Xtampza ER

Xtampza ER is part of the drug class:

• Natural opium alkaloids

Serious side effects have been reported. See "Xtampza ER Drug Precautions" section.

Common side effects of Xtampza ER include:

• nausea
• headache
• constipation
• feeling tired
• itching
• vomiting
• dizziness

This is not a complete list of Xtampza ER side effects. Ask your doctor or pharmacist for more information.

Tell your healthcare provider if you have any side effect that bothers you or does not go away. 

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor if you are pregnant or plan to become pregnant.

There are no well-done studies that have been done in humans with Xtampza ER. Prolonged use of Xtampza ER during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.

Tell your doctor if you are breastfeeding or plan to breastfeed. 

Xtampza ER has been detected in human breast milk. Because of the possibility for adverse reactions in nursing infants from Xtampza ER, a choice should be made whether to stop nursing or to stop the use of this medication. It is recommended not to breastfeed while taking this medication. 

Use Xtampza ER as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take by mouth only.
• Do not inject or snort this medicine. Doing any of these things can cause very bad side effects like trouble breathing and death from overdose.
• To gain the most benefit, do not miss doses.
• Swallow whole. Do not chew, break, crush, or melt before swallowing. Doing these things can cause very bad side effects and death.
• Do not use for fast pain relief or on an as needed basis.
• Do not use for pain relief after surgery if you have not been taking drugs like Xtampza ER (oxycodone extended-release capsules).
• Take this medicine with food. Always take with the same amount of food each time.
• You may sprinkle contents of the capsule on applesauce or other soft food. You may also sprinkle the contents of the capsule into a cup and put directly into the mouth. Do not chew. Swallow right away and rinse your mouth to make sure that all capsule contents were swallowed.
• Those who have feeding tubes may use Xtampza ER. Use as you have been told. Flush the feeding tube after this medicine is given.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it, with food.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad dizziness or passing out.
• Feeling confused.
• Very hard stools (constipation).
• Very bad belly pain.
• Feeling very tired or weak.
• Trouble breathing, slow breathing, or shallow breathing.
• Trouble passing urine.
• Fast or slow heartbeat.
• A heartbeat that does not feel normal.
• Seizures.
• Shakiness.
• Change in eyesight.
• Chest pain or pressure.
• Hallucinations (seeing or hearing things that are not there).
• Mood changes.
• Memory problems or loss.
• Trouble walking.
• Trouble speaking.
• Swelling in the arms or legs.
• Feeling very sleepy.
• Fever.
• A very bad and sometimes deadly health problem called serotonin syndrome may happen if you take Xtampza ER with drugs for depression, migraines, or certain other drugs. Call your doctor right away if you have agitation; change in balance; confusion; hallucinations; fever; fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.
• Taking an opioid drug like this medicine may lead to a rare but very bad adrenal gland problem. Call your doctor right away if you have very bad dizziness or passing out, very bad upset stomach or throwing up, or if you feel less hungry, very tired, or very weak.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach or throwing up.
• Hard stools (constipation).
• Dizziness.
• Feeling sleepy.
• Headache.
• Not able to sleep.
• Feeling tired or weak.
• Itching.
• Dry mouth.
• Belly pain.
• Loose stools (diarrhea).
• Not hungry.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Controlled Substance

Xtampza ER contains oxycodone, a Schedule II controlled substance.

Abuse

Xtampza ER contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. Xtampza ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

The high drug content in extended-release formulations 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, since 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 to 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 healthcare 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. 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.

Xtampza ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful recordkeeping 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 reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Xtampza ER

Xtampza ER is for oral use only. Abuse of Xtampza ER poses a risk of overdose and death. The risk is increased with concurrent use of Xtampza ER with alcohol and other central nervous system depressants.

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

Abuse Deterrence Studies

Xtampza ER capsules contain microspheres formulated with inactive ingredients intended to make the formulation more difficult to manipulate for misuse and abuse.

In Vitro Testing

In vitro physical and chemical manipulation studies were performed to evaluate the success of different methods of defeating the extended-release formulation.

Results support that, relative to immediate-release oxycodone tablets, Xtampza ER is less susceptible to the effects of grinding, crushing, and extraction using a variety of tools and solvents.

Xtampza ER resisted attempts to pass the melted capsule contents or the microspheres suspended in water through a hypodermic needle.

Pharmacokinetic Studies

The pharmacokinetic profile of manipulated Xtampza ER capsule contents (36 mg; [equivalent to 40 mg oxycodone HCl]) was characterized following oral (two studies) and intranasal (two studies) administration. The studies were conducted in a randomized, cross-over design. In studies assessing manipulation by crushing, the most effective crushing method identified in previous in vitro studies was applied to the product(s).

Oral Pharmacokinetic Studies, Manipulated and Intact Xtampza ER

The effect of two types of product manipulation (crushing and chewing) on Xtampza ER pharmacokinetics was measured in two studies.

In Oral Pharmacokinetic Study 1, Xtampza ER capsule contents were crushed or chewed prior to oral administration in healthy, naltrexone blocked volunteers. The two comparators in this study were intact Xtampza ER capsules and an immediate-release solution of oxycodone.

In Oral Pharmacokinetic Study 2, Xtampza ER capsule contents were crushed prior to oral administration in healthy, naltrexone-blocked volunteers. The comparators in this study included intact Xtampza ER capsules and crushed immediate-release oxycodone tablets.

The pharmacokinetic data displayed in Table 3 illustrate the findings from these two studies. Collectively, the data from the two studies demonstrated that crushing or chewing Xtampza ER prior to administration did not increase the maximum observed plasma concentration (Cmax) or total exposure (AUC0-INF) relative to dosing the intact product under fed conditions. Relative to immediate-release oxycodone, the Cmax for all Xtampza ER treatments was significantly lower and the Tmax significantly longer, consistent with an extended-release profile.

Nasal Pharmacokinetic Studies

The pharmacokinetic profile following intranasal administration of crushed Xtampza ER capsule contents was characterized in two clinical studies.

In Nasal Pharmacokinetic Study 1, Xtampza ER capsule contents were crushed and intranasally administered by non-dependent, naltrexone-blocked subjects with a history of nasal abuse of opioids. The two comparators in this study were intact Xtampza ER capsules (oral) and oxycodone HCl powder (intranasal) at an equivalent dose.

In Nasal Pharmacokinetic Study 2, Xtampza ER capsule contents were crushed and intranasally administered by non-dependent subjects with a history of nasal abuse of opioids. The two comparators in this study were intact Xtampza ER capsules (oral) and crushed oxycodone immediate-release tablets (intranasal) at an equivalent dose.

The results of Nasal Pharmacokinetic Studies 1 and 2 are comparable and both studies demonstrated that intranasal administration of crushed Xtampza ER capsule contents did not result in higher peak plasma concentration (Cmax) or shorter time to peak concentration (Tmax) than taking Xtampza ER orally. The data from Nasal Pharmacokinetic Study 2 are displayed in Table 4 to represent these findings.

Clinical Studies

Oral Abuse Potential Study:

In the Oral Abuse Potential Study, a randomized, double-blind, active- and placebo-controlled, single-dose, six-way crossover pharmacodynamic study, 61 recreational opioid users with a history of oral drug abuse received orally administered active and placebo treatment. The six treatment arms were intact Xtampza ER (36 mg, fed and fasted); chewed Xtampza ER (36 mg, fed and fasted); crushed immediate-release oxycodone HCl in water (40 mg, fasted, equivalent to 36 mg of Xtampza ER), and placebo. Data for chewed Xtampza ER and crushed IR oxycodone in the fasted state are described below.

Drug Liking was measured on a bipolar 100-point Visual Analog Scale (VAS) where 50 represents a neutral response, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would take the study drug again was also measured on a bipolar 100-point VAS where 50 represents a neutral response, 0 represents the strongest negative response (e.g., 'definitely would not take drug again') , and 100 represents the strongest positive response (e.g., 'definitely would take drug again').

Thirty-eight subjects completed the study. The results are summarized in Table 5. The oral administration of chewed and intact Xtampza ER in the fasted state was associated with statistically lower mean Drug Liking scores compared with crushed immediate-release oxycodone. However, the differences for Xtampza ER chewed and intact compared with crushed immediate-release oxycodone for the Take Drug Again scores were small and not statistically significant.

Nasal Abuse Potential Study:

In a randomized, double-blind, active- and placebo-controlled, single-dose, four-way crossover pharmacodynamic study, 39 recreational opioid users with a history of intranasal drug abuse received nasally administered active and placebo drug treatment. The four treatment arms were crushed Xtampza ER 36 mg dosed intranasally; intact Xtampza ER 36 mg dosed orally; crushed immediate-release oxycodone HCl 40 mg (equivalent to 36 mg of Xtampza ER) dosed intranasally; and placebo. Data for intranasal Xtampza ER and crushed immediate-release oxycodone are described below.

Thirty-six subjects completed the study. Intranasal administration of crushed Xtampza ER was associated with statistically lower mean Drug Liking and Take Drug Again scores compared with crushed immediate-release oxycodone (summarized in Table 6).

Figure 1 demonstrates a comparison of Drug Liking for intranasal administration of crushed Xtampza ER compared to crushed immediate-release oxycodone in subjects who received both treatments (N=36). The Y-axis represents the percent of subjects attaining a percent reduction in drug liking for Xtampza ER vs. immediate-release oxycodone greater than or equal to the value on the X-axis. Approximately 92% (n = 33) of subjects had some reduction in drug liking with Xtampza ER relative to crushed immediate-release oxycodone HCl. 78% (n = 28) of subjects had a reduction of at least 30% in drug liking with Xtampza ER compared to crushed immediate-release oxycodone HCl, and approximately 58% (n = 21) of subjects had a reduction of at least 50% in drug liking with Xtampza ER compared to crushed immediate-release oxycodone HCl.

Figure 1: Percent Reduction Profiles for Emax of Drug Liking VAS for Crushed Xtampza ER vs. Crushed Immediate-release Oxycodone, N=36 Following Intranasal Administration

Summary

The in vitro data demonstrate that Xtampza ER has physicochemical properties expected to make abuse by injection difficult. The data from pharmacokinetic and human abuse potential studies, along with support from the in vitro data, also indicate that Xtampza ER has physicochemical properties that are expected to reduce abuse via the intranasal route. The data from the oral pharmacokinetic studies of manipulated Xtampza ER demonstrated a lack of dose dumping with no increase in oxycodone levels compared to intact Xtampza ER. Although the results of the oral human abuse potential study showed a difference in the Drug Liking endpoint, there was no statistically significant reduction in the response to Take Drug Again. Therefore, it cannot be concluded that Xtampza ER has physicochemical properties that are expected to reduce abuse via the oral route.

However, abuse of Xtampza ER by injection and by the nasal route of administration, as well as by the oral route is still possible.

Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of Xtampza ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate.

Xtampza ER contains oxycodone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit, including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. Xtampza ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.1)].

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.

Xtampza ER should not be abruptly discontinued [see Dosage and Administration (2.5)]. If Xtampza 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, 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 symptoms [see Use in Specific Populations (8.1)].

Applies to oxycodone: oral capsule, oral capsule extended release, oral solution, oral tablet, oral tablet extended release

Along with its needed effects, oxycodone (the active ingredient contained in Xtampza ER) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking oxycodone:

• Chills
• cold sweats
• confusion
• difficult or labored breathing
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fever
• tightness in the chest
• twitching

• Abdominal or stomach pain
• bloating or swelling of the face, arms, hands, lower legs, or feet
• blood in the urine
• burning while urinating burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain
• convulsions
• cough
• decrease in the frequency of urination
• decrease in urine volume
• decreased urine output
• difficult or painful urination
• difficulty in passing urine (dribbling)
• difficulty with swallowing
• dizziness
• dry mouth
• fainting
• fast, irregular, pounding, or racing heartbeat or pulse
• feeling of warmth or heat
• flushing or redness of the skin, especially on the face and neck
• frequent urination
• headache
• hives, itching, or skin rash
• increase in heart rate
• increased thirst
• increased volume of pale, dilute urine
• lightheadedness
• muscle pain or cramps
• nausea or vomiting
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• rapid breathing
• rapid weight gain
• severe constipation
• severe vomiting
• shakiness in the legs, arms, hands, or feet
• sunken eyes
• sweating
• swelling or puffiness of the face
• swollen, painful, or tender lymph glands in the neck, armpit, or groin
• thirst
• tingling of the hands or feet
• trembling or shaking of the hands or feet
• unusual tiredness or weakness
• unusual weight gain or loss
• wrinkled skin

• Blurred vision
• choking
• clay-colored stools
• cold, clammy skin
• dark urine
• diarrhea
• fast, weak pulse
• gagging
• irregular, fast, slow, or shallow breathing
• loss of appetite
• pale or blue lips, fingernails, or skin
• unconsciousness
• unpleasant breath odor
• very slow heartbeat
• yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur while taking oxycodone:

• Change in consciousness
• chest pain or discomfort
• constricted, pinpoint, or small pupils (black part of the eye)
• decreased awareness or responsiveness
• extreme drowsiness
• loss of consciousness
• no muscle tone or movement
• severe sleepiness
• slow or irregular heartbeat

Some side effects of oxycodone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Difficulty having a bowel movement (stool)
• drowsiness
• lack or loss of strength
• relaxed and calm feeling
• sleepiness or unusual drowsiness

• Abnormal dreams
• acid or sour stomach
• anxiety
• belching
• burning feeling in the chest or stomach
• false or unusual sense of well-being
• heartburn
• hiccups
• indigestion
• stomach discomfort, upset, or pain
• tenderness in the stomach area
• trouble sleeping
• weight loss

• Absent, missed, or irregular menstrual periods
• bad, unusual or unpleasant (after) taste
• bloated or full feeling
• body aches or pain
• change in taste
• change in walking and balance
• changes in vision
• clumsiness or unsteadiness
• congestion
• continuous ringing or buzzing or other unexplained noise in the ears
• crying
• decreased interest in sexual intercourse
• dental caries or tooth decay
• depersonalization
• depression
• difficulty with speaking
• dry skin
• dryness or soreness of the throat
• excess air or gas in the stomach or intestines
• excessive muscle tone
• feeling of constant movement of self or surroundings
• feeling of unreality
• general feeling of discomfort or illness
• headache, severe and throbbing
• hearing loss
• hoarseness
• hyperventilation
• inability to have or keep an erection
• increase in body movements
• increased appetite
• increased cough
• irritability
• loss in sexual ability, desire, drive, or performance
• loss of heat from the body
• loss of memory
• loss of strength or energy
• muscle pain or weakness
• muscle stiffness
• muscle tension or tightness
• neck pain
• paranoia
• passing of gas
• problems with memory
• quick to react or overreact emotionally
• rapidly changing moods
• red, swollen skin
• restlessness
• runny nose
• scaly skin
• sensation of spinning
• sense of detachment from self or body
• severe sleepiness
• stomach pain, fullness, or discomfort
• swelling or inflammation of the mouth
• tender, swollen glands in the neck
• unusual weak feeling
• voice changes

Applies to oxycodone: compounding powder, oral capsule, oral capsule extended release, oral concentrate, oral solution, oral tablet, oral tablet extended release

General

The most commonly reported adverse reactions in adults included constipation, nausea, somnolence, dizziness, vomiting, pruritus, headache, dry mouth, asthenia, and sweating. In pediatric patients, the most frequently observed adverse reactions included vomiting, nausea, headache, pyrexia, and constipation.[Ref]

Nervous system

Very common (10% or more): Headache (14%, pediatrics)
Common (1% to 10%): Dizziness (pediatrics)
Frequency not reported: Confusion, hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, migraine
Postmarketing reports: Serotonin syndrome[Ref]

Respiratory

Severe adverse effects such as respiratory depression can be treated with the opioid antagonist naloxone.[Ref]

Frequency not reported: Apnea, respiratory arrest, bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, sinusitis[Ref]

Gastrointestinal

Very common (10% or more): Nausea (23% to 27%), constipation (23% to 26%), vomiting (12% to 14%)
Frequency not reported: Abdominal pain, anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis[Ref]

In pediatric studies with the oral extended release product, gastrointestinal adverse events were reported in 40% of patients 11 to 16 years of age (56 of 140); vomiting, nausea, constipation, and diarrhea were experienced by 21%, 15%, 9%, and 6%, respectively. Abdominal pain and gastroesophageal reflux disease were reported in 1% to less than 5% of patients.[Ref]

Psychiatric

Frequency not reported: Paranoia, psychosis, hallucinations, agitation, anxiety[Ref]

Dermatologic

Common (1% to 10%): Pruritus, hyperhidrosis, rash
Frequency not reported: Herpes simplex, rash, sweating, urticaria[Ref]

Hepatic

Frequency not reported: Increased hepatic enzymes

Cardiovascular

Frequency not reported: QTc prolongation at higher doses, deep thrombophlebitis, heart failure, hemorrhage, hypotension, palpitation, tachycardia, edema, peripheral edema, vasodilation, circulatory collapse[Ref]

Genitourinary

Common (1% to 10%): Dysuria, urinary retention
Frequency not reported: Urinary tract infection[Ref]

Hypersensitivity

Frequency not reported: Allergic reaction
Postmarketing reports: Anaphylaxis[Ref]

Immunologic

Frequency not reported: Flu syndrome, infection, sepsis[Ref]

Metabolic

Common (1% to 10%): Decreased appetite (pediatrics)
Frequency not reported: Gout, hyperglycemia, iron deficiency anemia[Ref]

Musculoskeletal

Frequency not reported: Back pain, neck pain, arthralgia, arthritis, bone pain, myalgia, pathological fracture[Ref]

Ocular

Frequency not reported: Photosensitivity reaction, amblyopia[Ref]

Other

Very common (10% or more): Pyrexia (11%, pediatrics)
Frequency not reported: Chills and fever, accidental injury[Ref]

Endocrine

Opioids:
Postmarketing reports: Adrenal insufficiency, androgen deficiency[Ref]

Some side effects of Xtampza ER may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.