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

Tadalafil

Tadalafil is a selective phosphodiesterase (PDE) type 5 inhibitor similar to sildenafil and vardenafil. It is administered orally for the treatment of male erectile dysfunction (ED), pulmonary arterial hypertension (PAH), benign prostatic hypertrophy (BPH), or the concurrent treatment of erectile dysfunction and BPH. Tadalafil does not inhibit prostaglandins as do some agents for treating impotence (e.g., alprostadil). Unlike sildenafil, visual disturbances have not been reported with tadalafil, which is more selective for PDE5 than for PDE6 present in the retina. The duration of action of tadalafil for the treatment of ED (up to 36 hours) appears to be longer than that of sildenafil and vardenafil. Because PDE inhibitors promote erection only in the presence of sexual stimulation, the longer duration of action of tadalafil allows for more spontaneity in sexual activity. According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy.1 Tadalafil was in phase II trials for the treatment of female sexual dysfunction, however, further investigation was discontinued. FDA approval was granted November 2003 for treatment of male erectile dysfunction (ED), and in January 2008, approval was granted for once daily use without regard to timing of sexual activity. Tadalafil (Adcirca) was FDA approved for the treatment of pulmonary arterial hypertension (PAH) in May 2009. In clinical studies of patients with pulmonary arterial hypertension (PAH), tadalafil-treated patients experienced improved exercise capacity and less clinical worsening compared to placebo. In October 2011, tadalafil received FDA approval for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) and for the concurrent treatment of erectile dysfunction and BPH.

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.

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. 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.

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.

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. 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.

Tadalafil

Tadalafil 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. Tadalafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Tadalafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. In vitro studies show that tadalafil is selective for PDE5 and is 10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is 10,000 fold more potent for PDE5 than for PDE3 found in the heart and blood vessels. Also, tadalafil has 700-fold greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Compare this selectivity to the selectivity of sildenafil which has only a 10-fold selectivity for PDE5 versus PDE6. This lower selectivity of sildenafil for PDE5 vs PDE6 is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of sildenafil. Further, tadalafil is 9000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4. PDE11 is an enzyme found in human skeletal muscle, prostate, testes, and in other tissues. Inhibition of human recombinant PDE11A1, and to a lesser extent, PDE11A4 activities occur at tadalafil concentrations within the therapeutic range. The physiological role and clinical effects of PDE11 inhibition in humans have not been elucidated.

The mechanism by which tadalafil reduces the symptoms of benign prostatic hyperplasia (BPH) has not been established; however, the effect of PDE5 inhibition on cGMP concentrations in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, bladder, and their vascular supply.

Tadalafil can inhibit PDE5 present in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in relaxation of pulmonary vascular smooth muscle and subsequent pulmonary vasodilation, thereby making tadalafil an effective agent 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 most common adverse reactions associated with PDE5 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. 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.

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.

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.

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.

Tadalafil

Tadalafil is administered orally. The pharmacokinetics of tadalafil were evaluated in healthy young volunteers. Once absorbed, tadalafil is distributed into the tissues. Protein binding is 94% at therapeutic concentrations. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects. The primary route of elimination for tadalfil is via the hepatic cytochrome P450 isoenzyme CYP3A4, which metabolizes the drug to a catechol metabolite. The catechol metabolite undergoes extensive methylation to form the methylcatechol metabolite and then glucuronidation to the form the methylcatechol glucuronide conjugate. The major circulating metabolite is the methylcatechol glucuronide, which is 13,000 times less potent for PDE5 than tadalafil. Methylcatechol concentrations are less than 10% of glucuronide concentrations. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose). The mean elimination half-life is 17.5 hours in healthy subjects.

Special Populations:

Hepatic Impairment: In patients with mild to moderate hepatic impairment (Child-Pugh class A or B), the AUC following a 10 mg tadalafil dose was comparable to that of healthy subjects. There are no data available for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Tadalafil has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment: In clinical pharmacology studies involving persons with mild (CrCl 51—80 ml/min) or moderate renal impairment (CrCl 31—50 ml/min), tadalafil AUC was doubled after single doses of 5 to 10 mg compared to persons with normal renal function. In those with end-stage renal disease on hemodialysis, there was a two-fold increase in Cmax and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in patients with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) had negligible effects on tadalafil or metabolite clearance.

Pediatrics: Tadalafil has not been studied in persons less than 18 years of age.

Geriatric: In a healthy volunteer study of elderly males ( = 65 years) and younger males (19—45 years), the AUC of tadalafil was 25% higher in the elderly males with no effect on Cmax. In patients with benign prostatic hyperplasia (BPH) receiving single and multiple doses of tadalafil 20 mg, there were no statistically significant differences in AUC and Cmax in elderly (70—85 years of age) patients compared to younger patients (<= 60 years of age). No dosage adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered.

Diabetes mellitus: In male patients with diabetes mellitus after a 10 mg tadalafil dose, AUC was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dosage adjustment is necessary in diabetic patients as long as organ function is normal.

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.

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. Affected cytochrome P450 isoenzymes and drug transporters: CYP2B6, CYP2D6, CYP3A4 Tramadol is a substrate of CYP2B6, CYP2D6, and CYP3A4.

Tadalafil

Your health care provider needs to know if you have any of these conditions: bleeding disorders; eye or vision problems, including retinitis pigmentosa; Peyronie’s disease, or history of priapism (painful and prolonged erection); heart disease, angina, a history of heart attack, irregular heart beats; high or low blood pressure; history of blood diseases; history of stomach bleeding; kidney disease; liver disease; stroke; an unusual or allergic reaction to tadalafil. If you notice any changes in your vision while taking this drug, call your doctor or health care professional as soon as possible. Stop using this medicine and call your healthcare provider right away if you have a loss of sight in one or both eyes. Contact your healthcare provider right away if the erection lasts longer than 4 hours or if it becomes painful. If you experience symptoms of nausea, dizziness, chest pain or arm pain upon initiation of sexual activity after taking this medicine, you should refrain from further activity and call your healthcare provider immediately. Do not drink alcohol when taking this medicine as alcohol can increase your chances of getting a headache or getting dizzy, increasing your heart rate or lowering your blood pressure. Using this medicine does not protect you or your partner against HIV infection or other sexually transmitted infections.

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

Because the efficacy of concurrent use of tadalafil and alpha-blockers in the treatment of benign prostatic hyperplasia (BPH) has not been adequately studied, and due to the potential vasodilatory effects of such combination treatment, tadalafil is not recommended for use with alpha-blockers when treating BPH (see Drug Interactions).

Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Consistent with its known effects on the nitric oxide/cGMP pathway, tadalafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive tadalafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once tadalafil has been administered.

Use tadalafil cautiously in patients with renal impairment. Dosing recommendations vary depending upon the severity of renal impairment, indication, and the dosing regimen being used (see Dosage in renal impairment). Tadalafil is not recommended in patients receiving the drug on a once daily basis for erectile dysfunction, benign prostatic hyperplasia, or pulmonary arterial hypertension when the creatinine clearance is less than 30 ml/min or the patient has renal failure or is receiving dialysis.

Use tadalafil with caution in patients with altered hepatic function secondary to hepatic disease and/or drug-induced inhibition. Dosage modifications are needed in patients with mild to moderate hepatic impairment (see Dosage). In patients with severe hepatic impairment, use of tadalafil is not recommended because of insufficient data. Additionally, tadalafil is metabolized by CYP3A4 in the liver. Dosage adjustments are necessary in patients taking potent CYP3A4 inhibitors such as ritonavir, ketoconazole, and itraconazole (see Dosage and Drug Interactions).

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. Tadalafil and other PDE5 inhibitors have mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. The following groups of patients with cardiac disease were excluded from clinical safety and efficacy trials for tadalafil, and, therefore, the manufacturer does not recommend the use of tadalafil in these groups until more data are available: myocardial infarction within the last 90 days; coronary artery disease resulting in unstable angina or angina occurring during sexual intercourse; NYHA Class II or greater heart failure in the last 6 months; uncontrolled cardiac arrhythmias; hypotension (< 90/50 mmHg); uncontrolled hypertension ( 170/100 mmHg); or a stroke within the last 6 months. Based on recommendations for sildenafil by the American College of Cardiology, it is recommended that tadalafil be used with caution in the following: patients with active coronary ischemia (angina) 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 (hypovolemia); patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of tadalafil. Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Also, patients with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) or severely impaired autonomic control of blood pressure can be sensitive to the action of vasodilators, including PDE5 inhibitors. Due to the pulmonary vasodilation caused by tadalafil, patients with pulmonary veno-occlusive disease (PVOD) may experience significant worsening in cardiovascular status. Due to a lack of clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. The possibility of associated PVOD should be considered should signs of pulmonary edema occur when tadalafil is administered.

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. Use tadalafil, and other agents for the treatment of erectile dysfunction, 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).

Educate patients that tadalafil, when used for erectile dysfunction, offers no protection against sexually transmitted disease. Counsel patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, as appropriate to the individual circumstances.

Use tadalafil cautiously in patients with pre-existing visual disturbance. Post-marketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors. 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. Although visual disturbances have been reported rarely with tadalafil, there is no safety information on the administration of tadalafil to 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. Therefore, it is recommended that tadalafil not be administered to these patients until further data are available.

Geriatric patients ( = 65 years) made up approximately 25% of patients in the primary efficacy and safety studies of tadalafil for the treatment of erectile dysfunction and 28% of patients in the clinical study of tadalafil for pulmonary arterial hypertension. In clinical trials for benign prostatic hyperplasia, geriatric patients greater than 65 years of age accounted for 40% of study participants and those 75 years of age and older accounted for 10% of study participants. No overall differences in efficacy and safety were observed between older and younger patients for these indications. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered.

Prior to initiating treatment with tadalafil for benign prostatic hyperplasia (BPH), consideration should be given to other urological conditions that may cause similar symptoms. Prostate cancer and benign prostatic hyperplasia (BPH) cause many of the same symptoms and frequently they coexist. Prior to starting tadalafil therapy for BPH, patients should be evaluated to rule out the presence of prostate cancer.

Tadalafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies of tadalafil in pregnant women. According to the manufacturer, Adcirca should be used during pregnancy only if clearly needed; Tadalafil is not indicated for use in women.

Use tadalafil cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Like sildenafil, tadalafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility. Additionally, tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), which is found in platelets. Some data indicate that tadalafil does not potentiate the increase in bleeding time caused by aspirin. However, the manufacturer recommends caution when administering tadalafil to patients with significant active peptic ulcer disease (PUD) since the effects of the drug in this patient population have not been formally studied.

It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breast-feeding women; Tadalafil is not indicated for use in women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), which is found in platelets. Some data indicate that tadalafil does not potentiate the increase in bleeding time caused by aspirin. However, the manufacturer recommends caution when administering tadalafil to patients with significant hematological disease (e.g., bleeding disorders) since the effects of the drug in this patient population have not been formally studied.

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. 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. 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.

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.

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.

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.

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. 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.

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.

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. 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. 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.

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. 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. 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.

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.

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. 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. 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.

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. 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.

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.

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.

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.

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.

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.

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.

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.

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. 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. 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. n 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. 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.

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. 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. 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. 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).

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.

Tadalafil

Tadalafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies of tadalafil in pregnant women. According to the manufacturer, Adcirca should be used during pregnancy only if clearly needed; Tadalafil is not indicated for use in women.

Dextromethorphan HBr

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. 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.

Tramadol HCl

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. 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.

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. 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. 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.

Tadalafil

It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breast-feeding women; Tadalafil is not indicated for use in women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated coAnchorndition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Dextromethorphan HBr

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.

Tramadol HCl

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. 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. Alternative analgesics that previous American Academy of Pediatrics recommendations considered as usually compatible with breast-feeding include acetaminophen, ibuprofen, and morphine. 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. 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).

Tadalafil

Back pain; dizziness; flushing; headache; indigestion; muscle aches; nausea; stuffy or runny nose. This list may not describe all possible side effects. Call your healthcare provider immediate if you experience signs of an allergic reaction like skin rash, itching or hives, swelling of the face, lips, or tongue; breathing problems; changes in hearing; changes in vision; chest pain; erection lasting more than 4 hours; fast, irregular heartbeat; seizures.

Adverse reactions to tadalafil for the treatment of erectile dysfunction (ED) were evaluated based on worldwide clinical trials of tadalafil involving over 5700 men (mean age 59, range 22 to 88 years). Over 100 patients were treated for 1 year or longer and over 1300 were treated for 6 months or more. During placebo-controlled trials, the discontinuation rate for patients treated with tadalafil (10 or 20 mg) was 3.1% compared to 1.4% in placebo-treated patients. In the treatment of patients with elevated pulmonary arterial pressures (PAH), adverse reactions to tadalafil were evaluated based on worldwide clinical trials involving 398 patients; 311 patients were treated for at least 182 days and 251 patients were treated for at least 360 days. During placebo-controlled trials, the overall rate of discontinuation due to an adverse event was higher in placebo-treated patients than in patients treated with tadalafil 40 mg/day (15% vs. 9%, respectively). In addition, the rate of discontinuation due to an adverse event not related to worsening of PAH was 5% in placebo-treated patients compared to 4% in patients treated with tadalafil 40 mg/day. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the rate of discontinuation due to an adverse effect was 3.6% of tadalafil-treated patients versus 1.6% of placebo-treated patients, and the mean age of study participants was 63 years.

During clinical trials, hypotension was reported in < 2% and hypertension was reported in 1—3% of all tadalafil recipients. The risk for serious hypotension is augmented by the use of nitrates; therefore, the use of tadalafil in patients receiving nitrate therapy is contraindicated. Other cardiac effects reported in less than 2% of patients during clinical trials include angina, chest pain (unspecified), myocardial infarction, orthostatic hypotension, palpitations, syncope, and sinus tachycardia. Sudden cardiac death, stroke, chest pain, palpitations, and sinus tachycardia have all been noted in post-marketing experience with tadalafil. Most of the affected patients had pre-existing cardiovascular risk factors. Many of these events occurred during or shortly after sexual activity. In some cases, the symptoms occurred hours to days after the use of tadalafil and sexual activity. The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure (hypotension) were observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of nitrates. In addition, tadalafil (20 mg) had no significant effect on supine or standing systolic and diastolic blood pressure in healthy male subjects compared to placebo; there was also no significant effect on heart rate.

The effect of a single 100-mg dose of tadalafil on QT prolongation was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide)-controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc for tadalafil, relative to placebo, was 2.8 milliseconds using Individual QT correction and 3.5 milliseconds using Fridericia QT correction. A 100-mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100-mg dose of tadalafil compared to placebo was 3.1 beats per minute.

During clinical trials, adverse reactions occurring = 2% of patients with erectile dysfunction, = 9% of patients with pulmonary arterial hypertension, and more frequently in the tadalafil-treated groups than placebo included back pain (2—12%), myalgia (1—14%), and pain in limb (1—3%). Adverse musculoskeletal reactions reported in < 2% of tadalafil recipients included arthralgia and neck pain. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following musculoskeletal effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: back pain (2.4% vs 1.4%), extremity musculoskeletal pain (1.4% vs 0%), and myalgia (1.2% vs 0.3%). Adverse musculoskeletal effects reported in less than 1% of patients included arthralgia and muscle spasms. Myalgia lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia was described as diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. Generally, pain was reported as mild or moderate in severity and resolved without medical treatment; severe back pain was reported infrequently. When medical treatment was needed, acetaminophen or NSAIDs were generally effective; however, in a small number of patients who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all tadalafil-treated patients discontinued treatment due to back pain/myalgia. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no medically significant underlying pathology.

Headache occurred in 3—15% of patients during erectile dysfunction clinical trials and in 32—42% of patients during pulmonary arterial hypertension clinical trials; headache was reported more frequently in the tadalafil-treated groups than placebo. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following centrally-mediated effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: headache (4.1% vs 2.3%) and dizziness (1% vs 0.5%). Headache lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. Adverse reactions reported in < 2% of tadalafil recipients during clinical trials and affecting the nervous system included hypoesthesia, insomnia, dizziness, paresthesias, vertigo, and somnolence or drowsiness. Migraine, transient global amnesia, seizures, and seizure recurrence have been reported during post-marketing use of tadalafil; due to the voluntary nature of the reports, the frequency of post-marketing adverse reactions is unknown and causality to the drug has not been established.

Dyspepsia occurred in 1—10% of patients during erectile dysfunction (ED) clinical trials and in 10—13% of patients in pulmonary arterial hypertension clinical trials; dyspepsia was reported more frequently in the tadalafil-treated groups than placebo. Other gastrointestinal/digestive adverse reactions reported by tadalafil recipients and more frequently than placebo included nausea (1—11%), viral gastroenteritis (3—5%), gastroesophageal reflux (1—3%), abdominal pain (1—2%), and diarrhea (1—2%). During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following gastrointestinal effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: dyspepsia (2.4% vs 0.2%) and diarrhea (1.4% vs 1%). Adverse GI reactions reported in less than 1% of patients included gastroesophageal reflux disease, upper abdominal pain, nausea, and vomiting. Upper abdominal pain lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. Dysphagia, elevated hepatic enzymes, esophagitis, gastritis, vomiting, increased GGTP, loose stools, upper abdominal pain, hemorrhoidal hemorrhage, rectal hemorrhage, and xerostomia were reported in < 2% of patients treated with tadalafil during clinical trials.

Nasal congestion occurred in 2—4% of patients during erectile dysfunction clinical trials and in 9% of patients during pulmonary arterial hypertension clinical trials; nasal congestion was reported more frequently in the tadalafil-treated groups than placebo. In addition, pharyngitis (reported as nasopharyngitis, 1—13%), upper and lower respiratory tract infection (3—13%), influenza (2—5%), cough (2—4%), bronchitis (2%), and urinary tract infection (2%) were reported in tadalafil-treated patients during clinical trials. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, nasopharyngitis occurred more frequently in tadalafil-treated patients (2.1%) than placebo-treated patients (1.6%). Dyspnea, epistaxis, and pharyngitis were reported in less than 2% of patients in clinical trials.

Flushing occurred in 1—3% of patients during erectile dysfunction clinical trials and in 6—13% of patients during pulmonary arterial hypertension clinical trials; flushing was reported more frequently in the tadalafil-treated groups than those groups receiving placebo.

During clinical trials, blepharedema or swelling of the eyelids, conjunctivitis, increased lacrimation, and ocular pain were reported in < 2% of tadalafil recipients.

Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (n=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (< 0.1% of patients). Post-marketing reports have included cases of visual impairment such as retinal vein occlusion and visual field defects. Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors. 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 (< 2%) 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, high blood pressure, coronary artery disease, hyperlipidemia, and smoking. Additionally, two patients had retinal detachment and one patient had hypoplastic optic neuropathy. 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 tadalafil 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.

There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for PDE5 inhibitors, such as tadalafil. 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. During clinical trial evaluation of tadalafil, genitourinary effects including increased erection, spontaneous penile erection, and renal impairment (unspecified) were reported in less than 2% of study patients receiving the drug.

During clinical trial evaluation of tadalafil, the following general adverse events were reported in less than 2% of patients receiving tadalafil: asthenia, facial edema, fatigue, and pain (unspecified).

During clinical trial evaluation of tadalafil, the following dermatologic effects were reported in less than 2% of study patients: pruritus, rash (unspecified), and hyperhidrosis. Stevens-Johnson syndrome, exfoliative dermatitis, and urticaria have all been noted in post-marketing experience with tadalafil. Due to the uncontrolled and voluntary nature of post-marketing reports, neither the frequency nor a definitive causal relationship to tadalafil can be established.

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.

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.

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.

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.

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. 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. 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.

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.

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.

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.

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.

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.

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.

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. 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.

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.

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.

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. 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. 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.

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. 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. 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. In adult clinical trials, dyspnea has been reported in 5% or less of patients receiving tramadol.

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.

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%). 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. 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. 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. 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. Neonatal seizures, neonatal opioid withdrawal syndrome, fetal death, and still birth have been reported with tramadol in postmarketing experience.

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. 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. 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.

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.

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.

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.

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.

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.

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.

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.

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. 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.

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.

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.

You can order Tadalafil / Dextromethorphan HBr / Tramadol HCl Capsules from MediLab’s compounding pharmacy in the following Florida regions:

North Florida	South Florida
Jacksonville	Miami	West Palm Beach	Weston
Pensacola	Hialeah	Pompano Beach	Delray Beach
Tallahassee	Fort Lauderdale	Davie	Homestead
Ocala	Port St. Lucie	Miami Beach	Tamarac
Gainesville	Pembroke Pines	Plantation	Sarasota
Fort Walton Beach	Hollywood	Sunrise	Wellington
Panama City	Miramar	Boca Raton	Jupiter
Palm Coast	Coral Springs	Deerfield Beach	Margate
Dunnellon	Miami Gardens	Boynton Beach	Coconut Creek
	Naples	Lauderhill	Broward
	Spring hill	Orlando

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