Download NIZORAL 200 MG TABLETS

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8.12 ‫אושר‬
"‫"פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר‬
1.
TRADE NAME OF THE MEDICINAL PRODUCT
NIZORAL 200 MG TABLETS
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 200 mg ketoconazole.
For excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
White, circular, flat bevel-edged, half-scored tablet with the inscription
“JANSSEN” on one side and “K/200” on the reverse.
4.
CLINICAL PARTICULARS
4.1.
Therapeutic indications
Because of the risk for serious hepatic toxicity, NIZORAL tablets should be
used only when the potential benefits are considered to outweigh the
potential risks, taking into consideration the availability of other effective
antifungal therapy.
Indications are:
Infections of the skin, hair, and mucosa, induced by dermatophytes and/or
yeasts that cannot be treated topically because of the site or the extent of
the lesion or deep infection of the skin.
-
Dermatophytosis
-
Pityriasis versicolor
-
Pityrosporum folliculitis
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Cutaneous candidosis
-
Chronic mucocutaneous candidosis
-
Oropharyngeal and esophageal candidosis
-
Chronic, recurrent vaginal candidosis
Systemic fungal infections
Ketoconazole does not penetrate well in the CNS. Therefore, fungal
meningitis should not be treated with oral ketoconazole.
4.2.
-
Paracoccidioidomycosis
-
Histoplasmosis
-
Coccidioidomycosis
-
Blastomycosis
Posology and method of administration
NIZORAL should be taken during meals for maximal absorption.
- Infections of the skin, hair, and mucosa induced by dermatophytes and/or
yeasts, and systemic infections, that cannot be treated topically because of
the site or the extent of the lesion or deep infection of the skin:
Adults
One tablet (= 200 mg) once daily with a meal. When no adequate response is
obtained with this dose, the dose should be increased to 2 tablets (= 400 mg).
once daily.
-Adults with vaginal candidosis: two tablets (= 400 mg) once daily with a
meal.
Children
- Children weighing from 15 to 30 kg: half a tablet (=100 mg) once daily
with a meal.
- Children weighing more than 30 kg: same as for adults.
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The usual duration of treatment is:
- Vaginal candidosis: 5 consecutive days;
- Skin mycosis induced by dermatophytes: approximately 4 weeks;
- Pityriasis versicolor: 10 days;
- Oral and skin mycosis induced by Candida: 2-3 weeks;
- Hair infections: 1-2 months;
-
Paracoccidioidomycosis, histoplasmosis, coccidioidomycosis:
the usual duration of therapy is 6 months.
For all indications, treatment should be continued without interruption until
clinical parameters or laboratory tests indicate that the fungal infection has
resolved. An inadequate treatment period may lead to recurrence of the
active infection. However, treatment should be stopped immediately and
liver function testing should be conducted when signs and symptoms
suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, jaundice,
abdominal pain or dark urine occur.
Special Patient Population: Hepatic Impairment (see section 4.3
Contraindications)
4.3.
Contraindications
NIZORAL tablets are contraindicated in the following situations:
-
In patients with a known hypersensitivity to ketoconazole or to any of
the excipients.
-
In patients with acute or chronic liver disease.
-
Coadministration of a number of CYP3A4 substrates is contraindicated
with NIZORAL Tablets. Increased plasma concentrations of these drugs,
caused by coadministration with ketoconazole, may increase or prolong
both therapeutic and adverse effects to such an extent that a potentially
serious situation may occur. For example, increased plasma
concentrations of some of these drugs can lead to QT prolongation and
ventricular tachyarrhythmias including occurrences of torsade de pointes,
a potentially fatal arrhythmia. Specific examples are listed in Section 4.5
Interaction with other medicinal products and other forms of interaction.
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4.4.
Special warnings and special precautions for use
Because of the risk for serious hepatotoxicity, NIZORAL tablets should be
used only when the potential benefits are considered to outweigh the
potential risks, taking into consideration the availability of other effective
antifungal therapy.
Assess liver function, prior to treatment to rule out acute or chronic liver
disease, and monitor at frequent and regular intervals during treatment, and
at the first signs or symptoms of possible hepatotoxicity.
Hepatotoxicity
Very rare cases of serious hepatotoxicity including cases with a fatal
outcome or requiring liver transplantation have occurred with the use of oral
ketoconazole (see section 4.8 Undesirable effects). Some patients had no
obvious risk factors for liver disease. Cases have been reported that occurred
within the first month of treatment, including some within the first week.
The cumulative dose of the treatment is a risk factor for serious
hepatotoxicity.
Monitor liver function in all patients receiving treatment with NIZORAL
tablets (see Monitoring of hepatic function).
Patients should be instructed to promptly report to their physician signs and
symptoms suggestive of hepatitis such as anorexia, nausea, vomiting,
fatigue, jaundice, abdominal pain or dark urine. In these patients, treatment
should be stopped immediately and liver function testing should be
conducted.
Monitoring of hepatic function
Monitor liver function in all patients receiving treatment with NIZORAL
tablets. Monitor liver function prior to treatment to rule out acute or chronic
liver disease (see 4.3 Contraindications), at frequent and regular intervals
during treatment, and at the first signs or symptoms of possible hepatic
toxicity. When the liver function tests indicate liver injury, the treatment
should be stopped immediately.
In patients with elevated liver enzymes, 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 such cases close monitoring of
the liver enzymes is necessary.
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Monitoring of adrenal function
In volunteers on daily doses of 400 mg and more, ketoconazole has been
shown to reduce the cortisol response to ACTH stimulation. Therefore,
adrenal function should be monitored in patients with adrenal insufficiency
or with borderline adrenal function, in patients under prolonged periods of
stress (major surgery, intensive care, etc.), and in patients on prolonged
therapy presenting signs and symptoms suggestive of adrenal insufficiency.
Pediatric use
Documented use of NIZORAL tablets in children weighing less than
15 kg is very limited. Therefore, it is not recommended to administer
NIZORAL tablets to small children.
Reduced gastric acidity
When the gastric acidity is reduced, absorption of ketoconazole from
ketoconazole tablets is reduced. In subjects with reduced gastric acidity,
whether from disease (e.g. subjects with achlorhydria) or from concomitant
medication (e.g. subjects taking drugs that reduce gastric acidity), it is
advisable to administer NIZORAL Tablets with an acidic beverage (such as
non-diet cola). The antifungal activity should be monitored and the
ketoconazole dose increased as deemed necessary. See Section 4.5
Interaction with other medicinal products and other forms of interaction,
Drugs that may decrease ketoconazole plasma concentrations and Section
5.2 Pharmacokinetic properties/Absorption.
Drug interaction potential
Coadministration of specific drugs with ketoconazole may result in changes
in efficacy of ketoconazole and/or the coadministered drug, life-threatening
effects and/or sudden death. Drugs that are contraindicated, not
recommended or should be used with caution in combination with
ketoconazole are listed in see section 4.5. Interaction with other medicinal
products and other forms of interaction.
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4.5.
Interaction with other medicinal products and other forms of
interaction
Ketoconazole is mainly metabolized through CYP3A4. Other substances
that either share this metabolic pathway or modify CYP3A4 activity may
influence the pharmacokinetics of ketoconazole. Similarly, ketoconazole
may modify the pharmacokinetics of other substances that share this
metabolic pathway. Ketoconazole is a potent CYP3A4 inhibitor and a Pglycoprotein inhibitor. When using concomitant medication, the
corresponding label should be consulted for information on the route of
metabolism and the possible need to adjust dosages.
Interaction studies have only been performed in adults. The relevance of the
results from these studies in pediatric patients is unknown.
•
Drugs that may decrease ketoconazole plasma concentrations
Drugs that reduce the gastric acidity (e.g. acid neutralizing medicines such
as aluminium hydroxide, or acid secretion suppressors such as H2-receptor
antagonists and proton pump inhibitors) impair the absorption of
ketoconazole from ketoconazole tablets. These drugs should be used with
caution when coadministered with ketoconazole tablets:
Ketoconazole should be administered with an acidic beverage (such as nondiet cola) upon co-treatment with drugs reducing gastric acidity.
Acid neutralizing medicines
(e.g. aluminium hydroxide) should be
administered at least 1 hour before or 2 hours after the intake of NIZORAL
Tablets.
Upon coadministration, the antifungal activity should be monitored and the
ketoconazole dose increased as deemed necessary.
Coadministration of ketoconazole with potent enzyme inducers of CYP3A4
may decrease the bioavailability of ketoconazole to such an extent that
efficacy may be largely reduced. Examples include:
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•
Antibacterials: isoniazid, rifabutin, rifampicin.
•
Anticonvulsants: carbamazepine (see also under ‘Drugs that may have
their plasma concentrations increased’), phenytoin.
•
Antivirals: efavirenz, nevirapine.
Therefore, administration of potent enzyme inducers of CYP3A4 with
ketoconazole is not recommended. The use of these drugs should be avoided
from 2 weeks before and during treatment with ketoconazole, unless the
benefits outweigh the risk of potentially reduced ketoconazole efficacy.
Upon coadministration, the antifungal activity should be monitored and the
ketoconazole dose increased as deemed necessary.
•
Drugs that may increase ketoconazole plasma concentrations
Potent inhibitors of CYP3A4 (e.g. antivirals such as ritonavir, ritonavirboosted darunavir and ritonavir-boosted fosamprenavir) may increase the
bioavailability of ketoconazole. These drugs should be used with caution
when coadministered with ketoconazole tablets. Patients who must take
ketoconazole concomitantly with potent inhibitors of CYP3A4 should be
monitored closely for signs or symptoms of increased or prolonged
pharmacologic effects of ketoconazole, and the ketoconazole dose should be
decreased as deemed necessary. When appropriate, ketoconazole plasma
concentrations should be measured.
•
Drugs that may have their plasma concentrations increased by ketoconazole
Ketoconazole can inhibit the metabolism of drugs metabolized 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 ketoconazole. These elevated
plasma concentrations may increase or prolong both therapeutic and adverse
effects of these drugs. CYP3A4-metabolized drugs known to prolong the QT
interval may be contraindicated with ketoconazole, since the combination
may lead to ventricular tachyarrhythmias including occurrences of torsade de
pointes, a potentially fatal arrhythmia.
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The interacting drugs are categorized as follows:
− ‘Contraindicated’: Under no circumstances should the drug be
coadministered with ketoconazole, and up to one week after
discontinuation of treatment with ketoconazole.
− ‘Not recommended’: The use of the drug should be avoided during and
up to one week after discontinuation of treatment with ketoconazole,
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
interacting drug is recommended, and its dosage should be reduced or
interrupted as deemed necessary. When appropriate, plasma
concentrations should be measured.
− ‘Use with caution’: Careful monitoring is recommended when the drug is
coadministered with ketoconazole. Upon coadministration, patients
should be monitored closely for signs or symptoms of increased or
prolonged effects or side effects of the interacting drug, and its dosage
should be reduced as deemed necessary. When appropriate, plasma
concentrations should be measured.
Examples of drugs that may have their plasma concentrations increased by
ketoconazole presented by drug class with advice regarding coadministration
with ketoconazole:
Drug Class
Contraindicated
Alpha Blockers
Not
Recommended
Use with
Caution
tamsulosin
Analgesics
levacetylmethadol
(levomethadyl),
methadone
Antiarrhythmics
disopyramide,
dofetilide,
fentanyl
alfentanil,
buprenorphine
IV and
sublingual,
oxycodone
digoxin
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Drug Class
Contraindicated
Not
Recommended
Use with
Caution
dronedarone,
quinidine
Antibacterials
rifabutin
Anticoagulants and
Antiplatelet Drugs
rivaroxaban
Anticonvulsants
carbamazepine
Antidiabetics
coumarins,
cilostazol
repaglinide,
saxagliptin
Antihelmintics and
Antiprotozoals
halofantrine
praziquantel
Antihistamines
astemizole,
mizolastine,
terfenadine
ebastine
Antimigraine Drugs
ergot alkaloids,
such as
dihydroergotamine,
ergometrine
(ergonoine),
ergotamine,
methylergometrine
(methylergonovine)
eletriptan
Antineoplastics
irinotecan
dasatinib,
nilotinib,
trabectedin
bortezomib,
busulphan,
docetaxel,
erlotinib,
imatinib,
ixabepilone,
lapatinib,
trimetrexate,
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Drug Class
Contraindicated
Not
Recommended
Use with
Caution
vinca alkaloids
Antipsychotics,
Anxiolytics and
Hypnotics
lurasidone,
oral midazolam,
pimozide,
sertindole,
triazolam
alprazolam,
aripiprazole,
brotizolam,
buspirone,
haloperidol,
midazolam IV,
perospirone,
quetiapine,
ramelteon,
risperidone
Antivirals
maraviroc,
indinavir,
saquinavir
Beta Blockers
nadolol
Calcium Channel
Blockers
bepridil,
felodipine,
lercanidipine,
nisoldipine
other
dihydropyridine
s, including
verapamil
Cardiovascular
Drugs,
Miscellaneous
ivabradine,
ranolazine
aliskiren
Diuretics
eplerenone
Gastrointestinal
Drugs
cisapride,
domperidone
Immunosuppressants
aprepitant
everolimus
budesonide,
ciclesonide,
cyclosporine,
dexamethasone,
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Drug Class
Contraindicated
Not
Recommended
Use with
Caution
fluticasone,
methylpredniso
lone,
rapamycin (also
known as
sirolimus),
tacrolimus,
temsirolimus
Lipid Regulating
Drugs
lovastatin,
simvastatin
Respiratory Drugs
atorvastatin
salmeterol
SSRIs, Tricyclics
and Related
Antidepressants
reboxetine
Urological Drugs
Other
colchicine, in
subjects with renal
or hepatic
impairment
vardenafil
fesoterodine.
imidafenacin,
sildenafil,
solifenacin,
tadalafil,
tolterodine
colchicine
*alcohol,
alitretinoin
(oral
formulation),
cinacalcet,
mozavaptan,
tolvaptan
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*Exceptional cases have been reported of a disulfiram-like reaction to
alcohol, characterized by flushing, rash, peripheral oedema, nausea and
headache. All symptoms completely resolved within a few hours.
1.1.
Pregnancy and lactation
4.6.1. Use during pregnancy
There is limited information on the use of NIZORAL tablets during
pregnancy. Animal studies have shown reproductive toxicity (see section
5.3 Preclinical safety data). The potential risk to humans is unknown.
Therefore, NIZORAL tablets should not be used during pregnancy unless the
potential benefit to the mother outweighs the possible risk to the foetus.
4.6.2. Use during lactation
Since ketoconazole is excreted in the milk, mothers who are under treatment
should not breast-feed.
1.2.
Effects on ability to drive and use machines
No effects have been observed.
1.3.
Undesirable effects
4.8.1. Clinical trial data
The safety of NIZORAL Tablets was evaluated in 4735 subjects in 92 clinical trials
where NIZORAL Tablets were administered to treat a fungal infection or to healthy
volunteers.
Adverse drug reactions that were reported ≥1% of NIZORAL Tablets-treated subjects
are shown in Table 1.
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Table 1. Adverse Drug Reactions Reported in ≥1% of 4735 NIZORAL Tablets-treated Subjects
in 92 Clinical Trials
System Organ Class
%
Preferred Term
Gastrointestinal Disorders
Abdominal pain
1.2
Diarrhoea
1.8
Nausea
2.5
Hepato-biliary Disorders
Hepatic function abnormal
1.2
Nervous System Disorders
Headache
2.4
Additional adverse drug reactions that occurred in <1% of NIZORAL Tablets-treated
subjects in the clinical datasets are listed in Table 2.
Table 2. Adverse Drug Reactions Reported in < 1% of 4735 NIZORAL Tablets-treated Subjects
in 92 Clinical Trials
System Organ Class
Preferred Term
Endocrine Disorders
Gynaecomastia
Eye Disorders
Photophobia
Gastrointestinal Disorders
Abdominal pain upper
Constipation
Dry mouth
Dysgeusia
Dyspepsia
Flatulence
Tongue discolouration
Vomiting
General Disorders and Administration Site Conditions
Asthenia
Chills
Fatigue
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Hot flush
Malaise
Oedema peripheral
Pyrexia
Hepato-biliary Disorders
Hepatitis
Jaundice
Immune System Disorders
Anaphylactoid reaction
Investigations
Platelet count decreased
Metabolism and Nutrition Disorders
Alcohol intolerance
Anorexia
Hyperlipidaemia
Increased appetite
Musculoskeletal and Connective Tissue Disorders
Myalgia
Nervous System Disorders
Dizziness
Paraesthesia
Somnolence
Psychiatric Disorders
Insomnia
Nervousness
Reproductive System and Breast Disorders
Menstrual disorder
Respiratory, Thoracic and Mediastinal Disorders
Epistaxis
Skin and Subcutaneous Tissue Disorders
Alopecia
Dermatitis
Erythema
Erythema multiforme
Pruritus
Rash
Urticaria
Xeroderma
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Vascular Disorders
Orthostatic hypotension
4.8.2. Post-marketing experience
Very common ≥1/10
Common ≥1/100 and < 1/10
Uncommon ≥1/1,000 and <1/100
Rare ≥1/10,000 and <1/1,000
Very rare <1/10,000, including isolated reports
In Table 3, ADRs are presented by frequency category based on spontaneous
reporting rates.
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Table 3. Adverse Drug Reactions Identified During Postmarketing Experience with
NIZORAL Tablets by Frequency Category Estimated from Spontaneous Reporting
Rates
Blood and Lymphatic System Disorders
Very rare
thrombocytopenia;
Immune System Disorders
Very rare
allergic conditions including anaphylactic shock, anaphylactic reaction
and angioneurotic oedema
Endocrine Disorders
Very rare
adrenocortical insufficiency
Nervous System Disorders
Very rare
reversible intracranial pressure increased (e.g. papilloedema, fontanelle
bulging in infants)
Hepato-biliary Disorders
Very rare
serious hepatotoxicity, including hepatitis cholestatic, biopsyconfirmed hepatic necrosis, cirrhosis, hepatic failure including cases
resulting in transplantation or death. (see section 4.4 Special warnings
and special precautions for use)
Skin and Subcutaneous Tissue Disorders
Very rare
acute generalised exanthematous pustulosis, photosensitivity
Musculoskeletal and Connective Tissue Disorders
Very rare
arthralgia
Reproductive System and Breast Disorders
Very rare
erectile dysfunction ; with doses higher than the recommended
therapeutic dose of 200 or 400mg daily azoospermia,
4.9 Overdose
There is no known antidote to ketoconazole.
Symptoms:
Adverse drug reactions reported by patients taking high doses of NIZORAL
are available in 6 clinical trials in a total of 459 patients where NIZORAL
was administered at doses of 1,200 mg daily either in tablet form or as an
oral suspension. The most commonly reported adverse drug reactions were
nausea (27.2%), fatigue (including somnolence and lethargy) (14.2%),
vomiting (12.6%), gastrointestinal pain (including abdominal discomfort,
gastrointestinal disorder, stomach discomfort) (12.0%), anorexia (including
weight decreased, decreased appetite) (7.4%), flushing (including
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hyperhidrosis) (6.3%), oedema (5.7%), gynaecomastia (4.8%), rash
(including eczema, purpura, dermatitis) (3.3%), diarrhoea (2.2%), headache
(2.0%), dysgeusia (1.3%), and alopecia (1.1%).
Treatment:
In the event of acute accidental overdose, treatment consists of supportive
and symptomatic measures. Within the first hour after ingestion, activated
charcoal may be administered.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic classification: Antimycotics for systemic use,
imidazole derivatives
ATC code: J02A B02
Ketoconazole is a synthetic imidazole dioxolane derivative with a fungicidal
or fungistatic activity against dermatophytes, yeasts (Candida, Malassezia,
Torulopsis, Cryptococcus ), dimorphic fungi and eumycetes. Less sensitive
are: Aspergillus spp., Sporothrix schenckii, some Dematiaceae, Mucor spp.
and other phycomycetes, except Entomophthorales.
Ketoconazole inhibits the biosynthesis of ergosterol in fungi and changes the
composition of other lipid components in the membrane.
Data from some clinical PK/PD studies and drug interaction studies suggest
that oral dosing with ketoconazole at 200 mg twice daily for 3-7 days can
result in a small increase of the QTc interval: a mean maximum increase of
about 6 to 12 msec was seen at ketoconazole peak plasma levels, about 1-4
hours after ketoconazole administration. This small prolongation of the QTc
interval, however, is not considered to be clinically relevant.
At the therapeutic dosage of 200 mg once daily, a transient decrease in the
plasma concentrations of testosterone can be observed. Testosterone
concentrations return to pre-dose concentrations within 24 hours after
administration of ketoconazole. During long-term therapy at this dosage,
testosterone concentrations are usually not significantly different from
controls.
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In volunteers on daily doses of 400 mg and more, ketoconazole has been
shown to reduce the cortisol response to ACTH stimulation (see section 4.4
Special warnings and special precautions for use).
5.2 Pharmacokinetic properties
Absorption
Ketoconazole is a weak dibasic agent and thus requires acidity for
dissolution and absorption.
Mean peak plasma concentrations of approximately 3.5 µg/mL are reached
within 1 to 2 hours, following oral administration of a single 200 mg dose
taken with a meal. Oral bioavailability is maximal when the tablets are taken
with a meal.
Absorption of ketoconazole tablets is reduced in subjects with reduced
gastric acidity, such as subjects taking medications known as acid
neutralizing medicines (e.g. aluminium hydroxide) and gastric acid
secretion suppressors (e.g. H2-receptor antagonists, proton pump inhibitors)
or subjects with achlorhydria caused by certain diseases. (See Section 4.4
Special warnings and special precautions for use and Section 4.5 Interaction
with other medicinal products and other forms of interaction.) Absorption of
ketoconazole under fasted conditions in these subjects is increased when
ketoconazole tablets are administered with an acidic beverage (such as nondiet cola). After pretreatment with omeprazole, a proton pump inhibitor, the
bioavailability of a single 200-mg dose of ketoconazole under fasted
conditions was decreased to 17% of the bioavailability of ketoconazole
administered alone. When ketoconazole was administered with non-diet cola
after pretreatment with omeprazole, the bioavailability was 65% of that after
administration of ketoconazole alone.
Distribution
In vitro, the plasma protein binding is about 99% mainly to the albumin
fraction. Ketoconazole is widely distributed into tissues; however, only a
negligible proportion reaches the cerebrospinal fluid.
Metabolism
Following absorption from the gastrointestinal tract, ketoconazole is
converted into several inactive metabolites. In vitro studies have shown that
CYP3A4 is the major enzyme involved in the metabolism of ketoconazole.
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The major identified metabolic pathways are oxidation and degradation of
the imidazole and piperazine rings, by hepatic microsomal enzymes. In
addition, oxidative O-dealkylation and aromatic hydroxylation does occur.
Ketoconazole has not been demonstrated to induce its own metabolism.
Elimination
Elimination from plasma is biphasic with a half-life of 2 hours during the
first 10 hours and 8 hours thereafter.
Approximately 13% of the dose is excreted in the urine, of which 2 to 4% is
unchanged drug. The major route of excretion is through the bile into the
intestinal tract with about 57% being excreted in the feces.
Special Populations
Patients with Hepatic or Renal Impairment
In patients with hepatic or renal insufficiency the overall pharmacokinetics
of ketoconazole was not significantly different when compared with healthy
subjects.
Pediatric Patients
Limited pharmacokinetic data are available on the use of ketoconazole
tablets in the pediatric population.
Measurable ketoconazole plasma concentrations have been observed in preterm infants (single or daily doses of 3 to 10 mg/kg) and in pediatric patients
5 months of age and older (daily doses of 3 to 13 mg/kg) when the drug was
administered as a suspension, tablet or crushed tablet. Limited data suggest
that absorption may be greater when the drug is administered as a suspension
compared to a crushed tablet. Conditions that raise gastric pH may lower or
prevent absorption (see Section 4.4 Special warnings and special precautions
for use and Section 4.5 Interaction with other medicinal products and other
forms of interaction). Maximum plasma concentrations occurred 1 to 2 hours
after dosing and were in the same general range as those seen in adults who
received a 200-400 mg dose.
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5.3 Preclinical safety data
Ketoconazole has been tested in a standard battery of non-clinical safety
studies.
Hepatotoxic effects were seen in a 12-month repeated dose dog study. Slight
pathological changes in the kidney, adrenals and ovaries were noted in an
18-month repeated dose rat study. In addition, female rats showed an
increase in bone fragility. The No Observed Adverse Effect Level (NOAEL)
in both these studies was 10 mg/kg/day.
In reproduction studies, at very high, maternally toxic doses (80 mg/kg/day
and higher), ketoconazole impaired female fertility in the rat, and produced
embryotoxic and teratogenic (oligodactylia and syndactylia) effects in pups.
At 40 mg/kg in rats and rabbits, ketoconazole was devoid of embryotoxicity,
teratogenicity and effects on fertility. No teratogenic effects were observed
in mice at any dose level tested up to a maximum of 160 mg/kg.
Ketoconazole is not carcinogenic or genotoxic.
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 QT
interval.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
The inactive ingredients of the tablets are maize starch, lactose monohydrate,
povidone, microcrystalline cellulose, silicon dioxide and magnesium stearate
6.4 Special precautions for storage
Do not Store above 30° C.
The tablets must be stored in a dry place.
Keep out of reach of children.
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Manufacturer
Janssen Cilag, Latina, Italy
Registration Holder
J-C Health care Ltd. Kibbutz Shefayim, 60990.
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