Drug Safety-related Labeling Changes (SrLC)

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HYCOFENIX (NDA-022279)

(GUAIFENESIN; HYDROCODONE BITARTRATE; PSEUDOEPHEDRINE HYDROCHLORIDE)

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

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06/28/2018 (SUPPL-2)

Approved Drug Label (PDF)

Boxed Warning

(extensive additions, please refer to label)

4 Contraindications

(additions underlined)

HYCOFENIX is contraindicated for:

  • All children younger than 6 years of age.

HYCOFENIX 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.

  • Narrow angle glaucoma, urinary retention, severe hypertension, or severe coronary artery disease.

  • Hypersensitivity to hydrocodone, pseudoephedrine, guaifenesin, or any of the inactive ingredients in HYCOFENIX.

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 HYCOFENIX 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), HYCOFENIX 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.

5.11 Cardiovascular and Central Nervous System Effects

(additions underlined)

The pseudoephedrine contained in HYCOFENIX 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, HYCOFENIX is contraindicated in patients with severe hypertension or coronary artery disease , and should, be used with caution in patients with other cardiovascular disorders.

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 HYCOFENIX therapy. The co-ingestion of alcohol with HYCOFENIX 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)

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

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

The hydrocodone in HYCOFENIX 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 HYCOFENIX 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 HYCOFENIX 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 HYCOFENIX therapy.

7.10 Antihypertensive drugs

(new subsection added)

Due to the antagonistic pharmacologic effects of pseudoephedrine, one of the active ingredients in HYCOFENIX, the concomitant use of HYCOFENIX with antihypertensive drugs which interfere with sympathetic activity (e.g., methyldopa, mecamylamine, and reserpine) may reduce their antihypertensive effects. Use HYCOFENIX with caution in patients who are taking antihypertensive drugs.

7.11 Digitalis

(new subsection added)

Increased ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis. Use HYCOFENIX with caution in patients who are taking digitalis.

7.2 Inhibitors of CYP3A4 and CYP2D6

(new subsection added)

The concomitant use of HYCOFENIX 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 HYCOFENIX and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of HYCOFENIX 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 HYCOFENIX 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 HYCOFENIX 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 HYCOFENIX 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

(subsection revised, 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 HYCOFENIX in patients who are taking benzodiazepines or other CNS depressants, and instruct patients to avoid consumption of alcohol while on HYCOFENIX.

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 HYCOFENIX if serotonin syndrome is suspected.

7.6 Monoamine Oxidase Inhibitors (MAOIs)

(additions underlined)

Avoid the use of HYCOFENIX 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 HYCOFENIX, 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.

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 HYCOFENIX 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 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.

7.9 Anticholinergic Drugs

(additions underlined)

The concomitant use of anticholinergic drugs with HYCOFENIX 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 HYCOFENIX 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, please refer to label)

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Infertility

Chronic use of opioids, such as hydrocodone, a component of HYCOFENIX, 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)

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

8.5 Geriatric Use

(additions underlined)

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

Use caution when considering the use of HYCOFENIX 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 HYCOFENIX. 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 HYCOFENIX 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. HYCOFENIX 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 pseudoephedrine toxicity.

8.7 Hepatic Impairment

(additions underlined)

The pharmacokinetics of HYCOFENIX 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, HYCOFENIX 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

(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 HYCOFENIX, 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 HYCOFENIX 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 HYCOFENIX 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 HYCOFENIX is used with benzodiazepines or other CNS depressants, including alcohol. Because of this risk, patients should avoid concomitant use of HYCOFENIX with benzodiazepines or other CNS depressants, including alcohol.

MAOIs

Patients should be informed that due to its pseudoephedrine component, they should not use HYCOFENIX with an MAOI or within 14 days of stopping use of an MAOI.

MEDICATION GUIDE

(New section added, please refer to label)

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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