Summary of medicine characteristics - 0.9% SODIUM CHLORIDE INJECTION
1 NAME OF THE MEDICINAL PRODUCT
0.9% Sodium Chloride Injection.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
No active substance(s).
3 PHARMACEUTICAL FORM
50 ml of 0.9 % Sodium Chloride Injection solvent for solution for infusion, a colourless solution presented in a polypropylene bag.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Diluent and carrier solution for injectable drugs, intended to be used exclusively in combination with Sporanox™ IV.
4.2 Posology and method of administration
This product is supplied with an extension line with a 2-way stopcock and 0.2 gm in-line filter. The dedicated extension line including the in-line filter must be used to ensure the correct administration of the product.
Sporanox IV 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 IV twice daily (see section 6.6).
From day 3 on: one 1-hour infusion of 200 mg (60 mL of the admixed solution) Sporanox IV each day. Safety for periods longer than 14 days has not been established.
Paediatric population
The safety and efficacy of SPORANOX IV in children has not been established.
Currently available data are described in section 4.4 and 5.2 but no recommendation on a posology can be made.
The use of Sporanox IV in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks (see section 4.4).
Use in elderly
Since clinical data of the use of Sporanox IV in elderly patients are limited, it is advised to use Sporanox IV in these patients only if the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (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-P-cyclodextrin, a required component of Sporanox IV, 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).
Method of administration
Precautions to be taken before handling or administering the medicinal product. For instructions on handling of the medicinal product before administration, see section 6.6.
4.3 Contraindications
Sporanox IV is contraindicated in patients with a known hypersensitivity to itraconazole or to any of the excipients.
Sporanox IV cannot be used when administration of Sodium Chloride Injection is contraindicated.
The excipient hydroxypropyl-P-cyclodextrin is eliminated through glomerular filtration. Therefore, Sporanox IV is contraindicated in patients with severe renal impairment defined as creatinine clearance below 30 ml/min (see sections 4.4 and 5.2).
Co-administration of a number of CYP3A4 substrates is contraindicated with Sporanox IV (see sections 4.4 and 4.5). Sporanox IV 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 oedematous 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.
Use in children
Clinical data on the use of Sporanox IV in paediatric patients are limited. The use of Sporanox IV in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks.
Use in elderly
Since clinical data of the use of Sporanox IV in elderly patients are limited, it is advised to use Sporanox IV in these patients only if the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see section 4.4).
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. It is recommended that patients with impaired hepatic function be carefully monitored when taking itraconazole. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4.
In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with Sporanox is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications (see sections 4.2 and 5.2).
Renal impairment
Hydroxypropyl-P-cyclodextrin, when administered intravenously, is eliminated through glomerular filtration. Therefore, in patients with severe renal impairment defined as creatinine clearance below 30 ml/min Sporanox IV is contraindicated (see sections 4.3 and 5.2).
Sporanox IV should be used with caution in patients with a lesser degree of renal failure. In patients with mild or 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 IV, 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
Co-administration of specific drugs with itraconazole may result in changes in efficacy or safety of itraconazole and/or the co-administered drug. For example, the use of itraconazole with CYP3A4 inducing agents may lead to sub-therapeutic plasma concentrations of itraconazole and thus treatment failure. In addition, the use of itraconazole with some substrates of CYP3A4 can lead to increases in plasma concentrations of these drugs and to serious and/or potentially life threatening adverse events, such as QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. The prescriber should refer to the co-administered medicinal product information for further information regarding serious or life threatening adverse events that could occur in cases of increased plasma concentrations for that medication. For recommendations concerning the coadministration of medicinal products which are contraindicated, not recommended or recommended for use with caution in combination with itraconazole please refer to section 4.5.
4.5 Interaction with other medicinal products and other forms of interaction
Itraconazole is mainly metabolised through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Itraconazole is a strong CYP3A4 inhibitor and, a P-glycoprotein inhibitor and Breast Cancer Resistance Protein (BCRP) inhibitor.
Itraconazole may modify the pharmacokinetics of other substances that share this metabolic or these protein transporter pathways.
Examples of drugs that may impact on the plasma concentration of itraconazole are presented by drug class in Table 1 below. Examples of drugs that may have their plasma concentrations impacted by itraconazole are presented in Table 2 below. Due to the number of interactions, the potential changes in safety or efficacy of the interacting drugs are not included. Please refer to the prescribing information of the interacting drug for more information.
The interactions described in these tables are categorised as contraindicated, not recommended or to be used with caution with itraconazole taking into account the extent of the concentration increase and the safety profile of the interacting drug (see also sections 4.3 and 4.4 for further information). The interaction potential of the listed drugs was evaluated based on human pharmacokinetic studies with itraconazole, and/or human pharmacokinetic studies with other strong CYP3A4 inhibitors (e.g. ketoconazole) and/or in vitro data:
‘Contraindicated’: Under no circumstances is the drug to be co-administered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.
‘Not recommended’: The use of the drug should be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the concomitantly administered drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations of the co-administered drug be measured.
‘Use with caution’: Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon co-administration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations of the co-administered drug be measured.
The interactions listed in these tables have been characterised in studies that were performed with recommended doses of itraconazole. However, the extent of interaction may be dependent on the dose of itraconazole administered. A stronger interaction may occur at a higher dose or with a shorter dosing interval. Extrapolation of the findings with other dosing scenarios or different drugs should be done with caution.
Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole. (see section 5.2)
Table 1: Examples of drugs that may impact the plasma concentration of itraconazole, presented by drug class
| Medicinal products Per Orale [PO] Single Dose unless otherwise stated) within class | Expected/Potential effect on itraconazole levels (f = increase; = no change; | = decrease) | Clinical comment (see above for additional info and also sections 4.3 and 4.4) |
| Anti-bacterials for Systemic Use; Anti-mycobacterials | ||
| Isoniazid | Although not studied directly, isoniazid is likely to decrease the concentrations of itraconazole. | Not recommended |
| Rifampicin PO 600 mg OD | Itraconazole AUC j | Not recommended |
| Rifabutin PO 300 mg OD | Itraconazole Cmax j 71%, AUC j 74% | Not recommended |
| Ciprofloxacin PO 500 mg BID | Itraconazole Cmax f 53%, AUC f | Use with caution |
| 82% | ||
| Erythromycin 1 g | Itraconazole Cmax f 44%, AUC f 36% | Use with caution |
| Clarithromycin PO 500 mg BID | Itraconazole Cmax f 90%, AUC f 92% | Use with caution |
| Antiepileptics | ||
| Carbamazepine, Phenobarbital | Although not studied directly, these drugs are likely to decrease concentrations of itraconazole. | Not recommended |
| Phenytoin PO 300 mg OD | Itraconazole Cmax j 83%, AUC j 93% Hydroxyitraconazole Cmax j 84%, AUC | 95% | Not recommended |
| Antineoplastics Agents | ||
| Idelalisib | Although not studied directly, idelalisib is likely to increase the concentrations of itraconazole. | Use with caution |
| Antivirals for Systemic Use | ||
| Ombitasvir/Paritaprevir/Ritonavir (with or without Dasabuvir) | Although not studied directly, these drugs are expected to increase the concentrations of itraconazole. | Contraindicated |
| Efavirenz 600 mg | Itraconazole Cmx | 37%, AUC | 39%; Hydroxyitraconazole Cmax | 35%, AUC | 37% | Not recommended |
| Nevirapine PO 200 mg OD | Itraconazole Cmax | 38%, AUC | 62% | Not recommended |
| Cobicistat, Darunavir (boosted), Elvitegravir (ritonavir-boosted), Fosamprenavir (ritonavir-boosted), Ritonavir, Saquinavir (ritonavir-boosted) | Although not studied directly, these drugs are expected to increase the concentrations of itraconazole. | Use with caution |
| Indinavir PO 800 mg TID | Itraconazole concentration f | Use with caution |
| Calcium Channel Blockers | ||
| Diltiazem | Although not studied directly, diltiazem is likely to increase the concentration of itraconazole. | Use with caution |
| Respiratory System: Other Respiratory System Products | ||
| Lumacaftor/Ivacaftor PO 200/250 mg BID | Itraconazole concentration j | Not recommended |
| Miscellaneous | ||
| St. John's Wort (Hypericum perforatum) | Although not studied directly, St. John's Wort is likely to decrease the concentration of itraconazole. | Not recommended |
Table 2: Examples of drugs that may have their plasma concentrations impacted by itraconazole, presented by drug class
| Medicinal products (PO Single Dose unless otherwise stated) | Expected/Potential effect on drug levels | Clinical comment |
| within class | (t = increase; ↔ = no change; j = decrease) | (see above for additional info and also sections 4.3 and 4.4) |
| Analgesics; Anaesthetics | ||
| Ergot alkaloids (eg, dihydroergotamine, ergometrine, ergotamine, methylergometrine) | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Contraindicated |
| Eletriptan, Fentanyl | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Not recommended |
| Alfentanil, Buprenorphine (IV and sublingual), Cannabinoids, Methadone, Sufentanil | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Use with caution |
| Oxycodone PO 10 mg, | Oxycodone PO: Cmax f 45%, AUC f 2.4-fold | Use with caution |
| Oxycodone IV 0.1 mg/kg | Oxycodone IV: AUC f 51% | Use with caution |
| Anti-bacterials for Systemic Use; Anti-mycobacterials; Antimycotics for Systemic Use | ||
| Isavuconazole | Although not studied directly, itraconazole is likely to increase the concentrations of isavuconazole. | Contraindicated |
| Bedaquiline | Although not studied directly, itraconazole is likely to increase the concentrations of bedaquiline. | Not recommended |
| Rifabutin PO 300 mg OD | Rifabutin concentration f (extent unknown) | Not recommended |
| Clarithromycin PO 500 mg BID | Clarithromycin concentration f | Use with caution |
| Delamanid | Although not studied directly, itraconazole is likely to increase the concentrations of delamanid. | Use with caution |
| Antiepileptics | ||
| Carbamazepine | Although not studied directly, itraconazole is likely to increase the concentrations of carbamazepine. | Not recommended |
| Anti-inflammatory and Antirheumatic Products | ||
| Meloxicam 15 mg | Meloxicam Cmax j 64%, AUC 37% | Use with caution |
| Anthelmintics; Antiprotozoals | ||
| Halofantrine | Although not studied directly, itraconazole is likely to increase the concentrations of halofantrine. | Contraindicated |
| Artemether-lumefantrine, Praziquantel | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Use with caution |
| Quinine 300 mg | Quinine Cmax ← >, AUC f 96% | Use with caution |
| Antihistamines for Systemic Use | ||
| Astemizole, Mizolastine, Terfenadine | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Contraindicated |
| Ebastine 20 mg | Ebastine Cmax t 2.5-fold, AUC f 6.2-fold Carebastine Cmax ← >, AUC f 3.1-fold | Not recommended |
| Bilastine, Rupatadine | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Use with caution |
| Antineoplastic Agents | ||
| Irinotecan | Although not studied directly, itraconazole is likely to increase the concentrations of irinotecan and its active metabolite. | Contraindicated |
| Axitinib, Bosutinib, Cabazitaxel, Cabozantinib, Ceritinib, Crizotinib, Dabrafenib, Dasatinib, Docetaxel, Everolimus, Ibrutinib, Lapatinib, Nilotinib, Pazopanib, Regorafenib, Sunitinib, Temsirolimus, Trabectedin, Trastuzumab emtansine, Vinca alkaloids (eg, vinflunine, vinorelbine) | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs except for cabazitaxel and regorafenib. No statistically significant change in cabazitaxel exposure, but a high variability in the results was observed. Regorafenib AUC is expected to decrease (by estimation of active moiety) | Not recommended |
| Cobimetinib 10 mg | Cobimetinib Cmax f 3.2-fold, AUC f 6.7-fold | Not recommended |
| Olaparib 100 mg | Olaparib Cmax f 40%, AUC t 2.7-fold | Not recommended |
| Alitretinoin (oral), Bortezomib, Brentuximab vedotin, Erlotinib, Idelalisib, Imatinib, Nintedanib, Panobinostat, Ponatinib, Ruxolitinib, Sonidegib, | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs | Use with caution |
| Busulfan 1 mg/kg Q6h | Busulfan Cmax f, AUC f | Use with caution |
| Gefitinib 250 mg | Gefitinib 250 mg C« f, AUC f 78% | Use with caution |
| Antithrombotic Agents | ||
| Dabigatran, Ticagrelor | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Contraindicated |
| Apixaban, Rivaroxaban, Vorapaxar | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Not recommended |
| Cilostazol, Coumarins (eg, warfarin) | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs | Use with caution |
| Antivirals for Systemic Use | ||
| Ombitasvir/Paritaprevir/Ritonavir (with or without Dasabuvir) | Itraconazole may increase paritaprevir concentrations. | Contraindicated |
| Elbasvir/Grazoprevir, Simeprevir, Tenofovir alafenamide fumarate (TAF), Tenofovir disoproxil fumarate (TDF) | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Not recommended |
| Cobicistat, Elvitegravir (ritonavir-boosted), Glecaprevir/Pibrentasvir, Maraviroc, Ritonavir, Saquinavir | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Use with caution |
| Indinavir PO 800 mg TID | Indinavir Cmax ← >, AUC f | Use with caution |
| Cardiovascular System (Agents Acting on the Renin-Angiotensin System; Antihypertensives; Beta Blocking Agents; Calcium Channel Blockers; Cardiac Therapy; Diuretics) | ||
| Bepridil, Disopyramide, Dofetilide, Dronedarone, Eplerenone, Ivabradine, Lercanidipine, Nisoldipine, Ranolazine, Sildenafil (pulmonary hypertension) | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Contraindicated |
| Aliskiren 150 mg | Aliskiren Cmax f 5.8-fold, | Contraindicated |
| AUC f 6.5-fold | ||
| Quinidine 100 mg | Quinidine Cmax f 59%, AUC t 2.4-fold | Contraindicated |
| Felodipine 5 mg | Felodipine Cmax f 7.8-fold, AUC f 6.3-fold | Not recommended |
| Riociguat, Tadalafil (pulmonary hypertension) | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Not recommended |
| Bosentan, Diltiazem, Guanfacine, Other Dihydropyridines (eg, amlodipine, isradipine, nifedipine, nimodipine), Verapamil | Although not studied directly, itraconazole is likely to increase the concentrations of bosentan. | Use with caution |
| Digoxin 0.5 mg | Digoxin Cmax t 34%, AUC t 68% | Use with caution |
| Nadolol 30 mg | Nadolol Cmax t 4.7-fold, AUC f 2.2-fold | Use with caution |
| Corticosteroids for Systemic Use; Drugs for Obstructive Airway Diseases | ||
| Ciclesonide, Salmeterol | Although not studied directly, itraconazole is likely to increase the concentrations of salmeterol and the active metabolite of ciclesonide. | Not recommended |
| Budesonide INH 1 mg SD | Budesonide INH Cmax f 65%, AUC f 4.2-fold; Budesonide (other formulations) concentration t | Use with caution |
| Dexamethasone IV 5 mg Dexamethasone PO 4.5 mg | Dexamethasone IV: Cmax ← >, AUC f 3.3-fold Dexamethasone PO: Cmax f 69%, AUC f 3.7-fold | Use with caution |
| Fluticasone INH 1 mg BID | Fluticasone INH concentration f | Use with caution |
| Methylprednisolone 16 mg | Methylprednisolone PO Cmax t 92%, AUC t 3.9-fold Methylprednisolone IV AUC f 2.6-fold | Use with caution |
| Fluticasone nasal | Although not studied directly, itraconazole is likely to increase the concentrations of nasally-administered fluticasone. | Use with caution |
| Drugs Used in Diabetes | ||
| Repaglinide 0.25 mg | Repaglinide Cmax f 47%, AUC f 41% | Use with caution |
| Saxagliptin | Although not studied directly, itraconazole is likely to increase the concentrations of saxagliptin. | Use with caution |
| Gastrointestinal Drugs, including Antidiarrheals, Intestinal Anti-inflammatory/Anti-infective Agents; Antiemetics and Antinauseants; Drugs for Constipation; Drugs for Functional Gastrointestinal Disorders | ||
| Cisapride, Naloxegol | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Contraindicated |
| Domperidone 20 mg | Domperidone Cmax f 2.7-fold, AUC f 3.2-fold | Contraindicated |
| Aprepitant, Loperamide, Netupitant | Although not studied directly, itraconazole is likely to increase the concentrations of aprepitant. | Use with caution |
| Immunosuppressants | ||
| Sirolimus (rapamycin) | Although not studied directly, itraconazole is likely to increase the concentrations of sirolimus. | Not recommended |
| Cyclosporine, Tacrolimus | Although not studied directly, itraconazole is likely to increase the concentrations of cyclosporine. | Use with caution |
| Tacrolimus IV 0.03 mg/kg OD | Tacrolimus IV concentration f | Use with caution |
| Lipid Modifying Agents | ||
| Lomitapide | Although not studied directly, itraconazole is likely to increase the concentrations of lomitapide. | Contraindicated |
| Lovastatin 40 mg, | Lovastatin Cmax f 14.5->20-fold, AUC f >14.8 – >20-fold Lovastatin acid Cmax f 11.513-fold, AUC f 15.4–20-fold | Contraindicated |
| Simvastatin 40 mg | Simvastatin acid Cmax f 17fold, AUC f 19-fold | Contraindicated |
| Atorvastatin | Atorvastatin acid: Cmax ↔ to t2.5-fold, AUC f 40% to 3fold | Not recommended |
| Psychoanaleptics; Psycholeptics ( | eg, antipsychotics, anxiolytics, and hypnotics) | |
| Lurasidone, Pimozide, Quetiapine, Sertindole | Although not studied directly, itraconazole is likely to increase the concentrations of these | Contraindicated |
| drugs. | ||
| Midazolam (oral) 7.5 mg | Midazolam (oral) Cmax f 2.5 to 3.4-fold, AUC f 6.6 to 10.8-fold | Contraindicated |
| Triazolam 0.25 mg | Triazolam Cmax f, AUC f | Contraindicated |
| Alprazolam 0.8 mg | Alprazolam Cmax ← >, AUC f 2.8-fold | Use with caution |
| Aripiprazole 3 mg | Aripiprazole Cmax f 19%, AUC f 48% | Use with caution |
| Brotizolam 0.5 mg | Brotizolam Cmax ← >, AUC f 2.6-fold | Use with caution |
| Buspirone 10 mg | Buspirone Cmax f 13.4-fold, AUC f 19.2-fold | Use with caution |
| Midazolam (iv) 7.5 mg | Midazolam (iv) 7.5 mg: concentration f; Although not studied directly, itraconazole is likely to increase the concentrations of midazolam following oromucosal administration. | Use with caution |
| Risperidone 2–8 mg/day | Risperidone and active metabolite concentration f | Use with caution |
| Zopiclone 7.5 mg | Zopiclone Cmax Î 30%, AUC t 70% | Use with caution |
| Cariprazine, Galantamine, Haloperidol, Reboxetine, Venlafaxine | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Use with caution |
| Respiratory System: Other Respiratory System Products | ||
| Lumacaftor/Ivacaftor PO 200/250 mg BID | Ivacaftor Cmax f 3.6-fold, AUC f 4.3-fold Lumacaftor Cmax ← >, AUC <r+ | Not recommended |
| Ivacaftor | Although not studied directly, itraconazole is likely to increase the concentrations of ivacaftor. | Use with caution |
| Sex Hormones and Modulators of the Genital System; Other Gynaecologicals | ||
| Cabergoline, Dienogest, Ulipristal | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Use with caution |
| Urologicals | ||
| Avanafil, Dapoxetine, Darifenacin | Although not studied directly, itraconazole is likely to increase the concentrations of these | Contraindicated |
| drugs. | ||
| Fesoterodine | Although not studied directly, itraconazole is likely to increase the concentrations of the active metabolites, 5-hydroxymethyl tolterodine. | Moderate or severe renal or hepatic impairment: Contraindicated Mild renal or hepatic impairment: Concomitant use should be avoided Normal renal or hepatic impairment: Use with caution with a maximum fesoterodine dose of 4 mg. |
| Solifenacin | Although not studied directly, itraconazole is likely to increase the concentrations of solifenacin. | Severe renal impairment: Contraindicated Moderate or severe hepatic impairment: Contraindicated Use with caution in all other patients with a maximum solifenacin dose of 5 mg. |
| Vardenafil | Although not studied directly, itraconazole is likely to increase the concentrations of vardenafil. | Contraindicated in patients older than 75 years; otherwise not recommended. |
| Alfuzosin, Silodosin, Tadalafil (erectile dysfunction and benign prostatic hyperplasia), Tamsulosin, Tolterodine | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Not recommended |
| Dutasteride, Imidafenacin, Sildenafil (erectile dysfunction) | Although not studied directly, itraconazole is likely to increase the concentrations of these drugs. | Use with caution |
| Oxybutynin 5 mg | Oxybutynin Cmax f 2-fold, AUC f 2-fold N-desethyloxybutynin Cmax «->, AUC Following transdermal administration: Although not studied directly, itraconazole is likely to increase the concentrations of oxybutynin following transdermal administration. | Use with caution |
| Miscellaneous Drugs and Other Substances | ||
| Colchicine | Although not studied directly, itraconazole is likely to increase the concentrations of colchicine | Contraindicated in patients with renal or hepatic impairment. Not recommended in other |
| patients. | ||
| Eliglustat | Although not directly studied, itraconazole is expected to increase the concentrations of eliglustat. | Contraindicated in CYP2D6 poor metabolisers (PM). Contraindicated in CYP2D6 intermediate metabolisers (IMs) or extensive metabolisers (EMs) taking a strong or moderate CYP2D6 inhibitor. Use with caution in CYP2D6 IMs and EMs. In CYP2D6 EMs with mild hepatic impairment, an eliglustat dose of 84 mg/day should be considered. |
| Cinacalcet | Although not studied directly, itraconazole is likely to increase the concentrations of cinacalcet. | Use with caution |
4.6 Fertility, pregnancy and lactation
Pregnancy
SPORANOX Capsules 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 has shown 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. Itraconazole has been shown to cross the placenta in a rat model.
Women of childbearing potential
Women of childbearing potential taking SPORANOX Capsules should use contraceptive precautions. Highly effective contraception should be continued until the menstrual period following the end of SPORANOX therapy.
Breast-feeding
A very small amount of itraconazole is excreted in human milk. SPORANOX Capsules must not be used during lactation.
4.7 Effects on ability to drive and use machines None stated.
4.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse drug reactions (ADRs) with Sporanox Intravenous treatment identified from clinical trials and/or from spontaneous reporting were cough, diarrhoea, vomiting, nausea, rash, and oedema (including generalised oedema and face oedema). The most serious ADRs were serious allergic reactions, cardiac failure/congestive heart failure/pulmonary oedema, pancreatitis, serious hepatotoxicity (including some cases of fatal acute liver failure), and serious skin reactions. Refer to subsection Tabulated list of adverse reactions for the frequencies and for other observed ADRs. Refer to section 4.4 (Special warnings and precautions for use) for additional information on other serious effects.
Tabulated list of adverse reactions
The ADRs in the table below were derived from one randomized, active controlled, open-label clinical trial with Sporanox Intravenous involving 192 patients for empirical therapy of febrile neutropenia, and from spontaneous reporting.
The table below presents ADRs by System Organ Class. Within each System Organ Class, the ADRs are presented by incidence, using the following convention:
Very common (> 1/10); Common (> 1/100 to < 1/10); Uncommon (> 1/1,000 to < 1/100); Rare (> 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the available data).
| Adverse Drug Reactions | |
| Blood and lymphatic system disorders | |
| Common | Granulocytopenia |
| Uncommon | Thrombocytopenia |
| Immune system disorders | |
| Common | Anaphylactoid reaction, Hypersensitivity* |
| Not Known | Serum sickness, Angioneurotic oedema, Anaphylactic reaction |
| Metabolism and nutrition disorders | |
| Common | Hyperglycaemia, Hypomagnesaemia |
| Uncommon | Hyperkalaemia |
| Not Known | Hypertriglyceridaemia |
| Psychiatric disorders | |
| Common | Confusional state |
| Nervous system disorders | |
| Common | Dizziness, Headache, Somnolence, Tremor |
| Uncommon | Hypoaesthesia, Dysgeusia |
| Eye disorders | |
| Common | Visual disturbances, (including diplopia and blurred vision) |
| Ear and labyrinth disorders | |
| Uncommon | Transient or permanent hearing loss* |
| Cardiac disorders | |
| Common | Cardiac failure, Tachycardia |
| Uncommon | Left ventricular failure |
| Not Known | Congestive heart failure* |
| Vascular disorders | |
| Common | Hypertension, Hypotension |
| Respiratory, thoracic and mediastinal disorders | |
| Very Common | Cough |
| Common | Pulmonary oedema, Dyspnoea |
| Uncommon | Dysphonia |
| Gastrointestinal disorders | |
| Very Common | Diarrhoea, Vomiting, Nausea |
| Common | Constipation, Abdominal pain, Dyspepsia, Gastrointestinal disorder |
| Not Known | Pancreatitis |
| Hepatobiliary disorders | |
| Common | Hepatitis, Jaundice, Hyperbilirubinaemia |
| Not Known | Serious hepatotoxicity (including some cases of fatal acute liver failure) |
| Skin and subcutaneous tissue disorders | |
| Very Common | Rash |
| Common | Urticaria, Rash erythematous, Pruritus, Alopecia, Hyperhidrosis |
| Not Known | Toxic epidermal necrolysis, Stevens-Johnson syndrome, Acute generalised exanthematous pustulosis, Erythema multiforme, Exfoliative dermatitis, Leukocytoclastic vasculitis, Photosensitivity |
| Musculoskeletal and connective tissue disorders | |
| Common | Myalgia |
| Renal and urinary disorders | |
| Common | Renal impairment, Urinary incontinence |
| General disorders and administration site conditions | |
| Very Common | Oedema (including generalised oedema and face oedema) |
| Common | Chest pain, Injection site inflammation, Pyrexia, Pain, Fatigue, Chills |
| Investigations | |
| Common | Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood lactate dehydrogenase increased, Blood urea increased, Gammaglutamyltransferase increased, Urine analysis abnormal |
| Uncommon | Blood creatine phosphokinase increased, Hepatic enzyme increased |
see section 4.4.
Description of selected adverse reactions
The following is a list of additional ADRs associated with itraconazole that have been reported in clinical trials of Sporanox Oral Solution and Sporanox Capsules.
Infections and infestations: Sinusitis, Upper respiratory tract infection, Rhinitis
Blood and lymphatic system disorders: Leukopenia
Metabolism and nutrition disorders: Hypokalaemia
Nervous system disorders: Peripheral neuropathy, Paraesthesia
Ear and labyrinth disorders: Tinnitus
Gastrointestinal disorders: Flatulence
Hepatobiliary disorders: Hepatic failure*, Hepatic function abnormal Musculoskeletal and connective tissue disorders: Arthralgia
Renal and urinary disorders: Pollakiuria
Reproductive system and breast disorders: Erectile dysfunction, Menstrual disorder
Paediatric Population
The safety of Sporanox IV was evaluated in 36 paediatric patients aged 6 months to 17 years who participated in 3 open-label clinical trials. These patients received at least one dose of Sporanox IV for prevention or treatment of fungal infections and provided safety data.
Based on pooled safety data from these clinical trials, the very commonly reported adverse drug reactions (ADRs) in paediatric patients were Pyrexia (16.7%) and Vomiting (11.1%). The nature of ADRs in paediatric patients is similar to that observed in adult subjects, but in general, the incidence is higher in the adult subjects.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or_search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseSymptoms
In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this SmPC for itraconazole (see section 4.8).
Treatment
In the event of overdose, supportive measures should be employed. Itraconazole cannot be removed by haemodialysis. No specific antidote is available.
It is advisable to contact a poison control centre to determine the latest recommendations for the management of an overdose.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic classification: B05X A03 (IV solution additives, electrolyte solutions)
5.2 Pharmacokinetic properties None stated.
5.3 Preclinical safety data
5.3 Preclinical safety dataAcute oral toxicity studies with itraconazole in mice, rats, guinea-pigs and dogs indicate a wide safety margin (3– to 16-fold of Maximum Recommended Human Dose [MRHD] based on mg/m2).
Itraconazole is not a primary carcinogen in rats or mice up to 20 and 80 mg/kg, respectively.
Itraconazole
Nonclinical data on itraconazole revealed no indications for gene toxicity, primary carcinogenicity or impairment of fertility. At high doses, of 40 and 80 mg/kg/day in rats (1– and 2-fold of MRHD based on mg/m2), 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, (no toxicity was observed up to 20 mg/kg (2-fold of MRHD based on mg/m2), and in rats, a decreased bone plate activity, thinning of the zona compacta of the large bones, and an increased bone fragility was observed.
Hydroxypropyl-P-cyclodextrin
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicitv, genotoxicitv, and toxicitv to reproduction and deveiopment. In a rat carcinogenicitv studv (at 80 mg/kg dose (2-foid of MRHD based on mg/m2)), hydroxypropyi—P—cyciodextrin produced adenocarcinomas in the large intestine and exocrine pancreatic adenocarcinomas. These findings were not observed in a simiiar mouse carcinogenicity study. The ciinicai reievance of the iarge intestine adenocarcinomas is iow and the mechanism of exocrine pancreatic adenocarcinomas induction not considered reievant to humans.
Reproductive toxicology
Itraconazoie was found to cause a dose—reiated increase in maternai toxicity, embryotoxicity, and teratogenicity in rats and mice at 40, 80 and 160 mg/kg (0.5—, 1— and 4-fold of MRHD based on mg/m2). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and macroglossia. No teratogenic effects were found in rabbits up to 80 mg/kg dose (4-fold of MRHD based on mg/m2).
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride, water for injections.
6.2 Incompatibilities
The solution is compatible with a wide range of drugs, including Sporanox IV.
6.3 Shelf life
0.9% Sodium Chloride Injection: 3 years
6.4 Special precautions for storage
0.9% Sodium Chloride Injection:
Do not store above 25°C. Do not freeze.
6.5 Nature and contents of container
Flexible polypropylene infusion bag, equipped with a flexible inlet and outlet port, and containing 52 to 56 ml of 0.9% Sodium Chloride Injection.
6.6 Special precautions for disposal
6.6 Special precautions for disposalOpening sodium chloride bag:
Tear outer wrap at notch and remove infusion bag.
Flush procedure before the infusion
Before the infusion, the catheter should be flushed to avoid compatibility problems between residual amounts of other drugs and itraconazole.
– Fill the extension line provided with the kit containing the 0.2 ^m in-line filter with sterile 0.9% sodium chloride solution and connect directly to the indwelling intravenous catheter.
– Flush the extension line provided with the kit and indwelling intravenous catheter with sterile 0.9% sodium chloride solution.
7 MARKETING AUTHORISATION HOLDER
Janssen-Cilag Ltd.
50–100 Holmers Farm Way
High Wycombe
Buckinghamshire
HP12 4EG
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00242/0345
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
22/07/1999 / 21/07/2009