2.1 Important Dosage and Administration Instructions

Administer OBREDON by the oral route only.Administer OBREDON by the oral route only.

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

Advise patients not to increase the dose or dosing frequency of OBREDON because serious adverse events such as respiratory depression may occur with overdosage [ see Warnings and Precautions ( 5.2), Overdosage ( 10) ]. The dosage of OBREDON 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 and adolescents 18 years of age and older: 10 mL every 4 to 6 hours, not to exceed 6 doses (60 mL) in 24 hours.

2.3 Monitoring, Maintenance, and Discontinuation of Therapy

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

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

OBREDON contains hydrocodone, a Schedule II controlled substance. As an opioid, OBREDON 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 OBREDON 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 OBREDON, prescribe OBREDON 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 OBREDON. 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 OBREDON. 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 OBREDON. 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 OBREDON, OBREDON close observation, supportive measures, and use of opioid antagonists (e.g. naloxone), depending on the patient’s clinical status [ see Overdosage ( 10) ]. Carbon dioxide (CO 2) 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 OBREDON, the risk is greatest during the initiation of therapy, when OBREDON 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 OBREDON 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 OBREDON, 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, OBREDON is contraindicated in children less than 6 years of age [ see Contraindications ( 4) ].

Use of OBREDON 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, OBREDON is not indicated for use in patients younger than 18 years of age [ see Indications ( 1), Use in Specific Populations (8.4) ].

5.4 Risks with Use in Other At-Risk Populations

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

Asthma and Other Pulmonary DiseaseThe use of OBREDON in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated [ see Contraindications ( 4) ].

Opioid analgesics and antitussives, including hydrocodone, one of the active ingredients in OBREDON, 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.

OBREDON 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 OBREDON [ see Warnings and Precautions ( 5.2) ].

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

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

5.5 Risk of Accidental Overdose and Death due to Medication Errors

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

Advise patients to always use an accurate milliliter measuring device when measuring and administering OBREDON. Inform patients that household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions [ ]. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate calibrated measuring device and can provide instructions for measuring the correct dose. Advise patients to always use an accurate milliliter measuring device when measuring and administering OBREDON. Inform patients that household teaspoon is not an accurate measuring device and such use could lead to overdosage and serious adverse reactions [ see Overdosage ( 10) ]. For prescriptions where a measuring device is not provided, a pharmacist can provide an appropriate calibrated measuring device and can provide instructions for measuring the correct dose.

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

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

Concomitant use of OBREDON 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 OBREDON in patients who are taking a CYP3A4 inhibitor or inducer. If concomitant use of OBREDON 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 OBREDON, 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 [ ]. Concomitant use of opioids, including OBREDON, 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.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 OBREDON is used with benzodiazepines, alcohol, or other CNS depressants [ ]. Advise both patients and caregivers about the risks of respiratory depression and sedation if OBREDON 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 OBREDON therapy. The co-ingestion of alcohol with OBREDON 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

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

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

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

5.11 Increased Risk of Seizures in Patients with Seizure Disorders

The hydrocodone in OBREDON 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 OBREDON therapy.

5.12 Severe Hypotension

OBREDON 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 OBREDON.

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

5.13 Neonatal Opioid Withdrawal Syndrome

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

7.1 Alcohol

Concomitant use of alcohol with OBREDON 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 OBREDON therapy [ see Warnings and Precautions ( 5.8), Clinical Pharmacology (12.3) ].

7.2 Inhibitors of CYP3A4 and CYP2D6

The concomitant use of OBREDON 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 OBREDON and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of OBREDON 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 OBREDON 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 OBREDON 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 OBREDON 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 OBREDON 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 OBREDON [ 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 OBREDON if serotonin syndrome is suspected.

7.6 Monoamine Oxidase Inhibitors (MAOIs)

Avoid the use of OBREDON 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 OBREDON, 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 OBREDON in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

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 OBREDON 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 OBREDON is used concomitantly with anticholinergic drugs.

8.1 Pregnancy

Risk Summary

OBREDON 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 ( 5.13), Clinical Considerations ].

There are no available data with OBREDON 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 OBREDON; 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).

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 ( 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 ( 5.13) ].

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 OBREDON, 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

HydrocodoneA 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 DataReproductive toxicity studies have not been conducted with OBREDON; however, studies are available with individual active ingredients or related active ingredients.

HydrocodoneIn 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).

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 OBREDON.

There are no data on the presence of OBREDON in human milk, the effects of OBREDON on the breastfed infant, or the effects of OBREDON 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.

Clinical Considerations
Infants exposed to OBREDON 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 OBREDON, 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

OBREDON 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, OBREDON is contraindicated in children less than 6 years of age [ see Contraindications ( 4) ].

8.5 Geriatric Use

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

Use caution when considering the use of OBREDON 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 OBREDON. 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 OBREDON 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) ]. OBREDON 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 OBREDON 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, OBREDON 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

OBREDON contains hydrocodone, a Schedule II controlled substance.

9.2 Abuse

Hydrocodone
OBREDON contains hydrocodone, a substance with a high potential for abuse similar to other opioids including morphine and codeine. OBREDON can be abused and is subject to misuse, addiction, and criminal diversion [ see Warnings and Precautions ( 5.1) ].

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.

OBREDON, 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.

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

Risks Specific to Abuse of OBREDON
OBREDON is for oral use only. Abuse of OBREDON poses a risk of overdose and death. The risk is increased with concurrent use of OBREDON with alcohol and other central nervous system depressants [ see Warnings and Precautions ( 5.8), Drug Interactions ( 7.1, 7.4) ].

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

9.3 Dependence

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

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Hydrocodone

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 [ see Adverse Reactions ( 6) ]. 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 [ see Adverse Reactions ( 6) ].

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.

12.3 Pharmacokinetics

Absorption
Following a single 10 mL oral dose of OBREDON, the geometric mean C max and AUC 0-inf for hydrocodone were 12.6 ng/ml and 80.9 ng·hr/ml, respectively, and the geometric mean C max and AUC 0-inf for guaifenesin were 3.7 mcg/ml and 4.2 mcg·hr/ml, respectively. The median time to maximum concentration in plasma for hydrocodone and guaifenesin was about 1.25 hours and 20 minutes, respectively. 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.

Distribution
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.

Elimination

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 [see Drug Interactions ( 7)]. 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 is approximately 5 hours.

The mean plasma half-life of guaifenesin is approximately 1 hour.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Hydrocodone
Carcinogenicity studies were conducted with codeine, an opiate related to hydrocodone. 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/m 2 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/m 2 basis).

Mutagenicity studies with hydrocodone have not been conducted.

Fertility studies with hydrocodone have not been conducted.

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

Manufactured by:
Sovereign Pharmaceuticals, LLC
Fort Worth, TX 76118

U.S. Patent numbers 9,549,907; 9,808,431; 10,105,324