Drug Holidays – Temporary Suspension of Therapy; Drug Labeling Consultant’s Perspective

Taking a drug holiday

Drug holidays are not often described in the U.S. professional labeling of prescription drug products. However, they are routinely employed across various classes of drugs as well as a variety of patient populations. As the name implies, a drug holiday is the temporary suspension of active therapy[1], and is usually enacted to avoid adverse events associated with the use of a drug. The greater potential for such adverse events to occur over longer term use results in changing benefit/risk profiles for patients over time. In order to continue therapy for a condition with an overall benefit to the patient, a break in pharmacological treatment may be guided by a healthcare professional. Note, treatment re-initiation after a drug holiday can involve a different benefit/risk profile than the first or previous encounters with the drug product.

Why a Drug Holiday?

There are many medical and personal reasons health care professionals, patients and caregivers consider drug holidays. These include, but are not limited to, cessation of undesirable adverse side effects, reassessment of whether an illness is in remission, management of drug tolerance, pregnancy, or surgery. Personalization of care to address these types of issues may require a discontinuation of medication with a planned future re-initiation. Below, a number of drug classes are introduced to illustrate a variety of holidays documented in the medical literature. In certain instances, detailed descriptions of drug holiday regimes is not provided in medical reports or indicated in sponsor documents. This highlights the need to consult with a healthcare professional to personalize the medical treatment for each unique patient considering a drug holiday.

Examples of Drug Holiday Utilization

ADHD
Drug holidays are commonly used in the treatment of children with ADHD.[2], [3] While medical guidelines may recommend this practice, it is not systematically practiced.[4] However it has been reported that weekends and school vacations are generally a time when ADHD drugs are withheld.[5] Side effects that ADHD drugs are commonly given a holiday to prevent are appetite suppression, sleep problems, growth retardation. Holidays are also used to manage drug tolerance and as a negotiation tool for the child/caregiver.

In one study, methylphenidate was found to be discontinued and restarted in greater than half of the children being treated for ADHD.[6] Frequently ADHD drug holidays are parent initiated with as great as 70% of children stopping medication at some point.[7] Researchers note that drug holidays are especially used for stimulants (e.g. amphetamines) used to treat ADHD because the non-stimulants (e.g. atomoxetine) require a longer wash-out time (such as a summer vacation and not a weekend). The Medical Officer’s Review for the 2004 approval of Concerta[8] stated that a study by the sponsor reported that 22% of patients documented drug holidays (children 6 to 13 years). Unfortunately, in this study, a few of these breaks in treatment were associated with suicidal ideation.

IBD/Crohn’s/Ulcerative Colitis
Patients with irritable bowel disease (IBD; Crohn’s disease and ulcerative colitis) can experience an acute infusion reaction (AIR) with an anti-TNF treatment.[9] The IBD subset of anti-TNF patients appears to be at greater risk of AIR than the other types of patients (e.g. with psoriasis) being treated with these infusions of chimeric monoclonal antibodies. After several treatments there can be a hypersensitivity reaction, and a drug holiday is prevalent in the literature, especially for Infliximab.[10], [11], [12] The restart of therapy needs to be better studied across patients and currently is orchestrated around the levels of antibodies to infliximab (ATI) and co-administration of an immunomodulator. The U.S. professional labeling for Remicade notes in the Warnings and Precautions that infusion reactions are as high as 3% in adult patients and, in general recommends discontinuation of treatment with these reactions. However, this labeling also notes that there are infusion reactions following readministration. IBD treatment options are limited. Therefore, maintaining anti-TNF treatment as one of them necessitates consideration of a drug holiday.

Chemotherapy
Cancer chemotherapies historically are known to be toxic, and cycles of chemotherapy treatment are specifically designed with treatment cessation intervals. In particular, the treatment of castration-resistant prostate cancer (CRPC) has generated medical reports discussing the use of drug holidays. The first-line[13] and second-line[14] therapies for CRPC (docetaxel and cabazitaxel), are associated with both typical cumulative toxicity and cancer cell resistance to the drug, necessitating the holiday. Intermittent cycles of therapy can be as greater than 10 courses of treatment followed by a delayed re-challenge which is often guided by the reappearance of abnormal PSA levels.[15], [16] Other specific cancers have been reported to be treated with drug holidays, such as metastatic colorectal cancer and keratoacanthomas.[17], [18]

Biphosphonates
Certain bisphosphonates have a Limitations of Use statement in the treatment of osteoporosis. For example, U.S. alendronate labeling states, “Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use.” Bisphosphonates have been shown to accumulate in the bone and continue their inhibition of bone breakdown (osteoclasts) for years.[19] These drugs are highly effective in the reduction of osteoporotic fractures (i.e. vertebral and hip). However, with the inhibition of bone breakdown comes a reduction in stress fracture healing. Studies of long-term treatment in women with alendronate have not shown a fracture disadvantage with drug discontinuation at 5 years, except in rare cases for high risk of fracture (history of fractures of poor T-score).[20], [21], [22] Similar observations have been made with zoledronic acid and risedronate.[23] Long-term treatment with bisphosphonates could lead to the reduced bone repair which in turn could increase rare risks of non-healing such as osteonecrosis of the jaw (ONJ) or atypical femur fractures (AFF). After a drug holiday from bisphosphonates, regular bone mineral density (BMD) screenings may be used to indicate the need to reinitiate treatment.[24]

HIV
HIV treatments may provide increased efficacy with the employment of drug holidays. Certain patients are able to manage their viral load with less frequent drug therapy than others.[25] Intermittent therapy and longer suspensions of therapy are employed in tandem with monitoring for the need to reinitiate treatments and may also be termed medication “holidays.”[26] Unfortunately, it is well known that patients receiving anti-HIV treatments initiate their own drug holidays without medical supervision, compromising their antiviral therapy.[27]

Drug Labeling

Although the U.S. professional labeling of drug products often fails to mention drug holidays, there were other examples identified in our research. For example, the Precautions Section of the labeling for propofol notes drug holiday to replace zinc losses and the Dosage and Administration Section of the labeling for baclofen recommends holidays to manage drug tolerance.

Many drug products are being used in a manner that includes the use of drug treatment holidays. Not to be confused with outright discontinuation, a drug holiday indicates that the treatment of the condition ongoing with the intent of resumption. Patients and healthcare professionals can use a drug holidays as tools in the personalization of healthcare for better, safer treatment outcomes and overall well-being.

Dr. Catherine E. Patterson is Director of Scientific Research for PDG and offers expertise utilizing her background in Molecular Biology with academic experience in grant writing and publishing. She actively participates in safety surveillance activities, clinical trials and regulatory submissions on behalf of PDG clients.

Charles Jaap is Vice-President of Operations and Business Development for PDG, a global pharmaceutical and medical device consultant with extensive experience in the strategic development of drug products and medical devices. Please feel free to contact us for more information.

The opinions and statements in this paper are solely those of the authors and do not necessarily reflect those of PDG.

Sources:
[1] Lee, S. H., Gong, H. S., Kim, T. H., et. al. Position Statement: Drug Holiday in Osteoporosis Treatment with Bisphosphonates in South Korea. J Bone Metab., 2015, 22(4):167-174.
[2] Regnart, J., McCartney, J., & Truter, I. Drug holiday utilisation in ADHD-diagnosed children and adolescents in South Africa. J Child Adolesc. Ment. Health, 2014, 26(2):95-107.
[3] Ibrahim, K. & Donyai, P. Drug Holidays From ADHD Medication: International Experience Over the Past Four Decades. J Atten. Disord., 2015, 19(7):551-568.
[4] Ibrahim, K., Vogt, C., & Donyai, P. Caught in the eye of the storm: a qualitative study of views and experiences of planned drug holidays from methylphenidate in child and adolescent ADHD treatment. Child and Adolescent Mental Health., 2016 Epub.
[5] Shyu, Y. C., Lee, S. Y., Yuan, S. S., Yang, C. J., et. al. Seasonal Patterns of Medications for Treating Attention-Deficit/Hyperactivity Disorder: Comparison of Methylphenidate and Atomoxetine. Clin. Ther., 2016, 38(3):595-602.
[6] Ibid @ 2
[7] Ibid @ 3
[8] Drugs@FDA as accessed at www.fda.gov on September 19, 2016.
[9] Duron, C., Goutte, M., Pereira, B. et. al. Factors influencing acute infusion reactions in inflammatory bowel disease patients treated with infliximab in the era of scheduled maintenance therapy. Eur J Gastroenterol Hepatol., 2015, 27(6):705-711.
[10] Baert, F., Drobne, D., Gils, A. et. al. Early trough levels and antibodies to infliximab predict safety and success of reinitiation of infliximab therapy. Clin Gastroenterol Hepatol., 2014, 12(9):1474-1481.
[11] Ben-Horin, S., Kopylov, U., & Chowers, Y. Optimizing anti-TNF treatments in inflammatory bowel disease. Autoimmun. Rev., 2014, 13(1):24-30.
[12] Ibid @ 9
[13] Petrioli, R., Francini, E., & Roviello, G. Is there still a place for docetaxel rechallenge in prostate cancer? World J Clin. Oncol., 2015, 6(5): 99-103.
[14] Noronha, V., Joshi, A., & Prabhash, K. Beyond ten cycles of cabazitaxel for castrate-resistant prostate cancer. Indian J Cancer., 2014, 51(3): 363-365.
[15] Kume, H., Kawai, T., Nagata, M., Azuma, et. al. Intermittent docetaxel chemotherapy is feasible for castration-resistant prostate cancer. Mol. Clin Oncol., 2015, 3(2):303-307.
[16] Ibid @ 13
[17] Tonini, G., Imperatori, M., Vincenzi, B., et. al. Rechallenge therapy and treatment holiday: different strategies in management of metastatic colorectal cancer. J Exp. Clin. Cancer Res., 2013, 32:92.
[18] Thompson, B. J., Ravits, M., & Silvers, D. N. Clinical efficacy of short contact topical 5-Fluorouracil in the treatment of keratoacanthomas: a retrospective analysis. J Clin Aesthet. Dermatol., 2014, 7(11):35-37.
[19] Villa, J. C., Gianakos, A., & Lane, J. M. Bisphosphonate Treatment in Osteoporosis: Optimal Duration of Therapy and the Incorporation of a Drug Holiday. HSS.J., 2016, 12(1):66-73.
[20] Black, D. M., Schwartz, A. V., Ensrud, K. E., et. al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA., 2006, 296(24):2927-2938.
[21] Adler, R. A., El-Hajj, F. G., Bauer, D. C., et. al. Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner. Res., 2016, 31(1):16-35.
[22] Ibid @ 1
[23] Ibid @ 19
[24] Roberts, J., Castro, C., Moore, A. E., et. al. Changes in bone mineral density and bone turnover in patients on ‘drug holiday’ following bisphosphonate therapy: real-life clinic setting. Clin. Endocrinol. (Oxf.), 2016., 84(4):509-515.
[25] Leibowitch, J., Mathez, D., de, T. P., Perronne, C., et. al. Short cycles of antiretroviral drugs provide intermittent yet effective therapy: a pilot study in 48 patients with chronic HIV infection. FASEB.J, 2010, 24(6):1649-1655.
[26] Mitty, J. A., Macalino, G. E., Bazerman, L. B., et. al. The use of community-based modified directly observed therapy for the treatment of HIV-infected persons. J Acquir. Immune. Defic. Syndr, 2005, 39(5):545-550.
[27] Laws, M. B., Wilson, I. B., Bowser, D. M., et. al. Taking antiretroviral therapy for HIV infection: learning from patients’ stories. J Gen. Intern. Med. 2008, 15(12):848-858.
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