New molecular entities (NMEs), as defined by the FDA, are new drug products that have as their active ingredient a chemical substance marketed for the first time in the United States. The following descriptions of the NMEs approved during the first half of 2007 detail the pharmacotherapeutic design and mechanism of action of each new drug. Also included is a summary of selected clinical data presented to the FDA in support of the manufacturer's new drug application (NDA). The FDA classifies NMEs on the basis of therapeutic potential (Table). NMEs classified as priority review (P) represent significant improvement in comparison to marketed products in the treatment, diagnosis, or prevention of a disease. NMEs receiving standard review (S) are those that appear to have therapeutic qualities similar to those of one or more already marketed drugs.
This review is intended to be objective rather than evaluative in content. The information for each reviewed NME was obtained primarily from sources published prior to FDA approval. Experience clearly demonstrates that many aspects of a new drug's therapeutic profile, not detected in premarketing studies, surface after the drug is used in large numbers of patients. Studies have indicated the appearance of "new" adverse reactions for many NMEs within two to three years of the drug becoming available. Many of these drugs may eventually acquire at least one black box warning for serious adverse drug reactions or are withdrawn from the market for safety reasons that were not recognized at the time of approval. Hence, while this review offers a starting point for learning about new drugs, it is essential that practitioners be vigilant of changes in a drug's therapeutic profile as reported by their own patients and in the pharmaceutical literature.
Aliskiren (Tekturna, Novartis)
Indication and Clinical Profile:1,2 Hypertension is defined as a systolic blood pressure (BP) ?140 mmHg or diastolic BP ?90 mmHg. Untreated hypertension is a risk factor for heart attack, heart failure, stroke, aneurysm, and chronic renal failure. An estimated 72 million Americans have hypertension; the direct and indirect cost predicted for this disease in 2007 is $66.4 billion. Many patients, especially those with comorbid conditions, will require two or more antihypertensive agents to achieve the goal BP of <140/90 mmHg.
Aliskiren (Tekturna) was approved in March 2007 as the first direct renin inhibitor for the treatment of hypertension. It may be used as monotherapy or adjunctive therapy with other antihypertensives. Six clinical trials involving about 2,730 hypertensive patients demonstrated that aliskiren monotherapy significantly reduced BP in comparison to placebo. Clinical trials involving combination therapy with aliskiren and either hydrochlorothiazide, valsartan, or amlodipine demonstrated significantly greater BP reductions than with aliskiren monotherapy.
Pharmacology and Pharmacokinetics:2,3 The renin-angiotensin-aldosterone system (RAAS), a hormone system found in the kidneys, is involved in the regulation of BP and electrolyte homeostasis. The enzyme renin cleaves angiotensinogen to angiotensin I (Ang I), which is converted to angiotensin II (Ang II) by angiotensinogen-converting enzyme (ACE). Ang II is a potent hormone that causes vasoconstrictor, sodium reabsorption, and the release of aldosterone and vasopressin, leading to increased BP. RAAS is regulated by negative feedback in which the production of Ang II inhibits renin release. Aliskiren is an orally active, potent direct renin inhibitor. The agent decreases plasma renin activity (PRA) and inhibits the conversion of angiotensinogen to Ang I. During aliskiren treatment, the Ang I, Ang II, and PRA levels are reduced, resulting in lowered BP.
Aliskiren has poor oral bioavailability (approximately 2.5%), with a half-life of 24 hours. Peak plasma concentrations (Cmax) are reached in one to three hours, and steady-state blood levels are reached in seven to eight days. High-fat meals decrease the AUC (area under the curve) and Cmax by 71% and 85%, respectively. An estimated 25% of the absorbed drug is found in the urine as parent drug. The major enzyme responsible for metabolism is cytochrome P-450 (CYP) 3A4. The amount of absorbed drug that is metabolized is unknown.
Adverse Reactions:2,3 The most common adverse reaction in patients taking aliskiren during clinical trials was dose-related diarrhea (2.3%). Other gastrointestinal symptoms included abdominal pain, dyspepsia, and gastrointestinal reflux. A slight increase in cough was seen in 1.1% of patients, and 1% of patients exhibited increases in creatine kinase. Other adverse reactions occurring in ?1% of patients included rash, elevated uric acid, gout, renal stones, and hypotension. Increased serum potassium (>5.5 mEq/mL) was seen in 0.9% of patients receiving aliskiren monotherapy. The frequency of hyperkalemia increased by 5.5% when aliskiren was used concurrently with an ACE inhibitor in diabetic patients. Angioedema occurred in two patients (0.06%), and single episodes of tonic clonic seizures with loss of consciousness were reported in two patients.
Drug Interactions:2,3 Aliskiren is metabolized by the CYP3A4 system. It is not an inducer of CYP3A4, nor is it an inhibitor of isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A. It is unlikely to have any significant drug interactions with agents metabolized by the system. The coadministration of aliskiren with furosemide reduced the furosemide AUC and Cmax by approximately 30% and 50%, respectively. The concurrent multiple dosing of aliskiren with irbesartan reduced the Cmax of aliskiren by 50%. The AUC and Cmax of aliskiren were increased by about 50% with concurrent multiple dosing of aliskiren with atorvastatin. Twice-daily dosing of ketoconazole 200 mg with aliskiren caused an approximate 80% increase in aliskiren plasma levels. No study was conducted with ketoconazole 400 mg, but further increases in aliskiren levels would be expected.
Dosage and Administration: 2,3 Aliskiren is supplied as 150- and 300-mg tablets. The 150-mg tablet is round, light pink, biconvex, and unscored. The 300-mg tablet is light red, biconvex, and ovaloid. Aliskiren is available in bottles and unit-dose blister packs and should be stored at room temperature. The recommended initial dose of aliskiren is 150 mg once daily but may be increased to 300 mg per day if BP is not adequately controlled. Aliskiren should be taken regularly with regard to meals. The agent may be used as monotherapy or in combination with other antihypertensive medications. Dosage adjustment is not necessary in the elderly or in patients with renal or hepatic impairment.
Precautions and Counseling Points:2,3 Aliskiren is FDA pregnancy category C in the first trimester and category D in the second and third trimesters. Treatment with the agent should be discontinued as soon as possible in pregnant patients. It is not known if aliskiren is excreted in human breast milk; therefore, nursing is not advised during therapy. Patients taking aliskiren should be monitored routinely for electrolytes and renal function. Caution should be exercised when using the drug in patients with severe renal dysfunction due to potential for increased serum creatinine and blood urea nitrogen. Aliskiren may cause angioedema and/or hypotension; patients should be counseled concerning signs and symptoms.
Levocetirizine Dihydrochloride (Xyzal, UCB, Inc.)
Indication and Clinical Profile:4-6 As many as 50 million people in the U.S. suffer from symptoms associated with common allergic conditions. In allergy disease states, the immune system reacts to exposure to external substances in the environment, leading to symptoms affecting the respiratory system, eyes, and/or skin. Seasonal allergic rhinitis (SAR), commonly referred to as hay fever or outdoor allergies, is the most common form of allergic rhinitis. SAR includes allergies to seasonal pollens like grass, trees, and weeds, as well as mold. Perennial allergic rhinitis (PAR), referred to as year-round allergy or indoor allergy, is characterized by allergic symptoms lasting longer than four weeks. PAR is caused by house dust mites, animal dander, and mold. Chronic idiopathic urticaria (CIU), commonly known as hives of unknown origin, is defined as the occurrence of daily (or almost daily) wheals and itching for at least six weeks with no obvious cause. Historically, these disease states have been treated by various antihistamines (e.g., cetirizine, loratadine, desloratadine, and fexofenadine), mast cell stabilizers, leukotriene antagonists, corticosteroids, and decongestants.
Levocetirizine dihydrochloride (Xyzal) is a new once-daily prescription antihistamine that delivers a rapid and long-lasting effect for the relief of symptoms associated with SAR, PAR, and the uncomplicated skin manifestations of CIU in adults and children 6 years and older. Clinical trials in patients with allergic rhinitis demonstrated that levocetirizine significantly reduced the symptoms of sneezing, itchy nose, runny nose, and itchy eyes by 48%, improved quality of life, reduced absenteeism from work by 60%, and lowered the overall costs associated with SAR. Studies in CIU patients showed that levocetirizine significantly reduced the severity of itching and the number and size of wheals.
Pharmacology and Pharmacokinetics:5,6 Levocetirizine, the active enantiomer of cetirizine, is a histamine-1 receptor antagonist with an affinity for the human histamine-1 receptor that is twofold higher than that of cetirizine (Ki = 3 nmol/L vs. 6 nmol/L, respectively). Levocetirizine 5 mg inhibited the wheal and flare caused by intradermal injection of histamine in 14 pediatric subjects (ages 6-11 years), and the activity persisted for at least 24 hours.
Levocetirizine is rapidly and extensively absorbed following oral administration, reaching Cmax within one hour. Administration of this drug with a high-fat meal delays time to maximum plasma concentration (Tmax) by about 1.25 hours and decreases Cmax by about 36%. However, food has no effect on the extent of exposure (AUC); therefore, levocetirizine can be administered with or without food. The drug is widely distributed in body water, and mean plasma protein binding is about 90%. The extent of metabolism of levocetirizine in humans is less than 14% of the dose. Therefore, differences resulting from genetic polymorphism or concomitant intake of hepatic drug-metabolizing enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic oxidation, N- and O-dealkylation, and taurine conjugation. Dealkylation pathways are mediated primarily by CYP3A4, while aromatic oxidation involves multiple and/or unidentified CYP isoforms. The major route of excretion of levocetirizine and its metabolites is via urine, accounting for about 85% of the dose. Levocetirizine is excreted both by glomerular filtration and active tubular secretion. Renal clearance of levocetirizine correlates with that of creatinine clearance (CrCl). Thus, in patients with renal impairment, the clearance of levocetirizine is reduced. Excretion via feces accounts for only 13% of the dose.
Adverse Reactions:5,6 In clinical trials, the most common adverse reactions in ?2% of adult and adolescent patients (12 years and older) taking levocetirizine 5 mg were mild to moderate in intensity and included somnolence (6% vs. 2% placebo), nasopharyngitis (4% vs. 3% placebo), fatigue (4% vs. 2% placebo), and dry mouth (2% vs. 1% placebo). The most common adverse reactions in ?2% of pediatric patients (6-12 years old) taking levocetirizine 5 mg included pyrexia (4% vs. 2% placebo), cough (3% vs. <1% placebo), somnolence (3% vs. <1% placebo), and epistaxis (2% vs. <1% placebo).
Drug Interactions:5,6 In vitro data on metabolite interaction indicate that levocetirizine is unlikely to produce, or be subject to, metabolic interactions. Levocetirizine at concentrations well above the Cmax level achieved within the therapeutic dose range is not an inhibitor of CYP isoenzymes 1A2, 2C9, 2C19, 2A1, 2D6, 2E1, or 3A4, and levocetirizine is not an inducer of UGT1A or CYP isoenzymes 1A2, 2C9, or 3A4. While studies have been performed with the racemic cetirizine, no formal in vivo drug interaction studies have been performed with levocetirizine.
Dosage and Administration:5,6 Levocetirizine tablets are white, film-coated, oval-shaped, scored, and contain 5 mg of levocetirizine. The daily dosage in adults and adolescents 12 years and older should not exceed 5 mg once daily in the evening. In children 6 to 11 years old, the recommended dosage is 2.5 mg once daily in the evening. Patients should be advised to not ingest more than the recommended dose of levocetirizine because of the increased risk of somnolence at higher doses.
Precautions and Counseling Points:
5,6 The use of levocetirizine is contraindicated in patients with
end-stage renal disease (CrCl <10 mL/minute) and in patients undergoing
hemodialysis. Levocetirizine is also contraindicated in pediatric patients
ages 6 to 11 years with impaired renal function. Patients should be cautioned
against engaging in hazardous occupations that require complete mental
alertness and motor coordination, such as operating machinery or driving a
motor vehicle, after ingestion of levocetirizine. Concurrent use of
levocetirizine with alcohol or other central nervous system depressants should
be avoided because additional reductions in alertness and additional
impairment of central nervous system performance may occur. Since
levocetirizine is FDA pregnancy category B, use during nursing is not
Lisdexamfetamine Dimesylate (Vyvanse, Shire)
Indication and Clinical Profile:7-9 The National Institute for Mental Health estimates that between 3% and 5% of children have attention-deficit/hyperactivity disorder (ADHD) in the U.S. The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM–IV) recognizes three different types of ADHD. These types are predominantly hyperactive-impulsive, predominantly inattentive, and the combined type, which comprises both inattentive and hyperactive symptoms. Patients who display hyperactive-impulsive symptoms always seem to be "on the go," or they are unable to curb their immediate reactions or think before they act. Those that display the inattentive symptoms tend to have a hard time focusing on one topic and get bored easily with tasks after a short period of time. Diagnosis can be difficult due to the fact that children frequently display symptoms consistent with either type of ADHD and could be improperly diagnosed. In addition, symptoms can go unnoticed by parents and may be brought to parents' attention by other caretakers. However, diagnosis should ultimately be made by a qualified physician, such as a developmental/behavioral pediatrician who has expertise in the differential diagnosis of ADHD.
Lisdexamfetamine dimesylate (Vyvanse) is a new once-daily treatment indicated for patients ages 6 to 12 years who are diagnosed with any type of ADHD. Two clinical trials were conducted to support its FDA approval. In the first trial, 290 patients ages 6 to 12 years who met DSM-IV criteria for ADHD received 30-, 50-, or 70-mg doses of lisdexamfetamine versus placebo. Significant improvement was achieved in the group receiving lisdexamfetamine as opposed to placebo. In the second clinical trial, 52 patients were initially treated with amphetamine-dextroamphetamine (Adderall XR) and then were randomly switched to either lisdexamfetamine or placebo or continued treatment with amphetamine-dextroamphetamine. Patients receiving lisdexamfetamine showed significant improvement over placebo. A unique characteristic of lisdexamfetamine is that it may have a reduced abuse potential. The manufacturer (Shire) plans to continue to conduct studies that evaluate its abuse potential.
Pharmacology and Pharmacokinetics:7-9 Lisdexamfetamine is an amide prodrug of dextroamphetamine. Lisdexamfetamine is rapidly absorbed from the gastrointestinal tract and shortly after absorption is converted into the active form of the drug (dextroamphetamine) and L-lysine by hydrolysis during first-pass metabolism. Dextroamphetamine is thought to block the reuptake of norepinephrine and dopamine, as well as to promote the release of these monoamines from their presynaptic neurons, thereby increasing the concentrations of monoamine in the extraneuronal space. Following oral administration, the Tmax is approximately one hour for lisdexamfetamine and 3.5 hours for dextroamphetamine. The plasma half-life of lisdexamfetamine itself is less than one hour. Food does not alter the Cmax or AUC; however, it does postpone the Tmax by approximately one hour. Following oral administration, 96% of the dose is recovered in the urine and 0.3% in the feces over a 120-hour period. Only 2% of the recovered dose is intact lisdexamfetamine. CYP isozymes are not thought to metabolize lisdexamfetamine or its metabolites.
Adverse Reactions:7-9 Adverse reactions reported with the use of lisdexamfetamine were fairly consistent with the use of any amphetamine or dextroamphetamine product. In clinical trials (patient population, 218), the most commonly reported adverse effects included a decrease in appetite (39% vs. 4% placebo) and insomnia (19% vs. 3% placebo). Headache was also commonly reported (12%) but not as statistically significant when compared to placebo (10%). Irritability was reported at a rate of 10%, compared to no rate of irritability in the population receiving placebo. Historically, amphetamines have been extensively abused and associated with severe psychological dependence and disability. In a human study, lisdexamfetamine was found less likely to produce drug-liking effects than the corresponding dextroamphetamine.
Drug Interactions:7-9 In vitro lisdexamfetamine is not metabolized by any of the cytochrome isozymes; therefore, little risk for interaction exists with other drugs metabolized by these enzymes. However, certain medications can interact pharmacokinetically with lisdexamfetamine. Patients already receiving tricyclic antidepressants (TCAs) should not be coadministered lisdexamfetamine due to the possibility of enhancing the activity of both the TCA and lisdexamfetamine. The use of monoamine oxidase inhibitors (MAOIs) is contraindicated during or within 14 days of lisdexamfetamine therapy because MAOIs reduce the metabolism of amphetamines, thereby potentiating their effects. In addition, adrenergic blockers can interact competitively since lisdexamfetamine promotes extraneuronal catecholamines.
Dosage and Administration:7
Lisdexamfetamine is supplied as 30-, 50-, and 70-mg capsules designed for
once-daily oral administration. It may be taken with or without food with a
full glass of water. It is recommended that the initial dose (30 mg) be
initiated and then titrated to 20 mg/day in weekly intervals until the
patients' ADHD symptoms are controlled. The maximum daily dose, however,
should not exceed 70 mg/day.
Precautions and Counseling Points:7-9 Lisdexamfetamine should not be administered to patients concurrently with MAOIs due to the risk of detrimental cardiovascular or psychological side effects. Patients who already have a diagnosis of hypertension or any congenital heart defect should not receive lisdexamfetamine. Some possible side effects that do not require the immediate discontinuation of lisdexamfetamine are loss of appetite, irritability, and insomnia. Other possible side effects that may require the immediate discontinuation of lisdexamfetamine include a hypersensitivity reaction directly due to lisdexamfetamine administration, heart palpitations, or a severe increase in blood pressure. If patients taking lisdexamfetamine miss their dose and it is already in the afternoon or late evening, they should be counseled to skip that dose and take the next day's dose as they would normally.
Rotigotine Transdermal System (Neupro, Schwarz Pharma)
Indication and Clinical Profile:10-13 The Parkinson's Disease Foundation estimates that approximately 1 million Americans suffer from Parkinson's disease, with the risk increasing with age. Primary symptoms of Parkinson's disease include tremor of the extremities, jaw, and face, dystonia of the extremities and trunk, and bradykinesia during movement--all of which lead to postural instability and lack of balance and movement coordination. These pathologies result when dopamine-producing cells in the substantia nigra region of the brain no longer function and ultimately die. This brain region is responsible for initiating and coordinating movement. Parkinson's disease currently has no cure but is treated by medications that potentiate the remaining dopamine of the substantia nigra. It is not uncommon for Parkinson's patients to receive many medications with different mechanisms of action in order to produce a synergistic effect.
Rotigotine transdermal system (Neupro) is a new once-daily nonergolinic dopamine agonist indicated for the treatment of the early signs and symptoms of idiopathic Parkinson's disease. Compared to the other dopamine agonist available, rotigotine is supplied as a continuous-release patch, whereas the oral dosage forms must be taken three times daily.
Three clinical trials were performed to support rotigotine's approval by the FDA. The evaluating criteria used were symptomatic improvements based on the Unified Parkinson's Disease Rating Scale (UPDRS). The first trial evaluated efficacy related to four doses--a range of 2 to 8 mg/24 hours. From baseline, statistically significant outcomes (-4.5, -6.3, and -6.3) were achieved at the three highest doses (4, 6, and 8 mg), compared to placebo (-1.4). In the North American Study, patients who received 2, 4, or 6 mg/24 hours of rotigotine also showed statistically significant improvement from baseline (-4.0), compared to placebo (+1.39), according to the UPDRS scale. In a third multinational study, similar dosage ranges were compared to placebo and an active oral comparator. From baseline, there was a -6.83 change for rotigotine, compared to -2.33 for placebo, based on the UPDRS scale.
Pharmacology and Pharmacokinetics:10 Rotigotine is a non-ergolinic agonist at dopamine receptor types 1, 2, and 3. Although rotigotine's utility in parkinsonism is thought to be related to the D2 receptor stimulation located within the substantia nigra of the brain, the exact mechanism is unknown. After transdermal application, approximately 45% (0.2 mg/cm2) of rotigotine is released from the patch within 24 hours. Bioavailability is highly variable (1-64%) depending on the location of the patch. After application, there is a lag time of about three hours before detectable plasma levels are achieved; Tmax is typically achieved between 15 to 18 hours postdose but can vary from four to 27 hours. Food does not affect the kinetic profile of rotigotine due to its transdermal delivery. Rotigotine shows a biphasic elimination profile, with an initial half-life of three hours and a terminal half-life of five to seven hours. The majority of the absorbed dose is renally eliminated (~71%) primarily as inactive conjugates and N-desalkyl metabolites. Rotigotine undergoes extensive metabolism via oxidative N-dealkylation and conjugative pathways to form rotigotine sulfate (16-22%), rotigotine glucuronide (11-15%), N-despropyl-rotigotine sulfate (14-20%), and N-desthienylethyl-rotigotine sulfate (10-21%), which are excreted primarily in the urine. A smaller proportion of metabolites are excreted into the feces (~11%). After repeated dosing, the apparent volume of distribution (Vd/F) is approximately 84 L/kg, with 92% of rotigotine being bound to plasma proteins in vitro.
Adverse Reactions:10,13 In the three placebo-controlled studies with durations of three to nine months, the most common adverse reactions (incidence >5%) that occurred more frequently than in the placebo-controlled group were nausea, application site irritation, somnolence, excessive drowsiness, dizziness, headache, vomiting, and insomnia. The frequency at which adverse events caused discontinuation of rotigotine was approximately 13%, compared to 6% of the patients receiving placebo. Reactions causing discontinuation were site irritation (5% vs. 0% placebo), nausea (2% vs. 0% placebo), and vomiting (1% vs. 0% placebo). Many of the adverse reactions were more common with the higher dosages of rotigotine (8 mg/24 hours) and during the titration period.
Drug Interactions:10,13 Rotigotine undergoes cytochrome-mediated metabolism by many CYP isoforms. Therefore, when coincubated with specific inhibitors of cytochrome isozymes, no extensive inhibition of rotigotine occurred due to the ability of other isozymes to catalyze metabolism. Additionally, due to rotigotine's ability to be conjugated via numerous pathways, sulfotransferases and UDP glucuronosyltransferases (UGT1A9 and UGT2B15), inhibition of a single metabolic pathway is unlikely to alter rotigotine serum concentrations significantly. When analyzing any of the metabolites of rotigotine (e.g., 5-O-glucuronide, desalkyl and monohydroxy metabolites), it was determined that there was no risk for inhibition of CYP1A2, CYP2C9, and CYP3A4. When tested in vitro in human hepatocytes, there was no apparent risk for enzyme induction of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or 3A4.
Dosage and Administration: 10 Rotigotine is supplied as a transdermal delivery patch that is to be replaced daily. These patches were designed to deliver three different doses (2, 4, and 6 mg) in 24 hours. Patients should be titrated from a starting dosage of 2 mg/day, then the dosage should increase by 2 mg per week. The 4 mg/24 hours dosage was found to be the lowest effective dosage for patients with Parkinson's disease, but dosages can be titrated to the highest recommended dosage of 6 mg/24 hours by 2-mg increases weekly. If rotigotine is to be discontinued, it is suggested to be done gradually in 2 mg/24 hour increments, reducing the dosage every other day. Rotigotine can be applied any time of the day, but once a regimen has been started, rotigotine should be applied at the same time routinely. Rotation of sites is an important issue with rotigotine patches. Similar regions should be used due to bioavailability concerns; however, the same site should not be used again for 14 days.
Precautions and Patient Counseling Points:10-13Rotigotine can cause excessive drowsiness; thus, patients should be counseled to use caution while completing daily activities, such as driving and using power equipment, until they know how the drug is going to affect them. Patients should also be counseled on avoiding the application of heat to the area where the patch is located, as this may cause an amount of rotigotine higher than prescribed to reach systemic circulation. In addition, if patients miss a dose, they should apply the patch as soon as they remember but should never apply more than one patch at a time to make up for missed doses.
Retapamulin Ointment (Altabax, GlaxoSmithKline)
Indication and Clinical Profile:14-16 Impetigo is a highly contagious infection of the top layers of the skin that is caused most commonly by Staphylococcus aureus or Streptococcus pyogenes. It is most prevalent among infants and children ages 2 to 6 years, since their immune systems are still developing, but the infection also occurs in adults. Impetigo spreads easily in schools and child care settings, as well as in any location where groups of people are in close contact. Retapamulin is indicated specifically for use in adults and pediatric patients ages 9 months and older for the topical treatment of impetigo due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes. Retapamulin represents the first new class of prescription topical antibacterials to be approved by the FDA in nearly two decades. Retapamulin is indicated for use twice daily for a five-day period, while other prescription topical antibacterials are used as much as three times daily for up to 12 days.
FDA approval was based on results obtained from a randomized, double-blind, multicenter, placebo-controlled study that enrolled 210 adults and children with impetigo, of which 139 received topical retapamulin. Culture-proven pathogens were seen in 82% of these patients, and the most common bacteria causing these infections were S aureus and S pyogenes. In this trial, the rates of clinical success--defined as the response of impetigo at the end of five days of therapy wherein no further antibacterial treatment was needed--were greater in the retapamulin group (85.6%) than in the placebo group (52.1%). Microbiological success rates were also greater in the retapamulin group (91.2%) than in the placebo group (50.9%). Retapamulin was generally well tolerated throughout the study.
Pharmacology and Pharmacokinetics:14 Retapamulin is a bacterial protein synthesis inhibitor belonging to a class of compounds called pleuromutilins . These compounds act by inhibiting the initiation of protein synthesis at the level of bacterial 50S ribosome. This binding site involves ribosomal protein L3 and is in the region of the ribosomal P site and peptidyl transferase center. By virtue of binding to this site, pleuromutilins inhibit peptidyl transfer, block P-site interactions, and prevent the normal formation of active 50S ribosomal subunits required for bacterial protein biosynthesis.
Adverse Reactions and Drug Interactions:14-16 The most common drug-related adverse event in adults and pediatric patients treated with retapamulin was application site irritation (1.4%). Headache, nausea, diarrhea, and nasopharyngitis were also reported infrequently (<2%). Due to low systemic exposure to retapamulin following topical application in patients, dosage adjustments for retapamulin are unnecessary when coadministered with CYP3A4 inhibitors, such as ketoconazole, and drug interactions are unlikely to affect the metabolism of other P450 substrates. The effect of concurrent application of retapamulin and other topical products to the same area of skin has not been studied.
Dosage and Administration: 14 Retapamulin is supplied as a gel in 5-, 10-, and 15-g tubes for topical administration. The recommended initial dose of the drug is a thin layer over the infected area (up to 100 cm2 in total area in adults or 2% total body surface area in pediatric patients ages 9 months or older) twice daily for five days. The treated area may be covered with a sterile bandage or gauze dressing if desired. This may also be helpful for infants and young children who accidentally touch or lick the lesion site. A bandage will also avoid accidental transfer of ointment to the eyes or other areas. Hands should be washed after application (if the hands are not the area intended for treatment).
Counseling Points and Precautions:14-16 Retapamulin is for external use only and should not be applied to the eyes, mouth, inside of the nose, or inside the female genital area. The health care provider should be contacted if the area of application worsens in irritation, redness, itching, burning, swelling, blistering, or oozing. The medication should be used for the length of time recommended, even if symptoms have improved. If symptoms do not improve within three to four days after starting use, a health care practitioner should be notified. Retapamulin is FDA pregnancy category B drug; thus, it should be used in pregnancy only when the potential benefits outweigh the potential risks. It is not known if this drug distributes to breast milk; thus, caution should be exercised when it is administered while nursing.
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