2.1. Important Dosage and Administration Instructions

Ensure accuracy when prescribing, dispensing, and administering Oxycodone Hydrochloride Oral Solution to avoid

dosing errors due to confusion between mg and mL, and with other oxycodone hydrochloride solutions of different

concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and

dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume.

Always use the enclosed calibrated oral syringe when administering Oxycodone Hydrochloride Oral Solution 100 mg

per 5 mL (20 mg per mL) to ensure that the dose is measured and administered accurately.

Do not use household teaspoons or tablespoons to measure Oxycodone Hydrochloride Oral Solution, as using a

tablespoon instead of a teaspoon could lead to overdosage.

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 (5.2)].

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and

following dosage increases with Oxycodone Hydrochloride Oral Solution and adjust the dosage accordingly [see

Warnings and Precautions (5.3)].

2.2. Initial Dosage

Use of Oxycodone Hydrochloride Oral Solution as the First Opioid Analgesic

Initiate treatment with Oxycodone Hydrochloride Oral Solution in a dosing range of 5 to 15 mg every 4 to 6 hours

as needed for pain.

Conversion from Other Opioids to Oxycodone Hydrochloride Oral Solution

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative

approach is advised when determining the total daily dosage of Oxycodone Hydrochloride Oral Solution. It is safer

to underestimate a patient’s 24-hour Oxycodone Hydrochloride Oral Solution dosage than to overestimate the

24-hour Oxycodone Hydrochloride Oral Solution dosage and manage an adverse reaction due to overdose.

Conversion from Oxycodone Hydrochloride Oral Solution to Extended-Release Oxycodone Hydrochloride

The relative bioavailability of Oxycodone Hydrochloride Oral Solution compared to extended-release oxycodone is

unknown, so conversion to extended-release tablets must be accompanied by close observation for signs of excessive

sedation and respiratory depression.

2.3. Titration and Maintenance of Therapy

Individually titrate Oxycodone Hydrochloride Oral Solution to a dose that provides adequate analgesia and

minimizes adverse reactions. Continually reevaluate patients receiving Oxycodone Hydrochloride Oral Solution 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 (5.2)]. 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.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before

increasing the Oxycodone Hydrochloride Oral Solution dosage. 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. Discontinuation of Oxycodone Hydrochloride Oral Solution

When a patient who has been taking Oxycodone Hydrochloride Oral Solution regularly and may be physically

dependent no longer requires therapy with Oxycodone Hydrochloride Oral Solution, taper the dose gradually, by

25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient

develops 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. Do not abruptly discontinue

Oxycodone Hydrochloride Oral Solution in a physically-dependent patient [see Warnings and Precautions (5.13),

Drug Abuse and Dependence (9.3)].

5.1. Risk of Accidental Overdose and Death due to Medication Errors

Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion

between mg and mL and confusion with oxycodone hydrochloride solutions of different concentrations, when

prescribing, dispensing, and administering Oxycodone Hydrochloride Oral Solution. Ensure that the dose is

communicated clearly and dispensed accurately. Always use the enclosed calibrated oral syringe when administering

Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/ mL) to ensure the dose is measured and

administered accurately.

Do not use a teaspoon or a tablespoon to measure a dose. A household teaspoon or tablespoon is not an adequate

measuring device. Given the inexactitude of the household spoon measure and the possibility of using a tablespoon

instead of a teaspoon, which could lead to overdosage, it is strongly recommended that, if the enclosed calibrated

measuring syringe becomes lost, caregivers obtain and use a calibrated measuring device. Health care providers

should recommend a calibrated device that can measure and deliver the prescribed dose accurately, and instruct

caregivers to use extreme caution in measuring the dosage.

5.2. Addiction, Abuse, and Misuse

Oxycodone Hydrochloride Oral Solution contains oxycodone, a Schedule II controlled substance. As an opioid,

Oxycodone Hydrochloride Oral Solution exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse

and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed

Oxycodone Hydrochloride Oral Solution. Addiction can occur at recommended dosages and if the drug is misused or

abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Oxycodone Hydrochloride Oral

Solution, and monitor all patients receiving Oxycodone Hydrochloride Oral Solution 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 abuse or addiction) or mental illness (e.g., major depression). The potential for these

risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk

may be prescribed opioids such as Oxycodone Hydrochloride Oral Solution, but use in such patients necessitates

intensive counseling about the risks and proper use of Oxycodone Hydrochloride Oral Solution along with intensive

monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider

these risks when prescribing or dispensing Oxycodone Hydrochloride Oral Solution. 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.

5.3. 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 (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 Oxycodone

Hydrochloride Oral Solution, 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 Oxycodone Hydrochloride Oral Solution.

To reduce the risk of respiratory depression, proper dosing and titration of Oxycodone Hydrochloride Oral Solution

are essential [see Dosage and Administration (2)]. Overestimating the Oxycodone Hydrochloride Oral Solution

dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of Oxycodone Hydrochloride Oral Solution, especially by children, can result in

respiratory depression and death due to an overdose of oxycodone.

5.4. Neonatal Opioid Withdrawal Syndrome

Prolonged use of Oxycodone Hydrochloride Oral Solution 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)].

5.5. Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers

Concomitant use of Oxycodone Hydrochloride Oral Solution 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 oxycodone 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 Oxycodone Hydrochloride Oral Solution is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as

rifampin, carbamazepine, and phenytoin, in Oxycodone Hydrochloride Oral Solution-treated patients may increase

oxycodone plasma concentrations and prolong opioid adverse reactions. When using Oxycodone Hydrochloride Oral

Solution with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Oxycodone Hydrochloride Oral Solution -treated

patients, monitor patients closely at frequent intervals and consider dosage reduction of Oxycodone Hydrochloride

Oral Solution until stable drug effects are achieved [see Dosage and Administration (2.1), Drug Interactions (7)].

Concomitant use of Oxycodone Hydrochloride Oral Solution with CYP3A4 inducers or discontinuation of an CYP3A4

inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a

withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using Oxycodone

Hydrochloride Oral Solution 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 Dosage and Administration (2.1), 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 Oxycodone

Hydrochloride Oral Solution 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 Oxycodone

Hydrochloride Oral Solution are 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) and Patient Counseling

Information (17)].

5.7. Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of Oxycodone Hydrochloride Oral Solution 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: Oxycodone Hydrochloride Oral Solution-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 Oxycodone Hydrochloride Oral Solution [see Warnings and

Precautions (5.3)].

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 (5.7)].

Monitor such patients closely, particularly when initiating and titrating Oxycodone Hydrochloride Oral Solution and

when Oxycodone Hydrochloride Oral Solution is given concomitantly with other drugs that depress respiration [see

Warnings and Precautions (5.5)]. 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 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 adrenal insufficiency.

5.9. Severe Hypotension

Oxycodone Hydrochloride Oral Solution may cause severe hypotension including orthostatic hypotension and syncope

in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been

compromised by a reduced blood volume or 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 Oxycodone Hydrochloride Oral Solution. In patients with circulatory shock,

Oxycodone Hydrochloride Oral Solution may cause vasodilation that can further reduce cardiac output and blood

pressure. Avoid the use of Oxycodone Hydrochloride Oral Solution 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 CO2 retention (e.g., those with evidence of increased

intracranial pressure or brain tumors), Oxycodone Hydrochloride Oral Solution 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 Oxycodone Hydrochloride Oral Solution.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Oxycodone

Hydrochloride Oral Solution in patients with impaired consciousness or coma.

5.11. Risks of Use in Patients with Gastrointestinal Conditions

Oxycodone Hydrochloride Oral Solution is contraindicated in patients with known or suspected gastrointestinal

obstruction, including paralytic ileus.

5.11. Risks of Use in Patients with Gastrointestinal Conditions

Oxycodone Hydrochloride Oral Solution is contraindicated in patients with known or suspected gastrointestinal

obstruction, including paralytic ileus.

The oxycodone in Oxycodone Hydrochloride Oral Solution 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.

5.12. Increased Risk of Seizures in Patients with Seizure Disorders

The oxycodone in Oxycodone Hydrochloride Oral Solution 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 Oxycodone Hydrochloride

Oral Solution therapy.

5.13. Withdrawal

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 Oxycodone

Hydrochloride Oral Solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce

the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

When discontinuing Oxycodone Hydrochloride Oral Solution in a physically-dependent patient, gradually taper the

dosage [see Dosage and Administration (2.4)]. Do not abruptly discontinue Oxycodone Hydrochloride Oral Solution

in these patients [see Drug Abuse and Dependence (9.3)].

5.14. Risks of Driving and Operating Machinery

Oxycodone Hydrochloride Oral Solution may impair the mental or 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 Oxycodone Hydrochloride Oral Solution and know how they will

react to the medication [see Patient Counseling Information (17)].

8.1 Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see

Warnings and Precautions (5.4)]. Available data with Oxycodone Hydrochloride Oral Solution are insufficient to

inform a drug-associated risk for major birth defects and miscarriage. Animal reproduction studies with oral

administrations of oxycodone hydrochloride in rats and rabbits during the period of organogenesis at doses 2.6 and

8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal

toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and

below, resulted in neurobehavioral effects in offspring [see Data]. Based on animal data, advise pregnant women

of the potential risk to a fetus. The 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 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 (5.4)].

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. Oxycodone Hydrochloride Oral Solution is not recommended for use in pregnant women during

or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics,

including Oxycodone Hydrochloride Oral Solution, 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.

Data

Animal Data

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone

hydrochloride administered during the period of organogenesis up to 16 mg/kg/day and up 25 mg/kg/day,

respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The

highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of

60 mg/day, respectively, on a mg/m2 basis. In published studies, offspring of pregnant rats administered oxycodone

during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased

anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult

human dose of 60 mg/day, on a mg/m2 basis) and altered learning and memory (15 mg/kg/day orally from

breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m2 basis).

8.2 Lactation

Risk Summary

Oxycodone is present in breast milk. Published lactation studies report variable concentrations of oxycodone in

breast milk with administration of immediate-release oxycodone to nursing mothers in the early postpartum period.

The lactation studies did not assess breastfed infants for potential adverse reactions. Lactation studies have not been

conducted with Oxycodone Hydrochloride Oral Solution, and no information is available on the effects of the drug

on the breastfed infant or the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need

for Oxycodone Hydrochloride Oral Solution and any potential adverse effects on the breastfed infant from

Oxycodone Hydrochloride Oral Solution or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to Oxycodone Hydrochloride Oral Solution through breast milk for excess sedation and

respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an

opioid analgesic is stopped, or when breast-feeding is stopped.

8.3 Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known

whether these effects on fertility are reversible [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

8.4 Pediatric Use

The safety and effectiveness and the pharmacokinetics of Oxycodone Hydrochloride Oral Solution in pediatric

patients below the age of 18 have not been established.

8.5 Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when

selecting a dose 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 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 Oxycodone Hydrochloride Oral Solution slowly in geriatric patients and monitor

closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.7)].

Oxycodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may

be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal

function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Hepatic Impairment

Since oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic

impairment. Initiate therapy in these patients with a lower than usual dosage of Oxycodone Hydrochloride Oral

Solution and titrate carefully. Monitor closely for adverse events such as respiratory depression, sedation, and

hypotension [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Information from oxycodone tablets indicate that patients with renal impairment had higher plasma concentrations

of oxycodone than subjects with normal renal function. Initiate therapy with a lower than usual dosage of

Oxycodone Hydrochloride Oral Solution and titrate carefully. Monitor closely for adverse events such as respiratory

depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

9.1 Controlled Substance

Oxycodone Hydrochloride Oral Solution contains oxycodone, a Schedule II controlled substance.

9.2 Abuse

Oxycodone Hydrochloride Oral Solution contains oxycodone, a substance with a high potential for abuse similar to

other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxymorphone, and

tapentadol. Oxycodone Hydrochloride Oral Solution can be abused and is subject to misuse, addiction, and criminal

diversion [see Warnings and Precautions (5.2)].

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 health care provider(s). “Doctor shopping” (visiting multiple prescribers to

obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction.

Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should

be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in

all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Oxycodone Hydrochloride Oral Solution, 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 Oxycodone Hydrochloride Oral Solution

Oxycodone Hydrochloride Oral Solution is for oral use only. Abuse of oxycodone poses a risk of overdose and death.

The risk is increased with concurrent abuse of alcohol and other central nervous system depressants. Parenteral drug

abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.3 Dependence

Both tolerance 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 opioid usage.

Oxycodone Hydrochloride Oral Solution should not be abruptly discontinued in a physically-dependent patient [see

Dosage and Administration (2.4)]. If Oxycodone Hydrochloride Oral Solution 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, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit

respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

12.1 Mechanism of Action

Oxycodone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other

opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid

agonists, there is no ceiling effect for analgesia with oxycodone. 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.

12.2 Pharmacodynamics

Effects of the Central Nervous System (CNS)

Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory

depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in

carbon dioxide tension and electrical stimulation.

Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not

pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked

mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the

stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are

decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of

spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic

secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations

of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or

orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH, cortisol), and luteinizing hormone (LH) in

humans [see Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic

secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that

may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in

the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and

psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in

studies conducted to date [see Adverse Reactions (6)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and Animal

models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly

immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who

have been previously treated with potent agonist opioids The minimum effective analgesic concentration of

oxycodone 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, 2.2)].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing oxycodone plasma concentration and increasing frequency of

dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In

opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse

reactions [see Dosage and Administration (2.1, 2.2, 2.3)].

12.3 Pharmacokinetics

The activity of oxycodone hydrochloride is primarily due to the parent drug oxycodone.

Absorption

About 60 to 87% of an oral dose reaches the systemic circulation in comparison to a parenteral dose. This high oral

bioavailability (compared to other opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone.

Food Effect

When oxycodone capsules are administered with a high-fat meal, mean AUC values are increased by 23% and peak

concentrations are decreased by 14%. Food causes a delay in Tmax (1.00 to 3 hours). Similar effects of food are

expected with the oral solution.

Distribution

Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein

binding of oxycodone at 37 °C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk.

Elimination

Metabolism

Oxycodone hydrochloride is extensively metabolized by multiple metabolic pathways to noroxycodone,

oxymorphone, and noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated

N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a less contribution from

CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites

can, in theory, be affected by other drugs. The major circulating metabolite is noroxycodone with an AUC ratio of

0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than

oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low

concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that

seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known.

Excretion

Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have

been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%;

conjugated oxymorphone < 14%; both free and conjugated noroxycodone have been found in the urine but not

quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone

following the administration of oxycodone is approximately 4 hours.

Specific Populations

Age: Geriatric Population:

Information obtained from oxycodone tablets indicate that the plasma concentrations of oxycodone did not

appear to be increased in patients over of the age of 65.

Hepatic Impairment:

Because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic-impaired

patients. A dose adjustment is recommended in these patients [see Use in Specific Populations (8.6)].

Renal Impairment:

Because this drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this

drug may be greater in patients with impaired renal function, a dose reduction is recommended for renal

impaired patients [see Use in Specific Populations (8.7)].

Drug Interaction Studies

CYP3A4 Inhibitors

CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the

co-administration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold,

respectively.

CYP3A4 Inducers

A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer,

decreased oxycodone AUC and Cmax values by 86% and 63%, respectively.

CYP2D6 Inhibitors

Oxycodone is metabolized in part to oxymorphone via the cytochrome P450 isoenzyme CYP2D6. While this

pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such

blockade has not yet been shown to be of clinical significance with this agent.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of oxycodone have not been conducted.

Mutagenesis

Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma assay in the presence of metabolic

activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay (Salmonella

typhimurium and Escherichia coli) and in an assay for chromosomal aberrations (in vivo mouse bone marrow

micronucleus assay).

Impairment of Fertility

Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.