Lisinopril and Hydrochlorothiazide (Page 4 of 5)

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.

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 % and 1.5 vol %, 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 % 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 REACTIONS DURING MEMBRANE EXPOSURE), 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, inappropriate antidiuretic hormone secretion. Hematologic: Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia and thrombocytopenia have been reported in which a causal relationship to lisinopril can not 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, mood alterations (including depressive symptoms); hallucinations; Respiratory: Malignant lung neoplasms, hemoptysis, pulmonary edema, pulmonary infiltrates, bronchospasm, asthma, pleural effusion, pneumonia, eosinophilic pneumonitis, 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, psoriasis, rare cases of other severe skin reactions including toxic epidermal necrolysis and Stevens-Johnson Syndrome (causal relationship has not been established); Special Senses: Visual loss, diplopia, photophobia, taste alteration, olfactory disturbance; 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, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur alone or in combination with these symptoms.

Hydrochlorothiazide

Body as a Whole: Weakness; Digestive: Anorexia, gastric irritation, cramping, jaundice (intrahepatic cholestatic jaundice) (See WARNINGS, Hepatic Failure), pancreatitis, sialoadenitis, 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.