Increasing Awareness and Counseling on the Importance of Titration Schedules

This article was sponsored by SK Life Science, Inc.

Many medications require dose titration to minimize adverse drug reactions (ADRs) or to reach a desired clinical effect or both.¹ Titrating doses with slow escalation over time allows for a customized regimen based on patient-specific treatment responses.^1,2

From 2013 to 2017, the FDA approved several agents deemed amenable to titration, with those for metabolic or endocrine conditions (eg, antidiabetic agents) being the most titrated agents.³ Pharmacologic agents commonly encountered in community settings and for which titration is recommended include anticoagulants,⁴ antidiabetic agents,⁵ antidepressants,⁶ and antiseizure medications (ASMs).⁷

CLINICAL UTILITY OF TITRATION

Titration allows for personalizing treatment, maximizing outcomes, and reducing ADRs.^1-3 Titration starts with a generally well-tolerated low dose and the dose is increased until a particular outcome is achieved.^2,3,8,9

Titration can achieve the desired pharmacologic effect while avoiding toxicities.^1,2 At times, titration may achieve a benefit with doses below the recommended target dose.² Also, titration may be influenced by available formulations. Certain medications are available in liquid formulations and subcutaneous injections, allowing for titrations with precise dosing, versus tablets or capsules that are available in limited or fixed dosages.^3,5,10

Compared with standard care, titration improves outcomes, particularly when patients are being closely monitored by providers. For example, patients with diabetes showed improvements in their A1C levels with pharmacist-facilitated titration of insulin.¹¹ Similarly, a pharmacist-run warfarin titration led to an increased duration of target international normalized ratio and decreased thromboembolic events.¹²

REDUCING ADVERSE REACTIONS

Slowly acclimating a patient to a dose helps minimize potential treatment-related ADRs.^1,2,8,9 A slow uptitration can provide insight into individual dose responses and may help prevent serious ADRs, especially in patients with a new diagnosis or when introducing a new medication into a regimen.^1,9 Slow titration may help mitigate risk and may allow the clinician or patient to identify potentially serious idiosyncratic immune-related hypersensitivity reactions (eg, drug-related rash with eosinophilia and systemic symptoms [DRESS] and Stevens-Johnson syndrome [SJS]) before they become severe.¹³ Titration and monitoring are especially important for medications with a narrow therapeutic index, where there is a small difference between the dose that provides benefit versus toxicity (eg, digoxin, insulin, opioids, phenytoin, warfarin).²

Titrating antidepressants (eg, nefazodone, paroxetine) has been shown to reduce ADRs such as sexual dysfunction, nausea, and sedation.^10,14 With ASMs (eg, cenobamate, lamotrigine), slow titration may reduce the risk of idiosyncratic immune-related hypersensitivity reactions when initiating therapy.^7,15 Uptitration of one medication may also allow for downtitration of concomitant medications used for similar indications, thereby reducing additive ADRs associated with combination therapy. Conversely, when discontinuing medications, downtitration may prevent withdrawal or discontinuation syndromes.¹ A gradual decrease in the dose over 2 weeks may reduce the risk of recurrent seizures and status epilepticus when discontinuing uptitrated ASMs.⁷

SPECIAL POPULATIONS

Titration may provide benefits for at-risk patients, such as those with genetic variants or those with comorbidities who are being treated with multiple medications. With appropriate titration, patients with genetic polymorphisms that impact a medication’s metabolism (eg, warfarin) or ADR profile (eg, HLA-B*1502 haplotype) may be less likely to develop supratherapeutic concentrations or certain ADRs.^1,2,8,9 Titration also allows for close monitoring of the onset of ADRs in patients at risk for drug-drug interactions due to polypharmacy.¹ Elderly, frail, or malnourished patients may also benefit from a more cautious titration, especially when nutrition status and albumin concentrations impact a medication’s pharmacokinetics (eg, phenytoin, warfarin).^2,4

ROLE OF THE PHARMACIST

Pharmacists are ideally positioned to help patients understand titration.¹ They can counsel patients on titration goals and expectations, titration schedules, eventual target maintenance dose, and adherence strategies.^1,2

Pharmacists can help to ensure that patients understand that titrated medications are started at low doses and escalated upwards, reiterating that this can provide the flexibility to achieve a maintenance dose that is best suited for their individual needs.^1,2 Pharmacists can also provide patients with detailed titration instructions, stressing the importance of following the directions to achieve the therapeutic outcome.²

Setting Treatment Expectations

Setting treatment expectations is especially important for titrated medications. Pharmacists can educate patients on therapeutic goals, particularly when those goals may not be tangible or when objective measures objective measures of the medication’s efficacy are not readily seen.^1,2 Advising patients on the potential timing of clinical benefits can help manage expectations. Dose escalation is done slowly, with increases occurring every few days, weekly, or even biweekly, as many medications may take several days or weeks to reach steady state. As such, the full therapeutic benefit may not be realized for several weeks or months.^1,2

Importance of Adherence to Therapy

Prescriptions change as medications are titrated over time. Some titration schedules may seem overwhelming and can cause confusion, for example, when instructions include splitting tablets or taking different tablet strengths from one week to the next.¹ Pharmacists can emphasize that adhering to the titration schedule can help patients achieve their treatment goals.² They should also encourage patience and staying the course to achieve optimal results.

Safety Counseling

Finally, pharmacists should discuss the potential benefits and risks with patients upon initiation of any new therapy, including common ADRs, and how to recognize their early signs and symptoms and what to do if they occur. Pharmacists can help patients understand that slow uptitration is intended to help minimize potential ADRs while maximizing therapeutic effectiveness.²

REFERENCES

• Caffrey AR, Borrelli EP. The art and science of drug titration. Ther Adv Drug Saf. 2020;11:1-14.
• Maxwell S. Therapeutics and good prescribing. In: Walker BR, Colledge NR, Ralston SH, Penman ID, eds. Davidson’s Principles and Practice of Medicine. 22nd ed. Churchill Livingstone/Elsevier; 2014:17-40.
• Schuck RN, Pacanowski M, Kim S, Madabushi R, Zineh I. Use of titration as a therapeutic individualization strategy: an analysis of Food and Drug Administration-approved drugs. Clin Transl Sci. 2019;12(3):236-239. doi:10.1111/cts.12626
• Coumadin. Prescribing information. Bristol-Myers Squibb Company; 2011.
• Lantus. Prescribing information. Sanofi-Aventis U.S. LLC; 2019.
• Prozac. Prescribing information. Eli Lilly and Company; 2016.
• Xcopri. Prescribing information. SK Life Science, Inc; 2020.
• Cramer JA, Mintzer S, Wheless J, Mattson RH. Adverse effects of antiepileptic drugs: a brief overview of important issues. Expert Rev Neurother. 2010;10(6):885-891. doi:10.1586/ern.10.71
• Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neurol. 2012;11(9):792-802.
• Ielmini M, Poloni N, Caselli I, et al. Efficacy and tolerability of two different kinds of titration of paroxetine hydrochloride solution: an observational study. Psychopharmacol Bull. 2018;48(3):33- 41.
• Weidman-Evans E, Evans J, Eastwood R, Fort A. Implementation of a pharmacist-run telephonic insulin titration service. J Am Pharm Assoc (2003). 2012;52(6):e266-e272. doi:10.1331/JAPhA.2012.11225
• Bungard TJ, Gardner L, Archer SL, et al. Evaluation of a pharmacist-managed anticoagulation clinic: improving patient care. Open Med. 2009;3(1):e16-e21.
• Zaccara G, Franciotta D, Perucca E. Idiosyncratic adverse reactions to antiepileptic drugs. Epilepsia. 2007;48(7):1223-1244. doi:10.1111/j.1528-1167.2007.01041.x
• Practice guideline for the treatment of patients with major depressive disorder. American Psychiatric Association. 2010. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd
• Lamictal. Prescribing information. GlaxoSmithKline; 2019.