Vardenafil_Dextromethorphan_HBr_Capsules

Overview of Vardenafil / Dextromethorphan HBr / Tramadol HCl Capsules

Dosage Strengths of Vardenafil / Dextromethorphan HBr / Tramadol HCl Capsules

Tadalafil / Dextromethorphan HBr / Tramadol HCl 12.5/50/30 mg

General Information

Vardenafil

Vardenafil belongs to the phosphodiesterase type 5 (PDE5) inhibitors drug class, a class of drugs commonly indicated for treatment of erectile dysfunction (ED). It is a selective phosphodiesterase (PDE) type 5 inhibitor similar to sildenafil and tadalafil. This class of drugs does not inhibit prostaglandins as do some agents for treating ED (e.g., alprostadil). Vardenafil and tadalafil are more selective for PDE5 than PDE6, which is present in the retina. This leads to less visual adverse effects such as those reported in sildenafil-treated patients. The advantage of vardenafil may be that it achieves maximum plasma concentration sooner than sildenafil and tadalafil which may result in a faster onset of action. In an analysis of 580 patients, erections improved in 80% of men, and the ability to complete sexual intercourse with ejaculation was increased. Efficacy in treating diabetics and radical prostectomy patients has also been demonstrated. According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy.1 Vardenafil was approved by the FDA in August 2003 for erectile dysfunction. An orally disintegrating tablet was approved by the FDA in June 2010.

Dextromethorphan HBr

Dextromethorphan is an oral, non-opioid, non-prescription drug used as an antitussive. Although it is related to the opiate agonists (dextromethorphan is the methyl ether of the d-isomer of the codeine analog levorphanol), dextromethorphan does not exhibit typical opiate agonist characteristics. The only morphine-like characteristic dextromethorphan retains is its antitussive property. Dextromethorphan is a commonly used ingredient in many cough and cold preparations, and the drug is useful in treating chronic, nonproductive cough, but it has no expectorant activity. When ingested at recommended dosage levels for intended purposes, dextromethorphan is generally regarded as a safe and effective cough suppressant, particularly for patients with cough due to chronic bronchitis or COPD; the evidence for the drug’s utility for suppressing cough due to upper respiratory infection (URI) is less robust.2

Dextromethorphan has been identified as an antagonist to N-methyl-D-aspartate (NMDA) receptors. Dextromethorphan has been studied in the treatment of pain including cancer pain, postoperative pain, and neuropathic pain with mixed results and, in some cases, intolerable side effects. The FDA originally approved dextromethorphan in 1954. On May 20, 2005, the FDA made a public announcement regarding dextromethorphan (DXM) and new trends in the abuse of this drug. The ingestion of pure dextromethorphan in powdered form and in excessive dose can cause death as well as other serious adverse events such as brain damage, seizure, loss of consciousness, and irregular heart beat. Although the reported abuse of dextromethorphan is not new, dextromethorphan is increasingly offered for sale in pure powdered form from questionable sources (e.g., unsanctioned pharmacy websites) and street dealers, and health care professionals should be alert to these new trends.

Tramadol HCl

Tramadol is an oral opioid agonist indicated for the treatment of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. In addition to binding to mu-opioid receptors, tramadol is a norepinephrine and serotonin reuptake inhibitor. The analgesic effect of tramadol is believed to be due to both binding mu-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Tramadol demonstrated comparable efficacy to acetaminophen with codeine, aspirin with codeine, and acetaminophen with oxycodone when studied in 3 long-term controlled trials in patients with a variety of chronic painful conditions.3 Tramadol is conditionally recommended for treatment of osteoarthritis of the hand, knee, or hip in patients who may have contraindications to NSAIDs, find other therapies ineffective, or have no available surgical options.4

Seizures have been reported in patients receiving tramadol within the recommended dosage range; seizure risk is increased with doses of tramadol above the recommended range. Risk of seizure may also increase in patients with a seizure disorder, history of seizures, recognized risk for seizure, or concomitant use of other drugs that reduce the seizure threshold. In tramadol overdose, naloxone administration may increase the risk of seizure. Suicidal tendency possibly causally related to tramadol has been reported. Do not prescribe tramadol for patients who have suicidal ideation or are addiction-prone; consider use of non-narcotic analgesics in patients who are suicidal or depressed.3

The safety and efficacy of tramadol in pediatric patients has not been established. Tramadol is contraindicated in children younger than 12 years and for postoperative pain management in pediatric patients younger than 18 years after a tonsillectomy and/or adenoidectomy.3 5 Ultra-rapid metabolizers of CYP2D6 substrates may convert tramadol to its active metabolite, O-desmethyltramadol, more quickly and completely than usual, leading to higher than normal opioid blood concentrations that can result in fatal respiratory failure. Because some children who are normal metabolizers can covert opioids at similar rates to ultra-rapid metabolizers, this concern extends to all pediatric patients.6

Mechanism of Action

Vardenafil

Vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Vardenafil enhances the effect of NO by inhibiting PDE5, thereby raising concentrations of cGMP in the corpus cavernosum. Vardenafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. Vardenafil has a greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Sildenafil, another PDE inhibitor, has a lower selectivity for PDE5 vs PDE6 and is associated with abnormalities related to color vision with higher doses or plasma concentrations of the drug.

Phosphodiesterase type 5 is also abundant in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in pulmonary vasodilation which can be effective in treating pulmonary hypertension. Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Dyspepsia is one of the more common adverse reactions associated with PDE inhibitor therapy.

Dextromethorphan HBr

Dextromethorphan is a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors in the brain and spinal cord, and this activity is responsible for its therapeutic and toxic effects. 7 8 9 The NMDA receptor complex is a ligand-gated ion channel capable of allowing intracellular entry of calcium ions, which, in turn, stimulates second and third messenger signaling pathways. The NMDA receptor is found throughout the nervous system and is involved in processes such as development, learning, and memory. The NMDA receptor is also thought to sensitize interneurons following repetitive activation of nociceptors. Sustained activation of the NMDA receptor is believed to be involved in allodynia, hyperalgesia, and reduced efficacy of opioids. Activation of NMDA receptors by glutamate and aspartate may play a role in the “wind-up” phenomenon or secondary pain. Secondary pain occurs due to C-fiber stimulation of nociceptors. As compared to A-fibers, the afferent C-fibers are small and have slow conduction, resulting in delayed sensation of dull, persistent, poorly localized pain. The overactivity of these receptors has been shown to produce neurotoxicity that may lead to nerve death. NMDA antagonists, such as dextromethorphan, can block these actions and, in theory, may be neuroprotective. NMDA antagonists can also potentiate opioids and reduce the development of tolerance to opiates, which may be helpful in treating neuropathic pain.9 8

As an antitussive, dextromethorphan acts centrally on the cough center in the medulla to raise the threshold for coughing by decreasing the excitability of the cough center. Dextromethorphan is about equal to codeine in depressing the cough reflex. It is the d-isomer of levorphanol but has none of the analgesic, respiratory depressive, or sedative effects associated with opiate agonists when used in usual antitussive dosages. In therapeutic dosage dextromethorphan also does not inhibit ciliary activity. Naloxone, an opiate-antagonist, does not block the antitussive effects of dextromethorphan.7 10 11 12

Tramadol HCl

Tramadol has a unique dual mechanism of pain relief. It has central opiate receptor agonist activity and, thus, exerts an analgesic effect from binding of the parent drug and the O-desmethyltramadol metabolite (M1) to mu-receptors. The relative contribution of tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see Pharmacokinetics). There are limited data available on the efficacy of tramadol for pain in poor versus extensive CYP2D6 metabolizers. Data from a randomized, double-blind, crossover study suggest that receipt of tramadol 2 mg/kg orally produces a greater analgesic effect, especially after the first 4 hours after dosing in extensive metabolizers whereas the analgesic effect in poor metabolizers is more modest but is sustained up to 10 hours after dosing. The threshold for pressure pain detection, tolerance, nociceptive reflex, and peak pain as compared with placebo was greater in extensive metabolizers as compared with the difference between placebo and tramadol receipt in poor metabolizers.13

The affinity of tramadol for mu-receptors is 10-fold less than codeine, 60-fold less than propoxyphene, and 6000-fold less than morphine. The M1 metabolite has 4—200 times greater affinity for the µ-receptor than tramadol. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone (see Interactions). Opiate receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opiate agonists decrease intracellular cAMP by inhibiting adenylate cyclase which modulates the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and norepinephrine. The stimulatory effects of opioids are the result of ‘disinhibition’ as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The exact mechanism how opioid agonists cause both inhibitory and stimulatory processes is not well understood.

In addition to central opiate receptor agonist activity, tramadol exerts norepinephrine and serotonin reuptake inhibition in the CNS, which inhibits pain transmission in the spinal cord. The monoaminergic reuptake blockade, similar to MAOIs, is an important contribution to the analgesic and adverse event profile of tramadol. The inhibitory reuptake effects of tramadol on norepinephrine and serotonin are 100—1000 times less than those of imipramine.

Pharmacokinetics

Vardenafil

Vardenafil is extensively distributed throughout the body. Protein binding is approximately 95%. Clearance is primarily via the hepatic cytochrome P450 isoenzyme CYP3A4 with minor metabolism by CYP3A5 and CYP2C. The major metabolite, designated M1, is the result of desethylation at the piperazine moiety of vardenafil and is further metabolized. M1 has phosphodiesterase selectivity similar to that of vardenafil and an in vitro inhibitory potency for phosphodiesterase 5 (PDE5) that is 28% of that of vardenafil. M1 also accounts for about 7% of the total pharmacological activity. Vardenafil is excreted as metabolites predominantly in the feces (approximately 91—95% of an oral dose) and to a lesser extent in the urine (about 2—6% of an oral dose). The elimination half-life of vardenafil and M1 is about 4—5 hours with the use of the film-coated tablets. The elimination half-life of vardenafil is 4—6 hours and the elimination half-life of MI is 3—5 hours with the use of the orally disintegrating tablets.14 15

Route-Specific Pharmacokinetics:

Sublingual Administration: Orally disintegrating vardenafil tablets provide a higher systemic exposure than the film-coated tablets. In a study of patients with erectile dysfunction, the mean AUC was increased by 21—29% and the mean Cmax was decreased by 19% in elderly patients (>=65) and 8% in younger patients (18—45 years) as compared to the 10 mg film-coated tablets. In a study of healthy male volunteers (18—50 years), the mean Cmax was 15% higher and the mean AUC was 44% higher as compared to the 10 mg film-coated tablets. The median time to reach Cmax in a fasted stated was 1.5 h. High fat meals had no effect on vardenafil AUC or Tmax in healthy volunteers, but reduced the Cmax by 35%. When the orally disintegrating vardenafil tablets were administered with water, the vardenafil AUC was reduced by 29% and the median Tmax was shortened by 60 minutes, while Cmax was not affected.15

Special Populations:

Hepatic Impairment: Volunteers with mild hepatic impairment (Child-Pugh class A) showed an increase in vardenafil Cmax and AUC of 22% and 17%, respectively, following a 10 mg oral dose. In volunteers with moderate hepatic impairment (Child-Pugh class B), the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively, compared to healthy control subjects. Reduced doses are recommended for patients with moderate hepatic impairment (see Dosage). Vardenafil has not been studied in patients with severe (Child-Pugh class C) hepatic impairment.

Renal Impairment: In volunteers with mild renal impairment (CrCl 50—80 ml/min), vardenafil pharmacokinetics were similar to those observed in a control group with normal renal function. In those with moderate (CrCl 30—50 ml/min) or severe (CrCl < 30 ml/min) renal impairment, the AUC of vardenafil was 20—30% higher compared to that observed in a control group with normal renal function. No dosage modifications are required in patients with mild, moderate, or severe renal impairment; vardenafil pharmacokinetics have not been evaluated in patients needing renal dialysis.

Pediatrics: Pharmacokinetic trials have not been performed in pediatric patients.

Elderly: In a healthy volunteer study of elderly males (>= 65 years) and younger males (18—45 years), mean Cmax and AUC were 34% and 52% higher for vardenafil film-coated tablets, respectively, in the elderly males; lower starting doses of the film-coated tablets should be considered for patients >= 65 years of age (see Dosage).14 In a study of patients with erectile dysfunction using the 10 mg orally disintegrating tablets, the mean AUC was increased by 21—29% in elderly and young patients and the mean Cmax was decreased by 19% in elderly patients (>=65) as compared to the 10 mg film-coated tablets. In trials with the orally disintegrating tablets, the AUC of vardenafil in elderly patients (>= 65 years) was increased by 39% and the Cmax was increased by 21% as compared to patients <= 45 years; however, no differences in safety and efficacy were observed between elderly patients and those < 65 years old in placebo-controlled trials.15

Dextromethorphan HBr

Dextromethorphan is administered orally. Dextromethorphan is approximately 60% to 70% protein bound. Dextromethorphan is primarily metabolized in the liver by CYP2D6. When dextromethorphan is administered to extensive CYP2D6 metabolizers (normal metabolizers), the drug undergoes rapid and extensive hepatic metabolism to demethylated metabolites. Excretion of dextromethorphan is primarily by renal elimination of metabolites. In humans, (+)-3-hydroxy-N-methylmorphinan, (+)-3-hydroxy-morphinan, and traces of unmetabolized drug were found in urine after oral administration.

Affected Cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6
Dextromethorphan is primarily metabolized by the CYP2D6 isoenzyme and is a senstive substrate.16

Route-Specific Pharmacokinetics:

Oral Route: Dextromethorphan is rapidly absorbed from the GI tract, with antitussive activity appearing within 15 to 30 minutes. Food does not affect absorption. Antitussive activity can last for 3 to 6 hours.

Special Populations:

Hepatic Impairment: Dextromethorphan pharmacokinetics (exposure, maximum concentrations, clearance) are similar in patients with mild to moderate hepatic impairment and healthy subjects. The drug has not been studied in severe liver impairment. Monitor for adverse reactions in patients with severe hepatic disease.

Renal Impairment: Subjects with renal impairment show little difference in dextromethorphan pharmacokinetics compared to healthy subjects. Dose adjustment is not required. It is not known whether dextromethorphan or its active metabolite are removed by hemodialysis.

CYP2D6 Poor Metabolizers: The rate of dextromethorphan metabolism varies between individuals according to CYP2D6 phenotype (extensive or poor metabolizers). In poor metabolizers (PMs) of CYP2D6, dextromethorphan exposure is naturally increased and the action is prolonged, and dextromethorphan-related adverse effects may be possible in some of these patients. Approximately 7% to 10% of Caucasians and 3% to 8% of African Americans are classified as CYP2D6 PMs.

Tramadol HCl

Tramadol is administered orally. Tramadol has a high tissue affinity. Minimum protein binding occurs (about 20%) and appears to be independent of concentration up to 10 mcg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. The Vd ranges from 2.6 to 2.9 L/kg. Tramadol undergoes significant first-pass metabolism after oral administration. Hepatic metabolism takes place via 2 metabolic pathways to form N- and O-demethylated tramadol. Of a tramadol dose, 60% is metabolized by the liver. The metabolism is also stereoselective; the (-) enantiomer undergoes O-demethylation selectively, and the (+) enantiomer preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. O-demethylation is mediated by CYP2D6, and the O-demethylated metabolites are further conjugated. Of 11 identified metabolites, only the O-demethylated metabolite (M1) has analgesic activity, which appears to be critical to the activity of tramadol. The production of M1 depends on CYP2D6. Patients with impaired CYP2D6 activity or those receiving concurrent medications that affect CYP2D6 or CYP3A4 enzymes may experience an altered response to tramadol.

Excretion of tramadol and its metabolites is mostly renal. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. In normal healthy adults, the mean terminal plasma elimination half-lives of racemic tramadol and racemic M1, respectively, are approximately 6.3 and 7.4 hours after administration of immediate-release tramadol, 7.9 and 8.8 hours after administration of coated extended-release tablets, 6.5 and 7.5 hours after administration of dual-matrix extended-release tablets, and 10 and 11 hours after administration of extended-release capsules.3 17 18 19 Affected cytochrome P450 isoenzymes and drug transporters: CYP2B6, CYP2D6, CYP3A4 Tramadol is a substrate of CYP2B6, CYP2D6, and CYP3A4.17

Contraindications/Precautions

Vardenafil

Your health care provider needs to know if you have any of these conditions: bleeding disorders, eye or vision problems, including a rare inherited eye disease called retinitis pigmentosa, anatomical deformation of the penis, Peyronie’s disease, or history of priapism (painful and prolonged erection), heart disease, angina, a history of heart attack, irregular heartbeats, or other heart problems, high or low blood pressure, history of blood diseases, like sickle cell anemia or leukemia, history of stomach bleeding, kidney disease, liver disease, stroke, an unusual or allergic reaction to vardenafil, other medicines, foods, dyes, or preservatives, pregnant or trying to get pregnant, breast-feeding.

Vardenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet. The safety and efficacy of combinations of vardenafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

The safe and effective use of vardenafil in combination with other agents for treating erectile dysfunction has not been studied. Therefore, the use of such combinations is not recommended.

Vardenafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Consistent with its known effects on the nitric oxide/cGMP pathway, vardenafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive vardenafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once vardenafil has been administered. A suitable time interval following vardenafil dosing for safe administration of nitrates or nitric oxide donors has not been determined.

Vardenafil tablets are not recommended in patients with severe hepatic disease (Child-Pugh class C) or end stage renal disease requiring dialysis (severe renal impairment or renal failure). There are no controlled clinical studies on the safety and efficacy of vardenafil in these patients; therefore, vardenafil use is not recommended until further information is available. Patients with moderate hepatic impairment require a reduction in the starting dose of the regular tablets and a lower maximum dosage (see Indications/Dosage). Patients with mild hepatic impairment or mild to moderate renal impairment do not require adjustments in the vardenafil regular tablet dosage. The concomitant use of certain potent hepatic cytochrome P450 3A4 inhibitors may result in a requirement to adjust the vardenafil dosage (see Dosage and Drug Interactions).14 Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, the orally disintegrating tablets should not be used in patients with moderate or severe hepatic disease (Child-Pugh class B or C) or in patients on hemodialysis. Patients who require lower doses of vardenafil should use the regular tablets.15

Lower starting doses of vardenafil regular tablets should be considered for geriatric patients (>= 65 years) because elderly patients have higher plasma concentrations than younger males (18—45 years) (see Indications/Dosage).14 In phase III clinical trials of the regular tablets, 834 elderly patients participated and there was no difference in safety or effectiveness compared to younger patients.14 In trials with the orally disintegrating tablets, the vardenafil AUC in elderly patients (>= 65 years) was increased by 39% and the Cmax was increased by 21% as compared to patients <= 45 years; however, no differences in safety and efficacy were observed between elderly patients and those < 65 years old in placebo-controlled trials.15 Elderly patients may potentially have renal and hepatic impairment which can increase vardenafil plasma concentrations. Because higher plasma concentrations may increase the incidence of adverse reactions, the regular tablet starting dose should be reduced in these patients.14 Patients who require lower doses of vardenafil should use the regular tablets and not the orally disintegrating tablets.15

There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. In particular, caution should be used if vardenafil is prescribed in the following patient groups: patients who have suffered a myocardial infarction, stroke, or life-threatening cardiac arrhythmias in the last 6 months; patients with resting hypotension (BP < 90/50) or resting hypertension (BP > 170/110); patients with cardiac disease, severe heart failure or coronary artery disease (CAD) which causes unstable angina including those with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis). Based on recommendations for sildenafil by the American College of Cardiology, it is recommended that vardenafil be used with caution in the following: patients with active coronary ischemia who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status; patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of vardenafil. Vardenafil is contraindicated in patients currently onnitrate/nitrite therapy. In a double-blind, crossover, single-dose study of patients with stable CAD, vardenafil did not cause any impairment in exercise capabilities at levels equivalent to or greater than that achieved during sexual intercourse.20 The effects of vardenafil on QT prolongation were evaluated in 59 healthy males using moxifloxacin (400 mg) as an active control. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced similar increases in QTc interval (e.g., 4—6 msec calculated by individual QT correction) as moxifloxacin. When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed.14 The effect of vardenafil on the QT interval should be considered when prescribing the drug. The manufacturer recommends that vardenafil not be used in patients with congenital long QT syndrome and those taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs. Further, use vardenafil with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.21 22 23 24 25 26

Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been associated with PDE5 inhibitor administration. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Vardenafil and other agents for the treatment of erectile dysfunction should be used with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism).14 27

Patients should be reminded that vardenafil offers no protection against sexually transmitted disease. Counseling of patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, should be considered.

Use vardenafil cautiously in patients with pre-existing visual disturbance. Post-marketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors, including vardenafil. Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. This can cause permanent loss of vision. Vardenafil use should be discontinued in the event of sudden loss of vision in one or both eyes. Vardenafil use is not recommended in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa. A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. Vardenafil use is not recommended in these patients until further information is available.14 15

Vardenafil is not indicated for use in females. Vardenafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled trials of vardenafil in humans during pregnancy.14 15

Vardenafil is not indicated for use in females and is therefore not recommended during breast-feeding. It is not known if vardenafil is excreted in human breast milk; however, it is known that the drug is excreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma.14 15

There is no known indication for the use of vardenafil in neonates, infants, or children. Vardenafil should not be prescribed to these populations.

Vardenafil should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Like sildenafil, vardenafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.28

Vardenafil should be administered to patients with coagulopathy only after careful benefit vs. risk assessment. Vardenafil alone does not prolong the bleeding time nor does its use in combination with aspirin cause any additive prolongation of the bleeding time. However, vardenafil has not been studied or administered to patients with bleeding disorders or significant active peptic ulcer disease. Therefore administer to these patients after careful benefit-risk assessment.14

Patients with a sudden decrease or loss of hearing (hearing impairment) should stop taking vardenafil and seek prompt medical attention. Hearing loss, which may be accompanied by tinnitus and dizziness, has been reported in temporal association with the intake of PDE5 inhibitors, including vardenafil; however, it is unknown if the hearing loss is directly related to PDE5 inhibitors or to other factors.14 15

The vardenafil orally disintegrating tablets contain aspartame, which is a source of phenylalanine. This may be harmful for people with phenylketonuria. Each tablet contains 1.01 mg of phenylalanine.15

The vardenafil orally disintegrating tablets contain sorbitol. Patients with hereditary fructose intolerance should not take the orally disintegrating tablets.15

This list may not include all possible contraindications.

Dextromethorphan HBr

Dextromethorphan is contraindicated in the treatment of chronic cough, especially when associated with excessive bronchial secretion. This includes cough related to asthma, tobacco smoking, and emphysema. Dextromethorphan has no expectorant action and acts only to suppress the cough reflex. A recurrent or persistent cough (lasting for more than one week), or a cough accompanied by fever, nausea/vomiting, rash, or persistent headache may be signs of a more serious condition and should be evaluated by a physician.

Dextromethorphan is extensively metabolized by the liver and should be used with caution in patients with hepatic disease because of possible accumulation of the drug and resultant toxicity.

In January 2007, the CDC warned caregivers and healthcare providers of the risk for serious injury or fatal overdose from the administration of cough and cold products to children and infants less than 2 years of age.29 This warning followed an investigation of the deaths of three (3) infants less than 6 months of age that were attributed to the inadvertent inappropriate use of these products. The symptoms preceding these deaths have not been clearly defined, and there is a lack of conclusive data describing the exact cause of death. The report estimated that 1519 children less than 2 years of age were treated in emergency departments during 2004—2005 for adverse events related to cough and cold medications. In October 2007, the FDA Nonprescription Drug Advisory Committee and the Pediatric Advisory Committee recommended that nonprescription cough and cold products containing pseudoephedrine, dextromethorphan, chlorpheniramine, diphenhydramine, brompheniramine, phenylephrine, clemastine, or guaifenesin not be used in children less than 6 years of age. In January 2008, the FDA issued a Public Health Advisory recommending that OTC cough and cold products not be used in infants and children less than 2 years. An official ruling regarding the use of these products in children greater than 2 years has not yet been announced. The FDA recommends that if parents and caregivers use cough and cold products in children greater than 2 years, labels should be read carefully, caution should be used when administering multiple products, and only measuring devices specifically designed for use with medications should be used. While some combination cough/cold products containing these ingredients are available by prescription only and are not necessarily under scrutiny by the FDA, clinicians should thoroughly assess each patient’s use of similar products, both prescription and nonprescription, to avoid duplication of therapy and the potential for inadvertent overdose.

There are no adequate and well-controlled studies of dextromethorphan in pregnant women. Dextromethorphan is available without a prescription, and because it acts as a low affinity antagonist to the glutamate receptor subtype N-methyl-D-aspartate (NMDA) in the CNS, there has been some concern about its safe use during pregnancy. Dextromethorphan exhibited adverse developmental effects in avian embryos; however, the avian study data have limited applicability to human gestation.30 Human surveillance data and retrospective studies have shown dextromethorphan to be relatively safe during the first trimester; a human epidemiologic study and a smaller controlled study have not demonstrated elevated risks of congenital malformations. In one controlled study, there were no cases of neural tube defects, and no differences in number of live births, spontaneous or elective abortions, stillbirths, or major or minor malformations among infants exposed to dextromethorphan during the first trimester and those who were not. The results suggested that use during pregnancy does not pose a risk to the fetus; however, due to the small sample size, an increased risk of rare malformations could not be ruled out.31 32

Limited data are available regarding the use of dextromethorphan by breast-feeding women. It is not known whether dextromethorphan is excreted into human breast milk; however, based on dextromethorphan’s relatively low molecular weight, some transfer into breast milk is expected. Despite the lack of published data, dextromethorphan is often considered to be compatible with breast-feeding when usual antitussive doses are taken by the mother, due to the lack of expected harm in the breast-fed infant. Some dextromethorphan cough products contain alcohol and these products should be avoided while breast-feeding.33

Dextromethorphan may cause dizziness or confusion. Patients should be warned against driving or operating machinery, or doing anything that needs mental alertness until they know how dextromethorphan affects them.

Dextromethorphan should be used cautiously, if at all, in patients receiving MAOI therapy; dextromethorphan is usually contraindicated in patients receiving traditional non-selective inhibitors of MAO (e.g., isocarboxazid, tranycypromine, phenelzine).

There are no particular precautions for the use of dextromethorphan in the ambulatory, non-debilitated geriatric patient compared to use in younger adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities. According to the OBRA guidelines, cough, cold, and allergy medications should be used only for a limited duration (less than 14 days) unless there is documented evidence of enduring symptoms that cannot otherwise be alleviated and for which a cause cannot be identified and corrected.34

Tramadol HCl

Tramadol is contraindicated in patients with known tramadol hypersensitivity, opiate agonist hypersensitivity, or hypersensitivity to any other component of the product. Serious and rarely fatal anaphylactic reactions have been reported in patients receiving tramadol, often after the first dose. If anaphylaxis or other hypersensitivity occurs, discontinue tramadol and do not rechallenge with any formulation of tramadol. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction.3 17

Do not prescribe tramadol for patients who have suicidal ideation or are addiction-prone; consider use of non-narcotic analgesics in patients who are suicidal or depressed. Use tramadol with caution in patients with a history of misuse or who are taking central nervous system active drugs, including tranquilizers or antidepressants or alcohol in excess, and patients who suffer from emotional disturbance or depression. As an opioid, tramadol exposes users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed tramadol. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse before prescribing tramadol, and monitor all patients receiving tramadol for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including alcoholism) or mental illness (e.g., major depression). The potential for these risks should not prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as tramadol, but use in such patients necessitates intensive counseling about the risks and proper use of tramadol along with intensive monitoring for signs of addiction, abuse, and misuse. Abuse and addiction are separate and distinct from physical dependence and tolerance; patients with addiction may not exhibit tolerance and symptoms of physical dependence. Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Abuse or misuse of tramadol extended-release tablets or extended-release capsules by cutting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tramadol and can result in overdose and death.3 17 35 Discuss the availability of naloxone with all patients and consider prescribing it in patients who are at increased risk of opioid overdose, such as patients who are also using other CNS depressants, who have a history of opioid use disorder (OUD), who have experienced a previous opioid overdose, or who have household members or other close contacts at risk for accidental ingestion or opioid overdose.36

Like all opioid agonists, tramadol is associated with a significant potential for overdose or poisoning; proper patient selection and counseling is recommended. Extended-release tramadol is not intended for use in the management of acute pain or on an as-needed basis; it is intended only for patients requiring continuous, around-the-clock opioid analgesia for an extended period and requires an experienced clinician who is knowledgeable in the use of potent opioids for the management of chronic pain. Abuse or misuse of tramadol extended-release tablets or extended-release capsules by cutting, breaking, chewing, crushing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tramadol and can result in overdose and death. Dosing errors may result from confusion between mg and mL when prescribing, dispensing, and administering tramadol oral solution. Ensure that the dose is communicated clearly and dispensed accurately. Instruct patients on how to measure the dose and to use a calibrated oral dosing device. Tramadol should be kept out of the reach of pediatric patients, others for whom the drug was not prescribed, and pets as accidental exposure or improper use may cause respiratory failure and a fatal overdose.3 17 18 35 37 38

The safety and efficacy of tramadol in pediatric patients has not been established. Tramadol is contraindicated in neonates, infants, and children younger than 12 years and for postoperative pain management in pediatric patients younger than 18 years after a tonsillectomy and/or adenoidectomy.3 5 Avoid use in patients 12 to 18 years of age who have other risk factors for depressed respiration unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation such as postoperative status, obstructive sleep disorder, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other respiratory depressants. As with adults, when prescribing opioids for adolescents, use the lowest effective dose for the shortest period of time, and inform patients and caregivers about these risks and the signs of opioid overdose.3 5 Ultra-rapid metabolizers of CYP2D6 substrates may convert tramadol to its active metabolite, O-desmethyltramadol, more quickly and completely than usual, leading to higher than normal opioid blood concentrations that can result in fatal respiratory failure. Because some children who are normal metabolizers can covert opioids at similar rates to ultra-rapid metabolizers, this concern extends to all pediatric patients.6

Tramadol is contraindicated in patients with significant respiratory depression and those with acute or severe asthma in an unmonitored setting or in the absence of resuscitative equipment.3 Avoid coadministration with other CNS depressants when possible, as this significantly increases the risk for profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate; if concurrent use is necessary, use the lowest effective dosages and minimum treatment durations needed. Monitor patients closely for signs or symptoms of respiratory depression and sedation.3 39 Patients with chronic obstructive pulmonary disease (COPD), cor pulmonale, respiratory insufficiency, hypoxemia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive even at recommended doses. Patients with advanced age, cachexia, or debilitation are also at an increased risk for opioid-induced respiratory depression. Monitor such patients closely, particularly when initiating and titrating the opioid; consider the use of non-opioid analgesics in these patients. Opioids increase the risk of central sleep apnea (CSA) and sleep-related hypoxemia in a dose-dependent fashion. Consider decreasing the opioid dosage in patients with CSA. Respiratory depression, if left untreated, may cause respiratory arrest and death. Carbon dioxide retention from respiratory depression may also worsen opioid sedating effects. Careful monitoring and dose titration is required, particularly when CYP3A4 inhibitors or inducers and/or CYP2D6 inhibitors are used concomitantly. The effects of concomitant use or discontinuation of CYP3A4 inhibitors or inducers or CYP2D6 inhibitors on concentrations of tramadol and its active metabolite, M1, are complex and may potentiate the risk of fatal respiratory depression or result in opioid withdrawal and reduced efficacy. Management of respiratory depression may include observation, necessary supportive measures, and opioid antagonist use when indicated.3

Tramadol is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus. Tramadol may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.3 17 35

In studies including geriatric patients, treatment-limiting adverse events were higher in subjects older than 75 years compared to those younger than 65 years. Do not exceed a total dose of 300 mg/day in patients older than 75 years. Titrate the dosage of tramadol slowly in geriatric patients starting at the low end of the dosing range and monitor closely for signs of central nervous system and respiratory depression. Tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, take care in dose selection, and it may be useful to monitor renal function.3 According to the Beers Criteria, caution is recommended when using tramadol in older adults because the drug can cause or exacerbate hyponatremia and SIADH and the elderly are at increased risk of developing these conditions. Sodium concentrations should be closely monitored when starting or changing dosages in older adults. In addition, it is recommended to reduce the dose of immediate-release tramadol in geriatric patients with a creatinine clearance less than 30 mL/minute due to the potential for adverse CNS effects. Opioid agonists are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, except in the setting of severe acute pain, since opiates can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an opiate must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk. In patients receiving palliative care or hospice, the balance of benefits and harms of medication management may differ from those of the general population of older adults.40 The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). OBRA cautions that opioids may cause constipation, nausea, vomiting, sedation, lethargy, weakness, confusion, dysphoria, physical and psychological dependency, hallucinations, and unintended respiratory depression, especially in individuals with compromised pulmonary function. These adverse effects can lead to other consequences such as falls. The initiation of longer-acting opioids is not recommended unless shorter-acting opioids have been unsuccessful, or titration of shorter-acting doses has established a clear daily dose of opioid analgesic that can be provided by using a long-acting form.34

Avoid abrupt discontinuation of tramadol in a physically-dependent patient. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking tramadol, consider the dose of tramadol the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on tramadol who are physically opioid-dependent, initiate the taper by a small enough increment, (e.g., no more than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with a lower dosage strength to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. If withdrawal symptoms arise, it may be necessary to pause the taper for a period or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support, if needed, is in place before initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic.3 35 41 Consider tapering to reduced opioid dosage, or tapering and discontinuing long-term opioid therapy, when pain improves; the patient requests dosage reduction or discontinuation; pain and function are not meaningfully improved; the patient is receiving higher opioid doses without evidence of benefit from the higher dose; the patient has current evidence of opioid misuse; the patient experiences side effects that diminish quality of life or impair function; the patient experiences an overdose or other serious event (e.g., hospitalization, injury) or has warning signs for an impending event such as confusion, sedation, or slurred speech; the patient is receiving medications (e.g., benzodiazepines) or has medical conditions (e.g., lung disease, sleep apnea, liver disease, kidney disease, fall risk, advanced age) that increase risk for adverse outcomes; or the patient has been treated with opioids for a prolonged period and current benefit-harm balance is unclear. Opioids may be stopped, if appropriate, when taken less often than once daily. Advise patients that there is an increased risk for overdose on abrupt return to a previously prescribed higher dose; provide opioid overdose education, and consider offering naloxone.42

Avoid tramadol use in patients with CNS depression, impaired consciousness, or coma; opioids may obscure the clinical course in a patient with a head trauma injury. Monitor patients who may be susceptible to the intracranial effect of carbon dioxide retention (e.g., those with evidence of increased intracranial pressure, brain tumor, or intracranial mass) for signs of sedation and respiratory depression, particularly when initiating tramadol therapy. Tramadol may reduce respiratory drive and resultant carbon dioxide retention can further increase intracranial pressure.3 38

Warn patients against performing potentially hazardous activities such as driving or operating machinery unless they are tolerant to the effects of tramadol and know how they will react to the medication. Tramadol may impair mental or physical abilities required to perform such tasks.3

Tramadol may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by hypovolemia or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines, general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the opioid dosage. Avoid the use of tramadol in patients with circulatory shock; it may cause vasodilation that can further reduce cardiac output and blood pressure.3

Seizures have been reported in patients receiving tramadol within the recommended dosage range; seizure risk is increased with doses of tramadol above the recommended range. Risk of seizure may also increase in patients with a seizure disorder, history of seizures, recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections), or concomitant use of other drugs that reduce the seizure threshold. In tramadol overdose, naloxone administration may increase the risk of seizure.3

Dosing reduction is recommended for tramadol immediate-release formulations in patients with severe hepatic disease. Metabolism of tramadol and its active metabolite, M1, is reduced in patients with severe hepatic impairment. With the prolonged half-life in hepatic impairment, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop. Do not use extended-release tramadol formulations in patients with severe hepatic impairment (Child-Pugh Class C). Use of extended-release tramadol has not been studied in patients with hepatic impairment. The limited availability of dose strengths of extended-release tramadol formulations does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment.3 17 35 38

Dosing reduction is recommended for tramadol immediate-release formulations in patients with creatinine clearance less than 30 mL/minute. Renal impairment or renal failure results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. With the prolonged half-life in renal impairment, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop. Do not use extended-release tramadol formulations in patients with severe renal impairment. Use of extended-release tramadol has not been studied in patients with renal impairment. The limited availability of dose strengths of extended-release tramadol formulations does not permit the dosing flexibility required for safe use in patients with severe renal impairment.3 17 35 38

Use of tramadol is contraindicated in patients who are receiving or who have received MAOI therapy within the past 14 days. Additive CNS depression, drowsiness, dizziness, or hypotension may occur. Concomitant use may also increase the risk for serotonin syndrome.3 17 35

Data are insufficient to inform a drug-associated risk for major birth defects or miscarriage with tramadol use in human pregnancy. Tramadol crosses the placenta. Based on animal data, tramadol may cause fetal harm; advise pregnant women of the potential risk to the fetus. In animal studies of tramadol, decreased fetal weights and reduced ossification were observed in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD). Decreased body weight and increased mortality were observed in pups at tramadol doses of 1.2 and 1.9 times the MRHD. Tramadol is not recommended for use during and immediately before labor when other analgesic techniques are more appropriate. Opioids can prolong labor and obstetric delivery by temporarily reducing the strength, duration, and frequency of uterine contractions. This effect is not consistent and may be offset by an increased rate of cervical dilatation, which may shorten labor. Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in the neonate. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. An opioid antagonist (e.g., naloxone) should be available for reversal of opioid-induced respiratory depression in the neonate. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women treated with tramadol during labor.3 Further, prolonged maternal use of opioids during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). Monitor the exposed neonate for withdrawal symptoms, including irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight, and manage accordingly. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn.3 43 Guidelines recommend early universal screening of pregnant patients for opioid use and opioid use disorder at the first prenatal visit. Obtain a thorough history of substance use and review the Prescription Drug Monitoring Program to determine if patients have received prior prescriptions for opioids or other high-risk drugs such as benzodiazepines. Discuss the risks and benefits of opioid use during pregnancy, including the risk of becoming physiologically dependent on opioids, the possibility for NOWS, and how long-term opioid use may affect care during a future pregnancy.44 45 In women undergoing uncomplicated normal spontaneous vaginal birth, consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, use in combination with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate. Use immediate-release opioids instead of extended-release or long-acting opioids; order the lowest effective dosage and prescribe no greater quantity of opioids than needed for the expected duration of such pain severe enough to require opioids.45 For women using opioids for chronic pain, consider strategies to avoid or minimize the use of opioids, including alternative pain therapies (i.e., nonpharmacologic) and nonopioid pharmacologic treatments. Opioid agonist pharmacotherapy (e.g., methadone or buprenorphine) is preferable to medically supervised withdrawal in pregnant women with opioid use disorder.44

Breast-feeding is not recommended during treatment with tramadol because of the potential for serious adverse events, including excess sedation and respiratory depression in the breast-fed infant.3 5 If an infant is exposed to tramadol through breast milk, monitor for excessive sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal use of an opioid is stopped or when breast-feeding is stopped.3 Alternative analgesics that previous American Academy of Pediatrics recommendations considered as usually compatible with breast-feeding include acetaminophen, ibuprofen, and morphine.46 There is no information on the effects of tramadol on milk production. Tramadol and its metabolite (M1) are excreted into human milk. An infant nursing from an ultra-rapid metabolizer mother taking tramadol could potentially be exposed to high metabolite concentrations and experience life-threatening respiratory depression. In women with normal tramadol metabolism (normal CYP2D6 activity), the amount of tramadol secreted into human milk is low and dose-dependent. After a single IV dose of tramadol 100 mg, the cumulative excretion in breast milk within 16 hours was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.3 Samples of breast milk taken from 75 women 2 to 4 days postpartum after receiving at least 4 doses of tramadol indicated that an exclusively breast-fed infant would receive 2.24% of the maternal weight-adjusted dose of tramadol and 0.64% of its metabolite. Assessments of the infants of these mothers using the Neurologic and Adaptive Capacity Score found no difference compared to infants in a control group; 49% percent of mothers in the tramadol group and 100% of mothers in the control group were also receiving other opioids (mostly oxycodone).47

Chronic opioid use may influence the hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as hypogonadism (gonadal suppression) and pose a reproductive risk. Although the exact causal role of opioids in the clinical manifestations of hypogonadism is unknown, patients could experience libido decrease, impotence, amenorrhea, or infertility. It is not known whether the effects on fertility are reversible. Monitor patients for symptoms of opioid-induced endocrinopathy. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.3

Pregnancy

Vardenafil

Dextromethorphan HBr

Tramadol HCl

Breast-feeding

Vardenafil

Vardenafil is not indicated for use in females and is therefore not recommended during breastfeeding. It is not known if vardenafil is excreted in human breastmilk; however, it is known that the drug is excreted into the milk of lactating rats at concentrations approximately 10-fold greater than found in the plasma.14 15

Dextromethorphan HBr

Tramadol HCl

Adverse Reactions/Side Effects

Vardenafil

Side effects that you should report to your doctor or health care professional as soon as possible: allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue, breathing problems, changes in hearing, changes in vision, chest pain, fast, irregular heartbeat, prolonged or painful erection, seizures.

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome): back pain, dizziness, flushing, headache, indigestion, muscle aches, nausea, stuffy or runny nose.

Flushing occurred in 11% of those receiving vardenafil film-coated tablets and in 7.6% of patients receiving orally disintegrating tablets. The incidence of flushing appears to increase as the dose increases. Anaphylactoid reactions (including laryngeal edema) occurred in less than 2% of patients. Other events occurring in < 2% of patients include allergic edema, facial edema (angioedema), pruritus, photosensitivity reaction, sweating (hyperhidrosis), erythema, and rash (unspecified). The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.14 15

Headache occurred in 15% of those receiving vardenafil film-coated tablets and in 14.4% of those receiving the orally-disintegrating tablets. The incidence of headache appears to increase as the dose increases. Neurologic effects that occurred in less than 2% of patients included asthenia, hypertonia, hypesthesia, dysesthesia, sleep disorders, amnesia, seizures, and paresthesias. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo. Postmarketing reports indicate that seizures and seizure recurrence have occurred in temporal association with vardenafil use. The incidence of these adverse events is unknown. Transient global amnesia has been reported during post-marketing use of the drug.14 15

Gastrointestinal (GI) adverse reactions occurring in at least 2% of patients taking vardenafil film-coated tablets and more frequently than placebo included dyspepsia (4% vs 1%) and nausea/vomiting (2% vs 1%). Dyspepsia also occurred in 2.8% of patients receiving the orally disintegrating tablets. GI effects that occurred in less than 2% of patients included abdominal pain, diarrhea, dysphagia, esophagitis, gastritis, gastroesophageal reflux, vomiting, and xerostomia. Dyspepsia and nausea appear to increase as the dose increases. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.14 15

Arthralgia, myalgia, increased creatine phosphokinase (CPK), and increased muscle tone and cramping (muscle cramps) have been reported in less than 2% of patients receiving vardenafil during clinical trials. Neck pain has been reported with similar frequency. During controlled and uncontrolled clinical trials, back pain was reported in 2% of patients receiving vardenafil. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.14 15

Dizziness occurred in 2% of those receiving vardenafil film-coated tablets and 2.3% of patients receiving orally disintegrating tablets. Dizziness has been associated with a sudden decrease in hearing. Centrally-mediated effects occurring in less than 2% of patients included insomnia, somnolence (drowsiness), and vertigo. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.14 15

During clinical trials, cardiovascular adverse reactions that occurred in less than 2% of patients treated with vardenafil included angina pectoris, chest pain (unspecified), hypertension, hypotension, myocardial ischemia, myocardial infarction, orthostatic hypotension, palpitations, syncope, ventricular tachyarrhythmias (ventricular tachycardia), and sinus tachycardia. The effects of vardenafil on blood pressure were evaluated using single 20 mg doses of vardenafil in patients with erectile dysfunction. Vardenafil caused a mean maximum decrease in supine blood pressure of 7 mm Hg systolic and 8 mm Hg diastolic (compared to placebo), accompanied by a mean maximum increase in heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. After multiple dosing, the effects of vardenafil on blood pressure were similar on Day 31 as on Day 1. Vardenafil may add to the hypotensive effects of antihypertensive agents.14 15

Respiratory conditions occurring in at least 2% of patients taking vardenafil film-coated tablets and more frequently than placebo included rhinitis (9% vs 3%), sinusitis (3% vs 1%), and flu-like syndrome (3% vs 2%). The incidence of rhinitis appears to increase as the dose increases. Nasal congestion occurred in 3.1% of patients receiving the orally disintegrating tablets. Respiratory-related effects which occurred in less than 2% of patients included dyspnea, sinus congestion, and pharyngitis. The discontinuation rate due to adverse reactions in placebo-controlled trials was 3.4% for vardenafil and 1.1% for placebo.14 15

During clinical trials, ejaculation dysfunction occurred in less than 2% of patients treated with vardenafil. Prolonged erections greater than 4 hours and priapism have been reported rarely with PDE5 inhibitors, including vardenafil.

Epistaxis occurred in less than 2% of patients receiving vardenafil in clinical trials.14 15

Phosphodiesterase inhibitors, such as vardenafil, inhibit PDE6 in retinal rods and cones, which are involved in phototransduction in the retina. Changes in color vision were reported in < 2% of patients and occurred as a result of PDE6 inhibition. In single dose studies, dose-related impairment of color discrimination (blue/green) as well as reductions in electroretinogram (ERG) b-wave amplitudes were noted; peak effects were noted near the time of peak plasma levels (approximately 1 hour after dosing). These effects diminished but were still present 6 hours after administration. In a single dose study of 25 healthy males, vardenafil 40 mg did not alter visual acuity, intraocular pressure, or funduscopic and slit lamp findings.14 In an 8-week, multiple-dose, placebo-controlled clinical trial, clinically significant changes in retinal function did not occur as assessed by ERG amplitudes or the Farnsworth-Munsell 100-hue test. The trial was designed to detect retinal function changes that might occur in more than 10% of patients. Of 52 enrollees, 32 subjects completed the study. Two patients in the vardenafil group reported transient cyanopsia (objects appear blue). Other ophthalmic adverse reactions occurring in < 2% of patients receiving vardenafil include blurred vision, chromatopsia, conjunctivitis (increased redness of the eye), dim vision, glaucoma, ocular pain, photophobia, visual impairment, ocular hyperemia, increased intraocular pressure, and watery eyes (lacrimation). Post-marketing reports have included cases of visual disturbances including retinal vein occlusion, visual field defects, reduced visual acuity, and loss of vision (temporary or permanent).14 15 Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors.48 49 50 51 It is thought that the vasoconstrictive effect of phosphodiesterase inhibitors may decrease blood flow to the optic nerve, especially in patients with a low cup to disk ratio. Symptoms, such as blurred vision and loss of visual field in one or both eyes, are usually reported within 24 hours of use. Most, but not all, of these patients who reported this adverse effect had underlying anatomic or vascular risk factors for development of NAION. These risk factors include, but are not limited to: low cup to disc ratio (‘crowded disc’), age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Additionally, two patients had retinal detachment and one patient had hypoplastic optic neuropathy.48 It is not yet possible to determine if these adverse events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.

Adverse reactions affecting hearing or otic special senses and occurring in < 2% of patients in controlled clinical trials of vardenafil include hearing loss and tinnitus. In addition, 29 reports of sudden changes in hearing including hearing loss or decrease in hearing, usually in 1 ear only, have been reported to the FDA during post-marketing surveillance in patients taking sildenafil, tadalafil, or vardenafil; the reports are associated with a strong temporal relationship to the dosing of these agents. Many times, the hearing changes are accompanied by vestibular effects including dizziness, tinnitus, and vertigo. Follow-up has been limited in many of the reports; however, in approximately one-third of the patients, the hearing loss was temporary. Concomitant medical conditions or patient factors may play a role, although risk factors for the onset of sudden hearing loss have not been identified. Patients should be instructed to promptly contact their physician if they experience changes in hearing.14 15

The effects of vardenafil on QT prolongation were evaluated in 59 healthy males using moxifloxacin (400 mg) as an active control. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced similar increases in QTc interval (e.g., 4—6 msec calculated by individual QT correction) as moxifloxacin (7 msec). The potential effect of vardenafil on the QT interval should be considered when prescribing the drug; the manufacturer recommends against drug use in certain patient groups with risk factors for QT prolongation (see Precautions).14 15

Changes in laboratory values have occurred infrequently. During controlled and uncontrolled clinical trials of vardenafil in over 4430 men (mean age 56, range 18—89 years), increased creatine kinase was reported in 2% of those receiving vardenafil versus 1% of those in the placebo group. Increased GGTP and elevated hepatic enzymes (e.g., abnormal liver function tests) were reported in less than 2% of patients.14 15

This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.

Dextromethorphan HBr

Although adverse reactions to dextromethorphan are generally mild and infrequent, drowsiness, dizziness, and fatigue can occur with therapeutic dosage. Fixed drug eruptions like rash (unspecified) and anaphylactoid reactions, which included urticaria, have been reported rarely.52

Dextromethorphan is associated with serotonergic effects. Excessive dosage due to higher than recommended doses or substance abuse (e.g., in combination with products containing narcotics or sympathomimetics) may result in additional adverse effects consistent with the serotonin syndrome including: confusion, excitement, nervousness, restlessness, irritability, nausea, vomiting, and dysarthria (slurred speech). Although dextromethorphan is the dextro-isomer of levorphanol, it has little dependence liability since it lacks the opiate agonist effects. Overdose experience has shown it to be relatively safe, however, it is frequently implicated in pediatric overdosage. With dextromethorphan overdosage, CNS effects are most frequent and include stupor, ataxia, nystagmus, hyperexcitability, dystonia (e.g., dystonic reaction), coma, toxic psychosis (e.g., hallucinations) and changes in muscle reflexes. Other effects have included respiratory depression, sinus tachycardia, seizures including an increase in baseline seizure activity, nausea, and vomiting.52

Tramadol HCl

Dizziness and vertigo are among the most common adverse reactions associated with tramadol use. Dizziness or vertigo was reported in 26% of patients receiving immediate-release tramadol at 7 days of treatment and 33% of patients at 90 days of treatment. Dizziness was reported in 15.9% to 28.2% of patients who received 100 to 400 mg/day coated extended-release tramadol, 7% to 10% of patients who received 100 to 300 mg/day dual-matrix extended-release tramadol, and 9.6% to 13.6% of patients who received 100 to 300 mg/day extended-release capsules. Vertigo occurred in 0.5% to less than 1% of patients receiving extended-release dosage forms.3 17 18 35

Constipation is among the most common adverse reactions associated with tramadol use. Constipation was reported in 24% of patients receiving immediate-release tramadol at 7 days of treatment and 46% of patients at 90 days of treatment. It was reported in 12.2% to 29.7% of patients who received 100 to 400 mg/day coated extended-release tablets, 10% to 12% of patients who received 100 to 300 mg/day dual-matrix extended-release tablets, and 9.3% to 21.3% of patients who received 100 to 300 mg/day extended-release capsules.3 17 18 35

Gastrointestinal effects are among the most common adverse reactions associated with tramadol use. These effects may occur independently or may indicate tramadol-induced hyperserotonergic state; evaluate patients with GI symptoms as appropriate to rule out such a syndrome. In patients receiving immediate-release tramadol, nausea was reported in 24% at 7 days and 40% at 90 days of treatment; the use of extended-release preparations may decrease nausea, as reported rates were 15.1% to 26.2% with coated extended-release tablets, 13% to 14% with dual-matrix extended-release tablets, and 16.1% to 25.1% with extended-release capsules. Vomiting was reported with immediate-release tramadol in 9% at 7 days and 17% at 90 days of treatment; the use of extended-release preparations may decrease vomiting, as reported rates were 5% to 9.4% with coated extended-release tablets, 3% to 6% with dual-matrix extended-release tablets, and 6.5% to 10.4% with extended-release capsules.3 17 18 35 A slow oral dose titration (increasing immediate-release tramadol by 50 mg every 3 days) has been associated with a decreased incidence of nausea and vomiting.3 Concomitant administration of an antiemetic during the first few days of tramadol therapy or with dosage increases may be beneficial. Anorexia was reported in 0.7% to 5.9% of patients who received various forms of tramadol. Other GI effects reported in clinical trials include abdominal pain (1% to less than 5%), upper abdominal pain (1% to less than 5%), flatulence (0.5% to less than 5%), and sore throat (1% to less than 5%). Symptoms reported in less than 1% of study patients receiving some form of tramadol include appendicitis, gastroenteritis, hepatic failure, hepatitis, pancreatitis, stomatitis, toothache (i.e., dental pain), abdominal discomfort, abdominal distension, abdominal tenderness, change in bowel habit, diverticulitis, diverticulum, dysphagia, fecal impaction, GI bleeding, GI irritation, gastroesophageal reflux disease, rectal hemorrhage, rectal prolapse, and retching.3 17 18 35

Somnolence (drowsiness) is among the most common adverse reactions associated with tramadol use. In separate studies, somnolence was reported in 16% to 25% of patients receiving immediate-release tablets (incidence increasing with time up to 90 days), 7.3% to 20.3% of patients receiving extended-release coated tablets, 5% to 7% of those receiving dual-matrix extended-release tablets, and 11.7% to 16.1% of patients receiving extended-release capsules. Study patients experienced malaise at an incidence of 1% to less than 5% with immediate-release tramadol and less than 1% with extended-release tramadol. Lethargy was reported in 1% to less than 5% of patients receiving coated extended-release tablets, though not among those receiving the immediate-release product, dual-matrix extended-release tablets, or extended-release capsules. Similarly, 1% to less than 5% of patients receiving extended-release or dual-matrix extended-release tramadol experienced fatigue and/or weakness; this effect was not reported in patients receiving the immediate-release product or extended-release capsules.3 17 18 35

Pruritus is a common adverse reaction associated with tramadol use. This effect may occur independently or may indicate a hypersensitivity reaction; monitor as appropriate. In patients receiving immediate-release tramadol, pruritus was reported in 8% at 7 days and 11% at 90 days of treatment. Pruritus was reported in 6.2% to 11.9% of patients who received coated extended-release tablets, 3% to 5% of patients who received dual-matrix extended-release tablets, and 3% to 7.3% of patients who received extended-release capsules.3 17 18 35

Asthenia is a common adverse reaction associated with tramadol use. In patients receiving immediate-release tramadol, asthenia was reported in 6% at 7 days and 12% at 90 days of treatment. Asthenia was reported in 3.5% to 6.5% of patients who received coated extended-release tablets, less than 1% of patients who received dual-matrix extended-release tablets, and 3.5% to 8.6% of those who received extended-release capsules.3 17 18 35

Diaphoresis (increased sweating) is a common adverse reaction associated with tramadol use. This effect may occur independently or may indicate a hyperserotonergic state; monitor as appropriate. In patients receiving immediate-release tramadol, diaphoresis was reported in 6% at 7 days and 9% at 90 days of treatment. Diaphoresis was reported in 1.5% to 6.4% of patients who received coated extended-release tablets, 0% to 3% of patients who received dual-matrix extended-release tablets, and 4.2% to 6.7% of patients who received extended-release capsules.3 17 18 35

Dyspepsia is a common adverse reaction associated with tramadol use. In patients receiving immediate-release tramadol, dyspepsia was reported in 5% at 7 days and 13% at 90 days of treatment. Dyspepsia was reported in 1% to less than 5% of patients who received any form of extended-release tramadol.3 17 18 35

Diarrhea is a common adverse reaction associated with tramadol use. This effect may occur independently or may indicate a hyperserotonergic state; monitor as appropriate. In patients receiving immediate-release tramadol, diarrhea was reported in 5% at 7 days and 10% at 90 days of treatment. Diarrhea was reported in 3.7% to 8.5% of patients who received coated extended-release tablets and 1% to less than 5% of patients who received dual matrix extended-release tablets.3 17 18 35

Mouth, nose, or throat-related adverse reactions have been reported with tramadol use. In patients receiving immediate-release tramadol, xerostomia (dry mouth) was reported in 5% at 7 days and 10% at 90 days of treatment. Dry mouth was reported in 5% to 9.8% of patients who received coated extended-release tablets, 1% to 4% of patients who received dual matrix extended-release tablets, and 4.7% to 13.1% of patients who received extended-release capsules.3 17 18 35 Sneezing, cough, rhinorrhea, nasal congestion, and sinus congestion have been reported in 1% to less than 5% of patients receiving extended-release tramadol in clinical trials; yawning has been reported in less than 1% of patients.17

At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function, or cardiac index. Labile blood pressure and/or tachycardia may indicate a tramadol-induced hyperserotonergic state; evaluate any patient with cardiovascular changes as appropriate to rule out this syndrome. Abnormal ECG (0.5% to 1%), bradycardia (less than 1%), hypertension (less than 5%), aggravated hypertension, hypotension (less than 1%), orthostatic hypotension (less than 5.4%), syncope (less than 5%), peripheral vasodilation (less than 5%), palpitations (0.5% to 0.9%), sinus tachycardia (0.5% to 0.9%), flushing (less than 15.8%), hot flashes (or feeling hot; 1% to 4.9%), myocardial ischemia, myocardial infarction (0.5% to 0.9%), peripheral ischemia (0.5% to 0.9%), peripheral edema (1% to 4.9%), pulmonary edema, and pulmonary embolism were reported in clinical trials and/or in postmarketing experience; causal relationships are unknown. Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use; however, many of these cases were reported in patients taking a drug labeled for QT prolongation, in patients with risk factors for QT prolongation, or in tramadol overdose.3 17 18 35

Serotonin syndrome (less than 1%) may occur with tramadol within the recommended doses, especially when used with serotonergic drugs. Advise patients taking opioids concomitantly with a serotonergic medication to seek immediate medical attention if they develop symptoms such as agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea. Symptoms generally present within hours to days of taking an opioid with another serotonergic agent, but may also occur later, particularly after a dosage increase. If serotonin syndrome is suspected, either the opioid and/or the other agent should be discontinued.3 17 18 35 53

CNS stimulation (consisting of nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional lability, and hallucinations) has been reported in 7% of patients receiving immediate-release tramadol at 7 days and 14% at 90 days of treatment. Individual symptoms of CNS stimulation have been noted in trials for extended-release formulations of tramadol, including nervousness (less than 5%), anxiety (1% to less than 5%), agitation (less than 5%), depression (less than 5%), tremor (1% to less than 5%), euphoria (less than 5%), emotional disturbance (less than 1%), paresthesias (less than 5%), and hypertonia (less than 5%). As CNS changes may occur as part of the constellation of symptoms of tramadol-induced hyperserotonergic state, evaluate any patient with such symptoms as appropriate to rule out this syndrome. Insomnia or sleep disorder occurred in 1% to 10.9% of patients receiving immediate-release or extended-release forms of tramadol. Other CNS effects reported in 1% to less than 5% of patients in premarketing trials of 1 or more tramadol dosage formulations include blurred vision, confusion, coordination disturbance, depersonalization, hypoesthesia, indifference or apathy, miosis, restlessness, and visual impairment. Those reported in less than 1% of tramadol study patients include abnormal dreams, abnormal gait or ataxia, abnormal thinking, amnesia, clamminess, impaired cognition or difficulty in concentration, disorientation, hyperkinesis, irritability, night sweats, pallor, sedation, sleep apnea syndrome, suicidal ideation or tendency, and twitching. Dysphonia (speech disorders) and delirium have also been reported during postmarketing experience.3 17 18 35 Seizures (less than 1%) have been reported with tramadol use in humans; patients with an existing seizure disorder are at greatest risk. Seizures have occurred at recommended doses as well as at high doses. Concomitant treatment with drugs that lower the seizure threshold including selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics), tricyclic antidepressants, other opioid agonists, MAOIs, or neuroleptics may increase the risk of seizures.54 55 A case report details a fatal seizure reaction in an alcoholic adult concomitantly taking tramadol with acetaminophen and several other drugs that increase this risk.56

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression may lead to respiratory arrest and death if not immediately treated. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Administer naloxone cautiously in these situations due to an increased risk of seizures.3 Instruct patients and caregivers to stop use of tramadol and seek immediate medical attention if signs of overdose (slow or shallow breathing, difficult or noisy breathing, unusual sleepiness, or confusion) are observed.6 Severe respiratory depression has been reported in a 5-year-old child with ultra-rapid CYP2D6 genotype and obstructive sleep apnea, who received a single 20 mg dose (approximately 1 mg/kg) of tramadol for postoperative pain related to adenotonsillectomy.57 In adult clinical trials, dyspnea has been reported in 5% or less of patients receiving tramadol.3 17 18 58 35

Serious, and rarely fatal, anaphylactoid reactions have been reported in patients receiving tramadol. Other allergic manifestations associated with tramadol include urticaria (less than 1%), bronchospasm, angioedema, rash, vesicles (less than 1%), Stevens-Johnson syndrome (less than 1%), and toxic epidermal necrolysis (less than 1%). Dermatitis and rash have been reported in 1% to less than 5% of patients receiving extended-release tramadol and allergic dermatitis, undefined hair disorder, and undefined skin disorder have been reported in less than 1% of patients. In contrast to morphine, tramadol has not been shown to cause histamine release.3 17 18 35

As with other opioid agonists, tramadol presents the potential for abuse or psychological dependence. Accidental and non-accidental overdose of this medication may occur. Physiological dependence, as evidenced by a withdrawal syndrome occurring after abrupt discontinuation of the drug, has been reported and may occur in any patient during chronic opioid therapy. A withdrawal syndrome was reported during clinical trials of tramadol extended-release tablets (0.5% to less than 1%) and extended-release capsules (1% to less than 5%).17 35 Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate may also occur.3 With parenteral abuse of the extended-release tablets, the tablet excipients can result in local tissue necrosis, infections, pulmonary granulomas, embolism and death, and increased risk of endocarditis and valvular heart injury.17 Routine use of opioid agonists, such as tramadol, by an expectant mother can lead to depressed respiration in the newborn and a neonatal opioid withdrawal syndrome. Neonatal opioid withdrawal syndrome is estimated to occur in up to 50% of neonates born to opioid-dependent mothers.59 Withdrawal symptoms may include irritability, hyperactivity, abnormal sleep pattern, tremor, high-pitched crying, vomiting, diarrhea, poor feeding, failure to gain weight, rigidity, and seizures. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn. Monitor neonates exposed to tramadol closely as neonatal opioid withdrawal can be life-threatening if not recognized and treated. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal.3 Neonatal seizures, neonatal opioid withdrawal syndrome, fetal death, and still birth have been reported with tramadol in postmarketing experience.3 17 18 35

Headache was reported in 18% and 32% of patients treated with immediate-release tramadol at 7 and 90 days of treatment, respectively. It has also been reported in 11.5% to 15.8% of patients who received coated extended-release tablets, 3% to 5% of patients who received dual-matrix extended-release tablets, and 19% to 23.1% of patients who received extended-release capsules. Migraine has been reported infrequently in clinical trials and/or in postmarketing experience of immediate-release tramadol and in 0.5% to less than 1% of patients on some forms of extended-release tramadol.3 17 18 35 Overuse of analgesics such as tramadol products by headache-prone patients frequently produces drug-induced rebound headache accompanied by dependence on symptomatic medication, tolerance (refractoriness to prophylactic medication), and withdrawal symptoms. In this case, overuse of tramadol products has been defined as taking 3 or more doses per day more often than 3 to 5 days per week.60 The frequency of use may be more important than the dose. Features of a rebound headache include morning headache, end-of-dosing interval headache, or headache improvement with discontinuation of overused medication. Stopping the symptomatic medication may result in a period of increased headache and then headache improvement. Analgesic overuse may be responsible for the transformation of episodic migraine or episodic tension headache into daily headache and may perpetuate the syndrome.60

Urogenital adverse effects have been reported during tramadol use. Increased urinary frequency and urinary retention have been reported in 0.5% to less than 5% of patients who received tramadol. Unspecified urine abnormalities were reported in less than 5% of patients who received extended-release capsules. Other urogenital disorders that have been reported with tramadol in less than 1% of patients include dysuria, difficulty in micturition, urinary hesitation, hematuria, proteinuria, menopausal symptoms, and menstrual irregularity.3 17 18 35

Although no causal relationships have been established, infection and infestations have been reported during clinical trials with tramadol; 1% to less than 5% of patients experienced influenza-like illness, naso-pharyngitis, respiratory tract infection, chills, rhinitis, sinusitis, influenza, viral gastroenteritis, urinary tract infections, or bronchitis, and less than 1% of patients experienced cellulitis, cystitis, ear infection, gastroenteritis, pneumonia, or viral infection. Fever was reported in less than 5% of patients receiving tramadol.3 17 18 35

Laboratory abnormalities have rarely been reported with tramadol use; no causal relationships are established. In separate clinical studies, 1% to less than 5% of patients receiving some form of either immediate-release or extended-release tramadol have experienced increased blood creatine phosphokinase; less than 1% were noted to have abnormal blood potassium, decreased hemoglobin, thrombocytopenia, lowered or elevated hepatic enzymes (including decreased or increased alanine aminotransferase [ALT or SGPT], decreased or increased aspartate aminotransferase [AST or SGOT], and increased gamma glutamyltransferase [GGT]), increased blood amylase, increased serum creatinine, or increased blood urea nitrogen (BUN). Increased blood glucose or hyperglycemia was noted in 0.5% to less than 1% of patients who received coated extended-release tablets and 1% to less than 5% of those who received extended-release capsules in separate trials. Cases of hypoglycemia have been reported very rarely in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in geriatric patients.3 17 18 35 38

Unquantified weight loss has been reported during tramadol use. In separate trials, weight loss was noted in less than 1% of patients receiving immediate-release tramadol and 1% to less than 5% of patients receiving extended-release formulations.3 17 18 35

Hepatobiliary disorders have been reported infrequently during tramadol use. Cholelithiasis (less than 1%), cholecystitis (0.5% to 1%), or other biliary tract disorders (less than 1%) have been reported in patients receiving extended-release tablets; these effects were not noted in patients receiving the immediate-release product or extended-release capsules during clinical trials.3 17 18 35

Cataracts (less than 1%), lacrimation disorder (0.5% to less than 1%), undefined eye disorder (0.5% to less than 1%), hearing loss or deafness (less than 1%), tinnitus (1% or less), dysgeusia (less than 1%), and mydriasis have been reported during clinical trials or in postmarketing experience with various dosage forms of tramadol.3 17 18 35 38

Musculoskeletal adverse events have been noted during tramadol use. Arthralgia has been reported in 1% to 5.4% of patients using extended-release dosage forms. Pain, falls, rigors, back pain, pain in limb, pelvic pain, and neck pain have been reported in 1% to less than 5% of patients receiving various forms of extended-release tramadol during clinical trials; 0.5% to less than 1% reported ecchymosis, gout, arthrosis, neck rigidity, joint swelling, joint disorder, leg or muscle cramps, muscle spasms, joint stiffness, muscle twitching, and arthritis or aggravation of osteoarthritis. Accidental injury and myalgia were reported in 0.5% to 5% of patients. Contusion, joint sprain, and muscle injury were reported in less than 1% of patients receiving immediate-release tramadol.3 17 18 35

Opioid agonists can interfere with the endocrine system by inhibiting the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH), and by stimulating secretion of prolactin, growth hormone (GH), insulin, and glucagon. Chronic opioid use may influence the hypothalamic-pituitary-gonadal axis, leading to hormonal changes that may manifest as hypogonadism (gonadal suppression). Although the exact causal role of opioids in the clinical manifestations of hypogonadism is unknown, patients could experience libido decrease, impotence, amenorrhea, or infertility. Sexual dysfunction, including impotence (erectile dysfunction) and libido decrease, has been reported in less than 1% of patients receiving extended-release tramadol in clinical trials. In those taking extended-release tramadol capsules, unspecified prostatic disorders and sexual function abnormalities were reported in less than 5% and less than 1% of patients, respectively. Other various medical, physical, lifestyle, and psychological stressors may influence gonadal hormone concentrations; these stressors have not been adequately controlled for in clinical studies with opioids. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.3 17 18 35 53 A drug-induced decrease in thyrotropin release leads to a decrease in thyroid hormone. Morphine and related compounds can stimulate the release of vasopressin (ADH). Hyponatremia can occur as a result of SIADH.61 62 63

Opioids may interfere with the endocrine system by inhibiting the secretion of adrenocorticotropic hormone (ACTH) and cortisol. Rarely, adrenocortical insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency.53

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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