Appeal type: Experimental/Investigational
Decision: Overturned

Diagnosis: Headaches
Treatment: Emgality
The insurer denied Emgality.
The determination is overturned.

The patient has been diagnosed with severe migraine without aura, primary generalized epilepsy, and anxiety.
They became more severe and frequent and by the time she saw the current provider for the first time, she was having almost daily headaches. They were often triggered by strong smells, and were more frequent at the end of the day. The headaches were frontal. She was unable to describe the quality of the pain. The headaches were moderate to severe in intensity, and lasted around 2 hours. Severe headaches were associated with photophobia, phonophobia, and occasionally, nausea without vomiting. The headaches were improved by sleep, and became worse with physical activity.
The headaches had become particularly severe and she was having daily headaches. She was taking two migraine prophylactic medications, propranolol extended release (ER) 120 milligrams (mg) and Effexor 150 mg. She was missing 1-2 days of school each week. She was experiencing headaches on waking. These were very difficult to treat, requiring two doses of rizatriptan and ibuprofen.
She has tried numerous prophylactic medications for migraine, including cyproheptadine (ineffective), amitriptyline (blurred vision), nortriptyline (helped decrease headache frequency, tapered as psychiatrist wanted to increase dose of venlafaxine), propranolol (some help, but daily headaches at high dose), fluoxetine (ineffective).
Acute medications have included ibuprofen and acetaminophen (initially helpful but lost efficacy), Benadryl (initially helpful then ineffective), rizatriptan (dose increase needed for severe headache, still ineffective). She has had emergency room visits for migraine.
She has a history of primary generalized epilepsy. 
An electroencephalogram (EEG) was abnormal, with several generalized frontally predominant spike and wave, and polyspike and wave discharges, including a brief 3 hertz (Hz) run. The recording was consistent with primary generalized epilepsy.
A subsequent EEG was normal.  Her seizures have been controlled on lamotrigine 300 mg ER. Her examination is documented as being normal.
At her last visit, she was reported to have had only one headache since starting Emgality. She had had two doses, and was tolerating the medication well without side effects. The provider recommended continuing Emgality.
Whether Emgality is likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease is the issue in question in this review.

The proposed health service or treatment, Emgality is likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease.
The patient has a longstanding history of migraine without aura. She has tried numerous prophylactic medications alone and in combination without adequate prevention of severe and frequent headaches. Topiramate is relatively contraindicated given her history of anxiety. She has had an extremely good response to sample doses of Emgality, with only one headache in the last two months (as opposed to daily moderate to severe headaches requiring her to miss school before Emgality was started). She is tolerating Emgality without side effects.
Another treatment, Botox injections, is also off-label for adolescents, and takes longer to assess effectiveness.
Emgality is an injectable medication which blocks the activity of calcitonin gene-related peptide (CGRP) [1]. CGRP and its receptor play a key role in migraine [2]. Edvinsson [3] described that monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor (CLR) plus (+) receptor activity modifying protein (RAMP1)) offer considerable improvements over existing drugs in migraine prophylaxis and are the first designed to act on the trigeminal pain system.
Migraine is common in children and adolescents. The prevalence of migraine in children and adolescents is estimated at 7.7% in a systematic review of population-based studies [4]. The prevalence of chronic migraine in adolescents is estimated at 1.7% [5]. Frequent migraine and chronic migraine have been shown to cause significant adverse impact on quality of life of children and adolescents [6].
A paper published by Szperka et al [7] reviewed the opinion of numerous United States based pediatric headache specialists at major medical centers regarding the use of anti-CGRP monoclonal antibodies in children and adolescents with severe, refractory migraine. The stated "Given the above, and the unknowns of long-term use of the anti-CGRP mAbs particularly in the developing patient, we recommend an initial two-month trial at the lowest available dose. If no improvement is seen, a higher dose may then be trialed for another two months. If there is still no benefit with the higher dose, or it is not tolerated, the medication should be stopped. If improvement is seen, we recommend continuing the medication in an attempt to reach a patient-centered overall treatment goal of fewer than one headache per week. If this goal is attained, the patient can be continued on the medication for another few months and then efforts should be made to wean off the medication."
The authors went on to state: "Anti-CGRP mAbs have been shown to be effective for migraine prevention in adults and have not raised major safety issues, though long-term safety data are not yet available. Pediatric and adolescent trials of anti-CGRP monoclonal antibodies (mAbs) should be designed to maximize the chances of determining efficacy in these age groups, and should focus on those who have not been successful with current multidisciplinary care. In the interim, the use of anti-CGRP mAbs for the treatment of headache disorders in children and adolescents may be considered in appropriate cases, but should be done with close follow-up and attention to patient characteristics such as age, pubertal state, and medical comorbidities."
"Treatment trials of anti-CGRP mAbs in adults have demonstrated efficacy within the first two months of treatment, with therapeutic gains remaining stable over 6 months. Open label extension trials have demonstrated some gains at the one-year mark. Previous pediatric migraine studies have demonstrated that patients who initially improve with treatment are likely to maintain this improvement. The natural course of migraine may be more easily improved in the developing brain, potentially allowing for shorter treatment duration.
In order to justify taking on the possible risks of the anti-CGRP mAbs in this population, patients should have had adequate trials of, or contraindications to, established migraine preventive therapies. How many preventives should be tried first is a matter of clinical judgement and the authors of this manuscript had varied recommendations between two and three prior preventives."
Greene et al [8] published a retrospective multisite cohort study of 112 patients less than 18 years of age who received a calcitonin gene-related peptide monoclonal antibody for headache prevention. The authors described that "At first follow-up visit there was a significant reduction in headache frequency compared with baseline (-2.0 days; 95% confidence interval, -0.8 to -3.2). Significant benefit was perceived by 29.5% of patients at first follow-up visit (number [n] = 33/112) and 30.1% (n = 22/73) at second follow-up visit. A significant functional improvement was perceived by 31% of patients (n = 31/94) at the first follow-up visit and 22.4% (n = 15/67) at the second follow-up visit. The most common side effects were injection site reactions in 17.0% (n = 19) and constipation in 8.0% (n = 9). Five patients (4.5%) discontinued because of side effects." They concluded that side effects with calcitonin gene-related peptide monoclonal antibody treatment in adolescents were similar to those reported in adult trials. Calcitonin gene-related peptide monoclonal antibody treatment appears to benefit a proportion of adolescents with chronic refractory headache disorders.
The patient is adult sized. There is adequate support in the medical literature of the safe and effective use of anti-CGRP monoclonal antibodies including Emgality showing that the drugs are safe and effective treatments for refractory chronic migraine in adolescents. Szperka [7] described that a consortium of pediatric headache specialists in the United States supported the use of the drugs, and Greene et al [8] demonstrated their safety and efficacy in a cohort of 112 adolescents.
Use of drugs off-label in children that are Food and Drug Administration (FDA)-approved for adult use is very common. The Committee on Drugs of the American Academy of Pediatrics has addressed the off-label use of drugs in children in a Policy Statement [9,10]: "The absence of labeling for a specific age group or for a specific disorder does not necessarily mean that the drug's use is improper for that age or disorder. It only means that the evidence required by law to allow inclusion in the label has not been approved by the FDA. Additionally, a lack of labeling does not signify that therapy is unsupported by clinical experience or data in children. Instead, it specifically means that evidence for drug efficacy and safety in the pediatric population has not been submitted to the FDA for review or has not met the regulatory standards of "substantial evidence" for FDA approval."