Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Janssen-Cilag Ltd., 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK
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-β-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).
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.
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).
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.
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.
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).
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).
Hydroxypropyl-β-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).
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.
If neuropathy occurs that may be attributable to Sporanox IV, the treatment should be discontinued.
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.
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 co-administration of medicinal products which are contraindicated, not recommended or recommended for use with caution in combination with itraconazole please refer to section 4.5.
Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other substances that share this metabolic pathway. Itraconazole is a strong CYP3A4 inhibitor and a P-glycoprotein inhibitor. When using concomitant medication, it is recommended that the corresponding label be consulted for information on the route of metabolism and the possible need to adjust dosages.
Co-administration of itraconazole with strong enzyme inducers of CYP3A4 may decrease the exposure of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be reduced. Examples include:
Antibacterials: isoniazid, rifabutin (see also under ‘Drugs that may have their plasma concentrations increased by itraconazole’), rifampicin.
Anticonvulsants: carbamazepine, (see also under ‘Drugs that may have their plasma concentrations increased by itraconazole’), phenobarbital, phenytoin.
Antivirals: efavirenz, nevirapine.
Herbal medicine: Hypericum perforatum (St John’s Wort).
Therefore, administration of strong enzyme inducers of CYP3A4 with itraconazole is not recommended. It is recommended that the use of these drugs should be avoided from 2 weeks before and during treatment with itraconazole, unless the benefits outweigh the risk of potentially reduced itraconazole efficacy. Upon co-administration, it is recommended that the antifungal activity should be monitored and the itraconazole dose increased as deemed necessary.
Strong inhibitors of CYP3A4 may increase the exposure of itraconazole. Examples include:
Antibacterials: ciprofloxacin, clarithromycin, erythromycin.
Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir (see also under ‘Drugs that may have their plasma concentrations increased by itraconazole’), ritonavir (see also under ‘Drugs that may have their plasma concentrations increased by itraconazole’) and telaprevir.
It is recommended that these drugs be used with caution when co-administered with itraconazole IV. It is recommended that patients who must take itraconazole concomitantly with strong inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and itraconazole dose be decreased as deemed necessary. When appropriate, it is recommended that itraconazole plasma concentrations be measured.
Itraconazole and its major metabolite, hydroxy-itraconazole, can inhibit the metabolism of drugs metabolised by CYP3A4 and can inhibit the drug transport by P-glycoprotein which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with itraconazole. The full inhibitory effect of itraconazole is obtained after steady state in plasma is reached (see section 5.2). The effects of itraconazole in increasing the AUC of other drugs can be as high as 11-fold, as seen with oral midazolam (a sensitive CYP3A4 substrate) when co-administered with itraconazole 200 mg/d. These elevated plasma concentrations are likely to increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolized drugs known to prolong the QT interval may be contraindicated with itraconazole, since the combination may lead to ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Full inhibitory effect is not obtained until itraconazole steady state has been reached which takes approximately 2-4 days for Sporanox IV (see section 5.2). 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.
The interacting drugs are categorized 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. 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:
Examples of drugs that may have their plasma concentrations increased by itraconazole presented by drug class with advice regarding co-administration with itraconazole:
Co-administration of itraconazole with the NSAID meloxicam may decrease the plasma concentration of meloxicam. It is recommended that meloxicam be used with caution when co-administered with itraconazole, including monitoring for any reduction in efficacy of meloxicam with adjustments to the dose as necessary.
Interaction studies have only been performed in adults.
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. Itraconazole has been shown to cross the placenta in a rat model.
Women of childbearing 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.
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.
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.
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.
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).
Common: Granulocytopenia
Uncommon: Thrombocytopenia
Common: Anaphylactoid reaction, Hypersensitivity*
Not Known: Serum sickness, Angioneurotic oedema, Anaphylactic reaction
Common: Hyperglycaemia, Hypomagnesaemia
Uncommon: Hyperkalaemia
Not Known: Hypertriglyceridaemia
Common: Confusional state
Common: Dizziness, Headache, Somnolence, Tremor
Uncommon: Hypoaesthesia, Dysgeusia
Common: Visual disturbances, (including diplopia and blurred vision)
Uncommon
Transient or permanent hearing loss*
Common: Cardiac failure, Tachycardia
Uncommon: Left ventricular failure
Not Known: Congestive heart failure*
Common: Hypertension, Hypotension
Very Common: Cough
Common: Pulmonary oedema, Dyspnoea
Uncommon: Dysphonia
Very Common: Diarrhoea, Vomiting, Nausea
Common: Constipation, Abdominal pain, Dyspepsia, Gastrointestinal disorder
Not Known: Pancreatitis
Common: Hepatitis, Jaundice, Hyperbilirubinaemia
Not Known: Serious hepatotoxicity (including some cases of fatal acute liver failure)*
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
Common: Myalgia
Common: Renal impairment, Urinary incontinence
Very Common: Oedema (including generalised oedema and face oedema)
Common: Chest pain, Injection site inflammation, Pyrexia, Pain, Fatigue, Chills
Common: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood lactate dehydrogenase increased, Blood urea increased, Gamma-glutamyltransferase increased, Urine analysis abnormal
Uncommon: Blood creatine phosphokinase increased, Hepatic enzyme increased
* see section 4.4.
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
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 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.
Itraconazole has the potential to precipitate when Sporanox IV is diluted in solutions other than the 50 ml 0.9% sodium chloride injection supplied.
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