An Evidence-Based Look at Off-Label Drug Use

According to the U.S. Centers for Disease Control and Prevention, the average American’s life expectancy is 78.8 years.¹ While advances in medicine have allowed individuals to live longer, an increase in age is also connected to coexisting chronic conditions requiring multifaceted, individualized care.² Pharmacological treatment of patients with multiple chronic conditions has led to an increase in the use of drugs for purposes not approved by the U.S. Food and Drug Administration (FDA). Based on a literature review, this paper will provide an update on “off-label” drug use — and the implications for oral health care.

With current increases in polypharmacy and the number of drugs on the market, the identification of off-label drug uses has become common. Drug manufacturers benefit due to increased opportunities for the use of their drugs. Additionally, clinicians have more options to provide effective treatments for patients. For example, amoxicillin — approved by the FDA for treating respiratory tract infections — has been shown to be effective in treating stomach ulcers. Textbooks and medical guides discuss amoxicillin as a potential treatment of stomach ulcers, despite the fact that FDA phase II and III trials have not been completed for that use.³

Literature discussing common prescribing practices is limited, leaving a significant gap in evidence-based knowledge. Strom et al⁴ report that 31 of the 100 most common uses of marketed medications were for indications not initially approved by the FDA. In an effort to estimate the magnitude of off-label use and whether these uses were supported by scientific evidence, a data analysis of the National Disease and Therapeutic Index showed cardiac medications, anticonvulsants and anti-asthmatics were commonly prescribed for indications not approved by the FDA.⁵ As an example, albuterol sulfate, an FDA-approved anti-asthmatic, is used off-label for treating chronic obstructive pulmonary disorder due to the physiologic similarities between these two conditions.⁵ Gabapentin online, an FDA-approved anticonvulsant, is frequently used off-label to treat chronic nonspecific pain. The analysis also showed the biggest disparity between scientifically supported and unsupported use occurred among psychiatric and allergy therapies. In fact, data demonstrated that evidence of clinical efficacy is sparse among the medications with the highest proportion of off-label use. For example, gabapentin was only scientifically supported in 20% of its off-label uses, while the other 80% had limited or no scientific support for off-label use.⁵

Pediatrics is one area where off-label therapies are frequently prescribed. Due to practical and ethical considerations, clinical trials involving children are rare due to this population’s increased risk of adverse drug reactions.⁶ Bazzano et al⁷ analyzed data from the 2001–2004 National Ambulatory Medical Care Surveys and found that in 7901 outpatient visits of children ages 0 to 17, 2% of visits utilized off-label drug therapy. Of these prescriptions, 90% of the cardiovascular-renal medications, 80% of pain and gastrointestinal medications, 75% of pulmonary and dermatologic medications, and 42% of anti-infective uses were considered off-label.

Similar to pediatric populations, pregnant women are also typically excluded from clinical trials due to practical and ethical considerations, yet off-label drug use is prevalent in this group. Herring et al⁸ analyzed 17,694 prescriptions written for expectant mothers. The results revealed 84% of these prescriptions were for off-label or unlicensed indications. Additionally, 59% of these off-label drugs carried cautions or specific contraindications for use in pregnancy, and 16% were considered high risk.

Second-generation antipsychotic drugs are often prescribed for the treatment of dementia. Kamble et al⁹ conducted a study using cross-sectional data from the 2004 National Nursing Home Survey consisting of 1,317,205 elderly patients. Among these subjects, 23.5% had received at least one second-generation antipsychotic prescription, and 86.3% of these prescriptions were for off-label indications. Regardless of age, patients with psychiatric disorders are frequently prescribed drugs for off-label indications because this population is often excluded from clinical trials.¹⁰

Off-label drug therapy has become a standard of care in oncology and human immunodeficiency (HIV) disease treatment.¹¹ Most off-label drugs associated with HIV patients are related to opportunistic infections.¹¹ Oncology often relies on research report publications for off-label therapy recommendations; but there is typically a lag between when the research is conducted and its publication, so many relevant off-label therapies might be excluded from such publications.¹¹ A study by the U.S. General Accounting Office found that 56% of cancer patients were treated with at least one off-label drug therapy.¹¹

LACK OF SPECIFICITY

While the previously mentioned studies provide some insight into off-label prescriptions, a limitation in the literature is the lack of specificity in regard to the drugs being prescribed, and how they are being used off-label. Unfortunately, the information in these studies does not capture a true sense of what is really occurring. This lack of information presents challenges to oral health professionals, inasmuch that it may compromise the ability to modify treatment based on possible adverse effects of off-label uses.

Adverse reactions are a risk of off-label drug therapy among the pediatric population, but controversy remains over whether this is relative to the risk associated with FDA-approved uses. Commonly prescribed medications have received black box warnings after adverse reactions were documented in children. For example, the antidepressants paroxetine and citalopram contain warnings of suicide in children, while cisapride (used for gastric motility) has been linked to life-threatening arrhythmias.⁷

Aspirin, an FDA-approved analgesic, is commonly used to prevent cardiovascular problems due to its antiplatelet properties. Physician-recommended, long-term, low-dose aspirin therapy could be used as a primary or secondary prevention measure, although it is associated with upper gastrointestinal bleeding.¹² A nested, case-control study using The Health Improvement Network database identified 2049 cases of upper gastrointestinal bleeding and an additional 20,000 controls.¹² This research showed the relative risk for upper gastrointestinal bleeding in patients taking low-dose aspirin therapies was higher for primary cardiovascular disease prevention than secondary cardiovascular disease prevention.¹²

WHAT CLINICIANS CAN DO

To ensure patient safety, oral health providers should inquire about medications and conditions for which they are used, particularly when off-label use is suspected. Clinicians should thoroughly evaluate each patient’s medical history to reduce the risk of emergencies in the dental office, and monitor the patient for signs of possible adverse reactions when using off-label drug therapies.¹³ Drugs utilized in the dental office should also be evaluated for possible drug interactions with the patient’s off-label medications.¹³

As noted earlier, studies examining off-label prescribing practices and populations were not specific in describing the drugs and their uses; therefore, some of the drugs mentioned in these studies were cross-referenced with Lexicomp Online. This is a pharmacy, oral care and allied health database that contains drug information and educational resources. Oral care professionals, for example, may see patients using off-label indications for cardiac medications, anticonvulsants and anti-asthmatics. Expanded knowledge related to these common medications and off-label uses could help clinicians prevent medical emergencies and provide the safest care possible.

By way of example, digoxin, a cardiac glycoside approved for the treatment of heart failure and atrial fibrillation, can be used off-label for fetal tachycardia when administered to pregnant women. Digoxin has a narrow therapeutic index, therefore, its use should be monitored closely, as there is a high risk for adverse reactions and drug interactions (e.g., vasoconstrictors should be used with caution). Patients using digoxin may have a sensitive gag reflex, and elderly patients are at an increased risk for adverse reactions.

Labetalol is an antihypertensive beta-blocker that is FDA approved for treating hypertension in individuals age 18 and older. Vasoconstrictors must be used with caution in patients taking labetalol, and taste perversion may be noted. Off-label, labetalol is used to treat pregnant women in the acute onset of severe hypertension with preeclampsia or eclampsia. The calcium channel blocker nifedipine is also used off-label in pregnant women. Nifedipine is FDA approved for treating hypertension and managing angina in individuals age 18 and older, yet it has been used off-label in pregnant patients in hypertensive emergencies and to prolong pregnancy when preterm labor occurs. Additionally, this drug is used off-label for treating Raynaud’s syndrome, a vascular disorder of the extremities. Oral health considerations include gingival enlargement; in addition, elderly patients may potentially experience greater hypotensive effects.

Gabapentin is perhaps the most common FDA-approved anticonvulsant. Since increasing in popularity for off-label use, gabapentin has also been FDA approved for treating post-herpetic neuralgia in adults. Off-label uses include treating brachioradial pruritus, chronic cough, diabetic neuropathy, fibromyalgia syndrome, hot flashes, restless leg syndrome, social anxiety disorder, uremic pruritus, and neuropathic or postoperative pain. Its oral health implications include xerostomia, dry throat and dental abnormalities. Children taking gabapentin might experience central nervous system effects, such as changes in behavior or thinking and emotional lability.

Carbamazepine is another FDA anticonvulsant. Also approved to treat trigeminal neuralgia, it has been used off-label for treating restless leg syndrome in adults. Xerostomia is a dental implication, and clinicians should watch for latent psychosis, confusion or agitation in elderly patients utilizing this drug. In pediatric use, the exacerbation of certain seizure types in children with mixed seizure disorders can occur.

Valproate is an anticonvulsant that is also FDA approved for the treatment of mania associated with bipolar disorder and migraine prophylaxis. Off-label, valoproate is used for treating borderline personality disorder, diabetic neuropathy, post-herpetic neuralgia, and status epilepticus in children and adults. Children under 2 can be at risk for fatal hepatoxicity, and elderly patients may experience an increase in dehydration and sedating effects. Oral health implications include periodontal abscess and taste perversion.

Second-generation antipsychotics, such as risperidone, olanzapine and quetiapine, are FDA approved for treating schizophrenia and bipolar mania, but are also used off-label to treat psychosis and agitation associated with dementia in elderly patients. These drugs carry a warning stating studies have shown elderly patients with dementia-related psychosis treated with antipsychotics face an increased risk of death compared with control groups. Risperidone is also used off-label for post-traumatic stress disorder (PTSD), major depressive disorder and Tourette’s syndrome. Olanzapine is used off-label for chemotherapy-related nausea and vomiting, delirium, PTSD and Tourette’s. Quetiapine is used off-label for treating obsessive-compulsive disorder, delirium in critically ill patients, generalized anxiety disorder, PTSD, and psychosis in patients with Parkinson’s disease. Risperidone and quetiapine both require caution with the use of vasoconstrictors and may cause xerostomia.

OFF-LABEL USE IN DENTAL PRACTICE

In clinical practice, oral health professionals not only see patients who use drugs for off-label medical purposes, dental providers also employ drugs and medical devices for off-label indications. Clinicians should be aware of these off-label uses in order make the best evidence-based decision when providing treatment. For example, dental paste products containing casein phosphopeptide and amorphous calcium phosphate have been used off-label for treating xerostomia, Sjögrens syndrome, and penetrating and remineralizing subsurface lesions.¹⁴ In addition, FDA approval is granted as an adjunct to professional prophylaxis procedures, as well as for treating dentinal hypersensitivity and tooth hypersensitivity during dental procedures.¹⁴

Fluoride varnishes are used in the dental offices for multiple indications, including anti-caries treatment. The FDA-approved indications for fluoride varnish include treatment of hypersensitivity, sealing of dentinal tubules for cavity preparations or on sensitive root surfaces, and as a cavity liner.¹⁵ While the use of fluoride varnish is not FDA approved for caries prevention, there are benefits to its use for this purpose over that of fluoride foam.

Similarly, silver diamine fluoride (SDF) was cleared by the FDA for treating dentinal hypersensitivity, and had been used off-label for arresting caries. In late 2016, the FDA granted SDF its “Breakthrough Therapy Designation” for arresting caries in pediatric and adult populations. This designation expedites the review of drugs for which preliminary clinical evidence indicates they may demonstrate substantial improvement over existing therapies.

OnabotulinumtoxinA (commonly referred to by the trade name Botox) is a neuromuscular blocking agent that is FDA indicated for the treatment of overactive bladder, migraines, spasticity, cervical dystonia, severe axillary hyperhidrosis and strabismus.¹⁶ More recently, onabotulinumtoxinA has been used off-label in dentistry for treating pathologic clenching, masseteric hypertrophy, dysphagia, hypersalivation, bruxing and temporomandibular joint disorders. It has also been prescribed to drop the upper lip to reduce the amount of visible attached gingiva.^17,18

Chlorhexidine gluconate 0.12% (CHX) is an antimicrobial rinse used as a surgical/topical antiseptic; it is also used to treat gingivitis, and, in a gelatinous form, as an adjunctive therapy that is claimed to reduce periodontal pocket depths.¹⁹ Off-label, CHX has been used to treat caries; however, a systematic review of the efficacy of CHX alone or in combination with fluoride showed insufficient evidence to support its use to reduce cariogenic pathogens.²⁰

Povidone iodine is FDA approved as a broad-spectrum external antiseptic agent. More recently, oral health professionals have been using povidone iodine for subgingival irrigation. Hoang et al²¹ conducted a randomized split-mouth study comparing scaling and root planing with povidone iodine irrigation, and the effects on plaque and pocket depth. The authors found no significant difference in plaque reduction between the study groups. Povidone iodine has also been studied for management of early childhood caries.^22–24 Results have been mixed, as studies have shown either no difference in reduction in Streptococcus mutans between children in the control and experimental groups, or improvements within 6- and 12-month intervals.^22–24 Further study is needed to determine if reduction in caries experience over extended periods can be related to this intervention.

Tricyclic antidepressants (TCAs), such as amitriptyline and nortriptyline, are FDA approved for treating depression. Cascos-Romero et al²⁵ conducted a systematic review of papers discussing the effectiveness of tricyclic antidepressants in treating temporomandibular joint disorder. The review noted sufficient evidence to support the use of tricyclic antidepressants in treating temporomandibular joint disorder. Caution should be taken in the dental office when using vasoconstrictors on patients taking TCAs. Aspiration should be performed to avoid intravenous administration, and the dose should be limited to 0.04 mg of epinephrine. Additionally, care should be taken when recommending acetaminophen, as TCA levels may increase and acetaminophen levels may decrease when taken together.

IMPLICATIONS AND SUMMARY

As noted, a thorough review of the patient’s medical history and medications is essential to an accurate diagnosis and safe treatment, especially when administering or recommending drugs in a medical or dental setting. According to Tam et al,²⁶ a thorough knowledge of patients’ medications can help providers consider adverse drug reactions or noncompliance issues, which can aid in deciphering the causes of a patient’s illness.

Jacobsen and Chavez¹³ advise oral health professionals to address four questions when treating patients utilizing polypharmacy:

1. What are the medical conditions that necessitate the medications?
2. What impact do these conditions have on the provision of care?
3. What are the medications’ oral side effects?
4. How will the patient’s current list of medications alter the prescribing patterns for drugs used in dental care?

Considering these questions when evaluating a patient’s medication history may be beneficial in preparing for and/or preventing adverse reactions and drug interactions

Off-label drug therapy may offer benefits to patient care, as advances in off-label drug therapy have crossed over from medicine to dentistry. Oral health professionals must keep current with pharmacology and off-label drug use so they can make appropriate treatment modifications, as needed. This knowledge will also help clinicians better manage adverse events or medical emergencies that might occur in the dental setting.

---

REFERENCES

1. U.S. Centers for Disease Control and Prevention. Life expectancy; 2015. Available at: cdc.gov/nchs/fastats/life-expectancy.htm. Accessed December 4, 2017.
2. Dresser R, Frader, J. Off-label prescribing: a call for heightened professional and government oversight. J Law Med Ethics. 2009;37:476–486.
3. Klein DB, Tabarrok A. Do off-label drug practices argue against FDA efficacy requirements? A critical analysis of physicians’ argumentation for initial efficacy requirements. Am J Econ Sociol. 2008;67:743–775.
4. Strom BL, Melmon KL, Miettinen OS. Post-marketing studies of drug efficacy: Why? Am J Med. 1985;78:475–480.
5. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med. 2006;166:1021–1026.
6. Morais-Almeida A, Cabral AJ. Off-label prescribing for allergic diseases in pre-school children. Allergol Immunopathol (Madr). 2014;42:342–347.
7. Bazzano AT, Mangione-Smith R, Schonlau M, Suttorp MJ, Brook RH. Off-label prescribing to children in the United States outpatient setting. Acad Pediatr. 2009;9:81–88.
8. Herring C, McManus A, Weeks A. Off-label prescribing during pregnancy in the UK: an analysis of 18,000 prescriptions in Liverpool Women’s Hospital. Int J Pharm Pract. 2010;18;226–229.
9. Kamble P, Sherer J, Chen H, Aparasu R. Off-label use of second-generation antipsychotic agents among elderly nursing home residents. Psychiatr Serv. 2010;61:130–136.
10. Wittich CM, Burkle CM, Lanier WL. Ten common questions (and their answers) about off-label drug use. Mayo Clin Proc. 2012;87:982–990.
11. Henry V. Off-label prescribing legal implications. J Legal Med. 1999;20:365–383.
12. Lin KJ, De Caterina R, García Rodríguez LA. Low-dose aspirin and upper gastrointestinal bleeding in primary versus secondary cardiovascular prevention: a population-based, nested case-control study. Circ Cardiovasc Qual Outcomes. 2014;7:70–77.
13. Jacobsen PL, Chávez EM. Clinical management of the dental patient taking multiple drugs. J Contemp Dent Pract. 2005;6:1–16.
14. U.S. Food and Drug Administration. Inspections, Compliance, Enforcement, and Criminal Investigations. Available at: www.fda.gov/iceci/enforcementactions/warningletters/2012/ucm330758.htm. Accessed December 4, 2017.
15. U.S. Food and Drug Administration. Premarket notification: Dentsply International. Available at: www.accessdata.fda.gov/cdrh_docs/pdf12/k122331.pdf. Accessed December 4, 2017.
16. U.S. Food and Drug Administration. Botox label: Highlight of prescribing information. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2016/103000s5252lbl.pdf. Accessed December 4, 2017.
17. Nayyar P, Kumar P, Nayyar PV, Singh A. Botox: broadening the horizon of dentistry. J Clin Diagn Res. 2014;8:ZE25–ZE29.
18. Persaud R, Garas G, Silva S, Stamatoglou C, Chatrath P, Patel K. An evidence-based review of botulinum toxin (Botox) applications in non-cosmetic head and neck conditions. JRSM Short Rep. 2013;4:1–9.
19. Lexicomp. Chlorhexidine gluconate (Lexi-drugs). Available at: wolterskluwercdi.com/lexicomp-online. Accessed December 4, 2017.
20. Li Y, Tanner A. Effect of antimicrobial intervention on oral microbiota associated with early childhood caries. Pediatr Dent. 2015;37:226–244.
21. Hoang T, Jorgensen MG, Keim RG, Pattison AM, Slots J. Povidone-iodine as a periodontal pocket disinfectant. J Periodontal Res. 2003;38:311–317.
22. Amin MS, Harrison RL, Benton TS, Roberts M, Weinstein P. Effect of povidone-iodine on Streptococcus mutans in children with extenseive dental caries. Pediatr Dent. 2004;26:5–10.
23. Jayabal J, Mahesh R. Current state of topical antimicrobial therapy in management of early childhood caries. ISRN Dent. 2014;2014:762458.
24. Simratvir M, Singh N, Chopra S, Thomas Aml. Efficacy of 10% povidone iodine in children affected with early childhood caries: an in vivo study. J Clin Pediatr Dent. 2010;34:233–238.
25. Cascos-Romero J, Vázquez-Delgado E, Vázquez Rodríguez E, Gay-Escoda C. The use of tricyclic antidepressants in the treatment of temporomandibular joint disorders: Systematic review of the literature of the last 20 years. Med Oral Patol Oral Cir Bucal. 2009;14:E3–E7.
26. Tam VC, Knowles SR, Cornish PL, Fine N, Marchesano R, Etchells EE. Frequency, type and clinical importance of medication history errors at admission to hospital: a systematic review. CMAJ. 2005;173:510–515.

 

The authors have no commercial conflicts of interest to disclose.

FEATURED IMAGE BY CREDIT/ISTOCK/GETTY IMAGES PLUS

From Decisions in Dentistry. January 2018;4(1):40-43.