Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 15 June 2018

Indication(s)

1 INDICATIONS AND USAGE TUSSIGON is indicated for the symptomatic relief of cough in patients 18 years of age and older. TUSSIGON is a combination of hydrocodone, an opioid agonist, and homatropine, a muscarinic antagonist, indicated for the symptomatic relief of cough in patients 18 years of age and older. (1) Important Limitations of Use (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 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. 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.

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Advisory information

contraindications
4 CONTRAINDICATIONS TUSSIGON is contraindicated for: All children younger than 6 years of age [see Warnings and Precautions (5.2, 5.3), Use in Specific Populations (8.4)]. TUSSIGON is also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.2)]. Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.4)]. Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.9)]. Hypersensitivity to hydrocodone, homatropine, or any of the inactive ingredients in TUSSIGON [see Adverse Reactions (6)]. 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, homatropine, or any of the inactive ingredients in TUSSIGON. (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse events are described, or described in greater detail, in other sections: Addiction, abuse, and misuse [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.3)] Life-threatening respiratory depression [see Warnings and Precautions (5.2, 5.3, 5.8) and Overdosage (10)] Accidental overdose and death due to medication errors [see Warnings and Precautions (5.5)] Decreased mental alertness with impaired mental and/or physical abilities [see Warnings and Precautions (5.6)] Interactions with benzodiazepines and other CNS depressants [see Warnings and Precautions (5.8) and Drug Interactions (7.1, 7.5)] Paralytic ileus, gastrointestinal adverse reactions [see Warnings and Precautions (5.9)] Increased intracranial pressure [see Warnings and Precautions (5.10)] Obscured clinical course in patients with head injuries [see Warnings and Precautions (5.10)] Seizures [see Warnings and Precautions (5.11)] Severe hypotension [see Warnings and Precautions (5.12)] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.13)] Adrenal insufficiency [see Warnings and Precautions (5.14)] The following adverse reactions have been identified during clinical studies, in the literature, or during post-approval use of hydrocodone and/or homatropine. Because these reactions may be reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most common adverse reactions to TUSSIGON include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, and constipation. Other reactions include: Anaphylaxis: Anaphylaxis has been reported with hydrocodone, one of the ingredients in TUSSIGON. Body as a whole: Coma, death, fatigue, falling injuries, lethargy. Cardiovascular: Peripheral edema, increased blood pressure, decreased blood pressure, tachycardia, chest pain, palpitation, syncope, orthostatic hypotension, prolonged QT interval, hot flush. Central Nervous System: Facial dyskinesia, insomnia, migraine, increased intracranial pressure, seizure, tremor. Dermatologic: Flushing, hyperhidrosis, pruritus, rash. Endocrine/Metabolic: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Cases of androgen deficiency have occurred with chronic use of opioids. Gastrointestinal: Abdominal pain, bowel obstruction, decreased appetite, diarrhea, difficulty swallowing, dry mouth, GERD, indigestion, pancreatitis, paralytic ileus, biliary tract spasm (spasm of the sphincter of Oddi). Genitourinary: Urinary tract infection, ureteral spasm, spasm of vesicle sphincters, urinary retention. Laboratory: Increases in serum amylase. Musculoskeletal: Arthralgia, backache, muscle spasm. Ophthalmic: Miosis (constricted pupils), visual disturbances. Psychiatric: Agitation, anxiety, confusion, fear, dysphoria, depression. Reproductive: Hypogonadism, infertility. Respiratory: Bronchitis, cough, dyspnea, nasal congestion, nasopharyngitis, respiratory depression, sinusitis, upper respiratory tract infection. Other: Drug abuse, drug dependence, opioid withdrawal syndrome. Common adverse reactions include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, and constipation. (6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION 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. (2.2) 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) 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.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Avoid use in pregnant women. May cause fetal harm. (8.1) Lactation: Breast-feeding not recommended. (8.2) 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) 8.1 Pregnancy Risk Summary TUSSIGON is not recommended for use in pregnant women, including during or immediately prior to labor. Prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.14), Clinical Considerations]. There are no available data with TUSSIGON use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Published studies with hydrocodone have reported inconsistent findings and have important methodological limitations (see Data ). Reproductive toxicity studies have not been conducted with TUSSIGON; however, studies are available with individual active ingredients or related active ingredients (see Data ). In animal reproduction studies, hydrocodone administered by the subcutaneous route to pregnant hamsters during the period of organogenesis produced a teratogenic effect at a dose approximately 45 times the maximum recommended human dose (MRHD) (see Data ). Based on the animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.14)]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Opioids, including TUSSIGON, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioids during labor for signs of excess sedation and respiratory depression. Data Human Data Hydrocodone A limited number of pregnancies have been reported in published observational studies and postmarketing reports describing hydrocodone use during pregnancy. However, these data cannot definitely establish or exclude any drug-associated risk during pregnancy. Methodological limitations of these observational studies include small sample size and lack of details regarding dose, duration and timing of exposure. Animal Data Reproductive toxicity studies have not been conducted with TUSSIGON; however, studies are available with individual active ingredients or related active ingredients. Hydrocodone In an embryofetal development study in pregnant hamsters dosed on gestation day 8 during the period of organogenesis, hydrocodone induced cranioschisis, a malformation, at approximately 45 times the MRHD (on a mg/m2 basis with a maternal subcutaneous dose of 102 mg/kg). Reproductive toxicology studies were also conducted with codeine, an opiate related to hydrocodone. In an embryofetal development study in pregnant rats dosed throughout the period of organogenesis, codeine increased resorptions and decreased fetal weights at a dose approximately 65 times the MRHD of hydrocodone (on a mg/m2 basis with a maternal oral dose of codeine at 120 mg/kg/day); however, these effects occurred in the presence of maternal toxicity. In embryofetal development studies with pregnant rabbits and mice dosed throughout the period of organogenesis, codeine produced no adverse developmental effects at doses approximately 30 and 160 times, respectively, the MRHD of hydrocodone (on a mg/m2 basis with maternal oral doses of codeine at 30 mg/kg/day in rabbits and 600 mg/kg/day in mice). Homatropine Animal studies with homatropine are not available. 8.2 Lactation Risk Summary Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with TUSSIGON. There are no data on the presence of TUSSIGON in human milk, the effects of TUSSIGON on the breastfed infant, or the effects of TUSSIGON on milk production; however, data are available with hydrocodone and homatropine. Hydrocodone Hydrocodone is present in breast milk. Published cases report variable concentrations of hydrocodone and hydromorphone (an active metabolite) in breast milk with administration of immediate-release hydrocodone to nursing mothers in the early post-partum period with relative infant doses of hydrocodone ranging between 1.4 and 3.7%. There are case reports of excessive sedation and respiratory depression in breastfed infants exposed to hydrocodone. No information is available on the effects of hydrocodone on milk production. Homatropine No information is available on the levels of homatropine in breast milk or on milk production. The published literature suggests that homatropine may decrease milk production based on its anticholinergic effects (see Clinical Considerations ). Clinical Considerations Infants exposed to TUSSIGON through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid is stopped, or when breastfeeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids, such as hydrocodone, a component of TUSSIGON, may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6), Clinical Pharmacology (12.2)]. 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.

Interactions

7 DRUG INTERACTIONS No specific drug interaction studies have been conducted with TUSSIGON. Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue if serotonin syndrome is suspected. (7.5) Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of hydrocodone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping an MAOI. (7.6) Muscle Relaxants: Avoid concomitant use. (7.7) Diuretics: Hydrocodone may reduce the efficacy of diuretics. Monitor for reduced effect. (7.8) Anticholinergic drugs: Concurrent use may cause paralytic ileus. (5.9, 7.9) 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) and 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.

More information

Category Value
Authorisation number ANDA088508
Agency product number 68JRS2HC1C
Orphan designation No
Product NDC 61570-102
Date Last Revised 07-06-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling Store 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.
Marketing authorisation holder Pfizer Laboratories Div Pfizer Inc
Warnings 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 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 See full prescribing information for complete boxed warning. TUSSIGON exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor closely for these behaviors and conditions. (5.1) Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or when used in patients at higher risk. (5.2) Accidental ingestion of TUSSIGON, especially by children, can result in a fatal overdose of hydrocodone. (5.2) Ensure accuracy when prescribing, dispensing, and administering TUSSIGON. Dosing errors can result in accidental overdose and death. (2,1, 5.5) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone. Avoid the use of TUSSIGON in patients taking CYP3A4 inhibitors or inducers. (5.7, 7.2, 7.3) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid the use of TUSSIGON in patients taking benzodiazepines, other CNS depressants, or alcohol. (5.8, 7.4) Instruct patients not to consume alcohol or any products containing alcohol while taking TUSSIGON because co-ingestion can result in fatal plasma hydrocodone levels. (5.8, 7.1) TUSSIGON is not recommended for use in pregnant women. Prolonged use of TUSSIGON during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If TUSSIGON is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.13, 8.1) Addiction, Abuse, and Misuse TUSSIGON exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. 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 addition or abuse, and refill only after reevaluation of the need for continued treatment [see Warnings and Precautions (5.1)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of TUSSIGON. Monitor for respiratory depression, especially during initiation of TUSSIGON therapy or when used in patients at higher risk [see Warnings and Precautions (5.2)]. Accidental Ingestion Accidental ingestion of even one dose of TUSSIGON, especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions (5.2)]. Risk of Medication Errors Ensure accuracy when prescribing, dispensing, and administering TUSSIGON. Dosing errors can result in accidental overdose and death [see Dosage and Administration (2.1)] . Cytochrome P450 3A4 Interaction The concomitant use of TUSSIGON with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Avoid the use of TUSSIGON in patients taking a CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.7), Drug Interactions (7.2, 7.3)]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Avoid the use of TUSSIGON in patients taking benzodiazepines, other CNS depressants, or alcohol [see Warning and Precautions (5.8), Drug Interactions (7.4)]. Interaction with Alcohol Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking TUSSIGON. The co-ingestion of alcohol with TUSSIGON may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see Warnings and Precautions (5.8) and Drug Interactions (7.1]. Neonatal Opioid Withdrawal Syndrome TUSSIGON is not recommended for use in pregnant women [see Use in Specific Populations (8.1)]. Prolonged use of TUSSIGON during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If TUSSIGON is used for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.13)].