APO-TAPENTADOL

1 Adverse Reaction Overview Adverse effects of APO-TAPENTADOL (tapentadol) tablets are similar to those of other opioid analgesics, and represent an extension of pharmacological effects of the drug class. The major hazards of opioids include respiratory and central nervous system depression and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.

Tapentadol was studied in 10 multiple-dose, active- or placebo-controlled Phase 2/3 studies. A total of 2694 subjects with moderate to severe pain were treated with tapentadol every four to six hours. The population was 18 to 78 years old (median age 50 years).

1%) had no prior opioid use. 6%) >600 mg to 700 mg. Based on data from the placebo- and/or active-controlled studies that administered multiple doses of tapentadol, approximately 70 % of tapentadol-treated patients experienced adverse events.

These were predominantly of mild and moderate severity. The most common adverse events (reported by ≥10% in any tapentadol dose group) were: nausea, dizziness, vomiting, somnolence and headache. NAPO-TAPENTADOL (tapentadol) Page 24 of 58 No deaths were reported during the treatment period or within 30 days after treatment discontinuation in tapentadol-treated groups.

7 % of tapentadol-treated patients experienced a serious adverse event during the Phase 2/3 multi-dose studies vs. 4% on placebo. The reported serious adverse events were consistent with the safety profiles of tapentadol and the studied patient populations.

4% (2/483) discontinued during open-label treatment. 0% vs. 3% vs. 3% vs. 2% vs. 9% vs. 5% vs. 5% vs. 1%), respectively. 2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. Double-Blind Studies Treatment emergent adverse events (TEAEs) reported in ≥1% of tapentadol-treated patients with moderate to severe pain from ten double-blind, active and/or placebo-controlled studies are summarized in Table 3, if they occurred at an equivalent or higher rate with tapentadol than with placebo.

These adverse events were included regardless of any causal relationship to tapentadol. 9 Sedation: Sedation is a common side effect of opioid analgesics, especially in opioid naïve individuals. Sedation may also occur partly because patients often recuperate from prolonged fatigue after the relief of persistent pain.

Most patients develop tolerance to the sedative effects of opioids within three to five days and, if the sedation is not severe, will not require any treatment except reassurance. If excessive sedation persists beyond a few days, the dose of the opioid should be reduced and alternate causes investigated.

Please see 3. SERIOUS WARNINGS AND PRECAUTIONS BOX. NAPO-TAPENTADOL (tapentadol) Page 12 of 58 General Patients should be instructed not to give APO-TAPENTADOL (tapentadol) tablets to anyone other than the patient for whom it was prescribed, as such inappropriate use may have severe medical consequences, including death.

APO-TAPENTADOL should be stored securely to avoid theft or misuse. APO-TAPENTADOL should only be prescribed by persons knowledgeable in the administration of potent opioids, in the management of patients receiving potent opioids for the treatment of pain, and in the detection and management of respiratory depression, including the use of opioid antagonists.

Patients should be cautioned not to consume alcohol while taking APO-TAPENTADOL as it may increase the chance of experiencing serious adverse events, including death. Hyperalgesia that will not respond to a further dose increase of opioids can occur at particularly high doses.

A tapentadol dose reduction or change in opioid may be required. Abuse and Misuse Like all opioids, tapentadol is a potential drug of abuse and misuse, which can lead to overdose and death. Therefore, APO-TAPENTADOL should be prescribed and handled with caution.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids, such as tapentadol, should be used with particular care in patients with a history of alcohol and illicit/prescription drug abuse.

However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain. APO-TAPENTADOL is intended for oral use only. The tablets should be swallowed whole with sufficient liquid and not chewed or crushed.

Abuse of oral dosage forms can be expected to result in serious adverse events, including death. Carcinogenesis and Mutagenesis See 16. NON-CLINICAL TOXICOLOGY section. Cardiovascular Hypotension NAPO-TAPENTADOL (tapentadol) Page 13 of 58 Tapentadol administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquilizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics.