Ketoconazole 200 MG Tablets SMPC - Taj Pharmaceuticals

Ketoconazole 200 mg tablets SMPC, Taj Phar maceuticals
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At treatment initiation, 24-hour urinary free

RX cortisol should be controlled every few
days/weeks.
KETOCONAZOLE Adjustment of the posology
TABLETS Ketoconazole daily dose should be periodically
adjusted on an individual basis with the aim to
200MG normalise urinary free cortisol and/or plasma
cortisol levels.
1.NAME OF THE MEDICINAL PRODUCT
- A dose increase of 200 mg/day every 7 to 28
Ketoconazole 200 mg tablets days may be considered if urinary free cortisol
2. QUALITATIVE AND QUANTITATIVE and/or plasma cortisol levels are above the
COMPOSITION normal range, as long as the dose is tolerated by
the patient;
Each tablet contains 200 mg ketoconazole.
- A maintenance dose from 400 mg/day to a
Excipient with known effect: each tablet maximal dose of 1200 mg/day taken orally in 2
contains 19 mg of lactose (as lactose to 3 divided doses may be required to restore
monohydrate). normal cortisol levels. In most of the
publications the maintenance dose varied
For the full list of excipients, see section 6.1.
between 600 mg/day and 800 mg/day;
3. PHARMACEUTICAL FORM
- When the effective dose of Ketoconazole is
Tablet. established, monitoring of urinary free cortisol
and/or plasma cortisol levels may be performed
Off-white to light cream, round, 10 mm every 3 to 6 months (see section 4.4);
diameter, biconvex.
- In the case of adrenal insufficiency and
4. CLINICAL PARTICULARS depending on the severity of the event, the dose
4.1 Therapeutic indications of Ketoconazole should be decreased by at least
Ketoconazole is indicated for the treatment of 200 mg/day or the treatment should be
endogenous Cushing's syndrome in adults and temporarily discontinued and/or a corticosteroid
adolescents above the age of 12 years. therapy should be added until the resolution of
the event. Ketoconazole can be reintroduced
4.2 Posology and method of administration thereafter at a lower dose (see section 4.4);
Treatment should be initiated and supervised by - Treatment with Ketoconazole can be stopped
physicians experienced in endocrinology or abruptly without a need for progressive dose
internal medicine and having the appropriate decrease where a change in the therapeutic
facilities for monitoring of biochemical strategy (eg surgery) is desired.
responses since the dose must be adjusted to
meet the patient's therapeutic need, based on the Monitoring of liver function
normalisation of cortisol levels. Before starting the treatment, it is mandatory:
Posology - to measure liver enzymes (ASAT, ALAT,
Initiation gammaGT and alkaline phosphatase) and
bilirubin
The recommended dose at initiation in adults
and adolescents is 400-600 mg/day taken orally - to inform the patients about the risk of
in two or three divided doses and this dose can hepatotoxicity, including to stop the treatment
be increased rapidly to 800-1200 mg/day in two and to contact their doctor immediately if they
or three divided doses. feel unwell or in the event of symptoms such as
anorexia, nausea, vomiting, fatigue, jaundice,
abdominal pain or dark urine. If these occur, Subsequent maintenance therapy can be
treatment should be stopped immediately and administered in one of two ways:
liver function tests should be performed.
- Block-only regimen: the maintenance dose of
Due to the known hepatotoxicity of Ketoconazole may be continued as described
ketoconazole, the treatment must not be initiated above;
in patients with liver enzymes levels above 2
times the upper limit of normal (see section 4.3). - Block-and-replace regimen: the maintenance
dose of Ketoconazole should be further
During the treatment: increased by 200 mg and concomitant
corticosteroid replacement therapy should be
- close clinical follow-up should be undertaken added (see section 4.4).
- measurement of liver enzymes (ASAT, ALAT, Special populations
gamma GT and alkaline phosphatase) and
bilirubin, should be performed at frequent Paediatric population
intervals:
The safety and efficacy of Ketoconazole in
o weekly for one month after initiation of the children aged less than 12 years have not been
treatment established. No recommendation on posology
can be made for children under 12. The
o then monthly for 6 months posology in adolescents above the age of 12
o weekly during one month whenever the dose years is the same as in adults (see section 5.1
was increased. and 5.2).
In the case of an increase in liver enzymes of Elderly patients
less than 3 times the upper limit of normal, more
Data on the use of Ketoconazole in patients
frequent monitoring of liver function tests older than 65 years are limited, but there is no
should be performed and the daily dose should evidence to suggest that specific dose
be decreased by at least 200 mg.
adjustment is required in these patients (see
In the case of an increase in liver enzymes equal section 5.2).
to or greater than 3 times the upper limit of Patients with renal impairment
normal, Ketoconazole should be stopped
immediately and should not be reintroduced due Although data are limited, the pharmacokinetics
to the risk of serious hepatic toxicity. of Ketoconazole are not significantly different in
Ketoconazole should be discontinued without patients with renal failure compared to healthy
any delay if clinical symptoms of hepatitis subjects, and no specific dose adjustment is
develop. recommended in this population.
In case of long term treatment (more than 6 Patients with hepatic impairment
months):
Ketoconazole is contraindicated in patients with
Although hepatotoxicity is usually observed at acute or chronic hepatic impairment (see
treatment initiation and within the first six sections 4.3, 4.4 and 5.3).
months of treatment, monitoring of liver
Gender, weight and race
enzymes should be done under medical criteria.
As a precautionary measure, in case of a dose No formal evaluation has been conducted to
increase after the first six months of treatment, investigate the potential differences in
monitoring of liver enzymes should be repeated ketoconazole pharmacokinetics between males
on a weekly basis for one month. and females and data evaluating the effect of
Dosing regimens for maintenance therapy weight on pharmacokinetics of ketoconazole are
very limited.
Method of administration
Oral use. risk of hepatotoxicity and QT interval

prolongation
4.3 Contraindications
- Hypersensitivity to ketoconazole and/or to any o felodipine, nisoldipine due to an increased risk
imidazole antifungal medication, or to any of the of oedema and congestive heart failure
excipients listed in section 6.1
o colchicine in patients with renal impairment
- Acute or chronic liver disease and/or if pre- due to an increased risk of severe adverse
treatment liver enzymes levels are above 2 times reactions
the upper limit of normal (see sections 4.2 and
4.4) o irinotecan due to an alteration of the
metabolism of this medicinal product
- Pregnant women (see section 4.6)
o everolimus, sirolimus (also known as
- Breastfeeding women (see section 4.6) rapamycin) due to an increase of the plasma
concentrations of these medicinal products
- Congenital or documented acquired QTc
prolongation o vardenafil in men older than 75-years due to
increased risk of adverse events
- Concomitant therapy with any of the following
medicinal products which may interact and o paritaprevir/ombitasvir (ritonavir) due to
result in potentially life-threatening adverse increased risk of adverse reactions
reactions (sections 4.4 and 4.5):
o fesoterodine and solifenacin in patients with
o CYP3A4 metabolised HMG-CoA reductase renal impairment
inhibitors (eg simvastatin, atorvastatin and
The list above is not an inclusive list of
lovastatin) due to an increased risk of skeletal
muscle toxicity including rhabdomyolysis compounds that may interact with ketoconazole
and result in potentially life-threatening
o eplerenone due to an increased risk of reactions.
hyperkalemia and hypotension
4.4 Special Warnings and precautions for use
o substances that may have their plasma
Monitoring of liver function
concentrations increased and have QT
prolonging potential : methadone, disopyramide, Liver enzymes should be monitored in all
quinidine, dronedarone, pimozide, sertindole, patients receiving Ketoconazole. Due to the risk
saquinavir (saquinavir/ritonavir 1000/100 mg of serious hepatic toxicity, close follow-up of
bid), ranolazine, mizolastine, halofantrine patients is required (see section 4.2).
o dabigatran due to an increased bleeding risk Monitoring of adrenal function
o triazolam, oral midazolam and alprazolam due Adrenal function should be monitored at regular
to potential for prolonged or increased sedation intervals since adrenal insuficiency can occur
and respiratory depression during the treatment under conditions of a
o ergot alkaloids (eg dihydroergotamine, relative cortisol deficiency due to an increased
glucocorticoid demand (e.g. in case of stress,
ergometrine (ergonovine), ergotamine and
methylergometrine (methylergonovine) due to surgery, or infection); and/or in case of
an increased risk of ergotism and other serious Ketoconazole overtreatment (for the patients
vasospastic adverse events treated with a block-only regimen); or if there is
insufficient glucocorticoid replacement therapy
o lurasidone (for the patients treated with a block-and-replace
regimen). Serum or plasma and/or salivary
o quetiapine due to an increased risk of toxicity
cortisol and/or urinary free cortisol levels should
o telithromycin and clarithromycin in patients be monitored, within one week following
with severe renal impairment due to an increased Ketoconazole initiation as a minimum, and then
periodically thereafter. When urinary Decreased gastric acidity

free/serum/ plasma cortisol levels are normalised
or close to target and the effective dose of Absorption is impaired when gastric acidity is
Ketoconazole is established, monitoring can be decreased. Acid-neutralising medicines (e.g.
undertaken every 3 to 6 months (see section 4.2 aluminium hydroxide) should not be
for dose adjustment in case of adrenal administered for at least 2 hours after the intake
insufficiency). of Ketoconazole. In patients with achlorhydria,
such as certain AIDS patients and patients on
All patients should be monitored and informed acid secretion suppressors (e.g. H2-antagonists,
about the signs and symptoms associated with proton pump inhibitors), it is advised to
hypocortisolism (e.g. weakness, fatigue, administer Ketoconazole with an acidic
anorexia, nausea, vomiting, weight-loss, beverage eg cola beverage, orange juice.
hypotension, hyponatraemia, hyperkalaemia
and/or hypoglycaemia). If acid secretion suppressors are added to or
removed from the concomitant medication then
If clinical symptoms are suggestive of adrenal ketoconazole dose should be adjusted according
insufficiency, cortisol levels should be measured to cortisol levels.
and Ketoconazole should be temporarily
Potential interaction with medicinal products
discontinued or the dose reduced and if
necessary corticosteroid substitution should be Ketoconazole has a high potential for clinically
initiated. Ketoconazole can be resumed important medicinal products interactions.
thereafter at a lower dose (see section 4.2).
Ketoconazole is mainly metabolised through
Block and replace regimen CYP3A4. Coadministration of potent enzyme
Patients treated with a block-and-replace inducers of CYP3A4 may decrease the
regimen should be taught to adjust their bioavailibity of Ketoconazole. A review of
concomitant medicinal products should be
glucocorticoid replacement therapy dose under
conducted when initiating ketoconazole
conditions of stress (see section 4.2). In addition,
treatment since ketoconazole is a known strong
they should receive an emergency card and be
equipped with an emergency glucocorticoid set. CYP3A4 inhibitor. The SmPC for concomitantly
used products must be consulted for the
Monitoring of the QTc interval recommendations regarding co-administration
with strong CYP3A4 inhibitors.
Monitoring for an effect on the QTc interval is
advisable. An ECG should be performed: Ketoconazole is a potent inhibitor of CYP3A4:
inhibition of CYP3A4 by Ketoconazole can
- Prior to the start of Ketoconazole
increase patients' exposure to a number of
- Within one week after the beginning of the medicinal products which are metabolised
treatment through this enzymatic system (see section 4.5).
- As clinically indicated thereafter. Ketoconazole is also a potent inhibitor of P-gp:
inhibition of P-gp by Ketoconazole can increase
In case of co-administration of an agent known patients' exposure to medicinal products which
to increase QTc interval (see section 4.5), ECG are P-gp substrates (see section 4.5).
monitoring is recommended.
CYP3A4-metabolised and/or P-gp substrates
Contraception known to prolong the QT interval may be
Women must be provided with comprehensive contraindicated with Ketoconazole, since the
information on pregnancy prevention. As a combination may lead to an increased risk of
minimum requirement, women of childbearing ventricular tachyarrhythmias, including
potential must use an effective method of occurrences of torsade de pointes, a potentially
contraception (see section 4.6). fatal arrhythmia (see section 4.3).
Use with hepatotoxic medicinal products
Co-administration of Ketoconazole and other Enzyme-inducing drugs such as rifampicin,

medications known to have potentially rifabutin, carbamazepine, isoniazid, nevirapine,
hepatotoxic effect (eg paracetamol) is not mitotane and phenytoin may significantly reduce
recommended since the combination may lead to the bioavailability of Ketoconazole. Use of
increased risk of liver damage. Ketoconazole with potent enzyme inducers is
not recommended.
Use with Pasireotide
Potent inhibitors of CYP3A4 (e.g. antivirals
Co-administration of Ketoconazole and such as ritonavir, ritonavir-boosted darunavir
pasireotide is not recommended since the
and ritonavir-boosted fosamprenavir) may
combination can lead to QT prolongation in
increase the bioavailability of Ketoconazole,
patients with known cardiac rhythm disorders these drugs should be used with caution when
(see section 4.5).
co-administered with Ketoconazole and patients
Coexisting inflammatory/autoimmune disorders should be monitored closely for signs and
symptoms of adrenal insuficiency. Ketoconazole
Exacerbation or development of dose should be adjusted accordingly.
inflammatory/autoimmune disorders has been
described after Cushing's syndrome remission, Effects of Ketoconazole on the metabolism of
including after treatment with ketoconazole. the other medicinal products
Patients with Cushing's syndrome and coexisting - Ketoconazole is a potent inhibitor of CYP3A4
inflammatory/autoimmune disorders should be and can inhibit the metabolism of drugs
supervised after normalisation of cortisol levels metabolised by this enzyme. This can result in
on ketoconazole.
an increase and/or prolongation of their effects,
Alcohol including adverse effects.
Patients should be advised against alcohol - In vitro data indicate that ketoconazole is an
consumption while on treatment (see section inhibitor of CYP1A2 and does not significantly
4.5). inhibit CYP 2A6 and 2E1. At clinically relevant
concentrations inhibition of CYP2B6, 2C9/C8,
Warning regarding excipients 2C19 and 2D6 by ketoconazole cannot be
This medicinal product contains lactose. Patients excluded.
with rare hereditary problems of galactase - Ketoconazole can inhibit the transport of drugs
intolerance, Lapp lactase deficiency or glucose- by P-gp, which may result in an increased
galactose malabsorption should not take this plasma concentration of these drugs.
medicine.
- Ketoconazole inhibits BCRP (Breast Cancer
4.5 Interaction with other medicinal Resistance Protein) in in vitro studies. Data of
products and other forms of interaction inhibition indicate that risk of interaction with
See section 4.3 Contraindications for the list of BCRP substrates cannot be excluded at the
the medicinal products that are contraindicated systemic level with very high doses of
during treatment with Ketoconazole. ketoconazole. However ketoconazole may be an
inhibitor of BCRP at the intestinal level at
Medicinal products affecting the absorption of clinically relevant concentrations. Considering
Ketoconazole the rapid absorption of ketoconazole, intake of
Medicinal drugs affecting gastric acidity impair BCRP substrates should be postponed for 2
the absorption of Ketoconazole (see section 4.4). hours after ketoconazole intake.
Effects of other medicinal products on the Table 1 Interactions and recommendations for
metabolism of Ketoconazole co-administration.
Ketoconazole is mainly metabolised by Interactions between ketoconazole and other

cytochrome CYP3A4. medicinal products are listed in the table below
(increase is indicated as “↑”, decrease as “↓”, an Dronedarone concentration risk of serious

no change as “↔”). The degrees of interaction s of cardiovascular
mentioned below are not absolute values and disopyramide events
and quinidine including QT
may be dependent on the ketoconazole dose Repeated prolongation
given i.e. many results are reported following a doses of 200 (see section
ketoconazole dose of 200 mg and a stronger mg 4.3).
interaction may be expected at a higher dose ketoconazole
daily resulted
and/or shorter dosing interval. The following list in a 17-fold
is not an inclusive list of interactions between increase in
ketoconazole and other drugs dronedarone
exposure
Medicinal product by Expected Recommendat
Digoxin Potential ↑in Careful
therapeutic area effect on ion for co-
plasma monitoring of
drug levels administration
concentration digoxin levels
Analgesic opioid s of digoxine is
Methadone Potential ↑ in Contraindicate recommended.
plasma d due to the Anticoagulants and
concentration increased risk antiplatelet drugs
s of of serious Rivaroxaban Rivaroxaban: Not
methadone cardiovascular AUC: ↑ 2.6- recommended
events fold due to an
including QT Cmax: ↑1.7- increased
prolongation fold bleeding risk.
and torsade de
pointes, or Cilostazol Cilostazol: Careful
respiratory or AUC: ↑ 2.2 monitoring
CNS fold A cilostazol
depression The overall dosage of 50
(see section pharmacologi mg twice daily
4.3). cal activity of is
cilostazol recommended
Buprenorphine IV and Buprenorphin Careful increases in combination
sublingual e: monitoring. 35% when with
AUC: ↑ 1.5- The co- Ketoconazole.
fold buprenorphine administered
Cmax: ↑1.7- dose should be with
fold adjusted. ketoconazole
Alfentanil, fentanyl Potential ↑in Careful .
plasma monitoring of Warfarin and other Potential ↑in Careful
concentration adverse effects coumarin-like drugs plasma monitoring
s of alfentanil (respiratory concentration INR
and fentanyl depression, s of warfarin (international
sedation) is normalised
recommended. ratio)
It may be monitoring
necessary to recommended.
lower the dose
of alfentanil Dabigatran Dabigatran: Contraindicate
and fentanyl. AUC: ↑ 2.6- d due to an
fold increased
Oxycodone ↑in plasma Careful Cmax: ↑2.5- bleeding risk
concentration monitoring. fold (see section
s of The oxycodone 4.3).
oxycodone dose may be
have been adjusted. Apixaban Apixaban Not
observed AUC: ↑ 2-fold recommended
Cmax: ↑1.6- due to an
Antiarrhythmics fold increased
Disopyramide Potential ↑in Contraindicate bleeding risk.
Quinidine plasma d due to the Edoxaban AUC: ↑ 1.8- Dose of
fold edoxaban Potencial ↓ in products on the

Cmax: ↑ 1.8- needs to be plasma metabolism of
fold reduced when concentration Ketoconazole
used s of ”)
concomitantly, ketoconazole
please consult are
edoxaban expected.
SmPC. (CYP3A4
Anticonvulsants enzyme
induction)
Carbamazepine Potential ↑in Not
Telithromycin Telithromycin Not
Phenytoin plasma recommended.
concentration (See also Clarithromycin e: recommended.
s of “Effects of AUC: ↑ 2-fold Contraindicate
Cmax: ↑1.5- d in patients
carbamazepi other medicinal
fold with severe
ne and products on the
phenytoin metabolism of Potential ↑in renal
Potential ↓ in Ketoconazole plasma impairment due
concentration to the risk of
plasma ”).
s of QT interval
concentration
s of clarithromyci prolongation
ketoconazole n and serious
hepatic
are
adverse
expected.
(CYP3A reactions (see
enzyme section 4.3).
induction) Praziquantel ↑in plasma Careful
concentration monitoring.
Antidiabetics
s of Dose
Repaglinide Repaglinide: Careful praziquantel adjustment of
AUC: ↑ 1.2- monitoring. have been praziquantel
fold Dose observed may be
Cmax: ↑ 1.2- adjustement of required.
fold repaglinide
Isavuconazole AUC: ↑ 5-fold Not
may be
Cmax: ↑ 1.1 - recommended
required.
fold due to
Saxagliptin Saxagliptin: Careful increased risk
AUC: ↑ 2.5- monitoring. of
fold Dose isavuconazole
Cmax: ↑ 1.6- adjustment of adverse
fold saxagliptin may reactions,
Associated be required. please consult
with a isavuconazole
decrease in SmPC
correspondin
Antimigraine Drugs
g values for
the active Ergots alkaloids such Potential ↑in Contraindicate
metabolite as dihydroergotamine, plasma d due to the
ergometrine concentration increased risk
Tolbutamide Tolbutamide: Careful
AUC: ↑ 1.7- monitoring. (ergonovine), s of ergot of ergotism and
fold Dose ergotamine, alkaloids other serious
methylergometrine vasospastic
adjustment of
(methylergonovine) adverse events
tolbutamide
may be (see section
required. 4.3).
Eletriptan Eletriptan: Not
Anti-infectives
AUC: ↑ 5.9- recommended.
Rifabutin Potential ↑ in Not fold
Rifampicin plasma recommended. Cmax: ↑ 2.7-
Isoniazid concentration (See also fold
s of “Effects of
Antineoplastics
rifabutine. other medicinal
Sunitinib Sunitinib Not Busulfan AUC: ↑ 1.4- monitoring.

Dasatinib AUC: ↑ 1.5- recommended Docetaxel fold Dose
Lapatinib fold due to the risk Imatinib Imatinib: adjustment of
Nilotinib Cmax: ↑ 1.5- of increased Cabazitaxel AUC: ↑ 1.4- each drug may
Erlotinib fold exposure to fold be required.
Dabrafenib Lapatinib: these drugs Cmax: ↑ 1.3-
Cabozantinib AUC: ↑ 3.6- and QT fold
fold prolongation. ↑in plasma
Nilotinib: concentration
AUC: ↑ 3.0- s of
fold docetaxel
Erlotinib: have been
AUC: ↑ 1.9- observed
fold Potential ↑in
Cmax: ↑ 1.7- plasma
fold concentration
Dasatinib s of busulfan
↑in plasma Cabazitaxel
concentration AUC: ↑ 1.3-
s of fold
Dasatinib Paclitaxel Paclitaxel: Careful
have been No change in monitoring.
observed plasma Dose
Dabrafenib concentration adjustment of
AUC: ↑ 1.7- were shown paclitaxel may
fold with be required.
Cmax: ↑ 1.3- paclitaxel
fold concentrate.
Cabozantinib No studies
AUC: ↑ 1.4- were
fold performed
Cmax: ↔ with albumin
Ibrutinib Ibrutinib: Not bound
AUC: ↑ 24- recommended nanoparticule
fold as it may s.
Cmax: ↑ 29- increase Vincristine, vinblastine Potential ↑in Careful
fold ibrutinib-related (vinca alkaloids) plasma monitoring as it
toxicity. concentration may cause an
Crizotinib Crizotinib Not s of vinca earlier onset
AUC: ↑ 3.2- recommended alkaloids. and/or an
fold due to the risk increased
Cmax: ↑ 1.4- of QT interval severity of
fold prolongation side-effects.
and serious Antipsychotics,
hepatic Anxiolytics and
adverse Hypnotics
reactions.
Monitoring of Triazolam AUC: ↑ have Contraindicate
QT- Alprazolam been d due to the
prolongation if Midazolam oral observed risk of
used Cmax: ↑ potentially
concomitantly. have been prolonged or
observed increased
Irinotecan Irinotecan: Contraindicate sedation and
AUC: ↑ 2.1- d due to an respiratory
fold alteration of the depression
metabolism of (see section
this medicinal 4.3).
product (see
section 4.3). Midazolam IV Midazolam: Careful
AUC: ↑ 1.6- monitoring.
Bortezomib Bortezomib: Careful fold Dose
adjustment of therapeutic
midazolam IV margin.
may be Quetiapine Quetiapine: Contraindicate
required. AUC: ↑ 6.2- d as it may
Lurasidone Lurasidone: Contraindicate fold increase
AUC: ↑ 9 fold d due to the Cmax: ↑ 3.4- quetiapine-
Cmax: ↑ 6 increased risk fold related toxicity
fold of adverse (see section
events (see 4.3).
section 4.3). Risperidone Potential ↑in Careful
Pimozide Potential ↑in Contraindicate AUC of monitoring.
plasma d due to the risperidone: Dose
concentration risk of serious adjustment of
s of cardiovascular risperidone
pimozide. events may be
including QT required.
prolongation Antivirals products
(see section
4.3). Maraviroc Maraviroc: Careful
AUC: ↑ 5-fold monitoring.
Buspirone Potential ↑in Careful
Cmax: ↑ 3.4- Maraviroc dose
plasma monitoring.
fold should be
concentration Dose decreased to
s of adjustement of 150 mg twice
buspirone. buspirone may
daily.
be required.
Saquinavir Saquinavir: Contraindicate
Aripiprazole Aripiprazole Careful (saquinavir/ritonavir AUC: ↔ d due to the
AUC: ↑ 1.6- monitoring.
1000/100 mg bid) Cmax: ↔ risk of QT
fold Aripiprazole
Ketoconazol prolongation
Cmax: ↑ 1.4- dose should be e (see section
fold reduced to AUC: ↑ 2.7- 4.3).
approximatively
fold
one-half of its
Cmax:↑ 1.5-
prescribed fold
dose. (CYP3A4
Haloperidol Potential ↑in Not enzyme
plasma recommended inhibition by
concentration due to the ritonavir)
s of increased risk Indinavir Indinavir Careful
haloperidol. of QT
(600mg TID): monitoring.
prolongation
AUC= 0.8- Dose reduction
and fold of Indinavir to
extrapyramidal Cmin: ↑ 1.3- 600 mg every 8
symptoms. It
fold hours should
may be
(Relative to be considered.
necessary to Indinavir 800
reduce mg TID
haloperidol
alone)
dosage.
Ketoconazol Not
Sertindole Potential ↑in Contraindicate e: recommended
plasma d due to the
AUC: ↓0.28-
concentration risk of QT
fold
s of prolongation Cmax: ↓0.56-
sertindole. (see section fold
4.3). Nevirapine
Nevirapine:
Reboxetine Reboxetine: Not plasma
AUC: ↑ 1.5- recommended levels: ↑1.15-
fold of both because of 1.28-fold
enantiomers reboxetine compared to
narrow's historical
controls concentration Dose

(CYP3A s of these adjustment of
enzyme drugs dihydropyridine
induction) s and
Ketoconazol A dose verapamil may
e: reduction of be required.
AUC: ↑3.4- ketoconazole Cardiovascular
fold should be Drugs, Miscellaneous
Cmax: ↑1.6- considered Ranolazine Ranolazine: Contraindicate
fold when co- AUC: ↑ 3.0 to d due to the
(CYP3A administered 3.9-fold potential for
enzyme with ritonavir serious
inhibition) dosed as an cardiovascular
antiretroviral events
Ritonavir
agent or as a including QT
pharmacokineti prolongation
c enhancer. (see section
(See also 4.3).
“Effects of
other medicinal Aliskiren Aliskiren: Careful
products on the AUC: ↑ 1.8- monitoring.
metabolism of fold Dose
Ketoconazole adjustment of
”). aliskiren may
be required.
Paritaprevir: Contraindicate
AUC: ↑2.2- d due to the Bosentan Bosentan: Not
fold increased risk AUC: ↑ 2-fold recommended
Cmax: ↑1.7- of adverse Cmax: ↑ 2- due to the
fold reactions (see fold potential for
Ombitasvir: section 4.3). hepatic toxicity
AUC: ↑1.3- (see section
Paritaprevir/Ombitasvir fold 4.3).
(ritonavir) Cmax: ↔ Diuretics
Ketoconazol
Eplerenone Eplerenone: Contraindicate
e:
AUC: ↑ 5.5- d due to the
AUC: ↑2.1-
fold increased risk
fold
of
Cmax: ↑1.1-
hyperkalaemia
fold
and
t1/2: ↑ 4-fold
hypotension
Beta Blockers (see section
Nadolol ↑in plasma Careful 4.3).
concentration monitoring. Gastrointestinal
s of nadolol Dose Drugs
have been adjustment of
Aprepitant Aprepitant: Careful
observed nadolol may be
AUC: ↑ 5-fold monitoring.
required.
Dose
Calcium Channel adjustment of
Blockers aprepitant may
Felodipine AUC: ↑ has Contraindicate be required
Nisoldipine been d due to an Domperidone Domperidone Not
observed increase risk of : recommended
Cmax: ↑ has edema and AUC: ↑ 3.0 due to an
been congestive fold increased risk
observed heart failure Cmax: ↑ 3.0 in QT
(see section fold prolongation.
4.3).
Naloxegol Naloxegol Not
Other dihydropyridines Potential ↑in Careful AUC ↑ 12.9 recommended
Verapamil plasma monitoring. fold
Cmax ↑ 9.6 Solifenacin metabolite: due to an

fold AUC: ↑ 2.3- increased risk
Immunosuppressant fold of QT
s Cmax: ↑ 2.0- prolongation.
fold Fesoterodine
Everolimus Everolimus: Contraindicate Solifenacin: and solifenacin
Sirolimus (rapamycin) AUC: ↑ 15.3- d due to the AUC: ↑ 3.0- are
fold large increase fold contraindicated
Cmax: ↑ 4.1- in these drugs ↑in plasma in patients with
fold concentrations concentration renal
Sirolimus (see section s of impairment
(rapamycin): 4.3). tolterodine (see section
AUC: ↑ 10.9- have been 4.3).
fold observed
Cmax: ↑ 4.4-
fold Phosphodiesterase(P
DE5) inhibitors
Temsirolimus Temsirolimus Not
Tacrolimus : recommended Sildenafil Tadalafil: Not
Ciclosporine AUC: ↔ unless Tadalafil AUC: ↑ 4-fold recommended
Budesonide Cmax: ↔ necessary. Vardenafil Cmax: ↑ 1.2- due to the
Ciclesonide Ciclesonide Careful fold increased risk
active monitoring and Vardenafil: of adverse
metabolite: dose AUC: ↑ 10- events.
AUC: ↑ 3.5- adjustment of fold Vardenafil is
fold these drugs Cmax: ↑ 4- contraindicated
Rest of drugs may be fold in men older
↑in plasma required. Potential ↑in than 75 years
concentration plasma old (see
s of these concentration section 4.3).
drugs have s of sildenafil
been Other
observed Colchicine ↑in plasma Not
Dexamethasone, Potential ↑in Careful concentration recommended
fluticasone, plasma monitoring. s of due to a
methylprednisolone concentration Dose colchicine potential
s of these adjustment of have been increase in
drugs these drugs observed colchicine-
may be related toxicity.
required. Contraindicate
Lipid Lowering Drugs d in patients
with renal
Lovastatin, Potential ↑in Contraindicate impairment
simvastatin, plasma d due to an (see section
atorvastatin* concentration increased risk 4.3).
s of these of skeletal
drugs muscle toxicity, Tolvaptan ↑in plasma Contraindicate
including concentration d due to an
rhabdomyolysis s of tolvaptan increase in the
(see section have been plasma
4.3). observed concentrations
(see section
Respiratory Drugs 4.3).
Salmeterol Salmeterol Not Cinacalcet Cinacalcet Careful
AUC: ↑ 15- recommended AUC: ↑ 2 fold monitoring.
fold due to an Cmax: ↑ 2 Dose
Cmax: ↑ 1.4- increased risk fold adjustment of
fold in QT cinacalcet may
prolongation. be required.
Urological Drugs Ebastine ↑in plasma Not
Fesoterodine Fesoterodine Not concentration recommended
Tolterodine active recommended s of ebastine due to an
have been increased risk Since ketoconazole is excreted in the milk,

observed in QT mothers who are under treatment must not
prolongation. breast-feed whilst being treated with
Mizolastine Potential ↑in Contraindicate Ketoconazole (see section 4.3).
Halofantrine plasma d due to the
concentration potential for Fertility
s of these serious
drugs cardiovascular Studies in animals have shown effects on male
events and female reproductive parameters (see section
including QT
prolongation
5.3).
(see section
4.7 Effects on ability to drive and use
4.3).
machines
No specific studies have been conducted to
assess the effect of ketoconazole on the ability to
* Rosuvastatin is not a CYP 3A4 substrate.
drive or use machines. Patients should be
Ketoconazole did not produce any change in
warned about the potential for dizziness and
rosuvastatin pharmacokinetics, therefore, co-
somnolence (see section 4.8) and should be
administration of Ketoconazole and rosuvastatin
advised not to drive or operate machines if any
is unlikely to increase the risk of toxicity of
of these symptoms occur.
rosuvastatin. Other statins that are not CYP3A4
substrates (pravastatin and fluvastatin) can be 4.8 Undesirable Effects
co-administered with Ketoconazole. Summary of the safety profile
Other interactions The most frequent adverse reactions are adrenal
insufficiency, nausea, vomiting, abdominal pain,
Exceptional cases of a disulfiram-like reaction
diarrhoea, pruritus, rash and the hepatic enzymes
have been reported when ketoconazole was co-
increased.
administered with alcohol, characterised by
flushing, rash, peripheral oedema, nausea and The most serious adverse reaction is
headache, have been reported. All symptoms hepatotoxicity, primarily as acute hepatocellular
resolved completely within a few hours. toxicity but may also result in cholestatic injury
or a mixed pattern of toxicity. ASAT, ALAT,
Co-administration of ketoconazole and
gammaGT, bilirubin and alkaline phosphatase
pasireotide is not recommended since the
should be monitored at frequent intervals during
combination can lead to a QT prolongation in
treatment (see sections 4.2 and 4.4).
patients with known cardiac rhythm disorders.
Tabulated list of adverse reactions
There is no evidence to suggest that there is an
interaction between Ketoconazole and other The safety of Ketoconazole has been evaluated
steroidogenesis inhibitors (ie metyrapone). based on published literature and use of
ketoconazole as an antifungal treatment.
4.6 Fertility, Pregnancy and lactation
The adverse reactions listed below in table 2 are
Pregnancy
classified according to System Organ Class.
There are insufficient clinical data regarding the Frequency groupings are defined according to
use of Ketoconazole in pregnant women. the following convention: very common (≥ 1/10)
Preclinical data show that Ketoconazole crosses , common (≥ 1/100 to < 1/10), uncommon: (≥
the placenta and is teratogenic. Ketoconazole is 1/1,000 to < 1/100), rare:(≥ 1/10,000 to <
contraindicated during pregnancy and it should 1/1,000), very rare (< 1/10,000), not known:
not be used in women of childbearing potential cannot be estimated from the available data.
not using an effective method of contraception
Within each frequency grouping, undesirable
(see section 4.3).
effects are presented in order of decreasing
Breast-feeding seriousness.
Table 2: Incidence of adverse reactions and necrosis, hepatic

marked laboratory abnormalities reported in the cirrhosis, hepatic
literature in adults and adolescents patients failure including
cases necessitating
System organ Frequency Adverse reaction transplantation or
class resulting in death.
Blood and Uncommon Thrombocytopenia (see 4.4 Special
lymphatic warnings and
system special precautions
disorders for use)
Immune system Uncommon Allergic conditions Skin and Common Pruritus, rash
disorders including subcutaneous
anaphylactic shock, tissue disorders
anaphylactoid Uncommon Urticaria, alopecia
reaction and Not known Photosensitivity,
anaphylactic erythema
reaction and multiforme,
angioedema dermatitis,
Endocrine Common Adrenal erythema, ,
disorders insufficiency xeroderma
Psychiatric Not Known Insomnia, Musculoskeletal Not known Myalgia, arthralgia
disorders nervousness and connective
Metabolism and Not known Alcohol intolerance, tissue disorder
nutrition anorexia, increased Reproductive Not known Menstrual disorder,
disorders appetite system and azoospermia,
Nervous Uncommon Headache, breast erectile dysfunction,
system dizziness, disorders gynaecomastia
disorders somnolence General Uncommon Asthenia
Not known Intracranial pressure disorders and
increased administration
(papilloedema, site conditions
fontanelle bulging), Very rare Pyrexia
paraesthesia Not known Oedema peripheral,
Eye disorders Not known Photophobia malaise, hot flush
Respiratory, Not known Epistaxis Investigations Very Hepatic enzyme
thoracic and common increased
mediastinal Uncommon Platelet count
disorders decreased
Gastrointestinal Common Nausea, abdominal Not known Transient decrease
disorders pain, vomiting, of testosterone
diarrhoea concentrations
Not known Dyspepsia, Description of selected adverse reactions
flatulence, tongue
discoloration, dry Hepatotoxicity
mouth, dysgeusia
Serious hepatic toxicity caused by ketoconazole
Hepatobiliary Very Liver function tests
disorders common abnormal
treatment is rare (1/15000). Acute hepatocellular
injury has been primarily observed as has
Rare Serious cholestatic injury or a mixed pattern of toxicity.
hepatotoxicity,
including jaundice,
Fatal cases have been reported particularly when
hepatitis, hepatic treatment is continued despite liver enzyme
elevation. Increases in liver enzymes (≤ 5N and
> 5N) were observed in ~13.5 % and ~2.5% of among 24 paediatric patients treated with
patients respectively occurring mostly within the ketoconazole, two developed severe
first 6 months of treatment. Liver enzyme levels hepatoxicity. A 14 year-old girl who was treated
returned to normal within 2-12 weeks after a for Cushing's disease with ketoconazole 200 mg
dose decrease or withdrawal of ketoconazole. twice daily presented one month later with
Hepatotoxicity does not appear to be dose jaundice, fever anorexia, nausea and vomiting.
dependent. All potential associated factors of Ketoconazole was stopped but she deteriorated
hepatotoxicity, and abnormal liver enzyme rapidly and died. A 17 years old girl was treated
levels detected before Ketoconazole initiation, on ketoconazole 1200 mg/day for an adrenal
should be taken into account before considering carcinoma with liver metastasis and had altered
Ketoconazole treatment. Ketoconazole should liver function tests at 22 days. After
not be administered when liver enzymes are ketoconazole withdrawal, liver enzymes
greater than 2 times the upper limit of normal or returned to normal levels within 3 weeks
in association with other hepatotoxic drugs. (section 5.1).
Liver enzyme monitoring should be performed
Reporting of suspected adverse reactions
once weekly during the first month of treatment
and then monthly for 6 months. In the case an Reporting suspected adverse reactions after
increase of liver enzymes is detected which is authorisation of the medicinal product is
less than 3 times the upper limit of normal, important. It allows continued monitoring of the
closer monitoring of liver function should be benefit/risk balance of the medicinal product.
performed and the daily dose should be
decreased by at least 200 mg. In the case of 4.9 Overdose
increase of liver enzymes levels above 3 times There is no known antidote to Ketoconazole.
the upper limit of normal, Ketoconazole should The maximal dose that was used for treatment of
be stopped immediately and should not be Cushing's syndrome is 1600 mg/day.
reintroduced because of the risk of serious
hepatic toxicity. In the event of accidental overdose, treatment
consists of supportive measures. Within the first
Adrenal Insufficiency hour after ingestion gastric lavage may be
Adrenal insufficiency may occur in patients on performed. Activated charcoal may be given if
ketoconazole without corticosteroid substitution considered appropriate.
(block-only regimen) or if there is an insufficient In the case of signs suggestive of an adrenal
glucocorticoid replacement therapy (for the insufficiency, in addition to the general
patients treated with a block-and-replace measures to eliminate the drug and reduce its
regimen). Monitor and instruct patients on the absorption, a 100 mg dose of hydrocortisone
signs and symptoms associated with should be administered at once, together with
hypocortisolism (e.g. weakness, fatigue, saline and glucose infusions. Close surveillance
anorexia, nausea, vomiting, hypotension, will be necessary: blood pressure and fluid and
hyperkalemia, hyponatraemia, hyperkalaemia or electrolyte balance should be monitored for a
hypoglycaemia). Adrenal insufficiency may be few days.
detected by periodic clinical assessment and
monitoring of plasma/serum or salivary cortisol 5. PHARMACOLOGICAL PROPERTIES
levels. In case of adrenal insufficiency, 5.1 Pharmacodynamic properties
Ketoconazole treatment should be temporarily
discontinued or the dose reduced and, if needed, Pharmacotherapeutic group: Imidazole
a corticosteroid substitution therapy added. derivatives,
Paediatric population Mechanism of action
Frequency of hepatotoxicity could be higher in Ketoconazole is a steroidogenesis inhibitor.
adolescents than in adults. In the literature, Ketoconazole is an imidazole derivative that is a
potent inhibitor of cortisol synthesis resulting pituitary radiation. Overall, ketoconazole was
from its ability to inhibit several cytochrome shown to be an effective drug for normalising
P450 enzymes in the adrenal glands. cortisol levels in all causes of Cushing's
Ketoconazole inhibits primarily the activity of syndrome and, if tolerated, ketoconazole
17α-hydroxylase, but it also inhibits 11- treatment can be maintained for a long period.
hydroxylation steps, and at higher doses the
cholesterol side-chain cleavage enzyme. Escape phenomenon
Therefore, ketoconazole is an inhibitor of In approximately 10 to 15 % of ketoconazole
cortisol and aldosterone synthesis. Ketoconazole treated patients, an "escape phenomenon" is
is also a potent inhibitor of androgens synthesis, observed and reinforces the need for a long-term
inhibiting the activity of C17-20 lyase in the clinical and biochemical follow-up of these
adrenals and also in Leydig cells. patients. If such a phenomenon occurs, a further
Apart from adrenal blocking effect, dose increase may be required to maintain
cortisol levels within the normal range.
ketoconazole may also have direct effects on
corticotropic tumour cells in patients with Use in Cushing's disease
Cushing's disease.
Data from 535 patients with Cushing's disease
Clinical efficacy treated with ketoconazole, along with 13
The efficacy and safety of ketoconazole in the individual case reports are available in the
treatment of Cushing's syndrome from all causes literature. In a retrospective study conducted in
have been described through several published several French centres, 200 patients with
retrospective studies, chart reviews and case Cushing's disease were followed between 1995
reports. Control of cortisol levels, either in and 2012. At the last visit, 78 patients (49.3%)
were controlled, 37 patients (23.4%) had partial
serum/plasma or urine, was used to assess the
control with at least 50% decrease of UFC
efficacy of the treatment, along with the
evaluation of clinical symptoms of Cushing's (without normalisation), and 43 patients (27.2%)
syndrome. More than 800 patients have been had unchanged UFC levels. At the last follow-
treated with ketoconazole with variable up, clinical signs were improved in 74/134
treatment duration and modalities. About 200 patients (55.2%), hypertension in 36/90 patients
patients were treated for more than 6 months and (40), hypokalaemia in 10/26 patients (38.4%),
some of them were treated for several years. and diabetes mellitus in 23/39 patients (59%).
Urinary free cortisol (UFC) levels were Use in ectopic ACTH syndrome
normalised in about 50% of patients on Data from 91 patients with the ectopic ACTH
ketoconazole. Response rates varied between 43 syndrome treated with ketoconazole were
and 80% depending on the studies and the reviewed, along with 18 individual case reports.
criteria to define a response. About 75% of In a Canadian study, of the 12 assessable
patients achieved a decrease of more than 50% patients (out of 15), 10 showed a reduction in
of UFC levels on ketoconazole, compared to urinary free cortisol levels, but only five had
pre-treatment levels complete resolution on ketoconazole doses 400
Combination therapy to 1200 mg/day. Clinical improvement in
hypokalaemia, metabolic alkalosis, diabetes
Ketoconazole has been used both as sole mellitus, and hypertension occurred even in the
medical therapy and in combination with other absence of complete hormonal response.
drugs, mainly with metyrapone, in patients with
more severe disease or in those not completely Use in ACTH-independent Cushing's
responding to a single agent or in those requiring syndrome
a dose reduction of at least one of the drugs to Data from 17 patients with adrenal tumours and
improve tolerance. Ketoconazole has also been from 2 patients with primary nodular
used with other therapies including surgery and adrenocortical hyperplasia (NAH) treated with
ketoconazole are available in the literature along Ketoconazole is extensively metabolised to a

with 17 individual case reports of patients with large number of inactive metabolites. In vitro
benign or malignant tumours or NAH and 2 studies have shown that CYP3A4 is the major
paediatric cases of McCune Albright syndrome. enzyme involved in the metabolism of
Improvement of clinical symptoms was noted in ketoconazole.
most patients after initiation of treatment.
However in patients with adrenal cortical The major identified metabolic pathways are
oxidation and degradation of the imidazole and
carcinoma, improvement of hypercortisolism on
ketoconazole was limited in some cases. piperazine rings, oxidative O-dealkylation and
aromatic hydroxylation.
Paediatric population
Ketoconazole is a potent inhibitor of CYP3A4
Data on 24 paediatric patients with endogenous and P-gp. Ketoconazole has not been
Cushing's syndrome treated with ketoconazole demonstrated to induce its own metabolism.
are available in the literature, among which 16
were aged over 12 years old and 8 were aged Elimination
less than 12 years old. Plasma elimination is biphasic with a half-life of
2 hours during the first 10 hours and 8 hours
Treatment with ketoconazole in paediatric
patients allowed normalisation of urinary free thereafter. The half-life of ketoconazole
cortisol levels and clinical improvement, increases with dose and duration of treatment.
including recovering of growth rate and gonadal At doses > 400 mg/day, half-lives of 3 to 10
function, normalisation of blood pressure, hours have been reported. About 13% of the
Cushing's syndrome features and weight loss in dose is excreted in the urine, of which 2 to 4% is
most of the cases. The doses used in adolescents unchanged drug. The major route of excretion is
through the bile into the intestinal tract.
above 12 years old were similar to the doses
used in adults' patients with endogenous Special population
Cushing's syndrome.
Paediatrics
5.2 Pharmacokinetic properties
Based on limited data, pharmacokinetics
Absorption parameters (AUC, Cmax and half-life) of
ketoconazole for doses of 5 to 10 mg/kg/days,
Ketoconazole is a weak dibasic agent and thus
requires acidity for dissolution and absorption. corresponding approximately to daily doses of
200-800 mg, are similar in paediatric and adult
Mean peak plasma concentrations of
population.
approximately 3.5 μg/ml are reached within 1 to
2 hours, following oral administration of a single Renal impairment
200 mg dose taken with a meal.
The pharmacokinetics of ketoconazole were not
Cmax and AUC increase more than significantly different in patients with renal
proportionally with dose. At steady state, mean failure compared to healthy subjects.
peak concentrations of 1.7µg/mL to 15.6µg/mL
were reported for total daily doses of 200mg to Elderly patients
1200mg. No formal evaluation of the effect of age on the
Distribution pharmacokinetics of Ketoconazole has been
performed. There are no data suggesting a need
In vitro, the plasma protein binding is about 99% for a specific dose adjustment in this population.
mainly to the albumin fraction. Ketoconazole is
widely distributed into tissues; however, only a In vitro data indicate that ketoconazole is a
negligible proportion of ketoconazole reaches potent inhibitor of OATP1B1, OATP1B3,
the cerebral-spinal fluid. OAT3, OCT1 and OCT2 and to a lesser extent
of OAT1 and BSEP. Inhibition of these different
Biotransformation
transporters at clinically relevant concentrations juvenile rats for 30 day beginning at 21 days of
of ketoconazole cannot be excluded age delayed the puberty onset. Effects on human
reproduction cannot be excluded.
5.3 Preclinical safety data
Studies in pregnant rats and in guinea pigs
The toxicological profile of ketoconazole has with 3H-ketoconazole indicate that ketoconazole
been established from long term studies in rats crosses the placenta.
and dogs.
6. PHARMACEUTICAL PARTICULARS
Bone fragility and broken legs were reported in
rats but were not observed in other species.
6.1 List of excipients
Consistent with the pharmacological action of Maize starch
ketaconazole, effects were observed on adrenal Lactose monohydrate
and gonads in rats and dogs.
Povidone
Elevated liver enzymes and histological changes
in the liver consisting in dose–related lipofuscin Microcrystalline cellulose
accumulation in hepatocytes were reported in
Silica colloidal
rats and dogs after repeated administration of
ketoconazole. Magnesium stearate
Electrophysiological studies have shown that 6.2 Incompatibilities
ketoconazole inhibits the rapidly activating Not applicable.
component of the cardiac delayed rectifier
potassium current, prolongs the action potential 6.3 Shelf life
duration, and may prolong the QT interval. 3 years.
However no modifications of ECG were 6.4 Special precautions for storage
recorded in dogs at daily doses up to 40 mg/kg This medicinal product does not require any
administered for 12 months. special storage conditions.
Ketoconazole was not genotoxic in vitro and in 6.5 Nature and contents of container
vivo. However, the genotoxic potential was not
properly determined for the proposed dosing PVC/Alu blister of 10 tablets
regimen in the treatment of endogenous Pack sizes containing 6 blisters of 10 tablets.
Cushing's syndrome. Ketoconazole is not
carcinogenic. 6.6 Special precautions for disposal and
other handling
In reproduction studies, ketoconazole impaired
fertility in males and females. Doses of 25 No special requirements for disposal.
mg/kg and higher in male rats and dogs
Any unused medicinal product or waste material
produced sperm abnormalities and decreased
should be disposed of in accordance with local
fertility in rats. Ketoconazole at doses up to 40
requirements.
mg/kg had no effects on female fertility in the
rat, whilst doses of 75 mg/kg and higher 7. MANUFACTURER:
decreased the pregnancy rate and the number of
implantation sites. Doses of 80 and 160 mg/kg
inhibited ovulation in immature rats.
Ketoconazole at doses of 40 mg/kg/day and
higher produces evidence of embryotoxicity and Manufactured in India by:
teratogenicity in rats and rabbits. Observed TAJ PHARMACEUTICALS LTD.
teratogenic effects were mainly skeletal Mumbai, India
anomalies, including cleft palate, brachydactylia, At: 615, GIDC, Kerala, Bavla, Dist. Ahmedabad
ectrodactylia and syndactylia. Treatment of 438225, Gujarat, INDIA
This leaflet was last revised in October 2019

Ketoconazole 200 MG Tablets SMPC - Taj Pharmaceuticals

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Ketoconazole 200 mg tablets SMPC, Taj Phar maceuticals

At treatment initiation, 24-hour urinary free

Oral use. risk of hepatotoxicity and QT interval

periodically thereafter. When urinary Decreased gastric acidity

Co-administration of Ketoconazole and other Enzyme-inducing drugs such as rifampicin,

Ketoconazole is mainly metabolised by Interactions between ketoconazole and other

(increase is indicated as “↑”, decrease as “↓”, an Dronedarone concentration risk of serious

fold edoxaban Potencial ↓ in products on the

Sunitinib Sunitinib Not Busulfan AUC: ↑ 1.4- monitoring.

controls concentration Dose

Cmax ↑ 9.6 Solifenacin metabolite: due to an

have been increased risk Since ketoconazole is excreted in the milk,

Table 2: Incidence of adverse reactions and necrosis, hepatic

ketoconazole are available in the literature along Ketoconazole is extensively metabolised to a

This leaflet was last revised in October 2019

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