Label: FLOWTUSS- hydrocodone bitartrate, guaifenesin liquid

  • NDC Code(s): 0178-3482-16
  • Packager: Mission Pharmacal Company
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: CII
  • Marketing Status: New Drug Application

Drug Label Information

Updated July 24, 2018

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  • BOXED WARNING(What is this?)

    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

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use FLOWTUSS™ safely and effectively. See full prescribing information for FLOWTUSS.















    FLOWTUSS (hydrocodone bitartrate and guaifenesin) oral solution, CII















    Initial U.S. Approval: 2014

    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, 5.11, 5.12, 5.13, 5.14, 5.15) 5/2018

    INDICATIONS AND USAGE

    FLOWTUSS is a combination of hydrocodone, an opioid agonist; and guaifenesin an expectorant, indicated for the symptomatic relief of cough and to loosen mucus associated with the common cold in patients 18 years of age and older. (1) (1)

    Important Limitations of Use (1) (1)

    • Not indicated for pediatric patients under 18 years of age.
    • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve FLOWTUSS 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.

    DOSAGE AND ADMINISTRATION

    • Adults 18 years of age and older: 10 mL every 4 to 6 hours as needed, not to exceed 6 doses (60 mL) in 24 hours. (2.2)
    • Measure FLOWTUSS 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; 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)
    • Hypersensitivity to hydrocodone, guaifenesin, or any of the inactive ingredients in FLOWTUSS. (4)

    WARNINGS AND PRECAUTIONS

    • 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)
    • Seizures in patients with seizure disorders: Monitor during therapy. (5.11)
    • Severe hypotension: Monitor during initiation of therapy. Avoid use in patients with circulatory shock. (5.12)
    • Adrenal insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.14)

    WARNINGS AND PRECAUTIONS

    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 FLOWTUSS. (5.15)

    ADVERSE REACTIONS

    The most common adverse reactions of FLOWTUSS 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 FLOWTUSS; 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 Medication Guide.

    Revised: 5/2018

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  • 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 Important Dosage and Administration Instructions

    2.2 Recommended Dosage

    2.3 Monitoring, Maintenance, and Discontinuation of Therapy

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    5 WARNINGS AND PRECAUTIONS

    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

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

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

    5.8 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

    5.9 Risks of Use in Patients with Gastrointestinal Conditions

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

    5.11 Increased Risk of Seizures in Patients with Seizure Disorders

    5.12 Severe Hypotension

    5.13 Neonatal Opioid Withdrawal Syndrome

    5.14 Adrenal Insufficiency

    5.15 Drug/Laboratory Test Interactions

    6 ADVERSE REACTIONS

    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

    *
    Sections or subsections omitted from the full prescribing information are not listed.
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  • 1 INDICATIONS AND USAGE

    FLOWTUSS is indicated for the symptomatic relief of cough 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)].
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  • 2 DOSAGE AND ADMINISTRATION

    2.1 Important Dosage and Administration Instructions

    Administer FLOWTUSS by the oral route only.

    Always use an accurate milliliter measuring device when administering FLOWTUSS 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.

    2.2 Recommended Dosage

    Adults 18 years of age and older: 10 mL every 4 to 6 hours as needed, not to exceed 6 doses (60 mL) in 24 hours.

    2.3 Monitoring, Maintenance, and Discontinuation of Therapy

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  • 3 DOSAGE FORMS AND STRENGTHS

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

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  • 4 CONTRAINDICATIONS

    • Hypersensitivity to hydrocodone, guaifenesin, or any of the inactive ingredients in FLOWTUSS [ see Adverse Reactions (6)].
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  • 5 WARNINGS AND PRECAUTIONS

    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

    Advise patients to always use an accurate milliliter measuring device when measuring and administering FLOWTUSS. Inform patients that household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions [ 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 FLOWTUSS, 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 FLOWTUSS. Avoid concurrent use of FLOWTUSS 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

    5.8 Risks from Concomitant Use with Benzodiazepines or other CNS Depressants

    Concomitant use of opioids, including FLOWTUSS, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol [ 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 FLOWTUSS is used with benzodiazepines, alcohol, or other CNS depressants [ see Patient Counseling Information (17)] .

    5.9 Risks of Use in Patients with Gastrointestinal Conditions

    FLOWTUSS 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).

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

    Avoid the use of FLOWTUSS in patients with head injury, intracranial lesions, or a pre-existing increase in intracranial pressure. In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), FLOWTUSS may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Furthermore, opioids produce adverse reactions that may obscure the clinical course of patients with head injuries.

    5.11 Increased Risk of Seizures in Patients with Seizure Disorders

    5.12 Severe Hypotension

    5.13 Neonatal Opioid Withdrawal Syndrome

    5.14 Adrenal Insufficiency

    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.

    5.15 Drug/Laboratory Test Interactions

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  • 6 ADVERSE REACTIONS

    Use of hydrocodone bitartrate is associated with the following:

    • Respiratory depression [ see Warnings and Precautions ( 5.1) and Overdosage ( 10) ]
    • Drug dependence [ see Warnings and Precautions ( 5.2) and Drug Abuse and Dependence ( 9.3) ]
    • Increased intracranial pressure [ see Warnings and Precautions ( 5.3) ]
    • Decreased mental alertness with impaired mental and/or physical abilities [ see Warnings and Precautions ( 5.4) ]
    • Paralytic ileus [ see Warnings and Precautions ( 5.5) ]

    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 FLOWTUSS 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.

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  • 7 DRUG INTERACTIONS

    No specific interaction studies have been conducted with FLOWTUSS.

    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 FLOWTUSS may 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 FLOWTUSS 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 [ 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) ].

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Teratogenic Effects
    Pregnancy Category C
    There are no adequate and well controlled studies of FLOWTUSS in pregnant women. Reproductive toxicity studies have not been conducted with FLOWTUSS; 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, FLOWTUSS 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 27 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 40 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 20 and 100 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 FLOWTUSS 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 FLOWTUSS is administered to nursing mothers. Hydrocodone is 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 FLOWTUSS, 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 FLOWTUSS 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 ( 5.2) ].

    8.5 Geriatric Use

    Clinical studies have not been conducted with FLOWTUSS in geriatric populations. Other reported clinical experience with the individual active ingredients of FLOWTUSS 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.

    8.6 Renal Impairment

    FLOWTUSS should be given with caution in patients with severe impairment of renal function.

    8.7 Hepatic Impairment

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

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  • 9 DRUG ABUSE AND DEPENDENCE

    9.1 Controlled Substance

    FLOWTUSS 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 FLOWTUSS, 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, FLOWTUSS should be prescribed and administered with caution [ see Warnings and Precautions ( 5.3) ].

    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.

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  • 10 OVERDOSAGE

    No human overdosage data are available for FLOWTUSS.

    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.

    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 FLOWTUSS 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.

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  • 11 DESCRIPTION

    FLOWTUSS (hydrocodone bitartrate and guaifenesin) oral solution contains hydrocodone bitartrate (a centrally-acting opioid antitussive) and guaifenesin (an expectorant).

    Each 5 mL dose of FLOWTUSS contains: hydrocodone bitartrate, USP, 2.5 mg; and guaifenesin, USP, 200 mg.

    FLOWTUSS 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

    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:

    structure2

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  • 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.

    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 and guaifenesin after a single 10 mL oral dose administration of 5 mg hydrocodone bitartrate and 400 mg guaifenesin are equivalent to the respective reference solutions of 5 mL hydrocodone bitartrate (5 mg/5 mL), and 10 mL guaifenesin (200 mg/5 mL).

    Hydrocodone
    Following a single 10 mL oral dose of 5 mg hydrocodone bitartrate 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.

    Guaifenesin
    Following a single 10 mL oral dose of 5 mg hydrocodone bitartrate 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 and hydrocodone were administered in combination, the pharmacokinetics for each component was similar to those observed when each component was administered separately.

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  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenicity, mutagenicity, and reproductive studies have not been conducted with FLOWTUSS; 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 23 and 65 times, respectively, the MRHDD of hydrocodone on a mg/m 2 basis).

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

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  • 14 CLINICAL STUDIES

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

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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    FLOWTUSS (hydrocodone bitartrate and guaifenesin) oral solution is supplied as a violet-colored, black raspberry flavored liquid containing 2.5 mg hydrocodone bitartrate
    and 200 mg guaifenesin in each 5 mL. It is available in:
    White HDPE bottles of 16 fl. oz. (473 mL): NDC 0178-3482-16
    White HDPE bottles of 4 fl. oz. (118 mL): NDC 0178-3482-04
    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.

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  • 17 PATIENT COUNSELING INFORMATION

    Overdosage
    Advise patients not to increase the dose or dosing frequency of FLOWTUSS because serious adverse events such as respiratory depression may occur with overdosage [ see Warnings and Precautions ( 5.2) and Overdosage ( 10) ].

    Dosing

    Advise patients to measure FLOWTUSS 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 FLOWTUSS is used with benzodiazepines or other CNS depressants, including alcohol. Because of this risk, patients should avoid concomitant use of FLOWTUSS with benzodiazepines or other CNS depressants, including alcohol [ 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 FLOWTUSS may produce marked drowsiness [ see Warnings and Precautions ( 5.5) ].

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

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

    1120A00 R0916

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  • MEDICATION GUIDE

    MEDICATION GUIDE

    FLOWTUSS (Floh-tus)

    (hydrocodone bitartrate and guaifenesin) oral solution, C-II

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

    FLOWTUSS is not for children under 18 years of age.

    FLOWTUSS can cause serious side effects, including:

    Addiction, abuse and misuse. Taking FLOWTUSS 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 FLOWTUSS 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 FLOWTUSS with other people.
    Keep FLOWTUSS in a safe place away from children.

    Life-threatening breathing problems (respiratory depression). FLOWTUSS 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 FLOWTUSS, 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 FLOWTUSS exactly as prescribed by your healthcare provider.

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

    increased sleepiness
    confusion
    difficulty breathing

    shallow breathing
    limpness

    Keep FLOWTUSS in a safe place away from children. Accidental use of even 1 dose of FLOWTUSS, 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 FLOWTUSS, 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 FLOWTUSS. Always use an accurate milliliter (mL) measuring device to measure the correct amount of FLOWTUSS. 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 you should use 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 FLOWTUSS, 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 listed above.

    Severe drowsiness, breathing problems (respiratory depression), coma, and death can happen in people who take FLOWTUSS 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 FLOWTUSS.
    Do not drink alcohol or take prescription or over-the-counter medicines that contain alcohol during treatment with FLOWTUSS.

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

    What is FLOWTUSS?

    FLOWTUSS is a prescription medicine used in adults to treat a cough and to loosen mucus that you can have with a common cold. FLOWTUSS contains 2 medicines, hydrocodone and guaifenesin. Hydrocodone is an opioid (narcotic) cough suppressant. Guaifenesin is an expectorant.
    FLOWTUSS is a federal controlled substance (C-II) because it contains hydrocodone that can be abused or lead to dependence. Keep FLOWTUSS in a safe place to prevent misuse and abuse. Selling or giving away FLOWTUSS 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 FLOWTUSS?

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

    Do not take FLOWTUSS 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 FLOWTUSS?”
    have a blockage (obstruction) in your bowel such as a paralytic ileus.
    are allergic to hydrocodone, guaifenesin, or any of the ingredients in FLOWTUSS. 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 FLOWTUSS, 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 problem
    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 prostate problems
    have problems with your urinary tract or difficulty urinating
    have kidney or liver problems

    have adrenal gland problems
    have low blood pressure

    plan to have surgery

    are pregnant or plan to become pregnant. FLOWTUSS can harm your unborn baby. See “What is the most important information I should know about FLOWTUSS?”

    are breastfeeding or plan to breastfeed. Hydrocodone passes into your breast milk and can cause serious side effects in your baby including increased sleepiness, breathing problems (respiratory depression), and death. It is not known if guaifenesin passes into your breast milk. You and your healthcare provider should decide if you will take FLOWTUSS or breastfeed. You should not do both. See “What should I avoid while taking FLOWTUSS?”
    plan to have children. FLOWTUSS 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 FLOWTUSS. 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 FLOWTUSS with certain other medicines can cause side effects or affect how well FLOWTUSS 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:

    See “What is the most important information I should know about FLOWTUSS?”
    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.

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

    How should I take FLOWTUSS?

    See “What is the most important information I should know about FLOWTUSS?”
    Take FLOWTUSS exactly as your healthcare provider tells you to take it. Do not change your dose without talking to your healthcare provider.
    Take FLOWTUSS by mouth only.

    Take FLOWTUSS 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 FLOWTUSS. Do not use a household teaspoon to measure your medicine. You may accidently take too much.
    Do not overfill the measuring device.
    Rinse your measuring device with water after each use.

    If you take too much FLOWTUSS, 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 FLOWTUSS.

    What should I avoid while taking FLOWTUSS?

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

    Avoid the use of FLOWTUSS if you:

    are pregnant. Use of FLOWTUSS 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 FLOWTUSS 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 FLOWTUSS. Avoid starting FLOWTUSS if you stopped taking an MAOI in the last 14 days.

    What are the possible side effects of FLOWTUSS?

    FLOWTUSS can cause serious side effects, including:

    See “What is the most important information I should know about FLOWTUSS?”
    Bowel problems including severe constipation or stomach pain. See “Who should not take FLOWTUSS?”
    Increased pressure in your head (intracranial). Avoid the use of FLOWTUSS 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.

    Increased risk of seizures in people with seizure disorders. If you have a seizure disorder, FLOWTUSS may increase how often you have a seizure.
    Low blood pressure. A sudden drop in blood pressure can happen in some people during treatment with FLOWTUSS 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 FLOWTUSS with certain other medicines that lower blood pressure. If you have any of these symptoms while taking FLOWTUSS, sit or lie down. Do not change your body position too fast. Get up slowly from sitting or lying down.
    Adrenal gland problems. FLOWTUSS 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 FLOWTUSS include:

    sleepiness
    confusion
    coordination problems
    decrease in mental and physical performance
    lack of energy
    lightheadedness

    dizziness
    headache
    dry mouth
    nausea
    vomiting
    constipation

    These are not all the possible side effects of FLOWTUSS.

    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 FLOWTUSS?

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

    How should I dispose of FLOWTUSS?

    Remove unused FLOWTUSS 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 FLOWTUSS.

    General information about the safe and effective use of FLOWTUSS.

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FLOWTUSS for a condition for which it was not prescribed. Do not give FLOWTUSS 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 FLOWTUSS that is written for health professionals.

    What are the ingredients in FLOWTUSS?

    Active ingredients: hydrocodone bitartrate 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.flowtuss.com or call 1-800-298-1087.

    This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 10/2018

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  • INGREDIENTS AND APPEARANCE
    FLOWTUSS 
    hydrocodone bitartrate, guaifenesin liquid
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0178-3482
    Route of Administration ORAL DEA Schedule CII    
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    GUAIFENESIN (UNII: 495W7451VQ) (GUAIFENESIN - UNII:495W7451VQ) GUAIFENESIN 200 mg  in 5 mL
    HYDROCODONE BITARTRATE (UNII: NO70W886KK) (HYDROCODONE - UNII:6YKS4Y3WQ7) HYDROCODONE BITARTRATE 2.5 mg  in 5 mL
    Inactive Ingredients
    Ingredient Name Strength
    GLYCERIN (UNII: PDC6A3C0OX)  
    METHYLPARABEN (UNII: A2I8C7HI9T)  
    POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)  
    PROPYLPARABEN (UNII: Z8IX2SC1OH)  
    WATER (UNII: 059QF0KO0R)  
    SACCHARIN SODIUM (UNII: SB8ZUX40TY)  
    SODIUM CITRATE (UNII: 1Q73Q2JULR)  
    SORBITOL (UNII: 506T60A25R)  
    CITRIC ACID MONOHYDRATE (UNII: 2968PHW8QP)  
    D&C RED NO. 33 (UNII: 9DBA0SBB0L)  
    FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
    Product Characteristics
    Color purple Score     
    Shape Size
    Flavor RASPBERRY (black raspberry) Imprint Code
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:0178-3482-16 473 mL in 1 BOTTLE; Type 0: Not a Combination Product 08/18/2015
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA022424 08/18/2015 07/17/2019
    Labeler - Mission Pharmacal Company (008117095)
    Registrant - Mission Pharmacal Company (008117095)
    Establishment
    Name Address ID/FEI Business Operations
    Mikart, Inc. 030034847 manufacture(0178-3482) , repack(0178-3482)
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