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 mellitus1 or due to pelvic fracture urethral disruption.2 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.3 According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy.4 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).567 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.568 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.10 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.1012 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.