Nucynta (Page 3 of 7)

*A treatment-emergent adverse event refers to any untoward medical event associated with the use of the drug in humans, whether or not considered drug-related.

6.2 Other Adverse Reactions Observed During the Premarketing Evaluation of NUCYNTA®

The following adverse drug reactions occurred in <1% of NUCYNTA® -treated patients in the pooled safety data from nine Phase 2/3 studies that administered multiple doses (seven were placebo- and/or active-controlled, one noncontrolled, and one Phase 3 active-controlled safety study):

Cardiac disorders: heart rate increased, heart rate decreased

Eye disorders: visual disturbance

Gastrointestinal disorders: abdominal discomfort, impaired gastric emptying

General disorders and administration site conditions: irritability, edema, drug withdrawal syndrome, feeling drunk

Immune system disorders: hypersensitivity

Investigations: gamma-glutamyltransferase increased, alanine aminotransferase increased, aspartate aminotransferase increased

Musculoskeletal and connective tissue disorders: involuntary muscle contractions, sensation of heaviness

Nervous system disorders: hypoesthesia, paresthesia, disturbance in attention, sedation, dysarthria, depressed level of consciousness, memory impairment, ataxia, presyncope, syncope, coordination abnormal, seizure

Psychiatric disorders: euphoric mood, disorientation, restlessness, agitation, nervousness, thinking abnormal

Renal and urinary disorders: urinary hesitation, pollakiuria

Respiratory, thoracic and mediastinal disorders: oxygen saturation decreased, cough, dyspnea, respiratory depression

Skin and subcutaneous tissue disorders: urticaria

Vascular disorders: blood pressure decreased

In the pooled safety data, the overall incidence of adverse reactions increased with increased dose of NUCYNTA® , as did the percentage of patients with adverse reactions of nausea, dizziness, vomiting, somnolence, and pruritus.

6.3 Post-marketing Experience

The following additional adverse reactions have been identified during post-approval use of NUCYNTA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably.

Gastrointestinal disorders: diarrhea

Immune system disorders: angioedema

Nervous system disorders: headache

Psychiatric disorders: hallucination

7 DRUG INTERACTIONS

NUCYNTA® is mainly metabolized by glucuronidation. The following substances have been included in a set of interaction studies without any clinically significant finding: acetaminophen, acetylsalicylic acid, naproxen and probenecid [see Clinical Pharmacology (12.3)].

The pharmacokinetics of tapentadol were not affected when gastric pH or gastrointestinal motility were increased by omeprazole and metoclopramide, respectively [see Clinical Pharmacology (12.3)].

7.1 Drugs Metabolized by Cytochrome P450 Enzymes

In vitro investigations indicate that NUCYNTA® does not inhibit or induce P450 enzymes. Thus, clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur [see Clinical Pharmacology (12.3)].

7.2 Drugs That Inhibit or Induce Cytochrome P450 Enzymes

The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. To a lesser extent, tapentadol is additionally metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 to hydroxy tapentadol (2%) by CYP2D6, which are further metabolized by conjugation. Since only a minor amount of NUCYNTA® is metabolized via the oxidative pathway clinically relevant interactions mediated by the cytochrome P450 system are unlikely to occur [see Clinical Pharmacology (12.3)].

7.3 Centrally-Acting Drugs and Alcohol

Patients receiving other opioid agonist analgesics, general anesthetics, phenothiazines, antiemetics, other tranquilizers, sedatives, hypnotics, or other CNS depressants (including alcohol) concomitantly with NUCYNTA® may exhibit an additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with NUCYNTA®. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered [see Warnings and Precautions (5.2) and (5.6)].

7.4 Monoamine Oxidase Inhibitors

NUCYNTA® is contraindicated in patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels which may result in adverse cardiovascular events [see Contraindications (4.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C.

Tapentadol HCl was evaluated for teratogenic effects in pregnant rats and rabbits following intravenous and subcutaneous exposure during the period of embryofetal organogenesis. When tapentadol was administered twice daily by the subcutaneous route in rats at dose levels of 10, 20, or 40 mg/kg/day [producing up to 1 times the plasma exposure at the maximum recommended human dose (MRHD) of 700 mg/day based on an area under the time-curve (AUC) comparison], no teratogenic effects were observed. Evidence of embryofetal toxicity included transient delays in skeletal maturation (i.e. reduced ossification) at the 40 mg/kg/day dose which was associated with significant maternal toxicity. Administration of tapentadol HCl in rabbits at doses of 4, 10, or 24 mg/kg/day by subcutaneous injection [producing 0.2, 0.6, and 1.85 times the plasma exposure at the MRHD based on an AUC comparison] revealed embryofetal toxicity at doses ≥ 10 mg/kg/day. Findings included reduced fetal viability, skeletal delays and other variations. In addition, there were multiple malformations including gastroschisis/thoracogastroschisis, amelia/phocomelia, and cleft palate at doses ≥ 10 mg/kg/day and above, and ablepharia, encephalopathy, and spina bifida at the high dose of 24 mg/kg/day. Embryofetal toxicity, including malformations, may be secondary to the significant maternal toxicity observed in the study.

In a study of pre- and postnatal development in rats, oral administration of tapentadol at doses of 20, 50, 150, or 300 mg/kg/day to pregnant and lactating rats during the late gestation and early postnatal period [resulting in up to 1.7 times the plasma exposure at the MRHD on an AUC basis] did not influence physical or reflex development, the outcome of neurobehavioral tests or reproductive parameters. Treatment-related developmental delay was observed, including incomplete ossification, and significant reductions in pup body weights and body weight gains at doses associated with maternal toxicity (150 mg/kg/day and above). At maternal tapentadol doses ≥ 150 mg/kg/day, a dose-related increase in pup mortality was observed through postnatal Day 4.

There are no adequate and well controlled studies of NUCYNTA® in pregnant women. NUCYNTA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.2 Labor and Delivery

The effect of tapentadol on labor and delivery in humans is unknown. NUCYNTA® is not recommended for use in women during and immediately prior to labor and delivery. Due to the mu-opioid receptor agonist activity of NUCYNTA® , neonates whose mothers have been taking NUCYNTA® should be monitored for respiratory depression. A specific opioid antagonist, such as naloxone, should be available for reversal of opioid induced respiratory depression in the neonate.

8.3 Nursing Mothers

There is insufficient/limited information on the excretion of tapentadol in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the suckling child cannot be excluded. NUCYNTA® should not be used during breast-feeding.

8.4 Pediatric Use

The safety and effectiveness of NUCYNTA® in pediatric patients less than 18 years of age have not been established. NUCYNTA® is not recommended in this population.

8.5 Geriatric Use

Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA® , 19% were 65 and over, while 5% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The rate of constipation was higher in subjects greater than or equal to 65 years than those less than 65 years (12% vs. 7%).

In general, recommended dosing for elderly patients with normal renal and hepatic function is the same as for younger adult patients with normal renal and hepatic function. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients with the lower range of recommended doses [see Clinical Pharmacology (12.3)].

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