DRUGS & SUPPLEMENTS

Teva-Lisinopril Hctz Type P

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What are the side effects you encounter while taking this medicine?

Teva-Lisinopril Hctz Type P uses

Teva-Lisinopril Hctz Type P consists of Hydrochlorothiazide, Lisinopril Dihydrate.

Hydrochlorothiazide:


Teva-Lisinopril Hctz Type P information

Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) is an antihypertensive, diuretic drug that acts on the electrolyte reabsorption in the renal tubular mechanism increasing the excretion of chloride and sodium in equivalent amounts. The exact mechanism of its antihypertensive action is not known at this time.

Teva-Lisinopril Hctz Type P indications

Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) is typically employed for the treatment of patients suffering from hypertension, either as monotherapy or in combination with other antihypertensive medication. It is also employed in some cases as a diuretic agent. Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) therapy may also be prescribed for the treatment of hepatic cirrhosis, edema (in patients suffering from congestive heart failure), nephrotic syndrome, drug induced edema, chronic renal failure or acute glomerulonephritis. Health care professionals may prescribe this drug in order to treat other medical conditions as well; if you would like to know more about the reasons you have been prescribed this drug, it is advised to ask your personal physician.

Teva-Lisinopril Hctz Type P warnings

Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) may not be used in the treatment of patients who are allergic to this drug, any of its components or other sulfonamide-derived medication. Also, this drug may not be suitable for use in patients that are suffering from anuria, azotemia or impaired renal functions. Caution should be employed if the patient is suffering from hepatic disease. Other medical conditions may also influence the examining health care provider's decision of prescribing Teva-Lisinopril Hctz Type P (Hydrochlorothiazide); it is strongly recommended to make sure that the health care professional is fully aware of your health condition and medical history before starting a treatment with this drug.

Use of Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) during pregnancy or breast-feeding is also not recommended. This medicine may affect an unborn baby and it also passes into breast milk. As such, use of this drug in pregnant women or breast-feeding mothers should not be employed.

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Teva-Lisinopril Hctz Type P intake guidelines

You should always take Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) as you have been directed by the prescribing health care specialist. While in some cases daily administration of the drug is recommended, other patients may be prescribed an intermittent therapy. Also, the number of daily doses may vary. As such, it is best that you do not follow another patient's intake schedule. If you have difficulties understanding the intake guidelines that your prescribing health care professional has provided, you should ask for further explanations from an authorized health care specialist - such as a pharmacist, a doctor or a nurse.

Teva-Lisinopril Hctz Type P dosage

The exact Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) dosage may vary greatly from one case to another, depending on the condition being treated, on the patient's medical history and general health condition, on his or her age as well as on a number of other factors. As such you are advised to use the exact Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) dosage that has been prescribed to you and never use the dosage prescribed to another patient or a dosage that you have been prescribed in the past. Taking a different Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) dose may cause the treatment to not have the desired effect, and if you take this drug in larger doses you may have a higher risk of developing side effects, or you may suffer from an overdose.

Teva-Lisinopril Hctz Type P overdose

You should never exceed the Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) prescribed dosage, in order to avoid an overdose with this medication. However, if you consider that you are affected by an overdose with this drug it is advised to immediately consult your personal health care provider, the local poisons center or to go to the nearest medical facility to seek emergency medical attention. The common symptoms of an overdose with Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) are dehydration and cardiac arrhythmia. The patient may also suffer from electrolyte depletion and thus may present the relevant signs and symptoms.

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Teva-Lisinopril Hctz Type P missed dose

In case you have missed a dose of Teva-Lisinopril Hctz Type P (Hydrochlorothiazide), it is advised that you take the dose as soon as you remember. If the moment when you remember is too close to another intake of the medication, you should completely skip the missed Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) dose and take the next scheduled dose on time. You should never take a larger dose of the drug in order to make up for a missed dose, unless your prescribing health care provider directs you to do so.

Teva-Lisinopril Hctz Type P side effects

In some patients Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) may cause side effects. While they are not very common, it is recommended to let your personal health care provider know if you begin experiencing any side effects. Several types of symptoms are possible: dizziness, headache, paresthesias, gastric irritation, anorexia, nausea and vomiting, diarrhea or constipation, pancreatitis, jaundice, hypotension. Metabolic side effects may include glycosuria, hyperglycemia, hyperuricemia, hypokalemia or hyponatremia. Renal failure or dysfunction may develop, as well as interstitial nephritis. Some patients reported experiencing muscle spasms, restlessness, unusual weakness and blurred vision. In some cases photosensitivity, anaphylactic reactions, respiratory distress, fever, rashes, vasculitis or toxic epidermal necrolysis have occurred.

Teva-Lisinopril Hctz Type P drug reactions

Teva-Lisinopril Hctz Type P (Hydrochlorothiazide) may interact with barbiturates and narcotics, as well as with alcohol. If you are also following a treatment course with antidiabetic drugs, their dosage may need to be adjusted before starting to take Teva-Lisinopril Hctz Type P (Hydrochlorothiazide). This drug may have an additive effect with other antihypertensive medication. ACE inhibitors, ACTH, corticosteroids and skeletal muscle relaxants may also interact with this drug causing unwanted effects. This drug may not be properly absorbed if the patient is also taking Colestipol resins or Cholestyramine. NSAIDs, lithium and Pressor amines may affect or be affected by Teva-Lisinopril Hctz Type P (Hydrochlorothiazide), and as such it is strongly recommended to let the prescribing health care provider know if you are taking these or any other drugs before starting a therapy course with this medicine. Other drug interactions that are not listed here are also possible.

Lisinopril Dihydrate:


WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) as soon as possible [see Warnings and Precautions (5.1) ].
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1) ] .

WARNING: FETAL TOXICITY

See full prescribing information for complete boxed warning.

  • When pregnancy is detected, discontinue Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) 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

Teva-Lisinopril Hctz Type P tablets are an angiotensin converting enzyme (ACE) inhibitor indicated for:

  • Treatment of hypertension in adults and pediatric patients 6 years of age and older (1.1)
  • Adjunct therapy for heart failure (1.2)
  • Treatment of Acute Myocardial Infarction (1.3)

1.1 Hypertension

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) tablets are indicated for the treatment of hypertension in adult patients and pediatric patients 6 years of age and older to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal 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.

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 also have 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 (for example, 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.

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) tablets may be administered alone or with other antihypertensive agents [see Clinical Studies (14.1) ].

1.2 Heart Failure

Teva-Lisinopril Hctz Type P tablets are indicated to reduce signs and symptoms of systolic heart failure [see Clinical Studies (14.2) ].

1.3 Reduction of Mortality in Acute Myocardial Infarction

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) tablets are indicated for the reduction of mortality in treatment of hemodynamically stable patients within 24 hours of acute myocardial infarction. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers [see Clinical Studies (14.3) ].

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2 DOSAGE AND ADMINISTRATION

  • Hypertension: Initial adult dose is 10 mg once daily. Titrate up to 40 mg daily based on blood pressure response. Initiate patients on diuretics at 5 mg once daily
  • Pediatric patients with glomerular filtration rate greater than 30 mL/min/1.73m2: Initial dose in patients 6 years of age and older is 0.07 mg per kg (up to 5 mg total) once daily (2.1)
  • Heart Failure: Initiate with 5 mg once daily. Increase dose as tolerated to 40 mg daily (2.2)
  • Acute Myocardial Infarction (MI): Give 5 mg within 24 hours of MI. Followed by 5 mg after 24 hours, then 10 mg once daily (2.3)
  • Renal Impairment: For patients with creatinine clearance greater than or equal to 10 mL/min and less than or equal to 30 mL/min, halve usual initial dose. For patients with creatinine clearance less than 10 mL/min or on hemodialysis, the recommended initial dose is 2.5 mg (2.4)

2.1 Hypertension

Initial Therapy in Adults

The recommended initial dose is 10 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 20 mg to 40 mg per day administered in a single daily dose. Doses up to 80 mg have been used but do not appear to give greater effect.

Use with Diuretics in Adults

If blood pressure is not controlled with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) tablets alone, a low dose of a diuretic may be added (e.g., hydrochlorothiazide, 12.5 mg). After the addition of a diuretic, it may be possible to reduce the dose of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) tablets.

The recommended starting dose in adult patients with hypertension taking diuretics is 5 mg once per day.

Pediatric Patients 6 years of age and older with hypertension

For pediatric patients with glomerular filtration rate greater than 30 mL/min/1.73m2, the recommended starting dose is 0.07 mg per kg once daily (up to 5 mg total). Dosage should be adjusted according to blood pressure response up to a maximum of 0.61 mg per kg (up to 40 mg) once daily. Doses above 0.61 mg per kg (or in excess of 40 mg) have not been studied in pediatric patients [see Clinical Pharmacology (12.3) ].

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) tablets are not recommended in pediatric patients less than 6 years or in pediatric patients with glomerular filtration rate less than 30 mL/min/1.73m2 [see Use in Specific Populations (8.4) and Clinical Studies (14.1) ].

2.2 Heart Failure

The recommended starting dose for Teva-Lisinopril Hctz Type P tablets, when used with diuretics and (usually) digitalis as adjunctive therapy for systolic heart failure, is 5 mg once daily. The recommended starting dose in these patients with hyponatremia (serum sodium less than 130 mEq/L) is 2.5 mg once daily. Increase as tolerated to a maximum of 40 mg once daily.

Diuretic dose may need to be adjusted to help minimize hypovolemia, which may contribute to hypotension [see Warnings and Precautions (5.4), and Drug Interactions (7.1) ]. The appearance of hypotension after the initial dose of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) tablets does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.

2.3 Reduction of Mortality in Acute Myocardial Infarction

In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial infarction, give Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) tablets 5 mg orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily. Dosing should continue for at least six weeks.

Initiate therapy with 2.5 mg in patients with a low systolic blood pressure (less than or equal to 120 mmHg and greater than 100 mmHg) during the first 3 days after the infarct [see Warnings and Precautions (5.4) ]. If hypotension occurs (systolic blood pressure less than or equal to 100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than 1 hour) Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) tablets should be withdrawn.

2.4 Dose in Patients with Renal Impairment

No dose adjustment of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) tablets is required in patients with creatinine clearance greater than 30 mL/min. In patients with creatinine clearance greater than or equal to 10 mL/min and less than or equal to 30 mL/min, reduce the initial dose of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) tablets to half of the usual recommended dose i.e., hypertension, 5 mg; systolic heart failure, 2.5 mg and acute MI, 2.5 mg. Up titrate as tolerated to a maximum of 40 mg daily. For patients on hemodialysis or creatinine clearance less than 10 mL/min, the recommended initial dose is 2.5 mg once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ].

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3 DOSAGE FORMS AND STRENGTHS

2.5 mg are white, round, biconvex, uncoated tablets debossed “E25” on one side and plain on the other side.

5 mg are pink, oval, biconvex, uncoated tablets debossed “E54” on one side and bisected on the other side.

10 mg are pink, round, biconvex, uncoated tablets debossed “E101” on one side and plain on the other side.

20 mg are peach, round, biconvex, uncoated tablets debossed “E102” on one side and plain on the other side.

30 mg are red, round, biconvex, uncoated tablets debossed “E103” on one side and plain on the other side.

40 mg are yellow, round, biconvex, uncoated tablets debossed “E104” on one side and plain on the other side.

Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg (3)

4 CONTRAINDICATIONS

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) is contraindicated in patients with:

  • a history of angioedema or hypersensitivity related to previous treatment with an angiotensin converting enzyme inhibitor
  • hereditary or idiopathic angioedema

Do not co-administer aliskiren with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in patients with diabetes [see Drug Interactions (7.4) ]

  • Angioedema or a history of hereditary or idiopathic angioedema (4)
  • Hypersensitivity (4)
  • Co-administration of aliskiren with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in patients with diabetes (4, 7.4)

5 WARNINGS AND PRECAUTIONS

  • Angioedema: Discontinue Teva-Lisinopril Hctz Type P, provide appropriate therapy and monitor until resolved (5.2)
  • Renal impairment: Monitor renal function periodically (5.3)
  • Hypotension: Patients with other heart or renal diseases have increased risk, monitor blood pressure after initiation (5.4)
  • Hyperkalemia: Monitor serum potassium periodically (5.5)
  • Cholestatic jaundice and hepatic failure: Monitor for jaundice or signs of liver failure (5.6)

5.1 Fetal Toxicity

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) as soon as possible [see Use in Specific Populations (8.1) ].

5.2 Angioedema and Anaphylactoid Reactions

Patients taking concomitant mTOR inhibitor therapy may be at increased risk for angioedema [see Drug Interactions (7.7) ].

Angioedema

Head and Neck Angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx, including some fatal reactions, have occurred in patients treated with angiotensin converting enzyme inhibitors, including Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), at any time during treatment. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms of angioedema has occurred.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor [see Contraindications (4) ]. ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients.

Intestinal Angioedema

Intestinal angioedema has occurred in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. In some cases, the angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor.

Anaphylactoid Reactions

Anaphylactoid Reactions During Desensitization

Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life- threatening anaphylactoid reactions.

Anaphylactoid Reactions During Dialysis

Sudden and potentially life threatening anaphylactoid reactions have occurred in some patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

5.3 Impaired Renal Function

Monitor renal function periodically in patients treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate). Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, post-myocardial infarction or volume depletion) may be at particular risk of developing acute renal failure on Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate). Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) [see Adverse Reactions (6.1) , Drug Interactions (7.4) ].

5.4 Hypotension

Teva-Lisinopril Hctz Type P can cause symptomatic hypotension, sometimes complicated by oliguria, progressive azotemia, acute renal failure or death. Patients at risk of excessive hypotension include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg, ischemic heart disease, cerebrovascular disease, hyponatremia, high dose diuretic therapy, renal dialysis, or severe volume and/or salt depletion of any etiology.

In these patients, Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) and/or diuretic is increased. Avoid use of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in patients who are hemodynamically unstable after acute MI.

Symptomatic hypotension is also possible in patients with severe aortic stenosis or hypertrophic cardiomyopathy.

Surgery/Anesthesia

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

5.5 Hyperkalemia

Serum potassium should be monitored periodically in patients receiving Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate). Drugs that inhibit the renin angiotensin system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes [see Drug Interactions (7.1) ].

5.6 Hepatic Failure

ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical treatment.

6 ADVERSE REACTIONS

  • Common adverse reactions by use.
  • Hypertension: headache, dizziness and cough (6.1)
  • Heart Failure: hypotension and chest pain (6.1)
  • Acute Myocardial Infarction: hypotension (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials 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.

Hypertension

In clinical trials in patients with hypertension treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), 5.7% of patients on Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) discontinued with adverse reactions.

The following adverse reactions (events 2% greater on Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) than on placebo) were observed with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) alone: headache (by 3.8%), dizziness (by 3.5%), cough (by 2.5%).

Heart Failure

In patients with systolic heart failure treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) for up to four years, 11% discontinued therapy with adverse reactions. In controlled studies in patients with heart failure, therapy was discontinued in 8.1% of patients treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) for 12 weeks, compared to 7.7% of patients treated with placebo for 12 weeks.

The following adverse reactions (events 2% greater on Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) than on placebo) were observed with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate): hypotension (by 3.8%), chest pain (by 2.1%).

In the two-dose ATLAS trial [see Clinical Studies (14.2) ] in heart failure patients, withdrawals due to adverse reactions were not different between the low and high groups, either in total number of discontinuation (17% to 18%) or in rare specific reactions (less than 1%). The following adverse reactions, mostly related to ACE inhibition, were reported more commonly in the high dose group:


High Dose

(n=1,568)


Low Dose

(n=1,596)


Dizziness


19%


12%


Hypotension


11%


7%


Creatinine increased


10%


7%


Hyperkalemia


6%


4%


Syncope


7%


5%


Acute Myocardial Infarction

Patients treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) had a higher incidence of hypotension (by 5.3%) and renal dysfunction (by 1.3%) compared with patients not taking Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate).

Other clinical adverse reactions occurring in 1% or higher of patients with hypertension or heart failure treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in controlled clinical trials and do not appear in other sections of labeling are listed below:

Body as a Whole

Fatigue, asthenia, orthostatic effects.

Digestive

Pancreatitis, constipation, flatulence, dry mouth, diarrhea.

Hematologic

Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia and thrombocytopenia.

Endocrine

Diabetes mellitus, inappropriate antidiuretic hormone secretion.

Metabolic

Gout.

Skin

Urticaria, alopecia, photosensitivity, erythema, flushing, diaphoresis, cutaneous pseudolymphoma, toxic epidermal necrolysis, Stevens-Johnson syndrome, and pruritus.

Special Senses

Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances, olfactory disturbance.

Urogenital

Impotence.

Miscellaneous

A symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, leukocytosis, paresthesia and vertigo. Rash, photosensitivity or other dermatological manifestations may occur alone or in combination with these symptoms.

Clinical Laboratory Test Findings

Serum Potassium

In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in 2.2% and 4.8% of lisinopril-treated patients with hypertension and heart failure, respectively [see Warnings and Precautions (5.5) ].

Creatinine, Blood Urea Nitrogen

Minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 2% of patients with hypertension treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) alone. Increases were more common in patients receiving concomitant diuretics and in patients with renal artery stenosis [see Warnings and Precautions (5.4) ]. Reversible minor increases in blood urea nitrogen and serum creatinine were observed in 11.6% of patients with heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.

Patients with acute myocardial infarction in the GISSI-3 trial treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) had a higher (2.4% versus 1.1% in placebo) incidence of renal dysfunction in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration).

Hemoglobin and Hematocrit

Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.4 g% and 1.3 vol%, respectively) occurred frequently in patients treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) but were rarely of clinical importance in patients without some other cause of anemia. In clinical trials, less than 0.1% of patients discontinued therapy due to anemia.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) that are not included in other sections of labeling. 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.

Other Reactions Include

Metabolism and Nutrition Disorders

Hyponatremia [see Warnings and Precautions (5.4) ], cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin [see Drug Interactions (7.2) ]

Nervous System and Psychiatric Disorders

Mood alterations (including depressive symptoms), mental confusion, hallucinations

Skin and Subcutaneous Tissue Disorders

Psoriasis

7 DRUG INTERACTIONS

  • Diuretics: Excessive drop in blood pressure
  • NSAIDS: Increased risk of renal impairment and loss of antihypertensive efficacy (7.3)
  • Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension and hyperkalemia (7.4)
  • Lithium: Symptoms of lithium toxicity (7.5)
  • Gold: Nitritoid reactions have been reported (7.6)

7.1 Diuretics

Initiation of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in patients on diuretics may result in excessive reduction of blood pressure. The possibility of hypotensive effects with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate). If this is not possible, reduce the starting dose of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) [see Dosage and Administration (2.2) and Warnings and Precautions (5.4) ].

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently.

7.2 Antidiabetics

Concomitant administration of Teva-Lisinopril Hctz Type P and antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycemia.

7.3 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 ACE inhibitors, including Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), may be attenuated by NSAIDs.

7.4 Dual Blockade of the Renin-Angiotensin System

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.

The VA NEPHRON trial enrolled 1,448 patients with type 2 diabetes, elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 mL/min), randomized them to Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) or placebo on a background of losartan therapy and followed them for a median of 2.2 years. Patients receiving the combination of losartan and Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) did not obtain any additional benefit compared to monotherapy for the combined endpoint of decline in GFR, end state renal disease, or death, but experienced an increased incidence of hyperkalemia and acute kidney injury compared with the monotherapy group.

In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) and other agents that affect the RAS.

Do not co-administer aliskiren with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in patients with diabetes. Avoid use of aliskiren with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in patients with renal impairment (GFR less than 60 mL/min).

7.5 Lithium

Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs, which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible upon discontinuation of lithium and the ACE inhibitor. Monitor serum lithium levels during concurrent use.

7.6 Gold

Nitritoid reactions have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate).

7.7 mTOR Inhibitors

Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema [see Warnings and Precautions (5.2) ].

8 USE IN SPECIFIC POPULATIONS

  • Lactation: Advise not to breastfeed
  • Race: Less antihypertensive effect in Blacks than non-Blacks (8.6)

8.1 Pregnancy

Risk Summary

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin‑angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin‑angiotensin system from other antihypertensive agents. When pregnancy is detected, discontinue Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) as soon as possible.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions

Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occur in neonates with a history of in utero exposure to Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function.

8.2 Lactation

Risk Summary

No data are available regarding the presence of Teva-Lisinopril Hctz Type P in human milk or the effects of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) on the breast fed infant or on milk production. Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) is present in rat milk. Because of the potential for severe adverse reactions in the breastfed infant, advise women not to breastfeed during treatment with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate).

8.4 Pediatric Use

Antihypertensive effects and safety of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) have been established in pediatric patients aged 6 to 16 years [see Dosage and Administration (2.1) and Clinical Studies (14.1) ]. No relevant differences between the adverse reaction profile for pediatric patients and adult patients were identified.

Safety and effectiveness of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) have not been established in pediatric patients under the age 6 or in pediatric patients with glomerular filtration rate less than 30 mL/min/1.73 m2 [see Dosage and Administration (2.1), Clinical Pharmacology (12.3) and Clinical Studies (14.1) ].

Neonates with a history of in utero exposure to Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate)

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

8.5 Geriatric Use

No dosage adjustment with Teva-Lisinopril Hctz Type P is necessary in elderly patients. In a clinical study of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in patients with myocardial infarctions (GISSI-3 Trial) 4,413 (47%) were 65 and over, while 1,656 (18%) were 75 and over. In this study, 4.8% of patients aged 75 years and older discontinued Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) treatment because of renal dysfunction vs. 1.3% of patients younger than 75 years. No other differences in safety or effectiveness were observed between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Race

ACE inhibitors, including Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), have an effect on blood pressure that is less in Black patients than in non-Blacks.

8.7 Renal Impairment

Dose adjustment of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) is required in patients undergoing hemodialysis or whose creatinine clearance is less than or equal to 30 mL/min. No dose adjustment of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) is required in patients with creatinine clearance greater than 30 mL/min [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

Following a single oral dose of 20 g/kg no lethality occurred in rats, and death occurred in one of 20 mice receiving the same dose. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution.

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) can be removed by hemodialysis [see Clinical Pharmacology (12.3) ].

11 DESCRIPTION

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) is an oral long-acting angiotensin converting enzyme (ACE) inhibitor. Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), a synthetic peptide derivative, is chemically described as (S)-1-[N2 -(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate. Its empirical formula is C21H31N3O5 - 2H2O and its structural formula is:

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), USP is a white to off-white, crystalline powder, with a molecular weight of 441.53. It is soluble in water and sparingly soluble in methanol and practically insoluble in ethanol.

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) tablets, USP, for oral administration, are supplied as 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg and 40 mg tablets.

Inactive Ingredients:

2.5 mg tablets – dibasic calcium phosphate, magnesium stearate, mannitol, corn starch.

5 mg, 10 mg and 30 mg tablets – dibasic calcium phosphate, magnesium stearate, mannitol, corn starch, red iron oxide.

20 mg tablets – dibasic calcium phosphate, magnesium stearate, mannitol, corn starch, red iron oxide, yellow iron oxide.

40 mg tablets – dibasic calcium phosphate, magnesium stearate, mannitol, corn starch, yellow iron oxide.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Teva-Lisinopril Hctz Type P inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however, approximately 15% of patients had increases greater than 0.5 mEq/L and approximately 6% had a decrease greater than 0.5 mEq/L. In the same study, patients treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mEq/L; approximately 4% of patients had increases greater than 0.5 mEq/L and approximately 12% had a decrease greater than 0.5 mEq/L [see Clinical Studies (14.1) ]. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) remains to be elucidated.

While the mechanism through which Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) is antihypertensive even in patients with low-renin hypertension. Although Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than non-Black patients.

Concomitant administration of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) and hydrochlorothiazide further reduced blood pressure in Black and non-Black patients and any racial differences in blood pressure response were no longer evident.

12.2 Pharmacodynamics

Hypertension

Adult Patients

Administration of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) to patients with hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt-depleted patients [see Warnings and Precautions (5.4) ]. When given together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are approximately additive.

In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), with peak reduction of blood pressure achieved by 6 hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses; however, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was 6 hours after dosing.

The antihypertensive effects of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) are maintained during long-term therapy. Abrupt withdrawal of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) has not been associated with a rapid increase in blood pressure, or a significant increase in blood pressure compared to pretreatment levels.

Non-Steroidal Anti-Inflammatory Agents

In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) alone were compared to Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) given concomitantly with indomethacin, the use of indomethacin was associated with a reduced effect, although the difference between the two regimens was not significant.

12.3 Pharmacokinetics

Adult Patients

Following oral administration of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), peak serum concentrations of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. Food does not alter the bioavailability of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate). Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Upon multiple dosing, Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) exhibits an effective half-life of 12 hours.

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) does not appear to be bound to other serum proteins. Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the mean extent of absorption of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) is approximately 25%, with large intersubject variability (6% to 60%) at all doses tested (5 mg to 80 mg). The absolute bioavailability of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) is reduced to 16% in patients with stable NYHA Class II-IV congestive heart failure, and the volume of distribution appears to be slightly smaller than that in normal subjects. The oral bioavailability of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in patients with acute myocardial infarction is similar to that in healthy volunteers.

Impaired renal function decreases elimination of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), which is excreted principally through the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater impairment, however, peak and trough Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) levels increase, time to peak concentration increases and time to attain steady state is prolonged [see Dosage and Administration (2.4) ]. Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) can be removed by hemodialysis.

Pediatric Patients

The pharmacokinetics of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) were studied in 29 pediatric hypertensive patients between 6 years and 16 years with glomerular filtration rate greater than 30 mL/min/1.73 m2. After doses of 0.1 mg to 0.2 mg per kg, steady state peak plasma concentrations of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) occurred within 6 hours and the extent of absorption based on urinary recovery was about 28%. These values are similar to those obtained previously in adults. The typical value of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) oral clearance (systemic clearance/absolute bioavailability) in a child weighing 30 kg is 10 L/h, which increases in proportion to renal function. In a multicenter, open-label pharmacokinetic study of daily oral Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in 22 pediatric hypertensive patients with stable kidney transplant (ages 7 to 17 years; estimated glomerular filtration rate greater than 30 mL/min/1.73 m2), dose normalized exposures were in the range reported previously in children without a kidney transplant.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of a tumorigenic effect when Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) was administered for 105 weeks to male and female rats at doses up to 90 mg per kg per day (about 56 or 9 times* the maximum recommended daily human dose, based on body weight and body surface area, respectively). There was no evidence of carcinogenicity when Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) was administered for 92 weeks to (male and female) mice at doses up to 135 mg per kg per day (about 84 times* the maximum recommended daily human dose). This dose was 6.8 times the maximum human dose based on body surface area in mice.

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells. Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.

There were no adverse effects on reproductive performance in male and female rats treated with up to 300 mg per kg per day of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate). This dose is 188 times and 30 times the maximum human dose when based on mg/kg and mg/m2, respectively.

Studies in rats indicate that Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) crosses the blood brain barrier poorly. Multiple doses of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate). By whole body autoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.

*Calculations assume a human weight of 50 kg and human body surface area of 1.62m2

14 CLINICAL STUDIES

14.1 Hypertension

Two dose-response studies utilizing a once-daily regimen were conducted in 438 mild to moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An antihypertensive effect of Teva-Lisinopril Hctz Type P was seen with 5 mg of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in some patients. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10 mg, 20 mg or 80 mg of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) than patients treated with 5 mg of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate).

In controlled clinical studies of patients with mild to moderate hypertension, patients were treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) 20 mg to 80 mg daily, hydrochlorothiazide 12.5 mg to 50 mg daily or atenolol 50 mg to 200 mg daily; and in other studies of patients with moderate to severe hypertension, patients were treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) 20 mg to 80 mg daily or metoprolol 100 mg to 200 mg daily. Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) demonstrated superior reductions of systolic and diastolic compared to hydrochlorothiazide in a population that was 75% Caucasian. Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) was approximately equivalent to atenolol and metoprolol in reducing diastolic blood pressure, and had somewhat greater effects on systolic blood pressure.

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) had similar blood pressure reductions and adverse effects in younger and older (greater than 65 years) patients. It was less effective in reducing blood pressure in Blacks than in Caucasians.

In hemodynamic studies of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.

In patients with renovascular hypertension Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) has been shown to be well tolerated and effective in reducing blood pressure [see Warnings and Precautions (5.3) ].

Pediatric Patients

In a clinical study involving 115 hypertensive pediatric patients 6 to 16 years of age, patients who weighed less than 50 kg received either 0.625 mg, 2.5 mg or 20 mg of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) once daily and patients who weighed greater than or equal to 50 kg received either 1.25 mg, 5 mg, or 40 mg of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) once daily. At the end of 2 weeks, Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) lowered trough blood pressure in a dose-dependent manner with antihypertensive efficacy demonstrated at doses greater than 1.25 mg (0.02 mg per kg). This effect was confirmed in a randomized withdrawal phase, where the diastolic pressure rose by about 9 mmHg more in patients randomized to placebo than compared to patients who remained on the middle and high doses of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate). The dose-dependent antihypertensive effect of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) was consistent across several demographic subgroups: age, Tanner stage, gender, and race. In this study, Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) was generally well-tolerated.

In the above pediatric studies, Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) was given either as tablets or in a suspension for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form [see Dosage and Administration (2.1) ].

14.2 Heart Failure

In two placebo controlled, 12-week clinical studies compared the addition of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) up to 20 mg daily to digitalis and diuretics alone. The combination of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), digitalis and diuretics reduced the following signs and symptoms of heart failure: edema, rales, paroxysmal nocturnal dyspnea and jugular venous distention. In one of the studies, the combination of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), digitalis and diuretics reduced orthopnea, presence of third heart sound and the number of patients classified as NYHA Class III and IV; and improved exercise tolerance. A large (over 3,000 patients) survival study, the ATLAS Trial, comparing 2.5 mg and 35 mg of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) in patients with systolic heart failure, showed that the higher dose of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) had outcomes at least as favorable as the lower dose.

During baseline-controlled clinical trials, in patients with systolic heart failure receiving digitalis and diuretics, single doses of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) resulted in decreases in pulmonary capillary wedge pressure, systemic vascular resistance and blood pressure accompanied by an increase in cardiac output and no change in heart rate.

14.3 Acute Myocardial Infarction

The Gruppo Italiano per lo Studio della Sopravvienza nell’Infarto Miocardico (GISSI-3) study was a multicenter, controlled, randomized, unblinded clinical trial conducted in 19,394 patients with acute myocardial infarction (MI) admitted to a coronary care unit. It was designed to examine the effects of short-term (6 week) treatment with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), nitrates, their combination, or no therapy on short-term (6 week) mortality and on long-term death and markedly impaired cardiac function. Hemodynamically-stable patients presenting within 24 hours of the onset of symptoms were randomized, in a 2 x 2 factorial design, to six weeks of either 1) Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) alone (n=4,841), 2) nitrates alone (n=4,869), 3) Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) plus nitrates (n=4,841), or 4) open control (n=4,843). All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a beta blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.

The protocol excluded patients with hypotension (systolic blood pressure less than or equal to 100 mmHg), severe heart failure, cardiogenic shock, and renal dysfunction (serum creatinine greater than 2 mg per dL and/or proteinuria greater than 500 mg per 24 h). Patients randomized to Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) received 5 mg within 24 hours of the onset of symptoms, 5 mg after 24 hours, and then 10 mg daily thereafter. Patients with systolic blood pressure less than 120 mmHg at baseline received 2.5 mg of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate). If hypotension occurred, the Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) dose was reduced or if severe hypotension occurred Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) was stopped [see Dosage and Administration (2.3) ].

The primary outcomes of the trial were the overall mortality at 6 weeks and a combined end point at 6 months after the myocardial infarction, consisting of the number of patients who died, had late (day 4) clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction less than or equal to 35% or an akinetic-dyskinetic [A-D] score greater than or equal to 45%. Patients receiving Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) (n=9,646), alone or with nitrates, had an 11% lower risk of death (p = 0.04) compared to patients who did not receive Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) (n=9,672) (6.4% vs. 7.2%, respectively) at six weeks. Although patients randomized to receive Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) for up to six weeks also fared numerically better on the combined end point at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up echocardiography, and substantial excess use of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) between 6 weeks and 6 months in the group randomized to 6 weeks of Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), preclude any conclusion about this end point.

Patients with acute myocardial infarction, treated with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate), had a higher (9.0% versus 3.7%) incidence of persistent hypotension (systolic blood pressure less than 90 mmHg for more than 1 hour) and renal dysfunction (2.4% versus 1.1%) in-hospital and at six weeks (increasing creatinine concentration to over 3 mg per dL or a doubling or more of the baseline serum creatinine concentration) [see Adverse Reactions (6.1) ].

16 HOW SUPPLIED/STORAGE AND HANDLING

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) Tablets, USP, for oral administration, are available as

5 mg

Pink, oval, biconvex, uncoated tablets debossed “E54” on one side and bisected on the other side and supplied as:

NDC 0904-5811-43 bottles of 45

NDC 0904-5811-89 bottles of 90

NDC 0904-5811-80 bottles of 1000

NDC 0904-5811-61 blister pack of 10x10

10 mg

Pink, round, biconvex, uncoated tablets debossed “E101” on one side and plain on the other side and supplied as:

NDC 0904-5808-46 bottles of 30

NDC 0904-5808-43 bottles of 45

NDC 0904-5808-89 bottles of 90

NDC 0904-5808-80 bottles of 1000

NDC 0904-5808-61 blister pack of 10x10

20 mg

Peach, round, biconvex, uncoated tablets debossed “E102” on one side and plain on the other side and supplied as:

NDC 0904-5809-46 bottles of 30

NDC 0904-5809-89 bottles of 90

NDC 0904-5809-93 bottles of 180

NDC 0904-5809-80 bottles of 1000

NDC 0904-5809-61 blister pack of 10x10

40 mg

Yellow, round, biconvex, uncoated tablets debossed “E104” on one side and plain on the other side and supplied as:

NDC 0904-5810-46 bottles of 30

NDC 0904-5810-43 bottles of 45

NDC 0904-5810-89 bottles of 90

NDC 0904-5810-93 bottles of 180

NDC 0904-5810-80 bottles of 1000

NDC 0904-5810-61 blister pack of 10x10

Storage

Store at 20º to 25ºC (68º to 77ºF). Protect from moisture, freezing and excessive heat. Dispense in a tight container.

17 PATIENT COUNSELING INFORMATION

NOTE

This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

Pregnancy

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to notify their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ].

Angioedema

Angioedema, including laryngeal edema may occur at any time during treatment with angiotensin converting enzyme inhibitors, including Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate). Tell patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician.

Lactation

Advise women not to breastfeed during treatment with Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) [see Use in Specific Populations (8.2) ].

Symptomatic Hypotension

Tell patients to report light-headedness especially during the first few days of therapy. If actual syncope occurs, tell the patient to discontinue the drug until they have consulted with the prescribing physician.

Tell patients that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; advise patients accordingly.

Hyperkalemia

Tell patients not to use salt substitutes containing potassium without consulting their physician.

Hypoglycemia

Tell diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor to monitor for hypoglycaemia closely, especially during the first month of combined use [see Drug Interactions (7.2) ].

Leukopenia/Neutropenia

Tell patients to report promptly any indication of infection (e.g., sore throat, fever), which may be a sign of leukopenia/neutropenia.

Sandoz Inc.

Princeton, NJ 08540

46158592

Distributed by:

Major® Pharmaceuticals

31778 Enterprise Drive

Livonia, MI 48150

IH53870117

Rev. May 2016

MF0025REV05/16

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) Tablets USP

5 mg

100 Tablets

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) Tablets, USP

10 mg

100 Tablets

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) Tablets, USP

20 mg

100 Tablets

Teva-Lisinopril Hctz Type P (Lisinopril Dihydrate) Tablets, USP

40 mg

100 Tablets

Teva-Lisinopril Hctz Type P pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Teva-Lisinopril Hctz Type P available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Teva-Lisinopril Hctz Type P destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Teva-Lisinopril Hctz Type P Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Teva-Lisinopril Hctz Type P pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."HYDROCHLOROTHIAZIDE TABLET [QUALITEST PHARMACEUTICALS]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."AMLODIPINE BESYLATE; HYDROCHLOROTHIAZIDE; OLMESARTAN MEDOXOMIL: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."HYDROCHLOROTHIAZIDE; LISINOPRIL: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Teva-Lisinopril Hctz Type P?

Depending on the reaction of the Teva-Lisinopril Hctz Type P after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Teva-Lisinopril Hctz Type P not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Teva-Lisinopril Hctz Type P addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Teva-Lisinopril Hctz Type P, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Teva-Lisinopril Hctz Type P consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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