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COAG trials attempted to identify patients who are susceptible to having a supratherapeutic INR on warfarin , which can be caused by variations in vitamin K intake , medications , body size , and so on . These are variables that require prothrombin monitoring to adjust dosing . Genetics , on the other hand , don ’ t change ; they cannot be used to monitor and adjust warfarin dosing throughout the course of anticoagulation .
Dr . Cavallari : I completely agree that the
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true benefit of pharmacogenomic testing will be in helping us select an initial dose for patients starting warfarin . This approach may not be helpful in many patients because they will end up having a genotype that is associated with needing a normal warfarin dose ; the value of pharmacogenomics is limited to those individuals who will need a particularly low or high dose based on their genotypes .
Dr . Furie : Also , to continue the discussion
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about pharmacogenomics and patient safety , the primary endpoints in these trials focused on anticoagulation-related outcomes , not bleeding or thrombotic complications . We all know that , even when patients are in the therapeutic INR range , they can have thrombotic or bleeding complications , and these can be clinically silent events .
Dr . Cavallari : The Genetics Informatics Trial ( GIFT ) hopefully will help answer questions about genotype-guided dosing ’ s effect
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on patient safety . 3 The trial , which is nearly completed , is evaluating whether genotypeguided dosing can reduce the rate of adverse events in older patients who have undergone hip arthroplasty and are taking warfarin to prevent venous thromboembolism – a very different patient population than the EU-PACT and COAG trials . The primary endpoints in this very high-risk population include bleeding , thrombosis , and surrogate markers of excessive anticoagulation ( INR ≥4.0 ), and investigators are also looking at time in the therapeutic INR range . |
BRIEF SUMMARY OF PRESCRIBING INFORMATION INJECTAFER ® ( ferric carboxymaltose injection )
Rx Only
INDICATIONS AND USAGE : Injectafer ( ferric carboxymaltose injection ) is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients :
• who have intolerance to oral iron or who have had unsatisfactory response to oral iron ,
• who have non-dialysis dependent chronic kidney disease .
DOSAGE AND ADMINISTRATION : For patients weighing 50 kg ( 110 lb ) or more : Give Injectafer in two doses separated by at least 7 days . Give each dose as 750 mg for a total cumulative dose not to exceed 1500 mg of iron per course .
For patients weighing less than 50 kg ( 110 lb ): Give Injectafer in two doses separated by at least 7 days . Give each dose as 15 mg / kg body weight for a total cumulative dose not to exceed 1500 mg of iron per course .
Injectafer treatment may be repeated if iron deficiency anemia reoccurs .
Administer Injectafer intravenously , either as an undiluted slow intravenous push or by infusion . When administering as a slow intravenous push , give at the rate of approximately 100 mg ( 2 mL ) per minute . When administered via infusion , dilute up to 750 mg of iron in no more than 250 mL of sterile 0.9 % sodium chloride injection , USP , such that the concentration of the infusion is not less than 2 mg of iron per mL and administer over at least 15 minutes .
Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration . The product contains no preservatives . Injectafer is a single-use vial . Discard unused portion .
Avoid extravasation of Injectafer since brown discoloration of the extravasation site may be long lasting . Monitor for extravasation . If extravasation occurs , discontinue the Injectafer administration at that site .
DOSAGE FORMS AND STRENGTHS : Single-use vials containing 50 mg elemental iron per mL in the following presentation : 750 mg iron / 15 mL
CONTRAINDICATIONS : Hypersensitivity to Injectafer or any of its inactive components . WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions : Serious hypersensitivity reactions , including anaphylactic-type reactions , some of which have been life-threatening and fatal , have been reported in patients receiving Injectafer . Patients may present with shock , clinically significant hypotension , loss of consciousness , and / or collapse . Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer administration for at least 30 minutes and until clinically stable following completion of the infusion . Only administer Injectafer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions . In clinical trials , serious anaphylactic / anaphylactoid reactions were reported in 0.1 % ( 2 / 1775 ) of subjects receiving Injectafer . Other serious or severe adverse reactions potentially associated with hypersensitivity which included , but not limited to , pruritus , rash , urticaria , wheezing , or hypotension were reported in 1.5 % ( 26 / 1775 ) of these subjects .
Hypertension : In clinical studies , hypertension was reported in 3.8 % ( 67 / 1,775 ) of subjects in clinical trials 1 and 2 . Transient elevations in systolic blood pressure , sometimes occurring with facial flushing , dizziness , or nausea were observed in 6 % ( 106 / 1,775 ) of subjects in these two clinical trials . These elevations generally occurred immediately after dosing and resolved within 30 minutes . Monitor patients for signs and symptoms of hypertension following each Injectafer administration .
Laboratory Test Alterations : In the 24 hours following administration of Injectafer , laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in Injectafer .
ADVERSE REACTIONS
Adverse Reactions in Clinical Trials : Because clinical trials are conducted under widely varying conditions , the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice .
In two randomized clinical studies , a total of 1,775 patients were exposed to Injectafer 15 mg / kg body weight up to a maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative dose of 1500 mg of iron .
Adverse reactions reported by ≥ 1 % of treated patients are shown in the following table . Table 1 . Adverse reactions reported in ≥ 1 % of Study Patients in Clinical Trials 1 and 2
Term
Injectafer ( N = 1775 ) %
Pooled
Comparators a ( N = 1783 ) %
Oral iron ( N = 253 ) %
Nausea 7.2 1.8 1.2 Hypertension 3.8 1.9 0.4 Flushing / Hot Flush 3.6 0.2 0.0 Blood Phosphorus Decrease 2.1 0.1 0.0 Dizziness 2.0 1.2 0.0 Vomiting 1.7 0.5 0.4 Injection Site Discoloration 1.4 0.3 0.0 Headache 1.2 0.9 0.0 Alanine Aminotransferase Increase 1.1 0.2 0.0 Dysgeusia 1.1 2.1 0.0 Hypotension 1.0 1.9 0.0 Constipation 0.5 0.9 3.2 a
Includes oral iron and all formulations of IV iron other than Injectafer
Other adverse reactions reported by ≥ 0.5 % of treated patients include abdominal pain , diarrhea , gamma glutamyl transferase increased , injection site pain / irritation , rash , paraesthesia , sneezing .
Transient decreases in laboratory blood phosphorus levels (< 2 mg / dL ) have been observed in 27 % ( 440 / 1638 ) of patients in clinical trials .
Adverse Reactions from Post-marketing Experience : The following serious adverse reactions have been most commonly reported from the post-marketing spontaneous reports with Injectafer : urticaria , dyspnea , pruritis , tachycardia , erythema , pyrexia , chest discomfort , chills , angioedema , back pain , arthralgia , and syncope . One case of hypophosphatemic osteomalacia was reported in a subject who received 500 mg of Injectafer every 2 weeks for a total of 16 weeks . Partial recovery followed discontinuation of Injectafer .
DRUG INTERACTIONS : Formal drug interaction studies have not been performed with Injectafer . USE IN SPECIFIC POPULATIONS
Pregnancy Pregnancy Category C : Adequate and well controlled studies in pregnant women have not been conducted . Injectafer should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus .
Nursing Mothers : A study to determine iron concentrations in breast milk after administration of Injectafer ( n = 11 ) or oral ferrous sulfate ( n = 14 ) was conducted in 25 lactating women with postpartum iron deficiency anemia . Mean breast milk iron levels were higher in lactating women receiving Injectafer than in lactating women receiving oral ferrous sulfate .
Pediatric Use : Safety and effectiveness has not been established in pediatric patients .
Geriatric Use : Of the 1775 subjects in clinical studies of Injectafer , 50 % were 65 years and over , while 25 % were 75 years and over . No overall differences in safety or effectiveness were observed between these subjects and younger subjects , and other reported clinical experience has not identified differences in responses between the elderly and younger patients , but greater sensitivity of some older individuals cannot be ruled out .
OVERDOSAGE : Excessive dosages of Injectafer may lead to accumulation of iron in storage sites potentially leading to hemosiderosis . A patient who received Injectafer 18,000 mg over 6 months developed hemosiderosis with multiple joint disorder , walking disability and asthenia . Hypophosphatemic osteomalacia was reported in a patient who received Injectafer 4000 mg over 4 months . Partial recovery followed discontinuation of Injectafer .
CLINICAL STUDIES : The safety and efficacy of Injectafer for treatment of iron deficiency anemia were evaluated in two randomized , open-label , controlled clinical trials ( Trial 1 and Trial 2 ). In these two trials , Injectafer was administered at dose of 15 mg / kg body weight up to a maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative dose of 1500 mg of iron .
PATIENT COUNSELING INFORMATION
• Question patients regarding any prior history of reactions to parenteral iron products .
• Advise patients of the risks associated with Injectafer .
• Advise patients to report any signs and symptoms of hypersensitivity that may develop during and following Injectafer administration , such as rash , itching , dizziness , lightheadedness , swelling and breathing problems .
Injectafer is manufactured under license from Vifor ( International ) Inc , Switzerland .
This is not all the risk information for Injectafer . Please see www . injectafer . com for Full Prescribing Information .
IN0650BS Rev . 9 / 2015
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Dr . Furie : If GIFT or other trials do support the use of pharmacogenomic testing when initiating warfarin , the next challenge is making sure that everyone benefits equally from this approach . We work in a resourcepoor environment , where patients who live in urban areas and have access to anticoagulation clinics fare better with warfarin than those who live in rural areas . The question is : How do we bring the quality of the urban areas to the rural populations ?
We have more than 60 years of experience with warfarin and a standard – though cumbersome – system : A patient goes to the lab to have his or her PT measured ; the lab then performs the test and faxes that information to the doctor ’ s office ; the doctor or nurse then makes the decision about how the patient ’ s warfarin will be managed . I believe the infrastructure needs to be improved .
Dr . Cavallari : Turning around the genetic testing quickly could be quite labor-intensive for institutions , but we are slowly moving toward more widespread implementation of pharmacogenomics into practice . Also , as you said , a patient ’ s genetics don ’ t change : Genotyping only needs to be performed once in a patient ’ s lifetime . It is an expensive test , but unlike other tests such as creatinine , it needs to be done once and can have far-reaching implications .
Dr . Furie : The cost and reimbursement issues with genotype-guided warfarin dosing are a concern , but that issue is also tied up with clinical trials that may provide more answers in the future . For now , though , I think that there are ways of improving patient safety and monitoring techniques – and they don ’ t necessarily include pharmacogenomics .
Dr . Cavallari : Perhaps a combination of both approaches would work : Pharmacogenomics upfront to help with choosing the initial dose , then improved monitoring techniques to help with managing a patient ’ s chronic therapy . The two approaches might not be mutually exclusive . ●
REFERENCES
1 . Pirmohamed M , Burnside G , Eriksson N , et al . A randomized trial of genotype-guided dosing of warfarin . N Engl J Med . 2013 ; 369:2294-303 .
2 . Kimmel SE , French B , Kasner SE , et al . A pharmacogenetic versus a clinical algorithm for warfarin dosing . N Engl J Med . 2013 ; 369:2283-93 .
3 . Do EJ , Lenzini P , Eby CS , et al . Genetics informatics trial ( GIFT ) of warfarin to prevent deep vein thrombosis ( DVT ): rationale and study design . Pharmacogenomics J . 2012 ; 12 ; 417-24 .
December 2016