Hydromet Drug Information

Important Dosage and

Administration Instructions Administer hydrocodone bitartrate and homatropine methylbromide oral solution by the oral route only. Always use an accurate milliliter measuring device when administering hydrocodone bitartrate and homatropine methylbromide oral solution 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. Advise patients not to increase the dose or dosing frequency of hydrocodone bitartrate and homatropine methylbromide oral solution because serious adverse events such as respiratory depression may occur with overdosage . The dosage of hydrocodone bitartrate and homatropine methylbromide oral solution should not be increased if cough fails to respond; an unresponsive cough should be reevaluated for possible underlying pathology .

Recommended Dosage Adults 18 years of age and older: 5 mL of

the oral solution every 4 to 6 hours as needed; not to exceed 30 mL in 24 hours.

Monitoring, Maintenance, and Discontinuation of Therapy Prescribe hydrocodone bitartrate and homatropine methylbromide

oral solution for the shortest duration that is consistent with individual patient treatment goals . Monitor patients closely for respiratory depression, especially within the first 24 to 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 hydrocodone bitartrate and homatropine methylbromide oral solution, the relative incidence of adverse reactions, and the development of addiction, abuse, or misuse . Do not rapidly reduce or abruptly discontinue hydrocodone bitartrate and homatropine methylbromide oral solution in a physically-dependent patient . When a patient who has been taking hydrocodone bitartrate and homatropine methylbromide oral solution regularly and may be physically dependent no longer requires therapy with hydrocodone bitartrate and homatropine methylbromide oral solution, 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.

The following clinically significant adverse reactions are described elsewhere in labeling: 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 homatropine. Because these reactions may be reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most common adverse reactions to hydrocodone bitartrate and homatropine methylbromide oral solution 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 hydrocodone bitartrate and homatropine methylbromide oral solution. 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. Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term.

Common adverse reactions include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, and constipation. To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-888-838-2872 or FDA at 1-800-FDA-1088 or ww w. f d a.gov/medwatch.

Alcohol

Concomitant use of alcohol with hydrocodone bitartrate and homatropine methylbromide oral solution 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 hydrocodone bitartrate and homatropine methylbromide oral solution therapy .

Inhibitors of

CYP3A4 and CYP2D6 The concomitant use of hydrocodone bitartrate and homatropine methylbromide oral solution 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 hydrocodone bitartrate and homatropine methylbromide oral solution and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of hydrocodone bitartrate and homatropine methylbromide 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 hydrocodone bitartrate and homatropine methylbromide oral solution while taking a CYP3A4 or CYP2D6 inhibitor.

If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

CYP3A4 Inducers

The concomitant use of hydrocodone bitartrate and homatropine methylbromide oral solution 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 hydrocodone bitartrate and homatropine methylbromide oral solution in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.

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, gabapentinoids (gabapentin or pregabalin), and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of hydrocodone bitartrate and homatropine methylbromide oral solution in patients who are taking benzodiazepines, gabapentinoids, or other CNS depressants , and instruct patients to avoid consumption of alcohol while on hydrocodone bitartrate and homatropine methylbromide oral solution .

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 hydrocodone bitartrate and homatropine methylbromide oral solution if serotonin syndrome is suspected.

Monoamine Oxidase Inhibitors (MAOIs)

Avoid the use of hydrocodone bitartrate and homatropine methylbromide oral solution 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 hydrocodone bitartrate and homatropine methylbromide oral solution, 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).

Muscle Relaxants Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle

relaxants (e.g., cyclobenzaprine, metaxalone) and produce an increased degree of respiratory depression. Avoid the use of hydrocodone bitartrate and homatropine methylbromide oral solution in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.

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.

Anticholinergic Drugs

The concomitant use of anticholinergic drugs with hydrocodone bitartrate and homatropine methylbromide oral solution 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 hydrocodone bitartrate and homatropine methylbromide oral solution is used concomitantly with anticholinergic drugs.

Pregnancy Risk Summary Hydrocodone bitartrate and homatropine methylbromide oral solution 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 hydrocodone bitartrate and homatropine methylbromide oral solution 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 hydrocodone bitartrate and homatropine methylbromide oral solution; however, studies are available with individual active ingredients or related active ingredients (see Data). In animal reproduction studies, hydrocodone administered by the subcutaneous route to pregnant hamsters during the period of organogenesis produced a teratogenic effect at a dose approximately 45 times the maximum recommended human dose (MRHD) (see Data). Based on the animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate.

Opioids, including hydrocodone bitartrate and homatropine methylbromide, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioids during labor for signs of excess sedation and respiratory depression.

Data Human Data Hydrocodone A limited number of pregnancies have been reported in published observational studies and postmarketing reports describing hydrocodone use during pregnancy. However, these data cannot definitely establish or exclude any drug-associated risk during pregnancy. Methodological limitations of these observational studies include small sample size and lack of details regarding dose, duration and timing of exposure.

Animal Data Reproductive toxicity studies have not been conducted with hydrocodone bitartrate and homatropine methylbromide; however, studies are available with individual active ingredients or related active ingredients. H y d r ocodone 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). H omatropine Animal studies with homatropine are not available.

Pediatric Use Hydrocodone bitartrate and homatropine methylbromide oral solution is contraindicated in pediatric patients younger than 6 years of age because of life-threatening respiratory depression and death have occurred in pediatric patients who received hydrocodone . The safety and effectiveness of hydrocodone bitartrate and homatropine methylbromide oral solution have not been established in patients younger than 18 years of age. Hydrocodone bitartrate and homatropine methylbromide oral solution is not recommended 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 .

Hydrocodone bitartrate and homatropine methylbromide oral solution is contraindicated for: All pediatric patients younger than 6 years of age. 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, homatropine, or any of the inactive ingredients in hydrocodone bitartrate and homatropine methylbromide oral solution . Children younger than 6 years of age. Significant respiratory depression.

Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. Known or suspected gastrointestinal obstruction, including paralytic ileus. Hypersensitivity to hydrocodone, homatropine, or any of the inactive ingredients in hydrocodone bitartrate and homatropine methylbromide oral solution.

Clinical Presentation Hydrocodone 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, hypoglycemia, circulatory collapse, cardiac arrest, and death. Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. 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 . Homatropine Homatropine has broad, nonspecific anticholinergic / antimuscarinic activity that similar to, although less potent than, atropine. Overdosage of homatropine can cause mydriasis and cycloplegia (fixed and dilated pupils), dry mouth and eyes, decreased sweating, hyperthermia, flushing, headache, visual blurring, gastrointestinal symptoms, constipation, urinary retention, tachycardia and palpitations, anxiety, restlessness, agitation, hallucinations, convulsions, cardiac arrhythmias and coma. Anticholinergic agents can also precipitate acute narrow angle glaucoma.

Treatment of Overdose Treatment of overdosage is driven by the overall clinical presentation, and consists of discontinuation of hydrocodone bitartrate and homatropine methylbromide oral solution 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. For clinically significant respiratory or circulatory depression secondary to hydrocodone overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene.

An opioid overdose reversal agent 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 hydrocodone bitartrate and homatropine methylbromide oral solution, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product’s prescribing information.

Hemodialysis is not routinely used to enhance the elimination of hydrocodone from the body. Physostigmine may be used parenterally for the treatment of the signs and symptoms of homatropine toxicity.