Prescribing Information as of October, 2004
`Prescribing Information as of October, 2004
`
`REFLUDAN®
`REFLUDAN®
`
`[lepirudin (rDNA) for injection]
`[lepirudin (rDNA) for injection]
`
`Rx only
`Rx only
`
`DESCRIPTION
`DESCRIPTION
`
`REFLUDAN [lepirudin (rDNA) for injection] is a highly specific direct inhibitor of thrombin.
`REFLUDAN [lepirudin (rDNA) for injection] is a highly specific direct inhibitor of thrombin.
`Lepirudin, (chemical designation: [Leu1, Thr2]-63-desulfohirudin) is a recombinant
`Lepirudin, (chemical designation: [Leul , Thr2]-63-desulfohirudin) is a recombinant
`hirudin derived from yeast cells. The polypeptide composed of 65 amino acids has a
`hirudin derived from yeast cells. The polypeptide composed of 65 amino acids has a
`molecular weight of 6979.5 daltons. Natural hirudin is produced in trace amounts as a
`molecular weight of 6979.5 daltons. Natural hirudin is produced in trace amounts as a
`family of highly homologous isopolypeptides by the leech Hirudo medicinalis. The
`family of highly homologous isopolypeptides by the leech Hirudo medicinalis. The
`biosynthetic molecule (lepirudin) is identical to natural hirudin except for substitution of
`biosynthetic molecule (lepirudin) is identical to natural hirudin except for substitution of
`leucine for isoleucine at the N-terminal end of the molecule and the absence of a sulfate
`leucine for isoleucine at the N-terminal end of the molecule and the absence of a sulfate
`group on the tyrosine at position 63.
`group on the tyrosine at position 63.
`
`The activity of lepirudin is measured in a chromogenic assay. One antithrombin unit
`The activity of lepirudin is measured in a chromogenic assay. One antithrombin unit
`(ATU) is the amount of lepirudin that neutralizes one unit of World Health Organization
`(ATU) is the amount of lepirudin that neutralizes one unit of World Health Organization
`preparation 89/588 of thrombin. The specific activity of lepirudin is approximately
`preparation 89/588 of thrombin. The specific activity of lepirudin is approximately
`16,000 ATU/mg. Its mode of action is independent of antithrombin III. Platelet factor 4
`16,000 ATU/mg. Its mode of action is independent of antithrombin Ill. Platelet factor 4
`does not inhibit lepirudin. One molecule of lepirudin binds to one molecule of thrombin
`does not inhibit lepirudin. One molecule of lepirudin binds to one molecule of thrombin
`and thereby blocks the thrombogenic activity of thrombin. As a result, all thrombin-
`and thereby blocks the thrombogenic activity of thrombin. As a result, all thrombin-
`dependent coagulation assays are affected, eg, activated partial thromboplastin time
`dependent coagulation assays are affected, eg, activated partial thromboplastin time
`(aPTT) and prothrombin time (PT /INR) values increase in a dose-dependent fashion
`(aPTT) and prothrombin time (PT /INR) values increase in a dose-dependent fashion
`(Roethig 1991).
`(Roethig 1991).
`
`REFLUDAN is supplied as a sterile, white, freeze-dried powder for injection or infusion
`REFLUDAN is supplied as a sterile, white, freeze-dried powder for injection or infusion
`and is freely soluble in Sterile Water for Injection USP or 0.9% Sodium Chloride Injection
`and is freely soluble in Sterile Water for Injection USP or 0.9% Sodium Chloride Injection
`USP.
`USP.
`
`Each vial of REFLUDAN contains 50 mg lepirudin. Other ingredients are 40 mg mannitol
`Each vial of REFLUDAN contains 50 mg lepirudin. Other ingredients are 40 mg mannitol
`and sodium hydroxide for adjustment of pH to approximately 7.
`and sodium hydroxide for adjustment of pH to approximately 7.
`
`CLINICAL PHARMACOLOGY
`CLINICAL PHARMACOLOGY
`Pharmacokinetic Properties
`Pharmacokinetic Properties
`
`The pharmacokinetic properties of lepirudin following intravenous administration are well
`The pharmacokinetic properties of lepirudin following intravenous administration are well
`described by a two-compartment model. Distribution is essentially confined to
`described by a two-compartment model. Distribution is essentially confined to
`extracellular fluids and is characterized by an initial half-life of approximately 10 minutes.
`extracellular fluids and is characterized by an initial half-life of approximately 10 minutes.
`Elimination follows a first-order process and is characterized by a terminal half-life of
`Elimination follows a first-order process and is characterized by a terminal half-life of
`about 1.3 hours in young healthy volunteers. As the intravenous dose is increased over
`about 1.3 hours in young healthy volunteers. As the intravenous dose is increased over
`the range of 0.1 to 0.4 mg/kg, the maximum plasma concentration and the area-under-
`the range of 0.1 to 0.4 mg/kg, the maximum plasma concentration and the area-under-
`the-curve increase proportionally.
`the-curve increase proportionally.
`
`Lepirudin is thought to be metabolized by release of amino acids via catabolic hydrolysis
`Lepirudin is thought to be metabolized by release of amino acids via catabolic hydrolysis
`of the parent drug. However, conclusive data are not available. About 48% of the
`of the parent drug. However, conclusive data are not available. About 48% of the
`
`1
`1
`
`
`
`0001
`
`0001
`
`MYLAN - EXHIBIT 1057
`
`

`

`administration dose is excreted in the urine which consists of unchanged drug (35%) and
`administration dose is excreted in the urine which consists of unchanged drug (35%) and
`other fragments of the parent drug.
`other fragments of the parent drug.
`
`The systemic clearance of lepirudin is proportional to the glomerular filtration rate or
`The systemic clearance of lepirudin is proportional to the glomerular filtration rate or
`creatinine clearance. Dose adjustment based on creatinine clearance is recommended
`creatinine clearance. Dose adjustment based on creatinine clearance is recommended
`(see DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Use in
`(see DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Use in
`Renal Impairment). In patients with marked renal insufficiency (creatinine clearance
`Renal Impairment). In patients with marked renal insufficiency (creatinine clearance
`below 15 mL/min), and on hemodialysis, elimination half-lives are prolonged up to
`below 15 mL/min), and on hemodialysis, elimination half-lives are prolonged up to
`2 days.
`2 days.
`
`Lepirudin is thought to be metabolized by release of amino acids via catabolic hydrolysis
`Lepirudin is thought to be metabolized by release of amino acids via catabolic hydrolysis
`of the parent drug. However, conclusive data are not available. About 48 % of the
`of the parent drug. However, conclusive data are not available. About 48 % of the
`administration dose is excreted in the urine which consists of unchanged drug (35%) and
`administration dose is excreted in the urine which consists of unchanged drug (35%) and
`other fragments of the parent drug.
`other fragments of the parent drug.
`
`The systemic clearance of lepirudin in women is about 25% lower than in men. In elderly
`The systemic clearance of lepirudin in women is about 25% lower than in men. In elderly
`patients, the systemic clearance of lepirudin is 20% lower than in younger patients. This
`patients, the systemic clearance of lepirudin is 20% lower than in younger patients. This
`may be explained by the lower creatinine clearance in elderly patients compared to
`may be explained by the lower creatinine clearance in elderly patients compared to
`younger patients.
`younger patients.
`
`Table 1 summarizes systemic clearance (Cl) and volume of distribution at steady state
`Table 1 summarizes systemic clearance (CI) and volume of distribution at steady state
`(Vss) of lepirudin for various study populations.
`(Vss) of lepirudin for various study populations.
`
`
`Table 1: Systemic clearance (Cl) and volume of distribution at steady state (Vss) of
`Table 1: Systemic clearance (CI) and volume of distribution at steady state (Vss) of
`lepirudin
`lepirudin
`
`
`Cl (mL/min)
`CI (mL/min)
`Mean (%
`Mean (%
`CV*)
`CV*)
`164 (19.3%)
`164 (19.3%)
`139 (22.5%)
`139 (22.5%)
` 61 (89.4%)
`61 (89.4%)
`
`Vss (L)
`Vss (L)
`Mean (%
`Mean (%
`CV*)
`CV*)
`12.2 (16.4%)
`12.2 (16.4%)
`18.7 (20.6%)
`18.7 (20.6%)
`18.0 (41.1%)
`18.0 (41.1%)
`
`Healthy young subjects (n = 18, age 18-60 years)
`Healthy young subjects (n = 18, age 18-60 years)
`Healthy elderly subjects (n = 10, age 65-80 years)
`Healthy elderly subjects (n = 10, age 65-80 years)
`Renally impaired patients (n = 16, creatinine clearance below
`Renally impaired patients (n = 16, creatinine clearance below
`80 mL/min)
`80 mL/min)
`HIT patients (n = 73)
`HIT patients (n = 73)
`* CV: Coefficient of variation
`* CV: Coefficient of variation
` HAT: Heparin-associated thrombocytopenia
`HAT: Heparin-associated thrombocytopenia
`
`114 (46.8%)
`114 (46.8%)
`
`32.1 (98.9%)
`32.1 (98.9%)
`
`
`Pharmacodynamic Properties
`Pharmacodynamic Properties
`
`The pharmacodynamic effect of REFLUDAN on the proteolytic activity of thrombin was
`The pharmacodynamic effect of REFLUDAN on the proteolytic activity of thrombin was
`routinely assessed as an increase in aPTT. This was observed with increasing plasma
`routinely assessed as an increase in aPTT. This was observed with increasing plasma
`concentrations of lepirudin, with no saturable effect up to the highest tested dose
`concentrations of lepirudin, with no saturable effect up to the highest tested dose
`(0.5 mg/kg body weight intravenous bolus). Thrombin time (TT) frequently exceeded
`(0.5 mg/kg body weight intravenous bolus). Thrombin time (TT) frequently exceeded
`200 seconds even at low plasma concentrations of lepirudin, which renders this test
`200 seconds even at low plasma concentrations of lepirudin, which renders this test
`unsuitable for routine monitoring of REFLUDAN therapy.
`unsuitable for routine monitoring of REFLUDAN therapy.
`
`The pharmacodynamic response defined by the aPTT ratio (aPTT at a time after
`The pharmacodynamic response defined by the aPTT ratio (aPTT at a time after
`REFLUDAN administration over an aPTT reference value, usually median of the
`REFLUDAN administration over an aPTT reference value, usually median of the
`laboratory normal range for aPTT) depends on plasma drug levels which in turn depend
`laboratory normal range for aPTT) depends on plasma drug levels which in turn depend
`
`2
`2
`
`
`
`0002
`
`0002
`
`

`

`on the individual patient’s renal function (see CLINICAL PHARMACOLOGY:
`on the individual patient's renal function (see CLINICAL PHARMACOLOGY:
`Pharmacokinetic Properties). For patients undergoing additional thrombolysis, elevated
`Pharmacokinetic Properties). For patients undergoing additional thrombolysis, elevated
`aPTT ratios were already observed at low lepirudin plasma concentrations, and further
`aPTT ratios were already observed at low lepirudin plasma concentrations, and further
`response to increasing plasma concentrations was relatively flat. In other populations,
`response to increasing plasma concentrations was relatively flat. In other populations,
`the response was steeper. At plasma concentrations of 1500 ng/mL, aPTT ratios were
`the response was steeper. At plasma concentrations of 1500 ng/mL, aPTT ratios were
`nearly 3.0 for healthy volunteers, 2.3 for patients with heparin-associated
`nearly 3.0 for healthy volunteers, 2.3 for patients with heparin-associated
`thrombocytopenia, and 2.1 for patients with deep venous thrombosis.
`thrombocytopenia, and 2.1 for patients with deep venous thrombosis.
`
`CLINICAL TRIAL DATA
`CLINICAL TRIAL DATA
`
`Heparin-induced thrombocytopenia (HIT) is described as an allergy-like adverse reaction
`Heparin-induced thrombocytopenia (HIT) is described as an allergy-like adverse reaction
`to heparin. It can be found in about 1% to 2% of patients treated with heparin for more
`to heparin. It can be found in about 1% to 2% of patients treated with heparin for more
`than 4 days. The clinical picture of HIT is characterized by thrombocytopenia alone or in
`than 4 days. The clinical picture of HIT is characterized by thrombocytopenia alone or in
`combination with thromboembolic complications (TECs). These complications comprise
`combination with thromboembolic complications (TECs). These complications comprise
`the entire spectrum of venous and arterial thromboembolism including deep venous
`the entire spectrum of venous and arterial thromboembolism including deep venous
`thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, and occlusion
`thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, and occlusion
`of limb arteries, which may ultimately result in necroses requiring amputation.
`of limb arteries, which may ultimately result in necroses requiring amputation.
`Furthermore, there is evidence to suggest that warfarin-induced venous limb gangrene
`Furthermore, there is evidence to suggest that warfarin-induced venous limb gangrene
`may be associated with HIT. Without further treatment, the mortality in HIT patients with
`may be associated with HIT. Without further treatment, the mortality in HIT patients with
`new TECs is about 20% to 30% (Fondu 1995; Greinacher 1995; Warkentin, Chong, et
`new TECs is about 20% to 30% (Fondu 1995; Greinacher 1995; Warkentin, Chong, et
`al., Warkentin, Elavathil, et al. 1997).
`al., Warkentin, Elavathil, et al. 1997).
`
`The conclusion that REFLUDAN is an effective treatment for HIT is based upon the data
`The conclusion that REFLUDAN is an effective treatment for HIT is based upon the data
`of two prospective, historically controlled clinical trials (“HAT-1” study and “HAT-2”
`of two prospective, historically controlled clinical trials ("HAT-1" study and "HAT-2"
`study). The trials were comparable with regard to study design, primary and secondary
`study). The trials were comparable with regard to study design, primary and secondary
`objectives, and dosing regimens, as well as general study outline and organization. They
`objectives, and dosing regimens, as well as general study outline and organization. They
`both used the same historical control group for comparison. This historical control was
`both used the same historical control group for comparison. This historical control was
`mainly compiled from a recent retrospective registry of HIT patients.
`mainly compiled from a recent retrospective registry of HIT patients.
`
`Overall, 198 (HAT-1: 82, HAT-2: 116) patients were treated with REFLUDAN and 182
`Overall, 198 (HAT-1: 82, HAT-2: 116) patients were treated with REFLUDAN and 182
`historical control patients were treated with other therapies. All except 5 (HAT-1: 1,
`historical control patients were treated with other therapies. All except 5 (HAT-1: 1,
`HAT-2: 4) prospective patients and all historical control patients were diagnosed with
`HAT-2: 4) prospective patients and all historical control patients were diagnosed with
`HIT using the heparin-induced platelet activation assay (HIPAA) or equivalent assays for
`HIT using the heparin-induced platelet activation assay (HIPAA) or equivalent assays for
`testing. In total, 113 (HAT-1: 54, HAT-2: 59) prospective patients (“REFLUDAN”) and 91
`testing. In total, 113 (HAT-1: 54, HAT-2: 59) prospective patients ("REFLUDAN") and 91
`historical control patients (“historical control”) presented with TECs at baseline (day of
`historical control patients ("historical control") presented with TECs at baseline (day of
`positive test result) and qualified for direct comparison of clinical endpoints.
`positive test result) and qualified for direct comparison of clinical endpoints.
`
`The gender distribution was found to be similar in REFLUDAN patients and historical
`The gender distribution was found to be similar in REFLUDAN patients and historical
`control patients. Overall, REFLUDAN patients tended to be younger than historical
`control patients. Overall, REFLUDAN patients tended to be younger than historical
`control patients. Table 2 summarizes the demographic baseline characteristics of
`control patients. Table 2 summarizes the demographic baseline characteristics of
`patients presenting with TECs at baseline.
`patients presenting with TECs at baseline.
`
`3
`3
`
`
`
`0003
`
`0003
`
`

`

`
`
`
`
`Males
`Males
`Females
`Females
`Age <65 years
`Age <65 years
`Age >65 years
`Age >65 years
`Mean age ± SD (years)
`Mean age ± SD (years)
`
`Table 2: Demographic baseline characteristics of patients presenting with TECs
`Table 2: Demographic baseline characteristics of patients presenting with TECs
`
`REFLUDAN
`Historical
`REFLUDAN
`Historical
`Control
`Control
`
`(n = 91)
`(n = 91)
`35.2%
`35.2%
`64.8%
`64.8%
`44.0%
`44.0%
`56.0%
`56.0%
`64 ± 14
`64 ± 14
`
`HAT –1
`HAT —1
`(n = 54)
`(n = 54)
`27.8%
`27.8%
`72.2%
`72.2%
`63.0%
`63.0%
`37.0%
`37.0%
`57 ± 17
`57 ± 17
`
`HAT –2
`HAT —2
`(n = 59)
`(n = 59)
`44.1%
`44.1%
`55.9%
`55.9%
`67.8%
`67.8%
`32.2%
`32.2%
`58 ± 12
`58 ± 12
`
`
`The key criteria of efficacy from a laboratory standpoint (n = 115 evaluable patients)
`The key criteria of efficacy from a laboratory standpoint (n = 115 evaluable patients)
`were platelet recovery (increase in platelet count by at least 30% of nadir to values
`were platelet recovery (increase in platelet count by at least 30% of nadir to values
`>100,000) and effective anticoagulation (aPTT ratio >1.5 with a maximum total 40%
`>100,000) and effective anticoagulation (aPTT ratio >1.5 with a maximum total 40%
`increase in the initial infusion rate). The proportions of REFLUDAN patients presenting
`increase in the initial infusion rate). The proportions of REFLUDAN patients presenting
`with TECs at baseline who showed platelet recovery, effective anticoagulation, or both
`with TECs at baseline who showed platelet recovery, effective anticoagulation, or both
`(laboratory responders) are shown in Table 3. Comparable rates for the historical
`(laboratory responders) are shown in Table 3. Comparable rates for the historical
`control group cannot be given, because (1) platelet counts were not monitored as closely
`control group cannot be given, because (1) platelet counts were not monitored as closely
`as in the REFLUDAN group, and (2) most historical control patients did not receive
`as in the REFLUDAN group, and (2) most historical control patients did not receive
`therapies affecting aPTT.
`therapies affecting aPTT.
`
`
`Table 3: Proportions of laboratory responders among REFLUDAN patients presenting
`Table 3: Proportions of laboratory responders among REFLUDAN patients presenting
`with TECs
`with TECs
`
`Number of evaluable
`Number of evaluable
`patients
`patients
`Platelet recovery
`Platelet recovery
`Effective anticoagulation
`Effective anticoagulation
`Both
`Both
`
`HAT-1
`HAT-1
`55
`55
`
`90.9%
`90.9%
`81.8%
`81.8%
`72.7%
`72.7%
`
`HAT-2
`HAT-2
`60
`60
`
`95.0%
`95.0%
`75.0%
`75.0%
`71.7%
`71.7%
`
`
`
`Comparisons of clinical efficacy were made between REFLUDAN patients and historical
`Comparisons of clinical efficacy were made between REFLUDAN patients and historical
`control patients with regard to the combined and individual incidences of death, limb
`control patients with regard to the combined and individual incidences of death, limb
`amputation, or new TEC.
`amputation, or new TEC.
`
`The original main analyses included all events that occurred after laboratory confirmation
`The original main analyses included all events that occurred after laboratory confirmation
`of HIT. This approach revealed to be substantially confounded by the relative
`of HIT. This approach revealed to be substantially confounded by the relative
`contribution of the pretreatment period (time between laboratory confirmation of HIT and
`contribution of the pretreatment period (time between laboratory confirmation of HIT and
`start of treatment). Although short in duration (mean length 1.5 days in HAT-1 and 2.0
`start of treatment). Although short in duration (mean length 1.5 days in HAT-1 and 2.0
`days in HAT-2), the pretreatment period accounted for 45% and 26% of events observed
`days in HAT-2), the pretreatment period accounted for 45% and 26% of events observed
`in the main analyses of HAT-1 REFLUDAN patients and HAT-2 REFLUDAN patients,
`in the main analyses of HAT-1 REFLUDAN patients and HAT-2 REFLUDAN patients,
`respectively.
`respectively.
`
`
`4
`4
`
`
`
`0004
`
`0004
`
`

`

`Therefore, initiation of treatment was set as the starting point for the analyses. For the
`Therefore, initiation of treatment was set as the starting point for the analyses. For the
`historical control group, the first treatment selected within 2 days of laboratory
`historical control group, the first treatment selected within 2 days of laboratory
`confirmation of HIT was used for reference.
`confirmation of HIT was used for reference.
`
`Seven days after start of treatment, the cumulative risk of death, limb amputation, or new
`Seven days after start of treatment, the cumulative risk of death, limb amputation, or new
`TEC was 3.7% in the HAT-1 REFLUDAN patients and 16.9% in the HAT-2 REFLUDAN
`TEC was 3.7% in the HAT-1 REFLUDAN patients and 16.9% in the HAT-2 REFLUDAN
`patients, as compared to 24.9% in the historical control group. At 35 days, when
`patients, as compared to 24.9% in the historical control group. At 35 days, when
`approximately 10% of patients were still at risk, the cumulative risk was 13.0% in the
`approximately 10% of patients were still at risk, the cumulative risk was 13.0% in the
`HAT-1 REFLUDAN patients and 28.9% in the HAT-2 REFLUDAN patients, as compared
`HAT-1 REFLUDAN patients and 28.9% in the HAT-2 REFLUDAN patients, as compared
`to 47.8% in the historical control group.
`to 47.8% in the historical control group.
`
`In an additional meta-analysis, the pooled REFLUDAN patients of the HAT-1 and HAT-2
`In an additional meta-analysis, the pooled REFLUDAN patients of the HAT-1 and HAT-2
`studies who presented with TECs at baseline were compared to the respective historical
`studies who presented with TECs at baseline were compared to the respective historical
`control patients. Seven and 35 days after start of treatment, the cumulative risks of death
`control patients. Seven and 35 days after start of treatment, the cumulative risks of death
`were 4.4% and 8.9% in the REFLUDAN group, as compared to 1.4% and 17.6% in the
`were 4.4% and 8.9% in the REFLUDAN group, as compared to 1.4% and 17.6% in the
`historical control group. The cumulative risks of limb amputation were 2.7% and 6.5% in
`historical control group. The cumulative risks of limb amputation were 2.7% and 6.5% in
`the REFLUDAN group, as compared to 2.6% and 10.4% in the historical control group.
`the REFLUDAN group, as compared to 2.6% and 10.4% in the historical control group.
`Most importantly, the cumulative risks of new TEC were 6.3 % and 10.1% in the
`Most importantly, the cumulative risks of new TEC were 6.3 % and 10.1% in the
`REFLUDAN group, as compared to 22.2% and 27.2% in the historical control group. As
`REFLUDAN group, as compared to 22.2% and 27.2% in the historical control group. As
`shown in Fig 1, differences in the cumulative risk of death, limb amputation, or new TEC
`shown in Fig 1, differences in the cumulative risk of death, limb amputation, or new TEC
`between the groups were statistically significant in favor of REFLUDAN in the analysis of
`between the groups were statistically significant in favor of REFLUDAN in the analysis of
`time to event (P=0.004 according to log-rank test).
`time to event (P=0.004 according to log-rank test).
`
`5
`5
`
`
`
`0005
`
`0005
`
`

`

`
`Fig 1: Cumulative risk of death, limb amputation, or new thromboembolic complication
`Fig 17 Candoevo risk of axe; Int orrgp Th i Q mpg grOnitaninlIC 1,1111111X1tIon
`after start of treatment
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`t Unwed obeemtiona: Patients who did eat roach a Caeca endpotal during their girl d of follow-up
`
`The immediate impact of treatment on the combined risk of death, limb amputation, or
`Tie Irmallote Impact of beetrro:nt On ttm corrblred risk of doeli. Imb errata*" or
`new TEC is demonstrated by comparing pretreatment period and treatment period in
`new TLC Iv rle nolgtrobil by 1,1111110 final [imbue Irwin t [stud srd boo Irwin t mr1 al In
`regard to average combined event rates per patient day. In the pretreatment period,
`woad to mange corrblroxl rink robae pkw mead WY- In he Proboutinn Plank
`these rates were found to be 0.075 in the HAT-1 REFLUDAN patients, 0.052 in the HAT-
`Ulm rub. 0.3w bard tabu (LEM In he ERT-IFtERLDAN polonbk DIM In ho HAT-
`2 REFLUDAN patients, and 0.040 in the historical control group. In the treatment period,
`2 REFWDAN pants, teci 0.041:1 In he blubitul cantni grow kf tie Yawn( patal.
`the rates showed a marked reduction in the REFLUDAN patients, where they dropped
`tie rub. ohownil noted rOductIon In thi REFILICIAN pulent% Sun, trey dropped
`to 0.005 (HAT-1) and to 0.018 (HAT-2), while there was only a moderate decrease to
`to ELM
`urd b111313(1-19.1"-n 'Ode Use rnil Only fr rThIlatoi ducreueu
`0.030 in the historical control group.
`CAM In he hiturtcol =Doi Inv -
`
`In conclusion, REFLUDAN substantially reduced the risk of serious sequelae of HIT in
`In wash.; FEFILEPN ouboblikly ri dded [hi re of ourlounoquElkti d HT In
`comparison to a historical control group.
`mulpflani lo p hitabad cantn:11 IPotq
`
`
`
`
`6
`6
`
`
`
`0006
`
`

`

`INDICATIONS AND USAGE
`INDICATIONS AND USAGE
`
`Refludan is indicated for anticoagulation in patients with heparin-associated
`Refludan is indicated for anticoagulation in patients with heparin-associated
`thrombocytopenia (HIT) and associated thromboembolic disease in order to prevent
`thrombocytopenia (HIT) and associated thromboembolic disease in order to prevent
`further thromboembolic complications.
`further thromboembolic complications.
`
`CONTRAINDICATIONS
`CONTRAINDICATIONS
`
`REFLUDAN is contraindicated in patients with known hypersensitivity to hirudins or to
`REFLUDAN is contraindicated in patients with known hypersensitivity to hirudins or to
`any of the components in REFLUDAN [lepirudin (rDNA) for injection].
`any of the components in REFLUDAN [lepirudin (rDNA) for injection].
`
`WARNINGS
`WARNINGS
`
`Hemorrhagic Events
`Hemorrhagic Events
`
`As with other anticoagulants, hemorrhage can occur at any site in patients
`As with other anticoagulants, hemorrhage can occur at any site in patients
`receiving REFLUDAN. An unexpected fall in hemoglobin, fall in blood pressure or
`receiving REFLUDAN. An unexpected fall in hemoglobin, fall in blood pressure or
`any unexplained symptom should lead to consideration of a hemorrhagic event.
`any unexplained symptom should lead to consideration of a hemorrhagic event.
`While patients are being anticoagulated with REFLUDAN, the anticoagulation
`While patients are being anticoagulated with REFLUDAN, the anticoagulation
`status should be monitored closely using an appropriate measure such as the
`status should be monitored closely using an appropriate measure such as the
`aPTT (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION:
`aPTT (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION:
`Monitoring Section.)
`Monitoring Section.)
`
`Intracranial bleeding following concomitant thrombolytic therapy with rt-PA or
`Intracranial bleeding following concomitant thrombolytic therapy with rt-PA or
`streptokinase may be life-threatening. There have been reports of intracranial
`streptokinase may be life-threatening. There have been reports of intracranial
`bleeding with REFLUDAN in the absence of concomitant thrombolytic therapy
`bleeding with REFLUDAN in the absence of concomitant thrombolytic therapy
`(see ADVERSE REACTIONS.)
`(see ADVERSE REACTIONS.)
`
`For patients with increased risk of bleeding, a careful assessment weighing the
`For patients with increased risk of bleeding, a careful assessment weighing the
`risk of REFLUDAN administration vs its anticipated benefit has to be made by the
`risk of REFLUDAN administration vs its anticipated benefit has to be made by the
`treating physician:
`treating physician:
`In particular, this includes the following conditions:
`In particular, this includes the following conditions:
`
`
`• Recent puncture of large vessels or organ biopsy
`• Recent puncture of large vessels or organ biopsy
`
` •
`
` Anomaly of vessels or organs
`• Anomaly of vessels or organs
`
`
`
`
`
`
`
`
`
`
`
`7
`7
`
`
`
` •
`
` Recent cerebrovascular accident, stroke, intracerebral surgery, or
`• Recent cerebrovascular accident, stroke, intracerebral surgery, or
`other neuraxail procedures
`other neuraxail procedures
`
`• Severe uncontrolled hypertension
`• Severe uncontrolled hypertension
`
`• Bacterial endocarditis
`• Bacterial endocarditis
`
`• Advanced renal impairment (see also WARNINGS: Renal Impairment)
`• Advanced renal impairment (see also WARNINGS: Renal Impairment)
`
` •
`
` Hemorrhagic diathesis
`• Hemorrhagic diathesis
`
`• Recent major surgery
`• Recent major surgery
`
`0007
`
`0007
`
`

`

`• Recent major bleeding (eg, intracranial, gastrointestinal, intraocular, or
`• Recent major bleeding (eg, intracranial, gastrointestinal, intraocular, or
`pulmonary bleeding)
`pulmonary bleeding)
`
`
`
`• Recent active peptic ulcer
`• Recent active peptic ulcer
`
`
`
`
`Renal Impairment
`Renal Impairment
`
`With renal impairment, relative overdose might occur even with standard dosage
`With renal impairment, relative overdose might occur even with standard dosage
`regimen. Therefore, the bolus dose and the rate of infusion must be reduced in patients
`regimen. Therefore, the bolus dose and the rate of infusion must be reduced in patients
`with known or suspected renal insufficiency (see CLINICAL PHARMACOLOGY:
`with known or suspected renal insufficiency (see CLINICAL PHARMACOLOGY:
`Pharmacokinetic Properties and DOSAGE AND ADMINISTRATION: Monitoring and
`Phannacokinetic Properties and DOSAGE AND ADMINISTRATION: Monitoring and
`Adjusting Therapy; Use in Renal Impairment).
`Adjusting Therapy; Use in Renal Impairment).
`
`PRECAUTIONS
`PRECAUTIONS
`
`General
`General
`
`Antibodies. Formation of antihirudin antibodies was observed in about 40% of HIT
`Antibodies. Formation of antihirudin antibodies was observed in about 40% of HIT
`patients treated with REFLUDAN. This may increase the anticoagulant effect of
`patients treated with REFLUDAN. This may increase the anticoagulant effect of
`REFLUDAN possibly due to delayed renal elimination of active lepirudin-antihirudin
`REFLUDAN possibly due to delayed renal elimination of active lepirudin-antihirudin
`complexes (see also PRECAUTIONS: Animal Pharmacology and Toxicology).
`complexes (see also PRECAUTIONS: Animal Pharmacology and Toxicology).
`Therefore, strict monitoring of aPTT is necessary also during prolonged therapy (see
`Therefore, strict monitoring of aPTT is necessary also during prolonged therapy (see
`also PRECAUTIONS: Laboratory Tests and DOSAGE AND ADMINISTRATION:
`also PRECAUTIONS: Laboratory Tests and DOSAGE AND ADMINISTRATION:
`Monitoring and Adjusting Therapy; Standard Recommendations). No evidence of
`Monitoring and Adjusting Therapy; Standard Recommendations). No evidence of
`neutralization of REFLUDAN or of allergic reactions associated with positive antibody
`neutralization of REFLUDAN or of allergic reactions associated with positive antibody
`test results was found.
`test results was found.
`
`Liver Injury. Serious liver injury (eg, liver cirrhosis) may enhance the anticoagulant
`Liver Injury. Serious liver injury (eg, liver cirrhosis) may enhance the anticoagulant
`effect of REFLUDAN due to coagulation defects secondary to reduced generation of
`effect of REFLUDAN due to coagulation defects secondary to reduced generation of
`vitamin K-dependent coagulation factors.
`vitamin K-dependent coagulation factors.
`
`Reexposure. During the HAT-1 and HAT-2 studies, a total of 13 patients were
`Reexposure. During the HAT-1 and HAT-2 studies, a total of 13 patients were
`reexposed to REFLUDAN. One of these patients experienced a mild allergic skin
`reexposed to REFLUDAN. One of these patients experienced a mild allergic skin
`reaction during the second treatment cycle. In post marketing experience, anaphylaxis
`reaction during the second treatment cycle. In post marketing experience, anaphylaxis
`after reexposure has been repor