Drug Safety-related Labeling Changes (SrLC)
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Guide
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.
REZIRA (NDA-022442)
(HYDROCODONE BITARTRATE; PSEUDOEPHEDRINE HYDROCHLORIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
06/28/2018 (SUPPL-10)
Boxed Warning
(extensive additions, please refer to label)
4 Contraindications
(additions underlined)
REZIRA
is contraindicated for:
All children younger than 6 years of age.
REZIRA
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.
Patients with Known or suspected gastrointestinal obstruction, including paralytic ileus.
Narrow angle glaucoma, urinary retention, severe hypertension, or severe coronary artery disease.
Hypersensitivity to hydrocodone, pseudoephedrine, or any of the inactive ingredients in REZIRA
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 REZIRA 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), REZIRA 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.
(additions underlined)
The pseudoephedrine contained in REZIRA can produce cardiovascular and central nervous system effects in some patients such as, insomnia, dizziness, weakness, tremor, transient elevations in blood pressure, or arrhythmias. In addition, central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension has been reported. Therefore, REZIRA is contraindicated in patients with severe hypertension or coronary artery disease, and should, be used with caution in patients with other cardiovascular disorders.
(additions underlined)
…
Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on REZIRA therapy. The co-ingestion of alcohol with REZIRA may result in increased plasma levels and a potentially fatal overdose of hydrocodone.
(additions underlined)
REZIRA is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.The use of hydrocodone in REZIRA may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
The concurrent use of anticholinergics with REZIRA may produce paralytic ileus.
The hydrocodone in REZIRA 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 REZIRA 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
5.12 Increased Risk of Seizures in Patients with Seizure Disorders
5.13 Severe Hypotension
5.14 Neonatal Opioid Withdrawal Syndrome
5.15 Adrenal Insufficiency
5.16 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 REZIRA 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 REZIRA therapy.
(new subsection added)
Due to the antagonistic pharmacologic effects of pseudoephedrine, one of the active ingredients in REZIRA, the concomitant use of REZIRA with antihypertensive drugs which interfere with sympathetic activity (e.g., methyldopa, mecamylamine, and reserpine) may reduce their antihypertensive effects. Use REZIRA with caution in patients who are taking antihypertensive drugs.
(new subsection added)
Increased ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis. Use REZIRA with caution in patients who are taking digitalis.
(new subsection added)
The concomitant use of REZIRA 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 REZIRA and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of REZIRA 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 REZIRA while taking a CYP3A4 or CYP2D6 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.
(new subsection added)
The concomitant use of REZIRA 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 REZIRA in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.
(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 REZIRA in patients who are taking benzodiazepines or other CNS depressants, and instruct patients to avoid consumption of alcohol while on REZIRA.
(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 REZIRA if serotonin syndrome is suspected.
(additions underlined)
Avoid the use of REZIRA 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 REZIRA, 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). An increase in blood pressure or hypertensive crisis may also occur when pseudoephedrine containing preparations are used with MAOIs.
(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 REZIRA in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.
(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.
(additions underlined)
The concomitant use of anticholinergic drugs with REZIRA 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 REZIRA is used concomitantly with anticholinergic drugs.
8 Use in Specific Populations
8.1 Pregnancy(PLLR conversion, please refer to label)
(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 REZIRA.
There are no data on the presence of REZIRA in human milk, the effects of REZIRA on the breastfed infant, or the effects of REZIRA on milk production; however, data are available with hydrocodone and pseudoephedrine.
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. .
Pseudoephedrine
Pseudoephedrine is present in human milk. Pseudoephedrine has been reported to decrease milk production (see Data). Pseudoephedrine has been reported to cause “irritability” in a breastfed infant (see Clinical Considerations and Data).
Clinical Considerations
Infants exposed to REZIRA through breast milk should be monitored for excess sedation, respiratory depression, and irritability. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid is stopped, or when breastfeeding is stopped.
Data
Pseudoephedrine
In a study of eight lactating women, who were 8 to 76 weeks postpartum and received a single dose of 60 mg of pseudoephedrine, the mean 24-hour milk production was reduced by 24%. In the same study, the estimated mean relative infant dose from breast milk (assuming mean milk consumption of 150 ml/kg/day and a maternal dosing regimen of 60 mg pseudoephedrine four times per day) was calculated to be 4.3% of the weight-adjusted maternal dose.
(PLLR conversion)
Infertility
Chronic use of opioids, such as hydrocodone, a component of REZIRA, may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.
(additions underlined)
REZIRA 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, REZIRA is contraindicated in children less than 6 years of age.
(additions underlined)
Clinical studies have not been conducted with REZIRA geriatric populations.
Use caution when considering the use of REZIRA in patients 65 years of ageor 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 REZIRA. 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.
(additions underlined)
The pharmacokinetics of REZIRA has not been characterized in patients with renal impairment. Patients with renal impairment may have higher plasma concentrations than those with normal function.Pseudoephedrine is primarily excreted unchanged in the urine. Therefore, pseudoephedrine may accumulate in patients with renal impairment. REZIRA 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 signs of pseudoephedrine toxicity.
(additions underlined)
The pharmacokinetics of REZIRA 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, REZIRA 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)
(extensive additions, please refer to label)