LISINOPRIL-HYDROCHLOROTHIAZIDE TABLETS

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-Hydrochlorothiazide Tablets should be discontinued as soon as possible. See WARNINGS, Pregnancy, Lisinopril, Fetal/Neonatal Morbidity and Mortality.

Lisinopril-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 molecular 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 molecular formula is C₇H₈ClN₃O₄S₂ and its structural formula is:

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

Lisinopril-hydrochlorothiazide tablets are available for oral use in three tablet combinations of lisinopril with hydrochlorothiazide: Lisinopril-hydrochlorothiazide tablets 10-12.5 mg containing 10 mg lisinopril and 12.5 mg hydrochlorothiazide; Lisinopril-hydrochlorothiazide tablets 20-12.5 mg containing 20 mg lisinopril and 12.5 mg hydrochlorothiazide; and, Lisinopril-hydrochlorothiazide tablets 20-25 mg containing 20 mg lisinopril and 25 mg hydrochlorothiazide.

Inactive ingredients are dibasic calcium phosphate, magnesium stearate, mannitol, pregelatinized starch and starch (corn). Lisinopril-hydrochlorothiazide tablets 10-12.5 mg also contain FD&C blue #2 aluminum lake. Lisinopril-hydrochlorothiazide tablets 20-12.5 mg contain yellow iron oxide. Lisinopril-hydrochlorothiazide tablets 20-25 mg contain yellow and red iron oxide.

As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium. Administration of lisinopril blocks the renin-angiotensin aldosterone 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-hydrochlorothiazide tablets 10-12.5 mg combination worked equally well in black and white patients. The lisinopril-hydrochlorothiazide tablets 20-12.5 and lisinopril-hydrochlorothiazide tablet 20-25 mg combinations appeared somewhat less effective in black patients, but relatively few black patients were studied. In most patients, the antihypertensive effect of lisinopril-hydrochlorothiazide was sustained for at least 24 hours.

In a randomized, controlled comparison, the mean antihypertensive effects of Lisinopril-hydrochlorothiazide tablets 20-12.5 mg and lisinopril-hydrochlorothiazide tablets 20-25 mg were similar, suggesting that many patients who respond adequately to the latter combination may be controlled with lisinopril-hydrochlorothiazide tablets 20-12.5 mg. (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.

The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not usually affect normal blood pressure.

Hydrochlorothiazide is a diuretic and antihypertensive. It affects the distal renal tubular mechanism of electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.

After oral use diuresis begins within two hours, peaks in about four hours and lasts about 6 to 12 hours.

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier.

Lisinopril-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-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 the use of lisinopril-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, Angioedema).

Lisinopril-hydrochlorothiazide tablets 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.

When administered concurrently the following drugs may interact with thiazide diuretics.

Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS, Pregnancy, Lisinopril, Fetal/Neonatal Morbidity and Mortality.

It is not known whether lisinopril is excreted in human milk. However, milk of lactating rats contains radioactivity following administration of ¹⁴C lisinopril. In another study, lisinopril was present in rat milk at levels similar to plasma levels in the dams. Thiazides do appear in human milk. Because of the potential for serious adverse reactions in nursing infants from ACE inhibitors and hydrochlorothiazide, a decision should be made whether to discontinue nursing and/or discontinue lisinopril-hydrochlorothiazide tablets, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established.

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

In clinical trials with lisinopril-hydrochlorothiazide tablets 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 hydrochloro-thiazide in controlled clinical trials are shown below.

Clinical adverse experiences occurring in 0.3 to 1.0 percent of patients in controlled clinical 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-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-hydrochlorothiazide tablets should be discontinued and appropriate therapy instituted immediately. (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.

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

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 Reaction During Membrane Exposure).

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.

Lisinopril is an effective treatment of hypertension in once-daily doses of 10-80 mg, while hydrochlorothiazide is effective in doses of 12.5-50 mg per day. In clinical trials of lisinopril-hydrochlorothiazide combination therapy using lisinopril doses of 10-80 mg and hydrochlorothiazide doses of 6.25-50 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 dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of lisinopril and hydrochlorothiazide may 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.

A patient whose blood pressure is not adequately controlled with either lisinopril or hydrochlorothiazide monotherapy may be switched to lisinopril-hydrochlorothiazide tablets 10-12.5 mg or lisinopril-hydrochlorothiazide tablets 20-12.5 mg. Further increases of either or both components should 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-hydrochlorothiazide tablets 10-12.5 mg.

The combination may be substituted for the titrated individual components.

The usual regimens of therapy with lisinopril-hydrochlorothiazide tablets need not be adjusted as long as the patient's creatinine clearance is > 30 mL/min/1.73 m² (serum creatinine roughly ≤ 3 mg/dL or 265 mcmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so lisinopril-hydrochlorothiazide tablets is not recommended (see WARNINGS, Anaphylactoid reactions during membrane exposure).

In general, blood pressure response and adverse experiences were similar in younger and older patients given lisinopril-hydrochlorothiazide tablets. However, in a multiple dose pharmacokinetic study in elderly versus young patients using the lisinopril-hydrochlorothiazide combination, area under the plasma concentration time curve (AUC) increased approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older patients. Therefore, dosage adjustments in elderly patients should be made with particular caution.

Lisinopril-hydrochlorothiazide tablets 10-12.5 mg are blue, round, flat face, beveled edge tablets debossed with “RX536” on one side and plain on the other side. Each tablet contains 10 mg of lisinopril and 12.5 mg of hydrochlorothiazide.

They are supplied as follows:

Bottles of 100 (NDC 63304-536-01)

Bottles of 500 (NDC 63304-536-05)

Lisinopril-hydrochlorothiazide tablets 20-12.5 mg are yellow, round, flat face, beveled edge tablets debossed with “RX537” on one side and plain on the other side. Each tablet contains 20 mg of lisinopril and 12.5 mg of hydrochlorothiazide.

They are supplied as follows:

Bottles of 100 (NDC 63304-537-01)

Bottles of 500 (NDC 63304-537-05)

Lisinopril-hydrochlorothiazide tablets 20-25 mg are light peach, round, flat face, beveled edge tablets debossed with “RX538” on one side and plain on the other side. Each tablet contains 20 mg of lisinopril and 25 mg of hydrochlorothiazide.

They are supplied as follows:

Bottles of 100 (NDC 63304-538-01)

Bottles of 500 (NDC 63304-538-05)

Storage

Store at 20 - 25° C (68 - 77° F). (See USP Controlled Room Temperature).

Protect from excessive light and humidity.

Dispense in a well closed container, if product package is subdivided.

Manufactured for:

Ranbaxy Pharmaceuticals Inc.

Jacksonville, FL 32257 USA

by: Ohm Laboratories Inc.

North Brunswick, NJ 08902 USA

November 2006