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).
|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
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)].
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)].
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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