DESCRIPTION

Lisinopril and hydrochlorothiazide tablets combines an angiotensin converting enzyme inhibitor, lisinopril, and a diuretic,

hydrochlorothiazide.

Lisinopril, a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme inhibitor. It 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:

Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.52. It is soluble in water, sparingly soluble in

methanol, and practically insoluble in ethanol.

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

and its structural formula is:

Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.73, which is slightly soluble in

water, but freely soluble in sodium hydroxide solution.

Lisinopril and hydrochlorothiazide tablets are available for oral use in three tablet combinations of lisinopril with hydrochlorothiazide:

lisinopril and hydrochlorothiazide tablets 10 mg/12.5 mg, containing 10 mg lisinopril and 12.5 mg hydrochlorothiazide, lisinopril and

hydrochlorothiazide tablets 20 mg/12.5 mg, containing 20 mg lisinopril and 12.5 mg hydrochlorothiazide and lisinopril and

hydrochlorothiazide tablets 20 mg/25 mg, containing 20 mg lisinopril and 25 mg hydrochlorothiazide.

Inactive ingredients are dibasic calcium phosphate, magnesium stearate, mannitol, pregelatinized starch and starch. Lisinopril and

hydrochlorothiazide tablets 10 mg/12.5 mg also contains FD&C Blue No. 2 Aluminum Lake. Lisinopril and hydrochlorothiazide tablets 20

mg/12.5 mg also contains yellow iron oxide and lisinopril and hydrochlorothiazide tablets 20 mg/25 mg also contain red iron oxide.

CLINICAL PHARMACOLOGY

Lisinopril-Hydrochlorothiazide

As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases

serum potassium. Administration of lisinopril blocks the reninangiotensinaldosterone axis and tends to reverse the potassium loss

associated with the diuretic.

In clinical studies, the extent of blood pressure reduction seen with the combination of lisinopril and hydrochlorothiazide was

approximately additive. The lisinopril and hydrochlorothiazide 10 mg/12.5 mg combination worked equally well in Black and Caucasian

patients. The lisinopril and hydrochlorothiazide 20 mg/12.5 mg and lisinopril and hydrochlorothiazide 20 mg/25 mg combinations appeared

somewhat less effective in Black patients, but relatively few Black patients were studied. In most patients, the antihypertensive effect of

lisinopril and hydrochlorothiazide was sustained for at least 24 hours.

In a randomized, controlled comparison, the mean antihypertensive effects of lisinopril and hydrochlorothiazide 20 mg/12.5 mg and

lisinopril and hydrochlorothiazide 20 mg/25 mg were similar, suggesting that many patients who respond adequately to the latter

combination may be controlled with lisinopril and hydrochlorothiazide 20-12.5. (See DOSAGE AND ADMINISTRATION.)

Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the bioavailability of either drug. The combination

tablet is bioequivalent to concomitant administration of the separate entities.

Lisinopril

Mechanism of Action

Lisinopril 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. 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. Removal of angiotensin II

negative feedback on renin secretion leads to increased plasma renin activity. In hypertensive patients with normal renal function treated

with lisinopril alone for up to 24 weeks, the mean increase in serum potassium was less than 0.1 mEq/L; however, approximately 15

percent of patients had increases greater than 0.5 mEq/L and approximately six percent had a decrease greater than 0.5 mEq/L. In the

same study, patients treated with lisinopril plus a thiazide diuretic showed essentially no change in serum potassium.  (See

PRECAUTIONS.)

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 lisinopril remains to be elucidated.

While the mechanism through which lisinopril lowers  blood pressure is believed to be primarily suppression of the renin-angiotensin-

aldosterone system, lisinopril is antihypertensive even in patients with low-renin hypertension. Although lisinopril was antihypertensive in

all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to lisinopril

monotherapy than non-Black patients.

INDICATIONS AND USAGE

Lisinopril and hydrochlorothiazide tablets are indicated for the treatment of hypertension.

These fixed-dose combinations are not indicated for initial therapy (see DOSAGE AND ADMINISTRATION).

In using lisinopril and hydrochlorothiazide tablets, consideration should be given to the fact that an angiotensin converting enzyme

inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that

available data are insufficient to show that lisinopril does not have a similar risk. (See WARNINGS.)

In considering use of lisinopril and hydrochlorothiazide tablets, it should be noted that Black patients receiving ACE inhibitors have been

reported to have a higher incidence of angioedema compared to non- Blacks. (See WARNINGS, Head and Neck Angioedema.)

CONTRAINDICATIONS

Lisinopril and hydrochlorothiazide is contraindicated in patients who are hypersensitive to any component of this product and in patients

with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary

or idiopathic angioedema. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or

hypersensitivity to other sulfonamide-derived drugs.

WARNINGS

GENERAL

Lisinopril

Anaphylactoid and Possibly Related Reactions:

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including

endogenous bradykinin, patients receiving ACE inhibitors (including lisinopril and hydrochlorothiazide) may be subject to a variety of

adverse reactions, some of them serious.

Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in

patients treated with angiotensin converting enzyme inhibitors, including lisinopril. This may occur at any time during treatment. In such

cases lisinopril and hydrochlorothiazide should be promptly discontinued and appropriate therapy and monitoring should be provided until

complete and sustained resolution of signs and symptoms has occurred. ACE inhibitors have been associated with a higher

rate of angioedema in Black than in non-Black patients. Even in those instances where swelling of only the tongue is involved, without

respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be

sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with

involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery.

Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, subcutaneous epinephrine solution 1:1000

(0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided.(See ADVERSE REACTIONS.)

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE

inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS).

Intestinal Angioedema: Intestinal angioedema has been reported 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. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and

symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on

ACE inhibitors presenting with abdominal pain.

Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while

receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when

ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-

flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing

low-density lipoprotein apheresis with dextran sulfate absorption.

Hypotension and Related Effects: Excessive hypotension was rarely seen in uncomplicated hypertensive patients but is a possible

consequence of lisinopril use in salt/volume-depleted persons, such as those treated vigorously with diuretics or patients on dialysis.

(See PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS.)

Syncope has been reported in 0.8 percent of patients receiving lisinopril and hydrochlorothiazide. In patients with hypertension receiving

lisinopril alone, the incidence of syncope was 0.1 percent. The overall incidence of syncope may be reduced by proper titration of the

individual components. (See PRECAUTIONS, Drug Interactions, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.)

In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been

observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. Because of

the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should

be followed closely for the first two weeks of treatment and whenever the dose of lisinopril and/or diuretic is increased. Similar

considerations apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result

in a myocardial infarction or cerebrovascular accident. I

If hypotension occurs, the patient should be placed in supine position and, if  necessary, receive an intravenous infusion of normal saline.

A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood

pressure has increased after volume expansion.

Neutropenia/Agranulocytosis:

Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression,

rarely in uncomplicated patients but more frequently in patients with renal impairment, especially if they also have a collagen vascular

disease. Available data from clinical trials of lisinopril are insufficient to show that lisinopril does not cause agranulocytosis at similar

rates. Marketing experience has revealed rare cases of neutropenia and bone marrow depression in which a causal relationship to

lisinopril cannot be excluded. Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease

should be considered.

Hepatic Failure:

Rarely, 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

follow-up.

Hydrochlorothiazide

Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia.

Cumulative effects of the drug may develop in patients with impaired renal function. Thiazides should be used with caution in patients

with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic

coma.

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

Lithium generally should not be given with thiazides (see PRECAUTIONS, Drug Interactions, Lisinopril and Hydrochlorothiazide).

Pregnancy

Lisinopril-Hydrochlorothiazide

Teratogenicity studies were conducted in mice and rats with up to 90 mg/kg/day of lisinopril in combination with 10 mg/kg/day of

hydrochlorothiazide. This dose of lisinopril is 5 times (in mice) and 10 times (in rats) the maximum recommended human daily dose

(MRHDD) when compared on a body surface area basis (mg/m2); the dose of hydrochlorothiazide is 0.9 times (in mice) and 1.8 times (in

rats) the MRHDD. Maternal or fetotoxic effects were not seen in mice with the combination. In rats decreased maternal weight gain

and decreased fetal weight occurred down to 3/10 mg/kg/day (the lowest dose tested). Associated with the decreased fetal weight was

a delay in fetal ossification. The decreased fetal weight and delay in fetal ossification were not seen in saline-supplemented animals

 given 90/10 mg/kg/day.

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus.

When pregnancy is detected, lisinopril and hydrochlorothiazide should be discontinued as soon as possible. (See Lisinopril,

Fetal/Neonatal Morbidity and Mortality, below.)

Lisinopril

Fetal/Neonatal Morbidity and Mortality: ACE inhibitors can cause fetal and neonatal morbidity and death when administered to

pregnant women. Several dozen cases have been reported in the world literature.  When pregnancy is detected, ACE inhibitors should

be discontinued as soon as possible.

In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor drug during the first trimester of

pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not

undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study

have not yet been repeated.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury,

including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been

reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb

contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent

ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.

These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless,

when patients become pregnant, physicians should make every effort to discontinue the use of lisinopril and hydrochlorothiazide as soon

as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases,

the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to

assess the intraamniotic environment.

If oligohydramnios is observed, lisinopril and hydrochlorothiazide should be discontinued unless it is considered lifesaving for the mother.

Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of

pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained

irreversible injury.

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If

oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may

be required as means of reversing hypotension and/or substituting for disordered renal function. Lisinopril, which crosses the placenta,

has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by

exchange transfusion, although there is no experience with the latter procedure.

No teratogenic effects of lisinopril were seen in studies of pregnant mice, rats, and rabbits. On a body surface area basis, the doses

used were up 55 times, 33 times, and 0.15 times, respectively, the MRHDD.

Hydrochlorothiazide

Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major

organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus. These doses are more

than 150 times the MRHDD on a body surface area basis. Thiazides cross the placental barrier and appear in cord blood. There is a risk

of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults.

PRECAUTIONS

ADVERSE REACTIONS

Lisinopril and hydrochlorothiazide has been evaluated for safety in 930 patients, including 100 patients treated for 50 weeks or more.

In clinical trials with lisinopril and hydrochlorothiazide no adverse experiences peculiar to this combination drug have been observed.

Adverse experiences that have occurred have been limited to those that have been previously reported with lisinopril or

hydrochlorothiazide.

The most frequent clinical adverse experiences in controlled trials (including open label extensions) with any combination of lisinopril and

hydrochlorothiazide were: dizziness (7.5 percent), headache (5.2 percent), cough (3.9 percent), fatigue (3.7 percent) and orthostatic

effects (3.2 percent), all of which were more common than in placebo-treated patients. Generally, adverse experiences were mild and

transient in nature; but see WARNINGS regarding angioedema and excessive hypotension or syncope. Discontinuation of therapy due to

adverse effects was required in 4.4 percent of patients, principally because of dizziness, cough, fatigue and muscle cramps. Adverse

experiences occurring in greater than one percent of patients treated with lisinopril plus hydrochlorothiazide in controlled clinical trials are

shown below.

                            Percent of Patients in Controlled Studies

	Lisinopril-Hydrochlorothiazide (n=930) Incidence (discontinuation)	Placebo (n=207) Incidence
Dizziness	7.5(0.8)	1.9
Headache	5.2(0.3)	19
Cough	3.9(0.6)	1.0
Fatigue	3.7(0.4)	1.0
Orthostatic Effects	3.2(0.1)	1.0
Diarrhea	2.5(0.2)	2.4
Nausea	2.2(0.1)	2.4
Upper Respiratory Infection	2.2(0.0)	0.0
Muscle Cramps	2.0(0.4)	0.5
Asthenia	1.8(0.2)	1.0
Paresthesia	1.5(0.1)	0.0
Hypotension	1.4(0.3)	0.5
Vomiting	1.4(0.1)	0.5
Dyspepsia	1.3(0.0)	0.0
Rash	1.2(0.1)	0.5
Impotence	1.2(0.3)	0.0

Clinical adverse experiences occurring in 0.3 to 1.0 percent of patients in controlled trials included:

Body as a Whole: Chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, virus infection. Cardiovascular: Palpitation,

orthostatic hypotension. Digestive: Gastrointestinal cramps, dry mouth, constipation, heartburn. Musculoskeletal: Back pain, shoulder

pain, knee pain, back strain, myalgia, foot pain. Nervous/Psychiatric: Decreased libido, vertigo, depression, somnolence. Respiratory:

Common cold, nasal congestion, influenza, bronchitis, pharyngeal pain, dyspnea, pulmonary congestion, chronic sinusitis, allergic rhinitis,

pharyngeal discomfort. Skin: Flushing, pruritus, skin inflammation, diaphoresis. Special Senses: Blurred vision, tinnitus, otalgia.

Urogenital: Urinary tract infection.

Angioedema: Angioedema has been reported in patients receiving lisinopril and hydrochlorothiazide, with an incidence higher in Black

than in non-Black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips,

tongue, glottis and/or larynx occurs, treatment with lisinopril and hydrochlorothiazide should be discontinued and appropriate therapy

instituted immediately. In rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors including

lisinopril. (See WARNINGS.)

Hypotension: In clinical trials, adverse effects relating to hypotension occurred as follows: hypotension (1.4), orthostatic hypotension

(0.5), other orthostatic effects (3.2). In addition syncope occurred in 0.8 percent of patients. (See WARNINGS.)

Cough: See PRECAUTIONS, Cough.

Clinical Laboratory Test Findings

Serum Electrolytes: See PRECAUTIONS.

Creatinine, Blood Urea Nitrogen: Minor reversible increases in blood urea nitrogen and serum creatinine were observed in patients

with essential hypertension treated with lisinopril and hydrochlorothiazide. More marked increases have also been reported and were

more likely to occur in patients with renal artery stenosis. (See PRECAUTIONS.)

Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: See PRECAUTIONS.

Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.5 g percent and 1.5

vol percent, respectively) occurred frequently in hypertensive patients treated with lisinopril and hydrochlorothiazide but were rarely of

clinical importance unless another cause of anemia coexisted. In clinical trials, 0.4 percent of patients discontinued therapy due to anemia.

Liver Function Tests:Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (see WARNINGS, Hepatic Failure).

Other adverse reactions that have been reported with the individual components are listed below:

Lisinopril — In clinical trials adverse reactions which occurred with lisinopril were also seen with lisinopril and hydrochlorothiazide. In

addition, and since lisinopril has been marketed, the following adverse reactions have been reported with lisinopril and should be

considered potential adverse reactions for lisinopril and hydrochlorothiazide: Body as a Whole: Anaphylactoid reactions (see

WARNINGS, Anaphylactoid and Possibly Related Reactions), malaise, edema, facial edema, pain, pelvic pain, flank pain, chills;

Cardiovascular: Cardiac arrest, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in

high risk patients (see WARNINGS, Hypotension), pulmonary embolism and infarction, worsening of heart failure, arrhythmias (including

tachycardia, ventricular tachycardia, atrial tachycardia, atrial fibrillation, bradycardia, and premature ventricular contractions), angina

pectoris, transient ischemic attacks, paroxysmal nocturnal dyspnea, decreased blood pressure, peripheral edema,

vasculitis; Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (see WARNINGS, Hepatic Failure), gastritis,

anorexia, flatulence, increased salivation; Endocrine: Diabetes mellitus, syndrome of inappropriate antidiuretic hormone secretion

(SIADH) Hematologic: Rare cases of neutropenia, thrombocytopenia, and bone marrow depression have been reported. Hemolytic

anemia has been reported; a causal relationship to lisinopril cannot be excluded; Metabolic: Gout, weight loss, dehydration, fluid

overload, weight gain; Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, joint pain, leg pain, arm pain, lumbago; Nervous

System/Psychiatric: Ataxia, memory impairment, tremor, insomnia, stroke, nervousness, confusion, peripheral neuropathy (e.g.,

paresthesia, dysesthesia), spasm, hypersomnia, irritability; Respiratory: Malignant lung neoplasms, hemoptysis, pulmonary edema,

pulmonary infiltrates, eosinophilic pneumonitis, bronchospasm, asthma, pleural effusion, pneumonia, wheezing, orthopnea, painful

respiration, epistaxis, laryngitis, sinusitis, pharyngitis, rhinitis, rhinorrhea, chest sound abnormalities; Skin: Urticaria, alopecia, herpes

zoster, photosensitivity, skin lesions, skin infections, pemphigus, erythema. Other severe skin reactions (including toxic epidermal

necrolysis, Stevens-Johnson syndrome and cutaneous pseudolymphoma) have been reported rarely; causal relationship has not been

established; Special Senses: Visual loss, diplopia, photophobia, taste disturbances; Urogenital: Acute renal failure,oliguria, anuria,

 uremia, progressive azotemia, renal dysfunction (see PRECAUTIONS and DOSAGE AND ADMINISTRATION), pyelonephritis, dysuria,

breast pain. 

Miscellaneous: A symptom complex has been reported which may include a positive ANA, an elevatederythrocyte

sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, leukocytosis, eosinophilia,photosensitivity, rash, and other dermatological

manifestations. 

Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Pregnancy, Lisinopril, Fetal/Neonatal Morbidity and

Mortality.

Hydrochlorothiazide

Body as a Whole: Weakness; Digestive: Anorexia, gastric irritation, cramping, jaundice (intrahepatic cholestatic jaundice), pancreatitis,

sialadenitis, constipation; Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia;

Musculoskeletal: Muscle spasm; Nervous System/ Psychiatric: Restlessness; Renal: Renal failure, renal dysfunction,

interstitial nephritis (see WARNINGS); Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including

toxic epidermal necrolysis, alopecia; Special Senses: Xanthopsia; Hypersensitivity: Purpura, photosensitivity, urticaria, necrotizing

angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions.

OVERDOSAGE

No specific information is available on the treatment of overdosage with lisinopril and hydrochlorothiazide. Treatment is symptomatic and

supportive. Therapy with lisinopril and hydrochlorothiazide should be discontinued and the patient observed closely. Suggested measures

include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established

procedures.

Lisinopril

Following a single oral dose of 20 mg/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.

Lisinopril can be removed by hemodialysis. (See WARNINGS, Anaphylactoid reactions during membrane exposure.)

Hydrochlorothiazide

Oral administration of a single oral dose of 10 mg/kg to mice and rats was not lethal. The most common signs and symptoms observed 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.

DOSAGE AND ADMINISTRATION

Lisinopril is an effective treatment of hypertension in once-daily doses of 10 to 80 mg, while hydrochlorothiazide is effective in doses of

12.5 to 50 mg. In clinical trials of lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of 10 to 80 mg and

hydrochlorothiazide doses of 6.25 to 50 mg, the antihypertensive response rates generally increased with increasing dose of either

component.

The side effects (see WARNINGS) of lisinopril are generally rare and apparently independent of dose; those of  hydrochlorothiazide are a

mixture of dose-dependent phenomena (primarily hypokalemia) and doseindependent phenomena (e.g.,  pancreatitis), the former much

more common than the latter. Therapy with any combination of lisinopril and hydrochlorothiazide will be  associated with both sets of

dose-independent side effects, but addition of lisinopril in clinical trials blunted the hypokalemia normally seen with diuretics.

To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve

the desired effect with monotherapy.

Dose Titration Guided by Clinical Effect

A patient whose blood pressure is not adequately controlled with either lisinopril or hydrochlorothiazide monotherapy may be switched to

lisinopril and hydrochlorothiazide tablets 10 mg/12.5 mg or lisinopril and hydrochlorothiazide tablets 20 mg/12.5 mg. Further increases of

either or both components could depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2-3

weeks have elapsed. Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide, but who

experience significant potassium loss with this regimen, may achieve similar or greater blood pressure control with less potassium loss if

they are switched to lisinopril and hydrochlorothiazide tablets 10 mg/12.5 mg. Dosage higher than lisinopril 80 mg and hydrochlorothiazide

50 mg should not be used.

Replacement Therapy

The combination may be substituted for the titrated individual components.

Use in Renal Impairment

The usual regimens of therapy with lisinopril and hydrochlorothiazide tablets need not be adjusted as long as the patient’s creatinine

clearance is >30 mL/min/1.73 m2 (serum creatinine approximately ≤3 mg/dL or 265 μmol/L). In patients with more severe renal impairment,

loop diuretics are preferred to thiazides, so lisinopril and hydrochlorothiazide tablets are not recommended (see WARNINGS,

Anaphylactoid reactions during membrane exposure).

HOW SUPPLIED

Lisinopril and Hydrochlorothiazide Tablets USP, 10 mg/12.5 mg are blue, hexagonal tablets, with “LL” debossed on one side and “B01” on

other side.

They are supplied as follows:

NDC 54458-907-02 – in an adherence package of 30 tablets

Lisinopril and Hydrochlorothiazide Tablets USP, 20 mg/25 mg are peach, round tablets, with “LL” debossed on one side and “B03” on

other side.

They are supplied as follows:

NDC 54458-910-02 – in an adherence package of 30 tablets

Storage

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Protect from excessive light and humidity.

                                                                                Manufactured by:

                                                                                Lupin Limited

                                                                                    Goa 403 722

                                                                                        INDIA.

                                                                                            or

                                                                                   Lupin Limited

                                                                            Pithampur (M.P.) 454 775

                                                                                        INDIA.

                                                                                Packaged by:

                                                                            International Labs, Inc.

                                                                            St. Petersburg, FL 33710

                                                                                   Distributed by:

                                                                                   The Kroger Co.

                                                                                Cincinnati, OH 45202

Rev. 01/12                                                                                                                                                                    LI0047

PRINCIPAL DISPLAY PANEL

Lisinopril and Hydrochlorothiazide carton

 

PRINCIPAL DISPLAY PANEL

 

Lisinopril and Hydrochlorothiazide carton