Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

AZOR (NDA-022100)

(AMLODIPINE BESYLATE; OLMESARTAN MEDOXOMIL)

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

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10/02/2020 (SUPPL-39)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Fetal Toxicity

(Newly added section)

Azor 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. 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 Azor as soon as possible [see Use in Specific Populations (8.1)].

8 Use in Specific Populations

Lactation

(PLLR conversion. Please refer to label for complete information.)

Pediatric Use

(Newly added section)

Pregnancy

(PLLR conversion. Please refer to label for complete information.)

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

Patient Counseling Information

(Additions and/or revisions underlined)

Pregnancy: Advise female patients of childbearing age about the consequences of exposure to Azor during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible[see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

Lactation: Advise nursing women not to breastfeed during treatment with Azor [see Use in Specific Populations (8.2)].

Potassium Supplements: Advise patients not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider.

01/05/2017 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hypotension in Volume- or Salt-Depleted Patients

Additions and/or revisions underlined:

Olmesartan medoxomil. In patients with an activated renin-angiotensin system, such as volume and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Initiate treatment with Azor under close medical supervision. If hypotension does occur …

5.4 Impaired Renal Function

Additions and/or revisions underlined:

Olmesartan medoxomil. Changes in renal function may be anticipated …

5.5 Patients with Hepatic Impairment

Additions and/or revisions underlined:

Amlodipine. Patients with hepatic impairment have decreased clearance of amlodipine ...

Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment.

5.6 Sprue-like Enteropathy

Additions and/or revisions underlined:

Olmesartan medoxomil. Severe, chronic diarrhea with substantial weight loss …

6 Adverse Reactions

6.1 Clinical Trials Experience

Azor

Edema

Addition of the following:

There was a greater decrease in hemoglobin and hematocrit in patients treated with Azor as compared to patients receiving either component.

6.2 Post-Marketing Experience

Additions and/or revisions underlined:

Amlodipine. … have been reported in association with use of amlodipine. Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.

Olmesartan medoxomil. The following adverse reactions have been reported in post-marketing experience:

Addition underlined:

Urogenital System: acute renal failure, increased blood creatinine levels

7 Drug Interactions

7.2 Drug Interactions with Amlodipine

Additions and/or revisions underlined:

Simvastatin

Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Immunosuppressants

Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate.

CYP3A Inhibitors

Co-administration of amlodipine with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment.

CYP3A Inducers

No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co- administered with CYP3A inducers.

8 Use in Specific Populations

8.6 Hepatic Impairment

Additions and/or revisions underlined:

There are no studies of Azor in patients with hepatic insufficiency, but both

amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with severe hepatic impairment. The recommended initial dose of amlodipine in patients with severe hepatic impairment is 2.5 mg, a dose not available with Azor.

Amlodipine. Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with severely impaired hepatic function.

Olmesartan medoxomil. Increases in AUC0-infinity and peak plasma concentration (Cmax) for olmesartan were observed with moderate hepatic impairment compared to those in matched controls with an increase in AUC of about 60%.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Pregnancy: Tell female patients of childbearing age about the consequences of exposure to Azor during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.

11/01/2016 (SUPPL-32)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Electrolyte Imbalances (Added subsection)

Azor contains olmesartan, a drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically.

6 Adverse Reactions

6.2 Post-Marketing Experience

Olmesartan medoxomil. The following adverse reactions have been reported in post- marketing experience:

Metabolic and Nutritional Disorders: hyperkalemia