Which of the following medications—K‑bind (potassium binder), Pangraf (pimobendan) 2 mg twice daily, everolimus 0.5 mg twice daily, Thyronorm (levothyroxine) 50 µg, Pantocid (pantoprazole) delayed‑release twice daily, Telmisartan 40 mg, Pregabalin 75 mg, Sucrafil (insulin) twice daily, Shelcal M 500 mg twice daily, Lumia 60,000 IU weekly, Januvia (sitagliptin) 100 mg, and Humalog (insulin lispro)—is most likely responsible for severe itching?

Which Drug is Causing Severe Itching?

Among this medication list, Pangraf (tacrolimus) and everolimus are the most likely culprits for severe itching, with Pangraf being the primary suspect as a calcineurin inhibitor immunosuppressant commonly associated with pruritus in transplant recipients.

Primary Suspects: Immunosuppressants

Pangraf (Tacrolimus)

• Tacrolimus is a well-known cause of pruritus in transplant patients, particularly when used in combination with other immunosuppressants 1
• The itching typically develops several months after starting the medication and can be severe and persistent 1
• This patient appears to be a transplant recipient (given the combination of Pangraf + everolimus), which is the exact population at highest risk 1

Everolimus

• Everolimus has documented pruritus as an adverse effect, occurring in approximately 12% of patients in long-term safety data 2
• However, meta-analysis data shows everolimus has a low relative risk for high-grade pruritus (RR 0.49), making it less likely than other targeted agents to cause severe itching 3
• The FDA label confirms pruritus occurs but is generally mild 2
• When combined with other immunosuppressants (as in this case with Pangraf), the risk may be additive 1

Secondary Considerations

Januvia (Sitagliptin)

• DPP-4 inhibitors like sitagliptin can cause urticaria and bullous pemphigoid that present with itching 4
• This is less common than immunosuppressant-related pruritus but should be considered if skin lesions are present 4
• If itching occurs with sitagliptin, switching to alternative diabetes medications (metformin, GLP-1 agonists, or SGLT2 inhibitors) should be considered 4

Pregabalin

• Paradoxically, pregabalin is actually used to TREAT pruritus, not cause it 3
• ESMO guidelines recommend pregabalin (25-150 mg daily) as second-line treatment for drug-induced pruritus 3
• This medication is unlikely to be the culprit

Diagnostic Approach

Assess the temporal relationship between drug initiation and pruritus onset:

• If itching began 3-6 months after transplant, Pangraf is most likely 1
• If itching is recent and corresponds with everolimus initiation, consider everolimus 2
• Document whether itching is associated with visible skin changes (rash, urticaria) or occurs without lesions 4

Key clinical features to evaluate:

• Location: Distal extremities, face, and earlobes suggest immunosuppressant-related pruritus 1
• Severity: Assess using visual analog scale or numeric rating scale 3
• Associated symptoms: Look for rash (suggests everolimus or sitagliptin), cholestasis (check liver function), or signs of bullous pemphigoid 4, 2

Management Algorithm

Step 1: Initial symptomatic treatment while investigating

• Apply topical moderate-to-high potency corticosteroids (mometasone 0.1% or betamethasone 0.1%) 3
• Consider non-sedating antihistamines (loratadine 10 mg daily) for daytime 3
• Use sedating antihistamines (diphenhydramine 25-50 mg) at night if sleep is affected 3

Step 2: If symptoms persist after 2 weeks

• The pregabalin dose (75 mg) is already therapeutic for pruritus, so increasing it may help 3
• Consider temporary dose reduction of Pangraf (check with transplant team first) 1

Step 3: If severe and intolerable

• Switching from one mTOR inhibitor to another (sirolimus to everolimus or vice versa) may provide temporary relief but is not definitive 1
• Discontinuation of the causative immunosuppressant may be necessary, requiring alternative immunosuppression strategy 1
• Document the reaction thoroughly in the medical record for future prescribing decisions 4

Critical Pitfalls to Avoid

• Do not abruptly discontinue immunosuppressants without consulting the transplant team, as this risks organ rejection 1
• Do not assume all itching is drug-related—check for other causes including cholestasis (check bilirubin, alkaline phosphatase), uremia (check creatinine), or thyroid dysfunction (patient is on Thyronorm) 5
• Do not overlook the possibility of multiple contributing drugs in this polypharmacy scenario—the combination of Pangraf + everolimus may have additive effects 1