Tramadol Hydrochloride (Page 10 of 13)

11 DESCRIPTION

Tramadol hydrochloride tablets, USP, for oral use, are an opioid agonist. The chemical name for tramadol hydrochloride is (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride.

The structural formula is:

Structure

The molecular weight of tramadol hydrochloride is 299.8. Tramadol hydrochloride, USP is a white, bitter, crystalline and odorless powder. It is readily soluble in water and ethanol and has a pKa of 9.41. The n-octanol/water log partition coefficient (logP) is 1.35 at pH 7. Tramadol hydrochloride tablets, USP contain 50 mg of tramadol hydrochloride, USP, and are white in color. Inactive ingredients in the tablet are pregelatinized starch, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, titanium dioxide, hypromellose and polysorbate 80.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tramadol hydrochloride tablets contain tramadol, an opioid agonist and inhibitor of norepinephrine and serotonin re- uptake. Although the mode of action is not completely understood, the analgesic effect of tramadol is believed to be due to both binding to μ-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin.

Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O -demethylated metabolite M1 to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opioid antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound [see Clinical Pharmacology (12.2)].

Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.

12.2 Pharmacodynamics

Effects on the Central Nervous System

Tramadol produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Tramadol administration may produce a constellation of symptoms including nausea and vomiting, dizziness, and somnolence.

Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid- induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Tramadol produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of peripheral vasodilation may include pruritus, flushing, red eyes, sweating and/or orthostatic hypotension.

The effect of oral tramadol on the QTcF interval was evaluated in a double-blind, randomized, four-way crossover, placebo-and positive- (moxifloxacin) controlled study in 68 adult male and female healthy subjects. At a 600 mg/day dose (1.5-fold the maximum immediate-release daily dose), the study demonstrated no significant effect on the QTcF interval.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Warnings and Precautions (5.11); Adverse Reactions (6)].

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 causal 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 [see Adverse Reactions (6)].

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent opioid agonists. The minimum effective analgesic concentration of tramadol for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2)].

Concentration–Adverse Reaction Relationships

There is a relationship between increasing tramadol plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2)].

12.3 Pharmacokinetics

The analgesic activity of tramadol hydrochloride tablets is due to both parent drug and the M1 metabolite [see Clinical Pharmacology (12.1, 12.2)]. Tramadol is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

Absorption

The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of each enantiomer present.

Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with four times per day dosing. There is no evidence of self-induction (see Figure 1 and Table 3 below).

Figure 1: Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl given four times per day.
Figure 1
(click image for full-size original)

Table 3: Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite

Table 3: Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite
Population/ Dosage Regimena Parent Drug/ Metabolite Peak Conc. (ng/mL) Time to Peak (hrs) Clearance/Fb (mL/min/kg) t 1/2 (hrs)

Healthy Adults,100 mg q.i.d., MD p.o.

Tramadol

M1

592 (30)

110 (29)

2.3 (61)

2.4 (46)

5.90 (25)c

6.7 (15)

7.0 (14)

Healthy Adults,100 mg SD p.o.

Tramadol

M1

308 (25)

55.0 (36)

1.6 (63)

3.0 (51)

8.50 (31) c

5.6 (20)

6.7 (16)

Geriatric, (>75 yrs)50 mg SD p.o.

Tramadol

M1

208 (31) d

2.1 (19) d

6.89 (25) c

7.0 (23) d

Hepatic Impaired,50 mg SD p.o.

Tramadol

M1

217 (11)

19.4 (12)

1.9 (16)

9.8 (20)

4.23 (56) c

13.3 (11)

18.5 (15)

Renal Impaired,CLcr 10-30 mL/min 100 mg SD i.v.

Tramadol

M1

c

c

c

c

4.23 (54) c

10.6 (31)

11.5 (40)

Renal Impaired,CLcr <5 mL/min100 mg SD i.v.

Tramadol

M1

c

c

c

c

3.73 (17) c

11.0 (29)

16.9 (18)

a SD = Single dose, MD = Multiple dose, p.o. = Oral administration, i.v. = Intravenous administration, q.i.d. = Four times daily
b F represents the oral bioavailability of tramadol
c Not applicable
d Not measured

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2022. All Rights Reserved.