DESCRIPTION
Lisinopril and hydrochlorothiazide 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 C
21H
31N
3O
5 • 2H
2O and its structural formula is:
Lisinopril USP is a white to off-white, crystalline powder, with a molecular weight of 441.53. 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 C
7H
8ClN
3O
4S
2 and its structural formula is:
Hydrochlorothiazide USP is a white, or practically white, crystalline powder with a molecular weight of 297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
Lisinopril and hydrochlorothiazide is available for oral use in three tablet combinations of lisinopril with hydrochlorothiazide: lisinopril and hydrochlorothiazide tablets USP, 10 mg/12.5 mg containing 10 mg lisinopril USP and 12.5 mg hydrochlorothiazide USP; lisinopril and hydrochlorothiazide tablets USP, 20 mg/12.5 mg containing 20 mg lisinopril USP and 12.5 mg hydrochlorothiazide USP; and, lisinopril and hydrochlorothiazide tablets USP, 20 mg/25 mg, containing 20 mg lisinopril USP and 25 mg hydrochlorothiazide USP.
Inactive ingredients are dibasic calcium phosphate, magnesium stearate, mannitol, pregelatinized starch and starch. Lisinopril and hydrochlorothiazide 10 mg/12.5 mg and lisinopril and hydrochlorothiazide 20 mg/25 mg also contains ferric oxide red and ferric oxide yellow. Lisinopril and hydrochlorothiazide 20 mg/12.5 mg also contains ferric oxide yellow.
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%), 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 and 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
|
Fatigue
| 3.7 (0.4)
| 1
|
Orthostatic Effects
| 3.2 (0.1)
| 1
|
Diarrhea
| 2.5 (0.2)
| 2.4
|
Nausea
| 2.2 (0.1)
| 2.4
|
Upper Respiratory Infection
| 2.2 (0)
| 0
|
Muscle Cramps
| 2 (0.4)
| 0.5
|
Asthenia
| 1.8 (0.2)
| 1
|
Paresthesia
| 1.5 (0.1)
| 0
|
Hypotension
| 1.4 (0.3)
| 0.5
|
Vomiting
| 1.4 (0.1)
| 0.5
|
Dyspepsia
| 1.3 (0)
| 0
|
Rash
| 1.2 (0.1)
| 0.5
|
Impotence
| 1.2 (0.3)
| 0
|
Clinical adverse experiences occurring in 0.3% to 1% 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);
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, 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.
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) (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.
DOSAGE AND ADMINISTRATION
Lisinopril monotherapy is an effective treatment of hypertension in once-daily doses of 10 to 80 mg, while hydrochlorothiazide monotherapy is effective in doses of 12.5 to 50 mg per day. In clinical trials of lisinopril and hydrochlorothiazide combination therapy using lisinopril doses of 10 to 80 mg and hydrochlorothiazide doses of 6.25 to 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 either or both dose-independent or dose-dependent side effects, but addition of lisinopril in clinical trials blunted the hypokalemia normally seen with diuretics.
To minimize dose-dependent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.
Dose Titration Guided by Clinical Effect
A patient whose blood pressure is not adequately controlled with either lisinopril or hydrochlorothiazide monotherapy may be switched to lisinopril and hydrochlorothiazide tablets 10 mg/12.5 mg or lisinopril and hydrochlorothiazide tablets 20 mg/12.5 mg, depending on current monotherapy dose. Further increases of either or both components should depend on clinical response with blood pressure measured at the interdosing interval to ensure that there is an adequate antihypertensive effect at that time. The hydrochlorothiazide dose should generally not be increased until 2 to 3 weeks have elapsed. After addition of the diuretic it may be possible to reduce the dose of lisinopril. 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 without electrolyte disturbance if they are switched to lisinopril and hydrochlorothiazide tablets 10 mg/12.5 mg.
In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of lisinopril. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with lisinopril to reduce the likelihood of hypotension. (See
WARNINGS.) If the patient’s blood pressure is not controlled with lisinopril alone, diuretic therapy may be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg of lisinopril should be used under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see
WARNINGS and
PRECAUTIONS, Drug Interactions).
Concomitant administration of lisinopril and hydrochlorothiazide tablets with potassium supplements, potassium salt substitutes or potassium-sparing diuretics may lead to increases of serum potassium (see
PRECAUTIONS).
Replacement Therapy
The combination may be substituted for the titrated individual components.
Use in Renal Impairment
Regimens of therapy with lisinopril and hydrochlorothiazide tablets need not take account of renal function as long as the patient’s creatinine clearance is >30 mL/min/1.7 m
2 (serum creatinine roughly =3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so lisinopril and hydrochlorothiazide tablets are not recommended (see
WARNINGS, Anaphylactoid Reactions During Membrane Exposure).