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.

VITUZ (NDA-204307)

(CHLORPHENIRAMINE MALEATE; HYDROCODONE BITARTRATE)

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

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06/28/2018 (SUPPL-4)

Approved Drug Label (PDF)

Boxed Warning

(extensive additions, please refer to label)

4 Contraindications

(additions underlined)

VITUZ is contraindicated for:

All children younger than 6 years of age.

VITUZ 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, chlorpheniramine, or any of the inactive ingredients in VITUZ.

5 Warnings and Precautions

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 VITUZ therapy. The co-ingestion of alcohol with VITUZ may result in increased plasma levels and a potentially fatal overdose of hydrocodone.

5.9 Risks of Use in Patients with Gastrointestinal Conditions

(additions underlined)

VITUZ is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The use of hydrocodone in VITUZ may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

The concurrent use of anticholinergics with VITUZ may produce paralytic ileus.

The hydrocodone in VITUZ may result in constipation or obstructive bowel disease, especially in patients with underlying intestinal motility disorders. Use with caution in patients with underlying intestinal motility disorders.

The hydrocodone in VITUZ may cause spasm of the sphincter of Oddi, resulting in an increase in biliary tract pressure. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

(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

5.5 Risk of Accidental Overdose and Death due to Medication Errors

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

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

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 VITUZ 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 VITUZ therapy.

7.10 Anticholinergic Drugs

(additions underlined)

The concomitant use of anticholinergic drugs with VITUZ 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 VITUZ is used concomitantly with anticholinergic drugs.

Additive adverse effects resulting from cholinergic blockade (e.g., xerostomia, blurred vision, or constipation) may occur when anticholinergic drugs are administered with chlorpheniramine.

7.2 Inhibitors of CYP3A4 and CYP2D6

(new subsection added)

The concomitant use of VITUZ 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 VITUZ and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of VITUZ is achieved [see Warnings and Precautions (5.7)]. 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 VITUZ 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 VITUZ 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 VITUZ in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.

7.4 Phenytoin

(new subsection added)

Adverse event reports in the literature suggest a possible drug interaction involving increased serum phenytoin levels and phenytoin toxicity when chlorpheniramine and phenytoin are co-administered. The exact mechanism for this interaction is not known, however it is believed that chlorpheniramine may inhibit the hepatic metabolism of phenytoin. Avoid the use of VITUZ in patients who are taking phenytoin.

7.5 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 VITUZ in patients who are taking benzodiazepines or other CNS depressants, and instruct patients to avoid consumption of alcohol while on VITUZ.

7.6 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 VITUZ if serotonin syndrome is suspected.

7.7 Monoamine Oxidase Inhibitors (MAOIs)

(additions underlined)

Avoid the use of VITUZ 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 VITUZ, 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).

7.8 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 VITUZ in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

7.9 Diuretics

(new subsection added)

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.

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 VITUZ.

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

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.

Chlorpheniramine

Chlorpheniramine is present in human milk. Chlorpheniramine has not been reported to cause effects on the breastfed infant. The published literature suggests that chlorpheniramine may decrease milk production based on its anticholinergic effects. (see Clinical Considerations)

Clinical Considerations

Infants exposed to VITUZ 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 VITUZ, 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)

VITUZ 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, VITUZ is contraindicated in children less than 6 years of age.

8.5 Geriatric Use

(additions underlined)

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

Use caution when considering the use of VITUZ 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 VITUZ. 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 VITUZ has not been characterized in patients with renal impairment. Patients with renal impairment may have higher plasma concentrations than those with normal function. Chlorpheniramine maleate is cleared substantially by the kidney. As such, impaired renal function could potentially lead to the risk of decreased clearance and thereby increased retention or systemic levels of chlorpheniramine. Therefore, VITUZ should be used with caution in patients with severe impairment of renal function, and patients should be monitored closely for signs of hydrocodone toxicity (respiratory depression, sedation, and hypotension) and chlorpheniramine toxicity.

8.7 Hepatic Impairment

(additions underlined)

The pharmacokinetics of VITUZ 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. Chlorpheniramine maleate is extensively metabolized by liver before elimination from the body. As such, impaired hepatic function could potentially lead to the risk of decreased metabolism and thereby increased systemic levels of chlorpheniramine. Therefore, VITUZ should be used with caution in patients with severe impairment of hepatic function, and patients should be monitored closely for signs of hydrocodone toxicity (respiratory depression, sedation, and hypotension) and chlorpheniramine toxicity.

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-3)

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 REZIRA, 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 REZIRA 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)

(subsection revised, additions underlined)

The use of benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol) concomitantly with REZIRA Oral Solution 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

17.3 Interactions with Benzodiazepines and Other Central Nervous System Depressants

(subsection revised, additions underlined)

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

MEDICATION GUIDE

(New section added, please refer to label)