HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TUSSIGON® safely and effectively. See full prescribing information for TUSSIGON.
TUSSIGON (hydrocodone bitartrate and homatropine methylbromide) tablets, for oral administration, CII
Initial U.S. Approval: 1943
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; MEDICATION ERRORS; CYTOCHROME P450 3A4 INTERACTION; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; INTERACTION WITH ALCOHOL; NEONATAL OPIOID WITHDRAWAL SYNDROME
See full prescribing information for complete boxed warning.
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
TUSSIGON is a combination of hydrocodone, an opioid agonist, and homatropine, a muscarinic antagonist, indicated for the symptomatic relief of cough in patients 18 years of age and older. (1)
Important Limitations of Use (1)
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Tablets: 5 mg hydrocodone bitartrate and 1.5 mg homatropine methylbromide. (3)
WARNINGS AND PRECAUTIONS
See Boxed WARNINGS
Common adverse reactions include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, and constipation. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION.
5 WARNINGS AND PRECAUTIONS
5.9 Risks of Use in Patients with Head Injury, Impaired Consciousness, Increased Intracranial Pressure, or Brain Tumors
6 ADVERSE REACTIONS
The following serious adverse events are described, or described in greater detail, in other sections:
- Addiction, abuse, and misuse [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.3)]
- Life-threatening respiratory depression [see Warnings and Precautions (5.2, 5.3, 5.7) and Overdosage (10)]
- Accidental overdose and death due to medication errors [see Warnings and Precautions (5.4)]
- Decreased mental alertness with impaired mental and/or physical abilities [see Warnings and Precautions (5.5)]
- Interactions with benzodiazepines and other CNS depressants [see Warnings and Precautions (5.7, 7.1, 7.5)]
- Paralytic ileus, gastrointestinal adverse reactions [see Warnings and Precautions (5.8)]
- Increased intracranial pressure [see Warnings and Precautions (5.9)]
- Obscured clinical course in patients with head injuries [see Warnings and Precautions (5.9)]
- Seizures [see Warnings and Precautions (5.10)]
- Severe hypotension [see Warnings and Precautions (5.11)]
- Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.12)]
- Adrenal insufficiency [see Warnings and Precautions (5.13)]
The following adverse reactions have been identified during clinical studies, in the literature, or during post-approval use of hydrocodone. Because these reactions may be reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The most common adverse reactions to TUSSIGON include: Sedation (somnolence, mental clouding, lethargy), impaired mental and physical performance, lightheadedness, dizziness, headache, dry mouth, nausea, vomiting, and constipation.
Other reactions include:
Anaphylaxis: Anaphylaxis has been reported with hydrocodone, one of the ingredients in TUSSIGON.
Body as a whole: Coma, death, fatigue, falling injuries, lethargy.
Cardiovascular: Peripheral edema, increased blood pressure, decreased blood pressure, tachycardia, chest pain, palpitation, syncope, orthostatic hypotension, prolonged QT interval, hot flush.
Central Nervous System: Facial dyskinesia, insomnia, migraine, increased intracranial pressure, seizure, tremor.
Dermatologic: Flushing, hyperhidrosis, pruritus, rash.
Endocrine/Metabolic: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Cases of androgen deficiency have occurred with chronic use of opioids.
Gastrointestinal: Abdominal pain, bowel obstruction, decreased appetite, diarrhea, difficulty swallowing, dry mouth, GERD, indigestion, pancreatitis, paralytic ileus, biliary tract spasm (spasm of the sphincter of Oddi).
Genitourinary: Urinary tract infection, ureteral spasm, spasm of vesicle sphincters, urinary retention.
Laboratory: Increases in serum amylase.
Musculoskeletal: Arthralgia, backache, muscle spasm.
Ophthalmic: Miosis (constricted pupils), visual disturbances.
Psychiatric: Agitation, anxiety, confusion, fear, dysphoria, depression.
Reproductive: Hypogonadism, infertility.
Respiratory: Bronchitis, cough, dyspnea, nasal congestion, nasopharyngitis, respiratory depression, sinusitis, upper respiratory tract infection.
Other: Drug abuse, drug dependence, opioid withdrawal syndrome.
7 DRUG INTERACTIONS
No specific drug interaction studies have been conducted with TUSSIGON.
Concomitant use of alcohol with TUSSIGON can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone. Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products containing alcohol while on TUSSIGON therapy [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)].
7.2 Inhibitors of CYP3A4 and CYP2D6
The concomitant use of TUSSIGON and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of TUSSIGON and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of TUSSIGON is achieved [see Warnings and Precautions (5.6)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.
Avoid the use of TUSSIGON while taking a CYP3A4 or CYP2D6 inhibitor. If concomitant use is necessary, monitor patients for respiratory depression and sedation at frequent intervals.
7.3 CYP3A4 Inducers
The concomitant use of TUSSIGON and CYP3A4 inducers such as rifampin, carbamazepine, or phenytoin, can decrease the plasma concentration of hydrocodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see Warnings and Precautions (5.6)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Avoid the use of TUSSIGON in patients who are taking CYP3A4 inducers. If concomitant use of a CYP3A4 inducer is necessary, follow the patient for reduced efficacy.
7.4 Benzodiazepines and Other CNS Depressants
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Avoid the use of TUSSIGON in patients who are taking benzodiazepines or other CNS depressants [see Warnings and Precautions (5.7)], and instruct patients to avoid consumption of alcohol while on TUSSIGON [see Warnings and Precautions (7.1)].
7.5 Serotonergic Drugs
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation. Discontinue TUSSIGON if serotonin syndrome is suspected.
7.6 Monoamine Oxidase Inhibitors (MAOIs)
Avoid the use of TUSSIGON in patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken MAOIs within 14 days. The use of MAOIs inhibitors or tricyclic antidepressants with hydrocodone , one of the active ingredients in TUSSIGON, may increase the effect of either the antidepressant or hydrocodone. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
7.7 Muscle Relaxants
Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Avoid the use of TUSSIGON in patients taking muscle relaxants. If concomitant use is necessary, monitor patients for signs of respiratory depression that may be greater than otherwise expected.
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
7.9 Anticholinergic Drugs
The concomitant use of anticholinergic drugs with TUSSIGON may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus [see Warnings and Precautions (5.8)]. Monitor patients for signs of urinary retention or reduced gastric motility when TUSSIGON is used concomitantly with anticholinergic drugs.
8 USE IN SPECIFIC POPULATIONS
TUSSIGON is not recommended for use in pregnant women, including during or immediately prior to labor.
There are no available data with TUSSIGON use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Published studies with hydrocodone have reported inconsistent findings and have important methodological limitations (see Data).
Reproductive toxicity studies have not been conducted with TUSSIGON; however, studies are available with individual active ingredients (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 28 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.
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 TUSSIGON, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioids during labor for signs of excess sedation and respiratory depression.
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.
Reproductive toxicity studies have not been conducted with TUSSIGON; however, studies are available with individual active ingredients.
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 28 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 39 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 19 and 97 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).
Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with TUSSIGON.
There are no data on the presence of TUSSIGON in human milk, the effects of TUSSIGON on the breastfed infant, or the effects of TUSSIGON on milk production; however, data are available with hydrocodone and homatropine.
Hydrocodone 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.
No information is available on the levels of homatropine in breast milk or on milk production. The published literature suggests that homatropine may decrease milk production based on its anticholinergic effects (see Clinical Considerations).
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
TUSSIGON is not indicated for use in patients younger than 18 years of age because the benefits of symptomatic treatment of cough associated with allergies or the common cold do not outweigh the risks for use of hydrocodone in these patients.
Life-threatening respiratory depression and death have occurred in children who received hydrocodone [see Warnings and Precautions (5.2)]. Because of the risk of life-threatening respiratory depression and death, TUSSIGON is contraindicated in children less than 6 years of age [see Contraindications (4)].
8.5 Geriatric Use
Clinical studies have not been conducted with TUSSIGON in geriatric populations.
Use caution when considering the use of TUSSIGON in patients 65 years of age or older. Elderly patients may have increased sensitivity to hydrocodone; greater frequency of decreased hepatic, renal, or cardiac function; or concomitant disease or other drug therapy [see Warnings and Precautions (5.4)].
Respiratory depression is the chief risk for elderly patients treated with opioids, including TUSSIGON. Respiratory depression has occurred after large initial doses of opioids were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration [see Warnings and Precautions (5.3, 5.7)].
Hydrocodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, monitor these patients closely for respiratory depression, sedation, and hypotension.
8.6 Renal Impairment
The pharmacokinetics of TUSSIGON has not been characterized in patients with renal impairment. Patients with renal impairment may have higher plasma concentrations than those with normal function [see Clinical Pharmacology (12.3)]. TUSSIGON should be used with caution in patients with severe impairment of renal function, and patients should be monitored closely for respiratory depression, sedation, and hypotension.
8.7 Hepatic Impairment
The pharmacokinetics of TUSSIGON has not been characterized in patients with hepatic impairment. Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function [see Clinical Pharmacology (12.3)]. Therefore, TUSSIGON should be used with caution in patients with severe impairment of hepatic function, and patients should be monitored closely for respiratory depression, sedation, and hypotension.
9 DRUG ABUSE AND DEPENDENCE
TUSSIGON contains hydrocodone, a substance with a high potential for abuse similar to other opioids including morphine and codeine. TUSSIGON 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.
TUSSIGON, 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.
Risks Specific to Abuse of TUSSIGON
TUSSIGON is for oral use only. Abuse of TUSSIGON poses a risk of overdose and death. The risk is increased with concurrent use of TUSSIGON with alcohol and other central nervous system depressants [see Warnings and Precautions (5.7), Drug Interactions (7.1, 7.4)].
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, TUSSIGON 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 TUSSIGON 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)].
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 [see Clinical Pharmacology (12.2)].
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 TUSSIGON 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 TUSSIGON, 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.
Because of the potential for promethazine to reverse epinephrine's vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine overdose.
Hemodialysis is not routinely used to enhance the elimination of hydrocodone from the body.
TUSSIGON tablets contain hydrocodone an opioid agonist, and homatropine an anticholinergic.
Each tablet of TUSSIGON contains 5 mg of hydrocodone bitartrate and 1.5 mg of homatropine methylbromide for oral administration.
TUSSIGON also contains the following inactive ingredients: Colloidal Silicon Dioxide NF, FD & C Blue No. 1 Aluminum Lake, Lactose Monohydrate NF, Microcrystalline Cellulose NF, Pregelatinized Starch NF, Stearic Acid NF, Talc USP.
The chemical name for hydrocodone is 4,5α- epoxy-3-methoxy-17-methylmorphinan -6-one-tartrate (1:1) hydrate (2:5), a fine white crystal or crystalline powder which is derived from the opium alkaloid, thebaine, has a molecular weight of (494.50) and may be represented by the following structural formula:
C18H21N03 ∙ C4H606 ∙ 2½H20
Homatropine methylbromide is 8-Azoniabicyclo[3.2.1]octane, 3-(hydroxyphenylacetyl)oxy-8, 8-dimethyl-, bromide, endo-, a white crystal or fine white crystalline powder, with a molecular weight of (370.29).
Dissolution testing of TUSSIGON tablets is performed using Test 2 from USP <711>.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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.
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.
The median time to maximum concentration for hydrocodone was about 1.67 hours. Food has no significant effect on the extent of absorption of hydrocodone.
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.
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 (7.2)]. 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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity, mutagenicity, and fertility studies have not been conducted with TUSSIGON; 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 23 and 26 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 65 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
TUSSIGON is supplied in the following strength and package configuration:
|Package Configuration||Tablet Strength (mg)||NDC||Tablet Description|
|Bottles of 100||hydrocodone bitartrate (5 mg) and homatropine methylbromide (1.5 mg)||61570-102-01||blue, scored tablet|
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Addiction, Abuse, and Misuse
Inform patients that the use of TUSSIGON, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share TUSSIGON with others and to take steps to protect TUSSIGON from theft or misuse.
Important Dosing and Administration Instructions
Instruct patients how to take the correct dose of TUSSIGON. Advise patients not to increase the dose or dosing frequency of TUSSIGON because serious adverse events such as respiratory depression may occur with overdosage [see Warnings and Precautions (5.2), Overdosage (10)].
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting TUSSIGON and that it can occur even at recommended dosages [see Warnings and Precautions (5.2)]. 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 [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store TUSSIGON securely and to properly dispose of unused TUSSIGON in accordance with the local state guidelines and/or regulations.
Activities Requiring Mental Alertness
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 TUSSIGON may produce marked drowsiness [see Warnings and Precautions (5.5)].
Interactions with Benzodiazepines and Other Central Nervous System Depressants, Including Alcohol
Inform patients and caregivers that potentially fatal additive effects may occur if TUSSIGON is used with benzodiazepines or other CNS depressants, including alcohol. Advise patients to avoid concomitant use of TUSSIGON 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 TUSSIGON [see Warnings and Precautions (5.7), Drug Interactions (7.1, 7.4)].
Inform patients that anaphylaxis has been reported with ingredients contained in TUSSIGON. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Adverse Reactions (6)].
Inform patients not to take TUSSIGON while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking TUSSIGON [see Drug Interactions (7.6)].
Inform patients that TUSSIGON 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) [see Warnings and Precautions (5.11)].
Advise patients that use of TUSSIGON is not recommended during pregnancy [see Warnings and Precautions (8.1)].
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that use of TUSSIGON during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.12), Use in Specific Populations (8.1)].
Inform female patients of reproductive potential that TUSSIGON can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].
Advise women that breastfeeding is not recommended during treatment with TUSSIGON [see Use in Specific Populations (8.2)].
Inform patients that chronic use of opioids, such as hydrocodone, a component of TUSSIGON, may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Special Populations (8.3)].
Inform patients that TUSSIGON 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 [see Warnings and Precautions (5.13)].
Inform patients that TUSSIGON 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 [see Adverse Reactions (6), Drug Interactions (7.5)].
Disposal of Unused TUSSIGON
Advise patients to properly dispose of unused TUSSIGON. Advise patients to throw the drug in the household trash following these steps. 1) Remove them from their original containers and 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.