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Indo American Journal of Pharmaceutical Research, 2013 Journal home page: http://www.iajpr.com/index.php/en/ 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. www.iajpr.com Page 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. www.iajpr.com Page 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 7141 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 Vol 3, Issue 9, 2013. 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 www.iajpr.com Page 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 7142 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] www.iajpr.com 7143 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. Page 7144 REFERENCES: 1. Rajesh gaddam et.al, drug drug interaction between lovastatin and pioglitazone in rats, indo American journal of pharm research.2013:3(6). 2. Hashimoto H, Toide K, Kitamura R, Fujita M, Tagawa S, Itoh S, Kamataki T, Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control, Eur. J. Biochem. December 1993; 218:2: 585– 95. doi:10.1111/j.1432-1033.1993.tb18412.x. PMID 8269949. 3. Cowen PJ; Green AR, Nutt DJ, Ethyl beta-carboline carboxylate lowers seizure threshold and antagonizes flurazepaminduced sedation in rats, Nature March 1981; 290: 5801: 545.doi:10.1038/290054a0. PMID 6259533. 4. Product Information: KLONOPIN(R) Oral Tablet, KLONOPIN(R) WAFER orally disintegrating tablet, clonazepam oral tablet, orally disintegrating tablet. Roche Laboratories Inc, Nutley, NJ, 2001. 5. Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. Retrieved on December 25, 2008. 6. BoniElewski, Amir Tavakkol. “Safety and tolerability of oral antifungal agents in the treatment of fungal nail disease: a proven reality”.Therapeutics and Clinical Risk Management 2005:1(4) 299–306. 7. Product Information: KLONOPIN(R) TABLETS, KLONOPIN(R) WAFERS oral tablets, orally disintegrating tablets, clonazepam oral tablets, orally disintegrating tablets. Genentech USA, Inc, South San Francisco, CA, 2010. 8. Venkatakrishnan K, von Moltke LL, Greenblatt DJ: Effects of the antifungal agents oxidative drug metabolism: clinical relevance. ClinPharmacokinet 2000; 38:111-180 9. David L. Burrow et.al, “A Fatal Drug Interaction Between Oxycodone and Clonazepam*”, J Forensic Sci, May 2003, Vol. 48, No. 3. 10. Naranjo C.A, Busto U, Seliers E.M. A Method for Estimating the Probability of Adverse Drug Reactions. ClinPharmacolTher 1981; 30(2):239-245. 11. Amer K - Anti-Tuberculosis Drug - Induced Hepatitis – A Case Report, Indian Journal of Pharmacy Practice Volume 6 Issue 2 Apr - Jun, 2013 65. www.iajpr.com 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 Page 7145 Submit your next manuscript to IAJPR and take advantage of: • Access Online first • Double blind peer review policy • No space constraints • Rapid publication • International recognition Submit your manuscript at: [email protected] www.iajpr.com