August 2017 FAQs

What is the role of minocycline in the treatment of multidrug resistant organisms?

Introduction

Minocycline is a second-generation tetracycline and an antibiotic with a broad spectrum of activity against gram-positive, gram-negative, and atypical bacteria.¹ It is widely known as a treatment option for therapeutic indications such as acne vulgaris, lyme disease, skin and soft tissue infections, and certain inflammatory diseases. In recent years, however, there has been growing interest in minocycline as an agent for multidrug resistant (MDR) gram-negative infections.² Traditionally, carbapenems were considered the mainstay of therapy when treating highly resistant organisms, but increasing rates of resistance over the past decade have weakened their efficacy and reduced their clinical utility in some situations. ³ Although carbapenems continue to be invaluable antibiotics for a majority of gram-negative bacteria, other options are undoubtedly needed in the case of “super bugs”, or multidrug resistant organisms (MDRO) that are resistant to 3 or more antibiotics.⁴

Minocycline is an older drug and has been available as an oral formulation since the 1960s.⁵ Intravenous (IV) minocycline was withdrawn from the US market in 2005 given the availability of newer antibiotic options and its diminishing use. In 2009, it was reintroduced to the market as an addition to the limited arsenal of treatment options for increasingly drug-resistant bacteria.³ Minocycline’s brief time away from the market and decline in clinical use has proven to be a benefit. From the time of its withdrawal to the time of its reintroduction, minocycline rates of resistance decreased from 56.5% to 30.5% for a particularly difficult-to-treat species of MDRO, Acinetobacter baumanii.⁶ During this same period, rates of resistance to other broadly used antibiotic classes, including carbapenems and polymixins, more than doubled for this organism. In 2014, the Clinical Infectious Diseases Journal released a special supplement featuring minocycline and its potential for use in multidrug-resistant organisms.² In addition, renewed interest from pharmaceutical companies led to approval of an improved formulation of IV minocycline by the US Food and Drug Administration (FDA) in 2015.^4,7

Pharmacokinetics and Pharmacodynamics

Minocycline has a number of appealing advantages from a pharmacokinetic and pharmacodynamic standpoint. It achieves high serum concentrations compared to tigecycline which may translate into better efficacy for bloodstream infections.⁸ Due to its lipophilic nature, it also achieves good tissue penetration, and has been found to penetrate especially well into lung tissue and mucus.⁹

Per the manufacturer, minocycline does not require hepatic or renal dysfunction dosage adjustments which can be especially useful in a patient population with multiple comorbidities.¹⁰ Unlike others in its class, minocycline is available in both oral and IV formulations and the bioavailability of oral minocycline is very high (~90%), making IV to oral transition extremely feasible.⁷ This transition can lead to cost-savings for hospitals, as oral minocycline is an inexpensive antibiotic.¹

Minocycline is unaffected by some of the mechanisms of resistance that bacteria display against tigecycline.¹¹ Therefore, an organism that is resistant to tigecycline will not necessarily confer resistance to minocycline through the same methods. Previous studies have confirmed this by testing bacterial strains resistant to tigecycline and found that some strains still demonstrated susceptibility to minocycline.^2,12

Minimum inhibitory concentration (MIC) values for minocycline for Acinetobacter species have been established by the Clinical Laboratory Standards Institute. The determined MIC values are as follows: ≤ 4 mcg/mL is susceptible, ≥ 16 mcg/mL is resistant, and values falling in between are intermediate.² Multiple in vitro studies have shown that minocycline is highly active against A. baumanii with generally high susceptibility rates.⁵ A few studies have also explored the in vitro activity of minocycline for carbapenem-resistant Enterobactericae, such as carbapenemase-producing Klebsiella pneumonia (KPC), and found resistance rates ranging from 45 to 71%.^13-15 Minocycline may have lower rates of susceptibility in KPC organisms compared to other first-line antibiotics, but still presents a potential option in those strains that do demonstrate susceptibility. Different hospitals should conduct their own microbiological testing for minocycline when evaluating its place in clinical therapy, as rates of resistance are highly variable based on institution and geographic region.

Review of Literature

Efficacy

To date, 8 studies including 131 patients have examined the role of minocycline in the treatment of MDR infections (Table).^2,8,12,16-20 Most of the published in vivo data on IV minocycline describe its use in the treatment of pneumonia, bloodstream infections, and skin and skin structure infections caused by Acinetobacter sp. Minimal in vivo data are available to support the use of IV minocycline for other multidrug resistant organisms such as carbapenem-resistant K. pneumoniae.⁸ In their retrospective evaluation, Pogue et al examined 3 patients treated with IV minocycline in combination with other agents for KPC-producing K. pneumoniae infections. All 3 patients achieved microbiological cure (eradication of bacteria upon repeat cultures), and 2 out of 3 achieved clinical cure.

Available evidence is limited to case series or retrospective, observational analyses.^2,8,12,16-20 The studies generally utilized the FDA-approved dosing regimen of minocycline 100 mg twice daily, but were inconsistent in terms of formulation (oral or IV) and use of a loading dose. Duration and type of infection were also variable, but most patients had respiratory tract infections with A. baumanii (74.6%).

Overall, minocycline, whether used as monotherapy or in combination with other antibiotics, demonstrated clinical success for A. baumanii infections.^2,8,12,16-20 Clinical improvement, which was defined differently from study to study, ranged from 71.4% to 100% of patients. These results are significant given the severity of these infections and the high risk of mortality. Rates of improvement were similar between the minocycline monotherapy and minocycline in combination therapy groups.² Given the evidence is limited to observational data, the exact role of minocycline in the clinical improvement of these patients is not able to be separated from other antibiotics or confounding factors. This is especially true for clinical studies administering minocycline in combination with other standards of therapy such as carbapenems or colistin. Despite these limitations, the results are promising and provide real-world clinical support of the theoretical pharmacokinetic and pharmacodynamic benefits of minocycline.

Table. Summary of the available literature for the use of minocycline in multidrug resistant infections.^2,8,12,16-20

Safety

Minocycline is generally well tolerated.⁶ Common adverse effects of the drug include nausea, diarrhea, dizziness or lightheadedness. Other class effects including hepatotoxicity, dermatologic reactions, and hypersensitivity are also seen in minocycline.  Griffith et al reported 1 patient who developed eosinophilia and neutropenia while receiving long-term oral minocycline.¹³ Although available studies do not highlight any major safety concerns regarding minocycline use, it is important to note that these studies are largely retrospective in nature and are limited in their ability to assess adverse events through patient chart review.

Unlike many other antibiotics, the package insert for minocycline does not recommend any adjustment for renal or hepatic impairment aside from stating that patients with renal impairment should not exceed 200 mg of minocycline within 24 hours.⁶ Real-world data are limited on whether there is an increased risk of toxicity or adverse effects in patients with decreased renal function. However, minocycline is primarily eliminated via nonrenal routes (~88%), so it is unlikely that renal impairment will result in significantly elevated concentrations of drug.¹⁰ Although acute kidney injury was reported several times in the minocycline literature, these incidences appeared to be attributable to the other nephrotoxic medications patients were taking concomitantly. With regards to other special populations, minocycline should not be used in pregnant women as it is a member of the tetracycline class and may cause congenital defects.⁶

One important distinction for the IV formulation compared with the oral is that the manufacturer added magnesium sulfate to the most recent reformulation of IV minocycline to allow for administration of minocycline in smaller volumes of fluid.⁴ Therefore, patients receiving this medication should be monitored for magnesium intoxication. Particularly, patients with renal impairment risk the accumulation of magnesium that could potentially lead to severe cardiac or neurologic toxicities.

Conclusion

The favorable pharmacokinetic and safety profile of IV minocycline, along with its stability to many bacterial resistance mechanisms, suggests a potential role for minocycline for treatment of serious MDR Acinetobacter infections and other MDRO. The current body of literature supports this clinical practice, but given the low quality of evidence, minocycline should be reserved for situations in which other agents will not be effective or are contraindicated. Further studies evaluating minocycline’s place in therapy are needed to determine whether minocycline should be utilized as monotherapy or combination therapy and to establish efficacy outcomes for other multidrug resistant organisms such as carbapenem-resistant Klebsiella pneumoniae.

References

1. Shankar C, Nabarro LEB, Anandan S, Veeraraghavan B. Minocycline and tigecycline: what is their role in the treatment of carbapenem-resistant gram-negative organisms? Microb Drug Resist. 2017;23(4):437-446.

2. Goff DA, Bauer KA, Mangino JE. Bad bugs need old drugs: a stewardship program's evaluation of minocycline for multidrug-resistant Acinetobacter baumannii infections. Clin Infect Dis. 2014;59(Suppl 6):S381-387.

3. Lashinsky JN, Henig O, Pogue JM, Kaye KS. Minocycline for the treatment of multidrug and extensively drug-resistant A. baumannii: a review. Infect Dis Ther. 2017;6(2):199-211.

4. Bahrami F, Morris DL, Pourgholami MH. Tetracyclines: drugs with huge therapeutic potential. Mini Rev Med Chem. 2012;12:44-52.

5. Greig SL, Scott LJ. Intravenous minocycline: a review in Acinetobacter infections. Drugs. 2016;76(15):1467-1476.

6. Zilberberg MD, Kollef MH, Shorr AF. Secular trends in Acinetobacter baumannii resistance in respiratory and blood stream specimens in the United States, 2003 to 2012: a survey study. J Hosp Med. 2016;11(1):21-26.

7. Minocin [package insert]. Parsippany, NJ: The Medicines Company; 2016.

8. Pogue JM, Neelakanta A, Mynatt RP, Sharma S, Lephart P, Kaye KS. Carbapenem-resistance in gram-negative bacilli and intravenous minocycline: an antimicrobial stewardship approach at the Detroit Medical Center. Clin Infect Dis. 2014;59(Suppl 6):S388-393.

9. Naline E, Sanceaume M, Toty L, Bakdach H, Pays M, Advenier C. Penetration of minocycline into lung tissues. Br J Clin Pharmacol. 1991;32(3):402-404.

10. LexiComp Online [database online]. Hudson, OH: Lexicomp; 2017. http://online.lexi.com/lco/action/home. Accessed June 07, 2017.

11. Colton B, Mcconeghy KW, Schreckenberger PC, Danziger LH. I.V. minocycline revisited for infections caused by multidrug-resistant organisms. Am J Health Syst Pharm. 2016;73(5):279-285.

12. Jankowski C, Joan-Miquel B, Raczkowski M, Pancholi P, Goff D. A stewardship approach to combating multidrug-resistant Acinetobacter baumanii infections with minocycline. Infect Dis Clin Pract. 2012;20;184-187.

13. Livermore DM, Warner M, Mushtaq S, Doumith M, Zhang J, Woodford N. What remains against carbapenem-resistant Enterobacteriaceae? Evaluation of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline. Int J Antimicrob Agents. 2011;37(5):415-419.

14. Veeraraghavan B, Shankar C, Vijayakumar S. Can minocycline be a carbapenem sparing antibiotic? Current evidence. Indian J Med Microbiol. 2016;34(4):513-515.

15. Kmeid JG, Youssef MM, Kanafani ZA, Kanj SS. Combination therapy for Gram-negative bacteria: what is the evidence? Expert Rev Anti Infect Ther. 2013;11(12):1355-1362.

16. Wood GC, Hanes SD, Boucher BA, Croce MA, Fabian TC. Tetracyclines for treating multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia. Intensive Care Med. 2003;29(11):2072-2076.

17. Griffith ME, Yun HC, Horvath LL, Murray CK. Minocycline therapy for traumatic wound infections caused by the multidrug-resistant Acinetobacter baumannii–Acinetobacter calcoaceticus complex. Infect Dis Clin Pract. 2008;16:16-19.

18. Chan JD, Graves JA, Dellit TH. Antimicrobial treatment and clinical outcomes of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. J Intensive Care Med. 2010;25:343-348.

19. Bishburg E, Bishburg K. Minocycline–an old drug for a new century: emphasis on methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii. Int J Antimicrob Agents. 2009;34(5):395-401.

20. Ning F, Shen Y, Chen X, et al. A combination regimen of meropenem, cefoperazone-sulbactam and minocycline for extensive burns with pan-drug resistant Acinetobacter baumannii infection. Chin Med J. 2014;127(6):1177-1179.

Prepared by:
Jasmine Shah, PharmD
PGY2 Drug Information Resident
University of Illinois at Chicago College of Pharmacy
August 2017

The information presented is current as June 23, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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​What evidence supports the use of coenzyme Q10 supplementation to prevent or treat statin-associated myopathy?

Introduction

Statins represent the most widely prescribed and effective therapy for reducing low-density lipoprotein cholesterol and atherosclerotic cardiovascular disease (ASCVD).^1,2 Although statin therapy is normally well-tolerated, statin-associated myopathy (SAM) is common, occurring in up to 5% of patients in randomized controlled trials (RCTs) and reported in up to 33% of patients in clinical practice.^3-5 This adverse event can present a challenge in providing effective primary and secondary preventive care against ASCVD in patients with or at risk for cardiovascular events.^3,4

Statin-associated myopathy, which may include muscle cramps, weakness, or pain, is proposed to be caused by several mechanisms.^3,4,6-8 One involves the primary mode of statin action, inhibition of hydroxymethylglutaryl-coenzyme A. This in turn reduces production of farnesyl pyrophosphate and mevalonate. Both of these compounds are involved in production of coenzyme Q10 (CoQ10), an enzyme present in every cell in the human body that plays an essential role in cellular respiration and mitochondrial synthesis of adenosine triphosphate. Therefore, supplementation has been hypothesized to address this CoQ10 deficiency. The evidence to support the use of CoQ10 supplementation in prevention and treatment of SAM is the focus of this review.

Symptoms and classification of SAM

Statin-associated myopathy can present with diverse clinical symptomatology, including muscle pain, weakness, and cramps. Presentation may range from asymptomatic (although creatine kinase [CK] may be elevated) to severe manifestations such as rhabdomyolysis.^9-11 Effects of SAM are specific to skeletal muscles; damage to the myocardium and smooth muscle have not been reported.⁹ 

While various international organizations have each proposed definitions of SAM, differences remain in diagnosis and classification.^3,10-13 For example, in a statement by the National Lipid Association (NLA) Muscle Safety Expert Panel, “myopathy” represents muscle pain, whereas in a statement by the European Atherosclerosis Society Consensus Panel, myopathy is a general term referring to any muscle-related symptoms, with subgroups divided by the presence or absence of CK elevation.^12,14  The most recent statement by the NLA proposes a clinical index score based on several findings, which can help determine the likelihood of SAM (Table 1).¹³

These variations have also led to uncertainty in the true incidence of SAM. To address this, a recent randomized controlled trial in statin-naïve patients evaluated the incidence of SAM using rigorous study design and outcome definitions, finding incidences of 9.4% vs 4.6% in patients treated with atorvastatin vs placebo, respectively (p = 0.05).³ The presence of SAM in some placebo patients highlights the difficulty in assessing self-reported symptoms.¹³

Risk factors for SAM may be related to the statin and the individual patient. Statin-related factors include high lipophilicity, which may increase diffusion into cells, and statin dose, which may be increased by interacting medications or food (eg, cytochrome P450 [CYP450] 3A4 inhibitors or grapefruit juice).¹⁵ Patient-related factors increasing risk for SAM may include increased exercise, vitamin D deficiency, hypothyroidism, elderly age, and increased alcohol intake.^1,5,16

CoQ10 trials in stain-associated myopathy

The use of CoQ10 in both prevention and treatment of SAM has been investigated. Among the higher-quality evidence (eg, RCTs) available in the body of literature, substantial variability exists in the size of included patient samples, the type of statin evaluated, and the dosage and duration of CoQ10 treatment, which makes comparisons across trials difficult. Nonetheless, findings have generally shown a consistent lack of efficacy of CoQ10 in both settings.

CoQ10 for SAM prevention

Placebo-controlled RCTs evaluating the preventive effect of CoQ10 against SAM have generally not shown significant improvement. For example, a double-blind, placebo-controlled RCT in 44 patients initiating simvastatin 10 to 40 mg daily and CoQ10 200 mg daily showed no significant changes at 12 weeks in visual analogue scale score for myalgia, levels of plasma CK, or proportions of patients tolerating statin therapy.¹⁷ Similarly, a double-blind crossover trial in 38 patients with prior SAM who were receiving 20 mg simvastatin and CoQ10 600 mg daily found no significant differences in changes in mean pain score, muscle strength, or incidence of muscle pain at week 8 compared with placebo.¹⁸ Lastly, an RCT in 49 patients receiving atorvastatin 10 mg daily and CoQ10 100 mg daily found no improvement compared with placebo at week 10 in mean plasma CK levels, adverse events, myalgia, or muscle weakness despite an increase in plasma CoQ10 levels in the intervention group.¹⁹

CoQ10 for SAM treatment

A meta-analysis evaluated the effect of CoQ10 for treatment of SAM using data from 6 placebo- or active-controlled RCTs reporting outcomes of plasma CK levels or muscle pain.²⁰ Overall, no significant improvements were found with CoQ10 treatment in either outcome. These trials, while scoring well on the Jadad scale measuring trial quality, also suffered from small patient samples and variabilities in CoQ10 dosage and treatment duration. Notably, the highest-scoring trial found no significant improvement.²¹ Furthermore, among the two included trials that did report significant improvements with CoQ10 in muscle pain, other important limitations existed. One that used vitamin E as an active control had differences in baseline age, while another that used selenium as an active control had differences in baseline age and pain score, which could confound results.^4,7

Management of statin-associated myopathy

Because CoQ10 supplementation has not been proven to prevent or treat SAM, other management options may be considered. First, the diagnosis of SAM should be ensured to the extent possible.¹³ Because there are no validated diagnostic scales, risk factors, temporal pattern of symptoms, and response to statin dechallenge and rechallenge should be considered, as represented in the NLA’s clinical index score (Table 1).¹³ Future research may validate this scoring system. Laboratory testing (eg, plasma CK) may be performed to rule out rhabdomyolysis. However, definitive testing with muscle biopsy, because of its invasiveness, cost, and risk for false-positive results, should be reserved for more severe cases such as patients with myoglobinuria or myopathic electromyographic tests.

Second, because statin-associated myopathy is proposed to be a dose-dependent effect, potential drug interactions should be addressed.^1,16 Statins primarily metabolized by CYP 3A4 (eg, simvastatin and atorvastatin; Table 2) are more likely to have elevated serum levels when used with strong inhibitors (eg, protease inhibitors, azole antifungals, amiodarone).^2,5

For patients who must continue statin therapy despite symptoms, various strategies to mitigate SAM can be considered. First, if symptoms and/or CK abnormalities resolve after discontinuation, the same statin at a reduced dose may be considered, with upward titration as feasible.¹² Additionally, reduced-frequency administration of statins may be considered, especially those with longer action due to extended half-lives.^2,13,22 This strategy was explored in a meta-analysis of 10 studies, which found that various reduced-frequency regimens of atorvastatin and rosuvastatin allowed most patients to tolerate statin therapy and attain treatment goals without recurrence of treatment-limiting adverse events. Additionally, an alternative statin with lower lipophilicity (eg, pravastatin or rosuvastatin; Table 2) may be selected, as approximately 90% of patients experiencing SAM with one statin were able to tolerate an alternative after 12 months in one study.¹²

Despite the dearth of efficacy supporting the efficacy of CoQ10 in SAM, its benign safety profile may lead to its use in specific patients, including those who require statin treatment but continue experiencing SAM despite attempts to mitigate its occurrence. CoQ10 has a wide therapeutic window and the most common reported side effects are gastrointestinal symptoms, rash, and headache.^8,26 Because it is metabolized in the liver and eliminated via the biliary tract, CoQ10 should be avoided in patients who have severe liver impairment or biliary duct obstruction.²⁷ Caution should be exercised when CoQ10 is administered concomitantly with vitamin K antagonists, which may increase risk of thrombosis.²³

Lastly, although statins are the cholesterol-lowering medications of choice because of their consistent demonstration of risk reduction in cardiovascular events, non-statin lipid-lowering therapy may be considered.^2,12,13,28 Ideally, non-statins options should only be considered after a trial of at least 2 to 3 different statins. Ezetimibe is generally considered a first-line non-statin therapy by American and European guidelines because of its ability to reduce cardiovascular outcomes. Second-line options include bile acid absorption inhibitors, fibrates, or their combination, based on ASCVD risk and comorbidities.^2,12,29 Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors should be reserved for select patients.   

Conclusion

Although current evidence indicates that CoQ10 is not beneficial in the prevention or treatment of SAM, its use may persevere because of its benign safety profile. In patients with suspected SAM, other potential causes should be explored, and management options include modifications to the dosage or type of statin, avoidance of drug interactions, and non-statin therapy in appropriate patients. When CoQ10 is utilized, care should be taken to avoid its use in patients with hepatic impairment, biliary duct obstruction, or interacting medications.

References

1.         Chatzizisis YS, Koskinas KC, Misirli G, Vaklavas C, Hatzitolios A, Giannoglou GD. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf. 2010;33(3):171-187.

2.         Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC Expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016;68(1):92-125.

3.         Saxon DR, Eckel RH. Statin intolerance: A literature review and management strategies. Prog Cardiovasc Dis. 2016;59(2):153-164.

4.         Tan JT, Barry AR. Coenzyme Q10 supplementation in the management of statin-associated myalgia. Am J Health Syst Pharm. 2017;74(11):786-793.

5.         Magni P, Macchi C, Morlotti B, Sirtori CR, Ruscica M. Risk identification and possible countermeasures for muscle adverse effects during statin therapy. Eur J Intern Med. 2015;26(2):82-88.

6.         Wang LW, Jabbour A, Hayward CS, et al. Potential role of coenzyme Q10 in facilitating recovery from statin-induced rhabdomyolysis. Intern Med J. 2015;45(4):451-453.

7.         Banach M, Serban C, Ursoniu S, et al. Statin therapy and plasma coenzyme Q10 concentrations–A systematic review and meta-analysis of placebo-controlled trials. Pharmacol Res. 2015;99:329-336.

8.         Garrido-Maraver J, Cordero MD, Oropesa-Avila M, et al. Coenzyme q10 therapy. Mol Syndromol. 2014;5(3-4):187-197.

9.         Norata GD, Tibolla G, Catapano AL. Statins and skeletal muscles toxicity: from clinical trials to everyday practice. Pharmacol Res. 2014;88:107-113.

10.       Alfirevic A, Neely D, Armitage J, et al. Phenotype standardization for statin-induced myotoxicity. Clin Pharmacol Ther. 2014;96(4):470-476.

11.       Preiss D, Sattar N. Classification of reported statin intolerance. Curr Opin Lipidol. 2015;26(1):65-66.

12.       Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-1022.

13.       Rosenson RS, Baker SK, Jacobson TA, Kopecky SL, Parker BA, The National Lipid Association's Muscle Safety Expert Patel. An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol. 2014;8(3 Suppl):S58-71.

14.       Pasternak RC, Smith SC, Jr., Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI Clinical advisory on the use and safety of statins. Circulation. 2002;106(8):1024-1028.

15.       Pirillo A, Catapano AL. Statin intolerance: diagnosis and remedies. Curr Cardiol Rep. 2015;17(5):27.

16.       Pereda CA, Nishishinya MB. Is there really a relationship between serum vitamin D (25OHD) levels and the musculoskeletal pain associated with statin intake? A systematic review. Reumatol Clin. 2016;12(6):331-335.

17.       Young JM, Florkowski CM, Molyneux SL, et al. Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia. Am J Cardiol. 2007;100(9):1400-1403.

18.       Taylor BA, Lorson L, White CM, Thompson PD. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis. 2015;238(2):329-335.

19.       Mabuchi H, Nohara A, Kobayashi J, et al. Effects of CoQ10 supplementation on plasma lipoprotein lipid, CoQ10 and liver and muscle enzyme levels in hypercholesterolemic patients treated with atorvastatin: a randomized double-blind study. Atherosclerosis. 2007;195(2):e182-189.

20.       Banach M, Serban C, Sahebkar A, et al. Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. Mayo Clin Proc. 2015;90(1):24-34.

21.       Bookstaver DA, Burkhalter NA, Hatzigeorgiou C. Effect of coenzyme Q10 supplementation on statin-induced myalgias. Am J Cardiol. 2012;110(4):526-529.

22.       Keating AJ, Campbell KB, Guyton JR. Intermittent nondaily dosing strategies in patients with previous statin-induced myopathy. Ann Pharmacother. 2013;47(3):398-404.

23.       LexiComp Online [database online]. Hudson, OH: Lexicomp; 2017. http://online.lexi.com/lco/action/home. Accessed June 28, 2017.

24.       Facts and Comparisons eAnswers [database online]. Indianapolis, IN: 2017. http://online.factsandcomparisons.com/index.aspx. Accessed June 28, 2017.

25.       Clinical Pharmacology [database online]. Tampa, FL: 2017. http://clinicalpharmacology.com/. Accessed June 28, 2017.

26.       Hidaka T, Fujii K, Funahashi I, Fukutomi N, Hosoe K. Safety assessment of coenzyme Q10 (CoQ10). BioFactors. 2008;32(1-4):199-208.

27.       Greenberg S, Frishman WH. Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol. 1990;30(7):596-608.

28.       Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889-2934.

29.       Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.

Prepared by:
Vicky (Yu-Hsueh) Wu, PharmD
PGY1 International Pharmacy Resident
University of Illinois at Chicago College of Pharmacy
August 2017

The information presented is current as of June 12, 2017.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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What evidence is available on the use of intravenous sildenafil for pulmonary arterial hypertension?

Introduction

In the United States, the prevalence of pulmonary arterial hypertension (PAH) is 12.4 cases per million adults.^1,2 The World Health Organization (WHO) classifies pulmonary hypertension (PH) into 5 categories, PAH is group 1 (Table 1).³ The etiologies of PAH includes idiopathic, heritable, drug and toxin induced, and PAH associated with connective tissue disease, human immunodeficiency virus, portal hypertension, congenital heart disease, or schistosomiasis.^2,4,5 In PAH, pulmonary vascular remodeling involving the endothelin, nitric oxide, and prostacyclin pathways leads to the narrowing of the small pulmonary arteries because of an increase in endothelial and pulmonary vascular smooth muscle cells.^6,7,8 This causes an increase in blood pressure (BP) within the lungs putting strain on the right ventricle and can ultimately lead to heart failure. Hemodynamically, PAH is defined by a mean pulmonary artery pressure (mPAP) of ≥ 25 mmHg at rest, a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and a pulmonary vascular resistance (PVR) ≥ 3 Wood units.⁴ The signs and symptoms of PAH include hypoxia, dyspnea, decreased exercise tolerance, edema, hypotension, and heart failure.⁹ Since PAH is a progressive disease, the overall prognosis is poor.¹⁰

Phosphodiesterase-5 enzyme (PDE-5) inhibitors target the nitric oxide pathway to promote vasodilation by increasing the level of cyclic guanosine monophosphate (cGMP).⁷ Since PDE-5 is the major isoform of phosphodiesterase found in the lungs, its inhibition can reduce the pulmonary arterial pressure.^11,12 Sildenafil, a PDE-5 inhibitor, was first approved by the Food and Drug Administration (FDA) in 2005 as an oral formulation.⁶ The intravenous (IV) formulation was FDA-approved in 2009 for patients with PAH on continuous oral sildenafil who are temporarily unable to take sildenafil by mouth during hospitalization.^12,13 The approved sildenafil IV dose is 10 mg three times daily, which corresponds to the oral formulation dose of 20 mg three times daily.

Table 1. World Health Organization Classification of Pulmonary Hypertension.³

Several clinical guidelines provide recommendations on the use of sildenafil in patients with PAH, but do not specifically address the use of IV formulation. For example, the CHEST guidelines recommend endothelin receptor antagonists (ERA), PDE-5 inhibitor, or riociguat monotherapy for treatment-naïve patients who cannot take or failed calcium channel blocker therapy.⁸ Sildenafil can also be added to epoprostenol in patients with WHO Functional Class III or IV (Table 2) to improve the 6-minute walk distant (6MWD) test. An expert consensus on PH states that PDE-5 inhibitors may enhance or prolong vasodilator effects in patients with PH.¹⁴ The American Heart Association/American Thoracic Society (AHA/ATS) guideline on pediatric PH recommends oral therapy with either a PDE-5 inhibitor or an ERA in children with lower-risk PAH.¹⁵

Table 2. World Health Organization Functional Classification of PAH.⁹

Literature Summary

The approval for the IV sildenafil was based on the pharmacokinetic modeling of the oral formulation already on the market.¹⁶ The number of studies evaluating IV sildenafil for temporary short-term use during hospitalization in patients with PAH on continuous oral sildenafil is very limited because the sample size in rare diseases, such as PAH, tends to be small. Studies in patients unable to take oral sildenafil in the perioperative setting have been published in both the adult and pediatric populations, but are also limited by small sample sizes.

Adult Studies

PAH (WHO Group 1) and PH (undefined group)

Studies show that sildenafil IV is comparable to oral sildenafil. Vachiery et al. evaluated the use of a single sildenafil IV 10 mg dose in 10 patients with PAH on continuous sildenafil 20 mg by mouth three times daily in a single center, open-label study.¹⁷ All patients, except for 2 patients, were on background therapy with oral bosentan and 1 patient was also on treprostinil. The study found that sildenafil IV 10 mg was safe and tolerable, and maintained plasma levels similar to oral sildenafil 20 mg. Mikhail et al. evaluated the administration of sildenafil IV with titration followed by a switch to oral sildenafil 25 mg titrated to 50 mg in 10 patients with PH in a single center, open-label study.¹⁰ The authors found that sildenafil IV was safe and well tolerated in patients with PH. 

Surgery and PH

A retrospective study by Bonet et al. evaluated the use of sildenafil IV 10 mg every 8 hours administered for 48 hours then switched to oral sildenafil 20 mg three time daily in 5 patients with right ventricular dysfunction and PH after a heart transplant.¹⁸ A decrease in mPAP was observed 24 to 48 hours post-transplant in all patients, the hospital stay ranged from 3 to 25 days, and no deaths were reported. A prospective single site study by Suntharalingam et al. studied sildenafil IV doses equivalent to 25 mg and 50 mg of oral sildenafil following inhaled nitric oxide (iNO) treatment in 18 patients, 9 with de novo distal chronic thromboembolic pulmonary hypertension (CTEPH) and 9 with persistent PH more than 3 months post-pulmonary endarterectomy (PEA).¹⁹ Both doses led to significant decreases in mPAP. The only adverse effect reported was flushing secondary to peripheral vasodilation.

Pediatric Studies

PAH (WHO Group 1) and PH (undefined group)

Persistent pulmonary hypertension of the newborn (PPHN) is a subcategory of group 1 PAH.² A open-label, multi-center, dose-escalation study by Steinhorn et al. in 36 neonates with PPHN or hypoxemic respiratory failure associated with PPHN divided patients into 8 dosing groups with escalating loading and maintenance doses of sildenafil IV per group, except 1 group which did not receive a loading dose.²⁰ Treatment with iNO was allowed, and sildenafil IV could be discontinued at any time after 48 hours of administration. The authors stated that BP and heart rate did not change significantly during treatment (p-value not provided). Patients with an initial sildenafil concentration of 58.4 ± 44.8 ng/mL showed significant improvement in oxygenation index (OI), which assesses the need for ventilator support or ECMO therapy, after 4 hours of sildenafil infusion (p=0.0002).^2,20 Six patients experienced treatment-related adverse events that were mild to moderate in severity, 4 patients discontinued treatment, and 1 patient died.

Darland et al. conducted a observational matched-cohort safety study comparing sildenafil IV to oral sildenafil in 40 patients less than 1 year of age with PH.²¹ The primary outcome was the occurrence of hypotension. There was no difference between the IV and oral formulations in the occurrence of hypotension (6 vs. 2; p=0.24) or other secondary outcomes looking at flushing, intensive care unit (ICU) length of stay, or mortality. A retrospective chart review by Fender et al. evaluated the tolerability of intermittently dosed sildenafil IV in 37 patients less than 18 years of age who received at least 1 dose of sildenafil IV for the treatment of PH.²² Approximately more than 50% of patients were on oral sildenafil at baseline. The sildenafil IV dose was administered at half of the oral dose with the same frequency. For patients not on sildenafil, the dose was 0.25 mg/kg every 6 to 8 hours. Approximately 37% of patients were also on iNO when sildenafil IV was initiated. The study found a significant decrease in mean systolic blood pressure (SBP) (p=0.0045), but no change in DBP or heart rate. Four patients experienced hypotension and 1 or more doses of sildenafil IV were held.   

Two case series evaluated sildenafil IV in infants with PH. Stultz et al. looked at 3 infants, 1 with PH with bronchopulmonary dysplasia and 2 infants with continued PH after congenital diaphragmatic hernia (CDH).²³ All infants had a NPO, 'nothing by mouth’, status and received intermittent sildenafil IV in doses ranging from 0.4 to 2 mg/kg every 6 hours infused over 1 to 3 hours with a duration ranging from 5 to 50 days.  The BP varied during the initial dose. The fraction of inspired oxygen (FiO2) requirements decreased or remained stable during the first dose then decreased over time with an improvement in oxygenation. Steiner et al. looked at 6 critically ill pre-term infants with refractory PH who received a sildenafil IV loading dose of 0.1 mg/kg over 45 minutes and a maintenance dose of 0.5 to 1.2 mg/kg/day via a continuous infusion following an inadequate response to milrinone and iNO.²⁴ The OI decreased after the initiation of sildenafil IV, and the mean arterial BP trended downwards. A total of 4 patients died, of which 2 patients died from PH. Two patients developed pulmonary hemorrhage but survived.  

Surgery and PH

Inhaled nitric oxide is used for the management of PH associated with surgery.²⁵ The disadvantage of iNO is rebound PH. Other drugs used for this indication include epoprostenol, bosentan, and milrinone. Studies evaluating the use of sildenafil in patients with congenital heart disease requiring cardiac surgery for the management of PH mostly use the oral formulation and only a few studies have assessed sildenafil IV.^25-28 Two randomized placebo-controlled studies were conducted with sildenafil IV.^25,28 In 2015, Sharma et al. published a randomized placebo-controlled study in 46 patients with PH and congenital heart disease (CHD) undergoing cardiac surgery who received 2 doses of oral sildenafil pre-operatively, then continuous infusion with sildenafil IV for 24 hours, followed by a transition back to oral sildenafil.²⁵ The study found that more patients in the sildenafil group had an improved partial pressure arterial oxygen (PaO₂)-FiO₂ ratio, earlier extubation, and a shorter ICU stay. A dose-ranging study by Fraisse et al. in infant and children patients with PH post-cardiac surgery was inconclusive in determining efficacy and an appropriate sildenafil IV dose since it was terminated early due to difficulty in enrolling patients.²⁸ Two other interventional studies looked at sildenafil IV, the first study was sildenafil in combination with iNO, and the second study administered sildenafil in a stepwise infusion before or after iNO in patients with CHD post-cardiac surgery.^26,27 Sildenafil in combination with iNO was shown to enhance the effects of iNO, but also caused hypotension.²⁶ Sildenafil administered in a stepwise infusion with iNO showed that sildenafil IV may be as effective as iNO. 

A retrospective study by Bialkowski et al. looked at 9 infants with CDH who received continuous sildenafil IV infusion (dose range, 100 to 290 mcg/kg/h) for the treatment of PAH with cardiac dysfunction after surgery.²⁹ The results showed that at 24 to 48 hours and 72 to 96 hours after receiving sildenafil IV, OI was significantly lower compared to before the administration of sildenafil. In addition, there was no significant change in mean arterial BP. However, three infants died before discharge.

Summary

Studies evaluating the use of sildenafil IV in patients with PAH on continuous oral sildenafil therapy who require a brief interruption of treatment due to hospitalization necessitating the use of sildenafil IV is very limited, as are studies demonstrating a switch from the IV to oral formulations.¹⁷ Although sildenafil IV is only approved for PAH, well-designed studies evaluating the off-label use of sildenafil for other types of PH in patients who are unable to take oral sildenafil, such as in the perioperative setting, are also limited.^18,19,25-29 The available studies show that sildenafil IV can be used those for patients who are unable to take oral sildenafil, but more research is required to determine the clinical outcomes. The study limitations for the use of sildenafil IV are the small number of patients with PAH, and its intended short-term use to bridge therapy to oral sildenafil.

References

1.         Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how REVEAL differs from historic and non-US Contemporary Registries. Chest. 2011;139(1):128-137.

2.         Dynamed [database online]. Ipswich, MA: EBSCO Information Services; 2017. http://www.dynamed.com. Accessed June 9, 2017.

3.         Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34-D41.

4.         Bazan IS, Fares WH. Pulmonary hypertension: diagnostic and therapeutic challenges. Ther Clin Risk Manag. 2015;11:1221-1233.

5.         Lau EM, Giannoulatou E, Celermajer DS, Humbert M. Epidemiology and treatment of pulmonary arterial hypertension [published online ahead of print June 8, 2017]. Nat Rev Cardiol. doi: 10.1038/nrcardio.2017.84.

6.         Kanwar MK, Thenappan T, Vachiéry JL. Update in treatment options in pulmonary hypertension [published online ahead of print January 16, 2016]. J Heart Lung Transplant. doi: 10.1016/j.healun.2016.01.020.

7.         Hoeper MM, McLaughlin VV, Dalaan AM, Satoh T, Galiè N. Treatment of pulmonary hypertension. Lancet Respir Med. 2016;4(4):323-336.

8.         Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest. 2014;146(2):449-475.

9.         Moote R, Attridge RL, Levine DJ. Pulmonary arterial hypertension. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York, NY: McGraw-Hill; 2017. http://www.accesspharmacy.com. Accessed June 20, 2017.

10.       Mikhail GW, Prasad SK, Li W, et al. Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute and mid-term effects. Eur Heart J. 2004;25(5):431-436.

11.       Sanchez LS, de la Monte SM, Filippov G, Jones RC, Zapol WM, Bloch KD. Cyclic-GMP-binding, cyclic-GMP-specific phosphodiesterase (PDE5) gene expression is regulated during rat pulmonary development. Pediatr Res. 1998;43(2):163-168.

12.       Revatio [package insert]. Windsor, NJ: AuroMedics Pharma LLC; 2017.

13.       Clinical Pharmacology [database online]. Tampa, FL: Elsevier; 2017. http://www.clinicalpharmacology.com. Accessed June 9, 2017.

14.       McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53(17):1573-1619.

15.       Abman SH, Hansmann G, Archer SL, et al. Pediatric Pulmonary Hypertension: Guidelines from the American Heart Association and American Thoracic Society. Circulation. 2015;132(21):2037-2099.

16.       Drug Approval Package. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022473_revatio_toc.cfm. Published February 18, 2010. Accessed June 9, 2017.

17.       Vachiery JL, Huez S, Gillies H, et al. Safety, tolerability and pharmacokinetics of an intravenous bolus of sildenafil in patients with pulmonary arterial hypertension. Br J Clin Pharmacol. 2011;71(2):289-292.

18.       Bonet LA, Guillén RV, Lázaro IS, et al. Intravenous sildenafil in right ventricular dysfunction with pulmonary hypertension following a heart transplant. Heart Int. 2014;9(1):22-25.

19.       Suntharalingam J, Hughes RJ, Goldsmith K, et al. Acute haemodynamic responses to inhaled nitric oxide and intravenous sildenafil in distal chronic thromboembolic pulmonary hypertension (CTEPH). Vascul Pharmacol. 2007;46(6):449-455.

20.       Steinhorn RH, Kinsella JP, Pierce C, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr. 2009;155(6):841-847.

21.       Darland LK, Dinh KL, Kim S, et al. Evaluating the safety of intermittent intravenous sildenafil in infants with pulmonary hypertension. Pediatr Pulmonol. 2017;52(2):232-237.

22.       Fender RA, Hasselman TE, Wang Y, Harthan AA. Evaluation of the tolerability of intermittent intravenous sildenafil in pediatric patients with pulmonary hypertension. J Pediatr Pharmacol Ther. 2016;21(5):419-425.

23.       Stultz JS, Puthoff T, Backes C, Nahata MC. Intermittent intravenous sildenafil for pulmonary hypertension management in neonates and infants. Am J Health Syst Pharm. 2013;70(5):407-413.

24.       Steiner M, Salzer U, Baumgartner S, et al. Intravenous sildenafil i.v. as rescue treatment for refractory pulmonary hypertension in extremely preterm infants. Klin Padiatr. 2014;226(4):211-215.

25.       Sharma VK, Joshi S, Joshi A, Kumar G, Arora H, Garg A. Does intravenous sildenafil clinically ameliorate pulmonary hypertension during perioperative management of congenital heart diseases in children? A prospective randomized study. Ann Card Anaesth. 2015;18(4):510-516.

26.       Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS. Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery. Intensive Care Med. 2003;29(11):1996-2003.

27.       Schulze-Neick I, Hartenstein P, Li J, et al. Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation. 2003;108(Suppl 1):167-173.

28.       Fraisse A, Butrous G, Taylor MB, Oakes M, Dilleen M, Wessel DL. Intravenous sildenafil for postoperative pulmonary hypertension in children with congenital heart disease. Intensive Care Med. 2011;37(3):502-509.

29.       Bialkowski A, Moenkemeyer F, Patel N. Intravenous sildenafil in the management of pulmonary hypertension associated with congenital diaphragmatic hernia. Eur J Pediatr Surg. 2015;25(2):171-176.

Prepared by:
Vicky (Yu-Hsueh) Wu, PharmD
PGY1 International Pharmacy Resident
University of Illinois at Chicago College of Pharmacy
Revised by: Yesha Patel, PharmD, BCPS
August 2017

The information presented is current as of July 18, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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