The coumarin derivatives acenocoumarol, phenprocoumon and warfarin are vitamin K antagonists (VKAs) indicated for prophylaxis and therapy of thromboembolic diseases. Warfarin is prescribed in North America and in Europe, however, not in the Netherlands. Their anticoagulant effects occur by inhibiting the synthesis of vitamin K–dependent clotting factors II, VII, IX, and X. The international normalized ratio (INR) is a measure to monitor the anticoagulant effect of coumarins. VKAs have a narrow therapeutic range and are well known for their drug interactions which may result in increased or decreased serum levels leading to an increased risk of bleeding or thromboembolic events, respectively.
Noscapine is a non‐narcotic opioid alkaloid derived from the opium poppy Papaver somniferum. It has a central antitussive effect by acting on the sigma opioid receptors.1 Noscapine is indicated for cough and is readily available over the counter (OTC) in several countries. A series of cases of noscapine interacting with warfarin leading to an INR increase have been reported.2, 3 To the best of our knowledge, case reports involving drug interactions between noscapine and acenocoumarol or phenprocoumon have not yet been described in literature.
The Netherlands Pharmacovigilance Centre Lareb received six cases of a drug interaction between acenocoumarol and noscapine and two of noscapine and phenprocoumon. This letter to the editor describes these cases to emphasize the importance of this potential precarious drug‐drug interaction involving the readily available OTC drug noscapine.
Between April 2007 and April 2016, Lareb received eight reports of a possible drug interaction of acenocoumarol and phenprocoumon with noscapine (see Table 1). Six reports concerned acenocoumarol, and two reports concerned phenprocoumon. All patients had been using the coumarin derivatives for months to years and had stable INRs before noscapine was started. After the start of noscapine, patients experienced complaints (INR increase and/or bleeding) after a median of 5 days (with a range from 2 d to 3 wk). Only in case D, a latency of 3 weeks was reported. In cases B, C, G, and H, there was an increase in INR and case D described a dysregulation of the INR. In cases E and F, eye haemorrhage was reported and case A reported haemorrhage (unspecified). Patient F was using ticagrelor (which can also cause bleeding) as concomitant medication. Patient E described that sneezing and blowing her nose may have contributed to the eye haemorrhage. Case B reported an increase in INR to 6.2 with a latency of 6 days, and after cessation of noscapine and temporary withdrawal of acenocoumarol, the INR normalized to 2.9 in 1 week (target INR: 2.5‐3.5). Case H described an increase in INR to 5.7 which normalized after phenprocoumon was withdrawn. Patient G received treatment with vitamin K. The outcome is unknown in cases A and C, and patient E did not recover from eye haemorrhage at the time of reporting. The INR normalized in patients B, D, F, G, and H, and the eye haemorrhage stopped after noscapine was discontinued and the coumarin was temporarily withdrawn in patient F. The Naranjo score4 was rated for each individual case and was found to be probable in four cases and possible in the remaining four cases.
Table 1.
Cases of drug‐drug interactions between acenocoumarol and phenprocoumon with noscapine sent to Lareb
| Patient | Sex, Age, y | Drug, Dose Frequency,a Durationb Indication for Use | Co‐morbidity | Concomitant Medication | Other Reported Adverse Drug Reactions | Time to Onset After Start of Noscapine, Action with Drug(s), Outcome | Naranjo Score (WHO)c |
|---|---|---|---|---|---|---|---|
| A | F, 65 | Phenprocoumon tabl. 3 mg, once a day, indication unknown Noscapine tabl. 15 mg, twice a day, 7 d Indication unknown | COPD, asthma angina pectoris, thromboembolism, renal function disorder | Mesalazine, ezetimibe, ciclesonide, formoterol, salbutamol, paracetamol, atorvastatin, isosorbide mononitrate, glyceryl trinitrate, bumetanide, desloratadine, carvedilol, valsartan, pantoprazole, spironolactone, acetylcysteine, potassium chloride | Haemorrhage | 8 d, phenprocoumon discontinued, noscapine dosage not changed, unknown | 4 |
| B | M, 73 | Acenocoumarol tabl. 1 mg, indication unknown Noscapine tabl. 15 mg, 4 times a day, 6 d Cough | Not reported | Folic acid, metformin, enalapril, simvastatin, hydrochlorothiazide, Plantago ovata | INR increased (6.2) | 6 d, acenocoumarol temporarily withdrawn, noscapine discontinued, recovered within 1 wk | 5 |
| C | F, 38 | Acenocoumarol tabl. 1 mg, indication unknown Noscapine tabl. 15 mg, 1‐3 times per day, 3 d Dry cough | Not reported | Unknown | INR increased | 2 d, acenocoumarol dosage changed, noscapine discontinued, unknown | 4 |
| D | F, 71 | Acenocoumarol tabl. 1 mg, indication unknown Noscapine tabl. 15 mg, 2‐3 times per day, 2 mo Dry cough | Not reported | Hydrochlorothiazide, digoxin, losartan | INR fluctuation | 3 wk, acenocoumarol action unknown, noscapine discontinued, recovered | 5 |
| E | F, 80 | Acenocoumarol tabl. 1 mg, 3 y, indication unknown Noscapine tabl. 15 mg, 4 times a day, unknown Cough | Not reported | Unknown | Eye haemorrhage | 2 d, acenocoumarol discontinued, noscapine action unknown, not recovered | 4 |
| F | M, 75 | Acenocoumarol tabl. 1 mg, once a day, 4.5 y Thrombosis Noscapine tabl. 15 mg, 3 times per day, 4 d Cough | Not reported | Ticagrelor | Eye haemorrhage | 3 d, acenocoumarol dosage not changed, noscapine discontinued, recovered | 4 |
| G | M, 76 | Acenocoumarol tabl. 1 mg, 10.2 y Indication unknown Noscapine syrup 1 mg/mL, 15 mL, 3 times per day, 6 d Cough | Not reported | Salbutamol salmeterol/fluticasone | INR increased | 5 d, acenocoumarol dose reduced, noscapine withdrawn, recovered | 5 |
| H | M, 52 | Phenprocoumon tabl. 3 mg, once a day Indication unknown Noscapine syrup 1 mg/mL, 15 mg, 4 times per day, Unknown Dry cough | Not reported | Unknown | INR increased (5.7) | Unknown, phenprocoumon withdrawn, noscapine dose reduced, recovering | 5 |
Dose frequency is variable for coumarins, especially acenocoumarol (based on the INR goal).
For acenocoumarol and phenprocoumon, the duration in each case is several years (specific number of years is unknown in most cases).
Naranjo Score (WHO): ADR is certain >9; probable 5‐8; possible 1‐4; unlikely 0.
By inhibiting CYP3A4 and CYP2C9, noscapine may increase the effects of some drugs with a narrow therapeutic window, including acenocoumarol, phenprocoumon, and warfarin.5 Warfarin, acenocoumarol, and phenprocoumon exist as two enantiomers which are metabolized by cytochrome P450 (CYP) isoenzymes in the liver. The S‐enantiomers and R‐enantiomers are mainly metabolized by CYP2C9; however, the R‐enantiomers are also metabolized by CYP1A2 and CYP3A4.5, 6
To determine the nature of the drug interaction between noscapine and warfarin, in vitro experiments showed that noscapine inhibits CYP2C9 and CYP3A4 leading to higher warfarin plasma concentrations and an increase in INR.3 Inhibition of warfarin CYP3A4 and CYP2C9 isoenzymes by noscapine may cause the drug interaction.7 Noscapine is a competitive inhibitor of the (S)‐warfarin 7‐hydroxylation reaction by CYP2C9 causing the inactivation of CYP2C9 by noscapine. (S)‐warfarin exposure may increase up to seven times during therapy with noscapine.8 Based on the literature describing noscapine interactions with warfarin, it is likely that the drug interaction between noscapine and acenocoumarol or phenprocoumon occurs in a similar manner.
This case series is the first in contributing to a clinical relevant drug‐drug interaction between acenocoumarol and phenprocoumon with noscapine. Although the drug interaction with coumarins is mentioned in the package leaflet of noscapine, patients may not be aware of the risk. It is important to inform patients taking VKAs that noscapine can interact with them resulting in an INR increase and spontaneous haemorrhage.
1.1. Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY.9 and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18.10
COMPETING INTERESTS
There are no competing interests to declare.
Lokhorst B, Rolfes L, Jessurun NT. Interaction of OTC drug noscapine and acenocoumarol and phenprocoumon. Br J Clin Pharmacol. 2019;85:1041–1043. 10.1111/bcp.13887
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