Download respiratory depression due to clonazepam and fluconazole

Indo American Journal of Pharmaceutical Research, 2013
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ISSN NO: 2231-6876
INDO AMERICAN
JOURNAL OF
PHARMACEUTICAL
RESEARCH
RESPIRATORY DEPRESSION DUE TO CLONAZEPAM AND FLUCONAZOLE
INTERACTION: CASE REPORT AND DISCUSSION
MD Amer Khan *1, Nematullah K1, Mohammed Omer1, Aamer K1, Md. Javeedullah1, Md. Nasir1, M.S
Adil1, Maazuddin M1
PharmD, Clinical Pharmacist, Department Of Pharmacy Practice, Owaisi Hospital And Research Deccan School Of Pharmacy
(DSOP) Hyderabad – 500024, Andhra Pradesh
ARTICLE INFO
Article history
Received 04/09/2013
Available online
27/09/2013
Keywords
Drug Interaction, Clonazepam,
Fluconazole, CYP 3A,
Respiratory Depression,
Naranjo’s Scale.
ABSTRACT
This is a case report focusing on a 22 years female patient who experienced respiratory
depression after the concurrent use of clonazepam and fluconazole. Clonazepam is a
benzodiazepine
drug
having
anxiolytic, anticonvulsant, muscle
relaxant, sedative,
and hypnotic properties and is metabolized by CYP3A iso-enzyme. Fluconazole is an
antifungal used in the treatment and prevention of superficial and systemic fungal infections
and is known to inhibit the CYP 3A iso-enzymes. Pharmacokinetic studies have established
that fluconazole inhibits clonazepam metabolism which may lead to toxicity when these two
drugs are given concurrently. One needs to be aware that this drug combination predictably
causes adverse side effects hence, closely monitoring should be done in patient receiving longterm clonazepam therapy. We report a case of respiratory depression induced by the concurrent
administration of clonazepam and fluconazole. Naranjo's causality assessment algorithm was
used to assess the adverse effect and it indicated that concurrent use of clonazepam and
fluconazole as probable cause of respiratory depression. Although information is available
regarding an interaction between clonazepam and fluconazole, there are no large randomized
controlled studies reporting this interaction. This is the first report of clonazepam and
fluconazole interaction causing respiratory depression. Hence further detailed pharmacokinetic
and pharmacogenetic studies are needed before one a truly determine the possible effects of
this interaction.
Copy right © 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Please cite this article in press as M.D Amer Khan et.al. Respiratory depression due to clonazepam and fluconazole interaction:
case report and discussion. Indo American Journal of Pharm Research.2013:3(9).
7140
Corresponding author
Dr. MD Amer Khan
H.NO: 16-8-231, New Malakpet, Hyderabad, Andhra Pradesh, India – 500024,
PH.NO: +919700148228
E-mail: [email protected]
Vol 3, Issue 9, 2013.
M.D Amer Khan et al.
ISSN NO: 2231-6876
INTRODUCTION
Drug-drug interaction is defined as alteration of the effects of one drug by the prior or concomitant or simultaneous administration of
another drug. The concomitant use of multiple drugs, leads to possibility of occurring drug-drug interactions and these interactions
may be severe to cause morbidity & mortality [1].
Cytochrome 3A iso-enzyme, a member of cytochrome P450 mixed-function oxidase system, is one of the most important
enzymes involved in the drug metabolism. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As
a result, CYP3A4 is present in the largest quantity of all the CYPs in the liver.[2]Clonazepam is a benzodiazepine drug having
anxiolytic, anticonvulsant, muscle relaxant, sedative and hypnotic action which is metabolized by CYP3Aiso-enzyme.[3][4]
Fluconazole is an antifungal used in the treatment and prevention of superficial and systemic fungal infections which is known to
inhibit the CYP 3A.[5] It has been well established that inhibition of CYPs by one drug may increase the plasma concentration of
other drug. Thus, inhibition of CYP3A by fluconazole may cause increase in plasma concentration of clonazepam resulting in
increased adeverse drug events and toxicities. In practice, concurrent administration of azole antifungal agents and benzodiazepines
that undergo oxidative metabolism (including alprazolam, chlordiazepoxide, clonazepam, diazepam, estazolam, flurazepam,
halazepam, quazepam, and triazolam) are contraindicated.[6] Respiratory depression has been reported in patients treated with longterm clonazepam for seizure disorders.[7].
The most important problem in assessing an adverse drug reaction lies in establishing a causal relationship between the
untoward event and the drug. Many scales have been used to establish this causal relationship, but the Naranjo adverse drug reaction
probability scale is simple, specific and easy to use. The Naranjo criteria classify the probability that an adverse event is related to
drug therapy based on a list of weighted questions, which examine factors such as the temporal association of drug administration and
event occurrence, alternative causes for the event, drug levels, dose – response relationships and previous patient experience with the
medication. The ADR is assigned to a probability category from the total score as follows: definite if the overall score is 9 or greater,
probable for a score of 5-8, possible for 1-4 and doubtful if the score is 0. The present case reports and evaluates the interaction
between fluconazole and clonazepam as probable cause of respiratory depression.
STUDY SITE AND ETHICS
The study was carried out by clinical pharmacist in respiratory intensive care unit in Princess ESRA hospital situated in Hyderabad, a
group of Owaisi Hospital and Research Centre. Ethical clearance and verbal informed consent were obtained from the Ethics and
Research Committee of the hospital and participant respectively before the commencement of the study.
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The past illness of the patient was:
 History of Tinea Corporis (cracked nipples)
 History of Insomnia and Restlessness.
On further investigation on medical history, it was known that the following medication she was receiving as shown in Table: 1
Table 1: Patients past Medical Condition And History
Sl. No.
Past Medical Condition
Past Medication History
Dose
1.
Insomnia And Restlessness
Clonazepam
2 mg
2.
Tinea Corporis
Pantoprazole
20 mg
Multivitamin Tablet
one
Tab Fluconazole
400 mg
Tab Folic Acid
1500 mcg
Tab Calcium
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CASE REPORT:
A 22 year female was admitted in Princess Esra Hospital, Hyderabad with following complaints:
SOB since 8 days
Fever with chills on and off
Retrosternal right sided chest pain since 8 days
Epi-gastric pain
General weakness
Numbness of tongue with difficulty in speech
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M.D Amer Khan et al.
ISSN NO: 2231-6876
On the 1st day:
The Pulmonologist advised the following investigations and medications (Table: 2)
Complete blood picture
Biochemistry
USG of both breath
TSH test
Sl. No.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10
11.
12.
Drug
Oxygen Inhalation Immediately
Nebulization Ipratropium Bromide +
Salbutamol
Nebulization Budesonide
Tablet Pantoprazole
Tablet Domperidone
Syrup Mucaine Oxethazine + Aluminium
Hydroxide + Magnesium Hydroxide
Tablet Theophylline + Etophylline
Syrup Folic Acid
Normal Saline
Injection Multivitamin Infusion
Tablet Tramadol + Paracetamol
Injection Amoxicillin + Clavulanic Acid
Table 2: Treatment
Dose
2 litres oxygen per min
500mcg / 2.5mg
Route
Inhalation
Nasal
Frequency
whenever necessary
twice a day
40 mg
20 mg
10 ml
Nasal
Oral
Oral
Oral
twice a day
once a day
whenever necessary
thrice a day
150 mg
10 ml
30ml / hour
100 ml NS
37.5 mg + 375 mg
1.2 gm
Oral
Oral
IV
IV
Oral
IV
twice a day
once a day
whenever necessary
over 2 hours
twice a day
once a day
On the 2nd day:
Laboratory examinations (abnormal) revealed is shown in the Table: 3
On the 3rd day:
Shortness of breath decreased
Patient complaints of headache, restlessness and vomiting
Injection ondansetron 4 mg once a day was prescribed
Continue the same regimen
Table 3: Laboratory Values
Sl. No.
Lab Parameter
Lab Value
1.
WBC
11.6 × 103 / Mm3
2.
Platelet
528 × 103 / Mm3
3.
Plasma Drug Concentration Of Clonazepam
1.39 µg/Ml
4.
TSH
3.86 Ml U/L
Normal Value
4 – 10
150 – 500 [11]
0.069 µg/Ml
Upto 3
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On the 5th day:
No fresh complaints were seen
Patient was discharged.
On discharge the patient was appropriately counselled by a clinical pharmacist. The discharge medications included:
 tablet theophylline 150 mg twice daily
 tablet amoxicillin 500 mg twice daily
 tablet pantoprazole 20 mg once daily
 syrup sucralfate 10 ml thrice daily
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On the 4th day:
No episodes of vomiting is seen
Shortness of breath decreased
Continue the same regimen
Vol 3, Issue 9, 2013.
M.D Amer Khan et al.
ISSN NO: 2231-6876
 multivitamin tablet once daily
 The patient was also asked to discontinue clonazepam was switched over other non-benzodiazepine sedative (zolpidem).
The clinical pharmacist team also assessed the suspected adverse drug reactions during the course of the treatment which was
further evaluated and corrected. The following Table: 4 shows the suspected adverse drug reactions using Micromedex drugdex.
Table 4: Suspected Adverse Drug Reaction
2.
Vomiting
3.
Headache
4.
Restlessness
Sl. No.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Suspected Drug
Theophylline
Theophylline
Rabeprazole
Doxofylline
Budesonide
Pantoprazole
Montelukast
Ondansetron
Theophylline
Doxofylline
Onset
Day 3 And Day 4
Lab Parameter
Respiratory Rate: 32/Min
Severity
Severe
Day 3
-
Moderate
Day 3
-
Moderate
Day 3
-
Moderate
Table 5: The Naranjo adverse drug reaction probability scale:
Questionnaire
Yes
No
Are there previous conclusive reports on this reaction?
+1
0
Did the adverse event occur after the suspected drug was
+2
-1
administered?
Did the adverse reaction improve when the drug was discontinued or a
+1
0
specific antagonist was administered?
Did the adverse reaction reappear when the drug was readministered?
Are there alternative causes (other than the drug) that could have on
their own caused the reaction?
Did the reaction reappear when a placebo was given?
Was the blood detected in the blood (or other fluids) in concentrations
known to be toxic?
Was the reaction more severe when the dose was increased or less
severe when the dose was decreased?
Did the patient have a similar reaction to the same or similar drugs in
any previous exposure?
Was the adverse event confirmed by any objective evidence?
Do not know
0
Score
0
0
+2
0
0
+2
-1
0
0
-1
+2
0
+2
-1
+1
0
0
+1
0
0
+1
+1
0
0
0
+1
0
0
0
+1
0
0
Total Score
+1
=6
DISCUSSION:
Fluconazole is primarily known to inhibit the cytochrome P-450 2C iso-enzymes. It may also inhibit CYP3A4 iso-enzymes at high
doses. Venkatakrishnan et.al noted that interactions involving CYP3A4 were of a lesser magnitude and are generally not observed
unless fluconazole doses exceed 200 mg/day.[8] Consistent with this observation, our patient received fluconazole at 400 mg/day
throughout the 15-day course. The normal plasma drug concentration of clonazepam is reported to be 0.069 µg/Ml. [9] However, in
the present case the plasma drug concentration of clonazepam was increased to 1.39 µg/mL resulting in increased toxicity presenting
as respiratory depression. Our observations suggest that elevations in clonazepam serum concentrations can occur with concomitant
fluconazole therapy. Clonazepam is primarily metabolised by CYP3A4 iso-enzymes which may be inhibited when flucanozole is
administered concurrently. Inhibition of clonazepam metabolism is associated with an increase in its plasma drug concentration and
resulting toxicities. However, ours is the first report with elevated clonazepam serum concentrations after fluconazole therapy. Taking
all the information under consideration, a causality assessment of the entitled medical condition was done by using Naranjo Causality
Assessment Algorithm and the results indicated clonazepam and fluconazole as probable cause of respiratory depression with Naranjo
score of 6. [10]
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Suspected ADR
Tachypnoea
Page
Sl. No.
1.
Vol 3, Issue 9, 2013.
M.D Amer Khan et al.
ISSN NO: 2231-6876
CONCLUSION
Although information is available regarding an interaction between clonazepam and fluconazole, there are no large randomized
controlled studies reporting this interaction. This is the first report of clonazepam and fluconazole interaction causing respiratory
depression. Early recognition of this interaction will allow the clinician to ensure safe and effective therapy. Hence further detailed
pharmacokinetic and pharmacogenetic studies are needed before one a truly determine the possible effects of this interaction.
ACKNOWLEDGEMENT
We take this golden opportunity to express our thanks to Dr. S.A Azeez, Principal, Deccan school of pharmacy for providing
necessary facilities, valuable guidance and continuous encouragement. I would like to declare that there is no conflict of interest of
any of the authors of this article.
AUTHOR STATEMENT
There is no conflict of interest of any of the author in this work.
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7144
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Vol 3, Issue 9, 2013.
M.D Amer Khan et al.
ISSN NO: 2231-6876
LIST OF ABBREVIATIONS
CYP- Cytochrome
mg- milligram
mcg/µg- microgram
IV- intravenous
gm- gram
tab- tablet
mm3- cubic millimetre
ml- millimetre
min- minute
NS- normal saline
U/L- units/litre
54878478451001928
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