OBREDON (Page 5 of 10)

7 DRUG INTERACTIONS

No specific interaction studies have been conducted with 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 USE IN SPECIFIC POPULATIONS

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 Data Reproductive 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).

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