ADVERSE REACTIONS
PRINZIDE has been evaluated for safety in 930 patients, including 100 patients treated for 50 weeks or more.
In clinical trials with PRINZIDE 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) | 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 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 PRINZIDE, 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 PRINZIDE 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 PRINZIDE. 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 PRINZIDE 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 PRINZIDE. 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 PRINZIDE: 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 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.
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