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.

ADASUVE (NDA-022549)

(LOXAPINE)

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

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10/27/2021 (SUPPL-9)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866- 961-2388 or online at http://womensmentalhealth.org/clinical-and-research- programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs, including ADASUVE, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). The available data from published case reports and pharmacovigilance cases with loxapine, the active ingredient in ADASUVE, in pregnant women are insufficient to determine a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder, and with exposure to antipsychotics, including ADASUVE, during pregnancy (see Clinical Considerations).

In animal reproduction studies, increased embryofetal toxicity and death in rat fetuses and offspring were observed when pregnant rats were orally administered loxapine, during the period of organogenesis, at doses approximately less than or equal to the maximum recommended human dose (MRHD) based on mg/m2 body surface area (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including ADASUVE, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Animal Data

Pregnant rats were administered oral doses of 1, 4, and 12 mg/kg/day loxapine (~1, 4, and 12 times the MRHD of 10 mg/day based on mg/m2 body surface area, respectively) during the period of organogenesis. Embryofetal toxicity (increased fetal resorptions, reduced weights, and hydronephrosis with hydroureter) was observed at doses equal to the MRHD and higher based on mg/m2 body surface area.

Pregnant rabbits were administered oral doses of 20 and 60 mg/kg/day loxapine (~40 and 120 times the MRHD based on mg/m2 body surface area) during the period of organogenesis.

Loxapine did not cause adverse developmental effects in rabbits at doses up to 120 times the MRHD based on mg/m2 body surface area.

Pregnant rats were administered oral doses of 0.21, 0.62, and 1.86 mg/kg/day loxapine (~0.2, 0.6, and 1.8 times the MRHD based on mg/m2 body surface area) during the period of organogenesis and through lactation. Fetal toxicity (increased prenatal death, decreased postnatal survival, reduced fetal weights, delayed ossification, and/or distended renal pelvis with reduced or absent papillae) was observed at doses of 0.6 times the MRHD and higher based on mg/m2 body surface area.

8.2 Lactation

(PLLR conversion)

Risk Summary

There is no available information on the presence of loxapine in human milk, the effects of loxapine on the breastfed infant, or the effects of loxapine on milk production. Loxapine is present in the milk of lactating dogs. When a drug is present in animal milk, it is likely that the drug will be present in human milk. . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ADASUVE and any potential adverse effects on the breastfed child from ADASUVE or from the underlying maternal condition.

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

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

What should I tell my healthcare provider before taking ADASUVE?

Before you take ADASUVE, tell your healthcare provider if you:

have high or low blood pressure
have or have had heart problems or stroke
have or have had seizures (convulsions)
drink alcohol or use street drugs
have any other medical conditions
are pregnant or plan to become pregnant. It is not known if ADASUVE will harm your unborn baby. Talk to your healthcare provider about the risks to you and your unborn or newborn baby if you take ADASUVE during pregnancy.
- If you become pregnant while receiving ADASUVE, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866- 961-2388 or go to http://womensmentalhealth.org/clinical-and- research-programs/pregnancyregistry/
are breastfeeding or plan to breastfeed. It is not known if ADASUVE passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with ADASUVE.

…

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Pregnancy

Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ADASUVE. Advise patients that ADASUVE may cause extrapyramidal and/or withdrawal symptoms (agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder) in a neonate. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADASUVE during pregnancy [see Use in Specific Populations (8.1)].

02/23/2017 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Falls

(new subsection added)

ADASUVE may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

6 Adverse Reactions

(addition underlined)

…

• Falls

…

09/28/2016 (SUPPL-5)

Approved Drug Label (PDF)

Boxed Warning

(revised)

WARNING: BRONCHOSPASM and

INCREASED MORTALITY IN ELDERLY PATIENTS WITH

DEMENTIA-RELATED PSYCHOSIS

See full prescribing information for complete boxed warning.

Bronchospasm

• ADASUVE can cause bronchospasm that has the potential to lead to respiratory distress and respiratory arrest

• ADASUVE is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ADASUVE REMS

• Administer ADASUVE only in an enrolled healthcare facility that has immediate access on site to supplies and personnel trained to manage acute bronchospasm, and ready access to emergency response

services. Facilities must have a short-acting bronchodilator, including a nebulizer and inhalation solution, for the immediate treatment of bronchospasm

Increased Mortality in Elderly Patients with Dementia-Related

Psychosis

• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ADASUVE is not approved for the treatment of patients with dementia-related psychosis

5 Warnings and Precautions

5.1 Bronchospasm (revision underlined)

ADASUVE can cause bronchospasm that has the potential to lead to respiratory distress and respiratory arrest. Administer ADASUVE only in an enrolled healthcare facility that has immediate access on site to supplies and personnel trained to manage acute bronchospasm, and ready access to emergency response services. Facilities must have a short-acting bronchodilator (e.g., albuterol), including a nebulizer and inhalation solution, for the immediate treatment of bronchospasm.

5.2 ADASUVE REMS to Mitigate Bronchospasm (revision underlined)

Because of the risk of bronchospasm, ADASUVE is available only through a restricted program under a REMS called the ADASUVE REMS.

• Healthcare facilities that dispense and administer ADASUVE must be enrolled and

comply with the REMS requirements. Certified healthcare facilities must be able to

provide immediate access on site to supplies and personnel trained to manage acute

bronchospasm, and ready access to emergency response services. Facilities must have

a short-acting bronchodilator (e.g., albuterol), including a nebulizer and inhalation

solution, for the immediate treatment of bronchospasm.

• Wholesalers and distributors that distribute ADASUVE must distribute only to

enrolled healthcare facilities.

U.S. Food and Drug Administration

Drug Safety-related Labeling Changes (SrLC)

ADASUVE (NDA-022549)

(LOXAPINE)

10/27/2021 (SUPPL-9)

8 Use in Specific Populations

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

02/23/2017 (SUPPL-6)

5 Warnings and Precautions

6 Adverse Reactions

09/28/2016 (SUPPL-5)

Boxed Warning

5 Warnings and Precautions

Other