Tramadol Hydrochloride (Page 3 of 8)

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Tramadol Hydrochloride Extended-Release capsules were administered to a total of 1987 patients in clinical trials. These included four double-blind and one long-term, open-label study in patients with osteoarthritis of the hip and knee. A total of 812 patients were 65 years or older. Adverse reactions with doses from 100 mg to 300 mg in the four pooled, randomized, double-blind, placebo- controlled studies in patients with chronic non-malignant pain are presented in the following table (see Table1).

Table 1: Incidence (%) of patients with adverse reaction rates ≥ 5% from four double-blind, placebo controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1917).
TRAMADOL HYDROCHLORIDE EXTENDED-RELEASE PLACEBO
(N=429)n (%) (N=434)n (%) (N=1054)n (%) (N=646)n (%)
Headache 99 (23.1) 96 (22.1) 200 (19.0) 128 (19.8)
Nausea 69 (16.1) 93 (21.4) 265 (25.1) 37 (5.7)
Somnolence 50 (11.7) 60 (13.8) 170 (16.1) 26 (4.0)
Dizziness 41 (9.6) 54 (12.4) 143 (13.6) 31 (4.8)
Constipation 40 (9.3) 59 (13.6) 225 (21.3) 27 (4.2)
Vomiting 28 (6.5) 45 (10.4) 98 (9.3) 12 (1.9)
Arthralgia 23 (5.4) 20 (4.6) 53 (5.0) 33 (5.1)
Dry Mouth 20 (4.7) 36 (8.3) 138 (13.1) 22 (3.4)
Sweating 18 (4.2) 23 (5.3) 71 (6.7) 4 (0.6)
Asthenia 15 (3.5) 26 (6.0) 91 (8.6) 17 (2.6)
Pruritus 13 (3.0) 25 (5.8) 77 (7.3) 12 (1.9)
Anorexia 9 (2.1) 23 (5.3) 60 (5.7) 1 (0.2)
Insomnia 9 (2.1) 9 (2.1) 53 (5.0) 11 (1.7)

The following adverse reactions were reported from all chronic pain studies

(N=1917). The lists below include adverse reactions not otherwise noted in Table 1.

Adverse reactions with incidence rates of 1.0% to <5.0%

Cardiac disorders: hypertension

Gastrointestinal disorders: dyspepsia, flatulence

General disorders: abdominal pain, accidental injury, chills, fever, flu syndrome, neck pain, pelvic pain

Investigations: hyperglycemia, urine abnormality

Metabolism and nutrition disorders: peripheral edema, weight loss Musculoskeletal, connective tissue and bone disorders: myalgia Nervous system disorders: paresthesia, tremor, withdrawal syndrome

Psychiatric disorders: agitation, anxiety, apathy, confusion, depersonalization, depression, euphoria, nervousness

Respiratory, thoracic and mediastinal disorders: bronchitis, pharyngitis, rhinitis, sinusitis

Skin and subcutaneous tissue disorders: rash

Urogenital disorders: prostatic disorder, urinary tract infection

Vascular disorders: vasodilatation

Adverse reactions with incidence rates of 0.5% to <1.0% at any dose and serious adverse reactions reported in at least two patients.

Cardiac disorders: EKG abnormal, hypotension, tachycardia

Gastrointestinal disorders: gastroenteritis General disorders: neck rigidity, viral infection Hematologic/Lymphatic disorders: anemia, ecchymoses

Metabolism and nutrition disorders: blood urea nitrogen increased, GGT increased, gout, SGPT increased

Musculoskeletal disorders: arthritis, arthrosis, joint disorder, leg cramps

Nervous system disorders: emotional lability, hyperkinesia, hypertonia, thinking abnormal, twitching, vertigo

Respiratory disorders: pneumonia

Skin and subcutaneous tissue disorders: hair disorder, skin disorder, urticaria

Special Senses: eye disorder, lacrimation disorder

Urogenital disorders: cystitis, dysuria, sexual function abnormality, urinary retention

7 DRUG INTERACTIONS

7.1 Drugs Affecting Seizure Threshold

Concomitant use of tramadol increases the seizure risk in patients taking SSRI/SNRI antidepressants or anorectics, TCA antidepressants and other tricyclic compounds, other opioids, MAOIs, neuroleptics or other drugs that lower the seizure threshold [see WARNINGS AND PRECAUTIONS ( 5.1)].

7.2 CYP2D6 and/or CYP3A4 inhibitors

Tramadol is metabolized by CYP2D6 to form the active metabolite, O-desmethyl tramadol (M1). In vitro drug interaction studies in human liver microsomes indicate that concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, and amitriptyline could result in some inhibition of the metabolism of tramadol.

Tramadol is also metabolized by CYP3A4 [see CLINICAL PHARMACOLOGY ( 12.3)]. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin with Tramadol Hydrochloride Extended-Release may affect the metabolism of tramadol leading to altered tramadol exposure.

Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors, such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome [see CLINICAL PHARMACOLOGY ( 12.3)].

7. 3 Serotonergic Drugs

There have been post-marketing reports of serotonin syndrome with use of tramadol and SSRIs/SNRIs or MAOIs and α2-adrenergic blockers. Caution is advised when Tramadol Hydrochloride Extended-Release is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as SSRIs, MAOIs, triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, or St. John’s Wort. If concomitant treatment of Tramadol Hydrochloride Extended- Release with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see WARNINGS AND PRECAUTIONS ( 5.3)].

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