Appeal type: Medical necessity
Decision: Overturned

Diagnosis: Migraines. 
Treatment: Ajovy. 

The insurer denied the Ajovy. 
The determination is overturned. 

The patient has chronic migraine. At first the headaches were occurring around twice a week. At the time of her initial visit, she had been experiencing daily headaches for 3 weeks. She had sustained two mild blows to the head during tubing. She had not lost consciousness, and had not had nausea, vomiting, gait instability or confusion following the minor head trauma. The headaches were fronto-temporal, and were sometimes preceded by a visual aura, with a bright light on the left side of her visual fields. The headache was pressure-like, sharp or throbbing in nature. It was associated with photo-and phonophobia. The headache could occur at any time of day, and was continuous when she was first seen. Headache severity was up to an 8/10. The headache severity was decreased by sleep, and worsened by physical activity. Her headache frequency increased after orthodontic braces were placed. 

The patient's birth and development were normal. There was a strong family history of headaches (mother, sister and a maternal aunt). Her general and neurological examinations have always been normal. 

The patient has tried numerous migraine abortive and prophylactic medications without effective relief of her symptoms. Acute medications have included ibuprofen, naproxen, rizatriptan and naratriptan. Preventative medications used include nortriptyline, Topiramate extended release (ER) at a dose of 100 milligrams (mg) daily (with side effects of word-finding difficulty and slowness of thought), and Medrol pack. Given that the patient is pre-syncopal, beta blockers and channel blockers are contraindicated. As an adolescent female, she is at risk of weight gain and teratogenesis if valproic acid was used as a migraine preventative medication. 

Despite being on two migraine prophylactic medications (Topiramate ER 100 milligrams (mg) every night (QHS) and nortriptyline 50 mg QHS), the patient was still having 2 moderate to severe headaches per week. She has been taking samples of Ajovy 225 mg/1.5 milliliter (ml). She has had a decrease in her headache frequency to 1-2 headaches per week, and has started to wean her dose of topiramate. She is tolerating Ajovy well. 

At issue in this case is whether the requested health service/treatment of Ajovy syringe 225 mg/1.5 is medically necessary for this patient. 

The requested health service/treatment of Ajovy syringe 225 mg/1.5 is medically necessary for this patient. 

The patient has chronic migraine which has been refractory to all previously used prophylactic medications (Topiramate, nortriptyline) which have been used in appropriate doses for an adequate period of time, with documented good compliance. Given that she is pre-syncopal, beta blockers and channel blockers are contraindicated. As an adolescent female, she is at risk of weight gain and teratogenesis if valproic acid was used as a migraine preventative medication. Prior to starting Ajovy, which she has tolerated well, she was having 2 moderate-severe migraine headaches per week. Frequent migraine and chronic migraine have been shown to cause significant adverse impact on quality of life of children and adolescents [1]. Ajovy has decreased her headache frequency, and has permitted her to start weaning Topiramate, which was causing the common side effects of word finding difficulty and slowness of thought.
Ajovy (fremanezumab) is an injectable medication which blocks the activity of calcitonin gene-related peptide (CGRP). CGRP and its receptor play a key role in migraine. Edvinsson [2] described that monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor [CLR] +, receptor activity-modifying protein 1 [RAMP1]offer considerable improvements over existing drugs in migraine prophylaxis and are the first designed to act on the trigeminal pain system.
While the anti-CGRP monoclonal antibody drugs, including Ajovy, have not been approved by the Food and Drug Administration (FDA) for use in children and adolescents, criteria for their safe and appropriate use have been reported by a large consortium of pediatric headache specialists throughout the United States [3]. The authors stated: "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." They continued: "Anti-CGRP monoclonal antibodies (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 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 has 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." 

A retrospective multisite cohort study of patients less than 18 years of age who received a calcitonin gene-related peptide monoclonal antibody for headache prevention has since been published [4]. The authors described: "The study population comprised 112 adolescents who received at least one dose of a calcitonin gene-related peptide monoclonal antibody. Mean (standard deviation (SD).; range) age at first dose was 15.9 years (1.4; 10.3 to 17.8). Ninety-four patients (83.9%) had chronic migraine, 12 (10.7%) had new daily persistent headache, and six (5.4%) had persistent post-traumatic headache. At baseline, the mean (SD) number of headache days per month was 26.9 (6.1) (number [n] = 109) and headache was continuous in 75 of 111 (67.6%). 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 (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." The authors concluded: "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 reviewer notes that as a pediatric neurologist, a large proportion of the medications used for children are initially used on an off-label basis. Medications are almost always subjected to clinical trials only in adults. Clinical trials may not be conducted in children and adolescents for several years (if ever) after the drugs are released on the market.
The American Academy of Pediatrics issued a Policy Statement: Off-Label Use of Drugs in Children [5]. In it they stated that: "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. Rather, it only means that the evidence required by law to allow inclusion in the label has not been approved by the FDA. Additionally, in no way does a lack of labeling 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 FDA for review or has not met the regulatory standards of "substantial evidence" for FDA approval."