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HYSINGLA ER- hydrocodone bitartrate tablet, extended release Purdue Pharma LP
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)
Extended-release tablets: 20,
30, 40, 60, 80, 100, and 120 mg (3)
Most common treatment-emergent adverse events
(incidence ≥ 5%) are constipation, nausea, vomiting, fatigue, upper
respiratory tract infection, dizziness, headache, and somnolence.
To report SUSPECTED ADVERSE REACTIONS,
contact Purdue Pharma L.P. at 1-888-726-7535 or FDA at 1-800-FDA-1088
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Abuse, and MisuseHYSINGLA 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 HYSINGLA ER, and monitor all patients regularly for
the development of these behaviors and conditions [see Warnings
and Precautions (5.1)].
DepressionSerious, life-threatening, or fatal
respiratory depression may occur with use of HYSINGLA ER. Monitor
for respiratory depression, especially during initiation of HYSINGLA
ER or following a dose increase. Instruct patients to swallow HYSINGLA
ER tablets whole; crushing, chewing, or dissolving HYSINGLA ER tablets
can cause rapid release and absorption of a potentially fatal dose
of hydrocodone [see Warnings and Precautions (5.2)].
ingestion of even one dose of HYSINGLA ER, especially by children,
can result in a fatal overdose of hydrocodone [see Warnings
and Precautions (5.2)]
Neonatal Opioid Withdrawal SyndromeProlonged use of HYSINGLA 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
Cytochrome P450 3A4 InteractionThe concomitant use of HYSINGLA ER with all cytochrome P450 3A4
inhibitors may result in an increase in hydrocodone plasma concentrations,
which could increase or prolong adverse reactions 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 HYSINGLA ER and
any CYP3A4 inhibitor or inducer [see Warnings and Precautions
(5.4), Drug Interactions (7), and Clinical Pharmacology (12.3)].
Risks From Concomitant Use With Benzodiazepines
Or Other CNS DepressantsConcomitant 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
(5.5), Drug Interactions (7)].
HYSINGLA ER 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
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 HYSINGLA ER greater than or equal to 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.
patients to swallow HYSINGLA ER tablets whole, one tablet at a time,
with enough water to ensure complete swallowing immediately after
placing in the mouth [see Patient Counseling Information (17)]. Instruct patients not to
pre-soak, lick, or otherwise wet the tablet prior to placing in the
mouth [see Warnings and Precautions (5.11)]. Crushing, chewing, or dissolving HYSINGLA
ER tablets will result in uncontrolled delivery of hydrocodone and
can lead to overdose or death [see Warnings and Precautions
HYSINGLA ER is administered orally once daily (every 24 hours). Multiple
tablets of lower dose strengths that provide the desired total daily
dose can be taken as a once daily dose.
Use of HYSINGLA
ER as the First Opioid Analgesic (opioid-naïve patients)
Initiate therapy with HYSINGLA ER 20 mg orally
every 24 hours.
Use of HYSINGLA
ER in Patients who are not Opioid Tolerant (opioid non-tolerant
patients)The starting dose for patients who are not opioid
tolerant is HYSINGLA ER 20 mg orally every 24 hours.
Use of higher starting doses in patients who are not opioid tolerant
may cause fatal respiratory depression [see Warnings and Precautions
Conversion from Oral Hydrocodone Formulations to HYSINGLA
ERPatients receiving other oral hydrocodone-containing
formulations may be converted to HYSINGLA ER by administering the
patient's total daily oral hydrocodone dose as HYSINGLA ER once daily.
Conversion from Other Oral Opioids to HYSINGLA ERDiscontinue all other around-the-clock opioid drugs when
HYSINGLA ER therapy is initiated.
There is inter-patient
variability in the relative potency of opioid drugs and formulations.
Therefore, a conservative approach is advised when determining the
total daily dosage of HYSINGLA 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 HYSINGLA ER clinical trial with an open-label titration period,
patients were converted from their prior opioid to HYSINGLA ER using
Table 1 as a guide for the initial HYSINGLA ER dose.To obtain the
initial HYSINGLA 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.
the following when using the information found in Table 1.
calculate the estimated total hydrocodone daily dose using Table 1:
round the dose down, if necessary, to the nearest HYSINGLA ER tablet
strength available and initiate therapy with that dose. If the converted
HYSINGLA ER dose using Table 1 is less than 20 mg, initiate therapy
with HYSINGLA ER 20 mg.
Example conversion from
a single opioid to HYSINGLA ER:For example, a total daily
dose of oxycodone 50 mg would be converted to hydrocodone 50 mg based
on the table above, and then multiplied by 0.75 (ie, take a 25 % reduction)
resulting in a dose of 37.5 mg hydrocodone. Round this down to the
nearest dose strength available, HYSINGLA ER 30 mg, to initiate therapy.
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 HYSINGLA ER.
Conversion from Methadone to HYSINGLA ERClose
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 can accumulate in the plasma.
Conversion from Transdermal Fentanyl to HYSINGLA EREighteen hours following the removal of the transdermal
fentanyl patch, HYSINGLA ER treatment can be initiated. For each
25 mcg/hr fentanyl transdermal patch, a dose of HYSINGLA ER 20 mg
every 24 hours represents a conservative initial dose. Follow the
patient closely during conversion from transdermal fentanyl to HYSINGLA
ER, as there is limited experience with this conversion.
Conversion from Transdermal Buprenorphine to HYSINGLA
ERAll patients receiving transdermal buprenorphine
(≤ 20 mcg/hr) should initiate therapy with HYSINGLA ER 20 mg every
24 hours. Follow the patient closely during conversion from transdermal
buprenorphine to HYSINGLA ER, as there is limited experience with
Individually titrate HYSINGLA
ER to a dose that provides adequate analgesia and minimizes adverse
reactions. Continually reevaluate patients receiving HYSINGLA 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 the use of opioid
Patients who experience
breakthrough pain may require a dosage adjustment of HYSINGLA ER,
or may need 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 HYSINGLA ER dosage. Adjust the dose of HYSINGLA ER in increments
of 10 mg to 20 mg every 3 to 5 days as needed to achieve adequate
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.
severe hepatic impairment may have higher plasma concentrations of
hydrocodone than those with normal function. Initiate therapy with
one half the initial dose of HYSINGLA ER in these patients and monitor
closely for respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].
Patients with moderate to severe renal impairment,
and end-stage renal disease may have higher plasma concentrations
than those with normal function. Initiate therapy with one half the
initial dose of HYSINGLA ER in these patients and monitor closely
for respiratory depression, sedation, and hypotension [see
Clinical Pharmacology (12.3)].
Do not abruptly discontinue HYSINGLA ER. When
the patient no longer requires therapy with HYSINGLA ER, taper the
dose gradually by 25% to 50% every 2 to 4 days, while monitoring carefully
for signs and symptoms of withdrawal. If the patients develop these
signs or symptoms, raise the dose to the previous level and taper
more slowly, either by increasing the interval between decreases,
decreasing the amount of change in dose, or both. The dose may be
reduced every 2 to 4 days. The next dose should be at least 50% of
the prior dose. After reaching HYSINGLA ER 20 mg dose for 2 to 4
days, HYSINGLA ER can be discontinued.
HYSINGLA ER is contraindicated in patients with:
HYSINGLA ER contains hydrocodone, a Schedule II
controlled substance. As an opioid, HYSINGLA ER exposes users to
the risks of addiction, abuse, and misuse. Because extended-release
products such as HYSINGLA 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
Although the risk of addiction in any individual is unknown, it can
occur in patients appropriately prescribed HYSINGLA 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 HYSINGLA ER, and monitor all patients receiving
HYSINGLA 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 HYSINGLA ER
for the proper management of pain in any given patient. Patients
at increased risk may be prescribed opioids such as HYSINGLA ER, but
use in such patients necessitates intensive counseling about the risks
and proper use of HYSINGLA ER along with intensive monitoring for
signs of addiction, abuse, and misuse.
Abuse or misuse
of HYSINGLA 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), and 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 HYSINGLA
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
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 (CO2) 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 HYSINGLA 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 HYSINGLA ER.
To reduce the risk of
respiratory depression, proper dosing and titration of HYSINGLA ER
are essential [see Dosage and Administration (2.1, 2.2)]. Overestimating the HYSINGLA ER dosage when converting
patients from another opioid product can result in fatal overdose
with the first dose.
Accidental ingestion of
even one dose of HYSINGLA ER, especially by children, can result in
respiratory depression and death due to an overdose of hydrocodone.
Prolonged use of HYSINGLA 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 manage 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).
Concomitant use of HYSINGLA
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
(5.4)], particularly when
an inhibitor is added after a stable dose of HYSINGLA ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such
as rifampin, carbamazepine, and phenytoin, in HYSINGLA ER treated
patients may increase hydrocodone plasma concentrations and prolong
opioid adverse reactions. When using HYSINGLA ER with CYP3A4 inhibitors
or discontinuing CYP3A4 inducers in HYSINGLA ER treated patients,
monitor patients closely at frequent intervals and consider dosage
reduction of HYSINGLA ER until stable drug effects are achieved [see Drug Interactions (7)].
Concomitant use of HYSINGLA 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 HYSINGLA 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
Profound sedation, respiratory depression, coma,
and death may result from the concomitant use of HYSINGLA 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 durations 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 HYSINGLA 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 for overdose
and death associated with the use of additional CNS depressants including
alcohol and illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].
The use of
HYSINGLA ER in patients with acute or severe bronchial asthma in an
unmonitored setting or in the absence of resuscitative equipment is
Chronic Pulmonary Disease: HYSINGLA 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 HYSINGLA ER[see Warnings and Precautions (5.2)].
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 [see Warnings and Precautions (5.2)].
Monitor such patients
closely, particularly when initiating and titrating HYSINGLA ER and
when HYSINGLA ER is given concomitantly with other drugs that depress
respiration [see Warnings and Precautions (5.2, 5.5)]. Alternatively, consider the use of non-opioid analgesics
in these patients.
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 the 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 opioids as being more likely to be associated with
HYSINGLA ER may cause
severe hypotension including orthostatic hypotension and syncope in
ambulatory patients. There is an increased 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 HYSINGLA ER. In patients with circulatory
shock, HYSINGLA ER may cause vasodilation that can further reduce
cardiac output and blood pressure. Avoid the use of HYSINGLA ER in
patients with circulatory shock.
QTc prolongation has been
observed with HYSINGLA ER following daily doses of 160 mg [see Clinical Pharmacology (12.2)]. This observation should be considered in making clinical
decisions regarding patient monitoring when prescribing HYSINGLA ER
in patients with congestive heart failure, bradyarrhythmias, electrolyte
abnormalities, or who are taking medications that are known to prolong
the QTc interval.
HYSINGLA ER should be
avoided in patients with congenital long QT syndrome. In patients
who develop QTc prolongation, consider reducing the dose by 33 – 50%,
or changing to an alternate analgesic.
who may be susceptible to the intracranial effects of CO2 retention
(e.g., those with evidence of increased intracranial pressure or brain
tumors), HYSINGLA ER may reduce respiratory drive, and the resultant
CO2 retention can further increase intracranial pressure. Monitor
such patients for signs of sedation and respiratory depression, particularly
when initiating therapy with HYSINGLA ER.
may also obscure the clinical course in a patient with a head injury.
Avoid the use of HYSINGLA ER in patients with impaired consciousness
In the clinical
studies with specific instructions to take HYSINGLA ER with adequate
water to swallow the tablet, 11 out of 2476 subjects reported difficulty
swallowing HYSINGLA ER. These reports included esophageal obstruction,
dysphagia, and choking, one of which had required medical intervention
to remove the tablet [see Adverse Reactions (6)].
patients not to pre-soak, lick, or otherwise wet HYSINGLA ER tablets
prior to placing in the mouth, and to take one tablet at a time with
enough water to ensure complete swallowing immediately after placing
in the mouth [see Patient Counseling Information (17)].
with underlying gastrointestinal disorders such as esophageal cancer
or colon cancer with a small gastrointestinal lumen are at greater
risk of developing these complications. Consider use of an alternative
analgesic in patients who have difficulty swallowing and patients
at risk for underlying gastrointestinal disorders resulting in a small
Pediatric patients may
be at increased risk of esophageal obstruction, dysphagia, and choking
because of a smaller gastrointestinal lumen if they ingest HYSINGLA
ER [see Use in Specific Populations (8.4)].
is contraindicated in patients with known or suspected gastrointestinal
obstruction, including paralytic ileus.
in HYSINGLA 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 symptoms.
in HYSINGLA ER may increase the frequency of seizures in patients
with seizure disorders, and may increase the risk of seizures occurring
in other clinical settings associated with seizures. Monitor patients
with a history of seizure disorders for worsened seizure control during
HYSINGLA ER therapy.
Avoid the use of mixed agonist/antagonist analgesics
(e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist
(e.g., buprenorphine) analgesics in patients who are receiving a full
opioid agonist analgesic, including HYSINGLA 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)].
When discontinuing HYSINGLA ER, gradually taper
the dosage [see Dosage and Administration (2.6)]. Do not abruptly discontinue
HYSINGLA ER [see Drug Abuse and Dependence (9.3)].
ER may impair the mental and physical abilities needed to perform
potentially hazardous activities such as driving a car or operating
machinery. Peak blood levels of hydrocodone may occur 14 – 16 hours
(range 6 – 30 hours) after initial dosing of HYSINGLA ER tablet administration.
Blood levels of hydrocodone, in some patients, may be high at the
end of 24 hours after repeated-dose administration. Warn patients
not to drive or operate dangerous machinery unless they are tolerant
to the effects of HYSINGLA ER and know how they will react to the
medication [see Clinical Pharmacology (12.3), Patient Counseling Information
serious adverse reactions are described elsewhere in the labeling:
Because clinical trials are conducted
under widely varying conditions, adverse reaction rates observed in
the clinical trials of a drug cannot be directly compared to rates
in the clinical trials of another drug and may not reflect the rates
observed in practice.
A total of 1,827 patients were treated with HYSINGLA ER in controlled
and open-label chronic pain clinical trials. Five hundred patients
were treated for 6 months and 364 patients were treated for 12 months.
The clinical trial population consisted of opioid-naïve and opioid-experienced
patients with persistent moderate to severe chronic pain.
The common adverse reactions
(≥2%) reported by patients in clinical trials comparing HYSINGLA ER
(20-120 mg/day) with placebo are shown in Table 2 below:
The adverse reactions
seen in controlled and open-label chronic pain studies are presented
below in the following manner: most common (≥5%), common (≥1% to <5%),
and less common (<1%).
The most common adverse reactions (≥5%) reported by patients treated
with HYSINGLA ER in the chronic pain clinical trials were constipation,
nausea, vomiting, fatigue, upper respiratory tract infection, dizziness,
The common (≥1% to <5%) adverse events reported by patients treated
with HYSINGLA ER in the chronic pain clinical trials organized by
MedDRA (Medical Dictionary for Regulatory Activities) System Organ
Other less common adverse
reactions that were seen in <1% of the patients in the HYSINGLA
ER chronic pain clinical trials include the following in alphabetical
order: abdominal discomfort, abdominal distention, agitation, asthenia,
choking, confusional state, depressed mood, drug hypersensitivity,
drug withdrawal syndrome, dysphagia, dyspnea, esophageal obstruction,
flushing, hypogonadism, hypotension, hypoxia, irritability, libido
decreased, malaise, mental impairment, mood altered, muscle twitching,
edema, orthostatic hypotension, palpitations, presyncope, retching,
syncope, thinking abnormal, thirst, tremor, and urinary retention.
The following adverse reactions
have been identified during post approval use of hydrocodone. Because
these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition,
have been reported during concomitant use of opioids with serotonergic
Adrenal insufficiency: Cases of adrenal insufficiency
have been reported with opioid use, more often following greater than
one month of use.
Anaphylaxis: Anaphylaxis has been reported
with ingredients contained in HYSINGLA ER.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of
opioids [see Clinical Pharmacology (12.2)].
Table 3 includes clinically
significant drug interactions with HYSINGLA ER.
Risk SummaryProlonged use of opioid analgesics
during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. Available data with HYSINGLA ER in pregnant women are
insufficient to inform a drug-associated risk for major birth defects
and miscarriage. In animal reproduction studies with hydrocodone in
rats and rabbits no embryotoxicity or teratogenicity was observed.
However, reduced pup survival rates, reduced fetal/pup body weights,
and delayed ossification were observed at doses causing maternal toxicity.
In all of the studies conducted, the exposures in animals were less
than the human exposure [see Data].
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 ConsiderationsFetal/neonatal adverse reactionsProlonged use of opioid analgesics during pregnancy for medical
or nonmedical purposes can result in physical dependence in the neonate
and neonatal opioid withdrawal syndrome shortly after birth. Neonatal
opioid withdrawal syndrome presents as irritability, hyperactivity
and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea,
and failure to gain weight. The onset, duration, and severity of neonatal
opioid withdrawal syndrome vary based on the specific opioid used,
duration of use, timing and amount of last maternal use, and rate
of elimination of the drug by the newborn. Observe newborns for symptoms
of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)].
Labor and DeliveryOpioids 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.
HYSINGLA ER is not recommended for use in pregnant women during or
immediately prior to labor, when use of shorter-acting analgesics
or other analgesic techniques are more appropriate. Opioid analgesics,
including HYSINGLA 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 dilation, which tends to shorten labor. Monitor
neonates exposed to opioid analgesics during labor for signs of excess
sedation and respiratory depression.
DataAnimal DataNo evidence of embryotoxicity
or teratogenicity was observed after oral administration of hydrocodone
throughout the period of organogenesis in rats and rabbits at doses
up to 30 mg/kg/day (approximately 0.1 and 0.3 times, respectively,
the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons).
However, in these studies, reduced fetal body weights and delayed
ossification were observed in rat at 30 mg/kg/day and reduced fetal
body weights were observed in in rabbit at 30 mg/kg/day (approximately
0.1 and 0.3 times, respectively, the human hydrocodone dose of 120
mg/day based on AUC exposure comparisons). In a pre- and post-natal
development study pregnant rats were administered oral hydrocodone
throughout the period of gestation and lactation. At a dose of 30
mg/kg/day decreased pup viability, pup survival indices, litter size
and pup body weight were observed. This dose is approximately 0.1
times the human hydrocodone dose of 120 mg/day based on AUC exposure
Risk SummaryHydrocodone 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 HYSINGLA, 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 HYSINGLA ER.
Clinical ConsiderationsMonitor infants exposed to HYSINGLA 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 breastfeeding is stopped.
InfertilityChronic 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 [see Adverse Reactions (6.2)].
and effectiveness of HYSINGLA ER in pediatric patients have not been
ER gradually forms a viscous hydrogel (i.e., a gelatinous mass) when
exposed to water or other fluids. Pediatric patients may be at increased
risk of esophageal obstruction, dysphagia, and choking because of
a smaller gastrointestinal lumen if they ingest HYSINGLA ER [see Warnings and Precautions (5.11)]
In a controlled pharmacokinetic
study, elderly subjects (greater than 65 years) compared to young
adults had similar plasma concentrations of hydrocodone [see
Clinical Pharmacology (12.3)]. Of the 1827 subjects exposed to HYSINGLA ER in the pooled chronic
pain studies, 241 (13%) were age 65 and older (including those age
75 and older), while 42 (2%) were age 75 and older. In clinical trials
with appropriate initiation of therapy and dose titration, no untoward
or unexpected adverse reactions were seen in the elderly patients
who received HYSINGLA ER.
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 concomitant disease or other drug
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
HYSINGLA ER slowly in geriatric patients and monitor closely for signs
of central nervous system and respiratory depression [see
Warnings and Precautions (5.2)].
known to be substantially excreted by the kidney, and the risk of
adverse reactions to this drug may be greater in patients with impaired
renal function. Because elderly patients are more likely to have decreased
renal function, care should be taken in dose selection, and it may
be useful to monitor renal function.
No adjustment in starting dose
with HYSINGLA 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 these
patients [see Dosage and Administration (2.4)]. Monitor closely for respiratory
depression, sedation, and hypotension
No dose adjustment is needed in patients
with mild renal impairment. Patients with moderate or severe renal
impairment or end stage renal disease have higher plasma concentrations
than those with normal renal function [see Clinical Pharmacology
(12.3)]. Therefore, a
dosage reduction is recommended for these patients [see Dosage
and Administration (2.5)]. Monitor closely for respiratory depression, sedation, and hypotension.
HYSINGLA ER contains hydrocodone bitartrate, a Schedule II controlled
HYSINGLA ER contains hydrocodone,
a substance with a high potential for abuse similar to other opioids,
including fentanyl, hydromorphone, methadone, morphine, oxycodone,
oxymorphone, and tapentadol. HYSINGLA ER can be abused and is subject
to misuse, addiction, and criminal diversion [see Warnings
and Precautions (5.1)].
The high drug content in the
extended-release formulation adds to the risk of adverse outcomes
from abuse and misuse.
All patients treated with opioids require careful monitoring for
signs of abuse and addiction because use of opioid analgesic products
carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the
intentional non-therapeutic use of a prescription drug, even once,
for its rewarding psychological or physiological effects.Drug addiction is a cluster of behavioral, cognitive, and physiological
phenomena that develop after repeated substance use and includes:
a strong desire to take the drug, difficulties in controlling its
use, persisting in its use despite harmful consequences, a higher
priority given to drug use than to other activities and obligations,
increased tolerance, and sometimes a physical withdrawal.
"Drug-seeking" behavior is very
common in persons with substance use disorders. Drug seeking tactics
include emergency calls or visits near the end of office hours, refusal
to undergo appropriate examination, testing, or referral, repeated
“loss” of prescriptions, tampering with prescriptions, and reluctance
to provide prior medical records or contact information for other
treating healthcare provider(s). “Doctor shopping” (visiting multiple
prescribers to obtain additional prescriptions) is common among drug
abusers and people with untreated addiction. Preoccupation with achieving
adequate pain relief can be appropriate behavior in a patient with
poor pain control.
Abuse and addiction are separate and distinct from physical dependence
and tolerance. Healthcare providers should be aware that addiction
may not be accompanied by concurrent tolerance and symptoms of physical
dependence in all addicts. In addition, abuse of opioids can occur
in the absence of true addiction.
HYSINGLA ER, like other opioids, can be
diverted for non-medical use into illicit channels of distribution.
Careful record-keeping of prescribing information, including quantity,
frequency, and renewal requests, as required by state and federal
law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic
re-evaluation of therapy, and proper dispensing and storage are appropriate
measures that help to limit abuse of opioid drugs.
Risks Specific to Abuse of HYSINGLA
ERHYSINGLA ER is for oral use only. Abuse
of HYSINGLA ER poses a risk of overdose and death. Abuse may occur
by taking intact tablets in quantities greater than prescribed or
without legitimate purpose, by crushing and chewing or snorting the
crushed formulation, or by injecting a solution made from the crushed
formulation. The risk is increased with concurrent use of HYSINGLA
ER with alcohol or other central nervous system depressants. Taking
cut, broken, chewed, crushed, or dissolved HYSINGLA ER increases the
risk of overdose and death.
With parenteral abuse, the inactive ingredients
in HYSINGLA ER can result in local tissue necrosis, infection, pulmonary
granulomas, increased risk of endocarditis and valvular heart injury,
embolism, and death. Parenteral drug abuse is commonly associated
with transmission of infectious diseases, such as hepatitis and HIV.
Abuse Deterrence StudiesHYSINGLA ER is formulated with physicochemical properties
intended to make the tablet more difficult to manipulate for misuse
and abuse, and maintains some extended release characteristics even
if the tablet is physically compromised. To evaluate the ability of
these physicochemical properties to reduce the potential for abuse
of HYSINGLA ER, a series of in vitro laboratory studies,
pharmacokinetic studies and clinical abuse potential studies was conducted.
A summary is provided at the end of this section.
In Vitro TestingIn vitro physical and chemical tablet manipulation
studies were performed to evaluate the success of different extraction
methods in defeating the extended-release formulation. Results support
that HYSINGLA ER resists crushing, breaking, and dissolution using
a variety of tools and solvents and retains some extended-release
properties despite manipulation. When subjected to an aqueous environment,
HYSINGLA ER gradually forms a viscous hydrogel (i.e., a gelatinous
mass) that resists passage through a hypodermic needle.
Clinical Abuse Potential
StudiesStudies in Non-dependent Opioid
Abusers:Two randomized, double-blind, placebo
and active-comparator studies in non-dependent opioid abusers were
conducted to characterize the abuse potential of HYSINGLA ER following
physical manipulation and administration via the intranasal and oral
routes. For both studies, drug liking was measured on a bipolar drug
liking scale of 0 to 100 where 50 represents a neutral response of
neither liking nor disliking, 0 represents maximum disliking, and
100 represents maximum liking. Response to whether the subject would
take the study drug again was measured on a unipolar scale of 0 to
100 where 0 represents the strongest negative response (“definitely
would not take drug again”) and 100 represents the strongest positive
response (“definitely would take drug again”).
Intranasal Abuse Potential Study:In the intranasal abuse potential study, 31 subjects
were dosed and 25 subjects completed the study. Treatments studied
included intranasally administered tampered HYSINGLA ER 60 mg tablets,
powdered hydrocodone bitartrate 60 mg, and placebo. Incomplete dosing
due to granules falling from the subjects’ nostrils occurred in 82%
(n = 23) of subjects receiving tampered HYSINGLA ER compared to no
subjects with powdered hydrocodone or placebo.
The intranasal administration of tampered
HYSINGLA ER was associated with statistically significantly lower
mean and median scores for drug liking and take drug again (P<0.001 for both), compared with powdered hydrocodone
as summarized in Table 4.
Figure 1 demonstrates
a comparison of peak drug liking scores for tampered HYSINGLA ER compared
with powdered hydrocodone in subjects (n = 25) who received both treatments
intranasally. The Y-axis represents the percent of subjects attaining
a percent reduction in peak drug liking scores for tampered HYSINGLA
ER vs. hydrocodone powder greater than or equal to the value on the
80% (n = 20) of subjects had some reduction in drug liking with tampered
HYSINGLA ER relative to hydrocodone powder. Sixty-eight percent (n
= 17) of subjects had a reduction of at least 30% in drug liking with
tampered HYSINGLA ER compared with hydrocodone powder, and approximately
64% (n = 16) of subjects had a reduction of at least 50% in drug liking
with tampered HYSINGLA ER compared with hydrocodone powder. Approximately
20% (n = 5) of subjects had no reduction in liking with tampered HYSINGLA
ER relative to hydrocodone powder.
Figure 1: Percent Reduction Profiles
for Emax of Drug Liking VAS for Manipulated
HYSINGLA ER vs. Hydrocodone Powder, N = 25 Following Intranasal Administration
Oral Abuse Potential Study:In the oral abuse potential study, 40 subjects were dosed
and 35 subjects completed the study. Treatments studied included
oral administrations of chewed HYSINGLA ER 60 mg tablets, intact HYSINGLA
ER 60 mg tablets, 60 mg aqueous hydrocodone bitartrate solution, and
The oral administration
of chewed and intact HYSINGLA ER was associated with statistically
lower mean and median scores on scales that measure drug liking and
desire to take drug again (P<0.001), compared to hydrocodone solution
as summarized in Table 5.
Figure 2 demonstrates
a comparison of peak drug liking scores for chewed HYSINGLA ER compared
with hydrocodone solution in subjects who received both treatments
orally. The Y-axis represents the percent of subjects attaining a
percent reduction in peak drug liking scores for chewed HYSINGLA ER
vs. hydrocodone solution greater than or equal to the value on the
80% (n = 28) of subjects had some reduction in drug liking with chewed
HYSINGLA ER relative to hydrocodone solution. Approximately 69% (n
= 24) of subjects had a reduction of at least 30% in drug liking with
chewed HYSINGLA ER compared with hydrocodone solution, and approximately
60% (n = 21) of subjects had a reduction of at least 50% in drug liking
with chewed HYSINGLA ER compared with hydrocodone solution. Approximately
20% (n = 7) of subjects had no reduction in drug liking with chewed
HYSINGLA ER relative to hydrocodone solution.
Figure 2. Percent Reduction Profiles
for Emax of Drug Liking VAS for Chewed HYSINGLA
ER vs. Hydrocodone Solution, N = 35 Following Oral Administration
The results of a similar analysis of drug
liking for intact HYSINGLA ER relative to hydrocodone solution were
comparable to the results of chewed HYSINGLA ER relative to hydrocodone
solution. Approximately 83% (n = 29) of subjects had some reduction
in drug liking with intact HYSINGLA ER relative to hydrocodone solution.
Eighty-three percent (n = 29) of subjects had a reduction of at least
30% in peak drug liking scores with intact HYSINGLA ER compared to
hydrocodone solution, and approximately 74% (n = 26) of subjects had
a reduction of at least 50% in peak drug liking scores with intact
HYSINGLA ER compared with hydrocodone solution. Approximately 17%
(n = 6) had no reduction in drug liking with intact HYSINGLA ER relative
to hydrocodone solution.
SummaryThe in vitro data demonstrate that HYSINGLA ER has physical and chemical properties
that are expected to deter intranasal and intravenous abuse. The
data from the clinical abuse potential studies, along with support
from the in vitro data, also indicate that HYSINGLA
ER has physicochemical properties that are expected to reduce intranasal
abuse and oral abuse when chewed. However, abuse of HYSINGLA ER by
the intravenous, intranasal, and oral routes is still possible.
Additional data, including epidemiological
data, when available, may provide further information on the impact
of HYSINGLA ER on the abuse liability of the drug. Accordingly, this
section may be updated in the future as appropriate.
and physical dependence can develop during chronic opioid therapy.
Tolerance is the need for increasing doses of opioids to maintain
a defined effect such as analgesia (in the absence of disease progression
or other external factors). Tolerance may occur to both the desired
and undesired effects of drugs, and may develop at different rates
for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation
or a significant dosage reduction of a drug. Withdrawal also may be
precipitated through the administration of drugs with opioid antagonist
activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics
(e.g., pentazocine, butorphanol, nalbuphine), or partial agonists
(e.g., buprenorphine). Physical dependence may not occur to a clinically
significant degree until after several days to weeks of continued
ER should not be abruptly discontinued [see Dosage and Administration
(2.6)]. If HYSINGLA ER is
abruptly discontinued in a physically dependent patient, a withdrawal
syndrome may occur. Some or all of the following can characterize
this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration,
chills, myalgia, and mydriasis. Other signs and symptoms also may
develop, including irritability, anxiety, backache, joint pain, weakness,
abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea,
increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically
dependent on opioids will also be physically dependent and may exhibit
respiratory difficulties and withdrawal signs [see Use in
Specific Populations (8.1)].
Acute overdosage with HYSINGLA 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 re-establishment of a patent 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 opioid reversal
is expected to be less than the duration of action of hydrocodone
in HYSINGLA ER, carefully monitor the patient until spontaneous respiration
is reliably reestablished. HYSINGLA 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.
HYSINGLA ER (hydrocodone bitartrate) extended-release
tablets are supplied in 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg
and 120 mg film-coated tablets for oral administration. The tablet
strengths describe the amount of hydrocodone per tablet as the bitartrate
is an opioid agonist. Its chemical name is 4,5α-epoxy-3-methoxy-17-methylmorphinan-6-one
tartrate (1:1) hydrate (2:5). Its structural formula is:
Empirical formula: C18H21NO3 C4H6O6 2½H2O; Molecular weight: 494.49.
Hydrocodone bitartrate exists
as fine white crystals or a crystalline powder. It is affected by
light. It is soluble in water, slightly soluble in alcohol, and insoluble
in ether and chloroform.
The 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg and 120 mg tablets
contain the following inactive ingredients: Butylated Hydroxytoluene
(BHT, an additive in Polyethylene Oxide), Hydroxypropyl Cellulose,
Macrogol/PEG 3350, Magnesium Stearate, Microcrystalline Cellulose,
Polyethylene Oxide, Polysorbate 80, Polyvinyl Alcohol, Talc, Titanium
Dioxide, and Black Ink.
The 20 mg tablets also contain Iron Oxide Yellow and FD&C Blue
#2 Aluminum Lake/Indigo Carmine Aluminum Lake.
The 30 mg tablets also contain Iron Oxide
The 40 mg tablets
also contain Iron Oxide Yellow, Iron Oxide Red, and Iron Oxide Black.
The 60 mg tablets also contain
Iron Oxide Yellow and Iron Oxide Red.
The 80 mg tablets also contain Iron Oxide
The 100 mg tablets
also contain FD&C Blue #2 Aluminum Lake.
Black Ink Contains: Shellac Glaze (in Ethanol),
Isopropyl Alcohol, Iron Oxide Black, N-Butyl Alcohol, Propylene Glycol
and Ammonium Hydroxide.
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.
Cardiac ElectrophysiologyQTc interval prolongation was studied in a double-blind,
placebo- and positive-controlled 3-treatment parallel-group, dose-escalating
study of HYSINGLA ER in 196 healthy subjects. QTc interval prolongation
was observed following HYSINGLA ER 160 mg per day. The maximum mean
(90% upper confidence bound) difference in the QTc interval between
HYSINGLA ER and placebo (after baseline-correction) at steady state
was 6 (9) milliseconds, 7 (10) milliseconds, and 10 (13) milliseconds
at HYSINGLA ER doses of 80 mg, 120 mg and 160mg respectively. For
clinical implications of the prolonged QTc interval, see Warnings
and Precautions (5.9).
Effects on the Central Nervous
SystemHydrocodone produces respiratory depression
by direct action on brainstem 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 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
Effects on the Gastrointestinal
Tract and Other Smooth MuscleHydrocodone 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 biliary and
pancreatic secretions, spasm of sphincter of Oddi, and transient elevations
in serum amylase.
Effects on the Cardiovascular SystemHydrocodone
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,
sweating, and/or orthostatic hypotension.
Effects on the Endocrine SystemOpioids 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 SystemOpioids 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.
RelationshipsThe 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 the development of analgesic tolerance [see
Dosage and Administration (2.1, 2.3)].
RelationshipsThere is a relationship between
increasing hydrocodone plasma concentration and increasing frequency
of 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 [see Dosage and Administration (2.1, 2.2, 2.3)].
AbsorptionHYSINGLA ER is a single-entity extended-release formulation of hydrocodone
that yields a gradual increase in plasma hydrocodone concentrations
with a median Tmax of 14 – 16 hours noted for
different dose strengths. Peak plasma levels may occur in the range
of 6 -30 hours after single dose HYSINGLA ER administration.
Systemic exposure (AUC and Cmax) increased linearly with doses from 20 to 120 mg.
Both Cmax and AUC increased slightly more
than dose proportionally (Table 6). The mean terminal half-life (t1/2) was similar for all HYSINGLA ER dose strengths ranging
from 7 to 9 hours.
As compared to an immediate-release
hydrocodone combination product, HYSINGLA ER at the same daily dose
results in similar bioavailability but with lower maximum concentrations
at steady state (Figure 3).
Figure 3. Mean Steady-State Plasma
Hydrocodone Concentration Profile
Steady-state plasma hydrocodone concentrations
were confirmed on day 3 of once-daily dosing of HYSINGLA ER. The
extent of accumulation of systemic exposure was 1.3 and 1.1 fold with
respect to AUC and Cmax at steady-state. The
mean terminal half-life (t1/2) at steady state
was 7 hours. Median Tmax values were 14 hours
(range: 12 to 24 hours) on both Day 1 and Day 5 following once daily
administration of HYSINGLA ER for five days. Daily fluctuation in
peak to trough plasma levels of hydrocodone were higher at 80 mg and
120 mg doses of HYSINGLA ER compared to 30 mg dose (Table 7).
Food Effects Cmax and AUC of HYSINGLA ER 120
mg tablets were similar under low fat conditions relative to fasting
conditions (17% and 9% higher, respectively). Cmax was higher (54%) under high fat conditions relative to fasting conditions;
however, AUC of HYSINGLA ER 120 mg tablets was only 20% higher when
co-administered with a high fat meal. HYSINGLA ER may be administered
without regard to meals.
of HYSINGLA ER, the typical (70 kg adult) value of apparent volume
of distribution (V/F) is 402 L, suggesting extensive tissue distribution.
The extent of in vivo binding of hydrocodone to
human plasma proteins was minimal with a mean % bound at 36%.
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 inactive norhydrocodone is the primary metabolic
pathway of hydrocodone with a lower contribution from CYP2B6 and CYP2C19.
The minor metabolite hydromorphone (<3% of the circulating parent
hydrocodone) was mainly formed by CYP2D6 mediated O-demethylation with a smaller contribution by CYP2B6 and CYP2C19.
Hydromorphone may contribute to the total analgesic effect of hydrocodone.
ExcretionHydrocodone and its metabolites are cleared primarily by renal excretion.
The percent of administered dose excreted unchanged as hydrocodone
in urine was 6.5% in subjects with normal renal function, and 5.0%,
4.8%, and 2.3% in subjects with mild, moderate, and severe renal impairment,
respectively. Renal clearance (CLr) of hydrocodone in healthy subjects
was small (5.3 L/h) compared to apparent oral clearance (CL/F, 83
L/h); suggesting that non-renal clearance is the main elimination
route. Ninety-nine percent of the administered dose is eliminated
within 72 hours. The mean terminal half-life (t1/2) was similar for all HYSINGLA ER dose strengths ranging from approximately
7 to 9 hours across the range of doses.
Specific PopulationsAge: Geriatric PatientsFollowing
administration of 40 mg HYSINGLA ER, the pharmacokinetics of hydrocodone
in healthy elderly subjects (65 to 77 years) are similar to the pharmacokinetics
in healthy younger subjects (20 to 45 years). There were no clinically
meaningful increase in Cmax (16%) and AUC (15%)
of hydrocodone in elderly as compared with younger adult subjects [see Use in Specific Populations (8.5)].
SexSystemic exposure of hydrocodone (Cmax and AUC) was similar between males and females.
Hepatic ImpairmentAfter a single dose of 20 mg HYSINGLA ER in subjects
(8 each) with normal hepatic function, mild, moderate or severe hepatic
impairment based on Child-Pugh classifications, mean hydrocodone Cmax values were 16, 15, 17, and 18 ng/mL, respectively.
Mean hydrocodone AUC values were 342, 310, 390, and 415 ng.hr/mL for
subjects with normal hepatic function, mild, moderate or severe hepatic
impairment, respectively. Geometric mean hydrocodone Cmax values were -6%, 5%, and 5% and AUC values were -14%,
13%, and 4% in patients with mild, moderate or severe hepatic impairment,
respectively, when compared with subjects with normal hepatic function.
The mean in vivo plasma protein binding of hydrocodone across the groups was similar,
ranging from 33% to 37% [see Use in Specific Populations (8.6)].
Renal ImpairmentAfter a single dose of 60 mg HYSINGLA ER in subjects (8 each) with
normal renal function, mild, moderate, or severe renal impairment
based on Cockcroft-Gault criteria and end stage renal disease (with
dialysis) patients, mean hydrocodone Cmax values
were 40, 50, 51, 46, and 38 ng/mL, respectively. Mean hydrocodone
AUC values were 754, 942, 1222, 1220, and 932 ng.hr/mL for subjects
with normal renal function, mild, moderate or severe renal impairment
and ESRD with dialysis, respectively. Hydrocodone Cmax values were 14%, 23%, 11% and -13% and AUC values were 13%, 61%,
57% and 4% higher in patients with mild, moderate or severe renal
impairment or end stage renal disease with dialysis, respectively [see Use in Specific Populations (8.7)].
Drug Interaction StudiesCYP3A4Co-administration of HYSINGLA ER (20 mg single dose)
and CYP3A4 inhibitor ketoconazole (200 mg BID for 6 days) increased
mean hydrocodone AUC and Cmax by 135% and 78%,
respectively [see Warnings and Precautions (5.4) and Drug Interactions (7)].
confidence interval (CI) of the geometric means for hydrocodone AUCinf (98 to 115%), AUCt (98 to
115%), and Cmax (93 to 121%) values were within
the range of 80 to 125% when a single dose of HYSINGLA ER 20 mg was
co-administered with CYP2D6 inhibitor paroxetine (20 mg treatment
each morning for 12 days). No differences in systemic exposure of
hydrocodone were observed in the presence of paroxetine.
CarcinogenesisHydrocodone was evaluated for carcinogenic potential in rats and
mice. In a two-year bioassay in rats, doses up to 25 mg/kg in males
and females were administered orally and no treatment-related neoplasms
were observed (exposure is equivalent to 0.2 times the human hydrocodone
dose of 120 mg/day based on AUC exposure comparisons). In a two-year
bioassay in mice, doses up to 200 mg/kg in males and 100 mg/kg in
females were administered orally and no treatment-related neoplasms
were observed (exposure is equivalent to 3.5 times and 3.0 times,
respectively, the human hydrocodone dose of 120 mg/day based on AUC
MutagenesisHydrocodone was genotoxic
in the mouse lymphoma assay in the presence of rat S9 metabolic activation
but not in the absence of rat metabolic activation. However, hydrocodone
was not genotoxic in the mouse lymphoma assay with or without human
S9 metabolic activation. There was no evidence of genotoxic potential
with hydrocodone in an in vitro bacterial reverse mutation assay with
Salmonella typhimurium and Escherichia coli with or without metabolic
activation or in an in vivo mouse bone marrow micronucleus test with
or without metabolic activation.
Impairment of FertilityNo effect on fertility or general reproductive performance
was seen with oral administration of hydrocodone to male and female
rats at doses up to 25 mg/kg/day (approximately 0.06 times and 0.08
times, respectively, the human hydrocodone dose of 120 mg/day based
on AUC exposure comparisons).
The efficacy and safety of HYSINGLA ER
was evaluated in a randomized double-blind, placebo-controlled, multi-center,
12-week clinical trial in both opioid-experienced and opioid-naïve
patients with moderate to severe chronic low back pain.
A total of 905 chronic low
back pain patients (opioid naive and opioid-experienced) who were
not responsive to their prior analgesic therapy entered an open-label
conversion and dose- titration period for up to 45 days with HYSINGLA
ER. Patients were dosed once daily with HYSINGLA ER (20 to 120 mg).
Patients stopped their prior opioid analgesics and/or nonopioid analgesics
prior to starting HYSINGLA ER treatment. Optional use of rescue medication
(immediate-release oxycodone 5 mg) up to 2 doses (2 tablets) was permitted
during the dose titration period. For inadequately controlled pain,
HYSINGLA ER dose was allowed to be increased once every 3–5 days until
a stabilized and tolerable dose was identified. During the dose-titration
period, 65% of the patients achieved a stable HYSINGLA ER dose and
entered the double-blind treatment period. The remaining subjects
discontinued from the dose-titration period for the following reasons:
adverse events (10%); lack of therapeutic effect (5%); confirmed
or suspected diversion (3%); subject’s choice (5%); lost to follow-up
(2%); administrative reasons (2%); and failure to achieve protocol-defined
reduction in pain score (7%).
Following the dose titration period, 588
patients (65%) were randomized at a ratio of 1:1 into a 12-week double-blind
treatment period with their fixed stabilized dose of HYSINGLA ER (or
matching placebo). These patients met the study randomization criteria
of adequate analgesia (pain reduction of at least 2 points to a score
of 4 or less on a 0-10 numerical rating scale) and acceptable tolerability
of HYSINGLA ER. Patients randomized to placebo were given a blinded
taper of HYSINGLA ER according to a pre-specified tapering schedule,
3 days on each step-down dose (reduced by 25-50% from the previous
dose). Patients were allowed to use rescue medication (immediate-release
oxycodone 5 mg) up to 6 doses (6 tablets) per day depending on their
randomized HYSINGLA ER dose. During the double-blind period, 229
treated patients (77%) completed the 12-week treatment with HYSINGLA
ER and 210 patients (72%) completed on placebo. Overall, 10% of patients
discontinued due to lack of therapeutic effect (5% in HYSINGLA patients
and 15% in placebo patients); 5% of patients discontinued due to adverse
events (6% in HYSINGLA ER treated patients and 3% in placebo patients).
HYSINGLA ER provided greater
analgesia compared with placebo. There was a statistically significant
difference in the weekly average pain scores at Week 12 between the
percentage of patients (responders) in each group who demonstrated
improvement in their weekly average pain scores at Week 12, as compared
with screening is shown in Figure 4. The figure is cumulative, so
that patients whose change from screening is, for example, 30%, are
also included at every level of improvement below 30%. Patients who
did not complete the study were classified as non-responders. Treatment
with HYSINGLA ER resulted in a higher proportion of responders, defined
as patients with at least a 30% and 50% improvement, as compared with
4. Percent Improvement in Pain Intensity
HYSINGLA ER (hydrocodone
bitartrate) extended-release tablets 20 mg are round, green-colored,
bi-convex tablets printed with “HYD 20” and are supplied in child-resistant
closure, opaque plastic bottles of 60 (NDC 59011-271-60).
HYSINGLA ER (hydrocodone bitartrate)
extended-release tablets 30 mg are round, yellow-colored, bi-convex
tablets printed with “HYD 30” and are supplied in child-resistant
closure, opaque plastic bottles of 60 (NDC 59011-272-60).
HYSINGLA ER (hydrocodone bitartrate)
extended-release tablets 40 mg are round, grey-colored, bi-convex
tablets printed with “HYD 40” and are supplied in child-resistant
closure, opaque plastic bottles of 60 (NDC 59011-273-60).
HYSINGLA ER (hydrocodone bitartrate)
extended-release tablets 60 mg are round, beige-colored, bi-convex
tablets printed with “HYD 60” and are supplied in child-resistant
closure, opaque plastic bottles of 60 (NDC 59011-274-60).
HYSINGLA ER (hydrocodone bitartrate)
extended-release tablets 80 mg are round, pink-colored, bi-convex
tablets printed with “HYD 80” and are supplied in child-resistant
closure, opaque plastic bottles of 60 (NDC 59011-275-60).
HYSINGLA ER (hydrocodone bitartrate)
extended-release tablets 100 mg are round, blue-colored, bi-convex
tablets printed with “HYD 100” and are supplied in child-resistant
closure, opaque plastic bottles of 60 (NDC 59011-276-60).
HYSINGLA ER (hydrocodone bitartrate)
extended-release tablets 120 mg are round, white-colored, bi-convex
tablets printed with “HYD 120” and are supplied in child-resistant
closure, opaque plastic bottles of 60 (NDC 59011-277-60).
Store at 25°C (77°F); excursions
permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
Dispense in tight, light-resistant
container, as defined by the USP.
Advise the patient to read the FDA-approved patient labeling
Addiction, Abuse, and MisuseInform
patients that the use of HYSINGLA 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 HYSINGLA ER with others and to take steps to protect HYSINGLA
ER from theft or misuse.
Life-Threatening Respiratory DepressionInform patients of the risk of life-threatening respiratory depression,
including information that the risk is greatest when starting HYSINGLA
ER or when the dosage is increased, and that it can occur even at
recommended dosages [see Warnings and Precautions (5.2)]. Advise patients how to
recognize respiratory depression and to seek medical attention if
breathing difficulties develop.
Accidental IngestionInform patients that accidental ingestion, especially
by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)]. Instruct patients to take steps to store HYSINGLA ER
securely and to dispose of unused HYSINGLA ER by flushing the tablets
down the toilet.
Interaction with Benzodiazepines and other CNS DepressantsInform patients and caregivers that potentially fatal
additive effects may occur if HYSINGLA ER is used with benzodiazepines
or other CNS depressants, including alcohol, and not to use these
concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.5), Drug Interactions (7)].
SyndromeInform 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
healthcare providers if they are taking, or plan to take serotonergic
medications[see Drug Interactions (7)].
InteractionInform patients to avoid taking
HYSINGLA ER while using any drugs that inhibit monoamine oxidase.
Patients should not start MAOIs while taking HYSINGLA ER [see
Drug Interactions (7)].
Adrenal InsufficiencyInform 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 (5.7)].
Important Administration InstructionsInstruct patients how to properly take HYSINGLA ER, including
HypotensionInform patients that HYSINGLA 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
QTc interval prolongationInform patients that QT prolongation has been observed
with HYSINGLA ER [see Clinical Pharmacology (12.2)]. HYSINGLA ER should be
avoided in patients with congenital long QT syndrome. Instruct patients
with a history of congestive heart failure or bradyarrhythmias, and
patients at risk for electrolyte abnormalities or who are taking other
medications known to prolong the QT interval, that periodic monitoring
of electrocardiograms and electrolytes may be necessary during therapy
with HYSINGLA ER [see Warnings and Precautions (5.9)].
AnaphylaxisInform patients that anaphylaxis has been reported with ingredients
contained in HYSINGLA ER. Advise patients how to recognize such a
reaction and when to seek medical attention [see Contraindication
(4), Adverse Reactions (6)].
PregnancyNeonatal Opioid Withdrawal SyndromeInform
female patients of reproductive potential that prolonged use of HYSINGLA
ER during pregnancy can result in neonatal opioid withdrawal syndrome,
which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)].
Embryo-Fetal ToxicityInform female patients
of reproductive potential that HYSINGLA ER can cause fetal harm and
to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].
LactationAdvise patients that breastfeeding
is not recommended during treatment with HYSINGLA ER [see
Use in Specific Populations (8.2)]
InfertilityInform 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 MachineryInform patients that HYSINGLA 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
ConstipationAdvise 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)].
of unused HYSINGLA ERAdvise patients to dispose
of any unused tablets from a prescription as soon as they are no longer
needed by flushing down the toilet.
Healthcare professionals can telephone Purdue
Pharma’s Medical Services Department (1-888-726-7535) for information
on this product.
Purdue Pharma L.P.Stamford, CT 06901-3431
©2016, Purdue Pharma L.P.
U.S. Patent Numbers: 6,488,963;
6,733,783; 8,309,060; 8,361,499; 8,529,948; 8,551,520; 8,647,667 and
Guide has been approved by the U.S. Food and Drug Administration.Issue: 12/2016
NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.
The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected over dosage, the drug's identity should be verified by chemical analysis.