Lisinopril and Hydrochlorothiazide (Page 5 of 7)

Hydrochlorothiazide

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

Alcohol, barbiturates, or narcotics — potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin) — dosage adjustment of the antidiabetic drug may be required.

Other antihypertensive drugs — additive effect or potentiation.

Cholestyramine and colestipol resins — Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Corticosteroids, ACTH — intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., norepinephrine) — possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) — possible increased responsiveness to the muscle relaxant.

Lithium — should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with lisinopril and hydrochlorothiazide.

Non-Steroidal Anti-inflammatory Drugs — In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when lisinopril and hydrochlorothiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of lisinopril and hydrochlorothiazide is obtained.

Gold — Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including lisinopril and hydrochlorothiazide.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lisinopril and Hydrochlorothiazide

Lisinopril in combination with hydrochlorothiazide was not mutagenic in a microbial mutagen test using Salmonella typhimurium (Ames test) or Escherichia coli with or without metabolic activation or in a forward mutation assay using Chinese hamster lung cells. Lisinopril and hydrochlorothiazide did not produce DNA single strand breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, it 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.

Lisinopril

There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg/kg/day (about 56 or 9 times* the maximum daily human dose, based on body weight and body surface area, respectively). There was no evidence of carcinogenicity when lisinopril was administered for 92 weeks to (male and female) mice at doses up to 135 mg/kg/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.

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

Lisinopril 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. Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril 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/kg/day of lisinopril. This dose is 188 times and 30 times the maximum daily human dose based on mg/kg and mg/m² , respectively.

Hydrochlorothiazide

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). These doses are 150 times and 12 times for mice and 25 times and 4 times for rats the maximum human daily dose based on mg/kg and mg/m² , respectively. The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 mcg/mL to 1300 mcg/mL, and in the Aspergillus nidulans nondisjunction assay at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation. In mice this dose is 25 times and 2 times the maximum daily human dose based on mg/kg and mg/m² , respectively. In rats this dose is 1 times and 0.2 times the maximum daily human dose based on mg/kg and mg/m² , respectively.

Nursing Mothers

It is not known whether lisinopril is excreted in human milk. However, milk of lactating rats contains radioactivity following administration of ¹⁴ C 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 and hydrochlorothiazide, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a history of in utero exposure to lisinopril and hydrochlorothiazide:

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. 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.

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of lisinopril and hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Evaluation of the hypertensive patient should always include assessment of renal function.

ADVERSE REACTIONS

Lisinopril and hydrochlorothiazide have 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%), headache (5.2%), cough (3.9%), fatigue (3.7%) and orthostatic effects (3.2%), 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 % 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)	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)	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 % of patients in controlled trials and rarer, serious, possibly drug-related events reported in marketing experience are listed below:

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, cutaneous pseudolymphoma. Special Senses: Blurred vision, tinnitus, otalgia. Urogenital: Urinary tract infection.

Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (See WARNINGS).

In rare cases, intestinal angioedema has been reported in post marketing experience.

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% of patients. (See WARNINGS).

Cough: See PRECAUTIONS, Cough.