OBREDON (Page 7 of 10)

10 OVERDOSAGE

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, 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) ].

Guaifenesin
Overdosage with guaifenesin can cause depression of the central nervous system. While present in polypharmacy overdoses, one case of overdose with only significant levels of guaifenesin has been reported. Symptoms included slurred speech, shallow respirations, reduced heart rate with rhythm sinus bradycardia, followed by asystole.

Treatment of Overdose
Treatment of overdosage is driven by the overall clinical presentation, and consists of discontinuation of OBREDON 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 OBREDON, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

Hemodialysis is not routinely used to enhance the elimination of hydrocodone from the body.

11 DESCRIPTION

OBREDON (hydrocodone bitartrate and guaifenesin) oral solution contains hydrocodone, an opioid agonist; and guaifenesin, an expectorant.

Each 5 mL of OBREDON contains 2.5 mg of hydrocodone bitartrate and 200 mg of guaifenesin for oral administration.

OBREDON also contains the following inactive ingredients: artificial raspberry flavor, citric acid, glycerin, methylparaben, potassium citrate, potassium sorbate, propylene glycol, propylparaben, purified water, and saccharin sodium.

Hydrocodone BitartrateThe chemical name for hydrocodone bitartrate is morphinan-6-one, 4,5-epoxy-3-methoxy-17-methyl-, (5α)-, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1), hydrate (2:5). It is also known as 4,5α-Epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). It occurs as a fine white crystal or crystalline powder, which is derived from the opium alkaloid, thebaine. It has the following structural formula:

HCB structure
(click image for full-size original)

C 18 H 21 NO 3 • C 4 H 6 O 6 • 2½H 2 O MW= 494.50

Guaifenesin
The chemical name for guaifenesin is 3-(2-methoxyphenoxy)-1,2- propanediol. It occurs as a white powder and has the following structural formula:

GFN structure

C 10 H 14 O 4 MW= 198.22

12 CLINICAL PHARMACOLOGY

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.

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