Infusion Center Guidelines for Teprotumumab Infusions: Informed Consent, Safety, and Management of Side Effects

Abstract

Teprotumumab was the first and only medication approved by the US Food and Drug Administration for the treatment of Thyroid Eye Disease (TED) in January 2020. TED is a complex autoimmune inflammatory disease which can be sight-threatening, debilitating, and disfiguring to affected patients. While biologic therapies are a preferred treatment option for many complex immunologic and oncologic conditions, their use in ophthalmology and endocrinology may be more novel. The goals of this article are to introduce this new therapeutic option; discuss its mechanism of action, indications for use, administration protocol, infusion precautions, informed consent; and review common side effects and management.

Teprotumumab was the first medication approved by the US Food and Drug Administration (FDA) for the treatment of Thyroid Eye Disease (TED).¹ While biologic therapies are a preferred treatment option for many complex immunologic and oncologic conditions, their use in ophthalmology is more novel. As such, a thorough review of proper patient selection and how to manage adverse events and infusion related reactions is needed. Clinicians in these subspecialties rely on the expertise of the infusion center nurse to ensure safe delivery of the monoclonal antibody, teprotumumab. The goals of this article are to introduce this new therapeutic option; discuss the indications for its use, mechanism of action, patient education and informed consent, adverse events, side effects and their management; as well as administration protocol and infusion details.

TED is an unpredictable autoimmune inflammatory disease which can be sight-threatening, debilitating, and disfiguring to affected patients. The disease typically begins with an acute inflammatory/active phase that can last for 6 to 36 months or longer,^2–4 often resulting in proptosis (eye bulging), blurred vision, diplopia (double vision), tearing and irritation, photophobia, and pain (Figure 1). Over time, the inflammation subsides and the patient enters an inactive phase characterized by fibrosis and can be accompanied by permanent disfigurement, functional vision loss, psychosocial alterations and significant socioeconomic impact.^3,4 The numbers vary in different case series, but the incidence of developing TED is approximately 16 cases per 100 000 women and 3 cases per 100 000 men per year.⁵ Symptomatic TED occurs in 40% to 50%³ with subclinical extraocular muscle enlargement in up to 70% of adult patients with Graves’ hyperthyroidism.⁶ TED can also occur (approximately 10%) in patients with hypothyroidism or normal thyroid status (euthyroid).^6,7

Figure 1.

Thyroid eye disease causes bulging of the eyes (proptosis) redness and swelling (conjunctival and eyelid edema and erythema) due to enlargement of the extraocular muscles and soft tissue expansion.

INDICATIONS FOR USE

Although the clinical trials treated patients who had moderate to severe TED with an active inflammatory phase of 9 months or less, the FDA approval is for all patients with TED. In the pre-market clinical trials, 171 patients were randomized to receive either Teprotumumab or placebo. Eighty three percent of the Teprotumumab treated subjects demonstrated an improvement in proptosis of ≥ 2 mm compared to 10% of patients in the placebo group at 24 weeks.⁸ Notably, 56% of patients noticed this improvement in proptosis by 6 weeks. The mean change in proptosis from baseline was 3.32 mm, which is similar to what can be achieved via a single wall orbital decompression. The proptosis response was similar across age groups, genders and tobacco use.⁹ Diplopia improved by ≥ 1 grade in 68% vs in 29% with placebo⁸ and 53% had complete resolution of diplopia at 24 weeks.^8,10 Additionally, there was a significant improvement in redness, swelling and pain (inflammation) with an overall response (a reduction of ≥ 2 in the clinical activity score (redness, swelling, pain) plus a reduction in proptosis of ≥ 2 mm) in 78% of patients vs 7% with placebo at 24 weeks. A majority of treated patients (59%) had complete resolution of inflammation by 24 weeks.^8–10

Now with real world experience, numerous publications have documented that Teprotumumab works in a wide variety of patients not included in the original clinical trials, including those with inactive or non-inflammatory disease, TED-related optic neuropathy, prior surgery, and longer duration of disease (chronic). This suggests that the relationship between the thyroid-stimulating hormone receptor (TSH-R) and the insulin-like growth factor-1 receptor (IGF-1R) is unaltered by the duration of disease, current disease activity, prior surgery, or the specific manifestations of the patient’s TED.^1,10–33

MECHANISM OF ACTION

Teprotumumab is a targeted therapy; the monoclonal antibody blocks the IGF-1R that is co-located and co-acting with the TSH-R. Studies have shown that IGF-1R is overexpressed in TED orbital fibroblasts both in the active and inactive phase of disease.^35,36 Autoantibodies activate the IGF-1R and TSH-R-signaling complex, which stimulates orbital fibroblasts and leads to the release of inflammatory cytokines and hyaluronan production. Once activated, orbital fibroblasts cause inflammation and expansion of tissue, muscle, and fat cells behind the eyes (Figure 2).^34,35 Teprotumumab blocks the cell to cell signaling that upregulates pro-inflammatory cytokines and hyaluronan release. The myofibroblast activity is altered in TED. Teprotumumab is thought to not only suppress inflammation but to enhance tissue remodeling of the extraocular muscles and intraconal fat by blocking the IGF-1R that is co-located and co-acting with the TSH-R.^22,23,36,37

Figure 2.

Computed tomography scan showing mild enlargement of the extraocular muscles and severe expansion of the intraconal fat resulting in proptosis due to thyroid eye disease.

The most common manifestations of TED are redness (conjunctival injection and eyelid erythema), swelling (conjunctival chemosis and eyelid edema), proptosis, and diplopia. Visual blurring can also occur due to exposure of the eye surface (cornea) or optic nerve dysfunction. The process can be unilateral, asymmetric, or sequential. The symptoms and signs are caused by inflammation and alterations of the eye muscles and fat behind the eye.^{3,6,7,10,36,38,39}

Pain, facial disfigurement, and diplopia all have psychosocial impact. Diplopia in particular has been shown to have a detrimental effect on visual and general quality of life measures, and correction of diplopia may lead to substantial improvement in psychosocial and functional domains.⁴⁰ Validated questionnaires have been developed to allow researchers and clinicians to evaluate outcomes after medical or surgical interventions. These tools provide more detailed information than global assessments of the presence or absence of double vision. Traditionally, patients with red, swollen, bulging eyes (TED active phase) have been treated with oral or intravenous corticosteroids or orbital radiation therapy. Surgery is usually reserved for patients who have visual loss or pain in the active phase. Diplopia can improve with strabismus surgery during the inactive phase (after most of the inflammation has subsided) of the disease with varying degrees of success. Orbital decompression surgery (removal of bone and/or fat) to combat bulging can worsen or cause new onset diplopia in some patients. At best, strabismus surgery has a goal of restoring binocular vision in primary gaze. There is no current option that restores the eye movement and the muscle balance in extremes of gaze.^8,39–43 Teprotumumab is the only therapy shown to reduce the size and shape of extraocular muscles, thereby improving eye motion in all gazes (Figure 3).^12,15,23

Figure 3.

Thyroid eye disease computed tomography scan showing moderate expansion of the medial rectus muscles before treatment and improved muscle size after treatment with resolution of visual dysfunction.

Loss of central vision in TED can occur due to exposure keratopathy or optic neuropathy.⁴⁴ The optic nerve can be compressed due to the muscle enlargement seen in patients with TED and less commonly the optic nerve can be stretched due to extreme proptosis from intraconal fat expansion. Corticosteroids, radiation, and orbital decompression have all been used to combat optic nerve compression with varying degrees of success. Recently, case reports demonstrated that teprotumumab were effective in treating compressive optic neuropathy (CON) from TED^12,13,44. Sears et al, measured objective improvements in visual acuity, relative afferent pupillary defect (APD), color vision, proptosis, and visual field testing as early as 4 weeks after initiating teprotumumab for steroid resistant CON, with orbital magnetic resonance imaging (MRI) showing improvement in extraocular muscle size and optic nerve compression at 8 weeks.¹² Slentz et al measured an objective improvement in visual acuity, proptosis, optic nerve edema and optical coherence tomography retinal nerve fiber thickening 2 weeks after initiating teprotumumab for steroid naïve CON.¹³

PATIENT EDUCATION, ADVERSE EVENTS, AND INFORMED CONSENT

Timing of Beneficial Effects

Most TED patients begin to notice an improvement in symptoms (pain, grittiness, tearing, light sensitivity) and signs of inflammation (redness, swelling, and bulging) after the second or third infusion of teprotumumab. In the phase 3 clinical trial, proptosis was reduced by 2 mm or more at 6 weeks in 56% of patients and 83% of patients at 24 weeks. Diplopia improved in 70% and had complete resolution in 53% at 24 weeks (pooled phase 2 and 3 clinical results).^8,10 Pain, redness, and swelling also resolved rapidly in most patients; 59% had complete resolution by 24 weeks (phase 3 clinical trial). The reduction in proptosis response is similar across age groups, genders, and tobacco use.⁹

Possible Adverse Side Effects

In the clinical trial, side effects were experienced by 85% of patients on teprotumumab versus 69% on placebo, mostly grade 1 or 2. The most common were muscle spasms (30%), alopecia (20%,) hyperglycemia (10%), diarrhea (10%), fatigue, headache, and hearing impairment (10%) (Table 1).^8,10,45 If the patient is of childbearing age, they need to be on effective birth control and have a urine pregnancy test performed prior to each infusion. Teprotumumab is not FDA- approved for pregnant or lactating women and a 6-month waiting period after completion of therapy is recommended before conception. In addition, safety and effectiveness have not been established in pediatric patients. Finally, teprotumumab should be used with caution in patients with inflammatory bowel disease (IBD) or uncontrolled diabetes. Patients with, or at risk for, IBD, should seek medical advice immediately if they experience diarrhea, with or without blood or rectal bleeding, associated with abdominal pain or cramping/colic.⁴⁶ A pre-treatment questionnaire can be helpful to identify risk factors for side effects and adverse events (Figure 4).

Table 1.

Recommendations for Mitigation of Side Effects

Side Effect	Laboratory Panels	Supplement Considerations	Other Considerations	Rationale
Fatigue	Baseline comprehensive metabolic panel, vitamin D, B12, folic acid	Start magnesium supplements and multivitamins including vitamins D and B	Oral hydration prior to infusion and day to follow	Worsened fatigue is associated with a variety of deficits including dehydration
Transient headache	N/A	One gram of acetaminophen prior to infusion	Oral hydration prior to infusion and day to follow	Pretreatment with acetaminophen can alleviate pain
Intermittent muscle spasms	Baseline electrolytes and magnesium	Hydration, magnesium supplements	Epsom Salt bath on day of infusion and day to follow	Magnesium supplementation can prevent and minimize muscle spasms
Transient hearing alterations	Baseline audiogram and questionnaire	IGF-1R ear drops	Repeat audiogram if any new hearing symptoms	IGF-1 deficiency is associated with hearing loss; it’s unclear if ear drops could prevent this side effect
Intermittent hyperglycemia	Glucose and HbA1C	Continuous glucose monitoring may be helpful in select patients	Diabetic diet that avoids sugars and alcohol	Standard practices to prevent hyperglycemia should be implemented
Transient diarrhea in patients without IBD	Baseline electrolytes	Bismuth subsalicylate	Discontinue infusion and referral to GI for endoscopy if bloody diarrhea	Diarrhea is typically short lived but can be prevented or minimized with over-the-counter medications
Temporary changes in hair and nails	N/A	Biotin supplement	“Hair, nail, and skin” supplements	Usually temporary, but can be mitigated by using supplements prior to starting the infusions
Dry eyes and mouth	Hydration	Artificial tears	If symptomatic despite treatment prior to infusions, can initiate topical cyclosporine	Usually temporary
Urinary incontinence due to hyperglycemia	Careful monitoring of blood sugar in diabetics	Delay infusion until glucose monitoring and glycemic control improved	Referral to urology/gynecology indicated if persists despite discontinuation of infusions	Focus should also be on getting the hyperglycemia better controlled
Urinary tract infection	Careful monitoring of symptoms especially in elderly woman with history of UTI	Hydration and cranberry juice	Urinary analysis and culture prior to initiation of therapy and repeat if new symptoms develop	Focus should also be on getting the hyperglycemia better controlled.

Abbreviations: GI, gastrointestinal; HbA1c, hemoglobin A1c; IBD, inflammatory bowel disease; IGF-1R, insulin-like growth factor receptor; N/A, not applicable; UTI, urinary tract infection.

Figure 4.

Thyroid eye disease pre-treatment questionnaire.

The risks and benefits of teprotumumab should be discussed with each patient and an informed consent form be reviewed with and signed by the patient prior to the initial infusion by the prescribing physician and a copy provided to the infusion center (Figure 5). The infusion may take place at an outpatient infusion center, hospital infusion center, or in the patient’s home with an infusion nurse, if the first 2 doses are well-tolerated. Prior to the first infusion, weight should be recorded and a comprehensive metabolic panel, HgA1c, risk factor questionnaire, and pregnancy test (if applicable) should be performed.

Figure 5.

Informed consent for Teprotumumab.

INFUSION DETAILS

Teprotumumab is administered 3 weeks apart, dosed at 10 mg/kg over 90 minutes for the first infusion, 20mg/kg over 90 minutes for the second infusion, and then 20 mg/kg over 60 minutes for the remaining infusions. A pre-infusion phone call by the ordering provider or facility should specify the following information: Patients should be prepared to stay at the infusion center at least 3 hours which includes time to check in, have the vascular access device inserted, undergo the infusion, and then stay 30 minutes after the infusion for observation for signs of an infusion reaction. Patients should be warned, as with infusion of any biologic, that an infusion reaction may occur.^47,48 Infusion-related reactions have been reported in approximately 4% of patients treated with teprotumumab.^8,10 Patients should be instructed how to recognize the early signs and symptoms of infusion reactions and to contact their health care provider immediately when they suspect signs and symptoms of potential infusion-related reactions. Infusion reactions may occur during any of the infusions or within 1.5 hours after an infusion. Reported infusion reactions are usually mild or moderate in severity and can usually be successfully managed with corticosteroids and antihistamines (Table 2). In patients who experience an infusion reaction, consideration should be given to pre-medicating with an antihistamine, antipyretic, corticosteroid, and/or administering all subsequent infusions at a slower infusion rate. If infusions are not well tolerated, infusions can be slowed, and the minimum time for subsequent infusions can remain at 90 minutes. If an infusion reaction occurs, the prescribing provider or infusion center nurse (depending on the center’s protocol) should notify the safety division of the manufacturer, Horizon Therapeutics. Infusion reactions are then included in the adverse event reporting to the FDA.

Table 2.

Infusion Reactions to Teprotumumab

Mild	Oral antihistamine
Moderate	Oral antihistamine and IM corticosteroids
Severe	Oral antihistamine, IM/IV corticosteroids, airway support, admission

Abbreviations: IM, intramuscular; IV, intravenous.

The prescribing physician will explain the 24-week infusion plan and provided a description of what to expect. It is helpful for the infusion center staff to also provide an overview prior to the first infusion. The infusion nurse should reinforce the treatment plan with the patient and caregiver prior to the initial and subsequent infusion. While the protocol is for infusions every 3 weeks, if therapy is delayed, the timing of when therapy should be re-instituted should be discussed with the treating physician. Of key importance, glucose monitoring and labs need to be reviewed and signed off by the prescribing physician to confirm glucose and other parameters are remaining in an acceptable range. If glucose is too high, for example, the infusion may need to be delayed while diabetic medications are adjusted. In addition, the patient should be questioned about side effects prior to each infusion. This is crucial to avoid permanent adverse outcomes. Patients with persistent diarrhea for example–especially if bloody–should not undergo further infusions until full evaluation is performed including endoscopy.

AUTHORIZATION PROCESS

Prior to initiating the infusion, insurance authorization is often required which can take weeks or more. A reimbursement specialist is assigned to each patient to help the physician’s office complete this -at times -complicated and time-consuming process. The prescribing provider will be asked to outline the features of the thyroid eye disease that warrant infusion. See Table 3 for clinical characteristic document that can facilitate authorization. The authorization is obtained for the medication and for the infusion center. Teprotumumab now has a classified J code (J3241), which streamlines the authorization process. The medication can be provided through an intermediary pharmacy if it is not on formulary for the hospital or free-standing infusion center.

Table 3.

Clinical Activity Features Warranting Teprotumumab

Progressive Symptoms Interfering with Tasks of Daily Livinga
Conjunctival injection
Caruncular injection
Eyelid erythema
Conjunctival edema
Eyelid edema
Proptosis
Diplopia
Spontaneous eye pain/ache
Pain/ache with eye movement
Blurred vision

^aClinical Activity Scores (CAS) = how many features are present.

CONCLUSIONS

Teprotumumab is currently the only FDA-approved therapeutic option for patients with TED and has been shown to reduce the volume of the expanded extraocular muscles and intraconal fat^23,27. It is rapidly effective (usually by the second dose) in patients with TED including patients with chronic inactive TED, optic neuropathy, and those with prior surgical interventions. Eight infusions are delivered over 24 weeks and improvement of redness, swelling, diplopia, blurred vision, and proptosis is often seen after the second infusion. Infusion reactions are infrequent, and the side effect profile is well described, most events are mild and manageable. The infusion should be used with caution in diabetics and patients with a history of inflammatory bowel disease. Careful monitoring of side effects is crucial to prevent complications. Teprotumumab should be administered in a team approach with the patient’s oculoplastic/orbit specialist, neuro-ophthalmologist, endocrinologist, and primary care physician. Managing expectations in advance of the infusions and then communicating clearly the with team will optimize the patients’ experience and outcomes.

Biographies

Julia Kang, MD, MPH, is a board-certified ophthalmologist who completed her residency training at the Emory Eye Center. She is currently in fellowship training for oculoplastic and reconstructive surgery. She has co-authored multiple peer-reviewed publications and as an artist, she has contributed medical illustrations for oculoplastic surgery book chapters. After fellowship training, she will be returning to Atlanta, GA to join a private practice group.

Maria Lechuga, BSN, RN, has been registered nurse and an infusion nurse for more than a decade. She has been running Dr Raymond Douglas’ infusion center for the past 2 years. She is currently pursuing her nurse practitioner education and certification.

Jenna Braun, BS, is a clinical research coordinator for Raymond Douglas, MD, PhD, She received her Bachelor of Science degree in neurobiology at the University of Wisconsin and has worked as a clinical research coordinator for 1 year.

Andrea Kossler, MD, is a board-certified ophthalmologist with fellowship training in orbital disease and oculoplastic reconstruction. She has been caring for thyroid eye disease patients for more than a decade. She is an assistant professor in the Stanford department of ophthalmology. She has published more than 100 peer-reviewed articles and lectures on thyroid eye disease nationally and internationally.

Raymond Douglas, MD, PhD, is an experienced board-certified aesthetic and reconstructive oculoplastic specialist. Patients with Thyroid Eye Disease, Graves’ Eye Disease, previous unsuccessful surgery, cancers of the eyelids or face and trauma-induced injuries seek Dr Douglas’ expert, customized care at both his primary practice in Beverly Hills and international practice, LA Face, in Shanghai, China. His expertise in treating difficult cases of disfigurement due to thyroid-associated eye diseases, cosmetic and reconstruction surgeries has made him a highly respected educational and surgical authority for both reconstructive and cosmetics arts of facial plastics.

Kimberly Cockerham, MD, FACS, is a board-certified ophthalmologist with fellowship training in neuro-ophthalmology, orbital disease, and oculoplastic reconstruction. She has been caring for thyroid eye disease patients for several decades. She is currently an adjunct clinical associate professor in the Stanford department of ophthalmology. Dr. Cockerham was previously chief of Orbital Disease and Oculoplastic surgery at UCSF and Walter Reed Army Medical Center. She has published more than 100 peer-reviewed articless, co-authored a book on Orbital Disease Diagnosis and Management and lectures on thyroid eye disease nationally and internationally.