Clarithromycin is an inhibitor of thecytochrome P450 enzyme CYP3A4, carbamazepine and simvastatin are bothsubstrates of this enzyme (Baxter and Stockley, 2017).
Clarithromycin slowsdown the metabolism of carbamazepine and causes it to accumulate in the body; toxicitycan develop within 1-5 days (Baxter and Stockley, 2017). Clarithromycin alsocauses marketed increase in the concentration of simvastatin which canlead to muscle and livertoxicity (Baxter and Stockley, 2017). Tagline(2000) describes P-glycoprotein as a plasma membrane protein which acts as a trans-membrane pump to remove drugsfrom the cell membrane and cytoplasm. P glycoprotein is inhibited by clarithromycin and the active metabolite of dabigatran is asubstrate of P-glycoprotein so this interaction can result in increased dabigatran plasma concentrations (Baxterand Stockley, 2017). However, however thisinteraction is not deemed to be clinically significant (Baxter andStockley, 2017). Clarithromycin interacts with grapefruitjuice, however this interaction is not harmful as grapefruit juice delays theabsorption of clarithromycin, leaving its bioavailability unaffected (Baxter and Stockley, 2017).Grapefruit inhibits the activity of CYP3A4which metabolises simvastatin and carbamazepine.
Simultaneous grapefruitconsumption with simvastatin can lead to muscle and liver toxicity and concurrentuse with carbamazepine can lead to carbamazepine toxicity (Baxter and Stockley,2017). As well as being a substrate of CYP3A4, carbamazepine is also a potent inducer ofthis enzyme so simvastatin metabolism may be increased and the dose may need tobe subsequently increased (Baxter and Stockley, 2017). As grapefruit inhibitsmetabolism of simvastatin and carbamazepine induces the metabolism ofsimvastatin, there is a possibility that these interactions cancel each otherout but we cannot be sure of this. Carbamazepine is a p-glycoprotein inducer, dabigatranis a substrate of p-glycoprotein so the concurrent use of these drugs mayresult in sub-therapeutic doses of dabigatran (Baxter and Stockley, 2017).
Enoxaparin is a Low Molecular Weight Heparin(LMWH) so its concomitant use with dabigatran is not appropriate for Mr AB asbothmedicines are anticoagulants so concomitant use will increase the risk ofbleeding (European MedicinesAgency (EMEA), 2008). Clarithromycin and carbamazepine interactionClarithromycin should be stopped because it has multipledrug-drug interactions with Mr AB’s current treatment regimen (Baxter andStockley, 2017). Clarithromycin can be switched to doxycycline because it isnot a penicillin antibiotic, it doesn’t react with the rest of the medicationand it is effective in the treatment of pneumonia and other respiratory tractinfections (Baxter and Stockley, 2017; Medicines.org.uk, 2013). Clarithromycin and simvastatin interactionIf the doctor changes clarithromycin to doxycycline, MrAB can have simvastatin (Baxter and Stockley, 2017). Clarithromycin and dabigatran interactionThe interaction between clarithromycin and dabigatran isnot clinically significant and dabigatran doesn’t require any dose adjustment becauseit’s in vivo use has a relatively wide safety window between antithromboticefficacy and side effects such as bleeding (Baxter and Stockley, 2017; EMEA,2008). Clarithromycin andgrapefruit interactionThis is not a harmful interaction, so noaction needs to be taken (Baxter and Stockley, 2017).
Carbamazepine & simvastatin and grapefruitThe doctor and Mr AB should both be advisedthat is best for Mr AB to avoid grapefruit juice because it has clinicallysignificant interactions with carbamazepine and simvastatin, which can lead toharm (Baxter and Stockley, 2017). Carbamazepine and simvastatinAs carbamazepine is an inducer of simvastatin, the doctormay need to increase the dose of simvastatin if Mr AB’s non-HDL cholesterol hasn’t fallen by 40% in 3months (Baxter andStockley, 2017; NICE,2014a). If the doctor increases the dose of the simvastatin, MrAB should be counselled on the increased possibility of developing muscle pain,cramps and weakness which can occur as a result (Medicines.org.uk, 2017c).
Heshould be advised to stop taking his statin and seek medical advice if heexperiences any of these symptoms (Medicines.org.uk,2017c). Carbamazepine and dabigatran and enoxaparinThe doctor should be advised to stopdabigatran and switch it to enoxaparin injection (Baxter and Stockley, 2017). Ifdabigatran is stopped, the current dose of enoxaparin will need to beincreased. The dose of enoxaparin for DVT treatment for this patient is1.5mg/kg once daily which is 70mg (rounded up from 69mg) (BNF, 2017). Theminimum treatment duration for DVT is 3 months (Kearon and Akl, 2014;BNF Online, 2017).
Enoxaparin should be switched to an oral anticoagulantbecause repeated dosing of the injection may cause pain andbruising (BNF Online,2017; Anon, 2017). Although warfarin interacts withcarbamazepine, it seems to be the best choice of oral anticoagulant because itsregular monitoring is more easily available (than factor Xa inhibitors) inorder to ensure that adequate anticoagulation is maintained (Baxter andStockley, 2017). irst episodes of VTE should be treated with an INRtarget of 2Æ5 (1A).• Warfarin used for treatment of VTE should be introducedalong with parenteral anticoagulation (1A) which shouldcontinue for at least 5 d and until the INR is‡2 for atleast 24 h (1C).irst episodes of VTE should be treated with an INRtarget of 2Æ5 (1A).• Warfarin used for treatment of VTE should be introducedalong with parenteral anticoagulation (1A) which shouldcontinue for at least 5 d and until the INR is‡2 for atleast 24 h (1C) The doctor should be advised to refer to thehospital’s anticoagulation guidelines when initiating warfarin for thispatient. Mr AB will need bridging therapy which involves taking both enoxaparin(treatment dose of 70mg) and warfarin tablets for at least 5 days until the INRis within the desired range of 2-3 (Keeling et al, 2011). As Mr AB has a DVT,he should be loaded with warfarin using a rapid regimen but his initial doseshould be 5mg rather than 10mg as he has at least 2 risk factors for bleeding(low weight and age over 60) (Gloucestershire Hospitals, 2015).
Moreover, there is no evidence tosupport the use of a 10mg loading dose over a 5 mg dose (Keeling et al, 2011).The doctor will need to arrange an appointment (shortly after discharge) at anINR monitoring clinic prior to discharge. Priorto discharge, Mr AB will need to be counselled on the use of warfarin andserious side effects which will need medical attention to be sought (NationalPatient Safety Agency (NPSA), 2017). Counselling is usually done by the wardpharmacist using the patient warfarin pack and the hospital’s warfarincounselling checklist such as the one created by Royal Free hospital (2017).The warfarin pack includes: warfarin information booklet, Warfarin alert cardand warfarin INR monitoring book (NPSA, 2017).Claridge et al. (2010) foundthat 4g of paracetamol daily can be hepatotoxic in patients with a lowbodyweight. The BNF (2017)recommends an intravenous dose of 15mg/kg for patient’s who weigh less than50kg.
The current dose of 1g of paracetamol is too high for Mr AB as he weighs46kg. Mr AB should be given 690mg four times daily (BNF, 2017).St John’s Wort is not indicated for difficulty sleeping (MHRA,2017). Mr AB will still be taking warfarin one month after discharge.
St John’s Wort possibly inducesenzymes which metabolise coumarins and this results in an increase inmetabolism and clearance of coumarins so the Committee on Safety of Medicines (CSM) adviseagainst their concurrent use (Baxter and Stockley, 2017). St John’s Wort alsoreduces the lip-lowering effect of simvastatin (Baxter and Stockley, 2017). MrAB should also be counselled by the pharmacist on good sleep hygiene as this isa natural way to manage insomnia (NHS Choices, 2016).