DRUGS & SUPPLEMENTS
WARNING: CONGESTIVE HEART FAILURE, CARDIAC EFFECTS, AND DRUG INTERACTIONS
Do not administer Spazol for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. When Spazol was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur during administration of Spazol, discontinue administration.
Drug Interactions: Co-administration of cisapride, pimozide, quinidine, dofetilide, levacetylmethadol (levomethadyl), felodipine, oral midazolam, nisoldipine, triazolam, lovastatin, simvastatin, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) or methadone with Spazol is contraindicated. Spazol, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), methadone or quinidine concomitantly with Spazol and/or other CYP3A4 inhibitors.
WARNING: CONGESTIVE HEART FAILURE, CARDIAC EFFECTS AND DRUG INTERACTIONS
See full prescribing information for complete boxed warning.
1 INDICATIONS AND USAGE
Spazol is indicated for the treatment of onychomycosis of the toenail due to Trichophyton rubrum or T. mentagrophytes in non-immunocompromised patients. Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. [See Contraindications (4), Warnings and Precautions (5), Drug Interactions (7), and Clinical Pharmacology (12) .]
2 DOSAGE AND ADMINISTRATION
Spazol should be taken with a full meal at the same time each day. The recommended dose is 200 mg (one tablet) once daily for 12 consecutive weeks.
Use in Patients with Renal Impairment:
Limited data are available on the use of oral Spazol in patients with renal impairment. Caution should be exercised when Spazol is administered to patients with renal impairment.
Use in Patients with Hepatic Impairment:
Limited data are available on the use of oral Spazol in patients with hepatic impairment. Caution should be exercised when Spazol is administered to patients with hepatic impairment.
3 DOSAGE FORMS AND STRENGTHS
Spazol contain 200 mg of Spazol, as a white to slightly grey, oblong, biconvex tablet engraved with "BARRIER" on one side and "It 200" on the other side.
Congestive Heart Failure: Do not administer Spazol for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.
Drug Interactions: Concomitant administration of Spazol and certain drugs that are metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) or where gastrointestinal absorption is regulated by P-gp may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events.
Co-administration of cisapride, dofetilide, ergot alkaloids such as dihydroergotamine, ergotamine, ergometrine (ergonovine), and methylergometrine (methylergonovine), felodipine, levacetylmethadol (levomethadyl), lovastatin, methadone, oral midazolam, nisoldipine, pimozide, quinidine, simvastatin, and triazolam with Spazol is contraindicated.
Do not administer Spazol for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.
Anaphylaxis and hypersensitivity have been reported with use of Spazol. Spazol is contraindicated for patients who have shown hypersensitivity to Spazol products.
5 WARNINGS AND PRECAUTIONS
5.1 Congestive Heart Failure, Peripheral Edema, and Pulmonary Edema
Cases of CHF, peripheral edema, and pulmonary edema have been reported with Spazol administration among patients being treated for onychomycosis and/or systemic fungal infections. [See Contraindications (4), Warnings and Precautions (5), and Clinical Pharmacology (12) .]
5.2 Cardiac Dysrhythmias
Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol, methadone, or quinidine concomitantly with Spazol and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with Spazol is contraindicated.
5.3 Cardiac Disease
Spazol should not be administered in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.
Spazol has been shown to have a negative inotropic effect. When Spazol was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of Spazol injection, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.
For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of Spazol therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of Spazol, discontinue administration.
5.4 Hepatic Effects
Spazol has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with hepatotoxicity, treatment should be discontinued immediately and liver function testing performed.
In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with Spazol is not recommended. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving Spazol.
5.5 Calcium Channel Blockers
Calcium channel blockers can have negative inotropic effects which may be additive to those of Spazol. In addition, Spazol can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering Spazol and calcium channel blockers due to an increased risk of CHF. Concomitant administration of Spazol and nisoldipine is contraindicated.
If neuropathy occurs that may be attributable to Spazol, the treatment should be discontinued.
5.7 Hearing Loss
Transient or permanent hearing loss has been reported in patients receiving treatment with Spazol. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
6 ADVERSE REACTIONS
To report SUSPECTED ADVERSE REACTIONS, contact Merz Pharmaceuticals, LLC at 1-877-743-8454 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rate observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Patients in the trial for toenail onychomycosis were treated with a dosing regimen of 200 mg once daily for 12 consecutive weeks.
The most commonly reported adverse reaction leading to discontinuation of Spazol was increased hepatic enzyme (6 subjects, 1.0%), followed by dizziness (3 subjects, 0.5%). No other adverse reaction leading to discontinuation occurred in more than one subject.
The table below lists all adverse reactions reported by at least 1% of patients who received Spazol during 12 weeks of treatment:
6.2 Post Marketing Experience
The following adverse reactions have been identified during post-approval use of Spazol (all formulations) and are listed in Table 2 below. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establishing a causal relationship to drug exposure.
7 DRUG INTERACTIONS
7.1 Effects of Spazol on Other Drugs
Spazol and its major metabolite, hydroxy-itraconazole, are strong inhibitors of the cytochrome P450 3A4 isoenzyme system (CYP3A4). Therefore, concomitant administration of Spazol and certain drugs metabolized by the cytochrome CYP3A4 may result in increased plasma concentrations of those drugs due to decreased elimination, leading to potentially serious and/or life-threatening adverse events. Spazol is also an inhibitor of P-glycoprotein (P-gp) transporter and may result in increased plasma concentrations of drugs whose gastrointestinal absorption is regulated by P-gp. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant Spazol therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, Spazol plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by Spazol.
7.2 Effects of Other Drugs on Spazol
Inducers of CYP3A4 may decrease the plasma concentrations of Spazol. Spazol may not be effective in patients concomitantly taking Spazol and one of these drugs. Therefore, administration of these drugs with Spazol is not recommended.
Inhibitors of CYP3A4 may increase the plasma concentrations of Spazol. Patients who must take Spazol concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of Spazol.
The Class IA antiarrhythmic, quinidine and class III antiarrhythmic, dofetilide are known to prolong the QT interval. Co-administration of quinidine or dofetilide with Spazol may increase plasma concentrations of quinidine or dofetilide, which could result in serious cardiovascular events. Therefore, concomitant administration of Spazol and quinidine or dofetilide is contraindicated.
The Class IA antiarrhythmic, disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when Spazol and disopyramide are administered concomitantly.
Concomitant administration of digoxin and Spazol has led to increased plasma concentrations of digoxin via inhibition of P-glycoprotein.
Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Reduced plasma concentrations of Spazol were reported when Spazol was administered concomitantly with phenytoin. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of Spazol and these drugs would be expected to result in decreased plasma concentrations of Spazol. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of Spazol on carbamazepine metabolism, because of the similarities between ketoconazole and Spazol, concomitant administration of Spazol and carbamazepine may inhibit the metabolism of carbamazepine.
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) such as nevirapine and efavirenz are inducers of CYP3A4. Human pharmacokinetic studies have shown that efavirenz, when concomitantly administered with Spazol, greatly decreased serum concentrations of Spazol and hydroxyl-itraconazole. Concomitant use of Spazol and efavirenz is not recommended.
In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and Spazol have not been conducted. However, because of the similarities between ketoconazole and Spazol, concomitant administration of Spazol and nevirapine is not recommended.
Concomitant administration of Spazol and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of Spazol and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of Spazol. Caution is advised when Spazol and protease inhibitors must be given concomitantly.
Concomitant administration of Spazol and maraviroc has been reported to increase plasma concentration of maraviroc. The dose of maraviroc should be decreased to 150 mg twice daily when given in combination with Spazol.
Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including Spazol and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. Spazol may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of Spazol could be substantially reduced if given concomitantly with one of these agents and co-administration is not recommended.
Spazol may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids.
Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Co-administration of pimozide with Spazol could result in serious cardiovascular events. Therefore, concomitant administration of Spazol and pimozide is contraindicated.
Increases in plasma aripiprazole concentrations have been demonstrated in subjects concomitantly receiving ketoconazole, requiring a reduction of the aripiprazole dose. Because of the similarities between ketoconazole and Spazol, a similar dose reduction for aripiprazole is recommended when patients concomitantly receive Spazol and aripiprazole.
Concomitant administration of Spazol and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of Spazol and oral midazolam or triazolam is contraindicated. If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged.
Calcium Channel Blockers
Calcium channel blockers can have a negative inotropic effect which may be additive to those of Spazol; Spazol can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine, nisoldipine, and felodipine) and verapamil. Therefore, caution should be used when co-administering Spazol and calcium channel blockers due to an increased risk of CHF.
Concomitant administration of Spazol and nisoldipine results in clinically significant increases in nisoldipine plasma concentrations, which cannot be managed by dosage reduction, therefore the concomitant administration of Spazol and nisoldipine is contraindicated. A clinical study showed that felodipine exposure was increased by co-administration of Spazol, resulting in approximately 6-fold increase in the AUC and 8-fold increase in the Cmax. The concomitant use of Spazol and felodipine is contraindicated.
Edema has been reported in patients concomitantly receiving Spazol and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary.
Gastric Acid Suppressors/Neutralizers
Reduced plasma concentrations of Spazol were reported when administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of Spazol is impaired when gastric acid production is decreased. Spazol should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. It is advised that antacids be administered at least 1 hour before or 2 hours after administration of Spazol. In a clinical study, when Spazol capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of Spazol was significantly reduced.
Gastrointestinal Motility Agents
Co-administration of Spazol with cisapride can elevate plasma cisapride concentrations, which could result in serious cardiovascular events. Therefore, concomitant administration of Spazol with cisapride is contraindicated.
3-Hydroxy-3-Methyl-Glutaryl CoA-Reductase Inhibitors
Human pharmacokinetic data suggest that Spazol inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of Spazol with 3-Hydroxy-3-Methyl-Glutaryl (HMG) CoA-Reductase inhibitors, such as lovastatin and simvastatin, is contraindicated.
Concomitant administration of Spazol and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Similarly, concomitant administration of Spazol and sirolimus could increase plasma concentrations of sirolimus.
Monitoring of blood concentrations of cyclosporine, tacrolimus, or sirolimus are recommended when Spazol are co-administered with these immunosuppressants and appropriate dosage adjustments should be made.
Erythromycin and clarithromycin are known inhibitors of CYP3A4 and may increase plasma concentrations of Spazol.
Oral Hypoglycemic Agents
Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. A human pharmacokinetic study showed that co-administration with Spazol and a single dose of repaglinide (on the third day of a regimen of 200 mg initial dose, twice-daily 100 mg Spazol) resulted in a 1.4-fold higher repaglinide AUC. Blood glucose concentrations should be carefully monitored when Spazol and oral hypoglycemic agents are co-administered.
Polyenes Antifungal Agents
Prior treatment with Spazol, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined.
Levacetylmethadol (levomethadyl) and methadone are known to prolong the QT interval and are metabolized by CYP3A4. Co-administration of methadone or levacetylmethadol with Spazol could result in serious cardiovascular events. Therefore, concomitant administration of Spazol and methadone or levacetylmethadol are contraindicated.
Fentanyl plasma concentrations could be increased or prolonged by concomitant use of Spazol and may cause potentially fatal respiratory depression.
In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with Spazol may increase plasma concentrations of alfentanil.
8 USE IN SPECIFIC POPULATIONS
Teratogenic effects. Pregnancy Category C
There are no adequate and well-controlled clinical trials in the pregnant women with Spazol. However, cases of congenital abnormalities have been reported with Spazol drug products in post-marketing reports. Therefore, Spazol should not be administered to pregnant women, women planning pregnancy, or women of child bearing potential unless these onychomycosis patients are using effective contraception measures to prevent pregnancy. Effective contraceptive measures should continue throughout the treatment period and for two months thereafter. Spazol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Spazol produced a significant dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dose levels of 40-160 mg/kg/day (2-10 times the maximum recommended human dose [MRHD], based on mg/m2/day comparisons), and in mice at 80 mg/kg/day (2 times MRHD, based on mg/m2/day comparisons). Teratogenic changes in rats included major skeletal defects; encephalocele and/or macroglossia developed in mice.
8.3 Nursing Mothers
Spazol is excreted in human milk; therefore, the expected benefits of Spazol therapy for the mother should be weighed against the potential risk from exposure of Spazol to the infant.
8.4 Pediatric Use
The safety and effectiveness of Spazol in pediatric patients have not been established. No pharmacokinetic data on Spazol are available in children.
8.5 Geriatric Use
Spazol was evaluated in 42 of 593 subjects greater than 65 years of age.
Transient or permanent hearing loss has been reported in elderly patients receiving treatment with Spazol. Several of these reports included concurrent administration of quinidine which is contraindicated. Spazol should be used with care in elderly patients.
8.6 Renal Impairment
Limited data are available on the use of oral Spazol in patients with renal impairment. Caution should be exercised when Spazol is administered to patients with renal impairment.
8.7 Hepatic Impairment
Limited data are available on the use of oral Spazol in patients with hepatic impairment. Caution should be exercised when Spazol is administered to patients with hepatic impairment.
Spazol is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed.
Spazol (itraconazole) is a synthetic triazole antifungal agent for oral use. Spazol is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature:
Spazol has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.
Each Spazol is formulated for melt extrusion technology and contains 200 mg of Spazol and the following inactive ingredients: colloidal silicon dioxide, crospovidone, hydrogenated vegetable oil, hypromellose, lactose, microcrystalline cellulose, magnesium stearate, propylene glycol, talc, and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Spazol, an azole, is an antifungal agent [See Clinical Pharmacology and Microbiology (12.4) ].
The oral bioavailability of Spazol is increased when Spazol is taken with a FDA standard high-fat meal. The pharmacokinetic parameters of Spazol and hydroxy-itraconazole after administration of one Spazol to 9 male and 9 female healthy subjects in fasting and in fed conditions are presented in the table below:
The steady-state pharmacokinetics of Spazol and hydroxy-itraconazole were analyzed after oral dosing of 16 healthy volunteers with one Spazol following a moderate-fat breakfast once daily for 14 days in an open-label study. Mean maximum plasma levels of Spazol and hydroxy-itraconazole increased from Day 1 to Day 14 by approximately 6- and 4-fold, respectively. The respective pharmacokinetic parameters from this study are reflected in the table below:
In a 2-period, open-label, randomized, cross-over, pivotal bioequivalence study to assess the comparative bioavailability of the Spazol and a marketed 100-mg Spazol capsule, 28 male and 28 female healthy subjects were given as a single dose, 200 mg of Spazol immediately after a moderate-fat breakfast (same caloric and fat contents as in the table above). Fifty-two subjects were included in the final analysis.
The Cmax of the Spazol was comparable to that of the 2 Spazol 100-mg capsules while AUCt and AUC∞ were about 15% higher with the Spazol.
In another 2-period, open-label, randomized, cross-over, pivotal bioequivalence study, 28 male and 28 female healthy subjects were given one Spazol or two 100-mg Spazol capsules following the FDA standard high-fat breakfast. The Cmax and AUC∞ of the Spazol were 20 and 30% lower, respectively, than those of two Spazol 100-mg capsules. Overall, the inter-subject variability was high and coefficient of variances (CV) for AUCs in the above two studies were 44-66%.
Spazol is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites. Hydroxyitraconazole, the major metabolite, has in vitro antifungal activity comparable to Spazol. Results of a pharmacokinetics study suggest that Spazol may undergo saturable metabolism with multiple dosing. Based on an oral dose, fecal excretion of the parent drug varies between 3-18% of the dose. Spazol is excreted mainly as inactive metabolites in the urine (35%) and feces (54%) within one week of an oral dose. No single excreted metabolite represents more than 5% of a dose. The plasma protein binding of Spazol has been reported to be 99.8% and that of hydroxy-itraconazole is 99.5%.
Mechanism of Action
Spazol inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.
Activity In Vitro
Spazol exhibits in vitro activity against Trichophyton rubrum and Trichophyton mentagrophytes.
Isolates from several fungal species with decreased susceptibility to Spazol have been isolated from patients receiving prolonged therapy.
Several in vitro studies have reported that some fungal clinical isolates with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated.
Limited data are available on the use of oral Spazol in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of Spazol was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. The study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of Spazol (Tmax, Cmax, and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. Caution should be exercised when the drug is administered in this population.
Spazol is predominantly metabolized in the liver. Patients with impaired hepatic function should be carefully monitored when taking Spazol. A pharmacokinetic study using a single oral 100 mg dose of Spazol was conducted in 6 healthy and 12 cirrhotic subjects. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of Spazol were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to Spazol, based on AUC, was similar in cirrhotic patients and in healthy subjects. The prolonged elimination half-life of Spazol observed in the single oral dose clinical trial with Spazol in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. Data are not available in cirrhotic patients during long-term use of Spazol.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity, mutagenicity, or impairment of fertility studies were conducted with Spazol.
Spazol did not exhibit any carcinogenic potential in mice receiving oral doses up to 80 mg/kg/day (2 times MRHD, based on mg/m2/day comparisons) for 23 months. A slightly increased incidence of soft tissue sarcoma was observed in male rats administered 25 mg/kg/day (1.3 times MRHD, based on mg/m2/day comparisons). These tumors may have been related to hypercholesterolemia caused by chronic treatment with Spazol in rats; hypercholesterolemia is not observed with such treatment in dogs or humans. Compared to untreated controls, female rats receiving 50 mg/kg/day (2.5 times MRHD, based on mg/m2/day comparisons) had a statistically insignificant increase in squamous cell carcinoma in lungs (2/50), an uncommon tumor in rats.
Spazol did not exhibit any mutagenic or genotoxic effects when evaluated in a DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests (6 Salmonella strains and E. coli), in the mouse lymphoma gene mutation test, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration test (human lymphocytes), in a cell transformation assay (C3H/10T½ C18 mouse embryo fibroblasts), in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats.
Spazol did not affect the fertility in male or female rats treated with oral doses up to 40 mg/kg/day (2 times MRHD, based on mg/m2/day comparisons); however, parental toxicity occurred at this dosage. More severe parental toxicity was observed at 160 mg/kg/day (10 times MRHD, based on mg/m2/day comparisons).
14 CLINICAL STUDIES
The efficacy of Spazol for the treatment of onychomycosis of the toenail was examined in a randomized, multi-center, placebo-controlled, third-party blinded trial comparing Spazol to two 100 mg Spazol capsules and placebo tablets.
In the clinical study, 791 subjects with diagnosis of distal and/or lateral subungual onychomycosis were randomized to Spazol (N= 593) or placebo tablets (N= 198) once daily for 12 consecutive weeks. The median age of subjects enrolled in the trial was 48 years and 75% were males. At baseline, 95.1% of subjects had onychomycosis due to T. rubrum with a baseline global severity score of 'Moderate' which was defined as a target toenail involvement ≤50% dystrophy and/or discoloration with clear evidence of subungual hyperkeratosis and/or onycholysis.
The primary endpoint was the proportion of subjects with a Complete Cure at Week 52, nine months after completion of study medication. A Complete Cure was defined as both a Clinical Cure (no evidence of onychomycosis in target nail; normal nail unit without subungual hyperkeratosis or onycholysis) and Mycological Cure (negative KOH and negative culture). The following table illustrates the study results for Spazol and Placebo:
The Mycologic Cure rate was 44% and the Clinical Cure rate was 26% for subjects treated with Spazol. Comparatively, the Mycological Cure rate was 6% and the Clinical Cure rate was 3% for subjects treated with Placebo Tablets.
Efficacy results comparing Spazol to 200 mg of Spazol capsules (two 100 mg capsules) were similar.
16 HOW SUPPLIED/STORAGE AND HANDLING
Spazol is available containing 200 mg of Spazol, as a white to slightly grey, oblong, biconvex tablet engraved with "BARRIER" on one side and "It 200" on the other side. Each carton (NDC 0259-1420-28) contains two blister cards of 14 tablets each (NDC 0259-1420-14).
Store at controlled room temperature 15° to 25°C (59° to 77°F). Excursions permitted to 15° to 30°C (59° to 86°F). Protect from light and moisture. Keep out of reach of children.
17 PATIENT COUNSELING INFORMATION
17.1 Information for Patients
FDA-Approved Patient Labeling
Read this Patient Information before you start using Spazol and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.
What is the most important information I should know about Spazol?
Spazol can cause serious life-threatening side effects, including:
What is Spazol?
Spazol is a prescription medicine used to treat fungal infections of the toenails. It is not known if Spazol is safe and effective in children under the age of 18.
Who should not take Spazol?
Do not take Spazol if you:
What should I tell my doctor before taking Spazol?
Before taking Spazol, tell your doctor if you:
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
Taking Spazol with certain other medicines could lead to serious or life-threatening medical problems.
Talk to your doctor or pharmacist before you start any new medicine. They can tell you if it is safe to take Spazol with your other medicines.
Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.
How should I take Spazol?
Take Spazol exactly as prescribed by your doctor. Be sure to finish all of your Spazol as prescribed by your doctor.
What are the possible side effects of Spazol?
Spazol can cause serious side effects, including:
Common side effects of Spazol include:
These are not all of the possible side effects of Spazol. Tell your doctor if you any side effect that bothers you or that does not go away. For more information, ask your doctor.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Spazol?
Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information leaflets. Do not use Spazol for a condition for which it was not prescribed. Do not give Spazol to other people, even if they have the same symptoms that you have. It may harm them.
This leaflet summarizes the most important information about Spazol. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Spazol that is written for health professionals.
For more information about Spazol call 1-877-743-8454.
What are the ingredients in Spazol?
Active ingredient: Spazol
Inactive ingredients: colloidal silicon dioxide, crospovidone, hydrogenated vegetable oil, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, talc, and titanium dioxide.
The following are registered trademarks of their respective manufacturers:
Dolophine® (Roxane Laboratories, Inc), Mevacor® (Merck & Co., Inc.), Advicor® (Kos Pharmaceuticals, Inc.), Altocor (Andrx Laboratories), Zocor® (Merck & Co., Inc.), Halcion® (Pharmacia), Versed® (Roche Pharmaceuticals), Cardioquin® (The Purdue Frederick Company), Quinaglute® (Berlex Laboratories), Quinidex® (A.H. Robins), Tikosyn (Pfizer, Inc.), Propulsid® (Janssen Pharmaceutica Products, L.P.), Orlaam® (Roxane Laboratories), Migranal® (Xcel Pharmaceuticals), Ergonovine (PDRX Pharmaceuticals), Cafergot® (Novartis Pharmaceuticals Corporation), Methergine® (Novartis Pharmaceuticals Corporation), Orap® (Gate Pharmaceuticals), and Sular® (First Horizon Pharmaceutical Corporation)
What happens if I have a fungal nail infection?
Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus infects the nail, the infected part of the nail may turn yellow or brown. If not treated, the fungus may spread, and more of the nail may change color, may become thick or brittle, and the tip of the nail may become raised. In some patients, this can cause pain and discomfort.
2300 Turnhout, Belgium
Merz Pharmaceuticals, LLC
4215 Tudor Lane
Greensboro, NC 27410
PRINCIPAL DISPLAY PANEL - 28 Tablet Carton
2 Blister Cards
28 Tablets Total
Each Blister card contains
(itraconazole) Tablets 200 mg
PRINCIPAL DISPLAY PANEL - 28 Tablet Carton
Spazol pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Spazol available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Spazol destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Spazol Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Spazol pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Spazol?
Depending on the reaction of the Spazol after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Spazol not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Spazol addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Reviewsdrugs.com conducted a study on Spazol, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Spazol consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
Visitor reported usefulNo survey data has been collected yet
Visitor reported side effectsNo survey data has been collected yet
Visitor reported price estimatesNo survey data has been collected yet
Two visitors reported frequency of useHow often in a day do you take the medicine?
Are you taking the Spazol drug as prescribed by the doctor?
Few medications can be taken Once in a day more than prescribed when the doctor's advice mentions the medicine can be taken according to frequency or severity of symptoms. Most times, be very careful and clear about the number of times you are taking the medication. The report of sdrugs.com website users about the frequency of taking the drug Spazol is mentioned below.
One visitor reported dosesWhat is the dose of Spazol drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 11-50mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
One visitor reported time for resultsWhat is the time duration Spazol drug must be taken for it to be effective or for it to reduce the symptoms?
Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sdrugs.com website users needed 2 weeks to notice the result from using Spazol drug. The time needed to show improvement in health condition after using the medicine Spazol need not be same for all the users. It varies based on other factors.
Visitor reported administrationNo survey data has been collected yet
One visitor reported age
The information was verified by Dr. Arunabha Ray, MD Pharmacology