Section 1
200 mg Tablets added following Nizoral
Section 2
Reference is made to the active quantity per tablet . Reference is made to excipients section 6.1.
Section 3
Tablet markings (both sides), shape and score lines are described.
Section 4.2
The states that the dose is less suitable for young children, due to a lack of a suitable dosage form. The child dose is represented in terms of body weight rather than age as below:
Children (less suitable for young children, due to a lack of a suitable dosage form):
Mycoses and dermatophyte infections
Dosage should be reduced to 100 mg depending on body weight:
Children weighing from 15 kg to 30 kg: half a tablet (= 100 mg) once a day.
Children weighing more than 30 kg: same as for adults.
See also section 4.4 ‘Special warnings and precautions for use’ – Paediatric use.
Section 4.3.
The section is expanded to contraindicate the product in acute and chronic liver disease, with CYP3A4 inhibiting drugs
Section 4.4
Description of hepatoxicity has been reworded and updated. Monitoring of hepatic function should be considered in all patients receiving treatment with Nizoral tablets prior to and at frequent intervals during treatment.
Information on the monitoring of patients with adrenal disease has been expanded.
Drug interaction potential is noted with reference to section 4.5. The combined use of domperidone and ketoconazole is not recommended.
Section 4.5
The interactions section is amended highlighting that combined use of domperidone and ketoconazole is not recommended.
CYP3A4 drugs are clarified as being contraindicated with ketoconazole because of the risk of QTc prolongation or rare occurrences of torsades de pointes.
Changes to the part section 4.5 are shown in bold:
2. Effect of ketoconazole on the metabolism of other drugs
Ketoconazole can inhibit the metabolism of drugs metabolised by certain hepatic P450 enzymes, especially of the CYP3A family. This can result in an increase and/or prolongation of their effects including side effects.
Co-administration of ketoconazole and domperidone is not recommended since the combination can lead to increased plasma concentrations of domperidone and QTc prolongation. A pharmacokinetic study has demonstrated that the AUC and the peak plasma concentration of domperidone is increased by a factor 3 when oral ketoconazole is administered concomitantly (at steady state). A slight QT-prolonging effect (mean less than 10msec) of this combination was detected, which was greater than the one seen with ketoconazole alone.
Drugs that are contraindicated during treatment with ketoconazole:
Co-administration of the CYP3A4 inhibiting drugs terfenadine, mizolastine, cisapride, dofetilide, quinidine or pimozide with Nizoral tablets is contraindicated since increased plasma concentrations of these medicinal products can lead to QTc prolongation or rare occurrences of torsades de pointes.
Co-administration of triazolam and oral midazolam is contraindicated because of an exaggerated and prolonged pharmacodynamic response.
Co-administration of CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin.
Drugs that should be used with caution, whose plasma levels, effects or side effects should be monitored, and dosage reduced if necessary, when ketoconazole and the following drugs are co-administered:
· Ergot alkaloids (ergotamine and dihydroergotamine)
· Oral anticoagulants.
· HIV Protease Inhibitors such as indinavir, saquinavir.
· Certain Antineoplastic Agents such as vinca alkaloids, busulphan and docetaxel.
· CYP3A4 metabolised Calcium Channel Blockers such as dihydropyridines and probably verapamil.
· Certain Immunosuppressive Agents: ciclosporin, tacrolimus, sirolimus (= rapamycin)
· Others: digoxin, carbamazepine, buspirone, alfentanil, sildenafil, alprazolam, brotizolam, intravenous midazolam, rifabutin, methyl prednisolone, trimetrexate, ebastine and reboxetine
Exceptional cases of a ……..
Section 4.6
The pregnancy statement is expanded. The tablets should not be used in pregnancy unless the benefit outweighs the risk.
Lactation – minor amendment to the sentence.
Section 4.8
The data is represented in system organ class and relative frequency.
Section 4.9
Minor amendment made to sentence.
Section 5.3
Pre-clinical data is redrafted and expanded to include reproductive toxicology data and the following statement.
Electrophysiological studies have shown that ketoconazole inhibits the rapidly activating component of the cardiac delayed rectifier potassium current, prolongs the action potential duration, and may prolong the QTc interval.
Section 10.
The date is amended.
