Product Monograph - Prinivil (Merck Canada, 5 mg)
INDICATIONS AND CLINICAL USE
Hypertension
PRINIVIL® (lisinopril tablets) is indicated in the treatment of essential hypertension and in renovascular hypertension. It may be used alone or concomitantly with thiazide diuretics. A great majority of patients (>80%) with severe hypertension required combination therapy. PRINIVIL® has been used concomitantly with beta-blockers and calcium antagonists, but the data on such use are limited.
Heart Failure
PRINIVIL® is indicated in the management of symptomatic congestive heart failure as adjunctive treatment with diuretics and, where appropriate, digitalis. Treatment with PRINIVIL® should be initiated under close medical supervision, usually in a hospital.
Treatment Following Acute Myocardial Infarction
PRINIVIL® is indicated in the treatment of hemodynamically stable patients as early as within 24 hours following acute myocardial infarction, to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, ASA and beta-blocker(s).
Therapy with PRINIVIL® should be reassessed after six weeks. If there is no evidence of symptomatic or asymptomatic left ventricular dysfunction, treatment with PRINIVIL® can be stopped.
PRINIVIL® should not be used if systolic blood pressure is less than 100 mmHg, if clinically relevant renal failure is present, if there is a history of bilateral stenosis of the renal arteries (see PRECAUTIONS, Hypotension Following Acute Myocardial Infarction, Renal Impairment).
In using PRINIVIL®, attention should be given to the risk of angioedema (see WARNINGS).
CONTRAINDICATIONS
PRINIVIL® (lisinopril tablets) is contraindicated in patients who:
- are hypersensitive to any component of this product;
- have a history of angioneurotic edema relating to previous treatment with an angiotensin-converting enzyme inhibitor;
- have hereditary or idiopathic angioedema.
Concomitant use of angiotensin-converting enzyme inhibitors (ACEIs) – including PRINIVIL® – with aliskiren-containing drugs in patients with diabetes mellitus (type 1 or type 2) or moderate to severe renal impairment (GFR <60 ml/min/1.73 m2) is contraindicated (see WARNINGS, Dual Blockade of the Renin-Angiotensin System (RAS), PRECAUTIONS, Renal Impairment, and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) with ACEIs, ARBs or aliskiren-containing drugs).
WARNINGS
Serious Warnings and Precautions
- When used in pregnancy, angiotensin-converting enzyme (ACE) inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected, PRINIVIL® should be discontinued as soon as possible.
Angioedema
Angioedema has been reported in patients treated with PRINIVIL® (lisinopril tablets). This may occur at any time during treatment. Angioedema associated with shock may be fatal. If angioedema occurs, PRINIVIL® should be promptly discontinued and the patient should be observed until the swelling subsides. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. When there is airway obstruction, emergency therapy should be administered promptly when indicated. This includes giving subcutaneous adrenaline (0.5 mL 1:1000), and/or maintaining a patent airway. The patient should be under close medical supervision until complete and sustained symptom resolution has occurred.
The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in Black than in non-Black patients.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see CONTRAINDICATIONS).
Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema. Caution should be used when these drugs are used concomitantly.
Hypotension
Symptomatic hypotension has occurred after administration of PRINIVIL®, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, vomiting, or possibly in patients with renin-dependent renovascular hypertension (see 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 blood pressure could potentially fall, patients at risk for hypotension should start therapy under very close medical supervision, usually in a hospital. 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 (see ADVERSE REACTIONS).
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 may not be a contraindication to further doses. These can usually be given to hypertensive patients without difficulty once the blood pressure has increased after volume expansion. However, lower doses of PRINIVIL® and/or reduced concomitant diuretic therapy should be considered.
If hypotension occurs during treatment following acute myocardial infarction, consideration should be given to PRINIVIL® discontinuation (see ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION, Treatment Following Acute Myocardial Infarction).
In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with PRINIVIL®. If hypotension occurs, a reduction of dose or discontinuation of therapy should be considered.
Dual Blockade of the Renin-Angiotensin System (RAS)
There is evidence that co-administration of angiotensin-converting enzyme inhibitors (ACEIs), such as PRINIVIL®, or of angiotensin receptor antagonists (ARBs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal impairment (GFR <60 ml/min/1.73 m2). Therefore, the use of PRINIVIL® in combination with aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS). Further, co-administration of ACEIs, including PRINIVIL®, with other agents blocking the RAS, such as ARBs or aliskiren-containing drugs, is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia.
Neutropenia/Agranulocytosis
Agranulocytosis and bone marrow depression have been caused by angiotensin-converting enzyme inhibitors. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to lisinopril cannot be excluded. Current experience with the drug shows the incidence to be rare. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and renal disease.
Use in Pregnancy
ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, PRINIVIL® 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, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.
Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have also been reported following exposure in the first trimester of pregnancy.
Infants with a history 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 a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.
Lisinopril has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit and may, theoretically be removed by exchange transfusion, although there is no experience with the latter procedure.
Animal Data: Lisinopril was not teratogenic in mice treated on days 6–15 of gestation with up to 1000 mg/kg/day (625 times the maximum recommended human dose). There was an increase in fetal resorptions at doses down to 100 mg/kg; at doses of 1000 mg/kg this was prevented by saline supplementation. There was no fetotoxicity or teratogenicity in rats treated with up to 300 mg/kg/day (188 times the maximum recommended dose) of lisinopril at days 6–17 of gestation. In rats receiving lisinopril from day 15 of gestation through day 21 postpartum, there was an increased incidence in pup deaths on days 2–7 postpartum and a lower average body weight of pups on day 21 postpartum. The increase in pup deaths and decrease in pup weight did not occur with maternal saline supplementation.
Lisinopril, at doses up to 1 mg/kg/day, was not teratogenic when given throughout the organogenic period in saline supplemented rabbits. Saline supplementation (physiologic saline in place of tap water) was used to eliminate maternotoxic effects and enable evaluation of the teratogenic potential at the highest possible dosage level. The rabbit has been shown to be extremely sensitive to angiotensin-converting enzyme inhibitors (captopril and enalapril) with maternal and fetotoxic effects apparent at or below the recommended therapeutic dosage levels in man.
Fetotoxicity was demonstrated in rabbits by an increased incidence of fetal resorptions at an oral dose of lisinopril of 1 mg/kg/day and by an increased incidence of incomplete ossification at the lowest dose tested (0.1 mg/kg/day). A single intravenous dose of 15 mg/kg of lisinopril administered to pregnant rabbits on gestation days 16, 21 or 26 resulted in 88% to 100% fetal death.
By whole body autoradiography, radioactivity was found in the placenta following administration of labelled lisinopril to pregnant rats, but none was found in the fetuses.
Use in Nursing Mothers
The presence of concentrations of ACE inhibitor have been reported in human milk. Use of ACE inhibitors is not recommended during breast-feeding.
PRECAUTIONS
Renal Impairment
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.
The use of ACEIs – including PRINIVIL® – or ARBs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR <60 ml/min/1.73 m2) (see CONTRAINDICATIONS and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) with ACEIs, ARBs or aliskiren-containing drugs).
In acute myocardial infarction, treatment with lisinopril should not be initiated in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 177 µmol/L and/or proteinuria exceeding 500 mg/24 hour. If renal dysfunction develops during treatment with PRINIVIL® (lisinopril tablets) (serum creatinine concentration exceeding 265 µmol/L or a doubling from the pre-treatment value), then the physician should consider withdrawal of PRINIVIL®.
Use of PRINIVIL® should include appropriate assessment of renal function.
Hypotension Following Acute Myocardial Infarction
Lisinopril treatment following acute myocardial infarction must not be initiated in patients at risk of further serious hemodynamic deterioration after vasodilator treatment. These include patients with systolic blood pressure of 100 mmHg or lower or those in cardiogenic shock.
During the first three days following the infarction, dosage reduction should occur if systolic blood pressure is between 100 and 120 mmHg (see DOSAGE AND ADMINISTRATION, Treatment Following Acute Myocardial Infarction).
Patients with myocardial infarction in the GISSI-3 study treated with PRINIVIL® had a higher (9.0% vs 3.7%) incidence of persistent hypotension (systolic blood pressure less than 90 mmHg for more than 1 hour) than patients treated with placebo.
Hyperkalemia
In clinical trials hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 2.2% of hypertensive patients and 4.0% of patients with congestive heart failure. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in approximately 0.1% of hypertensive patients. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes (see also DRUG INTERACTIONS, Agents Increasing Serum Potassium).
The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalemia can cause serious, sometimes fatal, arrhythmias.
If concomitant use of PRINIVIL® and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.
Hypoglycemia
Diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor should be told to closely monitor for hypoglycemia, especially during the first month of combined use. In addition, hypoglycemia appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment (see DRUG INTERACTIONS).
Valvular Stenosis, Hypertrophic Cardiomyopathy
There is concern on theoretical grounds that patients with aortic stenosis or hypertrophic cardiomyopathy might be at particular risk of decreased coronary perfusion when treated with vasodilators.
PRINIVIL® should be given with caution to these patients.
Surgery/Anesthesia
In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril blocks angiotensin II formation, secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Patients with Impaired Liver Function
Hepatitis, jaundice (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with lisinopril in patients with or without pre-existing liver abnormalities (see ADVERSE REACTIONS). In most cases the changes were reversed on discontinuation of the drug.
Should the patient receiving PRINIVIL® experience any unexplained symptoms (see INFORMATION FOR PATIENTS), particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of PRINIVIL® should be considered when appropriate.
There are no adequate studies in patients with cirrhosis and/or liver dysfunction. PRINIVIL® should be used with particular caution in patients with pre-existing liver abnormalities. In such patients, baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.
Cough
A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of PRINIVIL® has been reported.
Such a possibility should be considered as part of the differential diagnosis of the cough.
Use in the Elderly
In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of PRINIVIL®. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients so that dosage adjustments should be made with particular caution (see DOSAGE AND ADMINISTRATION).
Use in Children
Antihypertensive effects of lisinopril have been established in hypertensive pediatric patient aged 6 to 16 years. There are no data of the effects of lisinopril in hypertensive patients under the age of 6 or in patients with glomerular filtration rate <30 mL/min/1.73 m2. (See ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, and Pharmacokinetics, and DOSAGE AND ADMINISTRATION, Pediatric Patients.)
Anaphylactoid Reactions during Membrane Exposure
Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Anaphylactoid Reactions during LDL Apheresis
Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Anaphylactoid Reactions during Hymenoptera Desensitization
There have been isolated reports of patients experiencing sustained life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasp) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.
DRUG INTERACTIONS
Hypotension—Patients on Diuretic Therapy
Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with lisinopril. The possibility of symptomatic hypotension with lisinopril can be minimized by discontinuing the diuretic prior to initiation of treatment with lisinopril and/or lowering the initial dose of lisinopril (see WARNINGS, Hypotension and DOSAGE AND ADMINISTRATION).
Agents Increasing Serum Potassium
Since lisinopril decreases aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution and with frequent monitoring of serum potassium since they may lead to a significant increase in serum potassium. Potassium-containing salt substitutes should also be used with caution (see also PRECAUTIONS, Hyperkalemia).
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.
Agents Causing Renin Release
The antihypertensive effect of PRINIVIL® is augmented by antihypertensive agents that cause renin release (e.g., diuretics).
Agents Affecting Sympathetic Activity
Agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) may be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to lisinopril.
NSAIDs
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of ACE inhibitors or angiotensin II receptor antagonists may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted including those on diuretic therapy) who are being treated with NSAIDs including selective COX-2 inhibitors, the co-administration of ACE inhibitors or angiotensin II receptor antagonists may result in further deterioration of renal function. Cases of acute renal failure, usually reversible, have been reported. This combination should therefore be administered with caution in this patient population.
Indomethacin may diminish the antihypertensive efficacy of concomitantly-administered PRINIVIL®.
Dual Blockade of the Renin-Angiotensin System (RAS) with ACEIs, ARBs or aliskiren-containing drugs
Dual Blockade of the Renin-Angiotensin System with ACEIs, ARBs or aliskiren-containing drugs is contraindicated in patients with diabetes and/or renal impairment, and is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia. See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, Dual Blockade of the Renin-Angiotensin System (RAS).
Lithium Salts
As with other drugs which eliminate sodium, the lithium elimination may be reduced. Therefore, the serum lithium levels should be monitored carefully if lithium salts are to be administered.
Mammalian Target of Rapamycin (mTOR) Inhibitors
Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema. Caution should be used when these drugs are used concomitantly (see WARNINGS).
INFORMATION FOR PATIENTS
Angioedema
Angioedema, including laryngeal edema, may occur especially following the first dose of lisinopril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.
Hypotension
Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.
All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume-depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.
Neutropenia
Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia.
Impaired Liver Function
Patients should be advised to return to the physician if he/she experiences any symptoms possibly related to liver dysfunction. This would include "viral-like symptoms" in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.
Hyperkalemia
Patients should be told not to use salt substitutes containing potassium without consulting their physician.
Pregnancy
Patients should be advised to stop taking the medication and to report promptly to their physician if they become pregnant, since the use of PRINIVIL® during pregnancy can cause injury and even death of the developing fetus.
Nursing Mothers
Patients should be advised not to breast-feed while taking PRINIVIL®, as it is possible that PRINIVIL® passes into breast milk.
NOTE: As with many other drugs, certain advice to patients being treated with PRINIVIL® is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
ADVERSE REACTIONS
In controlled clinical trials involving 3269 patients (2633 patients with hypertension and 636 patients with congestive heart failure), the most frequent clinical adverse reactions were: dizziness (4.4%), headache (5.6%), asthenia/fatigue (2.7%), diarrhea (1.8%) and cough (3.0%), all of which were more frequent than in placebo-treated patients. Discontinuation of therapy was required in 5.9% of patients.
For adverse reactions which occurred in hypertensive patients and patients with congestive heart failure treated with PRINIVIL® (lisinopril tablets) in controlled clinical trials, comparative incidence data are listed in the table below.
INCIDENCE OF ADVERSE REACTIONS
OCCURRING IN PATIENTS TREATED WITH PRINIVIL®
IN CONTROLLED CLINICAL TRIALS
HYPERTENSION (2633 PATIENTS) % | CONGESTIVE HEART FAILURE (636 PATIENTS) % | |||
| Cardiovascular | ||||
| Hypotension | 0.8 | 5.2 | ||
| Orthostatic effects | 0.9 | 1.3 | ||
| Chest pain | 1.1 | 7.4 | ||
| Angina | 0.3 | 3.8 | ||
| Edema | 0.6 | 2.5 | ||
| Palpitation | 0.8 | 1.9 | ||
| Rhythm disturbances | 0.5 | 0.6 | ||
| Gastrointestinal | ||||
| Diarrhea | 1.8 | 6.1 | ||
| Nausea | 1.9 | 4.9 | ||
| Vomiting | 1.1 | 2.4 | ||
| Dyspepsia | 0.5 | 1.9 | ||
| Anorexia | 0.4 | 1.4 | ||
| Constipation | 0.2 | 0.8 | ||
| Flatulence | 0.3 | 0.5 | ||
HYPERTENSION (2633 PATIENTS) % | CONGESTIVE HEART FAILURE (636 PATIENTS) % | |||
| Nervous System | ||||
| Dizziness | 4.4 | 14.2 | ||
| Headache | 5.6 | 4.6 | ||
| Paresthesia | 0.5 | 2.8 | ||
| Depression | 0.7 | 1.1 | ||
| Somnolence | 0.8 | 0.6 | ||
| Insomnia | 0.3 | 2.4 | ||
| Vertigo | 0.2 | 0.2 | ||
| Respiratory | ||||
| Cough | 3.0 | 6.4 | ||
| Dyspnea | 0.4 | 7.4 | ||
| Orthopnea | 0.1 | 0.9 | ||
| Dermatologic | ||||
| Rash | 1.0 | 5.0 | ||
| Pruritus | 0.5 | 1.4 | ||
| Musculoskeletal | ||||
| Muscle cramps | 0.5 | 2.2 | ||
| Back pain | 0.5 | 1.7 | ||
| Leg pain | 0.1 | 1.3 | ||
| Shoulder pain | 0.2 | 0.8 | ||
| Other | ||||
| Asthenia/Fatigue | 2.7 | 7.1 | ||
| Blurred vision | 0.3 | 1.1 | ||
| Fever | 0.3 | 1.1 | ||
| Flushing | 0.3 | 0.3 | ||
| Gout | 0.2 | 1.7 | ||
| Decreased libido | 0.2 | 0.2 | ||
| Malaise | 0.3 | 1.1 | ||
Angioedema
Angioedema has been reported in patients receiving PRINIVIL® (0.1%). Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with PRINIVIL® should be discontinued and appropriate therapy instituted immediately (see WARNINGS, Angioedema).
In very rare cases intestinal angioedema has been reported with angiotensin-converting enzyme inhibitors, including lisinopril.
Hypotension
In hypertensive patients, hypotension occurred in 0.8% and syncope occurred in 0.2% of patients. Hypotension or syncope was a cause for discontinuation of therapy in 0.3% of hypertensive patients (see WARNINGS).
In patients with congestive heart failure, hypotension occurred in 5.2% and syncope occurred in 1.7% of patients. Hypotension and dizziness were causes for discontinuation of therapy in 1.7% of these patients.
Treatment Following Acute Myocardial Infarction
In a controlled, open trial, involving 19,394 acute myocardial infarction patients (GISSI-3, see INDICATIONS AND CLINICAL USE, Treatment Following Acute Myocardial Infarction), comparing lisinopril alone, transdermal glycerol trinitrate, lisinopril and transdermal glycerol trinitrate, or control (no treatment), the most frequent in-hospital adverse events at 6 weeks were as follows:
| Control | Lisinopril | Lisinopril + GTN | GTN alone | |
| Event | n=4729 | n=4713 | n=4722 | n=4731 |
| % | % | % | % | |
| Persistent hypotension | 3.6 | 8.8 | 9.3 | 3.9 |
| Shock | 2.5 | 2.8 | 2.2 | 1.9 |
| Renal dysfunction | 1.1 | 2.4 | 2.4 | 1.1 |
| Stroke | 0.6 | 0.6 | 0.9 | 0.8 |
| Re-infarction | 2.2 | 2.2 | 2.2 | 1.9 |
| Hemorrhagic events | 1.2 | 1.3 | 1.1 | 0.9 |
| Post-infarction angina | 13.2 | 13.9 | 12.3 | 11.8 |
| Ventricular fibrillation | 3.1 | 2.5 | 2.4 | 2.2 |
| Sustained ventricular tachycardia | 2.5 | 2.1 | 1.8 | 2.3 |
| Atrial flutter or fibrillation | 6.4 | 6.3 | 5.3 | 5.7 |
| Complete atrioventricular block | 2.4 | 2.9 | 2.5 | 2.1 |
| Asystole | 1.2 | 1.2 | 1.3 | 1.2 |
| Intraventricular septal rupture | 0.3 | 0.4 | 0.2 | 0.2 |
| Papillary muscle rupture | 0.3 | 0.4 | 0.5 | 0.4 |
| Late CHF (>4 days) | 4.5 | 4.5 | 4.2 | 4.2 |
Other Events in Controlled Clinical Trials or Post-Marketing Experience
Additional adverse reactions which were reported rarely, either during controlled clinical trials or after the drug was marketed, include:
Cardiovascular
- Myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high-risk patients (see WARNINGS, Hypotension)
- Tachycardia
Dermatologic
- Alopecia
- Diaphoresis
- Pruritis
- Urticaria
Severe Skin Disorders
- Erythema multiforme
- Pemphigus
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
- Cutaneous pseudolymphoma
Endocrine
- Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Gastrointestinal
- Abdominal pain and indigestion
- Dry mouth
- Pancreatitis
- Vomiting
Hematologic
- Hemolytic anemia
Hepatic
- Hepatitis
- Jaundice (hepatocellular and/or cholestatic)
- Liver function abnormalities
- Hepatic failure
Metabolic
Cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin have been reported (see DRUG INTERACTIONS).
Nervous System
- Mental confusion
- Mood alterations
- Paresthesia
- Vertigo
Respiratory
- Bronchospasm
- Rhinitis
- Sinusitis
Special Senses
- Taste disorders
Urogenital
- Acute renal failure
- Impotence
- Oliguria/anuria
- Renal dysfunction
- Uremia
A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leukocytosis. Rash, photosensitivity, or other dermatologic manifestations may also occur.
Pediatric Patients
The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients.
Laboratory Test Findings
Serum Electrolytes
Hyperkalemia and hyponatremia have occurred (see PRECAUTIONS).
Creatinine, Blood Urea Nitrogen
Increases in blood urea nitrogen and serum creatinine, usually reversible upon discontinuation of therapy, were observed in 1.1 and 1.6% of patients, respectively, with essential hypertension treated with PRINIVIL® alone. Increases were more common in patients receiving concomitant diuretics and in patients with renal artery stenosis (see PRECAUTIONS). Reversible increases in blood urea nitrogen (14.5%) and serum creatinine (11.2%) were observed in approximately 12.0% of patients with congestive heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.
Hematology
Decreases in hemoglobin and hematocrit (mean decreases of approximately 0.9 g percent and 0.6 vol percent, respectively) occurred frequently in patients treated with PRINIVIL® but were rarely of clinical importance in patients without some other cause of anemia.
Rarely, hemolytic anemia has been reported.
Agranulocytosis and bone marrow depression, manifested as anemia, thrombocytopenia or leucopenia, have been caused by angiotensin-converting enzyme inhibitors, including lisinopril. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to lisinopril cannot be excluded (see WARNINGS, Neutropenia/Agranulocytosis).
Hepatic
Elevations of liver enzymes and/or serum bilirubin have occurred (see PRECAUTIONS).
Discontinuations
Overall, 1.0% of patients discontinued therapy due to laboratory adverse experiences, principally elevations in blood urea nitrogen (0.8%), serum creatinine (0.1%) and serum potassium (0.1%).
SYMPTOMS AND TREATMENT OF OVERDOSAGE
The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. If available, angiotensin II may be beneficial.
Lisinopril may be removed from the general circulation by hemodialysis (see PRECAUTIONS, Anaphylactoid Reactions during Membrane Exposure).
For management of a suspected drug overdose, contact your regional Poison Control Center.
DOSAGE AND ADMINISTRATION
Since absorption of PRINIVIL® tablets (lisinopril tablets) is not affected by food, the tablets may be administered before, during or after meals. PRINIVIL® should be administered in a single daily dose. PRINIVIL® should be taken at the same time each day. The splitting of PRINIVIL® tablets is not advised.
Dosage must be individualized.
Essential Hypertension
In patients with essential hypertension, not on diuretic therapy, the usual recommended starting dose is 10 mg once a day. Dosage should be adjusted according to blood pressure response: the usual dosage range is 10 to 40 mg per day, administered in a single daily dose. In some patients, achievement of optimal blood pressure reduction may require two to four weeks of therapy. The antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered dose, but most commonly with a dose of 10 mg daily. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, an increase in dose should be considered. The maximum dose used in long-term controlled clinical trials was 80 mg/day. If blood pressure is not controlled with PRINIVIL® alone, a low dose of a diuretic may be added. Hydrochlorothiazide 12.5 mg has been shown to provide an additive effect. After the addition of a diuretic, it may be possible to reduce the dose of PRINIVIL®.
Diuretic Treated Patients: In hypertensive patients who are currently being treated with a diuretic, symptomatic hypotension may occur occasionally following the initial dose of PRINIVIL®. The diuretic should be discontinued, if possible, for two to three days before beginning therapy with PRINIVIL® to reduce the likelihood of hypotension (see WARNINGS). The dosage of PRINIVIL® should be adjusted according to blood pressure response. If the patient’s blood pressure is not controlled with PRINIVIL® alone, diuretic therapy may be resumed as described above.
If the diuretic cannot be discontinued, an initial dose of 5 mg 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, Hypotension and PRECAUTIONS, Drug Interactions).
A lower starting dose is required in the presence of renal impairment, in patients in whom diuretic therapy cannot be discontinued, patients who are volume- and/or salt-depleted for any reason, and in patients with renovascular hypertension.
Dosage Adjustment in Renal Impairment: Dosage in patients with renal impairment should be based on creatinine clearance as outlined in the Table below:
| Creatinine Clearance | Starting Dose |
≤70 ≥30 mL/min (≤1.17 ≥0.5 mL/s) ≤30 ≥10 mL/min (≤0.5 ≥0.17 mL/s) <10 mL/min (<0.17 mL/s) | 5.0–10.0 mg/day 2.5–5.0 mg/day 2.5 mg/dayx (including patients on dialysis) |
| x Dosage and/or frequency of administration should be adjusted depending on the blood pressure response. | |
The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.
Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., polyacrylonitrile [PAN] and treated concomitantly with an ACE inhibitor) (see PRECAUTIONS, Anaphylactoid Reactions during Membrane Exposure).
Dosage in the Elderly: In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of PRINIVIL®. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients so that dosage adjustments should be made with particular caution.
Renovascular Hypertension
Some patients with renovascular hypertension, especially those with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, may develop an exaggerated response to the first dose of PRINIVIL®. Therefore, a lower starting dose of 2.5 or 5 mg is recommended. Thereafter, the dosage may be adjusted according to the blood pressure response.
Congestive Heart Failure
PRINIVIL® is to be used in conjunction with a diuretic and where appropriate digitalis. Therapy must be initiated under close medical supervision, usually in a hospital. Blood pressure and renal function should be monitored, both before and during treatment with PRINIVIL®, because severe hypotension and, more rarely, consequent renal failure have been reported (see WARNINGS, Hypotension and PRECAUTIONS, Renal Impairment).
Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt-/volume-depletion. If possible, the dose of diuretic should be reduced before beginning treatment.
The recommended initial dose is 2.5 mg per day. If required, the dose should be increased gradually, depending on the patient response. The usual effective dosage range is 5–20 mg per day administered in a single daily dose. Dose titration may be performed over a 2–4 week period, or more rapidly if indicated by the presence of residual signs and symptoms of heart failure.
Treatment Following Acute Myocardial Infarction
Treatment of hemodynamically stable patients may be started as early as within 24 hours following the onset of symptoms of myocardial infarction. Patients should receive, as appropriate, standard recommended treatments (see INDICATIONS AND CLINICAL USE, Treatment Following Acute Myocardial Infarction).
The first dose of PRINIVIL® is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily thereafter.
Patients with a low systolic blood pressure (between 100 and 120 mmHg) when treatment is started or during the first three days after the infarct should be given a lower dose, 2.5 mg orally. Treatment with PRINIVIL® must not be initiated in patients who are at risk of serious hemodynamic deterioration (see PRECAUTIONS, Hypotension Following Acute Myocardial Infarction). After three days if hypotension occurs (systolic blood pressure less than or equal to 100 mmHg), a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than one hour), PRINIVIL® should be withdrawn.
Renal function should be assessed before and during therapy with PRINIVIL® (see PRECAUTIONS, Renal Impairment).
Dosing should normally continue for six weeks. At that time, patients with signs or symptoms of heart failure should continue with PRINIVIL® (see DOSAGE AND ADMINISTRATION, Congestive Heart Failure).
PRINIVIL® is compatible with intravenous or transdermal glyceryl trinitrate.
Pediatric Patients
For patients who can swallow tablets, the dose should be individualized according to patient profile and blood pressure response. The recommended initial dose is 2.5 mg in patients 20 to <50 kg and 5 mg in patients ≥50 kg. PRINIVIL® is given once daily. The dosage should be adjusted according to the needs of the patient to a maximum of 20 mg daily in patients 20 to <50 kg and 40 mg in patients ≥50 kg (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, and Pharmacokinetics).
PRINIVIL® is not recommended in pediatric patients <6 years or with glomerular filtration rate <30 mL/min/1.73 m2 (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, and Pharmacokinetics).
PHARMACEUTICAL INFORMATION
I. DRUG SUBSTANCE
Proper name: Lisinopril
Chemical name: (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate.
Molecular formula: C21H31N305•2H2O
Molecular weight: 441.53
Structural formula:
Description:
Lisinopril is a white to off-white, crystalline powder. It is soluble in water and sparingly soluble in methanol and practically insoluble in ethanol.
II. COMPOSITION
PRINIVIL® is supplied as 5 mg, 10 mg and 20 mg tablets for oral administration. In addition to the active ingredient lisinopril, each tablet contains the following non-medicinal ingredients: calcium phosphate, corn starch, magnesium stearate, mannitol, and pregelatinized starch. The 10 mg and 20 mg tablets also contain iron oxide. The splitting of PRINIVIL® tablets is not advised.
III. STABILITY AND STORAGE RECOMMENDATIONS
Store at room temperature (15°C–30°C).
AVAILABILITY OF DOSAGE FORMS
Tablets PRINIVIL®, 5 mg, are white, oval-shaped compressed tablets, engraved MSD 19 on one side and scored on the other. Available in blister packages of 28 tablets.
Tablets PRINIVIL®, 10 mg, are light yellow, oval-shaped compressed tablets, engraved MSD 106 on one side and scored on the other. Available in blister packages of 28 tablets.
Tablets PRINIVIL®, 20 mg, are peach, oval-shaped compressed tablets, engraved MSD 207 on one side and scored on the other. Available in blister packages of 28 tablets.
The splitting of PRINIVIL® tablets is not advised.
PHARMACOLOGY
| Study | Species/Strain | No. of Animals/Group | Route | Dose | Results |
| MECHANISM OF ACTION | |||||
In vitro ACE inhibitory activity* | Hog plasma | In vitro | IC50=1.7 ± 0.5 nM | ||
Augmentation of contractile response to bradykinin | Guinea pig ileum | 7 segments | In vitro | AC50=1.6 nM | |
In vivo ACE inhibition in the rat** | Male Sprague/Dawley | 8 | I.V. | ID50=2.3 (1.7–3.1) μg/kg | |
Duration of ACE inhibitory activity of lisinopril in rats** | Male Sprague/Dawley | 4 | I.V. | 3 & 10 μg/kg | Duration approx. 110 min. |
In vivo ACE inhibitory activity of lisinopril in conscious rats** | Sprague/Dawley | 3–5 | P.O. | 0.03–3.0 mg/kg (single dose) | Duration of at least 360 min. |
In vivo ACE inhibition in anesthetized dogs** | Mongrel | 6 | I.V. | 1–30 μg/kg | ID50=6.5 μg/kg |
In vivo ACE inhibitory activity of lisinopril in conscious dogs** | Mongrel | 3 | P.O. | 0.05–1.0 mg/kg (single dose) | Duration of action between 6–24 hrs |
* Inhibition of enzymatic activity of hog plasma ACE using 14C labeled substrate.
** Blockage of functional (pressor) response to AI challenge.
| Study | Species/Strain | No. of Animals/Group | Route | Dose | Results |
| EFFECTS ON BLOOD PRESSURE | |||||
| Antihypertensive activity in renal hypertensive dogs (single doses) | Mongrel | 3 | P.O. | 0.3 mg/kg with and without hydrochlorothiazide | After 2 hours: Lisinopril alone: 5% reduction in mean systolic pressure vs pretreatment. Lisinopril + HCTZ=11% reduction in mean systolic pressure vs pre-treatment. |
| Antihypertensive activity in rats on a sodium-deficient diet (single doses) | Male Sprague/Dawley | 5 | P.O. | 0.03–3.0 mg/kg daily for 4 days | After 2 hours: 11% reduction in mean systolic pressure vs pretreatment at 1 mg/kg. 22% reduction in mean systolic pressure vs pre-treatment at 3 mg/kg. Consistent response over 4 days. |
| Antihypertensive activity in 2 kidney Grollman hypertensive rats (single doses) | Male Sprague/Dawley | 6–7 | P.O. | 1 & 3 mg/kg | At 2 hours: approx. 6% reduction in mean systolic pressure vs pretreatment with the antihypertensive effect lasting up to 24 hours. |
| Antihypertensive activity in spontaneously hypertensive rats with and without hydrochlorothiazide | SH rats | 3–6 | P.O. | 1.25 mg/kg HCTZ=50 mg/kg daily for 3 days | Enhancement of hypotensive activity over 3–5 days. 2 hours after drug administration, lisinopril alone reduced the average mean arterial pressure from 198 to 161 mmHg. In combination with HCTZ, the average mean arterial pressure was reduced from 202 to 132 mmHg. |
Antihypertensive activity in spontaneously hyper- tensive rats (single doses) | SH rats | 3–9 | P.O. & I.V. | 0.1–20 mg/kg | Slight fall in blood pressure at 0.312–5 mg/kg P.O. Pronounced fall at 20 mg/kg P.O. and 0.1 mg/kg I.V. with statistically significant reductions being observed for the majority of time points between 1/2-18 hours. |
TOXICOLOGY
A. Acute Toxicity of Lisinopril
- 1. LD50 Values:
| Species | Sex | Route | LD50 (g/kg) |
| Mouse | Male | Oral | >20 |
| Mouse | Female | Oral | >20 |
| Rat | Male | Oral | >20 |
| Rat | Female | Oral | >20 |
| Dog | Male | Oral | >6 |
| Dog | Female | Oral | >6 |
| Mouse | Male | Intravenous | >10 |
| Mouse | Female | Intravenous | >10 |
| Rat | Male | Intraperitoneal | >10 |
| Rat | Female | Intraperitoneal | >10 |
Signs of toxicity: Following oral administration to mice decreased activity and one male death (1/10) occurred. No signs of toxicity occurred in rats after oral administration. Dogs given 6 g/kg had transient diarrhea and increases in serum urea nitrogen. Intravenous administration to mice produced bradypnea, ataxia, clonic convulsions, exophthalmia, and tremors. After intraperitoneal administration in rats, ataxia and one female death (1/10) occurred. No signs of toxicity or death occurred in the males.
B. Subacute/Chronic Toxicology
| Species | Duration | No. of Animals/Group | Route | Dose mg/kg/day | Effects |
| Rat | 2-Week | 10 F + 10 M | Oral | 3, 10, 30 | At all doses, decreases of 2 to 16% in weight gain and 12 to 14% in heart weights were observed in female rats. | |||||
| Rat | 3-Month with 1-Month Interim | 25 F + 25 M | Oral | 3, 10, 30 | At all doses, increased serum urea nitrogen values (up to approximately 2-fold) and decreased heart weights (7 to 10%) were observed in female rats. At 10 and 30 mg, respectively, weight gain decreased 11 to 14% in males. An increased incidence of focal erosions of the gastric mucosa and focal renal tubular basophilia were also seen. | |||||
| Rat | 1-Year with 6-Month Interim | 25 F + 25 M | Oral | 2, 5, 10, 30, 90a | At all doses, a decrease in weight gain (up to 16%) was observed; serum urea nitrogen increased up to 4-fold; serum sodium decreased (average down to 3 mEq/L) and serum potassium increased (average up to 0.5 mEq/L). At 2, 5, 10 and 30 mg, heart weight decreased; at 5, 10 and 30 mg, kidney weight increased; and at 5, 10, 30 and 90 mg, renal tubular basophilia increased. At 10, 30 and 90 mg, focal interstitial nephritis was observed. | |||||
| Rat | 3-Month with a 1-Month Interim and a 1-Month Recovery | 30 F + 30 M | Oral | 3, 30, 300, 3000 | At all doses, weight gain decreased by 5 to 11% and increases were observed in serum urea nitrogen (up to approximately 3-fold) and serum potassium (average up to 0.4 mEq/L). At 30, 300 and 3000 mg there was an increased incidence of focal renal tubular basophilia and focal necrosis of the glandular mucosa of the stomach. An increased incidence of focal tubular basophilia persisted in rats given 300 or 3000 mg/kg/day. | |||||
| Rat | 1-Month | 15 F + 15 M | Oral | 30, 60 30, 60 (with saline) | Saline supplementation prevented decreased weight gain and elevations in serum urea nitrogen at 30 and 60 mg. Decreases in cardiac weight at 30 and 60 mg was suppressed by saline supplementation in males at 30 mg. At 30 and 60 mg, renal changes produced due to a low salt diet (renal tubular degeneration and renal tubular basophilia) were prevented by saline supplementation. Mild gastric erosions or necrotic changes were seen in 1 or 2 of 30 rats given 30 or 60 mg. These gastric changes were not seen in saline supplemented animals given these doses; however, the relationship of amelioration due to saline is uncertain because of the low incidence of this change, which is also occasionally seen in untreated animals. | |||||
| Rat | 5-Day 6-Day Recovery | 8 M | Oral | 5, 300 | Consumption of 2% saline increased during treatment at 5 mg and on Days 2 to 4 post-treatment at 300 mg. |
a Dosing terminated Week 11, rats killed Week 27.
B. Subacute/Chronic Toxicology (continued)
| Species | Duration | No. of Animals/Group | Route | Dose mg/kg/day | Effects |
| Dog | 2-Week | 3 F + 3 M | Oral | 3, 10, 30 | At 30 mg, mineralization of the papilla muscle of the heart was seen in 1 of 6 dogs. | |||||
| Dog | 3-Month with 1-Month Interim | 5 F + 5 M | Oral | 3, 10, 30 | At 10 mg, hemoglobin concentration, hematocrit, and erythrocyte count decreased in 2 dogs. Marked increases in serum urea nitrogen and creatinine were observed in 2 of 10 dogs. One of these dogs had marked renal tubular degeneration and ulcers of the tongue, gums and gastric pyloric mucosa related to uremia. At 30 mg, there was an increase in serum urea nitrogen (average up to 2-fold) and a decrease in serum sodium (down to 4 mEq/L) and serum chloride (down to 3 mEq/L). At 10 and 30 mg, average cardiac weight was decreased (13 to 15%). | |||||
| Dog | 1-Year with 6-Month Interim | 5 F + 5 M | Oral | 3, 5, 15 | At 15 mg, increases were observed in serum urea nitrogen (less than 2-fold). Decreases in serum sodium (average down to 2 mEq/L) and increases in serum potassium (average up to 0.5 mEq/L) occurred at all doses. | |||||
| Dog | 18-Day | 3 F + 3 M | Oral | 60/90 with and without saline | Saline supplementation prevented increases in serum urea nitrogen in dogs given 60 mg for 8 days followed by 90 mg for 8 or 9 days. | |||||
| Dog | 7-Day | 4 F + 4 M | I.V. | 60, 90 | Decreases in blood pressure and increases in serum urea nitrogen occurred in dogs given 60 or 90 mg/kg/day. Supplementation with physiologic saline (25 mL/kg one hour prior to dosing and 4 hours after dosing) prevented these changes. Increased serum potassium (average up to 0.6 mEq/L) and decreased serum chloride (average down to 0.4 mEq/L) values were seen in both supplemented and unsupplemented animals. |
| Dog | 1-Month | 2 F + 2 M | Oral | 3, 30, 300 and 1000 | At 30 mg or greater, BUN increased and specific gravity of the urine decreased. Hyperplasia of renal epithelial cells was observed and deaths occurred. Dogs that died had dilation of distal renal tubules and fatty degeneration of renal tubular epithelium. No drug-related effects were observed at 3 mg. |
B. Subacute/Chronic Toxicology (continued)
| Species | Duration | No. of Animals/Group | Route | Dose mg/kg/day | Effects | |||||
| Dog | 3-Month with 1-Month Recovery (high dose) | Control 5 M + 5 F 3, 10, 30 mg/kg/day 3 M + 3 F 100 mg/kg/day 8 M + 8 F Recovery Control 2 M + 2 F 100 mg/kg/day 5 M + 5 F | Oral | 3, 10, 30 and 100 | Eight of 16 dogs given 100 mg died or were killed because of poor physical condition. One of 6 dogs given 30 mg was killed because of poor physical condition. At 10 mg or greater increased BUN and dilation of renal tubules was seen. Fatty degeneration of renal tubular epithelium occurred at the 2 highest dosage levels. The changes are reversible as only slight dilation of renal tubules was present in some animals given 100 mg after 4 weeks of recovery. |
| Rabbit | 2-Week | 6 F | Oral | 15 (1, 6 & 13 doses) with and without saline | Renal tubular basophilia and renal tubular dilation (considered sequela to necrosis) were seen after 6 and 13 doses in unsupplemented rabbits. Two supplemented rabbits (6 doses) also had the same renal lesion. One rabbit drank very little saline and had increases in BUN, creatinine and potassium. Increases in these parameters were seen in unsupplemented animals after 1, 6, and 13 doses. |
C. Teratology Studies
| Species | No. of Animals/Group | Dose mg/kg/day | Route | Duration of Dosing | Results |
| Mice | 25 | 100, 300, 1000, 1000 with saline | Oral | Day 6 through Day 15 of gestation | No teratogenic effect was observed. There was an increased incidence of resorptions in all unsupplemented groups (no increase in serum urea nitrogen). | |||||
| Rat | 35 | 30, 100, 300, 300 with saline | Oral | Day 6 through Day 17 of gestation | No teratogenic effect was observed. Maternal weight gain decreased in all unsupplemented groups. The open field behavioral test (measure of spontaneous activity) showed increased activity in Week 5 postpartum F1 females at 300 mg with and without saline, but only in 300 mg with saline females in Week 6. When the open field test was repeated in males and females given 300 mg with and without saline in Week 11, no increase in activity was seen. | |||||
| Rabbit (New Zealand) | 18 | 0.1, 0.3, 1.0 all groups with saline | Oral | Day 6 through Day 18 of gestation | No teratogenic effect was observed. At all doses there was an increased incidence of incomplete ossification (sternebrae, metacarpals, forefoot phalanges, pelvic bones, and tali and/or calcanea) which was considered to represent a fetotoxic effect. At 1 mg one rabbit had a high incidence of resorptions. |
| Rabbit (New Zealand) | 18 | 0.031, 0.125, 0.5 | Oral | Day 6 through Day 18 of gestation | No fetotoxicity or embryotoxicity was observed at maternotoxic doses. At 0.125 and 0.5 mg maternal deaths, decreased maternal weight gain and food consumption, as well as increases in BUN, creatinine and potassium were seen. In addition, doses of 0.5 mg produced decreases in serum sodium and chloride, diffuse distention of the renal distal tubules and degeneration of renal tubules. |
D. Fertility and Late Gestation and Lactation with Postnatal Evaluation Studies
| Species | No. of Animals/Group | Dose mg/kg/day | Route | Duration of Dosing | Results |
| Rat | 24 F & 24 M | 30, 100, 300, 300 with saline | Oral | Males were dosed for 78 days prior to mating and females from 15 days prior to mating until sacrifice on Day 20 of gestation | Weight gain was reduced in unsupplemented males at all doses and during gestation in unsupplemented females. No effects on fertility and no signs of teratogenicity were observed. There was an increase in F1 pup deaths (3 to 8% vs control 1%) Day 1 to 7 postpartum in 100 and 300 mg (saline and nonsaline) groups. Decreased mean F1 pup weight (3 to 7% less than controls) on Day 0 postpartum was seen in all unsupplemented groups. |
| Rat | 20 F | 30, 100, 300, 300 with saline | Oral | Day 15 of gestation through Day 21 postpartum | On Days 2 to 7 postpartum, there was an increased number of dead pups (8 to 10% vs control 0%). On Day 21 postpartum, a decrease in pup weights (8% less than controls) was observed in the unsupplemented 100 and 300 mg groups. There was no effect in the supplemented group. Pup development was not altered. |
E. Genotoxicity Studies
| Study | Test System | Dose | Results |
| Mutagenesis | ||||||
| Microbial mutagen with and without metabolic activation | Salmonella typhimurium TA1535, TA1537, TA98, TA100 Escherichia coli WP2, WP2 uvrA | up to 2000 μg/plate up to 10 mg/plate | Negative for mutagenic potential |
| In vitro V-79 mammalian cell mutagenesis with and without metabolic activation | Chinese Hamster Lung Cell | up to 10 mM (4.42 mg/mL) | Negative for mutagenic potential |
| DNA Damage | ||||||
| In vitro alkaline elution | Rat Hepatocyte | up to 30 mM (13.25 mg/mL) | Negative for induction of DNA single strand breaks | |||
| Chromosomal Evaluation | ||||||
In vitro chromosomal aberration assay with and without metabolic activation | Chinese Hamster Ovary | up to 30 mM (13.25 mg/mL) | Negative for induction of chromosomal aberration |
| In vivo chromosomal aberration assay | Bone Marrow Cells of Male Mice | up to 5000 mg/kg | Negative for increases in chromosomal aberrations |
F. Carcinogenicity Studies
| Species | Duration | No. of Animals/Group | Route | Dose mg/kg/day | Effects |
Mice Crl:CD-1 (ICR)BR | 92-Week | 50 F & 50 M | Oral | 15, 45, 135 mg/kg/day | No evidence of carcinogenic effect was observed. Decreased weight gain (7 to 15%) was seen in females at 135 mg. A greater incidence and severity of chronic nephritis in females and males given 45 and 135 mg was also seen. |
| Rats Crl:CD (SD) BR | 105-Week | 50 F & 50 M | Oral | 10, 30, 90 mg/kg/day | No evidence of carcinogenic effect was observed. Decreased weight gain (5 to 14%) in male drug-treated rats during the first 67 weeks of the study was observed. Focal sacculations of the retinal vessels was more prevalent in rats given 30 or 90 mg than in controls in Drug Week 100. An increased incidence of renal tubular hypertrophy in drug-treated males at termination of study was seen (1 mg was considered the no-effect dose for this change in males based on an additional 105-week study at 1, 3, and 10 mg/kg/day). An increased incidence of chronic nephritis in drug-treated females (10 mg is the no-effect dose based on an additional 105-week study at 1, 3, and 10 mg/kg/day) was observed. |
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