Losartan Potassium-Hydrochlorothiazide

HYZAAR 50/12.5 (losartan potassium-hydrochlorothiazide), HYZAAR 100/12.5 (losartan potassiumhydrochlorothiazide) and HYZAAR 100/25 (losartan potassium-hydrochlorothiazide) tablets combine an angiotensin II receptor blocker acting on the AT 1 receptor subtype and a diuretic, hydrochlorothiazide.

Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[p-(o-1Htetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Its empirical formula is C22H22ClKN6O, and its structural formula is:

Losartan potassium is a white to off-white free-flowing crystalline powder with a molecular weight of 461.01. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone.

Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.

Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8ClN3O4S2 and its structural formula is:

Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

HYZAAR is available for oral administration in three tablet combinations of losartan and hydrochlorothiazide. HYZAAR 50/12.5 contains 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide. HYZAAR 100/12.5 contains 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide. HYZAAR 100/25 contains 100 mg of losartan potassium and 25 mg of hydrochlorothiazide. Inactive ingredients are microcrystalline cellulose, lactose hydrous, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose, and titanium dioxide. HYZAAR 50/12.5 and HYZAAR 100/25 also contain D&C yellow No. 10 aluminum lake. HYZAAR 50/12.5, HYZAAR 100/12.5, and HYZAAR 100/25 may also contain carnauba wax.

HYZAAR 50/12.5 contains 4.24 mg (0.108 mEq) of potassium, HYZAAR 100/12.5 contains 8.48 mg (0.216 mEq) of potassium, and HYZAAR 100/25 contains 8.48 mg (0.216 mEq) of potassium.

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.

Losartan potassium-hydrochlorothiazide has been evaluated for safety in 858 patients treated for essential hypertension and 3889 patients treated for hypertension and left ventricular hypertrophy. Most adverse reactions have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of therapy due to clinical adverse events was required in only 2.8% and 2.3% of patients treated with the combination and placebo, respectively.

In these double-blind controlled clinical trials, adverse reactions occurring in greater than 2% of subjects treated with losartan-hydrochlorothiazide and at a greater rate than placebo were: back pain (2.1% vs 0.6%), dizziness (5.7% vs 2.9%), and upper respiratory infection (6.1% vs 4.6%). The following additional adverse reactions have been reported in clinical trials with HYZAAR and/or the individual components:

Blood and the lymphatic system disorders: Anemia, aplastic anemia, hemolytic anemia, leukopenia, agranulocytosis.

Metabolism and nutrition disorders: Anorexia, hyperglycemia, hyperuricemia, electrolyte imbalance including hyponatremia and hypokalemia.

Psychiatric disorders: Insomnia, restlessness.

Nervous system disorders: Dysgeusia, headache, migraine, paraesthesias.

Eye disorders: Xanthopsia, transient blurred vision.

Cardiac disorders: Palpitation, tachycardia.

Vascular disorders: Dose-related orthostatic effects, necrotizing angiitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders: Nasal congestion, pharyngitis, sinus disorder, respiratory distress (including pneumonitis and pulmonary edema).

Gastrointestinal disorders: Dyspepsia, abdominal pain, gastric irritation, cramping, diarrhea, constipation, nausea, vomiting, pancreatitis, sialoadenitis.

Hepato-biliary disorders: Jaundice (intrahepatic cholestatic jaundice).

Skin and subcutaneous tissue disorders: Rash, pruritus, purpura, toxic epidermal necrolysis, urticaria, photosensitivity, cutaneous lupus erythematosus.

Musculoskeletal and connective tissue disorders: Muscle cramps, muscle spasm, myalgia, arthralgia.

Renal and urinary disorders: Glycosuria, renal dysfunction, interstitial nephritis, renal failure.

Reproductive system and breast disorders: Erectile dysfunction/impotence.

General disorders and administration site conditions: Chest pain, edema/swelling, malaise, fever, weakness.

Investigations: Liver function abnormalities.

Persistent dry cough has been associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy. Two prospective, parallel-group, double-blind, randomized, controlled trials were conducted to assess the effects of losartan on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to losartan 50 mg, lisinopril 20 mg, or either placebo (one study, n=97) or 25 mg hydrochlorothiazide (n=135). The double-blind treatment period lasted up to 8 weeks. The incidence of cough is shown in Table 1 below.

Table 1

These studies demonstrate that the incidence of cough associated with losartan therapy, in a population that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo therapy.

Cases of cough, including positive re-challenges, have been reported with the use of losartan in postmarketing experience.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of HYZAAR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

Digestive: Hepatitis has been reported rarely in patients treated with losartan.

Hematologic: Thrombocytopenia.

Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schönlein purpura, has been reported with losartan. Anaphylactic reactions have been reported.

Musculoskeletal: rhabdomyolysis

Skin: Erythroderma

HYZAAR®
(HY-zar)
(losartan potassium and hydrochlorothiazide tablets) 50/12.5 mg, 100/12.5 mg, 100/25 mg

Read the Patient Information that comes with HYZAAR® before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition and treatment.

What is the most important information I should know about HYZAAR?

• HYZAAR can cause harm or death to an unborn baby.
• Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant.
• If you get pregnant while taking HYZAAR tell your doctor right away.

What is HYZAAR?

HYZAAR contains 2 prescription medicines, an angiotensin receptor blocker (ARB) and a diuretic (water pill). It is used to:

• lower high blood pressure (hypertension). HYZAAR is not usually the first medicine used to treat high blood pressure.
• lower the chance of stroke in patients with high blood pressure and a heart problem called left ventricular hypertrophy (LVH). HYZAAR may not help Black patients with this problem.

HYZAAR has not been studied in children less than 18 years old.

High Blood Pressure (hypertension). Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. The losartan ingredient in HYZAAR can help your blood vessels relax so your blood pressure is lower. The hydrochlorothiazide ingredient in HYZAAR works by making your kidneys pass more water and salt.

Left Ventricular Hypertrophy (LVH) is an enlargement of the walls of the left chamber of the heart (the heart's main pumping chamber). LVH can happen from several things. High blood pressure is the most common cause of LVH.

Who should not take HYZAAR?

Do not take HYZAAR if you:

• are allergic to any ingredients in HYZAAR. See a complete list of ingredients in HYZAAR at the end of this leaflet.
• are not passing urine.
• have diabetes and are taking a medicine called aliskiren to reduce blood pressure.

What should I tell my doctor before taking HYZAAR?

Tell your doctor about all your medical conditions including if you:

• are pregnant or planning to become pregnant. See “What is the most important information I should know about HYZAAR?”
• are breastfeeding or plan to breastfeed. HYZAAR can pass into your milk and may harm your baby. You and your doctor should decide if you will take HYZAAR or breastfeed. You should not do both.
• have been vomiting (throwing up), having diarrhea, sweating a lot, or not drinking enough fluids. These could cause you to have low blood pressure.
• have liver problems
• have kidney problems
• have systemic lupus erythematosus (Lupus; SLE)
• have diabetes
• have gout
• have any allergies

Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

HYZAAR and certain other medicines may interact with each other. Especially tell your doctor if you are taking:

• potassium supplements
• salt substitutes containing potassium
• water pills (diuretics)
• lithium (a medicine used to treat a certain kind of depression)
• medicines used to treat pain and arthritis, called non-steroidal anti-inflammatory drugs (NSAIDs),
• including COX-2 inhibitors
• other medicines to reduce blood pressure.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I take HYZAAR?

• Take HYZAAR exactly as prescribed by your doctor. Your doctor may change your dose if needed.
• HYZAAR can be taken with or without food.
• If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Just take the next dose at your regular time.
• If you take too much HYZAAR, call your doctor or Poison Control Center, or go to the nearest hospital emergency room right away.
• Your doctor may do blood tests from time to time while you are taking HYZAAR.

What are the possible side effects of HYZAAR?

HYZAAR may cause the following side effects that may be serious:

• Injury or death of unborn babies. See “What is the most important information I should know about HYZAAR?”
• Allergic reaction. Symptoms of an allergic reaction are swelling of the face, lips, throat, or tongue. Get emergency medical help right away and stop taking HYZAAR.
• Low blood pressure (hypotension). Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy. Call your doctor right away.
• If you have kidney problems, you may see a worsening in how well your kidneys work. Call your doctor if you get swelling in your feet, ankles, or hands, or unexplained weight gain.
• A new or worsening condition called systemic lupus erythematosus (Lupus; SLE)
• Eye problems. One of the medicines in HYZAAR can cause eye problems that, if left untreated, may lead to vision loss. Symptoms of eye problems can happen within hours to weeks of starting HYZAAR. Tell your doctor right away if you have:
  • decrease in vision
  • eye pain

The most common side effects of HYZAAR in people with high blood pressure are:

• “colds” (upper respiratory infection)
• dizziness
• stuffy nose
• back pain

Tell your doctor if you get any side effect that bothers you or that won't go away. This is not a complete list of side effects. For a complete list, ask your doctor or pharmacist.

How should I store HYZAAR?

• Store HYZAAR at room temperature at 59°F to 86°F (15°C to 30°C).
• Keep HYZAAR in a tightly closed container, and keep HYZAAR out of the light.
• Keep HYZAAR and all medicines out of the reach of children.

General information about HYZAAR

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use HYZAAR for a condition for which it was not prescribed. Do not give HYZAAR to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarizes the most important information about HYZAAR. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information that is written for health professionals.

What are the ingredients in HYZAAR?

Active ingredients: losartan potassium, hydrochlorothiazide

Inactive ingredients:

microcrystalline cellulose, lactose hydrous, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose, titanium dioxide. HYZAAR 50/12.5 and HYZAAR 100/25 also contain D&C yellow No. 10 aluminum lake.

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Drinking alcohol can further lower your blood pressure and may increase certain side effects of hydrochlorothiazide and losartan.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Do not use potassium supplements or salt substitutes while you are taking hydrochlorothiazide and losartan, unless your doctor has told you to.