What should I consider in a 20-year-old with fatigue, low iron saturation, thrombocytosis, and migraine prophylaxis with Topamax (topiramate) 100 mg nightly and Ubrelvy (ubrogepant) PRN?

Evaluation of a 20-Year-Old with Fatigue, Low Iron Saturation, and Thrombocytosis on Topiramate

Primary Diagnosis: Iron Deficiency Anemia

You should diagnose and treat iron deficiency anemia as the primary cause of fatigue in this patient. With an iron saturation of 15% (well below the 20% threshold), this patient meets diagnostic criteria for iron deficiency even without documented anemia 1. The elevated platelet count of 445 is a classic reactive thrombocytosis seen with iron deficiency and should normalize with iron repletion 1.

Iron Deficiency Workup

• Obtain a complete iron panel including serum iron, transferrin, transferrin saturation (already 15%), ferritin, CRP, and evaluate red blood cell morphology to fully characterize the deficiency 1.
• Check hemoglobin level to determine severity—if hemoglobin is <110 g/L, this confirms iron deficiency anemia requiring more aggressive treatment 1.
• Measure ferritin levels: target ferritin ≥100 ng/mL for optimal iron stores 1.

Iron Replacement Strategy

• Start oral iron supplementation with 18-30 mg elemental iron daily as first-line therapy 1.
• If oral iron fails or is not tolerated, consider IV iron as a single 1g dose of ferric carboxymaltose infused over 15 minutes using recent carbohydrate formulations 1.
• Recheck iron studies in 8-10 weeks (not earlier, as ferritin levels are falsely elevated immediately after IV iron) 1.

Critical Topiramate-Related Considerations

Rule Out Topiramate as Contributing Factor

Topiramate at 100 mg nightly is within the therapeutic range for migraine prophylaxis but requires specific safety monitoring in this clinical context 2, 3.

• Assess for cognitive side effects: fatigue, mental clouding, and cognitive slowing occur commonly with topiramate and may be contributing to or mimicking the fatigue from iron deficiency 3.
• Evaluate for metabolic acidosis: topiramate's carbonic anhydrase inhibition can cause chronic fatigue as a manifestation of metabolic acidosis—check serum bicarbonate 4.
• Screen for nephrolithiasis: topiramate increases kidney stone risk through hypercalciuria and hypocitraturia, which can present with fatigue 4, 3.

Reproductive Health Counseling (Critical in 20-Year-Old Female)

Immediately counsel this patient about topiramate's teratogenic risks and contraceptive efficacy 4.

• Topiramate causes neural tube defects and orofacial clefts with first-trimester exposure (Pregnancy Category D) 4, 3.
• Topiramate reduces oral contraceptive efficacy, requiring alternative contraception methods 5, 4.
• Institute monthly pregnancy testing if the patient remains on topiramate 4.

Hematologic Monitoring

Although extremely rare, topiramate-associated agranulocytosis has been reported at doses of 200 mg daily 6. While this patient is on 100 mg, the elevated platelet count warrants:

• Obtain a complete blood count with differential to ensure the white blood cell count and absolute neutrophil count are normal 6.
• Monitor for signs of infection (sore throat, fever) that could indicate bone marrow suppression 6.

Differential Diagnosis for Persistent Fatigue

If fatigue persists after iron repletion, consider:

Medication-Induced Fatigue

• Topiramate-related CNS effects: paresthesias (occur in 30-50% at 100 mg/day), cognitive slowing, and fatigue are dose-dependent 4, 3.
• Consider dose reduction or extended-release formulation: XR topiramate (Qudexy XR or Trokendi XR) may reduce cognitive side effects through more stable plasma concentrations 3.

Migraine-Related Fatigue

• Chronic migraine itself causes significant fatigue and disability independent of medications 2.
• Evaluate migraine control: if the patient has ≥15 headache days per month with ≥8 migraine days, this is chronic migraine requiring optimization of preventive therapy 5, 2.

Ubrelvy (Ubrogepant) Safety

• Ubrogepant PRN use is safe and well-tolerated with topiramate prophylaxis 7, 8.
• Most common side effects are nausea (2.1-4.1%), somnolence, and dry mouth, which could contribute to fatigue 8.
• Limit to 8 doses per 4-week interval to avoid medication overuse headache 7.

Algorithmic Approach

1. Immediate actions:

   • Order complete iron panel, CBC with differential, serum bicarbonate 1, 4
   • Verify pregnancy status and contraception method 4
   • Start oral iron supplementation 18-30 mg daily 1

2. At 2-week follow-up:

   • Review lab results
   • Assess for topiramate side effects (paresthesias, cognitive changes, metabolic acidosis) 4, 3
   • Ensure adequate hydration to prevent kidney stones 3

3. At 8-10 week follow-up:

   • Recheck iron studies and CBC 1
   • If iron saturation >20%, ferritin >100 ng/mL, and platelets normalized, continue oral iron 1
   • If fatigue persists despite iron repletion, consider topiramate dose reduction or switch to XR formulation 3

4. If oral iron fails:

   • Administer IV iron 1g as single dose 1
   • Recheck iron studies 8-10 weeks after IV infusion 1

Common Pitfalls to Avoid

• Do not attribute all fatigue to topiramate without first correcting iron deficiency—iron saturation of 15% is definitively low and requires treatment 1.
• Do not overlook reproductive counseling in a 20-year-old female on topiramate—teratogenic risk is high and contraceptive efficacy is reduced 5, 4.
• Do not recheck iron studies too early after IV iron administration—wait 8-10 weeks for accurate assessment 1.
• Do not confuse reactive thrombocytosis with a primary hematologic disorder—platelets of 445 are expected with iron deficiency and should normalize with treatment 1.