Anti-Fungal Nail Solution
$150.00
Terbinafine
Terbinafine is an oral and topical antifungal agent that is pharmacologically similar to naftifine. Oral terbinafine is highly effective for treating onychomycosis due to its fungicidal activity and ability to concentrate within the nail. In clinical stud-
ies, the efficacy of oral terbinafine in the treatment of onychomycosis was found to be superior to both griseofulvin and itraconazole. Further, the rate of relapse with terbinafine were lower than those observed with griseofulvin. Onychomycosis clinical cure rates for terbinafine are approximately 50% to 70%. Oral terbinafine has also been utilized in small open-label studies as an alternative treatment for bronchopulmonary aspergillosis refractory to other treatments; in some cases terbinafine has suppressed or eradicated the disease. Topical terbinafine was approved by the FDA in 1993. Terbinafine oral tablets were approved May 1996. Terbinafine cream received approval as an over-the-counter treatment of tinea pedis in March 1999. Terbinafine oral granules were approved for use in pediatric patients, ages 4 years and older, for the treatment of tinea capitis in September 2007.
Itraconazole
Itraconazole is an oral azole antifungal agent indicated for the treatment of pulmonary and extrapulmonary blastomycosis, histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal disease, pulmonary and ex-
trapulmonary aspergillosis in patients who are intolerant or refractory to amphotericin B, onychomycosis of the toenail or fingernail in nonimmunocompromised patients, and oropharyngeal or esophageal candidiasis. FDA-approved indications
vary by dosage form, and dosage forms are not interchangeable. Itraconazole is closely related to ketoconazole but appears to have fewer adverse effects. Itraconazole is active against many of the same fungi as ketoconazole and fluconazole but has greater activity against Aspergillus.
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) of the propionic acid chemical class. Ibuprofen is a racemic mix-
ture of 2 isomers; however, only the l-isomer of ibuprofen has been shown to have clinical activity. Although d-isomer is considered inactive, it is slowly and incompletely converted to the l-isomer in adults and probably children and may serve
as a circulating reservoir for the active drug. All NSAIDs carry an increased risk of serious gastrointestinal adverse effects including bleeding, ulceration, and perforation of the stomach or intestines and may cause an increased risk of serious car-
diovascular (CV) thrombotic events, myocardial infarction, and stroke. FDA approved labeling of both the OTC and pre-
scription products stress dosing at the lowest effective ibuprofen dose for the shortest possible duration, as the risk for adverse effects may increase with increased use. A retrospective review by FDA Advisory Committees of short-term effica-
cy trials of a related non-prescription strength NSAID indicated that an increase in CV events was not apparent during the studies. However, it is important to note that CV risk was not the focus of the studies, and further information is needed to determine if a cause and effect relationship exists between non-prescription strength NSAID use and adverse cardiovascular
outcomes. Specific populations are at an increased risk of NSAID-induced adverse events. The American Geriatrics Society recommends that NSAIDs (nonselective and COX-2 inhibitors) not be used to treat persistent pain in elderly patients ex-
cept rarely, then only in patients who have failed other therapies and have a favorable benefits vs risks assessment; ex-
treme caution, continued therapy evaluation, and concurrent PPI or misoprostol is advised with ibuprofen use in this population. Ibuprofen is indicated for the treatment of rheumatoid arthritis, osteoarthritis, and dysmenorrhea. It also is used for its antipyretic effects and for the alleviation of mild to moderate pain. In addition, clinical studies have demonstrated its effectiveness in the treatment of ankylosing spondylitis, gout, and psoriatic arthritis. Topical use has been studied in minor muscle pain treatment. See separate ibuprofen lysine monograph for discussion of NeoProfen, the intravenous formulation indicated to close a clinically significant patent ductus arteriosus in premature infants. Oral ibuprofen was approved by the FDA in 1974.
Terbinafine
Terbinafine, an allylamine antifungal, displays activity against dermatophytes (Trichophyton mentagrophytes and T. rubrum), as well as in vitro activity against Candida albicans, Epidermophyton floccosum, and Scopulariopsis brevicaulis. The drug exerts its antifungal effect through interfering with fungal sterol biosynthesis by inhibiting the enzyme squalene epoxidase. Squalene epoxidase is a key enzyme in fungal sterol biosynthesis that is required to convert squalene to ergosterol (an essential component of fungal cell membranes). By blocking squalene monooxygenase, terbinafine creates a deficiency in ergosterol, thereby resulting in increased cell membrane permeability and fungal cell death.
Itraconazole
Like other azole antifungals, itraconazole exerts its effect by altering the fungal cell membrane. Itraconazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P-450 (CYP450) enzyme that is necessary for the conversion of lanosterol to ergosterol, an essential component of the membrane. In contrast, amphotericin B binds to ergosterol after it is synthesized. Inhibition of ergosterol synthesis results in increased cellular permeability, which causes leakage of cellular contents. Itraconazole does not appear to have the same effects on human cholesterol synthesis. Other antifungal effects of azole compounds have been proposed and include: inhibition of endogenous respiration, interaction with membrane phospholipids, and inhibition of yeast transformation to mycelial forms. Other mechanisms may involve inhibition of purine uptake and impairment of triglyceride and/or phospholipid biosynthesis.
Ibuprofen
Ibuprofen competitively inhibits both cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, by blocking arachidonate binding resulting in analgesic, antipyretic, and anti-inflammatory pharmacologic effects. The enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step of the synthesis prostaglandins and thromboxanes that are involved in rapid physiological responses. COX isoenzymes are also responsible for a peroxidase reaction, which is not affected by NSAIDs. In addition, NSAIDs do not suppress leukotriene synthesis by lipoxygenase pathways. COX-1 is constitutively expressed in almost all tissues, while COX-2 appears to only be constitutively expressed in the brain, kidney, bones, repro ductive organs, and some neoplasms (e.g., colon and prostate cancers). COX-1 is responsible for prostaglandin synthesis in response to stimulation by circulating hormones, as well as maintenance of normal renal function, gastric mucosal integrity, and hemostasis. However, COX-2 is inducible in many cells in response to certain mediators of inflammation (e.g., interleukin-1, tumor necrosis factor, lipopolysaccharide, mitogens, and reactive oxygen intermediates).
The anti-inflammatory mechanism of ibuprofen is due to decreased prostaglandin synthesis via inhibition of COX-1 and COX-2. It appears that the anti-inflammatory effects may be primarily due to inhibition of the COX-2 isoenzyme. However, COX-1 is expressed at some sites of inflammation. COX-1 is expressed in the joints of rheumatoid arthritis or osteoarthritis patients, especially the synovial lining, and it is the primary enzyme of prostaglandin synthesis in human bursitis. Ibuprofen is slightly more selective for COX-1 than COX-2
Terbinafine
Terbinafine is administered orally and topically. Although more than 99% protein-bound, the drug is widely distributed, including in the CNS, hair, and nail beds. It is detectable within the stratum corneum in as little as 24 hours after the initiation of therapy. After 2 weeks at the recommended doses, terbinafine remains in the skin for up to 3 months. The elimination half-life ranges from 26 to 36 hours. The terminal half-life is about 200 to 400 hours, representing the slow redistribution from skin and adipose tissue. The Drug may be detected in the nails within 1 week of starting therapy and last for up to 90 days after treatment has stopped. Terbinafine is extensively metabolized in the liver by at least 7 CYP isoenzymes, with major contributions from CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP3A4. Most of the oral dose is metabolized through N-demethylation, alkyl oxidation, and hydrolysis to 15 known metabolites that lack antifungal activity. The primary metabolite is N-desmethyl terbinafine (10% to 15%). Roughly 70% to 80% of an oral dose is excreted in the urine as these conjugated and unconjugated metabolites; 20% is eliminated via the feces.
Itraconazole
Itraconazole is administered orally. Both itraconazole and its major metabolite are highly bound to plasma protein (more than 99%), mainly to albumin. There is extensive distribution into lipophilic tissues, but aqueous tissues contain negligible amounts. Drug concentrations in the lung, kidney, liver, bone, stomach, spleen, and muscle are 2- to 3-times higher than in the plasma; concentrations in keratinous tissues (skin) are up to 4-times higher. Itraconazole accumulates in the stratum corneum and concentrations tend to increase with pulse dosing. Therapeutic concentrations may be detected in the nail for 6 to 9 months. Compared to plasma, drug concentrations in the cerebrospinal fluid are much lower.
Itraconazole is metabolized predominantly by hepatic CYP3A4 to at least 30 metabolites; the major metabolite, hydroxy itraconazole, has in vitro antifungal activity that is comparable to the parent compound. It appears itraconazole undergoes saturable metabolism with multiple dosing. The elimination half-life after single oral dose ranges from 16 to 28 hours; however, repeated dosing increases the half-life to 34 to 42 hours. Between 3% to 18% of the administered dose is excreted unchanged in the feces. There is minimal renal excretion of unchanged drug; however, about 35% is excreted in urine as inactive metabolites. Hydroxypropyl-beta-cyclodextrin is eliminated through the kidneys with little accumulation in body tissues.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, BCRP, P-gp. Itraconazole is a substrate of the CYP3A4 isoenzyme and drug transporter P-glycoprotein (P-gp). In addition, itraconazole is a strong CYP3A4 inhibitor and also inhibits P-gp and breast cancer resistance protein (BCRP).
Ibuprofen
Ibuprofen is a racemate, and, on average, 60% of R-ibuprofen is converted to S-ibuprofen. S-ibuprofen is metabolized via hepatic oxidation by cytochrome P450 (CYP) 2C9 to inactive metabolites. CYP2C9 is polymorphic; CYP2C9(1) is the wild-type, and CYP2C9(2) and CYP2C9(3) are the most common variants. The variant CYP2C9(3) allele decreases enzyme activity to a greater extent than does CYP2C9(2), but clearance of racemic ibuprofen was reduced among all variant genotypes as compared with the wild-type (1/1). Higher S-ibuprofen concentrations led to greater inhibition of COX-1 (reduced thromboxane B2 concentrations) and greater inhibition of COX-2 (reduced prostaglandin E2 concentrations). Importantly, both thromboxane B2 and prostaglandin E2 concentrations were reduced the most among patients with the CYP2C9 genotypes (3/3), (1/3), (2/3), and (2/2). Plasma half-life of both oral and parenteral forms is between 2 and 4 hours. Ibuprofen is excreted in the urine: 50 to 60% as metabolites and approximately 10% as unchanged drug. Some biliary excretion may occur. Excretion is usually complete within 24 hours of administration.
Terbinafine
Transient lymphopenia and neutropenia have occurred with oral terbinafine therapy. In patients with known or suspected immunodeficiency syndromes (e.g., human immunodeficiency virus (HIV) infection), or immunosuppression, complete blood counts are recommended at baseline and with any treatment lasting greater than 6 weeks. If signs or symptoms of secondary infection occur, a complete blood count should be obtained to rule out lymphopenia or neutropenia. If the neutrophil count is less than 1000/mm3, oral terbinafine should be discontinued.
Data from post marketing use of oral terbinafine in human pregnancy are insufficient to evaluate a drug-associated risk of ma jor birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, terbinafine did not cause malformations or fetal harm when administered orally to pregnant rats or rabbits during organogenesis at doses up to 23- times the maximum recommended human dose. There are no adequate and well-controlled studies with topical terbinafine in pregnant women. Use topical terbinafine during pregnancy only if clearly indicated.
After oral administration, terbinafine is present in human breast milk. After a single terbinafine 500 mg oral dose to 2 volunteers, the total excretion of terbinafine in human milk was 0.03% to 0.13%. There are no data on the effects on the breast-fed child or milk production. Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for oral terbinafine and any potential adverse effects on the breast-fed child from oral terbinafine or the underlying maternal condition. Advise breast-feeding mothers to avoid topical application of terbinafine to the breast. Further, given the limited data on neonatal exposure, discontinue breast-feeding or discontinue topical terbinafine, taking into account the importance of the drug to the mother.
Neuropsychiatric adverse reactions consisting of depression, suicidal ideation, and self-harm, have been reported in 3 children (ages 13 to 16 years) while taking oral terbinafine. Other symptoms included anxiety, insomnia, nausea, forgetfulness, and social withdrawal. Symptoms in all 3 children resolved after the discontinuation of the medication.
Oral terbinafine is contraindicated for use in patients with chronic or active hepatic disease (i.e., cirrhosis, hepatitis), as the systemic clearance may be decreased by approximately 50%; topical formulations are unlikely to be affected. In addition, use of oral terbinafine has been associated with serious hepatotoxicity (i.e., hepatic failure, some resulting in death or liver transplant). Although the majority of cases have been reported in patients with serious underlying conditions, hepatotoxicity has been reported in patients with and without preexisting hepatic disease. Prior to initiating therapy and periodically during therapy, monitor liver function tests. If elevations in liver function test are observed, immediately discontinue therapy. Counsel patients to discontinue use of the drug and immediately report any symptoms of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine, or pale stools as these may indicate hepatotoxicity.
In patients with renal impairment or renal failure (i.e., creatinine clearance 50 mL/min or less), the use of oral terbinafine formulations has not been studied, and therefore, is not recommended.
Terbinafine is contraindicated in patients that have a known or suspected hypersensitivity to terbinafine or any of its components. Occasionally the use of oral terbinafine has been associated with serious rash or hypersensitivity skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, and bullous dermatitis. If irritation, skin rash, or sensitivity occurs during use of terbinafine, treatment should be discontinued and appropriate therapy administered. Topical terbinafine formula tions should be kept away from the eyes, nose, and mouth during treatment.
Treatment with oral terbinafine has been associated with serious, and sometimes fatal, cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome. Closely evaluate drug recipients who develop unexplained thrombocytopenia and anemia. If clinical symptoms and laboratory findings are consistent with TMA, discontinue terbinafine therapy.
Itraconazole
Use itraconazole with caution in patients with hepatic disease. Itraconazole has been associated with serious hepatotoxicity, including hepatic failure leading to liver transplantation or death. Some cases had neither preexisting liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. In patients with elevated or abnormal liver enzymes or active hepatic disease, or who have experienced hepatotoxicity with other drugs, itraconazole treatment is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. Monitor liver function tests (LFTs) in all patients receiving itraconazole, particularly in patients with preexisting hepatic disease or patients who have experienced hepatic toxicity due to other medications. If clinical signs or symptoms develop that are consistent with hepatic disease, discontinue itraconazole and perform liver function testing. Continued use of itraconazole or reinstitution of treatment is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk.
Itraconazole has been shown to have a negative inotropic effect. Itraconazole is contraindicated for the treatment of ony chomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. For the treatment of life-threatening infections, the drug should be used with caution in patients with ventricular dysfunction as rare cases of CHF and pulmonary edema have been reported in patients treated with itraconazole for onychomycosis and/or systemic fungal infections. If signs or symptoms of CHF occur during administration of the capsules, discontinue treatment. If CHF symptoms occur during administration of the oral solution, continued use of itraconazole should be reassessed. For patients with risk factors for CHF, prescribers should carefully review the risks vs. benefits of therapy. These risk factors include ischemic coronary artery disease or valvular heart disease; significant pulmonary disease[e.g., chronic obstructive pulmonary disease (COPD)], renal disease requiring dialysis, or other edematous disorders. Such patients should be informed of the symptoms of CHF and closely monitored.
Due to its potent inhibition of the CYP3A4 enzyme system, itraconazole co administration with other drugs metabolized by CYP3A4 should be done with extreme caution, if at all. Itraconazole is contraindicated with selected drugs due to the potential for severe, and sometimes fatal, interactions which result from elevated plasma drug concentrations. For example, life threatening cardiac dysrhythmias (ventricular arrhythmias) and/or sudden death have occurred in patients receiving some of these medications concurrently with itraconazole and/or other CYP3A4 inhibitors.67 Itraconazole may produce QT prolonga
tion. Use itraconazole with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation
The pharmacokinetics of itraconazole may be significantly different in patients (both pediatric and adult) with cystic fibrosis; large variability was observed in the pharmacokinetic data during studies. Such variability might lead to therapeutic failure in some patients. If the cystic fibrosis patient does not respond to itraconazole, consideration should be given to switching to alternative therapy.
Because oral itraconazole capsules and tablets require an acidic environment for dissolution and absorption, patients with either achlorhydria or hypochlorhydria achieve poor plasma concentrations. Because hypochlorhydria has been reported in individuals with the human immunodeficiency virus (HIV) infection, the absorption of itraconazole capsules and tablets may be decreased in these patients. These patients should take itraconazole capsules and tablets with a cola beverage to achieve better serum concentrations. Dizziness or blurred/double vision may occur with itraconazole. Advise patients to avoid driving or operating machinery if they experience these effects. Patients with severe neutropenia were not enrolled in studies of itraconazole oral solution used in the treatment of oropharyngeal and esophageal candidiasis. The oral solution is not recommended for treatment of these indications in patients who are at immediate risk for systemic candidiasis.
Safe use of itraconazole in neonates, infants, children, and adolescents has not been established. A small number of pediatric patients aged 6 months to 16 years have been treated with itraconazole for systemic fungal infections, and no serious unexpected adverse effects have been reported. There are no studies on the potential side effects of long-term itraconazole therapy in pediatric patients.
Itraconazole can prolong the QT interval. Geriatric patients may be at increased risk for QT prolongation and for serious drug drug interactions that may increase the risk QT prolongation risk or may increase the risk for other serious side effects. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, systemic azole antifungals should be used in the lowest possible dose for the shortest possible duration, particularly in patients receiving other medications known to interact with these medications. Increased monitoring may be required to identify and minimize the toxicity of warfarin, phenytoin, theophylline, or sulfonylureas when an azole antifungal is co-administered; other medications such as rifampin and cimetidine may decrease the therapeutic effect of the antifungal. Some drug-drug combinations may be contraindicated. OBRA guidelines caution that azole antifungals may cause hepatotoxicityty, headaches, and GI distress.
Itraconazole is contraindicated in patients with itraconazole hypersensitivity. There is limited information regarding cross sensitivity between itraconazole and other azole antifungal agents. Use itraconazole with caution in patients with azole antifungals hypersensitivity.
Use of itraconazole to treat onychomycosis is contraindicated during pregnancy and in females contemplating pregnancy. Use itraconazole for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. There are no data on exposure to itraconazole during pregnancy for the approved indications. Epidemiologic studies of wom en exposed to short courses of itraconazole in the first trimester of pregnancy have reported no risk of major birth defects overall and inconclusive findings on the risk of miscarriage. However, post marketing reports for itraconazole have included cases of congenital abnormalities. Teratogenic effects have been demonstrated in animals. Guidelines for prevention of opportunistic infections in HIV-infected patients recommend that oral azole antifungals, including itraconazole, not be started during pregnancy and that these agents be discontinued in HIV-positive women who become pregnant.
Itraconazole is distributed into breast milk. Weigh the expected benefits of itraconazole therapy for the mother against the potential risk from exposure of itraconazole to the breast-feeding infant. Fluconazole and ketoconazole may be potential alternatives to consider during breast-feeding. However, assess site of infection, local susceptibility patterns, and specific microbial susceptibility before choosing an alternative agent. Additionally, itraconazole may be used to treat infections in patients with HIV, and guidelines advise against HIV-infected women breast-feeding to avoid postnatal transmission of HIV.
Itraconazole may be associated with reproductive risk. Discuss contraception requirements with the patient. Counsel women of childbearing potential to use highly effective contraception during itraconazole therapy and for 2 months after treatment discontinuation. Do not administer itraconazole to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day after menses.
Ibuprofen
Ibuprofen is contraindicated in patients with salicylate hypersensitivity or NSAID hypersensitivity who have experienced asthma, urticaria, or other allergic reactions (e.g., anaphylactic reactions and serious skin reactions) after taking ibuprofen, aspirin, or other NSAIDs. Severe, rarely fatal, anaphylactoid reactions to ibuprofen have been reported. Ibuprofen should not be used in patients with aspirin-sensitive asthma or the aspirin triad because of the approximate 5% cross-sensitivity that occurs between aspirin and NSAIDs. The triad typically occurs in patients with asthma who experience rhinitis with or without nasal polyps, or who experience severe, potentially fatal acute bronchospasm after taking aspirin or other NSAIDs. The use of NSAIDs, including ibuprofen, may cause serious and potentially fatal skin reactions including exfoliative dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis. Patients should be instructed to discontinue the medication and contact their health care provider if erythema, rash, blisters, or related skin reactions develop.15 Cautious use of ibuprofen is recommended in patients with asthma. Of 100 children 6 to 18 years of age with mild or moderate persistent asthma, 2% experienced a drop in forced expiratory volume in 1 second (FEV1) of more than 20% and 4% experienced a FEV1 decrease of greater than 15% within 1 hour of ibuprofen ingestion. None of these children had exposure to ibuprofen prior to the study, and none experienced a decline in lung function after placebo.
Due to the role of prostaglandins in renal function and hemodynamics, patients with renal disease or heart failure should be closely monitored during ibuprofen therapy. Avoid ibuprofen use in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. Congestive heart failure and hypertension can be exacerbated by ibuprofen. A meta-analysis of randomized, controlled trials demonstrated an approximately 2-fold increase in hospitalizations for heart failure among non-selective and COX-2 selective-treated patients compared to placebo. In patients with hyperten sion, monitor blood pressure during the initiation of NSAID treatment and throughout therapy. A meta-analysis demonstrated that the effect of NSAIDs on blood pressure is the greatest in hypertensive individuals receiving antihypertensive medication. Normotensive patients receiving antihypertensive therapy had higher increases in blood pressure than subjects with uncontrolled hypertension or normotensive subjects receiving no hypertensive therapy. Patients with renal impairment, renal fail ure, hepatic disease, diabetes mellitus, systemic lupus erythematosus, or congestive heart failure, rheumatoid arthritis, edema, extracellular volume depletion (i.e., hypovolemia or dehydration), sepsis; those taking diuretics or nephrotoxic drugs; and old er patients are at the highest risk for complications related to suboptimal renal perfusion. Patients must be properly hydrated prior to administration of parenteral ibuprofen to reduce the risk of renal adverse events.
Terbinafine
Data from post marketing use of oral terbinafine in human pregnancy are insufficient to evaluate a drug-associated risk of ma jor birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, terbinafine did not cause malformations or fetal harm when administered orally to pregnant rats or rabbits during organogenesis at doses up to 23- times the maximum recommended human dose. There are no adequate and well-controlled studies with topical terbinafine in pregnant women. Use topical terbinafine during pregnancy only if clearly indicated.
Itraconazole
Use of itraconazole to treat onychomycosis is contraindicated during pregnancy and in females contemplating pregnancy. Use itraconazole for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. There are no data on exposure to itraconazole during pregnancy for the approved indications. Epidemiologic studies of women ex posed to short courses of itraconazole in the first trimester of pregnancy have reported no risk of major birth defects overall and inconclusive findings on the risk of miscarriage. However, post marketing reports for itraconazole have included cases of congenital abnormalities. Teratogenic effects have been demonstrated in animals. Guidelines for prevention of opportunistic infections in HIV-infected patients recommend that oral azole antifungals, including itraconazole, not be started during pregnancy and that these agents be discontinued in HIV-positive women who become pregnant.
Ibuprofen
Avoid ibuprofen use during the third trimester of pregnancy (starting at 30 weeks of gestation) because use during this time period increases the risk of premature closure of the fetal ductus arteriosus. There are no adequate and well-controlled studies in pregnant women, and observational data regarding embryofetal risks of NSAID use during the first and second trimesters is inconclusive. During animal reproduction studies in rabbits and rats with intravenous ibuprofen, no developmental effects were reported at doses up to 0.4 to 0.5-times the maximum recommended human dose (MRHD) of 3,200 mg when dosed throughout gestation; however, membranous ventricular septal defects were reported in rats treated with 0.8-times the MRHD on days 9 and 10 of gestation. Administration of prostaglandin inhibitors, such as ibuprofen, during animal studies has been associated with increased pre- and post-implantation loss. During labor and obstetric delivery, NSAIDs have been associated with delayed parturition and an increased incidence of stillbirth.
Terbinafine
After oral administration, terbinafine is present in human breast milk. After a single terbinafine 500 mg oral dose to 2 volunteers, the total excretion of terbinafine in human milk was 0.03% to 0.13%. There are no data on the effects on the breast-fed child or milk production. Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for oral terbinafine and any potential adverse effects on the breast-fed child from oral terbinafine or the underlying maternal condition. Advise breast-feeding mothers to avoid topical application of terbinafine to the breast. Further, given the limited data on neonatal exposure, discontinue breast-feeding or discontinue topical terbinafine, taking into account the importance of the drug to the mother.
Itraconazole
Itraconazole is distributed into breast milk. Weigh the expected benefits of itraconazole therapy for the mother against the potential risk from exposure of itraconazole to the breast-feeding infant. Fluconazole and ketoconazole may be potential alternatives to consider during breast-feeding. However, assess site of infection, local susceptibility patterns, and specific microbial susceptibility before choosing an alternative agent. Additionally, itraconazole may be used to treat infections in patients with HIV, and guidelines advise against HIV-infected women breast-feeding to avoid postnatal transmission of HIV.
Ibuprofen
Because exposure to a nursing infant is low, especially after single or intermittent doses, ibuprofen is considered a preferred analgesic/anti-inflammatory for women who are breast-feeding. After oral administration, ibuprofen is present in breast milk at relative infant doses of 0.06% to 0.6% of the maternal weight-adjusted daily dose. There are no reports of adverse effects on milk production or on the breast-fed infant. In a study of milk samples from 13 women who took an ibuprofen regimen of approximately 1 g daily, the relative infant dose was less than 0.38% of the mean maternal weight-adjusted dose. The relative infant dose was highest when the milk protein content was highest during the colostral phase
Terbinafine
Topical formulations of terbinafine are well tolerated. In clinical trials for terbinafine topical cream, the manufacturer reported that only 6 of 2265 patients discontinued topical terbinafine therapy due to adverse effects; and only 52 patients reported events thought to be due to topical treatment The most common adverse effects were skin irritation (1%), application site burning (0.8%), pruritus (0.2%), and xerosis (skin dryness, 0.2%). Terbinafine dermal gel is associated with pruritus, skin irritation, and burning at the application site in 1% to 2% of patients. Similar incidences of these side effects are likely to occur with use of any topical non-prescription formulation. Pruritus may occur with oral therapy as well, and is reported in 1% to 2.8% of patients.
Itraconazole
Gastrointestinal adverse events were reported during clinical trials with itraconazole. The most commonly experienced GI events included nausea (1.7% to 11%), vomiting (5% to 7%), diarrhea (1.7% to 11%), abdominal pain or discomfort (1.7% to 6%), dyspepsia (4% or less), flatulence (4% or less), constipation (2% to 3%), gingivitis (3%), ulcerative stomatitis (3% or less), gastritis (2%), gastroenteritis (2%), and appetite stimulation (2%). Other adverse events noted in less than 2% of patients in clinical trials included anorexia (1%), dysgeusia, dysphagia, hemorrhoids, and weight loss. During post marketing experience, abdominal pain, constipation, diarrhea, dyspepsia, dysgeusia, nausea or vomiting, and pancreatitis have been reported.
Cardiovascular adverse events reported with itraconazole include edema (4% or less), hypertension (2% to 3%), hypotension and orthostatic hypotension (1%), sinus tachycardia, sinus bradycardia (1%), chest pain (unspecified) (3%), cardiac failure, and left ventricular failure. Rare cases of congestive heart failure, peripheral edema, and pulmonary edema have been reported with post marketing use. During animal studies and studies in healthy human volunteers, a negative inotropic effect (e.g., de creases in left ventricular ejection fraction) was observed with intravenous itraconazole. In these studies, the effect was transient and resolved prior to the next scheduled infusion, within 12 hours. Of heart failure cases deemed due to itraconazole, almost half were in patients given itraconazole to treat onychomycosis and most cases occurred at doses of 400 mg/day. Hospitalization was required in some patients and deaths were reported; however the casual relationship between itraconazole and the deaths is unclear because of confounding factors (i.e., serious underlying conditions). If signs or symptoms of heart failure occur, reassess or discontinue itraconazole. QT prolongation is possible with the use of itraconazole. Serious cardiovascular events, including sudden death, QT prolongation, ventricular arrhythmias, and torsade de pointes, have been observed in patients receiving itraconazole and other CYP3A4 inhibitors in combination with other QT-prolonging drugs.
Headache (1% to 10%) was the most common neurologic adverse event reported during itraconazole clinical trials. Other reported neurologic adverse events included abnormal dreams or nightmares (2%), anxiety (3%), confusion, depression (1% to 3%), dizziness (1.2% to 4%), drowsiness or somnolence (1%), insomnia (2%), libido decrease (1%), tremor (2%), and vertigo (1%). In addition, tremor, peripheral neuropathy, paresthesias, and hypoesthesia have been noted in post marketing reports. Isolated cases of neuropathy were reported rarely in clinical trials, but the association with itraconazole was unclear. If neuropathy occurs and is drug-related, discontinue itraconazole. Visual impairment has been reported in less than 2%. of patients in itraconazole clinical trials. Visual disturbances, including blurred vision and diplopia, have been noted in post marketing reports. Less than 2% of patients receiving treatment with itraconazole during clinical trials experienced episodes of tinnitus. Hypoacusis was noted in 3.3% of patients receiving the tablet dosage form during clinical trials. Cases of tinnitus and transient or permanent hearing loss have been reported in post marketing surveillance. Hearing loss was most notably reported with elderly patients; however, in many cases, quinidine was administered concurrently with itraconazole.
Rash was reported in 3% to 9% of patients treated with itraconazole during clinical trials and occurred more frequently in immunocompromised patients receiving immunosuppressive medications. Pruritus (5% or less) may be associated with the rash. Other dermatologic adverse events reported during clinical trials included hyperhidrosis (3% to 4%) and unspecified skin disorders (2%). Hypersensitivity reactions have been reported with post marketing use; these reactions include anaphylaxis, ana phylactoid reactions, angioedema, and serum sickness. Other adverse events noted in post marketing reports include toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, leukocytoclastic vasculitis, erythema multiforme, alopecia, photosensitivity, rash, urticaria, and pruritus.
General adverse reactions, affecting the body as a whole, were reported after use of itraconazole during clinical trials and included fever (2% to 7%), fatigue (1% to 3%), rigors (less than 2%), pain (2%), malaise (1% to 3%), and chills. Itraconazole has been associated with acute generalized exanthematous pustulosis (AGEP). The non-follicular, pustular, erythematous rash starts suddenly, is associated with fever above 38 degrees C. Drugs are the main cause of AGEP. A period of 2 to 3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional re-exposure may cause a second episode within 2 days.
Ibuprofen
Pruritus has been reported in 1—10% of patients taking oral ibuprofen or other NSAIDs and was cited as the most common cause of drug discontinuation in parenteral ibuprofen clinical trials (< 1%). Rash (unspecified), including maculopapular rash, has been reported in 1—10% of patients taking oral ibuprofen. Of patients taking oral ibuprofen, other dermatologic reactions occur less frequently (< 1%), including bullous rash, urticaria, erythema multiforme, Stevens-Johnson syndrome, alopecia, photosensitivity reactions, vesiculobullous eruptions, toxic epidermal necrolysis, and diaphoresis (no incidence reported). Exfoliative dermatitis, a serious and potentially fatal skin reaction, has been reported with other NSAIDs and may occur with ibuprofen. Patients should be instructed to discontinue the medication and contact their health care provider if erythema, rash, blisters, or related skin reactions develop.
Topical Ibuprofen may cause burning, itching, stinging, redness, or irritation may occur. Unlikely but serious side effects that may occur: unusual changes in the skin (e.g., blistering, peeling, turning white/soft/soggy from too much wetness), signs of skin infection. Very serious allergic reactions to lactic acid are rare. However, immediate medical attention should be sought any symptoms of a serious allergic reaction, including: rash, itching/swelling of the face/tongue/throat), severe dizziness, trouble breathing.