Sildenafil / Dextromethorphan HBr / Tramadol HCl Capsule

Sildenafil

Sildenafil is a vasoactive agent that is commonly prescribed to treat erectile dysfunction (impotence) in men, and to reduce symptoms in patients with pulmonary arterial hypertension (PAH). By decreasing vascular resistance and relaxing muscles, sildenafil increases blood flow to particular areas of the body including the penis. Sildenafil is generally taken 30 to 60 minutes prior to sexual intercourse, sildenafil troche may be taken up to 10 minutes before intercourse.

Sildenafil is regarded as the most popular erectile dysfunction drug. Sildenafil was developed by a group of pharmaceutical chemists at Pfizer’s facility in Kent, England who worked together to synthesize sildenafil. The medication was initially formulated to treat hypertension (a symptom of ischaemic heart disease) and chest pains caused from the inadequacy of the blood circulation to the heart. The drug was tried on men in Morriston Hospital (Swansea), in 1991 and 1992. Its clinical trials were conducted under the supervision of Ian Osterloh, who suggested that the drug had very little effects on treating angina, but effected significant changes in penile erections. Pfizer decided to commercialize the drug as a treatment for erectile dysfunction.

Sildenafil belongs to the phosphodiesterase type 5 (PDE5) inhibitors drug class. Sildenafil was originally developed as an antianginal agent but was found to be more effective in treating erectile dysfunction (ED). Sildenafil continues to be studied clinically to assess its utility in treating sexual dysfunction in females, but initial studies have found sildenafil to provide results similar to placebo in women. In regard to ED, sildenafil was tested in more than 4000 men in 21 clinical trials. The average age of these men was 55 years and they had ED for an average of 5 years before entering the study. Sildenafil was effective in roughly 70% of subjects. Response rates of 90% have been achieved in trials of male patients with psychogenic ED. Sildenafil may also be effective in male patients with ED related to diabetes mellitus or due to pelvic fracture urethral disruption. Sildenafil has been shown to be effective and well tolerated in patients on multidrug antihypertensive regimens and not associated with additional safety risks in these patients. According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy. Final FDA approval for sildenafil for the treatment of ED was granted in March 1998.

Shortly after approval for ED, studies showed sildenafil was effective in treating patients with pulmonary arterial hypertension (PAH). Sildenafil improved exercise capacity as well as mean pulmonary artery pressure and other measures of cardiac function in patients with PAH. Sildenafil is the first oral therapy approved for treating early stages of PAH. Although preliminary data from 12 patients with sickle cell anemia showed a decrease in PAH, a larger clinical trial (n = 134) investigating the use of sildenafil for pulmonary hypertension in adults with sickle cell anemia was stopped early due to an increased risk of severe adverse effects, especially sickle cell pain crises, compared to placebo (38% vs. 8%, respectively). The reason for the increased risk of pain is unknown; however, in the initial trial, patients were aggressively treated with transfusions and hydroxyurea to control crises; the larger trial offered no intervention for crises. Sildenafil has also shown efficacy in treating altitude sickness. The oral formulation of sildenafil (Revatio) was approved by the FDA for treatment of pulmonary arterial hypertension (PAH) in June 2005; the injectable formulation was approved in November 2009.

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.

Sildenafil

Sildenafil 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. Sildenafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Sildenafil 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 sildenafil is selective for PDE5 and its effect is more potent on PDE5 than on other known phosphodiesterases (>80-fold for PDE1, >1,000-fold for PDE2, PDE3, and PDE4). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is one-tenth as potent for PDE6, an enzyme found in the retina, as it is for PDE5; this lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of the drug.

As reported by the manufacturer, the pharmacodynamic response to sildenafil was assessed in eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction. In these studies sexual stimulation resulted in improved erections, as assessed by penile plethysmography, after sildenafil administration compared with placebo. Most studies evaluated the efficacy of sildenafil approximately 60 minutes post dose. The erectile response, as determined by penile plethysmography, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study. The effects of sildenafil were evident for up to 4 hours but the response was diminished compared to 2 hours.

Sildenafil can inhibit PDE5 present in esophageal smooth muscle, lung tissue, and brain tissue. Inhibition of PDE5 in lung tissue results in relaxation of pulmonary vascular smooth muscle and subsequently pulmonary vasodilation, thereby making sildenafil an effective agent in treating pulmonary hypertension. Inhibition of PDE5 present in esophageal smooth muscle can cause a marked inhibition of esophageal motility as well as a reduction 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). Sildenafil has been shown to cross the blood-brain barrier and inhibit PDE5 in cerebral blood vessels. The areas of the brain that have the highest activity of PDE5 are the hippocampus, cerebral cortex, and basal ganglia. Although clinical studies have not proven this effect, inhibition of PDE5 by sildenafil in the brain may result in emotional, neurological, and psychological effects (see Adverse Reactions).

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.

Sildenafil

Who should not take this medication? Do not take this medicine with any of the following medications: cisapride; methscopolamine nitrate; nitrates like amyl nitrite, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin; nitroprusside; other medicines for erectile dysfunction like tadalafil, vardenafil; other sildenafil products. 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; heart disease, angina, a history of heart attack, irregular heartbeats, or other heart problems; high or low blood pressure; history of blood diseases; history of stomach bleeding; kidney disease; liver disease; stroke; an unusual or allergic reaction to sildenafil or other products. If you notice any changes in your vision while taking this drug, call your healthcare provider immediately. 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 use alcohol while using this medicine. Using this medicine does not protect you or your partner against HIV infection or other sexually transmitted infections..

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

The use of sildenafil is not recommended in patients with pulmonary veno-occlusive disease (PVOD). Administration of sildenafil in this population may significantly worsen cardiovascular status. In addition, if signs of pulmonary edema occur during sildenafil administration, the possibility of associated PVOD should be considered.

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

The following factors are associated with up to an eight time increase in plasma concentrations of sildenafil compared with healthy subjects: geriatric patients (40% increase in sildenafil AUC), hepatic disease (e.g., cirrhosis, 80% increase), severe renal impairment (i.e., CrCl < 30 ml/min, 100% increase), concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin (182% increase), itraconazole, ketoconazole, saquinavir (210% increase)). Because higher plasma concentrations may increase the incidence of adverse reactions, the sildenafil starting dose should be 25 mg in these patients. Additionally, ritonavir greatly increased the systemic concentrations of sildenafil in a study of healthy, non-HIV infected volunteers (11-fold increase in AUC). Based on these pharmacokinetic data, it is recommended not to exceed a maximum single dose of 25 mg sildenafil in a 48 hour period.

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. Over 75 deaths due to cardiovascular events have been reported in association with sildenafil use. In a study conducted at the Mayo Clinic, sildenafil was shown to have limited cardiovascular effects during exercise in men with known or probable coronary artery disease. The study reported that sildenafil had no effect on exercise capacity or the hemodynamic response to exercise. Systolic blood pressure was reduced an average of 7 mmHg compared to baseline. Another study showed that sildenafil inhibited beta-adrenergic-stimulated systolic function. Using dobutamine in healthy volunteers, investigators reported that sildenafil suppressed the cardiac response to dobutamine but had minimal effect under resting conditions. It was also reported that the effects of sildenafil were independent of cardiac afterload or preload changes. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. In particular, caution should be used if sildenafil is prescribed in the following patient groups: patients who have suffered a myocardial infarction, stroke, or life-threatening cardiac arrhythmias in the last 6 months; patients with resting hypotension (BP < 90/50) or resting hypertension (BP > 170/100); patients with fluid depletion; patients with cardiac disease, heart failure or coronary artery disease which causes unstable angina. The American College of Cardiology recommends that sildenafil be used with caution in the following: patients with active coronary ischemia who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status; patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of sildenafil (see Drug Interactions). However, one study reported that sildenafil was effective and well tolerated in patients on multidrug antihypertensive regimens and was not associated with additional safety risks in these patients. Patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be particularly sensitive to the actions of sildenafil and other vasodilators. Doses of sildenafil above 25 mg should not be given within 4 hours of an alpha-blocker (e.g., doxazosin, see Drug Interactions).

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. Sildenafil and other agents for the treatment of erectile dysfunction should be used with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as such as sickle cell anemia, leukemia, multiple myeloma, polycythemia, or a history of priapism). However, in one retrospective study, treatment with sildenafil did not cause any worsening deformity or progression of Peyronie’s disease.

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

Sildenafil has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). There is no safety information on the administration of sildenafil to patients with a coagulopathy or active peptic ulcer disease. Therefore, sildenafil should be administered with caution to these patients.

Use sildenafil cautiously in patients with preexisting 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. Patients with a history of NAION are at increased risk for recurrence. Only use a PDE5 inhibitor in these individuals if the anticipated benefit outweighs the risk. Patients with low cup to disc ratio (‘crowded disc’) are also at increased risk; however, this condition is uncommon, and there is insufficient evidence to support screening of prospective users of a PDE5 inhibitor. There is no safety information on the administration of sildenafil 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, sildenafil should be used with caution in these patients.

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

It is not known if sildenafil or its metabolites are excreted in human breast milk. The prescribing information for Revatio recommends caution when the drug is administered to a nursing mother; Sildenafil 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.

In 2012, the FDA recommended against the use of sildenafil for the treatment of pulmonary hypertension in neonates, infants, children, or adolescents based on the results of a long-term pediatric clinical trial showing an increased risk of death in pediatric patients receiving a high dose of sildenafil compared to those receiving a low dose (HR 3.9, p = 0.007). The FDA has since clarified its recommendation stating that there may be patients in which the benefits of sildenafil therapy outweigh the risks, such as when other treatment options are limited and when close monitoring is available, and advises health care providers to weigh the risk-benefit profile for individual patients when deciding whether to initiate sildenafil. Despite the FDA’s caution against use, The Pediatric Pulmonary Hypertension Network (PPHNet) recommends cautious initiation and titration of sildenafil, avoidance of high doses (> 20 mg PO 3 times daily), and consultation and/or referral to providers experienced in the treatment of pulmonary hypertension in pediatric patients. PPHNet also recommends against the abrupt discontinuation of sildenafil in pediatric patients currently receiving it as this could lead to clinical worsening or death. The FDA warning is based on chronic use of sildenafil as monotherapy and, therefore, does not apply to short-term use in critically ill patients.

Sildenafil should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Sildenafil can decrease the tone of the lower esophageal sphincter and inhibit esophageal motility.

Safety and efficacy of sildenafil has not been established in the treatment of pulmonary hypertension secondary to sickle cell disease. Vaso-occlusive crisis (sickle-cell crisis) requiring hospitalization has been reported more frequently in patients with pulmonary hypertension secondary to sickle cell disease who received sildenafil than by those who received placebo. Also, when using for erectile dysfunction, use sildenafil with caution in patients with sickle cell disease because the risk of priapism may be increased.

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. 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.

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).

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.

This list may not include all contraindications.

Sildenafil

Sildenafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies of sildenafil in pregnant women. According to the manufacturers, Revatio should be used during pregnancy only if clearly needed; Sildenafil 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.

Sildenafil

It is not known if sildenafil or its metabolites are excreted in human breastmilk. The prescribing information for Revatio recommends caution when the drug is administered to a nursing mother. Sildenafil 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.

Dextromethorphan HBr

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

Tramadol HCl

Breastfeeding 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).

Sildenafil

During the marketing of sildenafil from late March through November 1998, more than 6 million outpatient prescriptions were dispensed. As of November 1998, 128 deaths had been reported to the FDA in association with sildenafil use. The cause of death was unknown for 48 patients. Three patients experienced a stroke and 77 patients had cardiovascular events. Cardiovascular events related to sildenafil included myocardial infarction, cardiac arrest, angina, ventricular tachycardia, hypertension, and other cardiac symptoms. Sixteen patients had received nitroglycerin or a nitrate, which is contraindicated with the use of sildenafil. Twenty-seven of these patients had died during or immediately after sexual intercourse. Other events were reported hours to days after use of sildenafil and participation in sexual activity. Larger but similarly transient effects on blood pressure were recorded among patients receiving concomitant nitrates. These effects are possibly related to the effects of sildenafil on PDE5 in vascular smooth muscle. In a study conducted at the Mayo Clinic, sildenafil was shown to have limited cardiovascular effects during exercise in men with known or probable coronary artery disease. The study reported that sildenafil had no effect on exercise capacity or the hemodynamic response to exercise. Systolic blood pressure was reduced an average of 7 mmHg compared to baseline. After chronic dosing (80 mg PO TID) in healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively. Post-marketing serious cardiovascular, cerebrovascular, and vascular adverse events were reported in temporal association with sildenafil use and include myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages or intracranial bleeding, and pulmonary hemorrhage.

The following adverse reactions affecting the hemic, lymphatic, metabolic, and nutritional systems occurred in < 2% of patients in controlled clinical trials of sildenafil: anemia, gout, hyperglycemia, hyperuricemia, hypoglycemia, hypernatremia, leukopenia, thirst or dipsia, and unstable diabetes mellitus. Additionally, cases of edema and peripheral edema were reported by <= 25% of persons receiving sildenafil during clinical trials. A causal relationship to sildenafil therapy is uncertain.

Adverse reactions affecting the body as whole and occurring in < 2% of patients in controlled clinical trials of sildenafil include abdominal pain, accidental fall, accidental injury, allergic reaction (angioedema or anaphylactoid reactions), asthenia, chills, photosensitivity reaction, and shock. A causal relationship to sildenafil therapy is uncertain.

CNS and respiratory adverse effects reported during sildenafil clinical trials include dyspnea (<= 7%), insomnia (<= 7%), paresthesias (<= 3%), and sinusitis (1-3%). CNS and respiratory adverse reactions that occurred in < 2% of patients in clinical trials, include: abnormal dreams, asthma, ataxia, bronchitis, cough increased, depression, hypertonia, hyperesthesia, insomnia, laryngitis, neuralgia, neuropathy, pharyngitis, hyporeflexia, somnolence or drowsiness, sputum increased, tremor, and vertigo. A causal relationship to sildenafil therapy is uncertain. Additionally, MedWatch lists over 274 reports implicating sildenafil as the primary suspect for emotional, neurological, and psychological disturbances during the time period January 4, 1998, through February 21, 2001. These adverse effects included abnormal dreams, abnormal thinking, aggression, agitation, anxiety, attempted suicide, attention disturbance, confusion, delirium, delusion, depersonalization, depression, disorientation, dizziness, emotional lability, euphoria, hostility, hallucinations, irritability, loss of consciousness, mania, nervousness, paranoia, personality disorders, suicide, and suicidal ideation. Dizziness has been associated with a sudden decrease in hearing. Sildenafil use has also been listed as a potential factor in a significant number of murder, physical assault, and rape cases. Since sildenafil does cross the blood-brain barrier, it is possible that sildenafil may be associated with these adverse effects. Further investigation is necessary to prove or disprove the role of sildenafil in these disturbances.

Transient global amnesia has been reported during post-marketing use of sildenafil. The frequency is unknown and causality has not been established.

Two cases of tonic-clonic seizures have been reported with sildenafil use. Seizure recurrence has also been included in post-marketing reports.

Adverse reactions occurring in < 2% of patients in controlled clinical trials of sildenafil and affecting the digestive and urogenital systems include ejaculation dysfunction, orgasm dysfunction or anorgasmia, breast enlargement, colitis, cystitis, dysphagia, esophagitis, gastroenteritis, testicular swelling or genital edema, gingivitis, glossitis, abnormal liver function tests, nocturia, rectal hemorrhage, stomatitis, increased urinary frequency, urinary incontinence, vomiting, and xerostomia. Other gastrointestinal and urogenital adverse reactions reported by persons receiving sildenafil include nausea (25%), gastritis (< 3%), and hematuria. A causal relationship to sildenafil therapy is uncertain.

Adverse reactions affecting the musculoskeletal system and occurring in < 2% of patients in controlled clinical trials of sildenafil include arthritis, arthrosis, bone pain, myasthenia, synovitis, tendon rupture, and tenosynovitis. Myalgia was reported by <= 7% of persons receiving sildenafil during clinical trials. A causal relationship to sildenafil therapy is uncertain.

Adverse reactions affecting the skin and appendages and occurring in < 2% of patients in controlled clinical trials of sildenafil include contact dermatitis, diaphoresis, exfoliative dermatitis, herpes simplex, pruritus, skin ulcer, and urticaria. During clinical trials, erythema was reported by 6% of sildenafil recipients. A causal relationship to sildenafil therapy is uncertain.

Adverse reactions affecting hearing or otic special senses and occurring in < 2% of patients in controlled clinical trials of sildenafil include hearing loss, otalgia, 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 contact their physician if they experience changes in hearing.

A thorough ophthalmic examination, in addition to cardiovascular risk assessment, should be considered for patients prior to prescribing phosphodiesterase inhibitors. Ophthalmic adverse events reported by >= 2% of patients treated with sildenafil and which were more frequent on drug than placebo in clinical studies include visual impairment (3-11% vs. 0%) including mild and transient color tinge to vision and blurred vision (3% vs. 0%). In these studies, only 1 patient discontinued drug due to abnormal vision. Abnormal vision (11%) was more common at 100 mg doses than at lower doses. Other ophthalmic adverse reactions occurring in < 2% of patients in controlled clinical trials of sildenafil include cataracts, conjunctivitis, mydriasis, ocular hemorrhage, ocular pain, photophobia, and xerophthalmia. A causal relationship to sildenafil therapy is uncertain. Post-marketing reports have included diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular irritation/burning, ocular swelling/pressure, increased intraocular pressure (ocular hypertension), retinal vascular disease or retinal hemorrhage (1.4%), vitreous detachment/traction, and paramacular edema, and epistaxis (9-13%). Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 males >= 50 years of age per year in the general population. An observational study found that episodic use of PDE5 inhibitors was associated with acute onset of NAION and suggested an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. 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 disc ratio. Symptoms, such as blurred vision and loss of visual field in one or both eyes, are usually reported within 24 hours of use. Most, but not all, of these patients who reported this adverse effect had underlying anatomic or vascular risk factors for development of NAION. These risk factors include, but are not limited to: low cup to disc ratio (‘crowded disc’), age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Additionally, 2 patients had retinal detachment, and 1 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.

Sickle-cell crisis (vaso-occlusive crisis) requiring hospitalization has been reported in patients treated with sildenafil for pulmonary hypertension secondary to sickle cell disease. The manufacturer warns the safety and efficacy of sildenafil have not been established in this population (see Contraindications/Precautions).

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.

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