HYCOFENIX- hydrocodone bitartrate, pseudoephedrine hydrochloride, guaifenesin liquid 
Mission Pharmacal Company

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use HYCOFENIXTM safely and effectively. See full prescribing information for HYCOFENIX.







HYCOFENIX (hydrocodone bitartrate, pseudoephedrine hydrochloride, and guaifenesin) oral solution, CII







Initial U.S. Approval: 2015

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; MEDICATION ERRORS; CYTOCHROME P450 3A4 INTERACTION; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; INTERACTION WITH ALCOHOL; NEONATAL OPIOID WITHDRAWAL SYNDROME

RECENT MAJOR CHANGES

Boxed Warning 5/2018

Indications and Usage (1) 5/2018

Dosage and Administration (2.1, 2.3) 5/2018

Contraindications (4) 5/2018

Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.7, 5.8. 5.9, 5.12, 5.13, 5.14, 5.15, 5.16) 5/2018

INDICATIONS AND USAGE

  • Adults 18 years of age and older: 10 mL every 4 to 6 hours as needed, not to exceed 4 doses (40 mL) in 24 hours. (2.2)
  • Measure HYCOFENIX with an accurate milliliter measuring device. (2.1, 5.5)
  • Do not increase the dose or dosing frequency. (2.1)
  • Prescribe for the shortest duration consistent with treatment goals. (2.3)
  • Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology. (2.3)
  • Reevaluate patient prior to refilling. (2.3)

DOSAGE AND ADMINISTRATION

  • Adults 18 years of age and older: 10 mL every 4 to 6 hours as needed, not to exceed 4 doses (40 mL) in 24 hours. (2.2)
  • Measure HYCOFENIX with an accurate milliliter measuring device. (2.1, 5.5)
  • Do not increase the dose or dosing frequency. (2.1)
  • Prescribe for the shortest duration consistent with treatment goals. (2.3)
  • Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology. (2.3)
  • Reevaluate patient prior to refilling. (2.3)

DOSAGE FORMS AND STRENGTHS

Oral solution: Each 5 mL contains hydrocodone bitartrate, USP, 2.5 mg; pseudoephedrine hydrochloride, USP, 30 mg; and guaifenesin, USP, 200 mg. ( 3)

CONTRAINDICATIONS

  • Children younger than 6 years of age. (4)
  • Significant respiratory depression. (4)
  • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. (4)
  • Known or suspected gastrointestinal obstruction, including paralytic ileus. (4)
  • Patients with narrow angle glaucoma, urinary retention, severe hypertension, or severe coronary artery disease (4)
  • Hypersensitivity to hydrocodone, pseudoephedrine, guaifenesin, or any of the inactive ingredients in HYCOFENIX. (4)

WARNINGS AND PRECAUTIONS

See Boxed WARNINGS (5)

  • Life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients: Monitor closely, particularly during initiation of therapy. (5.4)
  • Activities requiring mental alertness: Avoid engaging in hazardous tasks requiring mental alertness such as driving or operating machinery. (5.6)
  • Risks of use in patients with head injury, impaired consciousness, increased intracranial pressure, or brain tumors: Avoid use. May increase intracranial pressure and obscure the clinical course of head injuries. (5.10)
  • Cardiovascular and central nervous system effects: Use with caution in patients with cardiovascular disorders. (5.11)
  • Seizures in patients with seizure disorders: Monitor during therapy. (5.12)
  • Severe hypotension: Monitor during initiation of therapy. Avoid use in patients with circulatory shock. (5.13)
  • Adrenal insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.15)

ADVERSE REACTIONS

The most common adverse reactions of HYCOFENIX include: Dizziness, headache, sedation, nausea, and decreased blood pressure ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact Mission Pharmacal Company at 1-800-298-1087 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

  • Benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol): Avoid using with HYCOFENIX; may exhibit additive CNS depression. ( 7.1)
  • MAO inhibitors (MAOIs) or tricyclic antidepressants: Do not use. May increase the effect of either the antidepressant or hydrocodone. ( 7.2)
  • Anticholinergic drugs: Use with caution in order to avoid paralytic ileus and excessive anticholinergic effects. ( 7.3)

USE IN SPECIFIC POPULATIONS

  • Renal Impairment: Use with caution in patients with severe renal impairment. ( 8.6)
  • Hepatic Impairment: Use with caution in patients with severe hepatic impairment. ( 8.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 5/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

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

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

5.2 Respiratory Depression

5.3 Drug Dependence

5.4 Head Injury and Increased Intracranial Pressure

5.5 Activities Requiring Mental Alertness

5.6 Acute Abdominal Conditions

5.7 Co-administration with Anticholinergics

5.8 Co-administration with Monoamine Oxidase Inhibitors (MAOIs) or Tricyclic Antidepressants

5.9 Cardiovascular and Central Nervous System Effects

5.10 Persistent Cough

5.11 Dosing

5.12 Coexisting Conditions

5.13 Renal Impairment

5.14 Hepatic Impairment

6 ADVERSE REACTIONS

7 DRUG INTERACTIONS

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

7.2 MAO Inhibitors or Tricyclic Antidepressants

7.3 Anticholinergic Drugs

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

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

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; MEDICATION ERRORS; CYTOCHROME P450 3A4 INTERACTION; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; INTERACTION WITH ALCOHOL; NEONATAL OPIOID WITHDRAWAL SYNDROME

1 INDICATIONS AND USAGE

HYCOFENIX is indicated for the symptomatic relief of cough, nasal congestion, and to loosen mucus associated with the common cold in patients 18 years of age and older.

Important Limitations of Use:

  • Not indicated for pediatric patients under 18 years of age [ see Use in Specific Populations (8.4)].

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

Administer HYCOFENIX by the oral route only.

Always use an accurate milliliter measuring device when administering HYCOFENIX to ensure that the dose is measured and administered accurately. A household teaspoon is not an accurate measuring device and could lead to overdosage [see Warnings and Precautions (5.5)]. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate measuring device and can provide instructions for measuring the correct dose. Do not overfill. Rinse the measuring device with water after each use.

Advise patients not to increase the dose or dosing frequency of HYCOFENIX because serious adverse events such as respiratory depression may occur with overdosage [see Warnings and Precautions (5.2), Overdosage (10)]. The dosage of HYCOFENIX should not be increased if cough fails to respond; an unresponsive cough should be reevaluated for possible underlying pathology [see Dosage and Administration (2.3), Warnings and Precautions (5.4)].

2.2 Recommended Dosage

Adults 18 years of age and older: 10 mL every 4 to 6 hours as needed, not to exceed 4 doses (40 mL) in 24 hours.

2.3 Monitoring, Maintenance, and Discontinuation of Therapy

Prescribe HYCOFENIX for the shortest duration that is consistent with individual patient treatment goals [see Warnings and Precautions (5.1)].

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy [see Warnings and Precautions (5.2)].

Reevaluate patients with unresponsive cough in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [see Warnings and Precautions (5.4)]. If a patient requires a refill, reevaluate the cause of the cough and assess the need for continued treatment with HYCOFENIX, the relative incidence of adverse reactions, and the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)].

Do not abruptly discontinue HYCOFENIX in a physically-dependent patient [see Drug Abuse and Dependence (9.3)]. When a patient who has been taking HYCOFENIX regularly and may be physically dependent no longer requires therapy with HYCOFENIX, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both.

2.1 Recommended Dosage

Adults and adolescents 18 years of age and older: 10 mL every 4 to 6 hours, not to exceed 4 doses (40 mL) in 24 hours.

Administer HYCOFENIX by the oral route only. Measure HYCOFENIX with an accurate milliliter measuring device. Do not use a household teaspoon to measure the dose [ see Warnings and Precautions ( 5.11) ].

3 DOSAGE FORMS AND STRENGTHS

Oral solution: Each 5 mL contains hydrocodone bitartrate, USP, 2.5 mg; pseudoephedrine hydrochloride, USP, 30 mg; and guaifenesin, USP, 200 mg [ see Description ( 11) ].

4 CONTRAINDICATIONS

  • Narrow angle glaucoma, urinary retention, severe hypertension, or severe coronary artery disease [ see Warnings and Precautions (5.11)] .
  • Hypersensitivity to hydrocodone, pseudoephedrine, guaifenesin, or any of the inactive ingredients in HYCOFENIX [ see Adverse Reactions (6)].

5 WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse

HYCOFENIX contains hydrocodone, a Schedule II controlled substance. As an opioid, HYCOFENIX exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)], which can lead to overdose and death [see Overdosage (10)]. Reserve HYCOFENIX for use in adult patients for whom the benefits of cough suppression are expected to outweigh the risks, and in whom an adequate assessment of the etiology of the cough has been made. Assess each patient’s risk prior to prescribing HYCOFENIX, prescribe HYCOFENIX for the shortest duration that is consistent with individual patient treatment goals, monitor all patients regularly for the development of addiction or abuse, and refill only after reevaluation of the need for continued treatment.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed HYCOFENIX. Addiction can occur at recommended dosages and if the drug is misused or abused. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing HYCOFENIX. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including hydrocodone, one of the active ingredients in HYCOFENIX. Hydrocodone produces dose-related respiratory depression by directly acting on the brain stem respiratory center that controls respiratory rhythm and may produce irregular and periodic breathing. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression includes discontinuation of HYCOFENIX, close observation, supportive measures, and use of opioid antagonists (e.g. naloxone), depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of HYCOFENIX, the risk is greatest during the initiation of therapy, when HYCOFENIX is used concomitantly with other drugs that may cause respiratory depression [see Warnings and Precautions (5.8)], in patients with chronic pulmonary disease or decreased respiratory reserve, and in patients with altered pharmacokinetics or altered clearance (e.g. elderly, cachectic, or debilitated patients) [see Warnings and Precautions (5.4)].

To reduce the risk of respiratory depression, proper dosing of HYCOFENIX is essential [see Dosage and Administration (2.1), Warnings and Precautions (5.5)]. Monitor patients closely, especially within the first 24-72 hours of initiating therapy or when used in patients at higher risk.

Overdose of hydrocodone in adults has been associated with fatal respiratory depression, and the use of hydrocodone in children younger than 6 years of age has been associated with fatal respiratory depression when used as recommended. Accidental ingestion of even one dose of HYCOFENIX, especially by children, can result in respiratory depression and death.

5.3 Risks with Use in Pediatric Populations

Children are particularly sensitive to the respiratory depressant effects of hydrocodone [see Warnings and Precautions (5.2)]. Because of the risk of life-threatening respiratory depression and death, HYCOFENIX is contraindicated in children less than 6 years of age [see Contraindications (4)].

Use of HYCOFENIX in children also exposes them to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)], which can lead to overdose and death [see Warnings and Precautions (5.1), Overdosage (10)]. Because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks of use of hydrocodone in pediatric patients, HYCOFENIX is not indicated for use in patients younger than 18 years of age [see Indications (1), Use in Specific Populations (8.4)].

5.4 Risks with Use in Other At-Risk Populations
Unresponsive Cough

The dosage of HYCOFENIX should not be increased if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease [see Dosage and Administration (2.3)].

Asthma and Other Pulmonary Disease

The use of HYCOFENIX in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated [see Contraindications (4)].

Opioid analgesics and antitussives, including hydrocodone, one of the active ingredients in HYCOFENIX, should not be used in patients with acute febrile illness associated with productive cough or in patients with chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient’s respiratory function.

HYCOFENIX-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of HYCOFENIX [see Warnings and Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)].

Because of the risk of respiratory depression, avoid the use of opioid antitussives, including HYCOFENIX in patients with compromised respiratory function, patients at risk of respiratory failure, and in elderly, cachectic, or debilitated patients. If HYCOFENIX is prescribed, monitor such patients closely, particularly when initiating HYCOFENIX and when HYCOFENIX is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.8)].

5.5 Risk of Accidental Overdose and Death due to Medication Errors

Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and respiratory depression, ensure that the dose of HYCOFENIX is communicated clearly and dispensed accurately [see Dosage and Administration (2.1)].

Advise patients to always use an accurate milliliter measuring device when measuring and administering HYCOFENIX. Inform patients that household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions [see Overdosage (10)]. 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.

5.6 Activities Requiring Mental Alertness: Risks of Driving and Operating Machinery

Hydrocodone, one of the active ingredients in HYCOFENIX, may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of HYCOFENIX. Avoid concurrent use of HYCOFENIX with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur [see Warnings and Precautions (5.8)].

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

Concomitant use of HYCOFENIX with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.2)], particularly when an inhibitor is added after a stable dose of HYCOFENIX is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in HYCOFENIX-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions.

Concomitant use of HYCOFENIX with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone.

Avoid the use of HYCOFENIX in patients who are taking a CYP3A4 inhibitor or inducer. If concomitant use of HYCOFENIX with a CYP3A4 inhibitor or inducer is necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal [see Drug Interactions (7.2, 7.3)].

5.8 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

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 [see Drug Interactions (7.1, 7.4)].

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 [see Patient Counseling Information (17)].

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 [see Drug Interactions (7.1, 7.4)].

5.9 Risks of Use in Patients with Gastrointestinal Conditions

HYCOFENIX is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications (4)]. 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 [see Drug Interactions (7.9)].

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 [see Warnings and Precautions (5.16)]. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

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

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

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 [see Contraindications (4)], and should, be used with caution in patients with other cardiovascular disorders.

5.12 Increased Risk of Seizures in Patients with Seizure Disorders

The hydrocodone in HYCOFENIX may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during HYCOFENIX therapy.

5.13 Severe Hypotension

HYCOFENIX may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7.4)]. Monitor these patients for signs of hypotension after initiating HYCOFENIX.

In patients with circulatory shock, HYCOFENIX may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of HYCOFENIX in patients with circulatory shock.

5.14 Neonatal Opioid Withdrawal Syndrome

HYCOFENIX is not recommended for use in pregnant women. Prolonged use of HYCOFENIX during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. [see Use in Specific Populations (8.1), Patient Counseling Information (17)]

5.15 Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.16 Drug/Laboratory Test Interactions

Because opioid agonists may increase biliary tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after administration of a dose of HYCOFENIX.

5.1 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

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 [ see Drug Interactions ( 7.1) ].

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 [ see Patient Counseling Information ( 17) ].

5.2 Respiratory Depression

Hydrocodone bitartrate, one of the active ingredients in HYCOFENIX, produces doserelated respiratory depression by directly acting on brain stem respiratory centers. Overdose of hydrocodone bitartrate in adults has been associated with fatal respiratory depression, and the use of hydrocodone bitartrate in children less than 6 years of age has been associated with fatal respiratory depression. Exercise caution when administering HYCOFENIX because of the potential for respiratory depression. If respiratory depression occurs, it may be antagonized by the use of naloxone hydrochloride and other supportive measures when indicated [ see Overdosage ( 10) ].

5.3 Drug Dependence

Hydrocodone can produce drug dependence of the morphine type and therefore, has the potential for being abused. Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of HYCOFENIX. Prescribe and administer HYCOFENIX with the same degree of caution appropriate to the use of other opioid drugs [ see Drug Abuse and Dependence ( 9.2), ( 9.3) ].

5.4 Head Injury and Increased Intracranial Pressure

The respiratory depression effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Furthermore, opioids produce adverse reactions which may obscure the clinical course of patients with head injuries. The use of HYCOFENIX should be avoided in these patients.

5.5 Activities Requiring Mental Alertness

Hydrocodone bitartrate, one of the active ingredients in HYCOFENIX, may produce marked drowsiness and impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination after ingestion of HYCOFENIX. Concurrent use of HYCOFENIX with alcohol or other central nervous system depressants should be avoided because additional impairment of central nervous system performance may occur.

5.6 Acute Abdominal Conditions

HYCOFENIX should be used with caution in patients with acute abdominal conditions since the administration of hydrocodone may obscure the diagnosis or clinical course of patients with acute abdominal conditions. The concurrent use of other anticholinergics with hydrocodone may produce paralytic ileus [ see Drug Interactions ( 7.3) ].

5.7 Co-administration with Anticholinergics

The concurrent use of anticholinergics with hydrocodone may produce paralytic ileus. Exercise caution when using HYCOFENIX in patients taking anticholinergic medications [ see Drug Interactions ( 7.3) ].

5.8 Co-administration with Monoamine Oxidase Inhibitors (MAOIs) or Tricyclic Antidepressants

HYCOFENIX should not be used in patients receiving MAOI therapy or within 14 days of stopping such therapy. The use of MAOIs or tricyclic antidepressants with hydrocodone bitartrate may increase the effect of either the antidepressant or hydrocodone [ see Contraindications ( 4) and Drug Interactions ( 7.2) ].

5.9 Cardiovascular and Central Nervous System Effects

The pseudoephedrine hydrochloride contained in HYCOFENIX can produce cardiovascular and central nervous system effects in some patients such as insomnia, dizziness, weakness, tremor, or arrhythmias. In addition, central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension has been reported. Therefore, HYCOFENIX should be used with caution in patients with cardiovascular disorders, and should not be used in patients with severe hypertension or coronary artery disease.

5.10 Persistent Cough

HYCOFENIX should not be used in patients with a persistent or chronic cough such as occurs with smoking, asthma, chronic bronchitis, or emphysema, or where cough is accompanied by excessive phlegm (mucus).

5.11 Dosing

Patients should be advised to measure HYCOFENIX with an accurate milliliter measuring device. Patients should be informed that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions [ see Overdosage ( 10) ]. Patients should be advised to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose.

5.12 Coexisting Conditions

HYCOFENIX should be used with caution in patients with diabetes, thyroid disease, Addison’s disease, prostatic hypertrophy or urethral stricture, and asthma.

5.13 Renal Impairment

HYCOFENIX should be used with caution in patients with severe renal impairment [ see Use in Specific Populations ( 8.6) ].

5.14 Hepatic Impairment

HYCOFENIX should be used with caution in patients with severe hepatic impairment [ see Use in Specific Populations ( 8.7) ].

6 ADVERSE REACTIONS

Use of hydrocodone bitartrate is associated with the following:

  • Respiratory depression [ see Warnings and Precautions ( 5.2) and Overdosage ( 10) ]
  • Drug dependence [ see Warnings and Precautions ( 5.3) and Drug Abuse and Dependence ( 9.3) ]
  • Increased intracranial pressure [ see Warnings and Precautions ( 5.4) ]
  • Decreased mental alertness with impaired mental and/or physical abilities [ see Warnings and Precautions ( 5.5) ]
  • Paralytic ileus [ see Warnings and Precautions ( 5.6) ]

Use of pseudoephedrine, a sympathomimetic amine, may result in the following:

  • Central nervous system effects such as insomnia, dizziness, weakness, tremor, or convulsions [ see Warnings and Precautions ( 5.9) ]
  • Cardiovascular system effects such as arrhythmias, or increased blood pressure, cardiovascular collapse with accompanying hypotension [ see Warnings and Precautions ( 5.9) ]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most common adverse reactions experienced by subjects taking a single dose of HYCOFENIX in the clinical setting include the following: Central Nervous System: headache, dizziness, sedation (somnolence); Gastrointestinal System: nausea, diarrhea; Cardiovascular System: decreased blood pressure; Vascular System: hot flush.

7 DRUG INTERACTIONS

No specific interaction studies have been conducted with HYCOFENIX.

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

The use of benzodiazepines, opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants (including alcohol) concomitantly with HYCOFENIXmay cause an additive CNS depressant effect, profound sedation, respiratory depression, coma, and death and should be avoided [ see Warnings and Precautions ( 5.1) ].

7.2 MAO Inhibitors or Tricyclic Antidepressants

Do not prescribe HYCOFENIX if the patient is taking a prescription MAOI (i.e., certain drugs used for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping an MAOI drug. The use of MAOIs or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone. An increase in blood pressure of hypertensive crisis may also occur when pseudoephedrine containing preparations are used with MAOIs [ see Warnings and Precautions ( 5.8) ].

7.3 Anticholinergic Drugs

Hydrocodone should be administered cautiously to persons receiving anticholinergic drugs in order to avoid paralytic ileus and excessive anticholinergic effects [ see Warnings and Precautions ( 5.7) ].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects
Pregnancy Category C
There are no adequate and well controlled studies of HYCOFENIX in pregnant women. Reproductive toxicity studies have not been conducted with HYCOFENIX; however, studies are available with an individual active ingredient or related active ingredient. Hydrocodone was teratogenic in hamsters. Codeine, an opiate related to hydrocodone, increased resorptions and decreased fetal weight in rats. Because animal reproduction studies are not always predictive of human response, HYCOFENIX should be used during pregnancy only if the benefit justifies the potential risk to the fetus.

Hydrocodone
Hydrocodone has been shown to be teratogenic in hamsters when given in a dose approximately 35 times the maximum recommended human daily dose (MRHDD) (on a mg/m 2 basis at a single subcutaneous dose of 102 mg/kg on gestation day 8). Reproductive toxicology studies were also conducted with codeine, an opiate related to hydrocodone. In a study in which pregnant rats were dosed throughout organogenesis, a dose of codeine approximately 50 times the MRHDD of hydrocodone (on a mg/m 2 basis at an oral dose of 120 mg/kg/day of codeine) increased resorptions and decreased fetal weight; however, these effects occurred in the presence of maternal toxicity. In studies in which rabbits and mice were dosed throughout organogenesis, doses of codeine up to approximately 25 and 120 times, respectively, the MRHDD of hydrocodone (on a mg/m 2 basis at oral doses of 30 and 600 mg/kg/day, respectively), produced no adverse developmental effects.

Non-teratogenic Effects
Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose.

8.2 Labor and Delivery

As with all opioids, administration of HYCOFENIX to the mother shortly before delivery may result in some degree of respiratory depression in the newborn, especially if higher doses are used.

8.3 Nursing Mothers

Caution should be exercised when HYCOFENIX is administered to nursing mothers. Hydrocodone and pseudoephedrine are known to be excreted in human milk. No studies have been performed to determine if guaifenesin is excreted into breastmilk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from HYCOFENIX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness of HYCOFENIX in pediatric patients under 18 years of age has not been established. The use of hydrocodone in children less than 6 years of age is associated with fatal respiratory depression [ see Warnings and Precautions ( 5.1) ].

8.5 Geriatric Use

Clinical studies have not been conducted with HYCOFENIX in geriatric populations. Other reported clinical experience with the individual active ingredients of HYCOFENIX has not identified differences in responses between the elderly and patients younger than 65 years of age. In general, dose selection for an elderly patient should be made with caution, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The pseudoephedrine contained in HYCOFENIX is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Impairment

HYCOFENIX should be given with caution in patients with severe impairment of renal function. Pseudoephedrine is primarily excreted unchanged in the urine as unchanged drug with the remainder apparently being metabolized in the liver. Therefore, pseudoephedrine may accumulate in patients with renal impairment.

8.7 Hepatic Impairment

HYCOFENIX should be given with caution in patients with severe impairment of hepatic function.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

HYCOFENIX is a Schedule II controlled prescription containing hydrocodone bitartrate and should be prescribed and administered with caution.

9.2 Abuse

Hydrocodone can produce drug dependence of the morphine type and therefore, has the potential for being abused. Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of HYCOFENIX, and it should be prescribed and administered with the same degree of caution appropriate to the use of other opioid drugs.

Abuse of guaifenesin has been linked to the formation of kidney stones composed of the major metabolite β-(2-methoxyphenoxy) lactic acid.

9.3 Dependence

Psychic dependence, physical dependence, and tolerance may develop upon repeated administration of opioids; therefore, HYCOFENIX should be prescribed and administered with caution [ see Warnings and Precautions ( 5.2) ].

Physical dependence, the condition in which continued administration of the drug is required to prevent the appearance of a withdrawal syndrome, assumes clinically significant proportions only after several weeks of continued oral opioid use, although some mild degree of physical dependence may develop after a few days of opioid therapy.

10 OVERDOSAGE

No human overdosage data are available for HYCOFENIX.

Hydrocodone

Overdosage with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, dizziness, ringing in the ears, confusion, blurred vision, eye problems, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdose, apnea, circulatory collapse, cardiac arrest and death may occur.

Pseudoephedrine

Overdosage with sympathomimetics such as pseudoephedrine may give rise to giddiness, headache, nausea, vomiting, sweating, thirst, tachycardia, precordial pain, palpitations, difficulty in micturition, muscle weakness and tenseness, anxiety, restlessness, and insomnia. Many patients can present a toxic psychosis with delusion and hallucinations. Some may develop cardiac arrhythmias, circulatory collapse, convulsion, coma, and respiratory failure.

Guaifenesin

Overdosage with guaifenesin can cause depression of the central nervous system. While present in polypharmacy overdoses, one case of overdose with only significant levels of guaifenesin has been reported. Symptoms included slurred speech, shallow respirations, reduced heart rate with rhythm sinus bradycardia, followed by asystole.

Treatment of overdosage consists of discontinuation of HYCOFENIX together with institution of appropriate therapy. Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The opioid antagonist naloxone hydrochloride is a specific antidote for respiratory depression which may result from overdosage or unusual sensitivity to opioids including hydrocodone. Therefore, an appropriate dose of naloxone hydrochloride should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. For further information, see full prescribing information for naloxone hydrochloride. An antagonist should not be administered in the absence of clinically significant respiratory depression. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Gastric emptying may be useful in removing unabsorbed drug.

11 DESCRIPTION

HYCOFENIX (hydrocodone bitartrate, pseudoephedrine hydrochloride, and guaifenesin) oral solution contains hydrocodone bitartrate (a centrally-acting opioid antitussive), pseudoephedrine hydrochloride (an indirect sympathomimetic amine), and guaifenesin (an expectorant). Each 5 mL dose of HYCOFENIX contains: hydrocodone bitartrate, USP, 2.5 mg; pseudoephedrine hydrochloride, USP, 30 mg; and guaifenesin, USP, 200 mg.

HYCOFENIX also contains: black raspberry flavor, citric acid, D&C Red #33, FD&C Blue #1, glycerin, methylparaben, polyethylene glycol, propylparaben, purified water, saccharin sodium, sodium citrate, and sorbitol.

Hydrocodone Bitartrate
Hydrocodone bitartrate is a centrally-acting opioid antitussive and analgesic. It is affected by light and occurs as fine white crystals or crystalline powder which is derived from the opium alkaloid, thebaine. Its chemical name is morphinan-6-one, 4,5-epoxy-3-methoxy- 17-methyl-, (5α)-, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1), hydrate (2:5). It is also known as 4,5α-Epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5);and may be represented by the following structural formula:

structure1

Pseudoephedrine Hydrochloride
Pseudoephedrine hydrochloride is benzenemethanol, α-[1-(methylamino)ethyl]-, [S-(R*,R*)] hydrochloride and has the following chemical structure:

structure2

Guaifenesin
Guaifenesin is an expectorant and occurs as a white powder. Its chemical name is 3-(2-methoxyphenoxy)-1,2-propanediol, and may be represented by the following structural formula:

structure3

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Hydrocodone is a semisynthetic narcotic antitussive and analgesic with multiple actions qualitatively similar to those of codeine. The precise mechanism of action of hydrocodone and other opiates is not known; however, hydrocodone is believed to act directly on the cough center. In excessive doses, hydrocodone will depress respiration. Hydrocodone can produce miosis, euphoria, and physical and physiological dependence.

Pseudoephedrine hydrochloride is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa. Pseudoephedrine hydrochloride is recognized as an effective agent for the relief of nasal congestion due to upper respiratory allergies or common cold. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory side effects.

Guaifenesin is an expectorant the action of which promotes or facilitates the removal of secretions from the respiratory tract. The precise mechanism of action of guaifenesin is not known; however, it is thought to act as an expectorant by increasing the volume and reducing the viscosity of secretions in the trachea and bronchi. In turn, this may increase the efficiency of the cough reflex and facilitate removal of the secretions.

12.3 Pharmacokinetics

Systemic exposure (in terms of peak plasma concentrations and area under plasma concentration versus time curve) of hydrocodone bitartrate, pseudoephedrine hydrochloride, and guaifenesin after a single 10 mL oral dose administration of 5 mg hydrocodone bitartrate, 60 mg pseudoephedrine hydrochloride, and 400 mg guaifenesin are equivalent to the respective reference solutions of 5 mL hydrocodone bitartrate (5 mg/5 mL), 5 mL pseudoephedrine hydrochloride (30 mg/5 mL), and 10 mL guaifenesin (200 mg/5 mL).

Hydrocodone
Following a single 10 mL oral dose administration of 5 mg hydrocodone bitartrate, 60 mg pseudoephedrine hydrochloride, and 400 mg guaifenesin administered to 37 healthy adults, the geometric mean C max and AUC 0-inf for hydrocodone were 9.0 ng/mL and 61.2 ng·hr/mL, respectively. The median time to maximum concentration for hydrocodone was about 1.67 hours. Food has no significant effect on the extent of absorption of hydrocodone. The mean plasma half-life of hydrocodone is approximately 4 hours.

Pseudoephedrine
Following a single 10 mL oral dose administration of 5 mg hydrocodone bitartrate, 60 mg pseudoephedrine hydrochloride, and 400 mg guaifenesin administered to 37 healthy adults, the geometric mean C max and AUC 0-inf for pseudoephedrine were 0.19 mcg/mL and 1.9 mcg·hr/mL, respectively. The median time to maximum concentration for pseudoephedrine was about 2.5 hours. Food has no significant effect on the extent of absorption of pseudoephedrine. The mean plasma half-life of pseudoephedrine is approximately 6 hours.

Guaifenesin
Following a single 10 mL oral dose administration of 5 mg hydrocodone bitartrate, 60 mg pseudoephedrine hydrochloride, and 400 mg guaifenesin administered to 36 healthy adults, the geometric mean C max and AUC 0-inf for guaifenesin were 2.0 mcg/mL and 2.6 mcg·hr/mL, respectively. The median time to maximum concentration was about 25 minutes. The effect of food on guaifenesin systemic exposure is not considered to be clinically meaningful. The mean plasma half-life of guaifenesin is approximately 1 hour.

Drug interactions
When guaifenesin, pseudoephedrine, and hydrocodone were administered in combination, the pharmacokinetics for each component was similar to those observed when each component was administered separately.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and reproductive studies have not been conducted with HYCOFENIX; however, published information is available for the individual active ingredients or related active ingredients.

Hydrocodone
Carcinogenicity studies were conducted with codeine, an opiate related to hydrocodone. In 2 year studies in F344/N rats and B6C3F1 mice, codeine showed no evidence of tumorigenicity at dietary doses up to 70 and 400 mg/kg/day, respectively (approximately 30 and 80 times, respectively, the MRHDD of hydrocodone on a mg/m2 basis).

Pseudoephedrine
Two-year feeding studies in rats and mice demonstrated no evidence of carcinogenic potential with ephedrine sulfate, a structurally related drug with pharmacological properties similar to pseudoephedrine, at dietary doses up to 10 and 27 mg/kg, respectively (approximately 0.3 and 0.5 times, respectively, the MRHDD of pseudoephedrine hydrochloride on a mg/m 2 basis).

Guaifenesin
Carcinogenicity, genotoxicity, or reproductive toxicology studies have not been conducted with guaifenesin.

14 CLINICAL STUDIES

Efficacy studies were not conducted with HYCOFENIX. Efficacy of HYCOFENIX is based on demonstration of bioequivalence to the individual comparator products [ see Clinical Pharmacology ( 12.3) ].

16 HOW SUPPLIED/STORAGE AND HANDLING

HYCOFENIX (hydrocodone bitartrate, pseudoephedrine hydrochloride, and guaifenesin) oral solution is supplied as a violet-colored, black raspberry flavored liquid containing 2.5 mg hydrocodone bitartrate, 30 mg pseudoephedrine hydrochloride, and 200 mg guaifenesin in each 5 mL. It is available in:
White HDPE bottles of 16 fl. oz. (473 mL): NDC 0178-3291-16
White HDPE bottles of 4 fl. oz. (118 mL): NDC 0178-3291-04
Store solution at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Dispense in a tight, light-resistant container, as defined in the USP, with a childresistant closure.

17 PATIENT COUNSELING INFORMATION

Overdosage
Advise patients not to increase the dose or dosing frequency of HYCOFENIX because serious adverse events such as respiratory depression may occur with overdosage [ see Warnings and Precautions ( 5.1) and Overdosage ( 10) ].

Dosing
Advise patients to measure HYCOFENIX with an accurate milliliter measuring device. Patients should be informed that a household teaspoon is not an accurate measuring device and could lead to overdosage, especially when half a teaspoon is measured. Patients should be advised to ask their pharmacist to recommend an appropriate measuring device and for instructions for measuring the correct dose [ see Dosage and Administration ( 2) and Warnings and Precautions ( 5.10) ].

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 [ see Warnings and Precautions ( 5.1) and Drug Interactions ( 7.1) ].

Activities Requiring Mental Alertness
Advise patients to avoid engaging in hazardous tasks that require mental alertness and motor coordination such as operating machinery or driving a motor vehicle as HYCOFENIX may produce marked drowsiness [ see Warnings and Precautions ( 5.5) ].

Drug Dependence
Caution patients that HYCOFENIX contains hydrocodone bitartrate and can produce drug dependence [ see Warnings and Precautions ( 5.3) ].

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 [ see Warning and Precautions ( 5.8) ].

Manufactured for:
MISSION PHARMACAL COMPANY
San Antonio, TX 78230 1355

1133A00 R0916

MEDICATION GUIDE

HYCOFENIX® (Hye-koh-fee-niks)

(hydrocodone bitartrate, pseudoephedrine hydrochloride, and guaifenesin)

oral solution, C-II

What is the most important information I should know about HYCOFENIX?

HYCOFENIX is not for children under 18 years of age.

HYCOFENIX can cause serious side effects, including:

Addiction, abuse and misuse. Taking HYCOFENIX or other medicines that contain an opioid can cause addiction, abuse and misuse, which can lead to overdose and death. This can happen even if you take HYCOFENIX exactly as prescribed by your healthcare provider. Your risk of addiction, abuse, and misuse is increased if you or a family member has a history of drug or alcohol abuse or addiction, or mental health problems.

Do not share your HYCOFENIX with other people.
Keep HYCOFENIX in a safe place away from children.

Life-threatening breathing problems (respiratory depression). HYCOFENIX can cause breathing problems (respiratory depression) that can happen at any time during treatment and can lead to death. Your risk of breathing problems is greatest when you first start taking HYCOFENIX, are taking other medicines that can cause breathing problems, have certain lung problems, are elderly, or have certain other health problems. Children are at higher risk for respiratory depression. Breathing problems can happen even if you take HYCOFENIX exactly as prescribed by your healthcare provider.

Call your healthcare provider or get emergency medical help right away if anyone taking HYCOFENIX has any of the symptoms below:

increased sleepiness
confusion
difficulty breathing

shallow breathing
limpness

Keep HYCOFENIX in a safe place away from children. Accidental use of even 1 dose of HYCOFENIX, especially by a child, is a medical emergency and can cause breathing problems (respiratory depression) which can lead to death. If a child accidentally takes HYCOFENIX, get emergency medical help right away.

Overdose and death due to medicine dosing errors. Overdose and death can happen if you measure the wrong dose of HYCOFENIX. Always use an accurate milliliter (mL) measuring device to measure the correct amount of HYCOFENIX. Do not use a household teaspoon to measure your medicine. You may accidentally take too much. You can ask your pharmacist for the measuring device and how to measure the correct dose.
Breathing problems (respiratory depression) that can lead to death and opioid withdrawal can happen if you start taking or stop taking other medicines while taking HYCOFENIX, including:

certain antibiotics
certain medicines to treat a fungal infection
certain medicines to treat Human Immunodeficiency Virus (HIV)-1 infection, Acquired Immune Deficiency Syndrome (AIDS), or Hepatitis C
rifampin
carbamazepine
phenytoin

Tell your healthcare provider if you take any of these medicines. Ask your healthcare provider or pharmacist if you are not sure if your medicine is one listed above.

Severe drowsiness, breathing problems (respiratory depression), coma, and death can happen in people who take HYCOFENIX with benzodiazepines or other central nervous system depressants, including alcohol.

Do not take benzodiazepines or any medicine that can cause drowsiness or sleepiness during treatment with HYCOFENIX.
Do not drink alcohol or take prescription or over-the-counter medicines that contain alcohol during treatment with HYCOFENIX.

Opioid withdrawal in a newborn. Use of HYCOFENIX during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. You should not take HYCOFENIX if you are pregnant. Tell your healthcare provider right away if you are pregnant or think you may be pregnant.

What is HYCOFENIX?

HYCOFENIX is a prescription medicine used in adults to treat cough, a stuffy nose (nasal congestion), and loosen mucus that you can have with a common cold. HYCOFENIX contains 3 medicines, hydrocodone, pseudoephedrine and guaifenesin. Hydrocodone is an opioid (narcotic) cough suppressant. Pseudoephedrine is a decongestant. Guaifenesin is an expectorant.
HYCOFENIX is a federal controlled substance (C-II) because it contains hydrocodone that can be abused or lead to dependence. Keep HYCOFENIX in a safe place to prevent misuse and abuse. Selling or giving away HYCOFENIX may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.

Who should not take HYCOFENIX?

HYCOFENIX is not for children under 18 years of age. See “What is the most important information I should know about HYCOFENIX?”

Do not take HYCOFENIX if you:

have severe breathing problems (respiratory depression) or breathing problems caused by asthma. See “What is the most important information I should know about HYCOFENIX?”
have a blockage (obstruction) in your bowel such as a paralytic ileus.
have a type of glaucoma called “narrow angle glaucoma”.
have problems emptying your bladder (urinary retention).
have severe high blood pressure or certain heart problems (severe coronary artery disease).
are allergic to hydrocodone, pseudoephedrine, guaifenesin, or any of the ingredients in HYCOFENIX. See the end of this Medication Guide for a complete list of ingredients.

Ask your healthcare provider if you have any questions about this information.

Before you take HYCOFENIX, tell your healthcare provider about all of your medical conditions, including if you:

have a drug addiction
have lung or breathing problems
have a fever and are coughing up mucus
have had a recent head injury
have had a brain tumor or other brain problems
have or have had seizures
have pain in your stomach-area (abdomen)
have constipation or other bowel problems

have bile duct or pancreas problems

have glaucoma (increased pressure in your eyes)
have prostate problems
have problems with your urinary tract or difficulty urinating
have kidney or liver problems
have heart or blood vessel (cardiovascular) problems
have adrenal gland problems
plan to have surgery
have low blood pressure

are pregnant or plan to become pregnant. HYCOFENIX can harm your unborn baby. See “What is the most important information I should know about HYCOFENIX?”
are breastfeeding or plan to breastfeed. Hydrocodone and pseudoephedrine pass into your breast milk and can cause serious side effects in your baby including increased sleepiness, irritability, breathing problems (respiratory depression), and death. You and your healthcare provider should decide if you will take HYCOFENIX or breastfeed. You should not do both. See “What should I avoid while taking HYCOFENIX?”
plan to have children. HYCOFENIX may affect the ability to have a child in females and males (fertility problems). It is not known if these fertility problems will be reversible, even after you stop taking HYCOFENIX. Talk to your healthcare provider if this is a concern for you.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

Taking HYCOFENIX with certain other medicines can cause side effects or affect how well HYCOFENIX or the other medicines work. Do not start or stop taking other medicines without talking to your healthcare provider.

Especially tell your healthcare provider if you:

take pain medicines such as opioids (narcotics).
take cold or allergy medicines that contain antihistamines or cough suppressants.
drink alcohol.
take muscle relaxants.
take certain medicines used to treat mood, anxiety, psychotic or thought disorders, or depression, including monoamine oxidase inhibitors (MAOIs), tricyclics, selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), or antipsychotics.
take medicines to lower your blood pressure.
take water pills (diuretics).
take medicines called “anticholinergics” used to treat certain health problems including asthma, chronic obstructive pulmonary disease (COPD), or stomach problems.
take a medicine called “digitalis” used to treat certain heart problems.

Ask your healthcare provider if you are not sure if you take one of these medicines.

How should I take HYCOFENIX?

See “What is the most important information I should know about HYCOFENIX?”
Take HYCOFENIX exactly as your healthcare provider tells you to take it. Do not change your dose without talking to your healthcare provider.
Take HYCOFENIX using an accurate milliliter (mL) measuring device. If you do not have one, ask your pharmacist to give you a measuring device to help you measure the correct amount of HYCOFENIX. Do not use a household teaspoon to measure your medicine. You may accidentally take too much.
Do not overfill the measuring device.
Rinse your measuring device with water after each use.
If you take too much HYCOFENIX, call your healthcare provider or go to the nearest hospital emergency room right away.
Tell your healthcare provider if your cough does not get better within 5 days of treatment with HYCOFENIX.

What should I avoid while taking HYCOFENIX?

Avoid driving a car or operating machinery during treatment with HYCOFENIX. HYCOFENIX can cause you to be drowsy, slow your thinking and motor skills, and affect your vision.
Do not drink alcohol during treatment with HYCOFENIX. Drinking alcohol can increase your chances of having serious side effects.

Avoid the use of HYCOFENIX if you:

are pregnant. Use of HYCOFENIX during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. Tell your healthcare provider right away if you are pregnant or think you may be pregnant.
are breastfeeding. Use of HYCOFENIX while breastfeeding can cause severe breathing problems (respiratory depression) in your breastfed infant that could be life-threatening.
take a medicine called a monoamine oxidase inhibitor (MAOI). Avoid taking an MAOI within 14 days after you stop taking HYCOFENIX. Avoid starting HYCOFENIX if you stopped taking an MAOI in the last 14 days.

What are the possible side effects of HYCOFENIX?

HYCOFENIX can cause serious side effects, including:

See “What is the most important information I should know about HYCOFENIX?”
Bowel problems including severe constipation or stomach pain. See “Who should not take HYCOFENIX?”
Increased pressure in your head (intracranial). Avoid the use of HYCOFENIX if you have a head injury or have been told that you have changes in the tissue of your brain (brain lesions) or increased pressure in your head.
Heart and blood vessel (cardiovascular) and central nervous system (CNS) effects. Cardiovascular and CNS effects can happen in some people during treatment with HYCOFENIX, including trouble sleeping (insomnia), dizziness, weakness, tremors, temporary increases in blood pressure, abnormal heart beats (arrhythmias), seizures, and feeling faint. Call your healthcare provider right away if you have any of these symptoms.
Low blood pressure. A sudden drop in blood pressure can happen in some people during treatment with HYCOFENIX and this may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). Your risk of having this problem may be increased if you take HYCOFENIX with certain other medicines that lower blood pressure. If you have any of these symptoms while taking HYCOFENIX, sit or lie down. Do not change your body position too fast. Get up slowly from sitting or lying down.
Adrenal gland problems. HYCOFENIX can cause serious and life-threatening adrenal gland problems. Your healthcare provider may do blood tests to check for adrenal gland problems. Call your healthcare provider right away if you have any of these symptoms:

nausea
vomiting
not wanting to eat (anorexia)
fatigue

weakness
dizziness
low blood pressure

The most common side effects of HYCOFENIX include:

sleepiness
confusion
coordination problems
decrease in mental and physical performance
lack of energy
lightheadedness
dizziness
headache
dry mouth

nausea
vomiting
constipation
fast or irregular heart beat
irritability
anxiety
restlessness
nervousness
tremor

These are not all the possible side effects of HYCOFENIX.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store HYCOFENIX?

Store HYCOFENIX at room temperature between 68°F to 77°F (20°C to 25°C).
Store HYCOFENIX in a tightly closed container, in a dry, cool place away from heat or direct sunlight.
Keep HYCOFENIX and all medicines out of the reach of children.

How should I store dispose of HYCOFENIX?

Remove unused HYCOFENIX from the container and mix it with an undesirable, non-toxic substance such as cat litter or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw it away in the household trash. You can also follow your state or local guidelines on how to safely throw away HYCOFENIX.

General information about the safe and effective use of HYCOFENIX.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use HYCOFENIX for a condition for which it was not prescribed. Do not give HYCOFENIX to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about HYCOFENIX that is written for health professionals.

What are the ingredients in HYCOFENIX?

Active Ingredients: hydrocodone bitartrate, pseudoephedrine hydrochloride, and guaifenesin

Inactive Ingredients: black raspberry flavor, citric acid, D&C Red #33, FD&C Blue #1, glycerin, methylparaben, polyethylene glycol propylparaben, purified water, saccharin sodium, sodium citrate, and sorbitol

Manufactured for: MISSION PHARMACAL COMPANY San Antonio, TX 78230 1355

For more information, go to www.hycofenix.com or call 1-800-298-1087.

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 5/2018

hycofenix-container-carton-label
HYCOFENIX 
hydrocodone bitartrate, pseudoephedrine hydrochloride, guaifenesin liquid
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:0178-3291
Route of AdministrationORALDEA ScheduleCII    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
GUAIFENESIN (UNII: 495W7451VQ) (GUAIFENESIN - UNII:495W7451VQ) GUAIFENESIN200 mg  in 5 mL
HYDROCODONE BITARTRATE (UNII: NO70W886KK) (HYDROCODONE - UNII:6YKS4Y3WQ7) HYDROCODONE BITARTRATE2.5 mg  in 5 mL
PSEUDOEPHEDRINE HYDROCHLORIDE (UNII: 6V9V2RYJ8N) (PSEUDOEPHEDRINE - UNII:7CUC9DDI9F) PSEUDOEPHEDRINE HYDROCHLORIDE30 mg  in 5 mL
Inactive Ingredients
Ingredient NameStrength
WATER (UNII: 059QF0KO0R)  
SACCHARIN SODIUM (UNII: SB8ZUX40TY)  
SODIUM CITRATE (UNII: 1Q73Q2JULR)  
SORBITOL (UNII: 506T60A25R)  
D&C RED NO. 33 (UNII: 9DBA0SBB0L)  
CITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP)  
FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
GLYCERIN (UNII: PDC6A3C0OX)  
METHYLPARABEN (UNII: A2I8C7HI9T)  
POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)  
PROPYLPARABEN (UNII: Z8IX2SC1OH)  
Product Characteristics
ColorpurpleScore    
ShapeSize
FlavorRASPBERRY (blue raspberry) Imprint Code
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0178-3291-16473 mL in 1 BOTTLE; Type 0: Not a Combination Product08/18/2015
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02227908/18/201508/03/2018
Labeler - Mission Pharmacal Company (008117095)
Establishment
NameAddressID/FEIBusiness Operations
Mikart, Inc.030034847repack(0178-3291) , manufacture(0178-3291)

Revised: 7/2018
 
Mission Pharmacal Company