FDA label f19695c2-e2df-4059-9ec1-98c498baad15

USE IN PREGNANCY 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 WARNINGS, Pregnancy Lisinopril, Fetal/Neonatal Morbidity and Mortality .

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. 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. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have be useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there involvement of the tongue, glottis or Iarynx, 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 at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS ). 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. 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 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/m 2 ); 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. 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.

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 Linopril-Hydrochlorothiazide (n=930) Placebo Incidence (n=207) (discontinuation) Incidence Dizziness 7.5 (0.8) 1.9 Headache 5.2 (0.3) 1.9 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) 05 Asthenia 1.8 (0.2) 1.0 Paresthesia 1.5 (0.1) 0.0 Hypotension 1.4 (0.3) 0.5 Vomiting 1.4 (01) 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. (See WARNINGS . ) In rare cases, intestinal angioedema has been reported with angiotension 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 hydrochloro-thiazide. 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 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; 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 and Stevens-Johnson syndrome) 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 elevated erythrocyte 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.

<table ID="t300" width="100%"> <caption>Percent of Patients in Controlled Studies Linopril-Hydrochlorothiazide</caption> <col align="left" width="42.167%"/> <col align="left" width="39.700%"/> <col align="left" width="18.133%"/> <tbody> <tr> <td align="left" valign="top"/> <td align="center" valign="top">(n=930)</td> <td align="center" valign="top">Placebo</td> </tr> <tr> <td align="left" valign="top"/> <td align="center" valign="top">Incidence</td> <td align="center" valign="top">(n=207)</td> </tr> <tr> <td align="left" valign="top"/> <td align="center" valign="top">(discontinuation)</td> <td align="center" valign="top">Incidence</td> </tr> <tr> <td align="left" valign="top">Dizziness</td> <td align="center" valign="top">7.5 (0.8)</td> <td align="center" valign="top">1.9</td> </tr> <tr> <td align="left" valign="top">Headache</td> <td align="center" valign="top">5.2 (0.3)</td> <td align="center" valign="top">1.9</td> </tr> <tr> <td align="left" valign="top">Cough</td> <td align="center" valign="top">3.9 (0.6)</td> <td align="center" valign="top">1.0</td> </tr> <tr> <td align="left" valign="top">Fatigue</td> <td align="center" valign="top">3.7 (0.4)</td> <td align="center" valign="top">1.0</td> </tr> <tr> <td align="left" valign="top">Orthostatic Effects</td> <td align="center" valign="top">3.2 (0.1)</td> <td align="center" valign="top">1.0</td> </tr> <tr> <td align="left" valign="top">Diarrhea</td> <td align="center" valign="top">2.5 (0.2)</td> <td align="center" valign="top">2.4</td> </tr> <tr> <td align="left" valign="top">Nausea</td> <td align="center" valign="top">2.2 (0.1)</td> <td align="center" valign="top">2.4</td> </tr> <tr> <td align="left" valign="top">Upper Respiratory Infection</td> <td align="center" valign="top">2.2 (0.0)</td> <td align="center" valign="top">0.0</td> </tr> <tr> <td align="left" valign="top">Muscle Cramps</td> <td align="center" valign="top">2.0 (0.4)</td> <td align="center" valign="top">05</td> </tr> <tr> <td align="left" valign="top">Asthenia</td> <td align="center" valign="top">1.8 (0.2)</td> <td align="center" valign="top">1.0</td> </tr> <tr> <td align="left" valign="top">Paresthesia</td> <td align="center" valign="top">1.5 (0.1)</td> <td align="center" valign="top">0.0</td> </tr> <tr> <td align="left" valign="top">Hypotension</td> <td align="center" valign="top">1.4 (0.3)</td> <td align="center" valign="top">0.5</td> </tr> <tr> <td align="left" valign="top">Vomiting</td> <td align="center" valign="top">1.4 (01)</td> <td align="center" valign="top">0.5</td> </tr> <tr> <td align="left" valign="top">Dyspepsia</td> <td align="center" valign="top">1.3 (0.0)</td> <td align="center" valign="top">0.0</td> </tr> <tr> <td align="left" valign="top">Rash</td> <td align="center" valign="top">1.2 (0.1)</td> <td align="center" valign="top">0.5</td> </tr> <tr> <td align="left" valign="top">Impotence</td> <td align="center" valign="top">1.2 (0.3)</td> <td align="center" valign="top">0.0</td> </tr> </tbody> </table>