Xtrelus

Overdose

Acute overdose 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, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, partial or complete airway obstruction, atypical snoring, hypotension, circulatory collapse, cardiac arrest, and death.

Hydrocodone may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations .

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 is driven by the overall clinical presentation, and consists of discontinuation of Xtrelus 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 Xtrelus, 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.

Contraindications

Xtrelus is contraindicated for:

• All children younger than 6 years of age .

Xtrelus is also contraindicated in patients with:

• Significant respiratory depression .
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment .
• Known or suspected gastrointestinal obstruction, including paralytic ileus .
• Hypersensitivity to hydrocodone, guaifenesin, or any of the inactive ingredients in Xtrelus .

Undesirable effects

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Addiction, abuse, and misuse
• Life-threatening respiratory depression
• Accidental overdose and death due to medication errors
• Decreased mental alertness with impaired mental and/or physical abilities
• Interactions with benzodiazepines and other CNS depressants
• Paralytic ileus, gastrointestinal adverse reactions
• Increased intracranial pressure
• Obscured clinical course in patients with head injuries
• Seizures
• Severe hypotension
• Neonatal Opioid Withdrawal Syndrome
• Adrenal insufficiency

The following adverse reactions have been identified during clinical studies, in the literature, or during post-approval use of hydrocodone and/or guaifenesin. 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 Xtrelus 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 Xtrelus.

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.

Therapeutic indications

Xtrelus 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.

• Not indicated for pediatric patients under 18 years of age .
• Contraindicated in pediatric patients less than 6 years of age .
• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses , reserve Xtrelus 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.

Pharmacodynamic properties

Hydrocodone is an opioid agonist with relative selectivity for the mu-opioid receptor, although it can interact with other opioid receptors at higher doses. The precise mechanism of action of hydrocodone and other opiates is not known; however, hydrocodone is believed to act centrally on the cough center. In excessive doses, hydrocodone will depress respiration.

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.

Effects On The Central Nervous System

Hydrocodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and to electrical stimulation.

Hydrocodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects On The Gastrointestinal Tract And Other Smooth Muscle

Hydrocodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects On The Cardiovascular System

Hydrocodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension.

Effects On The Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date .

Effects On The Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Adverse Reaction Relationships

There is a relationship between increasing hydrocodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.

Following a single oral dose of 5 mg hydrocodone bitartrate and 400 mg guaifenesin administered to 40 healthy adults, the mean Cmax and AUC0-inf for hydrocodone were 10.7 ng/mL and 69.94 ng.hr/mL, respectively. The median time to maximum concentration for hydrocodone was about 1.7 hours. The mean Cmax and AUC0-inf for guaifenesin were 1.82 μg/mL and 2.67 μg.hr/mL, respectively. The median time to maximum concentration was for guaifenesin about 30 minutes. Food has no significant effect on the extent of absorption of hydrocodone; while the effect of food on guaifenesin systemic exposure is not considered to be clinically meaningful.

Although the extent of protein binding of hydrocodone in human plasma has not been definitively determined, structural similarities to related opioid analgesics suggest that hydrocodone is not extensively protein bound. As most agents in the 5-ring morphinan group of semi-synthetic opioids bind plasma protein to a similar degree (range 19% (hydromorphone) to 45% (oxycodone)), hydrocodone is expected to fall within this range.

Metabolism

Hydrocodone exhibits a complex pattern of metabolism, including N-demethylation, O-demethylation, and 6keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. CYP3A4 mediated N-demethylation to norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2D6 mediated O-demethylation to hydromorphone. Hydromorphone is formed from the O-demethylation of hydrocodone and may contribute to the total analgesic effect of hydrocodone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs . Published in vitro studies have shown that N-demethylation of hydrocodone to form norhydrocodone can be attributed to CYP3A4 while O-demethylation of hydrocodone to hydromorphone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity CYP enzyme.

Excretion

Hydrocodone and its metabolites are eliminated primarily in the kidneys. The mean plasma half-life of hydrocodone was approximately 5 hours.

The mean plasma half-life of guaifenesin was approximately 0.95 hours.

Name of the medicinal product

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Xtrelus contains hydrocodone, a Schedule II controlled substance. As an opioid, Xtrelus exposes users to the risks of addiction, abuse, and misuse , which can lead to overdose and death . Reserve Xtrelus 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 Xtrelus, prescribe Xtrelus 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 Xtrelus. 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 Xtrelus. 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 . 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.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, including hydrocodone, one of the active ingredients in Xtrelus. 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 Xtrelus, close observation, supportive measures, and use of opioid antagonists (e.g. naloxone), depending on the patient’s clinical status . 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 Xtrelus, the risk is greatest during the initiation of therapy, when Xtrelus is used concomitantly with other drugs that may cause respiratory depression , 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) .

To reduce the risk of respiratory depression, proper dosing of Xtrelus is essential . Monitor patients closely, especially within the first 2472 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 Xtrelus, especially by children, can result in respiratory depression and death.

Children are particularly sensitive to the respiratory depressant effects of hydrocodone . Because of the risk of life-threatening respiratory depression and death, Xtrelus is contraindicated in children less than 6 years of age .

Use of Xtrelus in children also exposes them to the risks of addiction, abuse, and misuse , which can lead to overdose and death . 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, Xtrelus is not indicated for use in patients younger than 18 years of age .

The dosage of Xtrelus should not be increased if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease .

The use of Xtrelus in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated . Opioid analgesics and antitussives, including hydrocodone, one of the active ingredients in Xtrelus, should not be used in patients with acute febrile illness associated with productive cough or in patients with chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient’s respiratory function.

Xtrelus-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Xtrelus .

Elderly, Cachectic, Or Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients .

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

Dosing errors can result in accidental overdose and death. To reduce the risk of overdose and respiratory depression, ensure that the dose of Xtrelus is communicated clearly and dispensed accurately .

Hydrocodone, one of the active ingredients in Xtrelus, 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 Xtrelus. Avoid concurrent use of Xtrelus with alcohol or other central nervous system depressants because additional impairment of central nervous system performance may occur .

Concomitant use of Xtrelus with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azoleantifungal 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 , particularly when an inhibitor is added after a stable dose of Xtrelus is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Xtrelus-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions.

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

Avoid the use of Xtrelus in patients who are taking a CYP3A4 inhibitor or inducer. If concomitant use of Xtrelus with a CYP3A4 inhibitor or inducer is necessary, monitor patients for signs and symptoms that may reflect opioid toxicity and opioid withdrawal .

Concomitant use of opioids, including Xtrelus, with benzodiazepines, or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Because of these risks, avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol .

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacologic properties, it is reasonable to expect similar risk with concomitant use of opioid cough medications and benzodiazepines, other CNS depressants, or alcohol.

Advise both patients and caregivers about the risks of respiratory depression and sedation if Xtrelus is used with benzodiazepines, alcohol, or other CNS depressants .

Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on Xtrelus therapy. The co-ingestion of alcohol with Xtrelus may result in increased plasma levels and a potentially fatal overdose of hydrocodone .

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

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

The hydrocodone in Xtrelus 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 Xtrelus may cause spasm of the sphincter of Oddi, resulting in an increase in biliary tract pressure. Opioids may cause increases in serum amylase . Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

Avoid the use of Xtrelus 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), Xtrelus 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.

The hydrocodone in Xtrelus 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 Xtrelus therapy.

Xtrelus 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) . Monitor these patients for signs of hypotension after initiating Xtrelus.

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

Xtrelus is not recommended for use in pregnant women. Prolonged use of Xtrelus 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.

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.

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 Xtrelus.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients that the use of Xtrelus, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death . Instruct patients not to share Xtrelus with others and to take steps to protect Xtrelus from theft or misuse.

Advise patients to take Xtrelus exactly as prescribed. Advise patients not to increase the dose or dosing frequency of Xtrelus because serious adverse events such as respiratory depression may occur with overdosage .

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Xtrelus and that it can occur even at recommended dosages . Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death . Instruct patients to take steps to store Xtrelus securely and to properly dispose of unused Xtrelus in accordance with the local state guidelines and/or regulations.

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 Xtrelus may produce marked drowsiness .

Inform patients and caregivers that potentially fatal additive effects may occur if Xtrelus is used with benzodiazepines or other CNS depressants, including alcohol. Advise patients to avoid concomitant use of Xtrelus 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 Xtrelus .

Advise patients of the potential for severe constipation .

Inform patients that anaphylaxis has been reported with ingredients contained in Xtrelus. Advise patients how to recognize such a reaction and when to seek medical attention .

Inform patients not to take Xtrelus while using or within 14 days of stopping any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Xtrelus .

Inform patients that Xtrelus 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) .

Advise patients that use of Xtrelus is not recommended during pregnancy .

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that use of Xtrelus during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated .

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that Xtrelus can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy .

Advise women that breastfeeding is not recommended during treatment with Xtrelus .

Inform patients that chronic use of opioids, such as hydrocodone, a component of Xtrelus, may cause reduced fertility. It is not known whether these effects on fertility are reversible .

Inform patients that Xtrelus 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 .

Inform patients that Xtrelus 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. .

Advise patients to properly dispose of unused Xtrelus. Advise patients to throw the drug in the household trash following these steps. 1) Remove them from their original containers and break the tablets, 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.

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

Carcinogenicity studies were conducted with codeine, an opiate related to hydrocodone. Two-year studies in F344/N rats and B6C3F1 mice were conducted to assess the carcinogenic potential of codeine. No evidence of tumorigenicity was observed in male and female rats at codeine dietary doses up to 70 and 80 mg/kg/day (approximately equivalent to 40 and 45 times the MRHD of hydrocodone on a mg/m² basis, respectively). No evidence of tumorigenicity was observed in male and female mice at codeine dietary doses up to 400 mg/kg/day (approximately equivalent to 110 times the MRHD of hydrocodone on a mg/m² basis).

Mutagenicity studies with hydrocodone have not been conducted. Fertility studies with hydrocodone have not been conducted.

Carcinogenicity, mutagenicity, and fertility studies with guaifenesin have not been conducted.

Xtrelus 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 .

There are no available data with Xtrelus 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 .

Reproductive toxicity studies have not been conducted with Xtrelus; however, studies are available with individual active ingredients or related active ingredients .

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) .

Guaifenesin administered by the oral route to pregnant rats during the period of organogenesis was embryolethal at a dose approximately 1 times the MRHD and produced teratogenic effects at a dose approximately 2 times the MRHD .

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.

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 .

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 Xtrelus, 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 dilatation, which tends to shorten labor. Monitor neonates exposed to opioids during labor for signs of excess sedation and respiratory depression.

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 Xtrelus; 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).

Guaifenesin

In an embryofetal development study in pregnant rats dosed throughout the period of organogenesis, guaifenesin resulted in fetal death at doses approximately 1 times the MRHD (on a mg/m² basis with maternal oral doses of 350 mg/kg/day and higher). Guaifenesin also induced hemorrhagic spots and decreases in fetal weight and lengths of full body, skull, fore- and hind-limbs, and tail at doses 1 times the MRHD (on a mg/m² basis with maternal oral doses of 250 mg/kg/day and higher). Limb and tail defects, increased intercostal space, and improper development of limbs were observed at doses 2 times the MRHD (on a mg/m² basis with maternal oral doses of 500 mg/kg/day and higher).

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 Xtrelus.

There are no data on the presence of Xtrelus in human milk, the effects of Xtrelus on the breastfed infant, or the effects of Xtrelus on milk production; however, data are available with hydrocodone.

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.

Guaifenesin

No information is available on the levels of guaifenesin in breast milk or on milk production.

Infants exposed to Xtrelus 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.

Chronic use of opioids, such as hydrocodone, a component of Xtrelus, may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible .

Xtrelus is not indicated for use in patients younger than 18 years of age because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks for use of hydrocodone in these patients .

Life-threatening respiratory depression and death have occurred in children who received hydrocodone . Because of the risk of life-threatening respiratory depression and death, Xtrelus is contraindicated in children less than 6 years of age .

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

Use caution when considering the use of Xtrelus in patients 65 years of age or older. Elderly patients may have increased sensitivity to hydrocodone; greater frequency of decreased hepatic, renal, or cardiac function; or concomitant disease or other drug therapy .

Respiratory depression is the chief risk for elderly patients treated with opioids, including Xtrelus. Respiratory depression has occurred after large initial doses of opioids were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration .

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

The pharmacokinetics of Xtrelus has not been characterized in patients with renal impairment. Patients with renal impairment may have higher plasma concentrations than those with normal function . Xtrelus should be used with caution in patients with severe impairment of renal function, and patients should be monitored closely for signs of hydrocodone toxicity including respiratory depression, sedation, and hypotension.

The pharmacokinetics of Xtrelus has not been characterized in patients with hepatic impairment. Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function . Therefore, Xtrelus should be used with caution in patients with severe impairment of hepatic function, and patients should be monitored closely for signs of hydrocodone toxicity including respiratory depression, sedation, and hypotension.

Dosage (Posology) and method of administration

Administer Xtrelus by the oral route only. Advise patients not to increase the dose or dosing frequency of Xtrelus because serious adverse events such as respiratory depression may occur with overdosage . The dosage of Xtrelus should not be increased if cough fails to respond; an unresponsive cough should be reevaluated for possible underlying pathology .

One tablet every 4 to 6 hours, not to exceed 6 tablets in 24 hours.

Prescribe Xtrelus for the shortest duration that is consistent with individual patient treatment goals .

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy .

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

Do not abruptly discontinue Xtrelus in a physically-dependent patient . When a patient who has been taking Xtrelus regularly and may be physically dependent no longer requires therapy with Xtrelus, 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.

Special precautions for disposal and other handling

Oral tablet: Each tablet contains hydrocodone bitartrate, USP 5 mg; and guaifenesin, USP 400 mg .

Xtrelus (hydrocodone bitartrate and guaifenesin) 5mg/400mg tablets are white, capsule-shaped, debossed “ECI” on one side and “601” on the other. It is supplied in the following configurations:

White HDPE bottles of 30 Counts: NDC 51293-601-30
White HDPE bottles of 100 Counts: NDC 51293-601-01
White HDPE bottles of 500 Counts: NDC 51293-601-05

Store at 20°C to 25°C (68°F to 77°F). Dispense in a tight, light-resistant container, as defined in the USP, with a child-resistant closure.

Marketed by: ECI Pharmaceuticals, LLC Fort Lauderdale, FL 33309. Revised: Oct 2018

Interaction with other medicinal products and other forms of interaction

No specific drug interaction studies have been conducted with Xtrelus.

Concomitant use of alcohol with Xtrelus 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 Xtrelus therapy .

The concomitant use of Xtrelus 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 Xtrelus and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Xtrelus is achieved . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.

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

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

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

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

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 Xtrelus if serotonin syndrome is suspected.

Avoid the use of Xtrelus 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 Xtrelus, 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).

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

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.

The concomitant use of anticholinergic drugs with Xtrelus may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus . Monitor patients for signs of urinary retention or reduced gastric motility when Xtrelus is used concomitantly with anticholinergic drugs.

Xtrelus contains hydrocodone, a Schedule II controlled substance.

Xtrelus contains hydrocodone, a substance with a high potential for abuse similar to other opioids including

morphine and codeine. Xtrelus can be abused and is subject to misuse, addiction, and criminal diversion .

All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic and antitussive products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Xtrelus, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

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

Xtrelus is for oral use only. Abuse of Xtrelus poses a risk of overdose and death. The risk is increased with concurrent use of Xtrelus with alcohol and other central nervous system depressants .

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Psychological dependence, physical dependence, and tolerance may develop upon repeated administration of opioids; therefore, Xtrelus 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 .

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 Xtrelus 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 .