PD-L1 inhibition in IO


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SELECTED SAFETY INFORMATION

KEYTRUDA® (pembrolizumab) 50 mg powder for solution for infusion. 100 mg/4 mL (25 mg/mL) concentrate for solution for infusion.

Patient Alert Card The prescriber must discuss the risks of KEYTRUDA therapy with the patient. The patient should be provided with the Patient Alert Card.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Immune-mediated Adverse Reactions

Immune-mediated adverse reactions including severe and fatal cases, have occurred in patients receiving KEYTRUDA. In clinical trials, most immune-mediated adverse reactions occurred during treatment, were reversible and managed with interruptions of KEYTRUDA, administration of corticosteroids and/or supportive care. Immune-related adverse reactions have also occurred after the last dose of KEYTRUDA. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and consider administration of corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less following corticosteroid taper. If another episode of a severe adverse reaction occurs, permanently discontinue KEYTRUDA.

Immune-mediated pneumonitis

Pneumonitis (including fatal cases) has been reported in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of pneumonitis. If pneumonitis is suspected, evaluate with radiographic imaging and exclude other causes. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Immune-mediated colitis

Colitis has been reported in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis and exclude other causes. The potential risk of gastrointestinal perforation should be taken into consideration. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Immune-mediated hepatitis

Hepatitis has been reported in patients receiving KEYTRUDA. Monitor patients for changes in liver function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and symptoms of hepatitis and exclude other causes. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Immune-mediated nephritis

Nephritis has been reported in patients receiving KEYTRUDA. Nephritis appears to be more common when pembrolizumab is used in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function and exclude other causes. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Immune-mediated endocrinopathies

Hypophysitis has been reported in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and secondary adrenal insufficiency) and exclude other causes. Administer corticosteroids to treat secondary adrenal insufficiency and other hormone replacement as clinically indicated. (See Recommended Dosing and Dose Modifications)

Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving KEYTRUDA. Monitor patients for hyperglycaemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes and withhold KEYTRUDA in cases of severe hyperglycaemia until metabolic control is achieved. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Thyroid disorders, including hyperthyroidism, hypothyroidism and thyroiditis, have been reported in patients receiving KEYTRUDA and can occur at any time during treatment, therefore monitor patients for changes in thyroid function and clinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Severe skin reactions

Immune-mediated severe skin reactions have been reported in patients treated with KEYTRUDA. Monitor patients for suspected severe skin reactions and exclude other causes. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Cases of Stevens-Johnson syndrome (SJS) toxic epidermal necrolysis (TEN) and bullous pemphigoid, have been reported in patients treated with KEYTRUDA. Some cases of SJS and TEN have had a fatal outcome. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other immune-mediated adverse reactions

The following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients treated with KEYTRUDA in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010: uveitis, myositis, Guillain-Barre syndrome, pancreatitis, encephalitis, sarcoidosis and myasthenic syndrome/myasthenia gravis (including exacerbation). Myocarditis has been reported in other clinical studies with KEYTRUDA or in post-marketing use.

Transplant-related adverse reactions

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA versus the risk of possible organ rejection in these patients.

Acute graft-versus-host-disease (GVHD), including fatal GVHD, after treatment with KEYTRUDA has been reported in patients with a history of allogeneic hematopoietic stem cell transplant (HSCT). Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after treatment with KEYTRUDA. Consider the benefit of treatment with KEYTRUDA versus the risk of possible GVHD in patients with a history of allogeneic HSCT.

Increased mortality in patients with multiple myeloma when KEYTRUDA is added to a thalidomide analogue and dexamethasone

In two randomized clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA versus the risk of possible organ rejection in these patients.

Infusion-related reactions

Severe infusion reactions, including hypersensitivity and anaphylaxis, have been reported in 6 (0.2%) of 2799 patients receiving KEYTRUDA in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006 and KEYNOTE-010. (See Recommended Dosing and Dose Modifications)

Effects on Fertility

Fertility studies have not been conducted with KEYTRUDA.

Use in Pregnancy (Category D) and Use in Lactation

There are no data on the use of pembrolizumab in pregnant women. KEYTRUDA is not recommended during pregnancy unless the clinical benefit outweighs the potential risk to the foetus. Women of childbearing potential should use effective contraception during treatment with KEYTRUDA and for at least 4 months following the last dose of KEYTRUDA.

It is unknown whether KEYTRUDA is secreted in human milk. A decision should be made whether to discontinue breast-feeding or to discontinue KEYTRUDA.

Paediatric Use

Efficacy for paediatric patients with MSI-H cancer is extrapolated from the results in the adult population.

Use in the elderly

No dose adjustment is necessary in this population.

Effects on ability to drive and use machines

KEYTRUDA may have an influence on the ability to drive and use machines. Fatigue has been reported following administration of KEYTRUDA.

Effect on Laboratory Tests

Thyroid and liver (hepatic transaminase and bilirubin levels) function tests should be performed at the start of treatment, periodically during treatment and as indicated based on clinical evaluation.

(See Adverse Effects)

INTERACTIONS WITH OTHER MEDICINES

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. The use of systemic corticosteroids or immunosuppressants before starting KEYTRUDA should be avoided, however, systemic corticosteroids or other immunosuppressants can be used after starting KEYTRUDA to treat immune-mediated adverse reactions. Corticosteroids can also be used as premedication, when Keytruda is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-elated adverse reactions.

ADVERSE EFFECTS

Clinical trials experience

The safety of KEYTRUDA was evaluated in 2799 patients with melanoma and NSCLC in controlled and uncontrolled studies. The median treatment duration was 4.2 months (range 1 day to 30.4 months) including 1153 patients treated for greater than or equal to six months and 600 patients treated for greater than or equal to one year.

KEYTRUDA was discontinued for treatment-related adverse reactions in 5% of patients. Treatment-related serious adverse events (SAEs) reported up to 90 days after the last dose occurred in 10% of patients receiving KEYTRUDA. Of these treatment-related SAEs, the most common were: pneumonitis, colitis, diarrhoea, and pyrexia. The most common treatment-related adverse reactions (reported in >10% of patients) were: fatigue, pruritus, rash, diarrhoea, and nausea.

Immune-mediated adverse reactions

In 2799 patients with melanoma and NSCLC, the following immune-mediated adverse reactions occurred in patients treated with KEYTRUDA 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks Hypothyroidism (8.5%), hyperthyroidism (3.4%), pneumonitis (3.4%), colitis (1.7%), adrenal insufficiency (0.8%), hepatitis (0.7%), hypophysitis (0.6%), nephritis (0.3%) and type 1 diabetes mellitus (0.2%).

In an on-going clinical study in patients with non-squamous NSCLC treated with KEYTRUDA 200 mg in combination with pemetrexed and platinum chemotherapy (n=405), the incidence of nephritis was 1.7%.

Other adverse events

The following additional adverse events have occurred in >10 % include:

  • In patients with melanoma: arthralgia, back pain, cough, vitiligo, lymphopenia, hypertriglyceridemia, abdominal pain, pruritus, rash, hyponatremia, hyperglycaemia, hyponatremia, hypoalbuminemia, increased aspartate aminotransferase, increased alkaline phosphatase, anaemia.
  • In patients with NSCLC receiving monotherapy: cough, rash, pruritis
  • In patients with NSCLC receiving combination treatment with pemetrexed and carboplatin: fatigue, asthenia, diarrhoea, neutropenia, rash, pruritus, dyspnoea, cough, hypothyroidism.

Adverse events occurring in patients with HNSCC, Urothelial carcinoma or cHL, or MSI-H/dMMR cancer were generally similar to those occurring in patients with melanoma or NSCLC (see Data Sheet for full list).

Paediatric Patients

The safety profile in paediatric patients was similar to that seen in adults treated with pembrolizumab. The most common adverse reactions (reported in at least 20% of paediatric patients) were pyrexia, vomiting, fatigue, constipation, abdominal pain and nausea.

Postmarketing experience

Musculoskeletal and connective tissue disorders: arthritis

Eye Disorders: Vogt-Koyanagi-Harada syndrome

Immune Disorder: haemophagocytic lymphohitiocytosis

DOSAGE AND ADMINISTRATION

Treatment must be initiated and supervised by specialised healthcare professionals experienced in the treatment of cancer.

Patient Selection

For single-agent treatment of Non-Small Cell Lung Carcinoma or Urothelial Carcinoma

Select patients for treatment with KEYTRUDA based on the presence of positive PD-L1 expression in:

  • stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation.
  • metastatic NSCLC.
  • locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

Determination of PD-L1 expression should be performed by laboratories with demonstrated proficiency in the in-vitro diagnostic technology being employed.

Recommended Dosing

KEYTRUDA is administered as an intravenous infusion over 30 minutes.

The recommended dose of KEYTRUDA in adults is:

  • Either 200 mg every 3 weeks or 400 mg every 6 weeks for adjuvant melanoma, head and neck cancer, classical Hodgkin Lymphoma, urothelial carcinoma, MSI-H/dMMR cancer or previously untreated NSCLC.
  • Either 2 mg/kg every 3 weeks or a fixed dose of 200 mg every 3 weeks or 400 mg every 6 weeks for unresectable or metastatic melanoma or previously treated NSCLC.

The recommended dose of KEYTRUDA in paediatric patients is 2 mg/kg (up to a maximum of 200 mg) every 3 weeks for MSI-H/dMMR cancer administered as an intravenous infusion over 30 minutes every 3 weeks.

When administering KEYTRUDA as part of a combination with chemotherapy, KEYTRUDA should be administered first. See also the Data Sheet for the selected chemotherapy agents administered in combination.

Patients should be treated with KEYTRUDA until disease progression or unacceptable toxicity.

For the adjuvant treatment of melanoma, KEYTRUDA should be administered for up to one year or until disease recurrence or unacceptable toxicity.

Dose Modifications

Withhold KEYTRUDA for adverse reactions including:

  • Immune-mediated pneumonitis - moderate (Grade 2)
  • Immune-mediated colitis - moderate or severe (Grade 2 or 3)
  • Immune-mediated nephritis - moderate (Grade 2)
  • Immune-mediated endocrinopathies - severe or life-threatening (Grade 3 or 4)
  • Haematological toxicity – life-threatening (Grade 4) in patients with cHL
  • Immune-mediated hepatitis associated with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 to 5 times ULN or total bilirubin >1.5 to 3 times ULN
  • Immune-mediated severe skin reactions (Grade 3) or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis
  • Other immune-mediated adverse reactions (Grade 2 or Grade 3)

Resume KEYTRUDA in patients whose adverse reactions recover to Grade 0-1.

Permanently discontinue KEYTRUDA:

  • If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks
  • If a treatment-related toxicity does not resolve to Grade 0-1 within 12 weeks after last dose of KEYTRUDA
  • If another episode of any severe toxicity occurs
  • For adverse reactions including:
    • Life-threatening (Grade 4) toxicity except for endocrinopathies that improve to Grade 2 or lower and are controlled with replacement hormones, or for haematological toxicity in patients with cHL
    • Immune-mediated pneumonitis - severe or life-threatening (Grade 3 or 4) or recurrent moderate (Grade 2)
    • Immune-mediated colitis – life-threatening (Grade 4) or recurrent severe (Grade 3)
    • Immune-mediated nephritis - severe or life-threatening (Grade 3 or 4)
    • Immune-mediated hepatitis associated with: AST or ALT >5 times ULN or total bilirubin >3 times ULN
    • - For patients with liver metastasis who begin treatment with moderate (Grade 2) elevation of AST or ALT, if AST or ALT increases ≥50% relative to baseline and lasts ≥1 week
    • Immune-mediated severe skin reactions (Grade 4) or confirmed SJS or TEN
    • Infusion-related reactions - severe or life-threatening (Grade 3 or 4)
    • Other immune-mediated reactions – Severe or life-threatening (Grade 4 or 4) myocarditis, encephalitis, or Guillain-Barré syndrome. Life-threatening (Grade 4) or recurrent severe (Grade 3)

Preparation and Administration

Preparation of KEYTRUDA 50 mg powder for injection

Add 2.3 mL of sterile water for injection to yield a 25 mg/mL (pH 5.2-5.8) solution of KEYTRUDA.

To avoid foaming, deliver the water along the walls of the vial and not directly on the lyophilised powder. Slowly swirl the vial to allow reconstitution of the lyophilised powder. Allow up to 5 minutes for the bubbles to clear. Do not shake the vials.

Visually inspect the solution for particulate matter and discoloration prior to administration. Reconstituted KEYTRUDA is a clear to slightly opalescent, colourless to slightly yellow solution. Discard the vial if visible particles are observed.

Withdraw the required volume up to 2 mL (50 mg) of KEYTRUDA and transfer into an intravenous bag containing 0.9% sodium chloride or 5% glucose (dextrose) to prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Mix diluted solution by gentle inversion.

Preparation of KEYTRUDA 100 mg/4 mL concentrated injection

Protect from light. Do not freeze. Do not shake.

Equilibrate the vial of KEYTRUDA to room temperature.

Visually inspect the solution for particulate matter and discoloration prior to administration.

KEYTRUDA is a clear to slightly opalescent, colourless to slightly yellow solution. Discard the vial if visible particles are observed.

Withdraw the required volume up to 4 mL (100 mg) of KEYTRUDA and transfer into an intravenous bag containing 0.9% sodium chloride or 5% glucose (dextrose) to prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Mix diluted solution by gentle inversion.

Administration

  • Administer infusion solution intravenously over 30 minutes using a sterile, non-pyrogenic, low-protein binding 0.2 to 5 μm in-line or add-on filter.
  • Do not co-administer other drugs through the same infusion line.
  • Discard any residue.

Storage

Powder for injection and concentrated injection vials

  • Store in refrigerator (2°C to 8°C). Do not freeze
  • Protect from light
  • Do not shake

Storage of reconstituted and diluted solutions:

  • The reconstituted and/or diluted product should be used immediately
  • Do not freeze the infusion solution
  • The product does not contain preservative
  • If not used immediately, reconstituted and diluted solutions of KEYTRUDA solutions may be stored at room temperature for a cumulative time of up to 6 hours. Reconstituted and diluted solutions of KEYTRUDA may also be stored under refrigeration at 2°C to 8°C; however, the total time from reconstitution or dilution of KEYTRUDA to completion of infusion should not exceed 24 hours. If refrigerated, allow the vials and/or IV bags to come to room temperature prior to use.

KEYTRUDA is a prescription only medicine, please review the full data sheet before prescribing available at www.medsafe.govt.nz. KEYTRUDA is a funded medicine for melanoma patients – restrictions apply. KEYTRUDA is an unfunded medicine for treatment of melanoma after surgery, NSCLC, HNSCC, cHL, urothelial carcinoma and MSI-H/dMMR cancer patients.

Based on Data Sheet dated 28 November 2019


SEE FULL INDICATIONS

KEYTRUDA is indicated:

Melanoma

  • as monotherapy for the treatment of unresectable or metastatic melanoma in adults.
  • for the adjuvant treatment of patients with melanoma with lymph node involvement who have undergone complete resection.

Lung Cancer

  • in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic non-squamous non-small cell lung carcinoma (NSCLC), with no EGFR or ALK genomic tumour aberrations.
  • in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.
  • P as monotherapy is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumour proportion score (TPS) ≥1%] as determined by a validated test, with no EGFR or ALK genomic tumour aberrations, and is
    • stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
    • metastatic.
  • as monotherapy is indicated for the treatment of patients with advanced NSCLC whose tumours express PD-L1 with a ≥1% TPS as determined by a validated test and who have received platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumour aberrations should have received prior therapy for these aberrations prior to receiving KEYTRUDA.

Classical Hodgkin Lymphoma

  • for the treatment of patients with refractory classical Hodgkin Lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy.

Urothelial Cancer

  • for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by a validated test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
  • for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have received platinum-containing chemotherapy.

Head and Neck Cancer

  • for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved based on overall response rate and duration of response. Improvements in overall survival, progression-free survival or health-related quality of life have not been established.

MSI/dMMR

  • in adult and paediatric patients for the treatment of unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication was approved based on objective response rate and response duration in a single-arm trials.
  • in adult and paediatric patients for the treatment of unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumours (non-colorectal) that have progressed following prior treatment and when there are no satisfactory alternative treatment options. This indication was approved based on the pooling of data on objective response rate and response duration across multiple different tissue types in a single-arm trial. Sample sizes for individual tissue types were too small to provide data on clinical utility of the MSI-H/dMMR tests for each of the tissue types, individually. The assumption that MSI-H/dMMR-status is predictive of the treatment effect of Keytruda for every tissue type has not been verified.

The safety and effectiveness of KEYTRUDA in paediatric patients with MSI-H central nervous system cancers have not been established.

Continued approval for MSI-H/dMMR indications depends on verification and description of clinical benefit in the confirmatory trials.

SELECTED SAFETY INFORMATION

KEYTRUDA® (pembrolizumab) 50 mg powder for solution for infusion. 100 mg/4 mL (25 mg/mL) concentrate for solution for infusion.

Patient Alert Card The prescriber must discuss the risks of KEYTRUDA therapy with the patient. The patient should be provided with the Patient Alert Card.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Immune-mediated Adverse Reactions

Immune-mediated adverse reactions including severe and fatal cases, have occurred in patients receiving KEYTRUDA. In clinical trials, most immune-mediated adverse reactions occurred during treatment, were reversible and managed with interruptions of KEYTRUDA, administration of corticosteroids and/or supportive care. Immune-related adverse reactions have also occurred after the last dose of KEYTRUDA. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and consider administration of corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less following corticosteroid taper. If another episode of a severe adverse reaction occurs, permanently discontinue KEYTRUDA.

Immune-mediated pneumonitis

Pneumonitis (including fatal cases) has been reported in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of pneumonitis. If pneumonitis is suspected, evaluate with radiographic imaging and exclude other causes. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Immune-mediated colitis

Colitis has been reported in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis and exclude other causes. The potential risk of gastrointestinal perforation should be taken into consideration. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Immune-mediated hepatitis

Hepatitis has been reported in patients receiving KEYTRUDA. Monitor patients for changes in liver function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and symptoms of hepatitis and exclude other causes. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Immune-mediated nephritis

Nephritis has been reported in patients receiving KEYTRUDA. Nephritis appears to be more common when pembrolizumab is used in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function and exclude other causes. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Immune-mediated endocrinopathies

Hypophysitis has been reported in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and secondary adrenal insufficiency) and exclude other causes. Administer corticosteroids to treat secondary adrenal insufficiency and other hormone replacement as clinically indicated. (See Recommended Dosing and Dose Modifications)

Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving KEYTRUDA. Monitor patients for hyperglycaemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes and withhold KEYTRUDA in cases of severe hyperglycaemia until metabolic control is achieved. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Thyroid disorders, including hyperthyroidism, hypothyroidism and thyroiditis, have been reported in patients receiving KEYTRUDA and can occur at any time during treatment, therefore monitor patients for changes in thyroid function and clinical signs and symptoms of thyroid disorders. Hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids. Hyperthyroidism may be managed symptomatically. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Severe skin reactions

Immune-mediated severe skin reactions have been reported in patients treated with KEYTRUDA. Monitor patients for suspected severe skin reactions and exclude other causes. (See Recommended Dosing, Dose Modifications and Adverse Effects)

Cases of Stevens-Johnson syndrome (SJS) toxic epidermal necrolysis (TEN) and bullous pemphigoid, have been reported in patients treated with KEYTRUDA. Some cases of SJS and TEN have had a fatal outcome. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other immune-mediated adverse reactions

The following additional clinically significant, immune-mediated adverse reactions were reported in less than 1% of patients treated with KEYTRUDA in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010: uveitis, myositis, Guillain-Barre syndrome, pancreatitis, encephalitis, sarcoidosis and myasthenic syndrome/myasthenia gravis (including exacerbation). Myocarditis has been reported in other clinical studies with KEYTRUDA or in post-marketing use.

Transplant-related adverse reactions

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA versus the risk of possible organ rejection in these patients.

Acute graft-versus-host-disease (GVHD), including fatal GVHD, after treatment with KEYTRUDA has been reported in patients with a history of allogeneic hematopoietic stem cell transplant (HSCT). Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after treatment with KEYTRUDA. Consider the benefit of treatment with KEYTRUDA versus the risk of possible GVHD in patients with a history of allogeneic HSCT.

Increased mortality in patients with multiple myeloma when KEYTRUDA is added to a thalidomide analogue and dexamethasone

In two randomized clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA versus the risk of possible organ rejection in these patients.

Infusion-related reactions

Severe infusion reactions, including hypersensitivity and anaphylaxis, have been reported in 6 (0.2%) of 2799 patients receiving KEYTRUDA in KEYNOTE-001, KEYNOTE-002, KEYNOTE-006 and KEYNOTE-010. (See Recommended Dosing and Dose Modifications)

Effects on Fertility

Fertility studies have not been conducted with KEYTRUDA.

Use in Pregnancy (Category D) and Use in Lactation

There are no data on the use of pembrolizumab in pregnant women. KEYTRUDA is not recommended during pregnancy unless the clinical benefit outweighs the potential risk to the foetus. Women of childbearing potential should use effective contraception during treatment with KEYTRUDA and for at least 4 months following the last dose of KEYTRUDA.

It is unknown whether KEYTRUDA is secreted in human milk. A decision should be made whether to discontinue breast-feeding or to discontinue KEYTRUDA.

Paediatric Use

Efficacy for paediatric patients with MSI-H cancer is extrapolated from the results in the adult population.

Use in the elderly

No dose adjustment is necessary in this population.

Effects on ability to drive and use machines

KEYTRUDA may have an influence on the ability to drive and use machines. Fatigue has been reported following administration of KEYTRUDA.

Effect on Laboratory Tests

Thyroid and liver (hepatic transaminase and bilirubin levels) function tests should be performed at the start of treatment, periodically during treatment and as indicated based on clinical evaluation.

(See Adverse Effects)

INTERACTIONS WITH OTHER MEDICINES

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. The use of systemic corticosteroids or immunosuppressants before starting KEYTRUDA should be avoided, however, systemic corticosteroids or other immunosuppressants can be used after starting KEYTRUDA to treat immune-mediated adverse reactions. Corticosteroids can also be used as premedication, when Keytruda is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-elated adverse reactions.

ADVERSE EFFECTS

Clinical trials experience

The safety of KEYTRUDA was evaluated in 2799 patients with melanoma and NSCLC in controlled and uncontrolled studies. The median treatment duration was 4.2 months (range 1 day to 30.4 months) including 1153 patients treated for greater than or equal to six months and 600 patients treated for greater than or equal to one year.

KEYTRUDA was discontinued for treatment-related adverse reactions in 5% of patients. Treatment-related serious adverse events (SAEs) reported up to 90 days after the last dose occurred in 10% of patients receiving KEYTRUDA. Of these treatment-related SAEs, the most common were: pneumonitis, colitis, diarrhoea, and pyrexia. The most common treatment-related adverse reactions (reported in >10% of patients) were: fatigue, pruritus, rash, diarrhoea, and nausea.

Immune-mediated adverse reactions

In 2799 patients with melanoma and NSCLC, the following immune-mediated adverse reactions occurred in patients treated with KEYTRUDA 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks Hypothyroidism (8.5%), hyperthyroidism (3.4%), pneumonitis (3.4%), colitis (1.7%), adrenal insufficiency (0.8%), hepatitis (0.7%), hypophysitis (0.6%), nephritis (0.3%) and type 1 diabetes mellitus (0.2%).

In an on-going clinical study in patients with non-squamous NSCLC treated with KEYTRUDA 200 mg in combination with pemetrexed and platinum chemotherapy (n=405), the incidence of nephritis was 1.7%.

Other adverse events

The following additional adverse events have occurred in >10 % include:

  • In patients with melanoma: arthralgia, back pain, cough, vitiligo, lymphopenia, hypertriglyceridemia, abdominal pain, pruritus, rash, hyponatremia, hyperglycaemia, hyponatremia, hypoalbuminemia, increased aspartate aminotransferase, increased alkaline phosphatase, anaemia.
  • In patients with NSCLC receiving monotherapy: cough, rash, pruritis
  • In patients with NSCLC receiving combination treatment with pemetrexed and carboplatin: fatigue, asthenia, diarrhoea, neutropenia, rash, pruritus, dyspnoea, cough, hypothyroidism.

Adverse events occurring in patients with HNSCC, Urothelial carcinoma or cHL, or MSI-H/dMMR cancer were generally similar to those occurring in patients with melanoma or NSCLC (see Data Sheet for full list).

Paediatric Patients

The safety profile in paediatric patients was similar to that seen in adults treated with pembrolizumab. The most common adverse reactions (reported in at least 20% of paediatric patients) were pyrexia, vomiting, fatigue, constipation, abdominal pain and nausea.

Postmarketing experience

Musculoskeletal and connective tissue disorders: arthritis

Eye Disorders: Vogt-Koyanagi-Harada syndrome

Immune Disorder: haemophagocytic lymphohitiocytosis

DOSAGE AND ADMINISTRATION

Treatment must be initiated and supervised by specialised healthcare professionals experienced in the treatment of cancer.

Patient Selection

For single-agent treatment of Non-Small Cell Lung Carcinoma or Urothelial Carcinoma

Select patients for treatment with KEYTRUDA based on the presence of positive PD-L1 expression in:

  • stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation.
  • metastatic NSCLC.
  • locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

Determination of PD-L1 expression should be performed by laboratories with demonstrated proficiency in the in-vitro diagnostic technology being employed.

Recommended Dosing

KEYTRUDA is administered as an intravenous infusion over 30 minutes.

The recommended dose of KEYTRUDA in adults is:

  • Either 200 mg every 3 weeks or 400 mg every 6 weeks for adjuvant melanoma, head and neck cancer, classical Hodgkin Lymphoma, urothelial carcinoma, MSI-H/dMMR cancer or previously untreated NSCLC.
  • Either 2 mg/kg every 3 weeks or a fixed dose of 200 mg every 3 weeks or 400 mg every 6 weeks for unresectable or metastatic melanoma or previously treated NSCLC.

The recommended dose of KEYTRUDA in paediatric patients is 2 mg/kg (up to a maximum of 200 mg) every 3 weeks for MSI-H/dMMR cancer administered as an intravenous infusion over 30 minutes every 3 weeks.

When administering KEYTRUDA as part of a combination with chemotherapy, KEYTRUDA should be administered first. See also the Data Sheet for the selected chemotherapy agents administered in combination.

Patients should be treated with KEYTRUDA until disease progression or unacceptable toxicity.

For the adjuvant treatment of melanoma, KEYTRUDA should be administered for up to one year or until disease recurrence or unacceptable toxicity.

Dose Modifications

Withhold KEYTRUDA for adverse reactions including:

  • Immune-mediated pneumonitis - moderate (Grade 2)
  • Immune-mediated colitis - moderate or severe (Grade 2 or 3)
  • Immune-mediated nephritis - moderate (Grade 2)
  • Immune-mediated endocrinopathies - severe or life-threatening (Grade 3 or 4)
  • Haematological toxicity – life-threatening (Grade 4) in patients with cHL
  • Immune-mediated hepatitis associated with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 to 5 times ULN or total bilirubin >1.5 to 3 times ULN
  • Immune-mediated severe skin reactions (Grade 3) or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis
  • Other immune-mediated adverse reactions (Grade 2 or Grade 3)

Resume KEYTRUDA in patients whose adverse reactions recover to Grade 0-1.

Permanently discontinue KEYTRUDA:

  • If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks
  • If a treatment-related toxicity does not resolve to Grade 0-1 within 12 weeks after last dose of KEYTRUDA
  • If another episode of any severe toxicity occurs
  • For adverse reactions including:
    • Life-threatening (Grade 4) toxicity except for endocrinopathies that improve to Grade 2 or lower and are controlled with replacement hormones, or for haematological toxicity in patients with cHL
    • Immune-mediated pneumonitis - severe or life-threatening (Grade 3 or 4) or recurrent moderate (Grade 2)
    • Immune-mediated colitis – life-threatening (Grade 4) or recurrent severe (Grade 3)
    • Immune-mediated nephritis - severe or life-threatening (Grade 3 or 4)
    • Immune-mediated hepatitis associated with: AST or ALT >5 times ULN or total bilirubin >3 times ULN
    • - For patients with liver metastasis who begin treatment with moderate (Grade 2) elevation of AST or ALT, if AST or ALT increases ≥50% relative to baseline and lasts ≥1 week
    • Immune-mediated severe skin reactions (Grade 4) or confirmed SJS or TEN
    • Infusion-related reactions - severe or life-threatening (Grade 3 or 4)
    • Other immune-mediated reactions – Severe or life-threatening (Grade 4 or 4) myocarditis, encephalitis, or Guillain-Barré syndrome. Life-threatening (Grade 4) or recurrent severe (Grade 3)

Preparation and Administration

Preparation of KEYTRUDA 50 mg powder for injection

Add 2.3 mL of sterile water for injection to yield a 25 mg/mL (pH 5.2-5.8) solution of KEYTRUDA.

To avoid foaming, deliver the water along the walls of the vial and not directly on the lyophilised powder. Slowly swirl the vial to allow reconstitution of the lyophilised powder. Allow up to 5 minutes for the bubbles to clear. Do not shake the vials.

Visually inspect the solution for particulate matter and discoloration prior to administration. Reconstituted KEYTRUDA is a clear to slightly opalescent, colourless to slightly yellow solution. Discard the vial if visible particles are observed.

Withdraw the required volume up to 2 mL (50 mg) of KEYTRUDA and transfer into an intravenous bag containing 0.9% sodium chloride or 5% glucose (dextrose) to prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Mix diluted solution by gentle inversion.

Preparation of KEYTRUDA 100 mg/4 mL concentrated injection

Protect from light. Do not freeze. Do not shake.

Equilibrate the vial of KEYTRUDA to room temperature.

Visually inspect the solution for particulate matter and discoloration prior to administration.

KEYTRUDA is a clear to slightly opalescent, colourless to slightly yellow solution. Discard the vial if visible particles are observed.

Withdraw the required volume up to 4 mL (100 mg) of KEYTRUDA and transfer into an intravenous bag containing 0.9% sodium chloride or 5% glucose (dextrose) to prepare a diluted solution with a final concentration ranging from 1 to 10 mg/mL. Mix diluted solution by gentle inversion.

Administration

  • Administer infusion solution intravenously over 30 minutes using a sterile, non-pyrogenic, low-protein binding 0.2 to 5 μm in-line or add-on filter.
  • Do not co-administer other drugs through the same infusion line.
  • Discard any residue.

Storage

Powder for injection and concentrated injection vials

  • Store in refrigerator (2°C to 8°C). Do not freeze
  • Protect from light
  • Do not shake

Storage of reconstituted and diluted solutions:

  • The reconstituted and/or diluted product should be used immediately
  • Do not freeze the infusion solution
  • The product does not contain preservative
  • If not used immediately, reconstituted and diluted solutions of KEYTRUDA solutions may be stored at room temperature for a cumulative time of up to 6 hours. Reconstituted and diluted solutions of KEYTRUDA may also be stored under refrigeration at 2°C to 8°C; however, the total time from reconstitution or dilution of KEYTRUDA to completion of infusion should not exceed 24 hours. If refrigerated, allow the vials and/or IV bags to come to room temperature prior to use.

KEYTRUDA is a prescription only medicine, please review the full data sheet before prescribing available at www.medsafe.govt.nz. KEYTRUDA is a funded medicine for melanoma patients – restrictions apply. KEYTRUDA is an unfunded medicine for treatment of melanoma after surgery, NSCLC, HNSCC, cHL, urothelial carcinoma and MSI-H/dMMR cancer patients.

Based on Data Sheet dated 28 November 2019

Merck Sharp & Dohme (New Zealand) Limited. Level 3, 123 Carlton Gore Road, Newmarket, Auckland. NZ-KEY-00157 DA2039MW MSD9119 Last Updated February 2020

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