CCDS 09/2010 Page 1 of 19

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1 PACKAGE INSERT SCHEDULING STATUS Schedule 4 PROPRIETARY NAME (and dosage form) SPORANOX 10 mg/ml Oral solution. COMPOSITION Each millilitre oral solution contains 10 mg of itraconazole. Sporanox Oral solution contains itraconazole as the active ingredient. Inactive ingredients include the following: Hydroxypropyl-β-cyclodextrin, sorbitol, propylene glycol, hydrochloric acid, cherry flavor 1, cherry flavor 2, caramel, sodium saccharin, sodium hydroxide, purified water. PHARMACOLOGICAL CLASSIFICATION A Antimicrobial (chemotherapeutic) agents. Fungicides. PHARMACOLOGICAL ACTION Pharmacodynamic properties Itraconazole is a triazole derivative. In vitro studies demonstrate that itraconazole inhibits the growth of the following fungi pathogenic for humans, at concentrations usually ranging from 0,025 0,8 g/ml: dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum); yeasts (Cryptococcus neoformans, Candida spp.); Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis; Sporothrix schenkii; Blastomyces dermatitidis; Pseudallescheria boydii, Penicillium marneffei. Page 1 of 19

2 Candida Krusei, Candida glabrata and Candida tropicalis are the least susceptible Candida species, with isolates showing unequivocal resistance to itraconazole in vitro. The principal fungus types that are not inhibited by itraconazole are Zygomycetes (e.g. Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp. In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect. In vitro activity does not necessarily imply clinical efficacy. Pharmacokinetic properties General pharmacokinetic characteristics Peak plasma concentrations are reached within 2,5 hours following administration of the oral solution. Itraconazole undergoes extensive hepatic metabolism to give numerous metabolites. The main metabolite is hydroxy-itraconazole, with plasma concentrations about twice those of the unchanged medicine. The terminal half-life of itraconazole is about 40 hours after repeated dosing. The pharmacokinetics of itraconazole is characterized by non-linearity and, consequently, shows accumulation in plasma after multiple dose administration. Steady state concentrations are reached within 15 days, with C max values of about 2 μg/ml after oral administration of 200 mg once daily. Itraconazole clearance decreases at higher doses due to a saturable mechanism of its hepatic metabolism. Itraconazole is excreted as inactive metabolites in the urine (~ 35 %) and in faeces (~ 54 %). Page 2 of 19

3 Absorption The observed absolute bioavailability of itraconazole under fed conditions is about 55 % and is increased by 30 % when the oral solution is taken in fasting conditions. 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 medicine. Itraconazole is distributed in a large apparent volume in the body (> 700 L): concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than the corresponding concentrations in plasma. Brain to plasma ratios were about 1. The uptake into keratinous tissues, skin in particular, is up to four times higher than in plasma. Metabolism Itraconazole is extensively metabolised by the liver into a large number of metabolites. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole. 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. Excretion Itraconazole is excreted as inactive metabolites to about 35 % in urine within one week and to about 54 % with faeces. Renal excretion of the parent drug accounts for less than 0,03 % of the dose, whereas faecal excretion of unchanged drug varies between 3 18% of the dose. Page 3 of 19

4 SPECIAL POPULATIONS 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: C max, AUC and terminal half-life of itraconazole were measured, and compared between groups. itraconazole C max was reduced significantly (by 47 %) in patients with cirrhosis. Mean Mean elimination half-life was prolonged significantly compared to that found in subjects without hepatic impairment (37 vs. 16 hours, respectively). Overall exposure to intraconazole, based on AUC was significantly increased in cirrhotic patients and in healthy subjects. Data are not available on efficacy and safety in cirrhotic patients during long-term use of itraconazole (See section on DOSAGE AND DIRECTIONS FOR USE and Special Precautions). Renal impairment Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when the medicine is administered in this patient population. The elimination t 1/2 was increased from 18 to 24 hours. There are no safety data of repeated dosages under renal impairment. INDICATIONS SPORANOX 10 mg/ml Oral solution is indicated: - For the treatment of oral and/or oesophageal candidiasis in HIV seropositive or AIDS or other immunocompromised patients. - As prophylaxis of deep fungal infections anticipated to be susceptible to itraconazole when standard therapy is considered inappropriate in patients with haematological malignancy or undergoing bone marrow transplant and who are expected to become neutropenic (i.e. Page 4 of 19

5 < 500 cells/ l). At present there are insufficient clinical efficacy data in the prevention of aspergillosis. CONTRA-INDICATIONS SPORANOX 10 mg/ml Oral solution is contra-indicated in pregnant women. Women of childbearing potential using SPORANOX 10 mg/ml oral solution should take adequate contraceptive precautions until the next menstrual period following the end of SPORANOX therapy. (See PREGNANCY and LACTATION). Co-administration of the following medicine is contra-indicated with SPORANOX oral solution: (See also WARNINGS and INTERACTIONS). CYP3A4 metabolised substrates can prolong the QT interval, e.g. bepridil, mizolastine, cisapride, dofetilide, quinidine, pimozide, levacetylmethadol, sertindole are contra-indicated with SPORANOX oral solution. CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin. Triazolam and oral midazolam. Ergotalkaloids such as dihydroergotamine, ergometrine, ergotamine and methylergometrine. Nisoldipine, nifedipine and felodipine. SPORANOX Oral solution should not be administered to patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections. (See WARNINGS and Special Precautions for use). Page 5 of 19

6 SPORANOX Oral solution must not be used during pregnancy. (See section on PREGNANCY and LACTATION). SPORANOX 10 mg/ml Oral solution is contra-indicated in patients with a known hypersensitivity to the medicine or its excipients. SPORANOX has been shown to have no benefit in the prophylaxis of cryptococcal meningitis in HIV infected patients. WARNINGS Hepatic effects: Cases of serious, usually reversible idiosyncratic hepatitis, which may be fatal, have been observed. Serious hepatotoxicity, including cases of fatal acute liver failure, has occurred with the use of SPORANOX. Most of these cases involved patients, who had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic medicines. Some patients had no obvious risk factors for liver disease. These cases have been observed within the first week of treatment up to 1½ years after continuous use of SPORANOX. Liver function should be monitored in patients receiving SPORANOX treatment. Patients should be instructed to promptly report to their medical practitioner 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 Page 6 of 19

7 testing should be conducted. In patients with raised liver enzymes or active disease, or who have experienced liver toxicity with other medicines, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In such cases liver enzyme monitoring is necessary. Treatment of severely neutropenic patients SPORANOX Oral solution as treatment for oral and/or oesophageal candidiasis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties, SPORANOX Oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidiasis. Neuropathy If neuropathy occurs that may be attributable to SPORANOX 10 mg/ml Oral solution, the treatment should be discontinued. Renal impairment Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when SPORANOX is administered in this patient population (See Pharmacokinetic properties, Special Populations). The elimination half-life was increased from 18 to 24 hours. There are no safety data of repeated dosages under renal impairment. Hearing Loss Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. The hearing loss may resolve when treatment is stopped, but can persist in some patients. Page 7 of 19

8 INTERACTIONS SPORANOX Oral solution has a potential for clinically important medicine interactions see below. 1. Medicines affecting the metabolism of SPORANOX Oral solution: Enzyme-inducing medicines such as rifampicin, rifabutin, carbamazepine, isoniazid and phenytoin significantly reduce the bioavailability of itraconazole. Monitoring of plasma concentrations of SPORANOX Oral solution is advised if these medicines are administered concomitantly. An increase in the dose of SPORANOX Oral solution may be necessary. As itraconazole is mainly metabolised through CYP3A4, potent inhibitors of this enzyme may increase the bioavailability of SPORANOX Oral solution. Examples are: ritonavir, indinavir, clarithromycin and erythromycin. 2. Effect of SPORANOX Oral solution on the metabolism of other medicines: 2.1 SPORANOX Oral solution can inhibit the metabolism of agents metabolised by the cytochrome 3A family. This can result in an increase and/or 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 levels decline gradually, depending on the dose and duration of treatment. (See Pharmacokinetic properties). This should be taken into account when the inhibitory effect of SPORANOX Oral solution on co-medicated medicines is considered. Examples are: Medicines that should not be used during treatment with SPORANOX Oral solution: Page 8 of 19

9 Bepridil, mizolastine, cisapride, dofetilide, quinidine, pimozide, levacetylmethadol and sertindole, since co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of Torsade de Pointes. Triazolam and oral midazolam. CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin. (See Contra-indications.) Ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine and methylergometrine. Nisoldipine Calcium channel blockers can have negative inotropic effects which may be additive to those of SPORANOX Oral solution; SPORANOX Oral solution can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when coadministering SPORANOX Oral solution and calcium channel blockers due to an increased risk of CHF. Medicines, whose plasma concentrations, effects or side effects should be monitored. Their dosage, if co-administered with SPORANOX Oral solution, should be reduced if necessary Oral anticoagulants; Prothrombin time should be carefully monitored. HIV Protease Inhibitors such as ritonavir, indinavir, saquinavir. Page 9 of 19

10 Certain antineoplastic agents such as vinca alkaloids, busulphan, docetaxel and trimetrexate. CYP3A4 metabolised calcium channel blockers such as dihydropyridine (e.g. nifedipine, felodipine, nisoldipine) and verapamil. Patients should be monitored for side effects, e.g. oedema. Certain immunosuppressive agents: cyclosporine, tacrolimus, rapamycin (also known as sirolimus). Certain CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin. Certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methyl prednisolone. Others: digoxin (via inhibition of P-glycoprotein), carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, ebastine, reboxetine, cilostazol, disopyramide, eletriptan, fentanyl, halofantrine and repaglinide. Severe hypoglycaemia has been reported in patients concomitantly receiving azole antifungal agents such as SPORANOX Oral solution and oral hypoglycaemic agents such as tolbutamide, chlorpropamide, glyburide and glipizide. Blood glucose concentrations should be carefully monitored when SPORANOX Oral solution and oral hypoglycaemic agents are coadministered. 2.2 No interaction of SPORANOX Oral Solution with zidovudine (AZT) and fluvastatin has been observed. No inducing effects of SPORANOX Oral Solution on the metabolism of ethinyloestradiol and norethisterone were observed. Page 10 of 19

11 3. Effect on protein binding: Despite the fact that SPORANOX Oral solution is 99,8 % bound to plasma proteins, in vitro studies have shown that there are no interactions on the plasma protein binding between itraconazole and imipramine, propranolol, diazepam, cimetidine, indomethacin, and sulfamethazine. PREGNANCY AND LACTATION Pregnancy SPORANOX Oral solution must not be used during pregnancy. (See CONTRA- INDICATIONS). In animal studies itraconazole has shown to cause congenital abnormalities. During post-marketing experience, cases of congenital abnormalities have been reported. These cases include skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations. Women of childbearing potential Women of childbearing potential taking SPORANOX Oral solution should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of SPORANOX Oral solution therapy. Lactation Itraconazole is excreted in human milk. The patient should not breast-feed. Page 11 of 19

12 DOSAGE AND DIRECTIONS FOR USE Treatment of oral and/or oesophageal candidiasis: 200 mg (2 x 10 ml measuring cups) per day in one or two intakes for 1 week. If there is no response after 1 week, treatment should be continued for another week. Prophylaxis of fungal infections: 5 mg/kg per day administered in two intakes. In clinical trials, prophylaxis treatment was started immediately prior to the cytostatic treatment and generally one week before transplant procedure. Treatment was continued until recovery of neutrophils (i.e. > cells/ l). Use in children: Since clinical data on the use of SPORANOX Oral solution in paediatric patients is limited, its use in children is not recommended. Use in elderly: As for paediatric use. Use in patients with hepatic impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Use in patients with renal impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment SIDE EFFECTS AND SPECIAL PRECAUTIONS Clinical trials The table below shows the adverse events reported among patients in clinical trials (pooled data) of SPORANOX Oral solution in the treatment of oropharyngeal and oesophageal Page 12 of 19

13 candidiosis. It includes all adverse events (with an incidence of 2 % or greater) reported among SPORANOX Oral solution -treated patients. About 44 % of patients treated with SPORANOX Oral solution experienced at least one adverse event. Page 13 of 19

14 Table 1: Adverse events reported among SPORANOX Oral solution -treated patients with an incidence of 2 %. SPORANOX Oral solution N= 543 % Body as a whole general disorders Fever Death Gastrointestinal disorders Diarrhoea Nausea Vomiting Abdominal pain Central and peripheral nervous system disorders Headache Respiratory system disorders Coughing Skin and appendages disorders Rash Special senses, other disorders Taste perversion 10,3 4,2 2,6 20,1 7,9 7,4 4,1 3,7 6,8 3,9 6,8 2,4 7,4 2,2 2,0 2,0 Post marketing experience Adverse drug reactions from spontaneous reports during the worldwide post marketing experience with SPORANOX are included in Table 2. Page 14 of 19

15 Table 2. Post marketing reports of adverse drug reactions. System organ class: Blood and lymphatic system disorders Leucopenia, neutropenia, thrombocytopenia. Immune system disorders Serum sickness, angio oedema, anaphylactic, anaphylactoid and allergic reactions. Metabolism and nutrition disorders Hypertriglyceridaemia, hypokalaemia. Nervous system disorders Peripheral neuropathy, paraesthesia, hypoaesthesia, headache, dizziness. Eye disorders Visual disturbances, including blurred vision and diplopia. Ear and labyrinth disorders Tinnitus, transient or permanent hearing loss. Cardiac disorders Congestive heart failure. Respiratory, thoracic and mediastinal disorders Pulmonary oedema, dyspnoea. Gastrointestinal disorders Pancreatitis, abdominal pain, vomiting, dyspepsia, nausea, diarrhoea, constipation, dysgeusia. Hepato-biliary disorders Serious hepatotoxicity (including cases of fatal acute liver failure), hepatitis, reversible Page 15 of 19

16 increases in hepatic enzymes. Skin and subcutaneous tissue disorders Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, urticaria, alopecia, rash, pruritus, photosensitivity. Musculoskeletal and connective tissue disorders Myalgia, arthralgia. Renal and urinary disorders Pollakiuria, urinary incontinence. Reproductive system and breast disorders Menstrual disorders, erectile dysfunction. General disorders and administrative site conditions Oedema, pyrexia. Less frequent cases of adrenal suppression have been reported, when high doses (600 mg/day) were given. Special Precautions Cardiac effects - SPORANOX Oral solution 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 SPORANOX Oral solution (see Contra- Indications). Page 16 of 19

17 SPORANOX Oral solution 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. This individual benefit/risk assessment should take into consideration factors such as the severity of the indication, the dosing regimen (e.g. total daily dose), and individual risk factors for congestive heart failure. 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 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 Oral solution should be discontinued. - Calcium channel blockers can have negative inotropic effects which may be additive to those of SPORANOX Oral solution. In addition SPORANOX Oral solution can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when coadministering SPORANOX Oral solution and calcium channel blockers, due to an increase of CHF (See INTERACTIONS). Cystic fibrosis: In cystic fibrosis patients, variability in therapeutic levels of SPORANOX Oral solution was observed with steady state dosing of oral solution using 2,5 mg/kg twice daily. Adequate steady state concentrations of > 250 ng/ml were achieved in approximately 50 % of subjects greater than 16 years of age, but in none of the patients less than 16 years of age. Efficacy and safety of SPORANOX Oral solution in cystic fibrosis patients and children has not been demonstrated. Page 17 of 19

18 KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT In the event of an overdose, supportive measures should be employed. Within the first hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate. No specific antidote is available. Itraconazole cannot be removed by haemodialysis. IDENTIFICATION A yellow to slightly amber, clear solution with a cherry odour. PRESENTATION 150 ml amber glass bottles with a 10 ml measuring cup. STORAGE CONDITIONS Store at or below 25 o C. KEEP OUT OF REACH OF CHILDREN. Use the solution within 3 months after first opening. REGISTRATION NUMBER 30/20.2.2/0429. NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION Page 18 of 19

19 JANSSEN PHARMACEUTICA (PTY) LTD (Reg. No. 1980/011122/07) Building 6, Country Club Estate, 21 Woodlands Drive, Woodmead, Nam. Reg. No. 04/20.2.2/0265 NS 2 DATE OF PUBLICATION OF THIS PACKAGE INSERT 20 th June 2011 Page 19 of 19