Zohydro ER 30 MG 12HR Extended Release Oral Capsule
Generic Name: HYDROCODONE BITARTRATE
Brand Name: ZOHYDRO ER
- Substance Name(s):
- HYDROCODONE BITARTRATE
DRUG INTERACTIONS
7 Alcohol Clinical Impact: Concomitant use of alcohol with ZOHYDRO ER can result in an increase of hydrocodone plasma levels and potentially fatal overdose of hydrocodone.
Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on ZOHYDRO ER therapy [see Clinical Pharmacology (12.3) ].
Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of ZOHYDRO ER and CYP3A4 inhibitors can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects.
These effects could be more pronounced with concomitant use of ZOHYDRO ER and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of ZOHYDRO ER is achieved [see Warnings and Precautions (5.5) ] .
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.
Intervention: If concomitant use is necessary, consider dosage reduction of ZOHYDRO ER until stable drug effects are achieved.
Monitor patients for respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the ZOHYDRO ER dosage until stable drug effects are achieved.
Monitor for signs of opioid withdrawal.
Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.
ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of ZOHYDRO ER and CYP3A4 inducers 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 (5.5) ] .
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.
Intervention: If concomitant use is necessary, consider increasing the ZOHYDRO ER dosage until stable drug effects are achieved.
Monitor for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider ZOHYDRO ER dosage reduction and monitor for signs of respiratory depression.
Examples: Rafampin, carbamazepine, phenytoin Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Limit dosages and durations to the minimum required.
Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6) ].
Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome .
Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.
Discontinue ZOHYDRO ER if serotonin syndrome is suspected.
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Drug Interactions (7) ].
Intervention: The use of ZOHYDRO ER is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of ZOHYDRO ER and/or precipitate withdrawal symptoms.
Intervention: Avoid concomitant use.
Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of ZOHYDRO ER and/or the muscle relaxant as necessary.
Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when ZOHYDRO ER is used concomitantly with anticholinergic drugs.
Serotonergic Drugs: Concomitant use may result in serotonin syndrome.
Discontinue ZOHYDRO ER if serotonin syndrome is suspected.
( 7 ) Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of hydrocodone.
Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping an MAOI.
( 7 ) Mixed Agonists/Antagonists and Partial Agonist Opioid Analgesics: Avoid use with ZOHYDRO ER because they may reduce analgesic effect of ZOHYDRO ER or precipitate withdrawal symptoms.
( 7 )
OVERDOSAGE
10 Clinical Presentation Acute overdosage with ZOHYDRO ER can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death.
Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2) ] .
Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation if needed.
Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated.
Cardiac arrest or arrhythmias will require advanced life support techniques.
The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdosage.
For clinically significant respiratory or circulatory depression secondary to hydrocodone overdose, administer an opioid antagonist.
Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to hydrocodone overdose.
Because the duration of reversal is expected to be less than the duration of action of hydrocodone in ZOHYDRO ER, carefully monitor the patient until spontaneous respiration is reliably reestablished.
ZOHYDRO ER will continue to release hydrocodone and add to the hydrocodone load for 24 to 48 hours or longer following ingestion necessitating prolonged monitoring.
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.
In an individual physically dependent on opioids, administration of the recommended dose of the antagonist will precipitate an acute withdrawal syndrome.
The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered.
If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.
DESCRIPTION
11 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: C 18 H 21 NO 3 ∙ C 4 H 6 O 6 ∙ 2½ H 2 O MW = 494.50 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.
Chemical Structure
CLINICAL STUDIES
14 The efficacy and safety of ZOHYDRO ER have been evaluated in a randomized double-blind, placebo-controlled, multi-center clinical trial in opioid-experienced subjects with moderate to severe chronic low back pain.
Placebo-Controlled Study in Opioid-Experienced Subjects with Moderate to Severe Chronic Lower Back Pain A total of 510 subjects currently on chronic opioid therapy entered an open-label conversion and titration phase (up to 6 weeks) with ZOHYDRO ER dosed every 12 hours at an approximated equianalgesic dose of their pre-study opioid medication.
For inadequately controlled pain, ZOHYDRO ER was increased by 10 mg per 12-hour dose, once every 3–7 days until a stabilized dose was identified, or a maximum dosage of 100 mg every 12 hours.
There were 302 subjects (59%) randomized at a ratio of 1:1 into a 12-week double-blind treatment phase with their fixed stabilized dose of ZOHYDRO ER (40-200 mg daily taken as 20-100 mg, every 12 hours) or a matching placebo.
Subjects randomized to placebo were given a blinded taper of ZOHYDRO ER according to a pre-specified tapering schedule.
During the treatment phase, subjects were allowed to use rescue medication (hydrocodone 5 mg/500 mg acetaminophen) up to 2 doses (2 tablets) per day.
There were 124 treated subjects (82%) that completed the 12-week treatment with ZOHYDRO ER and 59 subjects (39%) with placebo.
ZOHYDRO ER provided greater analgesia compared to placebo.
There was a significant difference in the mean changes from Baseline to Week 12 in average weekly pain intensity Numeric Rating Scale (NRS) scores between the two groups.
The percentage of subjects in each group who demonstrated improvement in their NRS pain score at End-of-Study, as compared to Screening is shown in the figure below.
The figure is cumulative, so subjects whose change from Screening is, for example, 30% are also included at every level of improvement below 30%.
Subjects who did not complete the study were classified as non-responders.
Treatment with ZOHYDRO ER produced a greater number of responders, defined as subjects with at least a 30% improvement, as compared to placebo (67.5% vs.
31.1%).
Figure
HOW SUPPLIED
16 /STORAGE AND HANDLING ZOHYDRO ER extended-release capsules are supplied in 60-count bottles with a child-resistant closure as follows: Strength Capsule Color(s) Capsule Text NDC Number 10 mg White opaque “Z310 10 mg” in black ink 65224-310-60 15 mg Light green and white opaque “Z315 15 mg” in black ink 65224-315-60 20 mg Light green opaque “Z320 20 mg” in black ink 65224-320-60 30 mg Dark blue and white opaque “Z330 30 mg” in black ink 65224-330-60 40 mg Dark brown and white opaque “Z340 40 mg” in black ink 65224-340-60 50 mg Dark brown opaque “Z350 50 mg” in black ink 65224-350-60 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) ].
RECENT MAJOR CHANGES
Dosage and Administration ( 2.5 ) 10/2019 Warnings and Precautions ( 5.3 , 5.13 ) 10/2019
GERIATRIC USE
8.5 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 (5.7) ] .
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.
DOSAGE FORMS AND STRENGTHS
3 10 mg White opaque “Z310 10 mg” in black ink 15 mg Light green and white opaque “Z315 15 mg” in black ink 20 mg Light green opaque “Z320 20 mg” in black ink 30 mg Dark blue and white opaque “Z330 30 mg” in black ink 40 mg Dark brown and white opaque “Z340 40 mg” in black ink 50 mg Dark brown opaque “Z350 50 mg” in black ink Extended-release capsules: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, and 50 mg ( 3 )
MECHANISM OF ACTION
12.1 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.
INDICATIONS AND USAGE
1 ZOHYDRO ® ER (hydrocodone bitartrate) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
ZOHYDRO ER is an opioid agonist indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
( 1 ) Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve ZOHYDRO ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
( 1 ) ZOHYDRO ER is not indicated as an as-needed (prn) analgesic.
( 1 ) Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations [see Warnings and Precautions (5.1) ] , reserve ZOHYDRO ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
ZOHYDRO ER is not indicated as an as-needed (prn) analgesic.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of ZOHYDRO ER in pediatric patients below the age of 18 years have not been established.
PREGNANCY
8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ] .
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 (5.4) ] .
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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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).
BOXED WARNING
WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANTS; and INTERACTION WITH ALCOHOL.
WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES AND OTHER CNS DEPRESSANT; INTERACTION WITH ALCOHOL See full prescribing information for complete boxed warning.
ZOHYDRO ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death.
Assess patient’s risk before prescribing, and monitor regularly for these behaviors and conditions.
( 5.1 ) To ensure that the benetfits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products.
( 5.2 ) Serious, life-threatening, or fatal respiratory depression may occur.
Monitor closely, especially upon initiation or following a dose increase.
Instruct patients to swallow ZOHYDRO ER whole to avoid exposure to a potentially fatal dose of hydrocodone.
( 5.3 ) Accidental ingestion of ZOHYDRO ER, especially in children, can result in a fatal overdose of hydrocodone.
( 5.3 ) Prolonged use of ZOHYDRO ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.
If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
( 5.4 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone.
( 5.5 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.
Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.
( 5.6 , 7 ) Instruct patients not to consume alcohol or any products containing alcohol while taking ZOHYDRO ER because co-ingestion can result in fatal plasma hydrocodone levels.
( 5.6 ) Addiction, Abuse, and Misuse ZOHYDRO ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death.
Assess each patient’s risk prior to prescribing ZOHYDRO ER and monitor all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1) ] .
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS): To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products [ see Warnings and Precautions (5.2) ].
Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers.
Healthcare providers are strongly encouraged to complete a REMS-compliant education program, counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety.
Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of ZOHYDRO ER.
Monitor for respiratory depression, especially during initiation of ZOHYDRO ER or following a dose increase .
Instruct patients to swallow ZOHYDRO ER capsules whole; crushing, chewing, or dissolving ZOHYDRO ER capsules can cause rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions (5.3) ] .
Accidental Ingestion Accidental ingestion of even one dose of ZOHYDRO ER, especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions (5.3) ] .
Neonatal Opioid Withdrawal Syndrome Prolonged use of ZOHYDRO ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.4) ].
Cytochrome P450 3A4 Interaction The concomitant use of ZOHYDRO ER with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.
In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration.
Monitor patients receiving ZOHYDRO ER and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3) ] .
Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [ see Warnings and Precautions (5.6) , Drug Interactions (7) ] .
Reserve concomitant prescribing of ZOHYDRO ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
Limit dosages and durations to the minimum required.
Follow patients for signs and symptoms of respiratory depression and sedation.
Interaction with Alcohol Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products that contain alcohol while taking ZOHYDRO ER.
The co-ingestion of alcohol with ZOHYDRO ER may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) ] .
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration.
( 5.3 ) Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
( 5.8 ) Severe Hypotension: Monitor during dosage initiation and titration.
Avoid use of ZOHYDRO ER in patients with circulatory shock.
( 5.9 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression.
Avoid use of ZOHYDRO ER in patients with circulatory shock.
( 5.10 ) 5.1 Addiction, Abuse, and Misuse ZOHYDRO ER contains hydrocodone, a Schedule II controlled substance.
As an opioid, ZOHYDRO ER exposes users to the risks of addiction, abuse, and misuse.
Because extended-release products such as ZOHYDRO ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydrocodone present [see Drug Abuse and Dependence (9.1) ] .
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed ZOHYDRO ER.
Addiction can occur at recommended doses and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing ZOHYDRO ER, and monitor all patients receiving ZOHYDRO ER for the development of these behaviors and conditions.
Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression).
The potential for these risks should not, however, prevent the prescribing of ZOHYDRO ER for the proper management of pain in any given patient.
Patients at increased risk may be prescribed opioids such as ZOHYDRO ER, but use in such patients necessitates intensive counseling about the risks and proper use of ZOHYDRO ER along with intensive monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of ZOHYDRO ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death [see Drug Abuse and Dependence (9.1) , Overdosage (10) ] .
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.
Consider these risks when prescribing or dispensing ZOHYDRO ER.
Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17) ] .
Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products.
Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers.
Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed.
The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.
To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com.
The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.
5.3 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.
Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.
Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10) ] .
Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ZOHYDRO ER, the risk is greatest during the initiation of therapy or following a dosage increase.
Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of ZOHYDRO ER.
To reduce the risk of respiratory depression, proper dosing and titration of ZOHYDRO ER are essential [see Dosage and Administration (2.3) ] .
Overestimating the ZOHYDRO ER dose when converting patients from another opioid product can result in fatal overdose with the first dose.
Accidental ingestion of even one dose of ZOHYDRO ER, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia.
Opioid use increases the risk of CSA in a dose-dependent fashion.
In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5) ] .
5.4 Neonatal Opioid Withdrawal Syndrome Prolonged use of ZOHYDRO ER during pregnancy can result in withdrawal in the neonate.
Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.
Observe newborns for signs of neonatal opioid withdrawal syndrome and mange accordingly.
Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1) , Patient Counseling Information (17) ] .
5.5 Risks from Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of ZOHYDRO ER with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of hydrocodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.3) ] , particularly when an inhibitor is added after a stable dose of ZOHYDRO ER is achieved .
Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in ZOHYDRO ER-treated patients may increase hydrocodone plasma concentrations and prolong opioid adverse reactions.
When using ZOHYDRO ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in ZOHYDRO ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of ZOHYDRO ER until stable drug effects are achieved [see Drug Interactions (7) ].
Concomitant use of ZOHYDRO ER with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease hydrocodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone.
When using ZOHYDRO ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7) ] .
5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of ZOHYDRO ER with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol).
Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone.
Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7) ].
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum duration of concomitant use.
In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response.
If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.
Follow patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when ZOHYDRO ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs).
Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined.
Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk of overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17) ].
Patients must not consume alcoholic beverages, or prescription or non-prescription products containing alcohol, while on ZOHYDRO ER therapy.
The co-ingestion of alcohol with ZOHYDRO ER may result in increased plasma levels and a potentially fatal overdose of hydrocodone [see Clinical Pharmacology (12.3) ] .
5.7 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of ZOHYDRO ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients with Chronic Pulmonary Disease: ZOHYDRO ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of ZOHYDRO ER.
Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
Monitor such patients closely, particular when initiating and titrating ZOHYDRO ER and when ZOHYDRO ER is given concomitantly with other drugs that depress respiration.
Alternatively, consider the use of non-opioid analgesics in these patients.
5.8 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.
If adrenal insufficiency is suspected, confirm diagnosis with diagnostic testing as soon as possible.
If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.
Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.
Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency.
The information available does not identify any particular opioid as being more likely to be associated with adrenal insufficiency.
5.9 Severe Hypotension ZOHYDRO ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients.
There is an added risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or after concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7) ] .
Monitor these patients for signs of hypotension after initiating or titrating the dosage of ZOHYDRO ER.
In patients with circulatory shock, ZOHYDRO ER may cause vasodilation that can further reduce cardiac output and blood pressure.
Avoid the use of ZOHYDRO ER in patients with circulatory shock.
5.10 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ZOHYDRO ER may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure.
Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ZOHYDRO ER.
Opioids may also obscure the clinical course in a patient with a head injury.
Avoid the use of ZOHYDRO ER in patients with impaired consciousness or coma.
5.11 Risks of Use in Patients with Gastrointestinal Conditions ZOHYDRO ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
Hydrocodone in ZOHYDRO ER may cause spasm of the sphincter of Oddi.
Opioids may cause increases in serum amylase.
Monitor patients with biliary tract disease, including acute pancreatitis, for worsening of symptoms.
5.12 Increased Risk of Seizures in Patients with Seizure Disorders The hydrocodone in ZOHYDRO ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk occurring in other clinical settings associated with seizures.
Monitor patients with a history of seizure disorders for worsened seizure control during ZOHYDRO ER therapy.
5.13 Withdrawal Do not abruptly discontinue ZOHYDRO ER in a patient physically dependent on opioids.
When discontinuing ZOHYDRO ER in a physically dependent patient, gradually taper the dosage.
Rapid tapering of hydrocodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5) , Drug Abuse and Dependence (9.3) ] .
Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including ZOHYDRO ER.
In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms [see Drug Interactions (7) ].
5.14 Risks of Driving and Operating Machinery ZOHYDRO ER may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.
Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ZOHYDRO ER and know how they will react to the medication [see Clinical Pharmacology (12.3) , Patient Counseling Information (17) ] .
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA approved patient labeling (Medication Guide).
Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store ZOHYDRO ER securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions (5.1) , Drug Abuse and Dependence (9.2) ] .
Inform patients that leaving ZOHYDRO ER unsecured can pose a deadly risk to others in the home.
Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly.
Expired, unwanted, or unused ZOHYDRO ER should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available.
Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.
Addiction, Abuse, and Misuse Inform patients that the use of ZOHYDRO ER, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see Warnings and Precautions (5.1) ].
Instruct patients not to share ZOHYDRO ER with others and to take steps to protect ZOHYDRO ER from theft or misuse.
Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting ZOHYDRO ER or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.3) ] .
Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3) ] .
Interaction with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if ZOHYDRO ER is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider.
Instruct patients not to consume alcoholic beverages, as well as prescription and over-the-counter products that contain alcohol, during treatment with ZOHYDRO ER [see Warnings and Precautions (5.6) , Drug Interactions (7) ].
Serotonin Syndrome Inform patients that opioids 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 Drug Interactions (7) ] .
MAOI Interaction Inform patients to avoid taking ZOHYDRO ER while using any drugs that inhibit monoamine oxidase.
Patients should not start MAOIs while taking ZOHYDRO ER [see Drug Interactions (7) ].
Adrenal Insufficiency Inform patients that opioids 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 (5.8) ] .
Important Administration Instructions [see Dosage and Administration (2) ] Instruct patients how to properly take ZOHYDRO ER, including the following: Use ZOHYDRO ER exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression) [see Warnings and Precautions (5.3) ] .
Swallow ZOHYDRO ER capsules whole.
Do not crush, chew, or dissolve the capsule or its contents.
Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue ZOHYDRO ER without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5) ] .
Hypotension Inform patients that ZOHYDRO ER 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 (5.9) ] ).
Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in ZOHYDRO ER.
Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4) , Adverse Reactions (6) ].
Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that prolonged use of ZOHYDRO ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ].
Embryo-Fetal Toxicity Inform female patients of reproductive potential that ZOHYDRO ER can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1) ].
Lactation Advise patients that breastfeeding is not recommended during treatment with ZOHYDRO ER [see Use in Specific Populations (8.2) ] .
Infertility Inform patients that chronic use of opioids may cause reduced fertility.
It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2) , Use in Specific Populations (8.3) ].
Driving or Operating Heavy Machinery Inform patients that ZOHYDRO ER may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery.
Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated dose administration.
Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.14) ] .
Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.
Instruct patients to monitor their analgesic response following the use of strong laxatives and to contact the prescriber if changes are noted [see Adverse Reactions (6) , Clinical Pharmacology (12.2) ].
Disposal of Unused ZOHYDRO ER Advise patients to flush the unused capsules down the toilet when ZOHYDRO ER is no longer needed.
DOSAGE AND ADMINISTRATION
2 To be prescribed only by healthcare providers knowledgeable in use of potent opioids for management of chronic pain Daily doses of ZOHYDRO ER, a single dose greater than 40 mg, or a total daily dose greater than 80 mg are only for use in patients in whom tolerance to an opioid of comparable potency has been established.
( 2.1 ) Patients considered opioid-tolerant are those taking, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
( 2.1 ) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
( 2.1 ) Individualize dosing based on severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse.
( 2.1 ) Instruct patients to swallow ZOHYDRO ER intact and not to cut, break, chew, crush, or dissolve the capsules (risk of potentially fatal overdose).
( 2.1 , 5.1 ) For opioid-naïve and opioid non-tolerant patients, initiate with 10 mg capsules orally every 12 hours.
( 2.2 ) To convert to ZOHYDRO ER from another opioid, use available conversion factors to obtain estimated dose.
( 2.2 ) Dose titration of ZOHYDRO ER may occur every 3 to 7 days, using increments of 10 mg every 12 hours (i.e., 20 mg per day).
( 2.3 ) Patients with Severe Hepatic Impairment: Initiate dosing with 10 mg every 12 hours and titrate carefully, while monitoring for respiratory depression, sedation, and hypotension.
No adjustment in starting dose with ZOHYDRO ER is required in patients with mild or moderate hepatic impairment.
( 2.4 ) Do not abruptly discontinue ZOHYDRO ER in a physically dependent patient.
( 2.5 ) 2.1 Important Dosage and Administration Information ZOHYDRO ER should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.
Daily doses of ZOHYDRO ER, a single dose of greater than 40 mg, or a total daily dose of greater than 80 mg, are only for use in patients in whom tolerance to an opioid of comparable potency has been established.
Patients who are opioid tolerant are those receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5) ] .
Initiate the dosing regimen for each patient individually, taking into account the patient’s severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1) ] .
Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with ZOHYDRO ER and adjust the dosage accordingly [see Warnings and Precautions (5.3) ].
Instruct patients to swallow ZOHYDRO ER capsules whole [see Patient Counseling Information (17) ] .
Crushing, chewing, or dissolving the beads in ZOHYDRO ER capsules will result in uncontrolled delivery of hydrocodone and can lead to overdose or death [see Warnings and Precautions (5.1) ] .
ZOHYDRO ER is administered orally twice daily (every 12 hours).
2.2 Initial Dosage Use of ZOHYDRO ER as the First Opioid Analgesic (opioid-naïve patients) Initiate therapy with ZOHYDRO ER with one 10 mg capsule every 12 hours.
Use of ZOHYDRO ER in Patients Who Are Not Opioid Tolerant The starting dose for patients who are not opioid tolerant is ZOHYDRO ER 10 mg orally every 12 hours.
Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression [see Warnings and Precautions (5.3) ] .
Conversion from Oral Hydrocodone Formulations to ZOHYDRO ER Patients receiving other oral hydrocodone-containing formulations may be converted to ZOHYDRO ER by dividing the patient’s total daily oral hydrocodone dose in half and administrating as ZOHYDRO ER every 12 hours.
Conversion from Other Oral Opioid to ZOHYDRO ER Discontinue all other around-the-clock opioid drugs when ZOHYDRO ER therapy is initiated.
There is inter-patient variability in the relative potency of different opioid drugs and products.
Therefore, a conservative approach is advised when determining the total daily dosage of ZOHYDRO ER.
It is safer to underestimate a patient’s 24-hour oral hydrocodone dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydrocodone dosage and manage an adverse reaction due to an overdose.
In a ZOHYDRO ER clinical trial with an open label titration period, patients were converted from their prior opioid to ZOHYDRO ER using Table 1 as a guide for the initial ZOHYDRO ER dose.
To obtain the initial ZOHDYRO ER dose, first use Table 1 to convert the prior oral opioids to a total hydrocodone daily dose and then reduce the calculated daily hydrocodone dose by 25% to account for interpatient variability in relative potency of different opioids.
Consider the following when using the information in Table 1: This is not a table of equianalgesic doses.
The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to ZOHYDRO ER.
The table cannot be used to convert from ZOHYDRO ER to another opioid.
Doing so will result in an over-estimation of the dose of the new opioid and may result in fatal overdose.
Table 1.
Conversion Factors to ZOHYDRO ER (Not Equianalgesic Doses) Prior Oral Opioid Oral Dose (mg) Approximate Oral Conversion Factor The conversion ratios in this table are only to be used for the conversion from current opioid therapy to ZOHYDRO ER.
Hydrocodone 10 1 Oxycodone 10 1 Methadone 10 1 Oxymorphone 5 2 Hydromorphone 3.75 2.67 Morphine 15 0.67 Codeine 100 0.10 To calculate the estimated daily ZOHYDRO ER dose using Table 1: For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the approximate oral conversion factor to calculate the approximate oral hydrocodone daily dose.
Divide the daily dose in half for administration every 12 hours.
For patients on a regimen of more than one opioid, calculate the approximate oral hydrocodone dose for each opioid and sum the totals to obtain approximate total hydrocodone daily dose.
The daily dose should then be divided in half for administration every 12 hours.
For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.
Reduce the calculated daily oral hydrocodone dose by 25% Always round the dose down, if necessary, to the nearest ZOHYDRO ER strength(s) available and initiate therapy with that dose.
Example conversion from a single opioid to ZOHYDRO ER Step 1: Sum the total daily dose of the opioid (in this case, extended-release oxymorphone); 15 mg oxymorphone twice daily = 30 mg total daily dose of oxymorphone.
Step 2: Calculate the approximate equivalent dose of oral hydrocodone based on the total daily dose of the current opioid using Table 1; 30 mg total daily dose of oxymorphone × 2 = 60 mg of oral hydrocodone daily.
The daily dose should then be divided in half for administration every 12 hours.
Step 3: Calculate the approximate starting dose which is 30 mg ZOHYDRO ER every 12 hours.
Round down, if necessary, to the appropriate ZOHYDRO ER capsule strengths available.
Close observation and frequent titration are warranted until pain management is stable on the new opioid.
Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to ZOHYDRO ER.
The dose of ZOHYDRO ER can be gradually adjusted preferably at increments of 10 mg every 12 hours every 3 to 7 days, until adequate pain relief and acceptable adverse reactions have been achieved.
Conversion from Methadone to ZOHYDRO ER Close monitoring is of particular importance when converting from methadone to other opioid agonists.
The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure.
Methadone has a long half-life and tends to accumulate in the plasma.
Conversion from Transdermal Fentanyl to ZOHYDRO ER ZOHYDRO ER treatment can be initiated 18 hours following the removal of the transdermal fentanyl patch.
Although there has been no systematic assessment of such conversion, a conservative hydrocodone dose, approximately 10 mg every 12 hours of ZOHYDRO ER, should be initially substituted for each 25 mcg/hr fentanyl transdermal patch.
Follow the patient closely during conversion from transdermal fentanyl to ZOHYDRO ER, as there is limited documented experience with this conversion.
2.3 Titration and Maintenance of Therapy Individually titrate ZOHYDRO ER to a dose that provides adequate analgesia and minimizes adverse reactions.
Continually reevaluate patients receiving ZOHYDRO ER to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1) ] .
Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.
During chronic therapy, periodically reassess the continued need for opioid analgesics.
Patients who experience breakthrough pain may require a dosage adjustment of ZOHYDRO ER, or may need a rescue medication with an appropriate dose of an immediate-release analgesic.
If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the ZOHYDRO ER dosage.
Because steady-state plasma concentrations are approximated within 3 days, ZOHYDRO ER dosage adjustments, preferably at increments of 10 mg every 12 hours, may be done every 3 to 7 days.
If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage.
Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
2.4 Dosage Modifications in Patients with Severe Hepatic Impairment Patients with severe hepatic impairment may have higher plasma concentrations of hydrocodone than those with normal function.
Therefore, initiate therapy with 10 mg every 12 hours and titrate carefully, while monitoring for respiratory depression, sedation, and hypotension.
No adjustment in starting dose with ZOHYDRO ER is required in patients with mild or moderate hepatic impairment [see Clinical Pharmacology (12.3) ] .
2.5 Safe Reduction or Discontinuation of ZOHYDRO ER Do not abruptly discontinue ZOHYDRO ER in patients who may be physically dependent on opioids.
Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide.
Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.
Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.
When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking ZOHYDRO ER, there are a variety of factors that should be considered, including the dose of ZOHYDRO ER the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient.
It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic.
When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder.
Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder.
Complex patients with co- morbid pain and substance use disorders may benefit from referral to a specialist.
There are no standard opioid tapering schedules that are suitable for all patients.
Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually.
For patients on ZOHYDRO ER who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks.
Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.
It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper.
Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge.
Common withdrawal symptoms include 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.
If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper.
In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.
When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper.
A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.13) , Drug Abuse and Dependence (9.3) ] .