Important Limitations of Use:

• Not indicated for pediatric patients under 18 years of age [see Use in Specific Populations (8.4)].
• Contraindicated in pediatric patients less than 6 years of age [see Contraindications (4)].
• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions (5.1)], reserve TUSSIGON 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.

2.1 Important Dosage and Administration Instructions

Administer TUSSIGON by the oral route only.

Advise patients not to increase the dose or dosing frequency of TUSSIGON because serious adverse events such as respiratory depression may occur with overdosage [see Warnings and Precautions (5.2), Overdosage (10)]. The dosage of TUSSIGON 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: One (1) tablet every 4 to 6 hours as needed; not to exceed six (6) tablets in 24 hours.

2.3 Monitoring, Maintenance, and Discontinuation of Therapy

Prescribe TUSSIGON 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 TUSSIGON, the relative incidence of adverse reactions, and the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)].

Do not abruptly discontinue TUSSIGON in a physically-dependent patient [see Drug Abuse and Dependence (9.3)]. When a patient who has been taking TUSSIGON regularly and may be physically dependent no longer requires therapy with TUSSIGON, 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.

5.1 Addiction, Abuse, and Misuse

TUSSIGON contains hydrocodone, a Schedule II controlled substance. As an opioid, TUSSIGON 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 TUSSIGON 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 TUSSIGON, prescribe TUSSIGON 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 TUSSIGON. 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 TUSSIGON. 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 TUSSIGON. 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 TUSSIGON, 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 TUSSIGON, the risk is greatest during the initiation of therapy, when TUSSIGON 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 TUSSIGON 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 TUSSIGON, 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, TUSSIGON is contraindicated in children less than 6 years of age [see Contraindications (4)].

Use of TUSSIGON 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, TUSSIGON 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

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 TUSSIGON is communicated clearly and dispensed accurately [see Dosage and Administration (2.1)].

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

Hydrocodone, one of the active ingredients in TUSSIGON, 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 TUSSIGON. Avoid concurrent use of TUSSIGON 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 TUSSIGON 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 TUSSIGON is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in TUSSIGON-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions.

Concomitant use of TUSSIGON with CYP3A4 inducers or discontinuation of a 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 TUSSIGON in patients who are taking a CYP3A4 inhibitor or inducer. If concomitant use of TUSSIGON 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 TUSSIGON, 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 TUSSIGON 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 TUSSIGON therapy. The co-ingestion of alcohol with TUSSIGON may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see Drug Interactions (7.1)].

5.9 Risks of Use in Patients with Gastrointestinal Conditions

TUSSIGON is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications (4)]. The use of hydrocodone in TUSSIGON may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

The concurrent use of anticholinergics with TUSSIGON may produce paralytic ileus [see Drug Interactions (7.9)].

The hydrocodone in TUSSIGON 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 TUSSIGON 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 (5.15)]. 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 TUSSIGON 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), TUSSIGON 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 Increased Risk of Seizures in Patients with Seizure Disorders

The hydrocodone in TUSSIGON 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 TUSSIGON therapy.

5.12 Severe Hypotension

TUSSIGON 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 TUSSIGON.

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

5.13 Neonatal Opioid Withdrawal Syndrome

TUSSIGON is not recommended for use in pregnant women. Prolonged use of TUSSIGON 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)].

5.14 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

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 TUSSIGON.

7.1 Alcohol

Concomitant use of alcohol with TUSSIGON can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone. Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on TUSSIGON therapy [see Warnings and Precautions (5.8), Clinical Pharmacology (12.3)].

7.2 Inhibitors of CYP3A4 and CYP2D6

The concomitant use of TUSSIGON and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of TUSSIGON and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of TUSSIGON is achieved [see Warnings and Precautions (5.7)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.

Avoid the use of TUSSIGON while taking a CYP3A4 or CYP2D6 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

7.3 CYP3A4 Inducers

The concomitant use of TUSSIGON and CYP3A4 inducers such as rifampin, carbamazepine, or phenytoin, can decrease the plasma concentration of hydrocodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see Warnings and Precautions (5.7)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

Avoid the use of TUSSIGON in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.

7.4 Benzodiazepines and Other CNS Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of TUSSIGON in patients who are taking benzodiazepines or other CNS depressants [see Warnings and Precautions (5.8)], and instruct patients to avoid consumption of alcohol while on TUSSIGON [see Drug Interactions (7.1), Patient Counseling Information (17)].

7.5 Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation. Discontinue TUSSIGON if serotonin syndrome is suspected.

7.6 Monoamine Oxidase Inhibitors (MAOIs)

Avoid the use of TUSSIGON in patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken MAOIs within 14 days. The use of MAOIs or tricyclic antidepressants with hydrocodone, one of the active ingredients in TUSSIGON, may increase the effect of either the antidepressant or hydrocodone. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

7.7 Muscle Relaxants

Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Avoid the use of TUSSIGON in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

7.8 Diuretics

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

7.9 Anticholinergic Drugs

The concomitant use of anticholinergic drugs with TUSSIGON may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus [see Warnings and Precautions (5.9)]. Monitor patients for signs of urinary retention or reduced gastric motility when TUSSIGON is used concomitantly with anticholinergic drugs.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

TUSSIGON is not indicated for use in patients younger than 18 years of age because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks for use of hydrocodone in these patients [see Indications (1), Warnings and Precautions (5.3)].

Life-threatening respiratory depression and death have occurred in children who received hydrocodone [see Warnings and Precautions (5.2)]. Because of the risk of life-threatening respiratory depression and death, TUSSIGON is contraindicated in children less than 6 years of age [see Contraindications (4)].

8.5 Geriatric Use

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

Use caution when considering the use of TUSSIGON in patients 65 years of age or older. Elderly patients may have increased sensitivity to hydrocodone; greater frequency of decreased hepatic, renal, or cardiac function; or concomitant disease or other drug therapy [see Warnings and Precautions (5.4)].

Respiratory depression is the chief risk for elderly patients treated with opioids, including TUSSIGON. Respiratory depression has occurred after large initial doses of opioids were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration [see Warnings and Precautions (5.4, 5.8)].

Hydrocodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, monitor these patients closely for respiratory depression, sedation, and hypotension.

8.6 Renal Impairment

The pharmacokinetics of TUSSIGON has not been characterized in patients with renal impairment. Patients with renal impairment may have higher plasma concentrations than those with normal function [see Clinical Pharmacology (12.3)]. TUSSIGON should be used with caution in patients with severe impairment of renal function, and patients should be monitored closely for respiratory depression, sedation, and hypotension.

8.7 Hepatic Impairment

The pharmacokinetics of TUSSIGON has not been characterized in patients with hepatic impairment. Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function [see Clinical Pharmacology (12.3)]. Therefore, TUSSIGON should be used with caution in patients with severe impairment of hepatic function, and patients should be monitored closely for respiratory depression, sedation, and hypotension.

9.1 Controlled Substance

TUSSIGON contains hydrocodone, a Schedule II controlled substance.

9.2 Abuse

9.3 Dependence

Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of opioids; therefore, TUSSIGON should be prescribed and administered for the shortest duration that is consistent with individual patient treatment goals and patients should be reevaluated prior to refills [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].

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.

If TUSSIGON is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Clinical Presentation

Treatment of Overdose

Treatment of overdosage is driven by the overall clinical presentation, and consists of discontinuation of TUSSIGON together with institution of appropriate therapy. Give primary attention to the reestablishment of adequate respiratory exchange through provision of a patent and protected airway and the institution of assisted or controlled ventilation. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques. Gastric emptying may be useful in removing unabsorbed drug.

The opioid antagonists, naloxone and nalmefene, are specific antidotes for respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to hydrocodone overdose, administer an opioid antagonist. An antagonist should not be administered in the absence of clinically significant respiratory depression. Because the duration of opioid reversal is expected to be less than the duration of action of hydrocodone in TUSSIGON, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information.

Hemodialysis is not routinely used to enhance the elimination of hydrocodone from the body.

Physostigmine may be used parenterally for the treatment of the signs and symptoms of homatropine toxicity.

Hydrocodone Bitartrate

The chemical name for hydrocodone bitartrate 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). It occurs as a fine white crystal or crystalline powder, which is derived from the opium alkaloid, thebaine. It has a molecular weight of 494.50 and has the following chemical structure:

C18H21NO3 ∙ C4H6O6 ∙ 2½H2O MW 494.490

Homatropine Methylbromide

The chemical name for homatropine methylbromide is 8-Azoniabicyclo [3.2.1]octane,3-[(hydroxyphenyl-acetyl)oxy]-8,8-dimethyl-,bromide, endo-. It occurs as a white crystal or fine white crystalline powder. It has a molecular weight of 370.29 and has the following chemical structure:

	C17H24BrNO3 HOMATROPINE METHYLBROMIDE

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Store tablets at controlled room temperature 68°F to 77°F (20°C to 25°C) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.

Oral prescription where permitted by state law.

Addiction, Abuse, and Misuse

Inform patients that the use of TUSSIGON, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share TUSSIGON with others and to take steps to protect TUSSIGON from theft or misuse.

Important Dosing and Administration Instructions

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

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting TUSSIGON and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store TUSSIGON securely and to properly dispose of unused TUSSIGON in accordance with the local state guidelines and/or regulations.

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 TUSSIGON may produce marked drowsiness [see Warnings and Precautions (5.6)].

Interactions with Benzodiazepines and Other Central Nervous System Depressants, Including Alcohol

Inform patients and caregivers that potentially fatal additive effects may occur if TUSSIGON is used with benzodiazepines or other CNS depressants, including alcohol. Advise patients to avoid concomitant use of TUSSIGON with benzodiazepines or other CNS depressants and instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with TUSSIGON [see Warnings and Precautions (5.8), Drug Interactions (7.1, 7.4)].

Constipation

Advise patients of the potential for severe constipation [see Warnings and Precautions (5.9), Adverse Reactions (6)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in TUSSIGON. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].

MAOI Interaction

Inform patients not to take TUSSIGON while using or within 14 days of stopping any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking TUSSIGON [see Drug Interactions (7.6)].

Hypotension

Inform patients that TUSSIGON may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.12)].

Pregnancy

Advise patients that use of TUSSIGON is not recommended during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise women that breastfeeding is not recommended during treatment with TUSSIGON [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids, such as hydrocodone, a component of TUSSIGON, may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

Adrenal Insufficiency

Inform patients that TUSSIGON could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.14)].

Serotonin Syndrome

Inform patients that TUSSIGON could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Adverse Reactions (6), Drug Interactions (7.5)].

Disposal of Unused TUSSIGON

Advise patients to properly dispose of unused TUSSIGON. Advise patients to throw the drug in the household trash following these steps. 1) Remove them from their original containers and mix them with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs). 2) Place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or breaking out of a garbage bag, or to dispose of in accordance with local state guidelines and/or regulations.