CLINICAL NEWS iron-regulating effects in larger , longitudinal analyses . “ There was a significant effect on serum iron , but further studies should examine changes in tissue iron concentrations and non – transferrin bound iron ,” Dr . Lal explained .
The findings of LJPC-401 , a synthetic endogenous human hepcidin , represent the first insight into the investigational therapy ’ s effects on iron metabolism . “ These data will pave a way for future studies and clinical trials to evaluate clinical application of synthetic hepcidin in several clinical conditions including iron overload anemias , hemochromatosis , and myelodysplastic syndromes ( MDS ),” co-author and presenter Vip Viprakasit , MD , DPhil , from the Mahidol University in Bangkok , Thailand , commented .
“ Complications secondary to iron overload are the chief cause of morbidity in thalassemia and hereditary hemochromatosis ,”
Dr . Lal added . “ If it is shown in subsequent studies that treatment with synthetic hepcidin can reduce the toxic forms of iron , decrease gastrointestinal iron absorption or control abnormal tissue distribution of iron , then it would be an important therapeutic advance in this group of patients .”
PTG-300 The injectable hepcidin mimetic PTG-300 is also under development for the treatment of The opening ceremony of the 23rd EHA Congress .
Venous thromboembolic events ( VTE ) occurred in 4.7 % of patients treated with POMALYST and Low-dose Dex , and 1.3 % of patients treated with high-dose dexamethasone . Arterial thromboembolic events include terms for arterial thromboembolic events , ischemic cerebrovascular conditions , and ischemic heart disease . Arterial thromboembolic events occurred in 3.0 % of patients treated with POMALYST and Low-dose Dex , and 1.3 % of patients treated with high-dose dexamethasone .
Patients with known risk factors , including prior thrombosis , may be at greater risk , and actions should be taken to try to minimize all modifiable factors ( e . g ., hyperlipidemia , hypertension , smoking ). Thromboprophylaxis is recommended , and the choice of regimen should be based on assessment of the patient ’ s underlying risk factors .
5.4 Increased Mortality in Patients with Multiple Myeloma When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone In two randomized clinical trials in patients with multiple myeloma , the addition of pembrolizumab 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 .
5.5 Hematologic Toxicity In trials 1 and 2 in patients who received POMALYST + Low-dose Dex , neutropenia was the most frequently reported Grade 3 / 4 adverse reaction , followed by anemia and thrombocytopenia . Neutropenia of any grade was reported in 51 % of patients in both trials . The rate of Grade 3 / 4 neutropenia was 46 %. The rate of febrile neutropenia was 8 %.
Monitor patients for hematologic toxicities , especially neutropenia . Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter . Patients may require dose interruption and / or modification [ see Dosage and Administration ( 2.2 )].
5.6 Hepatotoxicity Hepatic failure , including fatal cases , has occurred in patients treated with POMALYST . Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST . Monitor liver function tests monthly . Stop POMALYST upon elevation of liver enzymes and evaluate . After return to baseline values , treatment at a lower dose may be considered .
5.7 Severe Cutaneous Reactions Including Hypersensitivity Reactions Angioedema and severe cutaneous reactions including Stevens-Johnson syndrome ( SJS ), toxic epidermal necrolysis ( TEN ) and drug reaction with eosinophilia and systemic symptoms ( DRESS ) have been reported . DRESS may present with a cutaneous reaction ( such as rash or exfoliative dermatitis ), eosinophilia , fever , and / or lymphadenopathy with systemic complications such as hepatitis , nephritis , pneumonitis , myocarditis , and / or pericarditis . Discontinue POMALYST for angioedema , skin exfoliation , bullae , or any other severe cutaneous reactions such as SJS , TEN or DRESS , and do not resume therapy [ see Dosage and Administration ( 2.2 )].
5.8 Dizziness and Confusional State In trials 1 and 2 in patients who received POMALYST + Low-dose Dex , 14 % of patients experienced dizziness and 7 % of patients experienced a confusional state ; 1 % of patients experienced Grade 3 or 4 dizziness , and 3 % of patients experienced Grade 3 or 4 confusional state . Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice .
5.9 Neuropathy In trials 1 and 2 in patients who received POMALYST + Low-dose Dex , 18 % of patients experienced neuropathy , with approximately 12 % of the patients experiencing peripheral neuropathy . Two percent of patients experienced Grade 3 neuropathy in trial 2 . There were no cases of Grade 4 neuropathy adverse reactions reported in either trial .
5.10 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma .
5.11 Tumor Lysis Syndrome Tumor lysis syndrome ( TLS ) may occur in patients treated with pomalidomide . Patients at risk for TLS are those with high tumor burden prior to treatment . These patients should be monitored closely and appropriate precautions taken .
6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections :
• Fetal Risk [ see Boxed Warning , Warnings and Precautions ( 5.1 , 5.2 )]
• Venous and Arterial Thromboembolism [ see Boxed Warning , Warnings and Precautions ( 5.3 )]
• Increased Mortality in Patients with Multiple Myeloma When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [ see Warnings and Precautions ( 5.4 )]
• Hematologic Toxicity [ see Warnings and Precautions ( 5.5 )]
• Hepatotoxicity [ see Warnings and Precautions ( 5.6 )]
• Severe Cutaneous Reactions Including Hypersensitivity Reactions [ see Warnings and Precautions ( 5.7 )]
• Dizziness and Confusional State [ see Warnings and Precautions ( 5.8 )]
• Neuropathy [ see Warnings and Precautions ( 5.9 )]
• Risk of Second Primary Malignancies [ see Warnings and Precautions ( 5.10 )]
• Tumor Lysis Syndrome [ see Warnings and Precautions ( 5.11 )]
6.1 Clinical Trials Experience Multiple Myeloma Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice .
In Trial 1 , data were evaluated from 219 patients ( safety population ) who received treatment with POMALYST + Low-dose Dex ( 112 patients ) or POMALYST alone ( 107 patients ). Median number of treatment cycles was 5 . Sixty-seven percent of patients in the study had a dose interruption of either drug due to adverse reactions . Forty-two percent of patients in the study had a dose reduction of either drug due to adverse reactions . The discontinuation rate due to adverse reactions was 11 %.
In Trial 2 , data were evaluated from 450 patients ( safety population ) who received treatment with POMALYST + Low-dose Dex ( 300 patients ) or Highdose Dexamethasone ( High-dose Dex ) ( 150 patients ). The median number of treatment cycles for the POMALYST + Low-dose Dex arm was 5 . In the POMALYST + Low-dose Dex arm , 67 % of patients had a dose interruption of POMALYST , the median time to the first dose interruption of POMALYST was 4.1 weeks . Twenty-seven percent of patients had a dose reduction of POMALYST , the median time to the first dose reduction of POMALYST was 4.5 weeks . Eight percent of patients discontinued POMALYST due to adverse reactions .
Tables 2 and 3 summarize the adverse reactions reported in Trials 1 and 2 , respectively .
In Trial 1 of 219 patients who received POMALYST alone a ( N = 107 ) or POMALYST + Low-dose Dex ( N = 112 ), all patients had at least one adverse reaction .*
Adverse reactions ≥10 % in either arm , respectively , included : Blood and lymphatic system disorders : Neutropenia b ( 53 %, 49 %), Anemia b ( 38 %, 42 %), Thrombocytopenia b ( 26 %, 23 %), Leukopenia ( 13 %, 20 %), Febrile neutropenia b (< 10 %, < 10 %), Lymphopenia ( 4 %, 15 %); General disorders and administration site conditions : Fatigue and asthenia b ( 58 %, 63 %), Edema peripheral ( 25 %, 17 %), Pyrexia b ( 23 %, 32 %), Chills ( 10 %, 13 %);
Gastrointestinal disorders : Nausea b ( 36 %, 24 %), Constipation b ( 36 %, 37 %), Diarrhea ( 35 %, 36 %), Vomiting b ( 14 %, 14 %); Musculoskeletal and connective tissue disorders : Back pain b ( 35 %, 32 %), Musculoskeletal chest pain ( 23 %, 20 %), Muscle spasms ( 22 %, 20 %), Arthralgia ( 17 %, 15 %), Muscular weakness ( 14 %, 13 %), Bone pain ( 12 %, 7 %), Musculoskeletal pain ( 12 %, 17 %), Pain in extremity ( 8 %, 14 %); Infections and infestations : Upper respiratory tract infection ( 37 %, 29 %), Pneumonia b ( 28 %, 34 %), Urinary tract infection b ( 10 %, 17 %), Sepsis b (< 10 %, < 10 %); Metabolism and nutrition disorders : Decreased appetite ( 23 %, 19 %), Hypercalcemia b ( 22 %, 12 %), Hypokalemia ( 12 %, 12 %), Hyperglycemia ( 11 %, 15 %), Hyponatremia ( 11 %, 13 %), Dehydration b (< 10 %, < 10 %), Hypocalcemia ( 6 %, 12 %); Respiratory , thoracic and mediastinal disorders : Dyspnea b ( 36 %, 45 %), Cough ( 17 %, 22 %), Epistaxis ( 17 %, 11 %), Productive cough ( 9 %, 13 %), Oropharyngeal pain ( 6 %, 11 %); Nervous system disorders : Dizziness ( 22 %, 18 %), Peripheral neuropathy ( 22 %, 18 %), Headache ( 15 %, 13 %), Tremor ( 10 %, 13 %); Skin and subcutaneous tissue disorders : Rash ( 21 %, 16 %), Pruritus ( 15 %, 9 %), Dry skin ( 9 %, 11 %), Hyperhidrosis ( 8 %, 16 %), Night sweats ( 5 %, 13 %); Investigations : Blood creatinine increased b ( 19 %, 10 %), Weight decreased ( 15 %, 9 %), Weight increased ( 1 %, 11 %); Psychiatric disorders : Anxiety ( 13 %, 7 %), Confusional state b ( 12 %, 13 %), Insomnia ( 7 %, 16 %); Renal and urinary disorders : Renal failure b ( 15 %, 10 %).
In Trial 1 , Grade 3 / 4 at least one adverse reaction reported in 92 % of patients treated with POMALYST a alone ( N = 107 ) and 91 % with POMALYST + Low-dose Dex ( N = 112 ).*
Grade 3 / 4 Adverse Reactions ≥ 5 % in either arm , respectively , included : Blood and lymphatic system disorders : Neutropenia b ( 48 %, 41 %), Anemia b ( 23 %, 21 %), Thrombocytopenia b ( 22 %, 19 %), Leukopenia ( 7 %, 10 %), Febrile neutropenia b ( 6 %, 3 %), Lymphopenia ( 2 %, 7 %); General disorders and administration site conditions : Fatigue and asthenia b ( 12 %, 17 %), Edema peripheral ( 0 %, 0 %), Pyrexia b (< 5 %, < 5 %), Chills ( 0 %, 0 %); Gastrointestinal disorders : Nausea b (< 5 %, < 5 %), Constipation b (< 5 %, < 5 %), Diarrhea (< 5 %, < 5 %), Vomiting b (< 5 %, 0 %); Musculoskeletal and connective tissue disorders : Back pain b ( 14 %, 10 %), Musculoskeletal chest pain (< 5 %, 0 %), Muscle spasms (< 5 %, < 5 %), Arthralgia (< 5 %, < 5 %), Muscular weakness ( 6 %, 4 %), Bone pain (< 5 %, < 5 %), Musculoskeletal pain (< 5 %, < 5 %), Pain in extremity ( 0 %, < 5 %); Infections and infestations : Upper respiratory tract infection (< 5 %, < 5 %), Pneumonia b ( 20 %, 29 %), Urinary tract infection b ( 2 %, 9 %), Sepsis b ( 6 %, 5 %); Metabolism and nutrition disorders : Decreased appetite (< 5 %, 0 %), Hypercalcemia b ( 10 %, 1 %), Hypokalemia (< 5 %, < 5 %), Hyperglycemia (< 5 %, < 5 %), Hyponatremia (< 5 %, < 5 %) Dehydration b ( 5 %, 5 %), Hypocalcemia ( 0 %, < 5 %); Respiratory , thoracic and mediastinal disorders : Dyspnea b ( 8 %, 13 %), Cough ( 0 %, 0 %), Epistaxis (< 5 %, 0 %), Productive cough ( 0 %, 0 %), Oropharyngeal pain ( 0 %, 0 %); Nervous system disorders : Dizziness (< 5 %, < 5 %), Peripheral neuropathy ( 0 %, 0 %), Headache ( 0 %, < 5 %), Tremor ( 0 %, 0 %); Skin and subcutaneous tissue disorders : Rash ( 0 %, < 5 %), Pruritus ( 0 %, 0 %), Dry skin ( 0 %, 0 %), Hyperhidrosis ( 0 %, 0 %), Night sweats ( 0 %, 0 %); Investigations : Blood creatinine increased b ( 6 %, 3 %), Weight decreased ( 0 %, 0 %), Weight increased ( 0 %, 0 %); Psychiatric disorders : Anxiety ( 0 %, 0 %), Confusional state b ( 6 %, 3 %), Insomnia ( 0 %, 0 %); Renal and urinary disorders : Renal failure b ( 8 %, 7 %).
* Regardless of attribution of relatedness to POMALYST . a POMALYST alone arm includes all patients
randomized to the POMALYST alone arm who took study drug ; 61 of the 107 patients had dexamethasone added during the treatment period . b Serious adverse reactions were reported in at least
2 patients in any POMALYST treatment arm . Data cutoff : 01 March 2013