• The most common serious ARs with PEMAZYRE were:¹
• Hyponatraemia (2.0%)
• Blood creatinine increase (1.4%)
• No serious AR led to PEMAZYRE dose reduction¹
• One serious AR of hyponatraemia (0.7%) led to dose interruption. One serious AR of blood creatinine increase (0.7%) led to dose discontinuation¹
• Eye disorder serious ARs were retinal detachment (0.7%), non-arteritic optic ischaemic neuropathy (0.7%) and retinal artery occlusion (0.7%)¹

Hyperphosphataemia

• Hyperphosphataemia was reported in 60.5% of all patients treated with PEMAZYRE and usually developed within the first 15 days. None of the reactions were ≥ Grade 3 in severity, serious or led to discontinuation of PEMAZYRE¹
• Dose interruption occurred in 1.4% of patients and dose reduction in 0.7% of patients¹
• These results suggest that dietary phosphate restriction and/or administration of phosphate-lowering therapy along with the 1-week dose holiday were effective strategies for managing this on-target effect of PEMAZYRE¹

Hypophosphataemia

• Hypophosphataemia reactions were Grade ≥3 in 14.3% of patients¹

Serous retinal detachment

• Serous retinal detachment occurred in 4.8% of all patients treated with PEMAZYRE¹
• Reactions were generally Grade 1 or 2 (4.1%) in severity; ≥ Grade 3 and serious reactions included retinal detachment in one patient (0.7%)¹
• Two ARs of retinal detachment (0.7%) and detachment of retinal pigment epithelium (0.7%) led to dose interruption. None of the reactions led to dose reduction or discontinuation¹

Creatinine increase

• An increase from baseline in mean creatinine levels of approximately 16 μmol/L occurred on Days 8 and 15 of the 1^st cycle. These higher lever generally returned close to baseline by Cycle 2 Day 1. Above-normal creatinine values occurred in 12.9% of patients at baseline, increased to 34% on Day 15 of Cycle 1 and were observed in approximately 20% to 30% of participants on Day 1 of subsequent cycles¹
• The reactions were Grade 1 or 2 with the exception of 2 patients (1.4%) with Grade 3 changes, and resolved without sequelae¹
• However, normal creatinine values were observed after a one-week treatment suspension period¹

Hyperphosphataemia

• Hyperphosphataemia is a pharmacodynamic effect expected with PEMAZYRE administration¹
• Prolonged hyperphosphataemia can cause precipitation of calcium-phosphate crystals that can lead to hypocalcaemia, soft tissue mineralisation, secondary hyperparathyroidism, muscle cramps, seizure activity, QT interval prolongation and arrhythmias. Soft tissue mineralisation, including cutaneous calcification and calcinosis, have been observed with PEMAZYRE treatment¹
• Recommendations for management of hyperphosphataemia include dietary phosphate restriction, administration of phosphate-lowering therapy and dose modification when required¹
• Phosphate-lowering therapy was used by 19% of patients during treatment with PEMAZYRE¹

Hypophosphataemia

• Discontinuing phosphate-lowering therapy and diet should be considered during PEMAZYRE treatment breaks or if serum phosphate level falls below normal range¹
• Severe hypophosphataemia may present with confusion, seizures, focal neurological findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis, and hemolytic anaemia¹

For patients presenting with hyperphosphataemia or hypophosphataemia, additional close monitoring and follow-up is recommended regarding dysregulation of bone mineralisation¹

Serous retinal detachment

• PEMAZYRE can cause serous retinal detachment reactions, which may present with symptoms such as blurred vision, visual floaters or photopsia. This can moderately influence the ability to drive and use machines¹
• Ophthalmological examination, including OCT, should be performed prior to initiation of therapy and every 2 months for the first 6 months of treatment, every 3 months afterwards, and urgently at any time for visual symptoms. For serous retinal detachment reactions, the dose modification guidelines should be followed¹
• During the conduct of the clinical study, there was no routine monitoring, including OCT, to detect asymptomatic serous retinal detachment; therefore, the incidence of asymptomatic serous retinal detachment with PEMAZYRE is unknown
• Careful consideration should be taken with patients that have clinically significant medical eye disorders, such as retinal disorders, including but not limited to, central serous retinopathy, macular/retinal degeneration, diabetic retinopathy and previous retinal detachment¹

Dry eye

• PEMAZYRE can cause dry eye. Patients should use ocular demulcents in order to prevent or treat dry eye as needed¹

Embryo-foetal toxicity

• Based on the mechanism of action and findings in an animal reproduction study, PEMAZYRE can cause foetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the foetus¹
• Women of childbearing potential should be advised not to become pregnant and men should be advised not to father a child during treatment¹
• An effective method of contraception should be used during treatment with PEMAZYRE and for 1 week following completion of therapy¹
• A pregnancy test should be performed before treatment initiation to exclude pregnancy¹

Blood creatinine increase

• PEMAZYRE may increase serum creatinine by decreasing renal tubular secretion of creatinine; this may occur due to inhibition of renal transporters OCT2 and MATE1 and may not affect glomerular function¹
• Within the first cycle, serum creatinine increased (mean increase of 0.2 mg/dL) and reached steady state by Day 8, and then decreased during the 7 days off therapy. Alternative markers of renal function should be considered if persistent elevations in serum creatinine are observed¹

CNS metastasis

• Since untreated or progressing brain/CNS metastasis were not allowed in the study, efficacy in this population has not been evaluated and no dose recommendations can be made; however, the blood-brain barrier penetration of PEMAZYRE is expected to be low¹