Nucynta

Tapentadol may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• headache
• heartburn
• stomach pain
• dry mouth
• excessive tiredness
• anxiety
• drowsiness
• difficulty falling asleep or staying asleep
• abnormal dreams
• irritability
• sudden feeling of warmth

Some side effects can be serious. If you experience any of these symptoms or those listed in the SPECIAL PRECAUTIONS or IMPORTANT WARNING sections, call your doctor immediately or get emergency medical treatment:

• seizures
• agitation, hallucinations (seeing things or hearing voices that do not exist), fever, sweating, confusion, fast heartbeat, shivering, severe muscle stiffness or twitching, loss of coordination, nausea, vomiting, or diarrhea
• nausea, vomiting, loss of appetite, weakness, or dizziness
• inability to get or keep an erection
• irregular menstruation
• decreased sexual desire
• rash
• itching
• hives
• swelling of the eyes, face, lips, tongue, or throat
• hoarseness
• difficulty breathing or swallowing
• chest pain
• feeling lightheaded when you change positions
• feeling faint
• loss of consciousness
• feeling overheated
• heavy sweating

Tapentadol may cause other side effects. Call your doctor if you have any unusual problems while you are taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

• Nucynta^®
• Nucynta^® ER

Nucynta is available in immediate release tablets of: 50 milligrams (mg), 75 mg, and 100 mg, taken every four to six hours to control pain, with a maximum dose of 600 mg per 24 hours. (700 mg for day one).

It is also available in extended-release tablets in 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg. Extended use tablets are dosed every 12 hours and should not be crushed to maximize dosage, as this could lead to fast absorption, which can result in ingestion of toxic levels.

The prescribing physician should frequently re-evaluate the dosage and lower it as pain decreases.

Nucynta Overdose

Call 911 or the poison help line at 1-800-222-1222. An overdose can be fatal, especially to someone using the medicine without a prescription, or a child.

Symptoms of an overdose include:

• Slow heart rate
• Slow breathing
• Severe drowsiness
• Weakness
• Fainting
• Pin-point pupils

Missed Dose of Nucynta

Patients experiencing pain seldom miss a dose. However, if a dose is missed, take the medication as soon as possible, or wait until the next scheduled dose. Do not take extra medicine.

The common side effects with Nucynta are nausea, dizziness, vomiting, sleepiness, and itching.

Constipation is a common side effect of all opioid medicines. Talk to your doctor about the use of laxatives and stool softeners to prevent or treat constipation while taking Nucynta.

These are not all the possible side effects of Nucynta. For a complete list, ask your doctor or pharmacist.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Using Nucynta with other medicines can cause serious side effects. The doses of some other medicines may need to be changed. Your doctor can tell you what medicines can be safely taken with Nucynta. 

Especially tell your doctor if you take:

• Monoamine Oxidase Inhibitors (MAOIs)
• Any medicine that makes you sleepy. Nucynta can make you sleepy and affect your breathing. Taking these medicines together can be dangerous.

Nucynta can cause serious side effects including:

• Life-threatening breathing problems. Call your doctor right away or get emergency medical help if you:
  • have trouble breathing, or have slow or shallow breathing 
  • have a slow heartbeat 
  • have severe sleepiness 
  • have cold, clammy skin 
  • feel faint, dizzy, confused, or can not think, walk or talk normally 
  • have a seizure 
  • have hallucinations
• Physical Dependence. Nucynta can cause physical dependence. Talk to your doctor about slowly stopping Nucynta to avoid getting sick with withdrawal symptoms. You could become sick with uncomfortable symptoms because your body has become used to the medicine. Tell your doctor if you have any of these symptoms of withdrawal: feeling anxious, sweating, sleep problems, shivering, pain, nausea, tremors, diarrhea, upper respiratory symptoms, hallucinations, hair "standing on end." Physical dependence is not the same as drug addiction. Your doctor can tell you more about the differences between physical dependence and drug addiction. 
• Serotonin syndrome. Serotonin syndrome is a rare, life-threatening problem that could happen if you take Nucynta with Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), Monoamine Oxidase Inhibitors (MAOIs), triptans or certain other medicines. Call your doctor or get medical help right away if you have any one or more of the these symptoms: you feel agitated, have hallucinations, coma, rapid heart beat, feel overheated, loss of coordination, over active reflexes, nausea, vomiting, or diarrhea. 
• Seizures. Nucynta can cause seizures in people who are at risk for seizures or who have epilepsy. Tell your doctor right away if you have a seizure and stop taking Nucynta.
• Low blood pressure. This can make you feel dizzy if you get up too fast from sitting or lying down.

Do not drive, operate machinery, or participate in any other possibly dangerous activities until you know how you react to this medicine. Nucynta can make you sleepy. 

Do not take Nucynta if you:

• have severe asthma, trouble breathing, or other lung problems
• a bowel blockage or have narrowing of the stomach or intestines.
• taken a monoamine oxidase inhibitor (MAOI) medicine or have taken a MAOI medicine within the last 14 days.

You should not drink alcohol while using Nucynta. Alcohol increases your chance of having dangerous side effects.

Follow all directions on your prescription label. Tapentadol can slow or stop your breathing, especially when you start using this medicine or whenever your dose is changed. Never use tapentadol in larger amounts, or for longer than prescribed. Tell your doctor if the medicine seems to stop working as well in relieving your pain.

Tapentadol may be habit-forming, even at regular doses. Never share this medicine with another person, especially someone with a history of drug abuse or addiction. MISUSE OF NARCOTIC MEDICINE CAN CAUSE ADDICTION, OVERDOSE, OR DEATH, especially in a child or other person using the medicine without a prescription. Selling or giving away tapentadol is against the law.

Take this medicine with a full glass of water. Tapentadol can be taken with or without food.

Stop taking all other around-the-clock narcotic pain medications when you start taking tapentadol extended-release tablets.

Do not crush, break, or open an extended-release pill. Swallow it whole to avoid exposure to a potentially fatal dose.

Tapentadol can cause constipation. Talk to your doctor before using a laxative or stool softener to treat or prevent this side effect.

While using tapentadol, you may need frequent blood tests.

Do not stop using tapentadol suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to safely stop using tapentadol.

Never crush or break a tapentadol pill to inhale the powder or mix it into a liquid to inject the drug into your vein. This practice has resulted in death with the misuse of tapentadol and similar prescription drugs.

Store at room temperature away from moisture and heat.

Keep track of the amount of medicine used from each new bottle. Tapentadol is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.

Do not keep leftover tapentadol pills. Ask your pharmacist where to locate a drug take-back disposal program. If there is no take-back program, flush any unused pills down the toilet.

Do not drink alcohol. Dangerous side effects or death could occur.

This medication may impair your thinking or reactions. Avoid driving or operating machinery until you know how tapentadol will affect you. Dizziness or severe drowsiness can cause falls or other accidents.

Contraindications

• Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.1 9

• Substantial respiratory depression in unmonitored settings or in the absence of resuscitative equipment.1

• Acute or severe bronchial asthma or hypercapnia in unmonitored settings or in the absence of resuscitative equipment.1

• Known or suspected paralytic ileus.1

Warnings/Precautions

Opiate Agonist Precautions

May cause effects similar to those produced by other opiate agonists;1 2 3 9 12 13 observe many of the usual precautions of opiate agonist therapy.1

Respiratory Depression

The major toxicity associated with opiate agonists.1

Occurs more frequently in geriatric and debilitated patients and those with conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction when even moderate therapeutic doses may dangerously decrease pulmonary ventilation.1

Use with caution in patients having a substantially decreased respiratory reserve, hypoxia, or hypercapnia, including patients with asthma, COPD, cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis, CNS depression, or coma.1 In such patients, even therapeutic tapentadol doses may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.1 Consider alternative nonopiate agonists; use tapentadol only under careful medical supervision and at the lowest effective dosage.1

If respiratory depression occurs, follow usual guidelines for management of opiate agonist-induced respiratory depression.1

CNS Depression

Performance of activities requiring mental alertness and physical coordination (e.g., driving, operating machinery) may be impaired, especially at the beginning of therapy, during periods of dosage adjustment, or with concomitant use of alcohol or tranquilizers.1 (See Advice to Patients.)

Concurrent use of other CNS depressants may cause additive CNS depression, possibly resulting in respiratory depression, hypotension, profound sedation, coma, or death; if concomitant therapy is necessary, consider reducing the dosage of one or both drugs.1 9 (See Specific Drugs under Interactions.)

Increased Intracranial Pressure or Head Injury

The respiratory depressant effects of tapentadol (with carbon dioxide retention and secondary elevation of CSF pressure) may be markedly exaggerated in the presence of head injury or other intracranial lesions.1

Opiate agonists produce effects (e.g., pupillary changes, altered consciousness) that may obscure neurologic signs of a further increase in pressure in patients with head injuries.1

Use with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.1 Avoid use in patients susceptible to effects of increased CSF pressure (e.g., those with evidence of head injury and increased intracranial pressure).1

Dependence and Abuse

Physical and psychic dependence and tolerance may develop with repeated administration; abuse potential exists.1 13

Abuse potential similar to that of hydromorphone.1 9 Abuse of tapentadol poses a risk of overdose and death; concurrent abuse of alcohol and other substances increases risk of toxicity.1

Consider abuse potential when prescribing or dispensing tapentadol in situations where increased risk of misuse and abuse may be present.1 Carefully monitor all patients receiving opiate agonists for signs of abuse and addiction; however, concerns about abuse and addiction should not prevent the proper management of pain.1

Abrupt cessation of therapy may result in withdrawal symptoms (e.g., anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and, rarely, hallucinations).1 6 7 To reduce symptoms, taper dosage when discontinuing the drug.1

Seizures

Seizures reported in <1% of tapentadol-treated patients in clinical studies.1

Not systematically evaluated in patients with seizure disorders; such patients were excluded from clinical studies.1 Use with caution in patients with a history of seizure disorder and those at increased risk for seizures.1 (See Advice to Patients.)

Serotonin Syndrome

Potentially life-threatening serotonin syndrome with SNRIs, including tapentadol, particularly with concurrent use of other serotonergic drugs or drugs that impair serotonin metabolism (e.g., MAO inhibitors).1 4 5 400 (See Actions and see Interactions.)

Serotonin syndrome may occur with usual dosages of tapentadol.1 Manifestations may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1 4 5 400

Adrenal Insufficiency

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists.400 Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.400

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function.400 If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.400

Pancreatic and Biliary Disease

May cause spasm of the sphincter of Oddi.1 Use with caution in patients with biliary tract disease, including acute pancreatitis.1

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy;400 401 402 403 404 causality not established.400 Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility.400 Perform appropriate laboratory testing in patients with manifestations of hypogonadism.400

Specific Populations

Pregnancy

Category C.1

Effect on labor and delivery unknown.1 Not recommended for use during and immediately prior to labor and delivery.1 Neonates born to women who have received tapentadol should be monitored for respiratory depression and withdrawal symptoms; an opiate antagonist (e.g., naloxone) should be available to reverse opiate-induced respiratory depression in the neonate.1

Lactation

May distribute into milk; do not use in nursing women.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 Not recommended for use in this population.1

Geriatric Use

No overall differences in efficacy of tapentadol in those ≥65 years of age compared with younger adults.1 Incidence of constipation was higher in patients ≥65 years of age compared with those <65 years of age (12 versus 7%).1 (See Special Populations under Pharmacokinetics: Absorption.)

Because of possible renal or hepatic impairment in geriatric patients, consider initiating therapy at the lower end of the recommended dosage range.1

Hepatic Impairment

Higher serum tapentadol concentrations reported in patients with hepatic impairment compared with individuals without impairment.1 (See Special Populations under Pharmacokinetics: Absorption.) Use with caution in moderate hepatic impairment.1 Not studied and, therefore, not recommended in severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Safety and efficacy not established in severe renal impairment; use in this population not recommended.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea,1 2 3 7 9 dizziness,1 2 3 7 9 vomiting,1 2 3 7 9 somnolence,1 2 3 7 9 constipation,1 2 3 7 pruritus,1 2 3 7 dry mouth,1 7 hyperHIDrosis,1 2 fatigue1 3 7 . In several clinical studies, adverse GI effects (nausea, vomiting, constipation) reported more commonly with oxycodone than with tapentadol.2 3 6 7

Metabolized primarily by glucuronidation.1 6 8

Metabolized to a lesser extent by CYP isoenzymes 2C9, 2C19, and 2D6.1 8

Does not induce CYP isoenzymes 1A2, 2D6, or 3A4 and does not inhibit CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2E1, or 3A4 in vitro.1 6 8 Inhibits CYP2D6 to a limited extent in vitro.8

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically relevant CYP-mediated interactions are unlikely.1 6 8

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic agents.1 4 5 19 400 May occur at usual dosages.19 400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400 (See Advice to Patients and see Actions.)

If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.19 400

If serotonin syndrome is suspected, discontinue tapentadol, other opiate therapy, and/or any concurrently administered serotonergic agents.400

Protein-bound Drugs

Pharmacokinetic interaction unlikely.1 6 8

Specific Drugs

Drug	Interaction	Comments
Acetaminophen	Acetaminophen did not affect pharmacokinetics of tapentadol1 14
Alcohol	Additive CNS effects causing CNS depression, cognitive/physical impairment, respiratory depression, hypotension, profound sedation, coma, death1 Increased risk of overdosage and death with concurrent abuse1	Avoid concomitant use1
Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), SNRIs (e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine), tricyclic antidepressants (TCAs), mirtazapine, nefazodone, trazodone, vilazodone	Risk of serotonin syndrome19 400	Use with caution;19 if concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases19 400 If serotonin syndrome suspected, discontinue tapentadol, the antidepressant, and/or any concurrently administered opiates or serotonergic agents400
Antiemetics, 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron)	Risk of serotonin syndrome400	Use with caution;19 if concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases19 400 If serotonin syndrome suspected, discontinue tapentadol, the 5-HT3 receptor antagonist, and/or any concurrently administered opiates or serotonergic agents400
Aspirin	Aspirin did not affect pharmacokinetics of tapentadol1 14
Buspirone	Risk of serotonin syndrome400	Use with caution;19 if concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases19 400 If serotonin syndrome suspected, discontinue tapentadol, buspirone, and/or any concurrently administered opiates or serotonergic agents400
CNS depressants (e.g., other opiate agonists, general anesthetics, antiemetics, tranquilizers, sedatives and hypnotics, phenothiazines)	Additive CNS depression with possible respiratory depression, hypotension, profound sedation, coma, or death1 9	If concomitant therapy is necessary, consider reducing dosage of one or both agents1
Cyclobenzaprine	Risk of serotonin syndrome400	Use with caution;19 if concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases19 400 If serotonin syndrome suspected, discontinue tapentadol, cyclobenzaprine, and/or any concurrently administered opiates or serotonergic agents400
Dextromethorphan	Risk of serotonin syndrome400	Use with caution;19 if concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases19 400 If serotonin syndrome suspected, discontinue tapentadol, dextromethorphan, and/or any concurrently administered opiates or serotonergic agents400
5-HT1 receptor agonists (triptans; e.g., almotriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan)	Risk of serotonin syndrome19 400	Use with caution;19 if concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue tapentadol, the triptan, and/or any concurrently administered opiates or serotonergic agents400
Lithium	Risk of serotonin syndrome400	Use with caution;19 if concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases19 400 If serotonin syndrome suspected, discontinue tapentadol, lithium, and/or any concurrently administered opiates or serotonergic agents400
MAO inhibitors (e.g., isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, tranylcypromine)	Risk of serotonin syndrome19 400 Potential adverse cardiovascular effects secondary to increased norepinephrine levels1 9	Tapentadol contraindicated in patients currently receiving or having recently (within 2 weeks) received MAO inhibitors1 9
Metoclopramide	Metoclopramide did not affect pharmacokinetics of tapentadol1
Naproxen	Naproxen increased tapentadol AUC by 17%; not considered clinically relevant1 14	Dosage adjustments not necessary1
Omeprazole	Omeprazole did not affect pharmacokinetics of tapentadol1
Probenecid	Probenecid increased tapentadol AUC by 57%; not considered clinically relevant1	Dosage adjustments not necessary1
St. John’s wort (Hypericum perforatum)	Risk of serotonin syndrome400	Use with caution;19 if concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases19 400 If serotonin syndrome suspected, discontinue tapentadol, St. John's wort, and/or any concurrently administered opiates or serotonergic agents400
Tryptophan	Risk of serotonin syndrome400	Use with caution;19 if concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases19 400 If serotonin syndrome suspected, discontinue tapentadol, tryptophan, and/or any concurrently administered opiates or serotonergic agents400

Nucynta (tapentadol) tablets are a mu-opioid receptor agonist, available in immediate-release film-coated tablets for oral administration, containing 58.24, 87.36 and 116.48 mg of tapentadol hydrochloride in each tablet strength, equivalent to 50, 75, and 100 mg of tapentadol free-base, respectively. The chemical name is 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride, and it has the following chemical structure:

The molecular weight of tapentadol HCl is 257.80, and the molecular formula is C14H23NO·HCl. The n-octanol:water partition coefficient log P value is 2.87. The pKa values are 9.34 and 10.45.

The inactive ingredients in Nucynta tablets include: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone. The film coatings for all tablet strengths contain polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and the colorant FD&C Yellow #6 aluminum lake; the film coatings for the 50 mg and 75 mg tablets also contain the additional colorant D&C Yellow #10 aluminum lake.

Mechanism of Action

Tapentadol is a centrally-acting synthetic analgesic. The exact mechanism of action is unknown. Although the clinical relevance is unclear, preclinical studies have shown that tapentadol is a mu-opioid receptor (MOR) agonist and a norepinephrine reuptake inhibitor (NRI). Analgesia in animal models is derived from both of these properties.

Pharmacodynamics

Effects on the Central Nervous System

Tapentadol produces respiratory depression by direct action on the 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.

Tapentadol 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.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Tapentadol produces respiratory depression by direct action on the 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.

Tapentadol 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.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Tapentadol 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

There was no effect of therapeutic and supratherapeutic doses of tapentadol on the QT interval. In a randomized, double-blind, placebo- and positive-controlled crossover study, healthy subjects were administered five consecutive doses of Nucynta 100 mg every 6 hours, Nucynta 150 mg every 6 hours, placebo and a single oral dose of moxifloxacin. Similarly, Nucynta had no relevant effect on other ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave morphology).

Tapentadol 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 System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

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 tapentadol 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)].

Concentration-Adverse Experience Relationships

There is a relationship between increasing tapentadol plasma concentration and increasing frequency of dose-related 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)].

Pharmacokinetics

Absorption

The mean absolute bioavailability after single-dose administration (fasting) of Nucynta is approximately 32% due to extensive first-pass metabolism. Maximum serum concentrations of tapentadol are typically observed at around 1.25 hours after dosing.

Dose-proportional increases in the Cmax and AUC values of tapentadol have been observed over the 50 to 150 mg dose range.

A multiple (every 6 hour) dose study with doses ranging from 75 to 175 mg tapentadol showed a mean accumulation factor of 1.6 for the parent drug and 1.8 for the major metabolite tapentadol-O-glucuronide, which are primarily determined by the dosing interval and apparent half-life of tapentadol and its metabolite.

Food Effect

The AUC and Cmax increased by 25% and 16%, respectively, when Nucynta was administered after a high-fat, high-calorie breakfast. Nucynta may be given with or without food.

Distribution

Tapentadol is widely distributed throughout the body. Following intravenous administration, the volume of distribution (Vz) for tapentadol is 540 +/- 98 L. The plasma protein binding is low and amounts to approximately 20%.

Elimination

Metabolism

In humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized via Phase 2 pathways, and only a small amount is metabolized by Phase 1 oxidative pathways. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% (55% O-glucuronide and 15% sulfate of tapentadol) of the dose is excreted in urine in the conjugated form. A total of 3% of drug was excreted in urine as unchanged drug. Tapentadol is additionally metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolized by conjugation. Therefore, drug metabolism mediated by cytochrome P450 system is of less importance than phase 2 conjugation.

None of the metabolites contribute to the analgesic activity.

Excretion

Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. The terminal half-life is on average 4 hours after oral administration. The total clearance is 1530 +/- 177 mL/min.

Special Populations

Age:Geriatric Patients

The mean exposure (AUC) to tapentadol was similar in elderly subjects compared to young adults, with a 16% lower mean Cmax observed in the elderly subject group compared to young adult subjects.

Hepatic Impairment

Administration of Nucynta resulted in higher exposures and serum levels to tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The ratio of tapentadol pharmacokinetic parameters for the mild hepatic impairment group (Child-Pugh Score 5 to 6) and moderate hepatic impairment group (Child-Pugh Score 7 to 9) in comparison to the normal hepatic function group were 1.7 and 4.2, respectively, for AUC; 1.4 and 2.5, respectively, for Cmax; and 1.2 and 1.4, respectively, for t½. The rate of formation of tapentadol-O-glucuronide was lower in subjects with increased liver impairment.

Renal Impairment

AUC and Cmax of tapentadol were comparable in subjects with varying degrees of renal function (from normal to severely impaired). In contrast, increasing exposure (AUC) to tapentadol O glucuronide was observed with increasing degree of renal impairment. In subjects with mild (CLCR = 50 to <80 mL/min), moderate (CLCR = 30 to <50 mL/min), and severe (CLCR = <30 mL/min) renal impairment, the AUC of tapentadol-O-glucuronide was 1.5 , 2.5-, and 5.5-fold higher compared with normal renal function, respectively.

Drug Interaction Studies

Pharmacokinetic Drug Interactions

Tapentadol is mainly metabolized by Phase 2 glucuronidation, a high capacity/low affinity system; therefore, clinically relevant interactions caused by Phase 2 metabolism are unlikely to occur. Naproxen and probenecid increased the AUC of tapentadol by 17% and 57%, respectively. These changes are not considered clinically relevant and no change in dose is required.

No changes in the pharmacokinetic parameters of tapentadol were observed when acetaminophen and acetylsalicylic acid were given concomitantly.

In vitro studies did not reveal any potential of tapentadol to either inhibit or induce cytochrome P450 enzymes. Furthermore, a minor amount of Nucynta is metabolized via the oxidative pathway. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur.

The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal motility were increased by omeprazole and metoclopramide, respectively.

Plasma protein binding of tapentadol is low (approximately 20%). Therefore, the likelihood of pharmacokinetic drug-drug interactions by displacement from the protein binding site is low.

Nucynta Tablets are available in the following strengths and packages. All tablets are round and biconvex-shaped.

50 mg tablets are yellow and debossed with “O-M” on one side and “50” on the other side, and are available in bottles of 100 (NDC 69865-210-02) and hospital unit dose blister packs of 10 (NDC 69865-210-01).

75 mg tablets are yellow-orange and debossed with “O-M” on one side and “75” on the other side, and are available in bottles of 100 (NDC 69865-220-02) and hospital unit dose blister packs of 10 (NDC 69865-220-01).

100 mg tablets are orange and debossed with “O-M” on one side and “100” on the other side, and are available in bottles of 100 (NDC 69865-230-02) and hospital unit dose blister packs of 10 (NDC 69865-230-01).

Storage and Handling

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

Keep Nucynta tablets in a secure place out of reach of children.

Nucynta tablets that are no longer needed should be destroyed by flushing down the toilet.

You should not use Nucynta if you have severe breathing problems, or a bowel obstruction called paralytic ileus.

Do not use Nucynta if you have used a MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, or tranylcypromine.

Tapentadol can slow or stop your breathing, especially when you start using this medicine or whenever your dose is changed. Never take this medicine in larger amounts, or for longer than prescribed. Do not crush, break, or open an extended-release tablet. Swallow it whole to avoid exposure to a potentially fatal dose.

Tapentadol may be habit-forming, even at regular doses. Take this medicine exactly as prescribed by your doctor. Never share the medicine with another person. MISUSE OF NARCOTIC PAIN MEDICATION CAN CAUSE ADDICTION, OVERDOSE, OR DEATH, especially in a child or other person using the medicine without a prescription.

Tell your doctor if you are pregnant. Nucynta may cause life-threatening withdrawal symptoms in a newborn if the mother has taken this medicine during pregnancy.

Fatal side effects can occur if you use this medicine with alcohol, or with other drugs that cause drowsiness or slow your breathing.

You should not use Nucynta if you are allergic to tapentadol, or if you have:

• severe asthma or breathing problems; or

• a blockage in your digestive tract (stomach or intestines).

Do not use Nucynta if you have taken a MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, and tranylcypromine.

Tapentadol may be habit forming. Never share Nucynta with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it. Selling or giving away Nucynta to any other person is against the law

Some medicines can interact with tapentadol and cause a serious condition called serotonin syndrome. Be sure your doctor knows if you also take medicine for depression, mental illness, Parkinson's disease, migraine headaches, serious infections, or prevention of nausea and vomiting. Ask your doctor before making any changes in how or when you take your medications.

To make sure this medicine is safe for you, tell your doctor if you have ever had:

• any type of breathing problem or lung disease;

• a head injury, brain tumor, or seizures;

• drug or alcohol addiction, or mental illness;

• urination problems;

• liver or kidney disease;

• problems with your gallbladder, pancreas, or thyroid; or

• if you use a sedative like Valium (diazepam, alprazolam, lorazepam, Ativan, Klonopin, Restoril, Tranxene, Versed, Xanax, and others).

If you use tapentadol while you are pregnant, your baby could become dependent on the drug. This can cause life-threatening withdrawal symptoms in the baby after it is born. Babies born dependent on habit-forming medicine may need medical treatment for several weeks. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether tapentadol passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Do not give Nucynta to a child.

Common side effects of Nucynta include: drowsiness, nausea, and vomiting. Other side effects include: constipation, pruritus, and xerostomia. See below for a comprehensive list of adverse effects.