1. Name Of The Medicinal Product
Sporanox® I.V. 10 mg/ml concentrate and solvent for solution for infusion.
2. Qualitative And Quantitative Composition
Each ml of the Sporanox IV concentrate contains 10 mg itraconazole.
One ampoule with 25 ml contains 250 mg itraconazole (itraconazole trihydrochloride salt formed in situ).
Each ml of the admixed solution contains 3.33 mg itraconazole.
One single dose of 200 mg itraconazole corresponds to 60 ml of the admixed solution.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Concentrate and solvent for solution for infusion.
Sporanox IV 10 mg/ml concentrate and solvent (0.9% Sodium Chloride Injection) for solution for infusion is presented in a procedure pack consisting of:
(a) 25ml of Sporanox IV 10 mg/ml concentrate for infusion, a colourless solution presented in a glass ampoule.
(b) 50ml of 0.9 % Sodium Chloride Injection solvent for solution for infusion, a colourless solution presented in a polypropylene bag.
(c) Extension line with 2-way stopcock and in-line filter
4. Clinical Particulars
4.1 Therapeutic Indications
Sporanox I.V. is indicated for the treatment of histoplasmosis.
Sporanox I.V. is indicated in the following systemic fungal conditions when first-line systemic anti-fungal therapy is inappropriate or has proved ineffective. (This may be due to underlying pathology, insensitivity of the pathogen or drug toxicity).
Treatment of aspergillosis, candidosis and cryptococcosis (including cryptococcal meningitis): in immunocompromised patients with cryptococcosis and in all patients with cryptococcosis of the central nervous system.
Consideration should be given to national and/or local guidance regarding the appropriate use of antifungal agents.
4.2 Posology And Method Of Administration
This product is supplied with an extension line with a 2-way stopcock and 0.2 μm in-line filter. The dedicated extension line including the in-line filter must be used to ensure the correct administration of the product (see section 6.6).
Sporanox I.V. is given on the first two days in a loading dose twice daily, followed by once daily dosing.
Day 1 and 2 of the treatment: 1-hour infusion of 200 mg (60 ml of the admixed solution) Sporanox I.V. twice daily. (See section 6.6).
From day 3 on: one 1-hour infusion of 200 mg (60 ml of the admixed solution) Sporanox I.V. each day. Safety for periods longer than 14 days has not been established.
Use in children: Since clinical data on the use of Sporanox I.V. in paediatric patients are unavailable, Sporanox I.V. should not be used in children unless the potential benefit outweighs the potential risk. (See section 4.4).
Use in elderly: Since clinical data of the use of Sporanox I.V. in elderly patients are limited, it is advised to use Sporanox I.V. in these patients only if the potential benefit outweighs the potential risk. (See section 4.4).
Use in patients with renal impairment: Limited data are available on the use of intravenous itraconazole in patients with renal impairment.
Hydroxypropyl-β-cyclodextrin, a required component of Sporanox intravenous formulation, is eliminated through glomerular filtration. Therefore, in patients with severe renal impairment defined as creatinine clearance below 30 ml/min the use of Sporanox IV is contraindicated. (See section 4.3).
In patients with mild and moderate renal impairment, Sporanox IV should be used with caution. Serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to changing to the oral capsule formulation. (See sections 4.4. and 5.2).
Use in patients with hepatic impairment: Limited data are available on the use of itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See section 5.2).
4.3 Contraindications
− Sporanox I.V. is contraindicated in patients with a known hypersensitivity to itraconazole or to any of the excipients.
− Sporanox I.V. cannot be used when administration of Sodium Chloride Injection is contraindicated.
− The excipient hydroxypropyl-β-cyclodextrin is eliminated through glomerular filtration. Therefore, Sporanox I.V. is contraindicated in patients with severe renal impairment (defined as creatinine clearance below 30 ml/min). (See section 4.4 and section 5.2).
− Coadministration of the following drugs is contraindicated with Sporanox I.V. (see section 4.5):
• CYP3A4 metabolised substrates that can prolong the QT-interval e.g., terfenadine, astemizole, bepridil, mizolastine, cisapride, dofetilide, levacetylmethadol (levomethadyl), quinidine, sertindole or pimozide coadministration may result in increased plasma levels of these substrates which can lead to QTc prolongation and rare occurrences of torsades de pointes.
• CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin, lovastatin and atorvastatin
• Triazolam and oral midazolam
• Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).
• Eletriptan
• Nisoldipine
− Sporanox I.V. must not be used during pregnancy for non life-threatening indications (see section 4.6 ).
4.4 Special Warnings And Precautions For Use
Cross hypersensitivity
There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing Sporanox IV to patients with hypersensitivity to other azoles
Cardiac effects
In a healthy volunteer study with Sporanox IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion. A similar investigation was not performed in the target patient population.
Itraconazole has been shown to have a negative inotropic effect and Sporanox has been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400 mg total daily dose than among those of lower total daily doses, suggesting that the risk of heart failure might increase with the total daily dose of itraconazole.
Sporanox should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk.
Physicians should carefully review the risks and benefits of Sporanox therapy for patients with known risk factors for congestive heart failure. These risk factors include cardiac disease, such as ischaemic 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 congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment. If such signs or symptoms do occur during treatment, Sporanox should be discontinued.
Caution should be exercised when co-administering itraconazole and calcium channel blockers (see section 4.5).
Hepatic effects
Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Sporanox. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving SPORANOX treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted. Most cases of serious hepatotoxicity involved patients who had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. In patients with raised liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In patients with impaired hepatic function liver enzyme should be carefully monitored when taking itraconazole.
Use in children
Since clinical data on the use of Sporanox I.V. in paediatric patients are unavailable, Sporanox I.V. should not be used in children unless the potential benefit outweighs the potential risk.
Use in elderly
Since clinical data of the use of Sporanox I.V. in elderly patients are limited, it is advised to use Sporanox I.V. in these patients only if the potential benefit outweighs the potential risk.
Hepatic impairment
Studies have not been conducted with intravenous itraconazole in patients with hepatic impairment. Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when the drug is administered to this patient population. (See Section 4.2 and 5.2).
Renal impairment
Hydroxypropyl-β-cyclodextrin, when administered intravenously, is eliminated through glomerular filtration. Therefore, in patients with renal impairment defined as creatinine clearance below 30 ml/min Sporanox IV is contraindicated (see sections 4.3 and 5.2).
Sporanox I.V. should be used with caution in patients with a lesser degree of renal failure. In patients with mild and moderate renal impairment, serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to changing to the oral capsule formulation. (See section 4.4).
Hearing Loss
Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see sections 4.3 and 4.5). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
Neuropathy
If neuropathy occurs that may be attributable to Sporanox I.V., the treatment should be discontinued.
Cross-resistance
In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence their sensitivity should be tested before the start of itraconazole therapy.
Interaction potential
Sporanox has a potential for clinically important drug interactions (see section 4.5).
Itraconazole should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John´s wort). The use of itraconazole with these drugs may lead to subtherapeutic plasma levels of itraconazole and thus treatment failure.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
1. Drugs affecting the metabolism of itraconazole:
Itraconazole is mainly metabolised through the cytochrome CYP3A4. Interaction studies have been performed with rifampicin, rifabutin and phenytoin, which are potent enzyme inducers of CYP3A4. Since the bioavailability of itraconazole and hydroxy-itraconazole was decreased in these studies to such an extent that efficacy may be largely reduced, the combination of itraconazole with these potent enzyme inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, Hypericum perforatum (St John's Wort), phenobarbital and isoniazid but similar effects should be anticipated.
Potent inhibitors of CYP3A4 such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of itraconazole.
2. Effect of itraconazole on the metabolism of other drugs:
Itraconazole can inhibit the metabolism of drugs metabolised by the cytochrome 3A family. This can result in an increase and/or a prolongation of their effects, including side effects. When using concomitant medication, the corresponding label should be consulted for information on the route of metabolism. After stopping treatment, itraconazole plasma concentrations decline gradually, depending on the dose and duration of treatment (see section 5.2). This should be taken into account when the inhibitory effect of itraconazole on co-medicated drugs is considered.
Drugs which are contraindicated with itraconazole:
• Terfenadine, astemizole, bepridil, mizolastine, levacetylmethadol (levomethadyl), cisapride, dofetilide, quinidine, sertindole or pimozide are contraindicated with Sporanox I.V. since coadministration may result in increased plasma levels of these substrates which can lead to QTc prolongation and rare occurrences of torsades de pointes (see section 4.3).
• CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin, lovastatin and atorvastatin.
• Triazolam and oral midazolam.
• Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).
• Eletriptan.
• Nisoldipine
Caution should be exercised when co-administering itraconazole with calcium channel blockers due to an increased risk of congestive heart failure. In addition to possible pharmacokinetic interactions involving the drug metabolising enzyme CYP3A4, calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.
The following drugs should be used with caution and their plasma concentrations, effects or side effects should be monitored. Their dosage, if co-administered with itraconazole, should be reduced if necessary:
− Oral anticoagulants;
− HIV Protease Inhibitors such as ritonavir, indinavir, saquinavir;
− Certain antineoplastic agents such as vinca alkaloids, busulfan, docetaxel and trimetrexate;
− CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil;
− Certain CYP3A4 metabolised HMG-CoA reductase inhibitors such as cerivastatin (see also drugs which are contraindicated with itraconazole);
− Certain immunosuppressive agents: cyclosporine, tacrolimus, rapamycin (also known as sirolimus);
− Certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone;
− Digoxin: (via inhibition of P-glycoprotein);
− Others: carbamazepine, cilostazol, buspirone, alfentanil, alprazolam, brotizolam, midazolam I.V., rifabutin, disopyramide ebastine, fentanyl, halofantrine, repaglinide and reboxetine. The importance of the concentration increase and clinical relevance of these changes during co-administration with itraconazole remain to be established.
No interaction of itraconazole with zidovudine (AZT) and fluvastatine has been observed.
No inducing effects of itraconazole on the metabolism of ethinyloestradiol and norethisterone were observed.
3. Effect on protein binding:
In vitro studies have shown that there are no interactions on the plasma protein binding between itraconazole and imipramine, propranolol, diazepam, cimetidine, indometacin, tolbutamide and sulfamethazine.
4.6 Pregnancy And Lactation
Pregnancy
Sporanox IV must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus (see section 4.3).
In animal studies itraconazole shows reproduction toxicity (see section 5.3).
Epidemiological data on exposure to Sporanox during the first trimester of pregnancy – mostly in patients receiving short-term treatment for vulvovaginal candidosis – did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens.
Women of child bearing potential
Women of child-bearing potential receiving Sporanox IV should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of Sporanox IV therapy.
Lactation
A very small amount of itraconazole is excreted in human milk and must not be administered to lactating women. Breast-feeding is to be discontinued prior to taking itraconazole.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss (see section 4.8), which may occur in some instances, must be taken into account.
4.8 Undesirable Effects
In clinical trials with intravenous itraconazole, the most frequently reported adverse experiences were of gastrointestinal, metabolic and nutritional, and hepatobiliary origin.
The table below presents adverse drug reactions by System Organ Class. Within each System Organ Class, the adverse drug reactions are presented by incidence, using the following convention:
Very common (
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* see section 4.4.
4.9 Overdose
In the event of overdose, supportive measures should be employed. Itraconazole cannot be removed by haemodialysis. No specific antidote is available.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivatives
ATC code: J02A C02
Mode of action
Itraconazole inhibits fungal 14α-demethylase, resulting in a depletion of ergosterol and disruption of membrane synthesis by fungi.
PK/PD relationship
The PK/PD relationship for itraconazole, and for triazoles in general, is poorly understood and is complicated by limited understanding of antifungal pharmacokinetics.
Mechanism(s) of resistance
Resistance of fungi to azoles appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are:
• Over-expression of ERG11, the gene that encodes 14-alpha-demethylase (the target enzyme)
• Point mutations in ERG11 that lead to decreased affinity of 14-alpha-demethylase for itraconazole
• Drug-transporter over-expression resulting in increased efflux of itraconazole from fungal cells (i.e., removal of itraconazole from its target)
• Cross-resistance. Cross-resistance amongst members of the azole class of drugs has been observed within Candida species though resistance to one member of the class does not necessarily confer resistance to other azoles.
Breakpoints
Breakpoints for itraconazole have not yet been established for fungi using EUCAST methods.
Using CLSI methods, breakpoints for itraconazole have only been established for Candida species from superficial mycotic infections. The CLSI breakpoints are: susceptible
The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
The in vitro susceptibility of fungi to itraconazole depends on the inoculum size, incubation temperature, growth phase of the fungi, and the culture medium used. For these reasons, the minimum inhibitory concentration of itraconazole may vary widely. Susceptibility in the table below is based on MIC90 < 1 mg itraconazole/L. There is no correlation between in vitro susceptibility and clinical efficacy.
Commonly susceptible species |
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Species for which acquired resistance may be a problem |
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Inherently resistant organisms |
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1 These organisms may be encountered in patients who have returned from travel outside-Europe.
2 Itraconazole-resistant strains of Aspergillus fumigatus have been reported.
3 Natural intermediate susceptibility.
5.2 Pharmacokinetic Properties
General pharmacokinetic characteristics
The pharmacokinetics of intravenously administered itraconazole has been investigated in healthy subjects, and patients after single and multiple dosing and in special populations after single doses.
Peak plasma concentrations of itraconazole are reached at the end of the intravenous infusion, declining thereafter. Peak plasma concentrations of hydroxyl-itraconazole (see Biotransformation below) are reached within 3 hours of beginning of a one-hour infusion, declining thereafter.
Each 200 mg intravenous dose of itraconazole contains 8g hydroxypropyl-β-cyclodextrin to increase the solubility of itraconazole. The pharmacokinetic profiles of each are described below. (See Itraconazole; see Special populations-Renal Impairment, Hydroxypropyl-β-cyclodextrin.)
Distribution
Most of the itraconazole in plasma is bound to protein (99.8%) with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (>700 L), suggesting its extensive distribution into tissues: Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Brain to plasma ratios were about 1 as measured in beagle dogs.
Biotransformation
Itraconazole is extensively metabolised by the liver into a large number of metabolites. One of the main metabolites is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole. Trough plasma concentrations of the hydroxy-metabolite are about twice those of itraconazole.
As shown in in-vitro studies, CYP3A4 is the major enzyme that is involved in the metabolism of itraconazole.
Elimination
Itraconazole total plasma clearance following intravenous administration is on average 381 ml/min. Itraconazole is excreted as inactive metabolites to about 35% in urine within one week and about 54% with feces. Renal excretion of the itraconazole and the active metabolite hydroxy-itraconazole account for less than 1%of an intravenous dose. Based on an oral dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose. Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral dose.
Linearity/non-linearity
As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. In a multiple-dose pharmacokinetic study, itraconazole IV was administered as a 1-hour infusion of 200 mg itraconazole twice daily on days 1 and 2 of treatment, followed by a 1-hour infusion of 200 mg once daily from day 3 to 7. Steady-state concentrations were reached after the fourth dose of itraconazole IV and by the seventh dose for hydroxy-itraconazole. Mean Cmax and Cmin values after 4 doses of 200 mg itraconazole IV in healthy subjects were 3055 ng/ml and 687 ng/ml respectively, while mean values for hydroxy-itraconazole at the same time points were 1058 ng/ml and 1263 ng/ml respectively. Itraconazole mean total plasma clearance following intravenous administration is 278 ml/min. The mean elimination half-life of itraconazole is about 32.5 hours after repeated dosing.
Special Populations
Hepatic Impairment
Studies have not been conducted with intravenous itraconazole in patients with hepatic impairment. Itraconazole is predominantly metabolised in the liver. A single oral dose (100 mg capsule) was administered to 12 patients with cirrhosis and six healthy control subjects; Cmax, AUC and terminal half-life of itraconazole were measured and compared between groups. Mean itraconazole Cmax was reduced significantly (by 47%) in patients with cirrhosis. Mean elimination half-life was prolonged compared to that found in subjects without hepatic impairment (37 vs. 16 hours, respectively). Data are not available in cirrhotic patients during long-term use of itraconazole.
Renal Impairment
A small fraction (<1%) of an intravenous dose of itraconazole is excreted unchanged in urine.
After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (CrCl 50-79 ml/min), moderate (CrCl 20-49 ml/min), and severe renal impairment (CrCl <20 ml/min) were similar to that in healthy subjects, (range of means 42-49 hr vs 48 hr in renally impaired patients and healthy subjects, respectively.) Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function.
Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole.
Hydroxypropyl-ß-Cyclodextrin
In patients with normal renal function, the pharmacokinetic profile of hydroxypropyl- ß–cyclodextrin, an ingredient of Sporanox intravenous formulation, has a short half-life of 1 to 2 hours, and demonstrates no accumulation following successive daily doses. In healthy subjects and in patients with mild to severe renal insufficiency, the majority of an 8 g dose of hydroxypropyl-ß-cyclodextrin is eliminated in the urine. Following a single intravenous dose of itraconazole 200 mg, clearance of hydroxypropyl-ß-cyclodextrin was reduced in subjects with renal impairment, resulting in higher exposure to hydroxypropyl-ß-cyclodextrin. In subjects with mild, moderate, and severe renal impairment, half-life values were increased over normal values by approximately two-, four-, and six-fold, respectively. In these patients, successive infusions may result in accumulation of hydroxypropyl-ß-cyclodextrin until steady state is reached. Hydroxypropyl- ß-cyclodextrin is removed by hemodialysis.
5.3 Preclinical Safety Data
Nonclinical data on itraconazole revealed no indications for gene toxicity, primary carcinogenicity or impairment of fertility. At high doses, effects were observed in the adrenal cortex, liver and the mononuclear phagocyte system but appear to have a low relevance for the proposed clinical use. Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity and teratogenicity in rats and mice at high doses. A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole administration, and in rats, a decreased bone plate activity, thinning of the zona compacta of the large bones, and an increased bone fragility was observed.
6. Pharmaceutical Particulars
6.1 List Of Excipients
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6.2 Incompatibilities
Itraconazole has the potential to precipitate when Sporanox I.V. is diluted in solutions other than the 50ml 0.9% sodium chloride injection supplied.
6.3 Shelf Life
Sporanox I.V.:
Shelf life as packaged:
2 years
0.9% Sodium Chloride Injection:
3 years
Admixed Solution:
24 hours.
6.4 Special Precautions For Storage
Sporanox I.V.:
Do not store above 25°C. Store in the original container.
0.9% Sodium Chloride Injection:
Do not store above 25°C. Do not freeze.
Admixed solution:
Protect from direct sunlight.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless the dilution of the admixture has taken place in controlled and validated aseptic conditions.
6.5 Nature And Contents Of Container
Sporanox I.V.:
25 ml siliconised type I colourless glass ampoule with 25 ml containing 250 mg itraconazole.
0.9% Sodium Chloride:
Flexible 75ml polypropylene infusion bag, equipped with a flexible inlet and outlet port, and containing 52 to 56ml of 0.9% Sodium Chloride Injection.
Extension Line:
Polyvinylchloride tubing with 2-way stopcock and in-line filter.
6.6 Special Precautions For Disposal And Other Handling
Sporanox I.V.:
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