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Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that have been considered to be reasonably causally associated with the use of tramadol hydrochloride/paracetamol based on a comprehensive assessment of the available adverse event information. A causal relationship with tramadol hydrochloride/paracetamol cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical trial data: The safety of ULTRACET was evaluated in 3,175 patients, 16 to 90 years of age, who participated in a total of 21 clinical trials of which 20 were double-blind, controlled (i.e., placebo or active, or both) and 1 was open-label with no control group. These 20 double-blind, controlled trials comprised 11 multiple-dose and 9 single-dose. The duration of treatment ranged from one dose to up to 23 months. All patients received at least one dose of ULTRACET and provided safety data.
Placebo-controlled double-blind data - adverse reactions reported at ≥1% incidence: Sixteen of the 21 clinical trials were double-blind, placebo-controlled trials with a duration of treatment ranging from one dose to 91 days. Adverse reactions determined from all 21 clinical trials and reported in the 16 double-blind placebo-controlled clinical trials for ≥1% of ULTRACET-treated patients (N=1,669) and with an incidence greater than the rate in placebo-treated patients (N=1,531), are shown in Table 2. The most commonly occurring adverse reactions from the 16 placebo-controlled trials (>5% of patients) were nausea, dizziness, vomiting, headache, somnolence, and constipation. (See Table 2.)
Click on icon to see table/diagram/imagePlacebo-controlled, comparator-controlled, and open-label clinical trial data - adverse reactions reported by ≥1% of ULTRACET-treated patients: Adverse reactions not reported in Table 2 that were reported by ≥1% of ULTRACET-treated patients (N=3,175) in the 21 clinical trials of ULTRACET are shown in Table 3. All patients received at least one dose of ULTRACET and provided safety data. (See Table 3.)
Click on icon to see table/diagram/imagePlacebo-controlled, comparator-controlled, and open-label study data - adverse reactions reported at <1% incidence of ULTRACET-treated patients: Adverse reactions not reported previously, which were reported by <1% of ULTRACET-treated patients (N=3,175) in the previously mentioned clinical trial dataset are shown in Table 4. (See Table 4.)
Click on icon to see table/diagram/imageAdverse reactions reported with tramadol only: Table 5 lists the adverse reactions relating to the active moiety, tramadol, that were identified in clinical trials and/or postmarketing experience with tramadol but were not reported by any ULTRACET-treated patients in the ULTRACET clinical trials. (See Table 5.)
Click on icon to see table/diagram/imagePostmarketing data: In addition to the adverse reactions reported during clinical trials and listed previously, the following adverse reactions have been reported during postmarketing experience (Table 6). The frequencies are provided according to the following convention: Very common ≥1/10; Common ≥1/100 and <1/10; Uncommon ≥1/1000 and <1/100; Rare ≥1/10000 and <1/1000; Very rare <1/10000; Not known (cannot be estimated from the available data).
In Table 6, adverse reactions are presented by frequency category based on spontaneous reporting rates. (See Table 6.)
Click on icon to see table/diagram/imageSerotonin syndrome: (see Precautions).
Adrenal insufficiency: (see Precautions).
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids. 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 casual 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. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.
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.
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