Chemical formula: C6534H10004N1716O2036S46 Molecular mass: 149,000 g/mol
Pembrolizumab interacts in the following cases:
The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. However, systemic corticosteroids or other immunosuppressants can be used after starting pembrolizumab to treat immune-related adverse reactions. Corticosteroids can also be used as premedication, when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions.
There are no data on the use of pembrolizumab in pregnant women. Animal reproduction studies have not been conducted with pembrolizumab; however, in murine models of pregnancy blockade of PD-L1 signaling has been shown to disrupt tolerance to the foetus and to result in an increased foetal loss. These results indicate a potential risk, based on its mechanism of action, that administration of pembrolizumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth. Human immunoglobulins G4 (IgG4) are known to cross the placental barrier; therefore, being an IgG4, pembrolizumab has the potential to be transmitted from the mother to the developing foetus. Pembrolizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab.
It is unknown whether pembrolizumab is secreted in human milk. Since it is known that antibodies can be secreted in human milk, a risk to the newborns/infants cannot be excluded. A decision should be made whether to discontinue breast-feeding or to discontinue pembrolizumab, taking into account the benefit of breast-feeding for the child and the benefit of pembrolizumab therapy for the woman.
Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab.
No clinical data are available on the possible effects of pembrolizumab on fertility. There were no notable effects in the male and female reproductive organs in monkeys based on 1-month and 6-month repeat dose toxicity studies.
Pembrolizumab may have a minor influence on the ability to drive and use machines. Fatigue has been reported following administration of pembrolizumab.
Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of pembrolizumab (see “Description of selected adverse reactions” below).
The safety of pembrolizumab as monotherapy has been evaluated in 4,948 patients with advanced melanoma, resected Stage III melanoma (adjuvant therapy), NSCLC, cHL, urothelial carcinoma, or HNSCC across four doses (2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks) in clinical studies. The frequencies included below and in the following lists are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. In this patient population, the median observation time was 7.3 months (range: 1 day to 31 months) and the most frequent adverse reactions with pembrolizumab were fatigue (34.1%), rash (22.7%), nausea (21.7%), diarrhoea (21.5%), and pruritus (20.2%). The majority of adverse reactions reported for monotherapy were of Grade 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions.
The safety of pembrolizumab in combination with chemotherapy has been evaluated in 791 patients with NSCLC receiving 200 mg, 2 mg/kg or 10 mg/kg pembrolizumab every 3 weeks, in clinical studies. The frequencies included below and in the following lists are based on all reported adverse drug reactions, regardless of the investigator assessment of causality. In this patient population, the most frequent adverse reactions were nausea (49%), anaemia (48%), fatigue (38%), constipation (34%), diarrhoea (31%), neutropaenia (29%), and decreased appetite (28%). Incidences of Grade 3-5 adverse reactions were 67% for pembrolizumab combination therapy and 66% for chemotherapy alone.
Adverse reactions observed in clinical studies of pembrolizumab as monotherapy or in combination with chemotherapy, or reported from post-marketing use of pembrolizumab are listed below. Adverse reactions known to occur with pembrolizumab or chemotherapies given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical trials with combination therapy. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Adverse reactions in patients treated with pembrolizumab*:
Monotherapy:
Common: pneumonia
Very common: anaemia
Common: thrombocytopaenia, lymphopaenia
Uncommon: neutropaenia, leukopaenia, eosinophilia
Rare: immune thrombocytopenic purpura, haemolytic anaemia, pure red cell aplasia, haemophagocytic lymphohistiocytosis
Common: infusion related reactiona
Uncommon: sarcoidosis
Not known: solid organ transplant rejection
Very common: hypothyroidismb
Common: hyperthyroidism
Uncommon: hypophysitisc, thyroiditisd, adrenal insufficiency
Very common: decreased appetite
Common: hyponatraemia, hypokalaemia, hypocalcaemia
Uncommon: type 1 diabetes mellituse
Common: insomnia
Very common: headache
Common: dizziness, neuropathy peripheral, lethargy, dysgeusia
Uncommon: epilepsy
Rare: Guillain-Barré syndromef, myasthenic syndromeg, meningitis (aseptic), encephalitis
Common: dry eye
Uncommon: uveitish
Rare: Vogt-Koyanagi-Harada syndrome
Uncommon: pericardial effusion, pericarditis
Rare: myocarditis
Common: hypertension
Very common: dyspnoea, cough
Common: pneumonitisi
Very common: diarrhoea, abdominal painj, nausea, vomiting, constipation
Common: colitisk, dry mouth
Uncommon: pancreatitisl
Rare: small intestinal perforation
Uncommon: hepatitism
Very common: rashn, prurituso
Common: severe skin reactionsp, erythema, vitiligoq, dry skin, alopecia, eczema, dermatitis acneiform
Uncommon: lichenoid keratosisr, psoriasis, dermatitis, papule, hair colour changes
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema nodosum
Very common: musculoskeletal pains, arthralgia
Common: pain in extremity, myositist, arthritisu
Uncommon: tenosynovitisv
Uncommon: nephritisw
Very common: fatigue, asthenia, oedemax, pyrexia
Common: influenza like illness, chills
Common: aspartate aminotransferase increased, alanine aminotransferase increased, hypercalcaemia, blood alkaline phosphatase increased, blood bilirubin increased, blood creatinine increased
Uncommon: amylase increased
Combination with chemotherapy:
Common: pneumonia
Very common: neutropaenia, anaemia, thrombocytopaenia
Common: febrile neutropaenia, leukopaenia, lymphopaenia
Uncommon: eosinophilia
Common: infusion related reactiona
Common: hypothyroidism, hyperthyroidism
Uncommon: hypophysitisc, thyroiditis, adrenal insufficiency
Very common: decreased appetite
Common: hyponatraemia, hypokalaemia, hypocalcaemia
Uncommon: type 1 diabetes mellitus
Common: insomnia
Very common: dizziness, neuropathy peripheral, dysgeusia, headache
Common: lethargy
Uncommon: epilepsy
Common: dry eye
Uncommon: pericardial effusion, pericarditis
Common: hypertension
Very common: dyspnoea, cough
Common: pneumonitisi
__Very common:__diarrhoea, nausea, vomiting, constipation, abdominal painj
Common: colitisk, dry mouth
Uncommon: pancreatitisl
Common: hepatitism
Very common: rashn, alopecia, prurituso
Common: severe skin reactionsp, erythema, dermatitis acneiform, dry skin
Uncommon: psoriasis, dermatitis, eczema, hair colour changes, lichenoid keratosis, papule, vitiligoq
Very common: musculoskeletal pains, arthralgia
Common: myositist, pain in extremity, arthritisu
Uncommon: tenosynovitisv
Common: nephritisw, acute kidney injury
Very common: fatigue, asthenia, oedemax, pyrexia
Common: chills, influenza-like illness
Very common: alanine aminotransferase increased, blood creatinine increased
Common: aspartate aminotransferase increased, hypercalcaemia, blood alkaline phosphatase increased
Uncommon: amylase increased, blood bilirubin increased
* Adverse reaction frequencies presented may not be fully attributable to pembrolizumab alone but may contain contributions from the underlying disease or from other medicinal products used in a combination. The following terms represent a group of related events that describe a medical condition rather than a single event.
a infusion-related reaction (drug hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity and cytokine release syndrome)
b hypothyroidism (myxoedema)
c hypophysitis (hypopituitarism)
d thyroiditis (autoimmune thyroiditis and thyroid disorder)
e type 1 diabetes mellitus (diabetic ketoacidosis)
f Guillain-Barré syndrome (axonal neuropathy and demyelinating polyneuropathy)
g myasthenic syndrome (myasthenia gravis, including exacerbation)
h uveitis (iritis and iridocyclitis)
i pneumonitis (interstitial lung disease)
j abdominal pain (abdominal discomfort, abdominal pain upper and abdominal pain lower)
k colitis (colitis microscopic, enterocolitis, and autoimmune colitis)
l pancreatitis (autoimmune pancreatitis and pancreatitis acute)
m hepatitis (autoimmune hepatitis and drug induced liver injury)
n rash (rash erythematous, rash follicular, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular and genital rash)
o pruritus (urticaria, urticaria papular, pruritus generalised and pruritus genital)
p severe skin reactions (dermatitis bullous, dermatitis exfoliative, erythema multiforme, exfoliative rash, pemphigus, skin necrosis, toxic skin eruption and Grade ≥3 of the following: acute febrile neutropaenic dermatosis, contusion, decubitus ulcer, dermatitis psoriasiform, drug eruption, jaundice, pemphigoid, pruritus, pruritus generalised, rash, rash erythematous, rash generalised, rash maculo-papular, rash pruritic, rash pustular and skin lesion)
q vitiligo (skin depigmentation, skin hypopigmentation and hypopigmentation of the eyelid)
r lichenoid keratosis (lichen planus and lichen sclerosus)
s musculoskeletal pain (musculoskeletal discomfort, back pain, musculoskeletal stiffness, musculoskeletal chest pain and torticollis)
t myositis (myalgia, myopathy, polymyalgia rheumatica and rhabdomyolysis)
u arthritis (joint swelling, polyarthritis and joint effusion)
v tenosynovitis (tendonitis, synovitis and tendon pain)
w nephritis (nephritis autoimmune, tubulointerstitial nephritis and renal failure, renal failure acute, or acute kidney injury with evidence of nephritis, nephrotic syndrome)
x oedema (oedema peripheral, generalised oedema, fluid overload, fluid retention, eyelid oedema and lip oedema, face oedema, localised oedema and periorbital oedema)
Data for the following immune-related adverse reactions are based on patients who received pembrolizumab across four doses (2 mg/kg every 3 weeks, 10 mg/kg every 2 or 3 weeks, or 200 mg every 3 weeks) in clinical studies.
Pneumonitis occurred in 182 (3.7%) patients, including Grade 2, 3, 4 or 5 cases in 78 (1.6%), 48 (1.0%), 9 (0.2%) and 7 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of pneumonitis was 3.7 months (range 2 days to 21.3 months). The median duration was 1.9 months (range 1 day to 17.2+ months). Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (8.1%) than in patients who did not receive prior thoracic radiation (3.3%). Pneumonitis led to discontinuation of pembrolizumab in 75 (1.5%) patients. Pneumonitis resolved in 101 patients, 2 with sequelae.
In patients with NSCLC, pneumonitis occurred in 107 (4.9%), including Grade 2, 3, 4 or 5 cases in 39 (1.8%), 30 (1.4%), 10 (0.5%) and 9 (0.4%), respectively. In patients with NSCLC, pneumonitis occurred in 8.1% with a history of prior thoracic radiation.
Colitis occurred in 97 (2.0%) patients, including Grade 2, 3 or 4 cases in 28 (0.6%), 56 (1.1%) and 3 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of colitis was 3.8 months (range 7 days to 20.2 months). The median duration was 1.2 months (range 1 day to 8.7+ months). Colitis led to discontinuation of pembrolizumab in 28 (0.6%) patients. Colitis resolved in 75 patients, 1 with sequelae.
Hepatitis occurred in 39 (0.8%) patients, including Grade 2, 3 or 4 cases in 7 (0.1%), 26 (0.5%) and 4 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hepatitis was 2.8 months (range 8 days to 21.4 months). The median duration was 1.1 months (range 1 day to 20.9+ months). Hepatitis led to discontinuation of pembrolizumab in 14 (0.3%) patients. Hepatitis resolved in 27 patients.
Nephritis occurred in 17 (0.3%) patients, including Grade 2, 3 or 4 cases in 3 (0.1%), 12 (0.2%) and 1 (<0.1%) patients, respectively, receiving pembrolizumab as monotherapy. The median time to onset of nephritis was 5.1 months (range 12 days to 12.8 months). The median duration was 1.8 months (range 6 days to 10.5+ months). Nephritis led to discontinuation of pembrolizumab in 7 (0.1%) patients. Nephritis resolved in 9 patients, 1 with sequelae. In patients with non-squamous NSCLC treated with pembrolizumab in combination with pemetrexed and platinum chemotherapy (n=488), the incidence of nephritis was 1.4% (all Grades) with 0.8% Grade 3 and 0.4% Grade 4.
Hypophysitis occurred in 32 (0.6%) patients, including Grade 2, 3 or 4 cases in 13 (0.3%), 15 (0.3%) and 1 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypophysitis was 5.3 months (range 1 day to 17.7 months). The median duration was 1.7 months (range 3 days to 18.1+ months). Hypophysitis led to discontinuation of pembrolizumab in 8 (0.2%) patients. Hypophysitis resolved in 9 patients, 7 with sequelae.
Hyperthyroidism occurred in 197 (4.0%) patients, including Grade 2 or 3 cases in 52 (1.1%) and 5 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hyperthyroidism was 1.4 months (range 1 day to 21.9 months). The median duration was 1.7 months (range 4 days to 15.5+ months). Hyperthyroidism led to discontinuation of pembrolizumab in 3 (0.1%) patients. Hyperthyroidism resolved in 152 (77.2%) patients, 1 with sequelae.
Hypothyroidism occurred in 514 (10.4%) patients, including Grade 2 or 3 cases in 377 (7.6%) and 7 (0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of hypothyroidism was 3.5 months (range 1 day to 18.9 months). The median duration was not reached (range 2 days to 29.9+ months). Two patients (<0.1%) discontinued pembrolizumab due to hypothyroidism. Hypothyroidism resolved in 107 (20.8%) patients, 9 with sequelae. In patients with cHL (n=241) the incidence of hypothyroidism was 14.1% (all Grades) with 0.4% Grade 3. In patients with HNSCC (n=609), the incidence of hypothyroidism was 15.1% (all Grades) with 0.5% Grade 3.
Immune-related severe skin reactions occurred in 66 (1.3%) patients, including Grade 2, 3 or 5 cases in 6 (0.1%), 48 (1.0%) and 1 (<0.1%) patients, respectively, receiving pembrolizumab. The median time to onset of severe skin reactions was 3.2 months (range 4 days to 19.4 months). The median duration was 1.6 months (range 1 day to 16.1+ months). Severe skin reactions led to discontinuation of pembrolizumab in 5 (0.2%) patients. Severe skin reactions resolved in 46 patients.
Rare cases of SJS and TEN, some of them with fatal outcome, have been observed (see sections 4.2 and 4.4).
Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with pembrolizumab, 6 patients (26%) developed GVHD, one of which was fatal, and 2 patients (9%) developed severe hepatic VOD after reduced-intensity conditioning, one of which was fatal. The 23 patients had a median follow-up from subsequent allogeneic HSCT of 5.1 months (range: 0-26.2 months).
In patients treated with pembrolizumab monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 10.8% for lymphocytes decreased, 7.6% for sodium decreased, 6.5% for haemoglobin decreased, 5.2% for phosphate decreased, 5.2% for glucose increased, 2.9% for alkaline phosphatase increased, 2.6% for AST increased, 2.3% for ALT increased, 2% for potassium decreased, 1.8% for bilirubin increased, 1.6% for potassium increased, 1.5% for albumin decreased, 1.5% for calcium increased, 1.4% for creatinine increased, 1.4% for platelets decreased, 1.4% for neutrophils decreased, 1.2% for calcium decreased, 0.8% for magnesium increased, 0.6% for leucocytes decreased, 0.5% for glucose decreased, 0.2% for magnesium decreased, and 0.2% for sodium increased.
In patients treated with pembrolizumab in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 23.8% for neutrophils decreased, 20.2% for lymphocytes decreased, 16.2% for haemoglobin decreased, 14.6% for leucocytes decreased, 10.3% for platelets decreased, 7.9% for glucose increased, 7.8% for phosphate decreased, 7.4% for sodium decreased, 4.6% for potassium decreased, 3.7% for ALT increased, 3.6% for creatinine increased, 3.5% for AST increased, 2.9% for calcium decreased, 2.6% for potassium increased, 2.5% for albumin decreased, 1.7% for calcium increased, 1.2% for alkaline phosphatase increased, 0.9% for glucose decreased, 0.7% for bilirubin increased, and 0.1% for sodium increased.
In clinical studies in patients treated with pembrolizumab 2 mg/kg every three weeks, 200 mg every three weeks, or 10 mg/kg every two or three weeks as monotherapy, 36 (1.8%) of 2,034 evaluable patients tested positive for treatment-emergent antibodies to pembrolizumab, of which 9 (0.4%) patients had neutralising antibodies against pembrolizumab. There was no evidence of an altered pharmacokinetic or safety profile with anti-pembrolizumab binding or neutralising antibody development.
The safety of pembrolizumab as monotherapy has been evaluated in 154 paediatric patients with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumours at 2 mg/kg every 3 weeks in the Phase I/II study KEYNOTE-051. The safety profile in these paediatric patients was generally similar to that seen in adults treated with pembrolizumab. The most common adverse reactions (reported in at least 20% of paediatric patients) were pyrexia (31%), vomiting (26%), headache (22%), abdominal pain (21%), anaemia (21%) and constipation (20%). The majority of adverse reactions reported for monotherapy were of Grade 1 or 2 severity. Sixty-nine (44.8%) patients had 1 or more Grades 3 to 5 adverse reactions of which 6 (3.9%) patients had 1 or more adverse reactions that resulted in death. The frequencies are based on all reported adverse drug reactions, regardless of the investigator assessment of causality.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
