Zohydro ER Capsules

Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. There are no studies of ZOHYDRO ER use in pregnant women. Rats administered oral hydrocodone during gestation and lactation showed increases in stillborn pups and decreases in pup survival at doses equivalent to the human dose of 100 mg/day. Reduced nursing behavior and decreased body weights were observed at 2 times the human dose. Reduced fetal weights were observed in rabbits administered hydrocodone during the period of organogenesis at doses equivalent to 5 times the human dose of 100 mg/day. In this study, increases in the number of umbilical hernias, irregularly shaped bones, and delays in fetal skeletal maturation were observed at doses 15 times the human dose of 100 mg/day. No fetal malformations were observed in animal reproduction studies with oral administration of hydrocodone bitartrate during organogenesis in rats and rabbits at doses approximately 2 and 10 times a human dose of 100 mg/day, respectively [see Data]. Based on animal data, advise pregnant women of the potential risks 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 2-4% and 15-20%, 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 newborn and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see Warnings and Precautions (5.3)].

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. ZOHYDRO ER is not recommended for use in women during and immediately prior to labor, when shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including ZOHYDRO ER, 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 dilatation, which tends to shorten labor.

Data

Animal Data

Oral doses of hydrocodone bitartrate up to 25 mg/kg/day in rats and 50 mg/kg/day in rabbits, equivalent to 2 and 10 times an adult human dose of 100 mg/day, respectively on a mg/m2 basis, did not result in any fetal malformations. Fetuses of rabbits administered oral doses of 75 mg/kg/day hydrocodone bitartrate (15 times an adult human dose of 100 mg/day on a mg/m2 basis) during the period of organogenesis exhibited an increased number of malformations consisting of umbilical hernia, and irregularly shaped bones (ulna, femur, tibia and/or fibula). Maternal toxicity was evident at this dose (decreased body weight). In addition, oral hydrocodone bitartrate reduced fetal weights at doses greater than or equal to 25 mg/kg/day (equivalent to approximately 5 times an adult human dose of 100 mg/day on a mg/m2 basis). Delays in fetal skeletal maturation (reduced ossification of hyoid bodies and xiphoid bones) were seen following dosing with 75 mg/kg/day (a dose equivalent to 15 times an adult human dose of 100 mg/day on a mg/m2 basis).

Hydrocodone bitartrate administered orally to female rats at oral doses of 10 and 25 mg/kg/day during gestation and lactation resulted in pups which were noted as cold to touch and caused a reduction in fetal viability (increases in the number of stillborn pups and/or pups dying postpartum). The doses causing these effects were equivalent to approximately 1 and 2.4 times an adult human dose of 100 mg/day, on a mg/m2 basis. Nursing was reduced in pups of mothers administered 25 mg/kg/day which correlated with decreased body weight/body weight gain and food consumption in male pups. Minimal maternal toxicity was evident at 25 mg/kg (decreased body weight).

Lactation

Risk Summary

Hydrocodone is present in human milk. A published lactation study reports 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. This lactation study did not assess breastfed infants for potential adverse drug reactions. Lactation studies have not been conducted with extended-release hydrocodone, including ZOHYDRO ER, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with ZOHYDRO ER.

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with ZOHYDRO ER.

Clinical Considerations

Monitor infants exposed to ZOHYDRO ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

In rat fertility studies, no effects on male fertility were observed with hydrocodone at doses equivalent to 10 times the human dose of 100 mg/day, however, decreases in the weight of male reproductive organs were observed in all treated groups at doses equivalent to 2.4 times the human dose of 100 mg/day and above. Reductions in female fertility indices were observed at doses of hydrocodone equivalent to 2 times the human dose of 100 mg/day and above. These changes are attributed to a hydrocodone-mediated decrease in prolactin levels in the rat. Unique to rodents, prolactin is required for normal estrous cycling and the effects on fertility observed in this study are most likely rodent-specific and not believed to be clinically relevant [see Nonclinical Toxicology (13)].

Pediatric Use

The safety and effectiveness of ZOHYDRO ER in pediatric patients below the age of 18 years have not been established.

Geriatric Use

Clinical studies of ZOHYDRO ER did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients (aged 65 years or older) may have increased sensitivity to hydrocodone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of the concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of ZOHYDRO ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6)].

Hydrocodone is known to be substantially secreted by the kidney and the risk 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, care should be taken in dose selection, and it may be useful to monitor renal function.

Hepatic Impairment

No adjustment in starting dose with ZOHYDRO ER is required in patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function [see Clinical Pharmacology (12.3)]. Therefore, a dosage reduction is recommended for patients with severe hepatic impairment [see Dosage and Administration (2.4)]. Monitor patients with severe hepatic impairment closely for respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

Renal Impairment

Patients with renal impairment have higher plasma concentrations than those with normal function. Use a low initial dose of ZOHYDRO ER in patients with renal impairment and monitor closely for respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

ZOHYDRO ER (hydrocodone bitartrate) extended-release capsules are hard gelatin capsules for oral administration. Hydrocodone bitartrate is an opioid agonist and occurs as fine, white crystals, or as a crystalline powder.

The chemical name is 4,5(alpha)-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5) or morphinan-6-one, 4,5-epoxy-3-methoxy-17-methyl-, (5 alpha)-, [R (R*, R*)]-2,3-dihydroxybutanedioate (1:1), hydrate (2:5). It has the following structural formula:

Each ZOHYDRO ER capsule contains either 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, or 50 mg of hydrocodone bitartrate and the following inactive ingredients: sugar spheres NF, hypromellose USP, ammonio methacrylate copolymer NF, silicon dioxide NF, talc USP, polyethylene oxide NF, and povidone USP. The capsule shells collectively contain titanium dioxide, FD&C Blue #1, FD&C Red #40, FDA Yellow iron oxide, FD&C Red #3, FDA Black iron oxide, FDA Red iron oxide, and gelatin.

Mechanism of Action

Hydrocodone is a full opioid agonist with relative selectivity for the mu-opioid receptor, although it can interact with other opioid receptors at higher doses. The principal therapeutic action of hydrocodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with hydrocodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

Pharmacodynamics

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 brainstem respiratory centers to both increases in carbon dioxide tension and 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 origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Overdosage (10)].

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 is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in gastric, 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 hypotenstion or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, 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 (6.2)]. 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 (6.2)].

Effects on the Immune System

In vitro and animal studies indicate that opioids have a variety of effects on immune functions, depending on the context in which they are used. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

ConcentrationEfficacy Relationships

The minimum effective analgesic concentration will vary widely among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of hydrocodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or potential development of analgesic tolerance. [see Dosage and Administration (2.1, 2.3)].

ConcentrationAdverse Experience Relationships

There is a relationship between increasing hydrocodone plasma concentration and increasing frequency of adverse experiences 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 [see Dosage and Administration (2.1, 2.2. 2.3)].

Pharmacokinetics

Absorption

As compared to immediate-release hydrocodone combination products, ZOHYDRO ER at similar daily doses results in similar overall exposure but with lower maximum concentrations. The half-life is also longer due to the prolonged duration of absorption. Based on the half-life of hydrocodone, steady-state should be obtained after 3 days of dosing. Following 7 days of dosing, AUC and Cmax increase approximately two-fold as compared to the first day of dosing. The pharmacokinetics of ZOHYDRO ER have been shown to be independent of dose up to a dose of 50 mg.

Zohydro ER Capsules exhibit peak plasma concentrations approximately 5 hours after dose administration.

Food Effects

Food has no significant effect on the extent of absorption of hydrocodone from ZOHYDRO ER. Although there was no evidence of dose dumping associated with this formulation under fasted and fed conditions, peak plasma concentration of hydrocodone increased by 27% when a ZOHYDRO ER 20 mg capsule was administered with a high-fat meal.

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 6-keto 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 (7.3)]. 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, with a mean apparent plasma half-life after ZOHYDRO ER administration of approximately 8 hours.

Special Populations

Age: Geriatric Patients

No significant pharmacokinetic differences by age were observed based on population pharmacokinetic analysis.

Sex: No significant pharmacokinetic differences by sex were observed based on population pharmacokinetic analysis.

Hepatic Impairment

After a single dose of 20 mg ZOHYDRO ER in 20 patients with mild to moderate hepatic impairment based on Child-Pugh classifications, mean hydrocodone Cmax values were 25 ± 5, 24 ± 5, and 22 ± 3.3 ng/mL for moderate and mild impairment, and normal subjects, respectively. Mean hydrocodone AUC values were 509 ± 157, 440 ± 124, and 391 ± 74 ng∙h/mL for moderate and mild impairment, and normal subjects, respectively. Hydrocodone Cmax values were 8-10% higher in patients with mild or moderate hepatic impairment, respectively, while AUC values were 10% and 26% higher in patients with mild and moderate hepatic impairment, respectively. Severely impaired subjects were not studied [see Use in Specific Populations (8.6)].

Renal Impairment

After a single dose of 20 mg ZOHYDRO ER in 28 patients with mild, moderate, or severe renal impairment based on Cockcroft-Gault criteria, mean hydrocodone Cmax values were 26 ± 6.0, 28 ± 7.5, 21 ± 5.1 and 19 ± 4.4 ng/mL for severe, moderate, mild renal impairment, and normal subjects, respectively. Mean hydrocodone AUC values were 487 ± 123, 547 ± 184, 391 ± 122 and 343 ± 105 ng∙h/mL for severe, moderate, mild renal impairment, and normal subjects, respectively. Hydrocodone Cmax values were 15%, 48%, and 41% higher and AUC values were 15%, 57% and 44% higher in patients with mild, moderate, and severe renal impairment, respectively [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Interactions with Alcohol

The rate of absorption of ZOHYDRO ER 50 mg was affected by co-administration with 40% alcohol in the fasted state, as exhibited by an increase in peak hydrocodone concentrations (on average 2.4-fold increase with maximum increase of 3.9-fold in one subject) and a decrease in the time to peak concentrations. The extent of absorption was increased on average 1.2-fold with maximum increase of 1.7-fold in one subject with 40% alcohol [see Warnings and Precautions (5.5)].

Cytochrome P450 Enzymes

While comprehensive PK drug-drug interaction studies (other than alcohol) have not been performed in humans receiving hydrocodone, published in vitro and human PK studies indicate that conversion of hydrocodone to its primary metabolite, norhydrocodone and lesser metabolite, hydromorphone, is mediated by the cytochrome P450 enzyme system. N-demethylation of hydrocodone to form norhydrocodone is attributed to CYP3A4 and O-demethylation of hydrocodone to hydromorphone is predominantly catalyzed by CYP2D6 and to a lesser extent by an unknown low affinity CYP enzyme.

CYP3A4 Inhibitors and Inducers

An increase in CYP3A4 activity by initiation of CYP3A4 inhibiting drugs or discontinuation of CYP3A4 inducing drugs could alter the metabolic profile of hydrocodone causing a slowing of hydrocodone clearance, and lead to elevated hydrocodone concentrations and effects, which could be more pronounced with concomitant use of cytochrome P450 CYP3A4 inhibitors. Initiation of a CYP3A4 inducing drug can lower hydrocodone plasma levels and may induce an opioid-withdrawal syndrome [see Warnings and Precautions (5.4) and Drug Interactions (7)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Hydrocodone was evaluated for carcinogenic potential in rats and mice. In a two-year bioassay in rats, doses up to 30 mg/kg in males and 100 mg/kg in females were administered orally and no treatment-related neoplasms were observed (exposure is equivalent to 0.1 times and 0.6 times for males and females, respectively, the human hydrocodone dose of 100 mg/day based on AUC exposure comparisons). In a two-year bioassay in mice, doses up to 100 mg/kg in males and females were administered orally and no treatment-related neoplasms were observed (exposure is equivalent to 0.8 times and 1.5 times, respectively, the human hydrocodone dose of 100 mg/day based on AUC exposure comparisons.

Mutagenesis

Hydrocodone bitartrate was genotoxic in an in vitro chromosomal aberration assay in the presence of metabolic activation. No evidence of clastogenicity was observed in this assay in the absence of metabolic activation. No evidence of DNA damage was found in an in vivo comet assay in mouse liver. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay (Salmonella typhimurium and Escherichia coli) or in an assay for chromosomal aberrations (in vivo mouse bone marrow micronucleus assay).

Impairment of Fertility

In a fertility study, rats were administered once daily by oral gavage the vehicle or hydrocodone bitartrate at doses of 25, 75, and 100 mg/kg/day (equivalent to approximately 2, 7, and 10 times an adult human dose of 100 mg/day, on a mg/m2 basis). Male and female rats were dosed before cohabitation (up to 28 days), during the cohabitation and until gestation day 7 (females) or necropsy (males; 2-3 weeks post-cohabitation). Hydrocodone bitartrate did not affect reproductive function in males, although the weights of male reproductive organs were decreased at all doses. Doses of 25 mg/kg/day and greater in females reduced the rate at which females became pregnant which correlated with suppression of estrous cyclicity, thought to be due to increases in prolactin. In hydrocodone bitartrate-treated rats that became pregnant, at 25 mg/kg early embryonic development was unaffected (approximately 2 times the adult human daily dose of 100 mg/day on a mg/m2 basis). In rats, prolactin plays a unique role in the estrous cycle and the clinical relevance of the female rat reproductive findings is uncertain.

ZOHYDRO ER extended-release capsules are supplied in 60-count bottles with a child-resistant closure as follows:

ZOHYDRO ER contains hydrocodone bitartrate which is a controlled substance and is controlled under Schedule II of the Controlled Substances Act. Hydrocodone, like all opioids, is liable to diversion and misuse and should be handled accordingly. Patients and their families should be instructed to dispose of any Zohydro ER Capsules that are no longer needed.

ZOHYDRO ER may be targeted for theft and diversion. Healthcare professionals should contact their State Medical Board, State Board of Pharmacy, or State Control Board for information on how to detect or prevent diversion of this product.

Healthcare professionals should advise patients to store ZOHYDRO ER in a secure place, preferably locked and out of the reach of children and other non-caregivers.

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Dispense in tight container as defined in the USP, with a child-resistant closure.

Advise patients to dispose of any unused capsules from a prescription as soon as they are no longer needed in accordance with local State guidelines and/or regulations [see Patient Counseling Information (17)].

Zohydro®ER

(hydrocodone bitartrate)
EXTENDED-RELEASE CAPSULES

NDC 65224-320-60
CII

Dispense the accompanying Medication Guide to each patient.
20 mg

Swallow capsules whole.
Do not chew, crush, or dissolve.

60 Capsules
Rx only

Zohydro®ER

(hydrocodone bitartrate)
EXTENDED-RELEASE CAPSULES

NDC 65224-330-60
CII

Dispense the accompanying Medication Guide to each patient.
30 mg

Swallow capsules whole.
Do not chew, crush, or dissolve.

60 Capsules
Rx only

Zohydro®ER

(hydrocodone bitartrate)
EXTENDED-RELEASE CAPSULES

NDC 65224-350-60
CII

Dispense the accompanying Medication Guide to each patient.
50 mg

Swallow capsules whole.
Do not chew, crush, or dissolve.

60 Capsules
Rx only