25 mg), olmesartan medoxomil/amlodipine 40/10 mg, olmesartan medoxomil/hydrochlorothiazide 40/25 mg, or amlodipine/hydrochlorothiazide 10/25 mg. Subjects who received triple combination therapy were treated between two and four weeks with one of the three dual combination therapies. Safety data from this study were obtained in 574 patients with hypertension who received Tribenzor for 8 weeks.

The frequency of adverse reactions was similar between men and women, patients <65 years of age and patients ≥65 years of age, patients with and without diabetes, and Black and non-Black patients. Discontinuations because of adverse events occurred in 4% of patients treated with Tribenzor 40/10/25 mg compared to 1% of patients treated with olmesartan medoxomil/amlodipine 40/10 mg, 2% of patients treated with olmesartan medoxomil/hydrochlorothiazide 40/25 mg, and 2% of patients treated with amlodipine/hydrochlorothiazide 10/25 mg. The most common reason for discontinuation with Tribenzor was dizziness (1%).

Dizziness was one of the most frequently reported adverse reactions with incidence of 1.4% to 3.6% in subjects continuing on dual combination therapy compared to 5.8% to 8.9% in subjects who switched to Tribenzor.

The other most frequent adverse reactions that occurred in at least 2% of subjects are presented in the table below:

Table 1

Syncope was reported by 1% of Tribenzor subjects compared to 0.5% or less for the other treatment groups.

Olmesartan medoxomil
Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 treated for at least 1 year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse reactions similar to that seen with placebo. Adverse reactions were generally mild, transient, and without relationship to the dose of olmesartan medoxomil.

Amlodipine
Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials.

The following adverse reactions occurred in <1% but >0.1% of patients in controlled clinical trials under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert physicians to a possible relationship:
Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis
Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo
Gastrointestinal: anorexia, constipation, dyspepsia*, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia
General: allergic reaction, asthenia*, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease
Musculoskeletal System: arthralgia, arthrosis, muscle cramps*, myalgia
Psychiatric: sexual dysfunction (male* and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization
Respiratory: dyspnea*, epistaxis
Skin and Appendages: angioedema, erythema multiforme, pruritus*, rash*, rash erythematous, rash maculopapular
Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus
Urinary System: micturition frequency, micturition disorder, nocturia
Autonomic Nervous System: dry mouth, sweating increased
Metabolic and Nutritional: hyperglycemia, thirst
Hemopoietic: leukopenia, purpura, thrombocytopenia
* = events that occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

The following adverse reactions occurred in <0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.

Hydrochlorothiazide
Other adverse reactions 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

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of the individual components of Tribenzor. 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.

Olmesartan medoxomil. The following adverse reactions have been reported in post-marketing experience:

Body as a Whole: asthenia, angioedema, anaphylactic reactions, peripheral edema

Gastrointestinal: vomiting, diarrhea, sprue-like enteropathy [see Warnings and Precautions (5.10)]

Metabolic and Nutritional Disorders: hyperkalemia

Musculoskeletal: rhabdomyolysis

Urogenital System: acute renal failure, increased blood creatinine

Skin and Appendages: alopecia, pruritus, urticaria

Data from one controlled trial and an epidemiologic study have suggested that high-dose olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive. The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo in patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease. The trial met its primary endpoint, delayed onset of microalbuminuria, but olmesartan had no beneficial effect on decline in glomerular filtration rate (GFR). There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization death) in the olmesartan group compared to the placebo group (15 olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18).

The epidemiologic study included patients 65 years and older with overall exposure of > 300,000 patient-years. In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of death (HR 2.0, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin receptor blockers. In contrast, high-dose olmesartan use in non-diabetic patients appeared to be associated with a decreased risk of death (HR 0.46, 95% CI 0.24, 0.86) compared to similar patients taking other angiotensin receptor blockers. No differences were observed between the groups receiving lower doses of olmesartan compared to other angiotensin blockers or those receiving therapy for < 6 months.

Overall, these data raise a concern of a possible increased CV risk associated with the use of high-dose olmesartan in diabetic patients. There are, however, concerns with the credibility of the finding of increased CV risk, notably the observation in the large epidemiologic study for a survival benefit in non-diabetics of a magnitude similar to the adverse finding in diabetics.

Amlodipine. The following post-marketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In post-marketing experience, 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. Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.

Tribenzor is usually taken once per day. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may take Tribenzor with or without food.

Your chest pain may become worse when you first start taking this medicine or when your dose is increased. Call your doctor if your chest pain is severe or ongoing.

Your blood pressure will need to be checked often.

Vomiting, diarrhea, or heavy sweating can cause you to become dehydrated. This can lead to very low blood pressure, electrolyte disorders, or kidney failure while you are taking Tribenzor. Drink plenty of water each day while you are 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 or medical tests, tell the surgeon ahead of time that you are using Tribenzor.

It may take up to 2 weeks before your blood pressure improves. Keep using Tribenzor 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.

Store at room temperature away from moisture and heat.

Get emergency medical help if you have signs of an allergic reaction to Tribenzor: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• worsening chest pain;

• a light-headed feeling, like you might pass out;

• an unusual skin rash;

• pain or burning when you urinate;

• severe or ongoing diarrhea with weight loss;

• blurred vision, tunnel vision, eye pain, or seeing halos around lights;

• signs of an electrolyte imbalance - dry mouth, increased thirst, lack of energy, confusion, vomiting, muscle pain or weakness, fast heartbeats, feeling restless, little or no urine, or a seizure (convulsions); or

• kidney problems - little or no urination, painful or difficult urination, swelling in your feet or ankles, feeling tired or short of breath.

Common Tribenzor side effects may include:

• dizziness;

• headache, tired feeling;

• nausea, diarrhea;

• runny or stuffy nose, sore throat;

• swollen joints; or

• painful urination.

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.