Is Headache an Established Side Effect with Cinacalcet?
Headache is not a statistically established side effect of cinacalcet based on the highest quality meta-analytic evidence, though it is listed in FDA labeling and occurs in clinical practice at rates that do not significantly differ from placebo.
Evidence Quality and Findings
The most rigorous evidence comes from a comprehensive meta-analysis of randomized controlled trials published in PLoS Medicine, which pooled data from 31 studies with 115 participants specifically evaluating headache as an adverse effect. 1
The relative risk for headache with cinacalcet versus placebo was 1.51 (95% CI: 0.95 to 2.42), which is not statistically significant (the confidence interval crosses 1.0, indicating no definitive increased risk). 1
The heterogeneity for headache was low (I² = 0.69), suggesting consistent findings across studies. 1
This contrasts sharply with well-established adverse effects like hypocalcemia (RR = 7.38), nausea (RR = 2.05), and vomiting (RR = 1.95), all of which show clear statistical significance. 1
FDA Labeling and Clinical Context
Despite the lack of statistical significance in pooled trial data, the FDA label does list headache as an observed adverse reaction in specific populations:
In patients with parathyroid carcinoma, headache occurred in 21% (6/29) of patients. 2
In a double-blind study of primary hyperparathyroidism patients, headache occurred in 12% (4/33) of cinacalcet-treated patients versus 6% (2/34) of placebo patients. 2
In parathyroid carcinoma studies, headache was reported among adverse events alongside nausea and vomiting. 3
Clinical Management Approach
When a patient on cinacalcet reports headache, do not automatically attribute it to the medication given the uncertain causal relationship. 4
Evaluate alternative causes systematically, particularly CKD-related triggers such as hypertension, uremia, or dialysis-related factors. 4
Check serum calcium levels immediately—if hypocalcemia is present (< 8.4 mg/dL), reduce or hold cinacalcet and provide calcium supplementation. 4
Treat headache symptomatically with standard therapies while monitoring for metabolic derangements. 4
Monitor serum calcium and phosphorus every 2 weeks for the first month after starting cinacalcet or dose changes, then monthly thereafter. 4
Important Caveats
The established adverse effects that should concern clinicians are hypocalcemia (occurring in 66-75% of dialysis patients), nausea (RR = 2.05), and vomiting (RR = 1.95)—these are statistically significant and clinically meaningful. 1, 5
Gastrointestinal symptoms can lead to dehydration and worsening hypercalcemia, requiring careful electrolyte monitoring. 2
In primary hyperparathyroidism studies, cinacalcet did not provide symptom relief and 21.6% of patients felt worse, though this was not specifically attributed to headache. 6