|Year : 2021 | Volume
| Issue : 1 | Page : 42-48
Drug interactions of ivermectin with a focus on COVID-19 treatment
Padmaja Udaykumar1, Bhavya Shetty1, Anurag Kundapur2
1 Department of Pharmacology, Father Muller Medical College, Mangalore, Karnataka, India
2 Department of Intern, Father Muller Medical College, Mangalore, Karnataka, India
|Date of Submission||21-May-2021|
|Date of Acceptance||16-Jun-2021|
|Date of Web Publication||03-Sep-2021|
Dr. Padmaja Udaykumar
Department of Pharmacology, Father Muller Medical College, Mangalore, Karnataka
Source of Support: None, Conflict of Interest: None
Treatment of COVID-19 largely depends on previously used drugs as there is no cure available coupled with shortage of effective vaccine with doubts about its long-term protection due to rapid viral mutations. Ivermectin, a derivative of avermectin, introduced as an antiparasitic agent, is effective against onchocerciasis, strongyloidiasis, ascariasis, filariasis, scabies, malaria, and has a good safety profile. Ivermectin is being promoted for the treatment of COVID-19, although US Food and Drug Administration has not approved its use for any viral infection. With increasing evidences indicating the efficacy of ivermectin in COVID-19 and post-COVID-19 syndrome, there is a need to focus on the drug interactions with the dose used for indication as most of the documented interactions are with the dose used for parasitic infections. As majority of the COVID-19 patients have comorbidities and on multiple drugs, it is necessary to understand the drug interactions of ivermectin.
Keywords: COVID-19 infection, drug interactions, ivermectin, post-COVID-19 syndrome
|How to cite this article:|
Udaykumar P, Shetty B, Kundapur A. Drug interactions of ivermectin with a focus on COVID-19 treatment. Muller J Med Sci Res 2021;12:42-8
|How to cite this URL:|
Udaykumar P, Shetty B, Kundapur A. Drug interactions of ivermectin with a focus on COVID-19 treatment. Muller J Med Sci Res [serial online] 2021 [cited 2021 Nov 27];12:42-8. Available from: https://www.mjmsr.net/text.asp?2021/12/1/42/325478
| Introduction|| |
The pandemic COVID-19, which terrified the world in 2020 is resurging in the many parts of the world in 2021, expecting to be worse than the previous year. Mutant strains are proving more fatal with higher mortality. As there is no cure available and shortage of effective vaccine with doubts about its long-term protection due to rapid viral mutations, previous drugs will still be tried in the treatment of COVID-19. Ivermectin is one such drug which has shown promising results. It has an advantage of having a stable area under the curve and maximum or peak serum concentration (Cmax ), independent of body weight or body mass index, making suitable for a wider population.
Ivermectin, a derivative of avermectin, introduced as an antiparasitic agent about four~4 decades ago, is effective against onchocerciasis, strongyloidiasis, ascariasis, filariasis, and scabies. It's role in reducing the transmission of malarial parasite has promoted its use as an antimalarial agent. Although it is widely used in veterinary practice, its use as antiparasitic and antimalarial agent in humans is well established with a good safety profile.,,,, Single dose of ivermectin 200 μg/kg, repeated on day 7 in those who continue to be hospitalized, has shown to reduce all-cause mortality in patients with COVID-19. Those with severe disease benefited the most with reduced mortality. Hydroxychloroquine was administered to 90% of patients along with ivermectin. Recommended maximum dose of ivermectin is 200 μg/kg and considered safe even at 10 times the recommended dose., Ivermectin is being promoted for the treatment of COVID-19, although US Food and Drug Administration (US FDA) has not approved its use for any viral infection. US FDA has issued warning in April 2020 against the use of veterinary preparations of ivermectin for COVID-19 in humans.
Mechanism of action of ivermectin against severe acute respiratory syndrome coronavirus 2 (SARS– CoV-2) is unclear. Importin alpha/beta-1 nuclear transport proteins, which are the important factors of intracellular transport processes, are used by the SARS-CoV-2 virus to increase the infection by suppressing the host response toward viral load. It is postulated that ivermectin inhibits these transport proteins, thereby suppressing the infection, which is a host-mediated effect. It also finds a place in the treatment of other viral infections such as Zika, human immunodeficiency virus, and yellow fever.,,, Ivermectin limits viral replication by blocking the entry of viral protein into the cell and it probably helps in breaking the transmission chain, which is much needed at the moment.
Its versatile therapeutic application comes along with caution. It is noteworthy to understand the drug interactions of ivermectin as clinical studies are exploring its use in COVID-19. In an extensive literature search, we found that one of the lesser-known areas in ivermectin use was the drug-interactions. There are few reviews, which focused on antiparasitic effect. Pharmacokinetic interactions of ivermectin with azithromycin and albendazole have indicated that coadministration of these drugs tends to increase the concentration of ivermectin and manifestation of central nervous system (CNS) effects. As azithromycin is being used frequently in COVID-19 patients, a possible interaction with ivermectin can be expected. Ivermectin is effective not only for mild-moderate COVID-19 infection; it is being increasingly used for post-COVID-19 syndrome. Innumerable drug interactions of ivermectin are a limitation to its therapeutic application though not all are clinically relevant. As polypharmacy is common in the treatment of COVID-19, it is required that physicians are aware of drug interactions of ivermectin.
We attempt to revisit these interactions which will be useful for the physicians while treating the patients with COVID-19, multiple comorbidities and on polypharmacy.
| Drug Interactions of Ivermectin|| |
Drug interactions of ivermectin are complex and have to be interpreted after careful evaluation and clinical correlation; there are many mechanisms by which ivermectin interacts with other drugs. Both pharmacokinetic (PK) and pharmacodynamic (PD) interactions have been reported, although latter are less frequent. Most of the reports on its interaction are with the drugs co-administered for the treatment of parasitic infections. Interestingly, PD interactions have been reported to be more frequent among the COVID-19 patients. We have highlighted a few important drug interactions of ivermectin in the following sections.
Synergistic reactions have been reported with doxycycline, nitazoxanide, and hydroxychloroquine sulfate, in combination with ivermectin for COVID-19.
Decrease in the elimination of certain concurrently administered drugs is an important drug interaction reported with ivermectin. Judicial use of ivermectin is advocated in those who have been prescribed cardiovascular drugs as the excretion of drugs such as bosentan, ambrisentan, atrasentan, bempedoic acid, ezetimibe, fimasartan, valsartan, temocapril, digoxin, ouabain is decreased, thereby increasing their serum concentration. In addition, ivermectin also decreases the excretion of hormones (conjugated estrogen, dinoprostone, raloxifene, liothyronine, liotrix, and elagolix), drugs meant to act on gastrointestinal tract (cholecystokinin and cholic acid), bronchodilators (salbutamol) and prostacycline receptor agonist (selexipag), which thereby increases the serum concentrations, calling for mandatory dose adjustments.
Apart from these compounds, elimination of certain commonly used antibiotics (erythromycin, rifampicin, and benzylpenicillin), antiviral (grazoprevir and asunaprevir), endocrine drugs (testosterone, raloxifene, and sincalide), anticancer drugs (gimatecan), antihistamines (fexofenadine), and centrally acting drugs (sumatriptan) is decreased when co-administered with ivermectin. Serum concentration of haloperidol and eluxadoline is reported to increase with ivermectin.
Anticoagulant activity of warfarin, acenocoumarol, dicoumarol, diphenadione, and phenindione is reported to decrease with the concurrent use of ivermectin. Increased toxicity of warfarin also has been reported.
Ivermectin is known to increase the metabolism of many drugs when co-administered.[Figure 1]; Vitamin D, bronchodilators (aminophylline and theophylline), anti-epileptics, antiemetic agents (netupitant and fosapripitant), ergot derivatives (dihydroergocornine, dihydroergocristine, and dihydroergocryptine), glucocorticoids (methylprednisolone), antiviral agents (atazanavir, famciclovir, tenofovir, tenofovir and alafenamide), antibiotics (lefamulin and cephalexin), antihistamines (ebastine), drugs acting on gastrointestinal tract (prucalopride, cisapride, and phenteramine), oral antidiabetic agent (linagliptin) and immunomodulatory drugs (siponimod, sirolimus, tacrolimus, everlimus, methotrexate, and temsirolimus) are reported to undergo increased metabolism in the presence of ivermectin. The therapeutic efficacy of lactulose, Bacille Calmette-Guarin vaccine, typhoid vaccine, and Vibrio cholera CVD103 is reduced when co-administered with ivermectin. [Figure 2] shows the drug interactions of ivermectin resulting in decreased excretion of coadministered drugs, thereby increasing their serum concentration.
|Figure 1: Drug interactions of ivermectin: increased metabolism of co-administered drugs|
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|Figure 2: Drug interactions of ivermectin: Decreased excretion of co-administered drugs resulting in increased serum concentration of the drugs|
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Serum concentration of ivermectin can be increased when combined with the antibiotic-azithromycin, antiviral-ritonavir, metalloproteinase inhibitor- abametapir (a pediculicide), anti-androgen darolutamide. Lasmiditan used for migraine and cardiovascular drug – tafamidis, used for certain types of heart failure.
Concurrent use of cenobamate, pitolisant, venlafaxine, and satralizumab reduces the serum concentration of ivermectin.
Levamisole can increase the bioavailability of ivermectin. Certain anticancer drugs (alectinib, brigatinib, sunitinib, dacomitinib, imatinib, vandetanib, enasidenib, erlotinib, nilotinib, nintedanib, ponatinib, vemufarenib, palbociclib, and venetoclax), immunomodulatory drugs (cyclosporine), antidiabetic drugs (metreleptin), and others such as zafirlukast, amlodipine, and isavuconazole increase the metabolism of ivermectin.
Commonly used statins, fibrates, certain endocrine drugs, antimicrobial agents, antiviral agents (stavudine, lamivudine, zidovudine, raltegravir, ganciclovir, and indinavir), CNS drugs, and drugs acting on the gut can cause increased risk and severity of myopathy, rhabdomyolysis, and myoglobinuria [Figure 3].
|Figure 3: Drug interactions causing increased risk of myopathy, rhabdimyolysis, and myoglobinuria. Hypolipidemic agents-atorvastatin, cerivastatin, fluvastatin, rosuvastatin, lovastatin, mevastatin, pitavastatin, simvastatin, Fibrates including bezafibrrate, ciprofibrate, clofibrate, ronifibrate, simifibrate, etofibrate, gemfibrozil, fenofibric acid, clofibrate, and niacin CNS drugs-Baclofen, methyldopa, propofol, triazolam, tacrine, ethanol, phenytoin, naltrexone, colchicine, penicillamine anticancer agents-cytarabine, cladribine, procarbazine, immunomodulatory agents-leflunomide, mycophenolate mofetil, infliximab RS drugs-Salmeterol, montelukast GI drugs-Nizatidine, ranitidine, cimetidine, metoclopramide, ipecac, and mebeverine. All figures are original, created based on the information from: Ivermectin. Drug Bank. Updated May 07, 2021|
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Although p-glycoprotein facilitates the absorption, metabolism and excretion of ivermectin, it is inhibited by the latter (ivermectin is a substrate and also inhibitor of p-glycoprotein); it is proposed that the drug-interactions of ivermectin are due to effects on p-glycoprotein. Azithromycin is similar to ivermectin, being a substrate but without inhibitory effects on p-glycoprotein. Its co-administration with the drugs (mainly anticancer agents) modify (induce, increase, or inhibit), the effect of p-glycoproteins and hence, needs careful monitoring. Jafari et al. have briefed the interactions of drugs including ivermectin used for COVID-19 with anticancer treatment. Similarly, ivermectin's metabolism in the liver is by CYP3A4 isoenzyme; hence, the drugs that are metabolized by this enzyme can affect the metabolism of ivermectin.
| Ivermectin and COVID-19|| |
It is more than a year that the world is battling the COVID-19 pandemic, which has no specific treatment and with focus only on symptomatic treatment. Although the severity of the disease has decreased over the period, rapid mutation of the virus resulting in emergence of more virulent strains is a major global concern. High mortality in the certain parts of the world and appearance of new waves of infection has driven the physicians to be ready with preventive and treatment strategies.
The inhibitory effect of ivermectin on the cell cultures of SARS-CoV-2 has prompted researchers to try it on human COVID-19 patients, but unfortunately the dose required is ~100 times greater than the recommended therapeutic dose in humans., Systemic drug concentration and drug in lung tissue were significantly lesser than the minimal inhibitory concentration of the drug, raising questions about its effect on the viral load.,,, On a positive note, ivermectin improved olfactory symptoms; its effect on reversing the interleukin 6 (IL-6:IL-10) ratio in lung tissues provides hope to its possible efficacy in controlling the respiratory symptoms.
During the pandemic, when the world was frantically searching for a wonder drug, the positive results on the respiratory symptoms prompted the researchers to carry forward the research on ivermectin. However, it yielded mixed, inconclusive results; from being ineffective,,, to shorter disease resolution time,,,, rapid viral load clearance,, significant reduction in inflammatory markers,, and decrease in mortality rates,, drove the physicians to try it in COVID-19, considering it a wonder drug in the midst of the pandemic. An Indian study has reported that, in comparison to placebo, ivermectin has no significant impact on either negative reverse transcription polymerase chain reaction status or on symptoms, discharge from the hospital, need for more intensive treatment, and assisted ventilation, but had better survival rate. However, sample size of this study is small to make any generalized conclusions. Based on the outcomes from a larger sample size of 600 patients, use of ivermectin early in the disease course has been suggested to minimize the disease complications and better results. As an adjuvant to the standard therapy (azithromycin, vitamin C, zinc, lactoferrin, acetylcysteine, and prophylactic or therapeutic anticoagulation if D-dimer >1000), ivermectin was effective and reduced mortality rate. Data from India on ivermectin as a prophylactic agent are promising.Initial data on ivermectin when used as a component of quadruple therapy (ivermectin, doxycycline, zinc, and Vitamin D3) for preventive and therapeutic effect have been encouraging; A convincing 93% of primary contacts of COVID-19 patients did not develop any symptom on receiving quadruple therapy, while 53% nonrecipient primary contacts were symptomatic. A New York-based study has shown reduced mortality in COVID-19 patients treated with ivermectin in combination with hydroxychloroquine, azithromycin, or both.
Oxford University has taken an initiative to test ivermectin in COVID-19 patients for a proper assessment, based on the reports of these initial clinical studies.
The studies done on humans with COVID-19 infection had limitations (small sample size, poor study design, not defining the outcomes clearly, and no uniform dosage), and therefore, could not strongly document the efficacy of ivermectin in these patients. Its use in pregnant women and lactating mothers is not recommended due to its teratogenic effect, and secretion into breast milk, and not to be prescribed to this subgroup till the safety is established., Its use in the pediatric population is not justified as the data on drug safety are not available, particularly in those weighing <15 kg.
Merck statement on February 11, 2021 has reaffirmed that there is a lack of evidence for the use of ivermectin in COVID-19, thereby putting a question mark over its use. The dose required for a favorable therapeutic outcome in COVID-19 infection is not yet established, which may be much higher than the recommended dose for other indications, raising concern over its safety and efficacy. Despite these limitations, ivermectin can be considered as an option for the treatment of COVID-19 till an effective therapy is introduced, a large majority of population is vaccinated and herd immunity develops.
The World Health Organization has still reservations in recommending ivermectin, the All India Institute of Medical Sciences has included ivermectin (200 μgms/kg, once a day for 3 days) in the treatment of mild-to-moderate COVID-19 infection in treatment guidelines. We recommend studies be conducted in the Indian population with COVID-19 infection for more evidences for its efficacy.
| More Clinical Application|| |
It is important to understand the PK of ivermectin while prescribing it for patients with comorbidities, on polypharmacy and there has to be an increased awareness among the physicians.
We suggest to have a readymade chart displaying the possible drug-interactions in the COVID-19 isolation wards and intensive care units for easy recollection and install drug-interaction checkers applications in the mobiles of the physicians or on the computers in the wards and intensive care units. All supporting staff to be trained to use these applications to identify the drug interactions.
The authors thank Dr M S Latha for editing.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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