RECOMMENDED DOSAGE MODIFICATIONS FOR PEMBROLIZUMAB |
Adverse Event | Grade / Severity | Treatment Modification |
Infusion reaction | Clinically significant but not severe infusion reaction | Interrupt the infusion in patients with clinically significant infusion reactions and consider resuming at a slower rate following resolution. If decision is made to restart, begin at ≤50% of the rate prior to the reaction and increase in 50% increments every 30 minutes if well tolerated. Infusions may be restarted at the full rate during the next cycle |
G3/4 (severe infusion reaction—pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria). Not rapidly responsive to brief interruption of infusion | Stop infusion and administer appropriate medical therapy (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and/or oxygen). Discontinue pembrolizumab |
Colitis | G1 | Loperamide 4 mg as starting dose, then 2 mg before each meal and after each loose stool until without diarrhea for 12 hours, with maximum of 16 mg loperamide per day. If G1 diarrhea or colitis persists >14 days, add prednisolone 0.5–1 mg/kg (non–enteric coated) or consider oral budesonide 9 mg daily if no bloody diarrhea |
G2/3 diarrhea or colitis | Withhold pembrolizumab. Loperamide 4 mg as starting dose, then 2 mg before each meal and after each loose stool until without diarrhea for 12 hours, with maximum of 16 mg loperamide per day. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg |
G4 diarrhea or colitis | Permanently discontinue pembrolizumab. Loperamide 4 mg as starting dose, then 2 mg before each meal and after each loose stool until without diarrhea for 12 hours, with maximum of 16 mg loperamide per day. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4 weeks when symptoms improve. If symptoms do not improve over 72 hours or worsen, perform flexible sigmoidoscopy/colonoscopy to document colitis, then begin infliximab 5 mg/kg (if no perforation, sepsis, TB, hepatitis, NYHA III/IV CHF). If no response, add MMF 500–1000 mg twice daily. If worse on MMF, consider addition of tacrolimus or ATG |
Pneumonitis | G2 | Withhold pembrolizumab. Consider pneumocystis prophylaxis depending on the clinical context and coverage with empiric antibiotics. Administer oral prednisone/prednisolone at a dosage of 1–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. If response is not adequate after 48 hours, administer 2–4 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 6 weeks when symptoms improve to G1, titrating to symptoms. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg |
G3/4 | Permanently discontinue pembrolizumab. Consider pneumocystis prophylaxis depending on the clinical context; cover with empiric antibiotics. Administer 2–4 mg/kg intravenous (methyl)prednisolone and convert to 1–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 8 weeks when symptoms improve to G1, titrating to symptoms. If, when initially treated, improvement does not occur within 48–72 hours, begin infliximab 5 mg/kg (if no perforation, sepsis, TB, hepatitis, NYHA III/IV CHF). If no response to infliximab, add MMF 500–1000 mg twice daily. Consider MMF especially if concurrent hepatic toxicity |
Hepatitis | G2 (AST or ALT >3–5× ULN or total bilirubin >1.5–3× ULN) | Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 1–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg |
G3/4 (AST or ALT >5× ULN or total bilirubin >3× ULN) | Permanently discontinue pembrolizumab. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 6 weeks when symptoms improve. If no response, add MMF 500–1000 mg twice daily. If worse on MMF, consider adding tacrolimus or ATG |
Hypophysitis | G2/3 (moderate symptoms, ie, headache but no visual disturbance or fatigue/mood alteration but hemodynamically stable, no electrolyte disturbance) | Administer analgesia as needed for headache. Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When improves to G1, begin a slow corticosteroid taper over at least 4 weeks. If no improvement in 48 hours, administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4 weeks when symptoms improve to 5 mg prednisone/prednisolone or equivalent; do not stop steroids. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg |
G4 (severe mass effect symptoms, ie, severe headache, any visual disturbance or severe hypoadrenalism, ie, hypotension, severe electrolyte disturbance) | Permanently discontinue pembrolizumab. Administer analgesia as needed for headache. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4 weeks when symptoms improve to 5 mg prednisone prednisolone or equivalent; do not stop steroids |
Adrenal insufficiency | G2 | Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Serially assess adrenal function and continue steroids at replacement doses (20–40 mg hydrocortisone daily ~2/3 dose in morning upon awakening and ~1/3 at 4 pm) until recovery of adrenal function is documented. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg |
G3/4 | Permanently discontinue pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Serially assess adrenal function and continue steroids at replacement doses (20–40 mg hydrocortisone daily ~2/3 dose in morning upon awakening and ~1/3 at 4 pm) until recovery of adrenal function is documented |
Type 1 diabetes mellitus | G3 hyperglycemia | Withhold pembrolizumab. Admit to hospital to manage hyperglycemia. Role of corticosteroids in preventing complete loss of insulin-producing cells is unknown, and use is not recommended. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg |
G4 hyperglycemia | Permanently discontinue pembrolizumab. Admit to hospital to manage hyperglycemia. Role of corticosteroids in preventing complete loss of insulin-producing cells is unknown, and use is not recommended. |
Nephritis and renal dysfunction | G2/3 (serum creatinine 1.5–6× ULN) | Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. If response is not adequate, administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg |
G4 (serum creatinine >6× ULN) | Permanently discontinue pembrolizumab. Administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. |
Skin | G1/2 | Continue pembrolizumab. Avoid skin irritants, avoid sun exposure; topical emollients recommended. Topical steroid (mild strength for G1, moderate/potent strength for G2) cream once or twice daily ± oral or topical antihistamines for itching |
G3 rash or suspected SJS or TEN | Withhold pembrolizumab. Avoid skin irritants, avoid sun exposure; topical emollients recommended. Administer oral or topical antihistamines for itching. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg or its equivalent daily for 3 days followed by a slow corticosteroid taper over at least 4 weeks when the rash improves to G1. If rash does not respond adequately, administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when the rash improves to G1. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg |
G4 rash or confirmed SJS or TEN | Avoid skin irritants, avoid sun exposure; topical emollients recommended. Administer oral or topical antihistamines for itching. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to oral steroids 0.5–2 mg/kg prednisone/prednisolone each day or its equivalent only after a response. Taper over at least 4 weeks when the rash improves to G1. Permanently discontinue pembrolizumab |
Encephalitis | Confusion or altered behavior, headaches, alteration in Glasgow coma scale, motor or sensory deficits, speech abnormality; may or may not be febrile | Initially withhold pembrolizumab, but permanently discontinue pembrolizumab if there is no doubt as to diagnosis. Exclude bacterial and ideally viral infections prior to high-dose steroids. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve, begin a slow corticosteroid taper over at least 4–8 weeks. If symptoms are severe, administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Consider concurrent empiric antiviral (intravenous acyclovir) and antibacterial therapy |
Aseptic meningitis | Headache, photophobia, neck stiffness with fever, or may be afebrile, vomiting; normal cognition/cerebral function (distinguishes from encephalitis) |
Other syndromes include neurosarcoidosis, posterior reversible leukoencephalopathy syndrome (PRES), Vogt-Harada-Koyanagi syndrome, demyelination, vasculitic encephalopathy, and generalized seizures |
Transverse myelitis | Acute or subacute neurologic signs/symptoms of motor, sensory, autonomic origin; most have sensory level; often bilateral symptoms | Initially withhold pembrolizumab, but permanently discontinue pembrolizumab if there is no doubt as to diagnosis. Administer 2 mg/kg intravenous (methyl)prednisolone or consider 1 g/day and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. When symptoms improve, begin a slow corticosteroid taper over at least 4–8 weeks. Plasmapheresis may be required if steroids do not bring about improvement |
Myocarditis | G3 | Permanently discontinue pembrolizumab. Administer 2 mg/kg intravenous (methyl)prednisolone or consider 1 g/day and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. When symptoms improve, begin a slow corticosteroid taper over at least 4–8 weeks. If no response, add MMF 500–1000 mg twice daily. If worse on MMF, consider adding tacrolimus |
Peripheral neurologic toxicity | Moderate: some interference with ADL, symptoms concerning to patient | Withhold pembrolizumab. Initial observation reasonable or initiate prednisone/prednisolone 0.5–1 mg/kg (if progressing, eg, from mild) and/or pregabalin or duloxetine for pain. When symptoms improve, begin a slow corticosteroid taper over at least 4 weeks. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg |
Severe: limits self-care and aids warranted, life-threatening, eg, respiratory problems | Permanently discontinue pembrolizumab. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4–8 weeks when symptoms improve to G1 |
Guillain-Barré syndrome | Progressive symmetrical muscle weakness with absent or reduced tendon reflexes—involves extremities; facial, respiratory, and bulbar and oculomotor muscles; dysregulation of autonomic nerves | Permanently discontinue pembrolizumab. Use of steroids not recommended in idiopathic Guillain-Barré syndrome; however, a trial of (methyl)prednisolone 1–2 mg/kg is reasonable, converting to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. If no improvement or worsening, plasmapheresis or IVIG is indicated |
Myasthenia gravis | Fluctuating muscle weakness (proximal limb, trunk, ocular, eg, ptosis/diplopia or bulbar) with fatigability; respiratory muscles may also be involved | Permanently discontinue pembrolizumab. Administer pyridostigmine at an initial dosage of 30 mg 3 times daily. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent or 1–2 mg/kg intravenous (methyl)prednisolone, depending on the severity of symptoms. If treatment begins with intravenous drug, convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. If no improvement or worsening, plasmapheresis or IVIG may be considered. Additional immunosuppressants used in myasthenia gravis include azathioprine, cyclosporine, and mycophenolate. Avoid certain medications, eg, ciprofloxacin and beta-blockers, that may precipitate cholinergic crisis |
Other syndromes, including motor and sensory peripheral neuropathy, multifocal radicular neuropathy/plexopathy, autonomic neuropathy, phrenic nerve palsy, cranial nerve palsies (eg, facial nerve, optic nerve, hypoglossal nerve) | Permanently discontinue pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent or 1–2 mg/kg intravenous (methyl)prednisolone, depending on the severity of symptoms. If treatment begins with intravenous drug, convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response |
Arthralgia | G1 (mild pain with inflammation, erythema, or joint swelling) | Continue pembrolizumab. Administer acetaminophen (paracetamol) and ibuprofen |
G2 (moderate pain with inflammation, erythema, or joint swelling that limits ADLs) | Withhold pembrolizumab. Administer higher doses of acetaminophen (paracetamol) and ibuprofen and use diclofenac or naproxen or etoricoxib. If inadequately controlled, consider intra-articular steroid injections for large joints or administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. If response is not adequate, administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg |
G3 (severe pain; irreversible joint damage; disabling; limits self-care ADLs) | Withhold pembrolizumab. Administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. In severe cases, infliximab or another anti-TNF-alpha drug may be required for improvement of arthritis. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg |
Other | First occurrence of other G3 | Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg |
Recurrence of same G3 | Permanently discontinue pembrolizumab. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4–8 weeks when symptoms improve to G1 |
Life-threatening or G4 |
Requirement for ³10 mg/day prednisone or equivalent for >12 weeks | Permanently discontinue pembrolizumab |
Persistent G2/3 adverse reactions lasting ³12 weeks |
ADL, activities of daily living; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATG, anti-thymocyte globulin; CHF, congestive heart failure; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; NYHA, New York Heart Association; PRES, posterior reversible leukoencephalopathy syndrome; SJS, Stevens-Johnson syndrome; TB, tuberculosis; TEN, toxic epidermal necrolysis; TNF, tumor necrosis factor; ULN, upper limit of normal |