Drug Safety-related Labeling Changes (SrLC)

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EPANED KIT (NDA-204308)

(ENALAPRIL MALEATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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07/28/2017 (SUPPL-7)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

EPANED is contraindicated in patients with:

  • a history of angioedema or hypersensitivity related to previous treatment with an angiotensin converting enzyme (ACE) inhibitor.
  • hereditary or idiopathic angioedema.

Do not co-administer aliskiren with EPANED in patients with diabetes.

EPANED is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer EPANED within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor.

5 Warnings and Precautions

5.2 Angioedema and Anaphylactoid Reactions

(additions underlined)

Angioedema

Head and Neck Angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx, including some fatal reactions, have occurred in patients treated with angiotensin converting enzyme inhibitors, including EPANED, at any time during treatment.   Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. EPANED should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms of angioedema has occurred.

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 (4)]. ACE inhibitors have been associated with a higher rate of angioedema in black than in non-black patients.

Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema.

7 Drug Interactions

7.7 Neprilysin Inhibitor

(new subsection added)

Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema.

03/22/2017 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Angioedema and Anaphylactoid Reactions

(Additions and/or revisions are underlined)

Angioedema

Anaphylactoid Reactions

Anaphylactoid Reactions during Desensitization

Two patients undergoing desensitizing treatment…

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following adverse reactions are described elsewhere:

  • Hyperkalemia

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion as below:

Risk Summary

EPANED 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 EPANED as soon as possible. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the general U.S. population, the estimated background risk of major birth 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 risk 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.

Adverse reactions in the fetus or in neonates with a history of in utero exposure to enalapril maleate.

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, oligohydramnios, fetal lung hypoplasia, 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 oligohydraminos may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to EPANED for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs in neonates with a history of in utero exposure to EPANED, 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.

 

8.2 Lactation
PLLR conversion:

Risk Summary

Enalapril and enalaprilat have been detected in human breast milk. Because of the potential for serious adverse reactions in the breastfed infant, including hypotension, hyperkalemia, and renal impairment, advise women not to breastfeed during treatment with EPANED.

 

8.4 Pediatric Use

Additions and/or revisions underlined:

Pediatric patients with hypertension

EPANED is not recommended in neonates (i.e., infants 1 month of age or less), preterm infants who have not reached a corrected post-conceptual age of 44 weeks, and in pediatric patients with glomerular filtration rate less than 30 mL/min/1.73 m2.

Enalapril lowers blood pressure in hypertensive pediatric patients age 6 years to 16 years. Use of enalapril in these age groups is supported by evidence from adequate and well-controlled studies of enalapril in pediatric and adult patients as well as by published literature in pediatric patients. Clinical efficacy studies of enalapril in pediatric patients with hypertension did not enroll patients less than 6 years of age.  In a previous clinical study in pediatric patients between 2 months and 6 years of age, a higher weight-based dose was required to match exposure in children aged 6 to 16 years.

It is unknown whether post-natal use of ACE inhibitors such as enalapril before maturation of renal function is complete has long-term deleterious effects on the kidney. In humans, nephrogenesis is thought to be complete around birth; however maturation of other aspects of kidney function (such as glomerular and tubular function) may continue until approximately 2 years of age.

Pediatric patients with heart failure or asymptomatic left ventricular dysfunction

Safety and effectiveness of enalapril have not been established in pediatric patients with heart failure or asymptomatic left ventricular dysfunction.

8.5 Geriatric Use

Newly added subsection:

This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. 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.

8.6 Race

Newly added subsection:

ACE inhibitors, including EPANED, as monotherapy have an effect on blood pressure that is less in Black patients than in non-Blacks.

8.7 Renal impairment

Additions and/or revisions underlined:

Use a lower initial dose of EPANED in patients undergoing hemodialysis and in patients whose eGFR is greater than or equal to 30 mL/min.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

  • Angioedema

Advise patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, or tongue, or difficulty in swallowing or breathing) and to consult with the prescribing physician before taking more drug.

  • Hyperkalemia

Tell patients to consult their physician prior to using salt substitutes containing potassium.

01/29/2016 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

Angioedema and Anaphylactoid Reactions

Head and Neck Angioedema

  • …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

7 Drug Interactions

mTOR Inhibitors

Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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