Lotensin 20 MG Oral Tablet
WARNINGS
Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Lotensin) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors.
In U.S.
clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received Lotensin.
Angioedema associated with laryngeal edema can be fatal.
If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Lotensin should be discontinued and appropriate therapy instituted immediately.
Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3 mL to 0.5 mL) should be promptly administered (see ADVERSE REACTIONS).
Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors.
These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.
The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor.
Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions.
In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.
Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not approved in the United States).
Hypotension Lotensin can cause symptomatic hypotension.
Like other ACE inhibitors, benazepril has been only rarely associated with hypotension in uncomplicated hypertensive patients.
Symptomatic hypotension is most likely to occur in patients who have been volume-and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.
Volume-and/or salt-depletion should be corrected before initiating therapy with Lotensin.
In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death.
In such patients, Lotensin therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of benazepril or diuretic is increased.
If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline.
Lotensin treatment usually can be continued following restoration of blood pressure and volume.
Neutropenia/Agranulocytosis Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma.
Available data from clinical trials of benazepril are insufficient to show that benazepril does not cause agranulocytosis at similar rates.
Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.
Fetal toxicity Pregnancy category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.
Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.
Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.
When pregnancy is detected, discontinue Lotensin as soon as possible.
These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy.
Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.
Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.
Perform serial ultrasound examinations to assess the intra-amniotic environment.
If oligohydramnios is observed, discontinue Lotensin, unless it is considered lifesaving for the mother.
Fetal testing may be appropriate, based on the week of pregnancy.
Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Closely observe infants with histories of in utero exposure to Lotensin for hypotension, oliguria, and hyperkalemia.
[see Precautions, Pediatric Use] No teratogenic effects of Lotensin were seen in studies of pregnant rats, mice, and rabbits.
On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman).
On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose.
Hepatic Failure Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death.
The mechanism of this syndrome is not understood.
Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
DRUG INTERACTIONS
Drug Interactions Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Lotensin.
The possibility of hypotensive effects with Lotensin can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Lotensin.
If this is not possible, the starting dose should be reduced (see DOSAGE AND ADMINISTRATION).
Potassium Supplements and Potassium-Sparing Diuretics: Lotensin can attenuate potassium loss caused by thiazide diuretics.
Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia.
Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently.
Oral Anticoagulants: Interaction studies with warfarin and acenocoumarol failed to identify any clinically important effects on the serum concentrations or clinical effects of these anticoagulants.
Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including benazepril) during therapy with lithium.
These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended.
If a diuretic is also used, the risk of lithium toxicity may be increased.
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.
Anti-diabetics : In rare cases, diabetic patients receiving an ACE inhibitor (including benazepril) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia.
Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure.
These effects are usually reversible.
Monitor renal function periodically in patients receiving benazepril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including benazepril, may be attenuated by NSAIDs.
Other: No clinically important pharmacokinetic interactions occurred when Lotensin was administered concomitantly with hydrochlorothiazide, chlorthalidone, furosemide, digoxin, propranolol, atenolol, or cimetidine.
Lotensin has been used concomitantly with beta-adrenergic-blocking agents, calcium-channel-blocking agents, diuretics, digoxin, and hydralazine, without evidence of clinically important adverse interactions.
Benazepril, like other ACE inhibitors, has had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system.
OVERDOSAGE
Single oral doses of 3 g/kg benazepril were associated with significant lethality in mice.
Rats, however, tolerated single oral doses of up to 6 g/kg.
Reduced activity was seen at 1 g/kg in mice and at 5 g/kg in rats.
Human overdoses of benazepril have not been reported, but the most common manifestation of human benazepril overdosage is likely to be hypotension.
Laboratory determinations of serum levels of benazepril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of benazepril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of benazepril and its metabolites.
Benazepril is only slightly dialyzable, but dialysis might be considered in overdosed patients with severely impaired renal function (see WARNINGS).
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities.
Because the hypotensive effect of benazepril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat benazepril overdose by infusion of normal saline solution.
DESCRIPTION
Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol.
Its chemical name is 3-[[1-(ethoxy-carbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1 H -1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is Its empirical formula is C 24 H 28 N 2 O 5 •HCl, and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is a non-sulfhydryl angiotensin-converting enzyme inhibitor.
Benazepril is converted to benazeprilat by hepatic cleavage of the ester group.
Lotensin is supplied as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of benazepril hydrochloride for oral administration.
The inactive ingredients are colloidal silicon dioxide, crospovidone, hydrogenated castor oil (5-mg, 10-mg, and 20-mg tablets), hypromellose, iron oxides, lactose, magnesium stearate (40-mg tablets), microcrystalline cellulose, polysorbate 80, propylene glycol (5-mg and 40-mg tablets), starch, talc, and titanium dioxide.
Benazepril hydrochloride structural formula.
HOW SUPPLIED
Lotensin is available in tablets of 20 mg, packaged with a desiccant in bottles of 30 tablets.
Each tablet is imprinted with LOTENSIN on one side and the tablet strength “20,” on the other.
Storage: Do not store above 30°C (86°F).
Protect from moisture.
Dispense in tight container (USP).
GERIATRIC USE
Geriatric Use Of the total number of patients who received benazepril in U.S.
clinical studies of Lotensin, 18% were 65 or older while 2% were 75 or older.
No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Benazepril and benazeprilat are substantially excreted by the kidney.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
MECHANISM OF ACTION
Mechanism of Action Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals.
ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II.
Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.
Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion.
The latter decrease may result in a small increase of serum potassium.
Hypertensive patients treated with Lotensin alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L.
Similar patients treated with Lotensin and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium (see PRECAUTIONS).
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.
ACE is identical to kininase, an enzyme that degrades bradykinin.
Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Lotensin remains to be elucidated.
While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension (see INDICATIONS AND USAGE).
INDICATIONS AND USAGE
Lotensin is indicated for the treatment of hypertension.
It may be used alone or in combination with thiazide diuretics.
In using Lotensin, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease.
Available data are insufficient to show that Lotensin does not have a similar risk (see WARNINGS).
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks.
It should also be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in nonblacks.
PEDIATRIC USE
Pediatric Use Neonates with a history of in utero exposure to Lotensin: 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.
Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers with another ACE inhibitor, but experience is limited.
The antihypertensive effects of Lotensin have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacodynamics, Hypertension).
The pharmacokinetics of Lotensin have been evaluated in pediatric patients 6 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism).
Lotensin was generally well tolerated and adverse effects were similar to those described in adults.
(See ADVERSE REACTIONS: Pediatric Patients ).
Treatment with Lotensin is not recommended in pediatric patients less than 6 years of age (see ADVERSE REACTIONS), and in children with glomerular filtration rate <30 mL/min as there are insufficient data available to support a dosing recommendation in these groups.
(See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism, In Pediatric Patients and DOSAGE AND ADMINISTRATION.)
NUSRING MOTHERS
Nursing Mothers Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with benazepril.
A newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of benazepril and benazeprilat.
BOXED WARNING
WARNING: FETAL TOXICITY When pregnancy is detected, discontinue Lotensin as soon as possible.
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
See Warnings: Fetal Toxicity
INFORMATION FOR PATIENTS
Information for Patients Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Lotensin during pregnancy.
Discuss treatment options with women planning to become pregnant.
Patients should be asked to report pregnancies to their physicians as soon as possible.
Angioedema: Angioedema, including laryngeal edema, can occur at any time with treatment with ACE inhibitors.
Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.
Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to the prescribing physician.
Patients should be told that if syncope occurs, Lotensin should be discontinued until the prescribing physician has been consulted.
All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.
Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.
DOSAGE AND ADMINISTRATION
Hypertension Adults The recommended initial dose for patients not receiving a diuretic is 10 mg once a day.
The usual maintenance dosage range is 20-40 mg per day administered as a single dose or in two equally divided doses.
A dose of 80 mg gives an increased response, but experience with this dose is limited.
The divided regimen was more effective in controlling trough (pre-dosing) blood pressure than the same dose given as a once-daily regimen.
Dosage adjustment should be based on measurement of peak (2-6 hours after dosing) and trough responses.
If a once-daily regimen does not give adequate trough response, an increase in dosage or divided administration should be considered.
If blood pressure is not controlled with Lotensin alone, a diuretic can be added.
Total daily doses above 80 mg have not been evaluated.
Concomitant administration of Lotensin with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium (see PRECAUTIONS).
In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of Lotensin.
To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with Lotensin (see WARNINGS).
Then, if blood pressure is not controlled with Lotensin alone, diuretic therapy should be resumed.
If the diuretic cannot be discontinued, an initial dose of 5 mg Lotensin should be used to avoid excessive hypotension.
Pediatrics In children, doses of Lotensin between 0.1 and 0.6 mg/kg once daily have been studied, and doses greater than 0.1 mg/kg were shown to reduce blood pressure (see Pharmacodynamics).
Based on this, the recommended starting dose of Lotensin is 0.2 mg/kg once per day as monotherapy.
Doses above 0.6 mg/kg (or in excess of 40 mg daily) have not been studied in pediatric patients.
For pediatric patients who cannot swallow tablets, or for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths for Lotensin, follow the suspension preparation instructions below to administer benazepril HCl as a suspension.
Treatment with Lotensin is not advised for children below the age of 6 years (see PRECAUTIONS, Pediatric Use) and in pediatric patients with glomerular filtration rate <30 mL, as there are insufficient data available to support a dosing recommendation in these groups.
For Hypertensive Patients with Renal Impairment For patients with a creatinine clearance 3 mg/dL), the recommended initial dose is 5 mg Lotensin once daily.
Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg (see WARNINGS).
Preparation of Suspension (for 150 mL of a 2 mg/mL suspension) Add 75 mL of Ora-Plus ® * oral suspending vehicle to an amber polyethylene terephthalate (PET) bottle containing fifteen Lotensin 20 mg tablets, and shake for at least 2 minutes.
Allow the suspension to stand for a minimum of 1 hour.
After the standing time, shake the suspension for a minimum of 1 additional minute.
Add 75 mL of Ora-Sweet ® * oral syrup vehicle to the bottle and shake the suspension to disperse the ingredients.
The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 30 days in the PET bottle with a child-resistant screw-cap closure.
Shake the suspension before each use.
*Ora-Plus ® and Ora-Sweet ® are registered trademarks of Paddock Laboratories, Inc.
Ora-Plus ® contains carrageenan, citric acid, methylparaben, microcrystalline cellulose, carboxymethylcellulose sodium, potassium sorbate, simethicone, sodium phosphate monobasic, xanthan gum, and water.
Ora-Sweet ® contains citric acid, berry citrus flavorant, glycerin, methylparaben, potassium sorbate, sodium phosphate monobasic, sorbitol, sucrose, and water.