Complete SPL Sections#
WARNING: FETAL TOXICITY
BOXED WARNING SECTION
When pregnancy is detected, discontinue valsartan and hydrochlorothiazide tablets as soon as possible. ( 5.1 ) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. ( 5.1 )
1 INDICATIONS AND USAGE
INDICATIONS & USAGE SECTION
Valsartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including hydrochlorothiazide and the angiotensin II receptor blocker (ARB) class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with valsartan and hydrochlorothiazide tablets. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality have also been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (e.g., patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Add-On Therapy: Valsartan and hydrochlorothiazide tablets may be used in patients whose blood pressure is not adequately controlled on monotherapy. Replacement Therapy: Valsartan and hydrochlorothiazide tablets may be substituted for the titrated components. Initial Therapy: Valsartan and hydrochlorothiazide tablets may be used as initial therapy in patients who are likely to need multiple drugs to achieve blood pressure goals. The choice of valsartan and hydrochlorothiazide tablets as initial therapy for hypertension should be based on an assessment of potential benefits and risks. Patients with stage 2 hypertension are at a relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk. Data from the high dose multifactorial trial [see Clinical Studies (14.1) ] provides estimates of the probability of reaching a target blood pressure with valsartan and hydrochlorothiazide tablets compared to valsartan or hydrochlorothiazide monotherapy. The figures below provide estimates of the likelihood of achieving systolic or diastolic blood pressure control with valsartan and hydrochlorothiazide tablets 320/25 mg, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling. The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures. For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 41% likelihood of achieving a goal of < 140 mmHg (systolic) and 60% likelihood of achieving < 90 mmHg (diastolic) on valsartan alone and the likelihood of achieving these goals on HCTZ alone is about 50% (systolic) or 57% (diastolic). The likelihood of achieving these goals on valsartan and hydrochlorothiazide tablets rises to about 84% (systolic) or 80% (diastolic). The likelihood of achieving these goals on placebo is about 23% (systolic) or 36% (diastolic).
2 DOSAGE AND ADMINISTRATION
DOSAGE & ADMINISTRATION SECTION
3 DOSAGE FORMS AND STRENGTHS
DOSAGE FORMS & STRENGTHS SECTION
Valsartan and Hydrochlorothiazide Tablets, USP are available containing 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg or 320 mg/25 mg of valsartan, USP and hydrochlorothiazide, USP. The 80 mg/12.5 mg tablets are orange, film-coated, round, unscored tablets debossed with M on one side of the tablet and V21 on the other side. The 160 mg/12.5 mg tablets are orange, film-coated, round, unscored tablets debossed with M on one side of the tablet and V22 on the other side. The 160 mg/25 mg tablets are orange, film-coated, oval, unscored tablets debossed with M on one side of the tablet and V23 on the other side. The 320 mg/12.5 mg tablets are orange, film-coated, oval, unscored tablets debossed with M on one side of the tablet and V24 on the other side. The 320 mg/25 mg tablets are beige, film-coated, oval, unscored tablets debossed with M on one side of the tablet and V25 on the other side.
4 CONTRAINDICATIONS
CONTRAINDICATIONS SECTION
Valsartan and hydrochlorothiazide tablets are contraindicated in patients who are hypersensitive to any component of this product. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Do not coadminister aliskiren with valsartan and hydrochlorothiazide tablets in patients with diabetes [see Drug Interactions (7) ] .
5 WARNINGS AND PRECAUTIONS
WARNINGS AND PRECAUTIONS SECTION
6 ADVERSE REACTIONS
ADVERSE REACTIONS SECTION
7 DRUG INTERACTIONS
DRUG INTERACTIONS SECTION
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 valsartan and hydrochlorothiazide tablets. Valsartan: Agents Increasing Serum 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, 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 valsartan and other agents that affect the RAS. Do not coadminister aliskiren with valsartan in patients with diabetes. Avoid use of aliskiren with valsartan in patients with renal impairment (GFR < 60 mL/min). 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. Nonsteroidal Anti-inflammatory Drugs (NSAIDs and COX-2 selective inhibitors): When valsartan and hydrochlorothiazide tablets and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the 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.
8 USE IN SPECIFIC POPULATIONS
USE IN SPECIFIC POPULATIONS SECTION
10 OVERDOSAGE
OVERDOSAGE SECTION
Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed level of consciousness, circulatory collapse and shock have been reported. If symptomatic hypotension should occur institute supportive treatment. Valsartan is not removed from the plasma by dialysis. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The most common signs and symptoms observed in patients are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. In rats and marmosets, single oral doses of valsartan up to 1524 and 762 mg/kg in combination with hydrochlorothiazide at doses up to 476 and 238 mg/kg, respectively, did not show any adverse treatment-related effects. These no adverse effect doses in rats and marmosets, respectively, represent 46.5 and 23 times the MRHD of valsartan and 188 and 113 times the MRHD of hydrochlorothiazide on a mg/m 2 basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.) Valsartan was without grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats and up to 1000 mg/kg in marmosets, except for salivation and diarrhea in the rat and vomiting in the marmoset at the highest dose (60 and 31 times, respectively, the MRHD on a mg/m 2 basis). (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.) The oral LD 50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, which represents 2027 and 4054 times, respectively, the MRHD on a mg/m 2 basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)
11 DESCRIPTION
DESCRIPTION SECTION
Valsartan and hydrochlorothiazide tablets, USP are a combination of valsartan, an orally active, specific angiotensin II receptor blocker (ARB) acting on the AT 1 receptor subtype, and hydrochlorothiazide, a diuretic. Valsartan, a nonpeptide molecule, is chemically described as N -[p-(o-1 H -Tetrazol-5-ylphenyl)benzyl- N -valeryl- L -valine. Its molecular formula is C 24 H 29 N 5 O 3 , its molecular weight is 435.5, and its structural formula is: Valsartan, USP is a white to practically white fine powder. It is soluble in ethanol and methanol and slightly soluble in water. Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n -butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide is chemically described as 6-Chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Hydrochlorothiazide is a thiazide diuretic. Its molecular formula is C 7 H 8 ClN 3 O 4 S 2 , its molecular weight is 297.73, and its structural formula is: Valsartan and hydrochlorothiazide tablets are formulated for oral administration to contain valsartan and hydrochlorothiazide 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg and 320 mg/25 mg. The inactive ingredients of the tablets are colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, pregelatinized starch (corn), sodium lauryl sulfate, titanium dioxide, triacetin and vanillin. The 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg and 320 mg/12.5 mg tablets also contain red iron oxide and yellow iron oxide. The 320 mg/25 mg tablet also contains FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.
12 CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY SECTION
13 NONCLINICAL TOXICOLOGY
NONCLINICAL TOXICOLOGY SECTION
14 CLINICAL STUDIES
CLINICAL STUDIES SECTION
16 HOW SUPPLIED/STORAGE AND HANDLING
HOW SUPPLIED SECTION
The 320 mg/25 mg tablets are beige, film-coated, oval, unscored tablets debossed with M on one side of the tablet and V25 on the other side. They are available as follows: NDC 51655-243-52 bottles of 30 tablets Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from moisture and heat. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
17 PATIENT COUNSELING INFORMATION
INFORMATION FOR PATIENTS SECTION
Information for Patients: Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Pregnancy: Advise female patients of childbearing age about the consequences of exposure to valsartan and hydrochlorothiazide tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Ask patients to report pregnancies to their physicians as soon as possible [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ] . Lactation: Advise women not to breastfeed during treatment with valsartan and hydrochlorothiazide tablets [see Use in Specific Populations (8.2) ] . Symptomatic Hypotension: Advise patients that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to their healthcare provider. Tell patients that if syncope occurs, to discontinue valsartan and hydrochlorothiazide tablets until the physician has been consulted. Caution all patients 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 [see Warnings and Precautions (5.2) ] . Potassium Supplements: Advise patients not to use salt substitutes without consulting their healthcare provider [see Drug Interactions (7) ] . Non-Melanoma Skin Cancer: Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.
FDA-Approved Patient Labeling
SPL PATIENT PACKAGE INSERT SECTION
Patient Information Valsartan and Hydrochlorothiazide Tablets, USP (val sar' tan) (hye" droe klor" oh thye' a zide) Read the Patient Information that comes with valsartan and hydrochlorothiazide tablets 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. If you have any questions about valsartan and hydrochlorothiazide tablets, ask your doctor or pharmacist. What is the most important information I should know about valsartan and hydrochlorothiazide tablets? Valsartan and hydrochlorothiazide tablets 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 valsartan and hydrochlorothiazide tablets, tell your doctor right away. What are valsartan and hydrochlorothiazide tablets? Valsartan and hydrochlorothiazide tablets contain 2 prescription medicines: valsartan, an angiotensin receptor blocker (ARB) hydrochlorothiazide (HCTZ), a water pill (diuretic) Valsartan and hydrochlorothiazide tablets may be used to lower high blood pressure (hypertension) in adults- when 1 medicine to lower your high blood pressure is not enough. as the first medicine to lower high blood pressure if your doctor decides you are likely to need more than 1 medicine. Valsartan and hydrochlorothiazide tablets have not been studied in children under 18 years of age. Who should not take valsartan and hydrochlorothiazide tablets? Do not take valsartan and hydrochlorothiazide tablets if you: are allergic to any of the ingredients in valsartan and hydrochlorothiazide tablets. See the end of this leaflet for a complete list of ingredients in valsartan and hydrochlorothiazide tablets. make less urine due to kidney problems. are allergic to medicines that contain sulfonamides. What should I tell my doctor before taking valsartan and hydrochlorothiazide tablets? Tell your doctor about all your medical conditions including if you: are pregnant or plan to become pregnant. See “What is the most important information I should know about valsartan and hydrochlorothiazide tablets?” are breastfeeding. Valsartan and hydrochlorothiazide pass into breast milk. It is not known if valsartan and hydrochlorothiazide affect your breastfed baby or milk production. Do not breastfeed while you are taking valsartan and hydrochlorothiazide tablets. have liver problems have kidney problems have or had gallstones have Lupus have low levels of potassium (with or without symptoms such as muscle weakness, muscle spasms, abnormal heart rhythm) or magnesium in your blood have high levels of calcium in your blood (with or without symptoms such as nausea, vomiting, constipation, stomach pain, frequent urination, thirst, muscle weakness and twitching) have high levels of uric acid in the blood. have ever had a reaction called angioedema, to another blood pressure medication. Angioedema causes swelling of the face, lips, tongue, throat and may cause difficulty breathing Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Some of your other medicines and valsartan and hydrochlorothiazide tablets could affect each other, causing serious side effects. Especially, tell your doctor if you take: other medicines for high blood pressure or a heart problem water pills (diuretics) potassium supplements. Your doctor may check the amount of potassium in your blood periodically. a salt substitute. Your doctor may check the amount of potassium in your blood periodically. antidiabetic medicines including insulin narcotic pain medicines sleeping pills lithium, a medicine used in some types of depression (Eskalith ® , Lithobid ® , Lithium Carbonate, Lithium Citrate) aspirin or other medicines called non-steroidal anti-inflammatory drugs (NSAIDs), like ibuprofen or naproxen digoxin or other digitalis glycosides (a heart medicine) muscle relaxants (medicines used during operations) certain cancer medicines, like cyclophosphamide or methotrexate certain antibiotics (rifamycin group), a drug used to protect against transplant rejection (cyclosporine) or an antiretroviral drug used to treat HIV/AIDS infection (ritonavir). These drugs may increase the effect of valsartan. Ask your doctor if you are not sure if you are taking one of these medicines. Know the medicines you take. Keep a list of your medicines with you to show to your doctor and pharmacist when a new medicine is prescribed. Talk to your doctor or pharmacist before you start taking any new medicine. Your doctor or pharmacist will know what medicines are safe to take together. How should I take valsartan and hydrochlorothiazide tablets? Take valsartan and hydrochlorothiazide tablets exactly as prescribed by your doctor. Your doctor may change your dose if needed. Take valsartan and hydrochlorothiazide tablets once each day. Valsartan and hydrochlorothiazide tablets 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 many valsartan and hydrochlorothiazide tablets, call your doctor or Poison Control Center, or go to the nearest hospital emergency room. What should I avoid while taking valsartan and hydrochlorothiazide tablets? You should not take valsartan and hydrochlorothiazide tablets during pregnancy. See “What is the most important information I should know about valsartan and hydrochlorothiazide tablets?” What are the possible side effects of valsartan and hydrochlorothiazide tablets? Valsartan and hydrochlorothiazide tablets may cause serious side effects including: Harm to an unborn baby causing injury and even death. See “What is the most important information I should know about valsartan and hydrochlorothiazide tablets?” Low blood pressure (hypotension). Low blood pressure is most likely to happen if you: take water pills are on a low-salt diet get dialysis treatments have heart problems get sick with vomiting or diarrhea drink alcohol Lie down if you feel faint or dizzy. Call your doctor right away. Allergic reactions. People with and without allergy problems or asthma who take valsartan and hydrochlorothiazide tablets may get allergic reactions. Worsening of Lupus. Hydrochlorothiazide, one of the medicines in valsartan and hydrochlorothiazide tablets may cause Lupus to become active or worse. Fluid and electrolyte (salt) problems. Tell your doctor about any of the following signs and symptoms of fluid and electrolyte problems: dry mouth thirst lack of energy (lethargic) weakness drowsiness restlessness confusion seizures muscle pain or cramps muscle fatigue very low urine output fast heartbeat nausea and vomiting Kidney problems. Kidney problems may become worse in people that already have kidney disease. Some people will have changes on blood tests for kidney function and may need a lower dose of valsartan and hydrochlorothiazide tablets. Call your doctor if you get swelling in your feet, ankles, or hands, or unexplained weight gain. If you have heart failure, your doctor should check your kidney function before prescribing valsartan and hydrochlorothiazide tablets. Skin rash. Call your doctor right away if you have an unusual skin rash. Eye problems. One of the medicines in valsartan and hydrochlorothiazide tablets can cause eye problems that may lead to vision loss. Symptoms of eye problems can happen within hours to weeks of starting valsartan and hydrochlorothiazide tablets. Tell your doctor right away if you have: decrease in vision eye pain Protect your skin from the sun and undergo regular skin cancer screening, as one of the medicines in valsartan and hydrochlorothiazide tablets may cause non-melanoma skin cancer. Other side effects were generally mild and brief. Th...
Principal Display Panel
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC: 51655-243-52
