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.

FLOWTUSS (NDA-022424)

(GUAIFENESIN; HYDROCODONE BITARTRATE)

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

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12/15/2023 (SUPPL-3)

Approved Drug Label (PDF)

6 Adverse Reactions

(Additions and/or revisions underlined)

The following serious adverse reactions are described, or described in greater detail, in other sections:

…

Other: Drug abuse, drug dependence, opioid withdrawal syndrome.

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g.,diabetes).

06/28/2018 (SUPPL-2)

Approved Drug Label (PDF)

Boxed Warning

(extensive additions, please refer to label)

4 Contraindications

(additions underlined)

FLOWTUSS is contraindicated for:

All children younger than 6 years of age.

FLOWTUSS is also contraindicated in patients with:

Significant respiratory depression.
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.
Known or suspected gastrointestinal obstruction, including paralytic ileus.
Hypersensitivity to hydrocodone, guaifenesin, or any of the inactive ingredients in FLOWTUSS

5 Warnings and Precautions

5.10 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial Pressure, or Brain Tumors

(additions underlined)

Avoid the use of FLOWTUSS in patients with head injury, intracranial lesions, or a pre-existing increase in intracranial pressure. In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), FLOWTUSS may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries.

5.5 Risk of Accidental Overdose and Death due to Medication Errors

(additions underlined)

Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and respiratory depression, ensure that the dose of FLOWTUSS is communicated clearly and dispensed accurately.

Advise patients to always use an accurate milliliter measuring device when measuring and administering FLOWTUSS. Inform patients that household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions.For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate calibrated measuring device and can provide instructions for measuring the correct dose.

5.8 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

(additions underlined)

…

Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on FLOWTUSS therapy. The co-ingestion of alcohol with FLOWTUSS may result in increased plasma levels and a potentially fatal overdose of hydrocodone.

(The following new subsections have been added, please refer to label for more information)

5.1 Addiction, Abuse, and Misuse

5.2 Life-Threatening Respiratory Depression

5.3 Risks with Use in Pediatric Populations

5.4 Risks with Use in Other At-Risk Populations

5.7 Risks from Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

5.9 Risks of Use in Patients with Gastrointestinal Conditions

5.11 Increased Risk of Seizures in Patients with Seizure Disorders

5.12 Severe Hypotension

5.13 Neonatal Opioid Withdrawal Syndrome

5.14 Adrenal Insufficiency

5.15 Drug/Laboratory Test Interactions

6 Adverse Reactions

(extensive additions, please refer to label)

7 Drug Interactions

7.1 Alcohol

(new subsection added)

Concomitant use of alcohol with FLOWTUSS can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone. Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on FLOWTUSS therapy.

7.2 Inhibitors of CYP3A4 and CYP2D6

(new subsection added)

The concomitant use of FLOWTUSS and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of FLOWTUSS and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of FLOWTUSS is achieved . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.

Avoid the use of FLOWTUSS while taking a CYP3A4 or CYP2D6 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

7.3 CYP3A4 Inducers

(new subsection added)

The concomitant use of FLOWTUSS and CYP3A4 inducers such as rifampin, carbamazepine, or phenytoin, can decrease the plasma concentration of hydrocodone , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

Avoid the use of FLOWTUSS in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.

7.4 Benzodiazepines, and Other CNS Depressants

(additions underlined)

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of FLOWTUSS in patients who are taking benzodiazepines or other CNS depressants, and instruct patients to avoid consumption of alcohol while on FLOWTUSS.

7.5 Serotonergic Drugs

(new subsection added)

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation. Discontinue FLOWTUSS if serotonin syndrome is suspected.

7.6 Monoamine Oxidase Inhibitors (MAOIs)

(additions underlined)

Avoid the use of FLOWTUSS in patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken MAOIs within 14 days. The use of MAOIs or tricyclic antidepressants with hydrocodone, one of the active ingredients in FLOWTUSS, may increase the effect of either the antidepressant or hydrocodone. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

7.7 Muscle Relaxants

(new subsection added)

Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Avoid the use of FLOWTUSS in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

7.8 Diuretics

(new subsection added0

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

7.9 Anticholinergic Drugs

(new subsection added)

The concomitant use of anticholinergic drugs with FLOWTUSS may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility when FLOWTUSS is used concomitantly with anticholinergic drugs.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, please refer to label)

8.2 Lactation

(PLLR conversion)

Risk Summary

Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with FLOWTUSS.

There are no data on the presence of FLOWTUSS in human milk, the effects of FLOWTUSS on the breastfed infant, or the effects of FLOWTUSS on milk production; however, data are available with hydrocodone.

Hydrocodone

Hydrocodone is present in breast milk. Published cases report variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in the early post-partum period with relative infant doses of hydrocodone ranging between 1.4 and 3.7%. There are case reports of excessive sedation and respiratory depression in breastfed infants exposed to hydrocodone. No information is available on the effects of hydrocodone on milk production.

Guaifenesin

No information is available on the levels of guaifenesin in breast milk or on milk production.

Clinical Considerations

Infants exposed to FLOWTUSS through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid is stopped, or when breastfeeding is stopped.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Infertility

Chronic use of opioids, such as hydrocodone, a component of FLOWTUSS, may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible

8.4 Pediatric Use

(additions underlined)

FLOWTUSS is not indicated for use in patients younger than 18 years of age because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks for use of hydrocodone in these patients.

Life-threatening respiratory depression and death have occurred in children who received hydrocodone. Because of the risk of life-threatening respiratory depression and death, FLOWTUSS is contraindicated in children less than 6 years of age.

8.5 Geriatric Use

(additions underlined)

Clinical studies have not been conducted with FLOWTUSS in geriatric populations.

Use caution when considering the use of FLOWTUSS in patients 65 years of age or older. Elderly patients may have increased sensitivity to hydrocodone; greater frequency of decreased hepatic, renal, or cardiac function; or concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, including FLOWTUSS. Respiratory depression has occurred after large initial doses of opioids were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration.

Hydrocodone 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, monitor these patients closely for respiratory depression, sedation, and hypotension.

8.6 Renal Impairment

(additions underlined)

The pharmacokinetics of FLOWTUSS has not been characterized in patients with renal impairment. Patients with renal impairment may have higher plasma concentrations than those with normal function. FLOWTUSS should be used with caution in patients with severe impairment of renal function, and patients should be monitored closely for respiratory depression, sedation, and hypotension.

8.7 Hepatic Impairment

(additions underlined)

The pharmacokinetics of FLOWTUSS has not been characterized in patients with hepatic impairment. Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function. Therefore, FLOWTUSS should be used with caution in patients with severe impairment of hepatic function, and patients should be monitored closely for respiratory depression, sedation, and hypotension.

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

MEDICATION GUIDE

(additions and revisions, please refer to label)

PATIENT COUNSELING INFORMATION

(extensive additions, please refer to label)

01/13/2017 (SUPPL-1)

Approved Drug Label (PDF)

Boxed Warning

(New section added)

WARNING: RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.

5 Warnings and Precautions

5.1 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

(subsection added)

Concomitant use of opioids, including FLOWTUSS, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol.

Advise both patients and caregivers about the risks of respiratory depression and sedation if FLOWTUSS is used with benzodiazepines, alcohol, or other CNS depressants.

7 Drug Interactions

7.1 Benzodiazepines, Opioids, Antihistamines, Antipsychotics, Anti-anxiety Agents, or Other CNS Depressants (Including Alcohol)

(additions underlined)

The use of benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol) concomitantly with FLOWTUSS may cause an additive CNS depressant effect, profound sedation, respiratory depression, coma, and death and should be avoided.

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

17 PATIENT COUNSELING INFORMATION

(additions underlined)

…

Interactions with Benzodiazepines and Other Central Nervous System Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if FLOWTUSS is used with benzodiazepines or other CNS depressants, including alcohol. Because of this risk, patients should avoid concomitant use of FLOWTUSS with benzodiazepines or other CNS depressants, including alcohol.

…

MEDICATION GUIDE

(new section added, please refer to label)