Lotensin Drug Information

Recommended Dosage

ADULTS The recommended initial dose for patients not receiving a diuretic is 10 mg once a day. The usual maintenance dosage range is 20 to 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. Use with diuretics in adults The recommended starting dose of Lotensin in a patient on a diuretic is 5 mg once daily. If blood pressure is not controlled with Lotensin alone, a low dose of diuretic may be added.

PEDIATRIC PATIENTS 6 YEARS OF AGE AND OLDER The recommended starting dose for pediatric patients is 0.2 mg/kg once per day. Titrate as needed to 0.6 mg/kg once per day. Doses above 0.6 mg/kg (or in excess of 40 mg daily) have not been studied in pediatric patients.

Lotensin is not recommended in pediatric patients less than 6 years of age or in pediatric patients with GFR less than 30 mL/min/1.73m².

Dose Adjustment for Renal Impairment For adults with a

GFR <30 mL/min/1.73 m² (serum creatinine >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. Lotensin can also worsen renal function.

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 two minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of one 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 2º to 8°C (36º to 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.

. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Lotensin has been evaluated for safety in over 6000 patients with hypertension; over 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in Lotensin and placebo patients.

The reported side effects were generally mild and transient, and there was no relation between side effects and age, duration of therapy, or total dosage within the range of 2 to 80 mg. Discontinuation of therapy because of a side effect was required in approximately 5% of U.S. patients treated with Lotensin and in 3% of patients treated with placebo. The most common reasons for discontinuation were headache (0.6%) and cough (0.5%). Adverse reactions seen in at least 1% greater frequency in patients treated with Lotensin than placebo were headache (6% vs. 4%), dizziness (4% vs. 2%), somnolence (2% vs. 0%) and postural dizziness (2% vs. 0%). Adverse reactions reported in controlled clinical trials (less than 1% more on benazepril than on placebo), and rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug use is uncertain): Dermatologic: Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions (manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing.

Gastrointestinal: Nausea, pancreatitis, constipation, gastritis, vomiting, and melena. Hematologic : Thrombocytopenia and hemolytic anemia. Neurologic/Psychiatric: Anxiety, decreased libido, hypertonia, insomnia, nervousness, and paresthesia.

Other: Fatigue, asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination, infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, sweating. Laboratory Abnormalities: Elevations of uric acid, blood glucose, serum bilirubin, and liver enzymes have been reported, as have incidents of hyponatremia, electrocardiographic changes, eosinophilia, and proteinuria. The most common adverse reactions leading to discontinuation were headache (0.6%) and cough (0.5%) To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-982-5438 (1-866-9VALIDUS) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Diuretics Hypotension 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 or decreasing the dose of diuretic prior to initiation of treatment with Lotensin. Hyperkalemia Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) can increase the risk of hyperkalemia.

Therefore, if concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently. Lotensin attenuates potassium loss caused by thiazide-type diuretics.

Antidiabetics

Concomitant administration of Lotensin and antidiabetic medicines (insulins, oral hypoglycemic agents) may increase the risk of hypoglycemia.

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, coadministration 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.

Dual Blockade of the Renin-Angiotensin System (RAS) Dual Blockade of the

RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors.

Closely monitor blood pressure, renal function and electrolytes in patients on Lotensin and other agents that affect the RAS. Do not coadminister aliskiren with Lotensin in patients with diabetes. Avoid use of aliskiren with Lotensin in patients with renal impairment (GFR < 60 mL/min).

Mammalian Target of Rapamycin (mTOR) Inhibitors Patients receiving coadministration of

ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema. Monitor for signs of angioedema .

Lithium Lithium toxicity has been reported in patients receiving lithium concomitantly with

Lotensin. Lithium toxicity was usually reversible upon discontinuation of lithium or Lotensin. Monitor serum lithium levels during concurrent use.

Neprilysin Inhibitor Patients taking concomitant neprilysin inhibitors may be at increased risk

for angioedema.

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.

Pregnancy Risk Summary Lotensin can cause fetal harm when administered to a pregnant woman. 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. 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.

When pregnancy is detected, discontinue Lotensin as soon as possible. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

In the general U.S. population, the estimated background risk of major defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal rush for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death. 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.

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.

If oliguria or hypotension occur in neonates with a history of in utero exposure to Lotensin, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function.

Pediatric Use The antihypertensive effects of Lotensin have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age . The pharmacokinetics of Lotensin have been evaluated in pediatric patients 6 to 16 years of age . Infants below the age of 1 year should not be given Lotensin because of the risk of effects on kidney development. Safety and effectiveness of Lotensin have not been established in pediatric patients less than 6 years of age or in children with glomerular filtration rate < 30 mL/min/1.73m².

4. CONTRAINDICATIONS Lotensin is contraindicated in patients: who are hypersensitive to benazepril or to any other ACE inhibitor with a history of angioedema with or without previous ACE inhibitor treatment Lotensin is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer Lotensin within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor. Do not coadminister aliskiren with angiotensin receptor blockers, ACE inhibitors, including Lotensin in patients with diabetes . Angioedema or history of hereditary or idiopathic angioedema Hypersensitivity Coadministration with aliskiren in patients with diabetes

. 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, for which the usual treatment would be intravenous infusion of normal saline solution. Hypotension can be associated with electrolyte disturbances and renal failure. Benazepril is only slightly dialyzable, but consider dialysis to support patients with severely impaired renal function.

If ingestion is recent, consider activated charcoal. Consider gastric decontamination (e.g., vomiting, gastric lavage) in the early period after ingestion. Monitor for blood pressure and clinical symptoms.

Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure. In the case of marked hypotension, infuse physiological saline solution; as needed, consider vasopressors (e.g., catecholamines i.v.).