Adverse reactions : תופעות לוואי

ADVERSE REACTIONS
Treatment with BUSULFEX (busulfan) at the recommended dose and schedule will result in profound myelosuppression in 100% of patients, including granulocytopenia, thrombocytopenia, anemia, or a combined loss of formed elements of the blood. All patients received 0.8 mg/kg BUSULFEX as a two-hour infusion every six hours for 16 doses over four days. Ninety percent (90%) of patients receiving this dose of BUSULFEX maintained AUCs less than 1,500 μMol•min which has generally been considered efficacious in terms of myelosuppression, engraftment and relapse prevention, and safe with respect to minimizing the risk of HVOD, acute infection and other causes of morbidity.

Patients undergoing high-dose busulfan therapy followed by hematopoietic progenitor cell transplantation experience a wide range of adverse experiences.
These may result from their disease, prior therapy, concomitant cytotoxic drugs or other medications, as well as from busulfan.

Hepatic veno-occlusive disease (HVOD) developed in 5.8% (6/103) (1 of 42 autologous and 5 of 61 allogeneic patients) of patients treated with BUSULFEX in these studies and was fatal in 1.9% (2/103) (2 of 61 allogeneic patients, one of which had a prior transplant). Of the two mortalities, one patient was heavily pre-treated and had undergone a prior transplant. Of the six patients identified by site investigators, four met the Jones’ criteria, including the two mortalities and two of the other identified cases, which both resolved. Therefore, the incidence of HVOD per the Jones’ criteria was 3.8% (4/103). Hepatic veno-occlusive disease was reported in 17% of patients treated with high-dose oral busulfan in the transplant setting; 5-6% of patients died. Serum transaminases, alkaline phosphatase, and bilirubin should be monitored regularly for early detection of hepatotoxicity.


As reported in the literature, HVOD is recognized as a common complication of pretransplant preparative regimens, and various preparative regimens have been implicated. Both oral and IV busulfan have been associated with the occurrence of HVOD. The incidences of HVOD were compared in patients undergoing allogeneic transplantation using an oral or IV busulfan /cyclophosphamide (BuCy2) conditioning regimen (see Table 1 below).

Table 1. Incidences of HVOD in Patients Undergoing Allogeneic
Transplantation: IV Bu vs. Oral Bu

HVOD
N           incidence
Conditioning                  (%)            HVOD
Publication Population regimen                                      criteria
IV Oral     IV    Oral
Bu Bu       Bu    Bu
CML, acute                                    8     33       Clinical leukemia,
BuCy2
Kashyap30      MDS, NHL,                         61   30     5      20 Baltimore
MM

AML, CML,
Lee31          ALL, MDS,       BuCy2             55 186 18.5 41.7 Seattle other
BuCy2: IV Busulfan was administered at 0.8 mg/kg over 2 hours every 6 hours for 16 doses (days –7 to –4). Oral busulfan was administered at a fixed dose of 1 mg/kg adjusted ideal body weight every 6 hours for a total of 16 dose (days –7 to –4).
Cyclophosphamide was then given at 60 mg/kg IV over 1 hour daily for 2 doses (days –3 and –2).

Although not seen with BUSULFEX, cardiac tamponade (often fatal), frequently preceded by abdominal pain and vomiting, has been reported in thalassemia patients who received high doses of oral busulfan and cyclophosphamide.

Clinical Trial and Literature Database Adverse Drug Reactions:
Adverse reaction information is derived from two clinical studies (n=103) of BUSULFEX (Tables 2 and 3) and the literature database (Table 4). The BUSULFEX studies prospectively identified events to be recorded and adverse experience incidence rates were calculated. All patients received 0.8 mg/kg BUSULFEX as a two-hour infusion every six hours for 16 doses over four days. Information from the literature database is limited to those events selected by the authors for reporting.
Incidence is approximated by considering the number of patients (n) equal to the sum of the patients included in those studies that reported a particular event. Seventy- seven percent (77%) of the patients in the literature database received a total busulfan dose of 16 mg/kg. Other than the expected bone marrow suppression often resulting in opportunistic infections that can be lethal, the most clinically relevant adverse events are for the liver, lung and brain.

Table 2: Summary of the Incidence (≥ 20%) of Hematologic Adverse Events in Patients Who Received BUSULFEX Prior to Autologous or Allogeneic Hematopoietic Progenitor Cell Transplantation (n=103)
Hematological Adverse Events                                Percent Incidence (# Patients)

Anemia
Grade 3 ( 65-79 g/L)                                               62 (64) 
Grade 4 (<65 g/L)                                                6 (6) 
Leukopenia
Grade 3 (1.0 x 109 – 1.9 x 109 cells/L)                          0 (0) Grade 4 (<1.0 x 109 cells/L))                                   96 (99) Thrombocytopenia
Grade 3 (25 x 109 – 49 x 109 cells/L)                             2 (2) Grade 4 (<25 x 109 cells/L)                                      91 (94) Median Number of Platelet transfusions per patient
Autologous (n=41)                                                  3 Allogeneic (n=60)                                                 6 Median Number of Red Blood Cells transfusions per patient
Autologous (n=37)                                                  3 Allogeneic (n=53)                                                 4 
Table 3: Summary of the Incidence (≥20%) of Non-Hematologic Adverse Events in Patients who Received BUSULFEX Prior to Autologous or Allogeneic Hematopoietic Progenitor Cell Transplantation (n=103) Through Blood and Marrow Transplant (BMT) Day +28

NON-HEMATOLOGICAL ADVERSE EVENTS*                    PERCENT INCIDENCE BODY AS A WHOLE
Fever                                                      87
Headache                                                   69
Abdominal Pain                                             62
Asthenia                                                   56
Chills                                                     47
Pain                                                       41
Allergic Reaction                                          32
Edema General                                              27
Inflammation at Injection site                             23
Chest pain                                                   22 CARDIOVASCULAR SYSTEM
Tachycardia                                                50
Thrombosis                                                   27 Hypertension                                                 25 Vasodilation                                                 23 DIGESTIVE SYSTEM
Nausea                                                     97
Stomatitis (Mucositis)                                       96 Vomiting                                                     91 Anorexia                                                     80 Diarrhea                                                     80 Dyspepsia                                                    40 Constipation                                                 31 Rectal Disorder                                              24 METABOLIC AND NUTRITIONAL SYSTEM
Hypomagnesemia                                               64 Hypokalemia                                                  58 Hyperglycemia                                                57 
Hypocalcemia                                                           43 Hyperbilirubinemia                                                     37 Edema                                                                  37 SGPT Elevation                                                         25 Hypophosphatema                                                        21 NERVOUS SYSTEM
Insomnia                                                               80 Anxiety                                                                65 Dizziness                                                              26 Depression                                                           20 RESPIRATORY SYSTEM
Rhinitis                                                               44 Cough                                                                  36 Lung Disorder                                                          34 Pharyngitis                                                            27 Epistaxis                                                              23 Dyspnea                                                              23 SKIN AND APPENDAGES
Rash                                                                  50 Pruritus                                                             29 *All reported adverse events regardless of severity (toxicity grades 1-4) 

Safety assessment of high-dose oral busulfan-based regimens prior to hematopoietic progenitor cell transplantation as reported from the literature is limited by the information selected for inclusion into published reports. Available adverse event information is derived from the Subset Literature Database and from the Overall Literature Database when it was provided. The denominator for incidence reporting is the sum of the patients in those studies that reported that event. The reported non- hematologic general toxicities are noted in Table 4.

Table 4: Percent Incidence of Non-hematologic Adverse Events Reported in a Review of 43 Publications Using High-Dose Oral Busulfan as a Conditioning Regimen Prior to Hematopoietic Progenitor Cell Transplant

Non- hematologic Adverse Events                    Percent Incidence (# Patients) Mucositis/Stomatitis                               85 (483/571) Fever                                              83 (379/457) Nausea/Vomiting                                    72 (52/172)
Rash                                               67 (38/57)
Diarrhea                                           58 (28/48)
Acute GVHD                                         45 (187/413) Chronic GVHD                                       35 (301/848) Infection                                          31 (128/407) Hemorrhagic cystitis                               15 (149/968) Hepatic veno-occlusive disease                     13 (153/1196) Interstitial pneumonitis                           11 (45/415)
Seizures                                           3 (15/482)

Acute graft versus host disease (GVHD) incidence was 26% (1153/4367 patients) in the Overall Literature Database. Chronic graft versus host disease of all grades was 28% (793/2846 patients) in the Overall Literature Database and 35% (301/848 patients) in the Subset Literature Database. The incidence of infection was 43% (911/2099 patients) in the Overall Literature Database and 31% (128/407 patients) in the Subset Literature Database. Allogeneic transplants were associated with a higher incidence of infection than autologous transplants (38% versus 22%, respectively).
The reported incidence of hepatic veno-occlusive disease (HVOD) was 17% (960/5798) in the Overall Literature Database and 13% (153/1196) in the Subset Literature Database [14% (43/316) for autologous and 12% (106/856) for allogeneic transplantation]. At least one publication reported that patients whose initial area under the plasma busulfan curve (AUC) >1,500 μMol•min were at an increased risk of developing VOD. Interstitial pneumonitis was reported at an incidence of 10% (262/2633) in the Overall Literature Database and 11% (45/415) in the Subset Literature Database. The incidence among allogeneic transplants was 11% (39/348) compared with 12% (4/34) for autologous transplants. Seizures were reported at an incidence of 7.4% (170/2303 patients) in the Overall Literature Database and 3.1% (15/482 patients) in the Subset Literature Database. For patients who received prophylactic anticonvulsant therapy there was a 1.7% (1/60) incidence of seizure.

The following sections describe clinically significant events occurring in the two BUSULFEX clinical trials regardless of an attribution.

Hematologic: At the indicated dose and schedule, BUSULFEX produced profound myelosuppression in 100% of patients. Severe leukopenia occurred in 92% of patients, thrombocytopenia in 86%, and anemia in 50%. Following hematopoietic progenitor cell infusion, recovery of neutrophil counts to ≥500 cells/mm3 occurred at median day 10 and 13, for autologous and allogeneic patients respectively.

Gastrointestinal: Gastrointestinal toxicities were frequent and generally considered to be related to the drug. Few were categorized as serious. Mild/moderate nausea occurred in 93% of patients and mild/moderate vomiting in 91% through blood and marrow transplant (BMT) Day +28; nausea was severe in 4%. The incidence of vomiting during BUSULFEX administration (BMT Day -7 to -4) was 38% (39/103).
Stomatitis was severe in 13% of patients and mild/moderate in 83%; 6% of patients developed mild/moderate esophagitis. Severe anorexia occurred in 16% of patients and was mild/moderate in 64%. Diarrhea was severe in 6% of patients and mild/moderate in 74%. Mild/moderate constipation occurred in 31% of patients; ileus developed in 7% and was severe in 2%. Forty percent (40%) of patients reported mild/moderate dyspepsia. Two percent (2%) of patients experienced mild hematemesis. Mild/moderate rectal discomfort occurred in 24% of patients. One patient (1%) developed gastrointestinal bleeding which was severe and considered serious.

Hepatic: Hyperbilirubinemia was observed in 37% of patients; it was life-threatening in 3% and associated with veno-occlusive disease, severe in 8%, and mild/moderate in 26%. It was associated with graft versus host disease in six patients. Severe serum glutamic pyruvic transaminase (SGPT) elevations occurred in 2% of patients.
There were mild/moderate increases in SGPT in 23% and in serum glutamic oxaloacetic transaminase (SGOT) in 10%. Alkaline phosphatase increases were mild/ moderate in 12% of patients. Mild/moderate jaundice developed in 8% of patients; it was associated with graft versus host disease or hepatic veno-occlusive disease in 4%. Mild/moderate hepatomegaly developed in 5% of patients.

Hepatic Veno-occlusive Disease: Hepatic veno-occlusive disease (HVOD) is a recognized potential complication of conditioning therapy prior to transplant. Six of 103 patients (6%) experienced HVOD; it was fatal in 2%, severe in 2% and moderate in 2%.


Graft Versus Host Disease: Graft versus host disease developed in 15% of patients (9/61) receiving allogeneic transplants; it was severe in 2%, and mild/moderate in 13%. After BMT day +28, an additional 3% developed graft versus host disease that was considered serious.

Edema: Seventy-one percent (71%) of patients exhibited some form of edema, hypervolemia, or weight increase; all events were mild/moderate. One patient (<1%) developed moderate capillary leak syndrome.

Infection/Fever: Although 39% of patients (40/103) experienced one or more episodes of infection, 83% (33/40) were rated as mild or moderate. Pneumonia was fatal in 1% and life-threatening in 3% of patients. Other infections were considered severe in 3% of patients. Fever was reported in 87% of patients; it was mild/moderate in 84% and severe in 3%. 47% of patients experienced chills which were mild/moderate in 46% and severe in 1%.

Cardiovascular: Mild/moderate tachycardia was reported in 50% of patients. Other rhythm abnormalities, which were all mild/moderate, included arrhythmia (3%), atrial fibrillation (2%), ventricular extrasystoles (1%), and bradycardia (1%). Mild/moderate thrombosis occurred in 27% of patients, usually associated with the central venous catheter. One patient (1%) experienced a severe femoral artery thrombosis, which was controlled with coagulation therapy. Hypertension was reported in 25% of patients and was severe in 1%. Hypotension occurred in 17% of patients and was severe in 2%. Mild vasodilation was reported in 23% of patients. Other cardiovascular events included mild cardiomegaly, mild ECG abnormality, moderate pericardial effusion, moderately decreased ejection fraction, and moderate pericarditis; all were reported at an incidence of ≤3% and mainly in the post- cyclophosphamide phase.

Pulmonary: Mild/moderate dyspnea occurred in 22% of patients and was severe in 2%. One patient (1%) experienced severe hyperventilation; and in 4 (4%) additional patients, it was mild/moderate. Respiratory failure occurred in two patients (2%), either in conjunction with HVOD and cerebral hemorrhage or pneumonia.
Mild/moderate rhinitis and cough were reported in 44% and 36% of patients, respectively; most events were mild. Epistaxis events were mild in 22% of patients and moderate in 1%. Alveolar hemorrhages were severe in 1% and life-threatening in 1% of patients. Other pulmonary events that were mild/moderate included abnormal breath sounds (34%), pharyngitis (27%), hiccup (17%), asthma (7%), atelectasis (3%), pleural effusion (3%), and hypoxia (1%).

Neurologic: The most commonly reported events involved nonspecific, global disturbances of the central nervous system: insomnia (80%), anxiety (65%), dizziness (26%), and depression (20%). Severity was mild/moderate except for one patient (1%) who experienced severe insomnia. One patient (1%) developed a life- threatening cerebral hemorrhage and a coma as a terminal event following multi- organ failure after HVOD. Other events considered severe included delirium (1%), nervousness (1%), confusion (2%), hallucination (1%), agitation (1%), and encephalopathy (1%). One patient (1%) experienced a mild seizure while receiving cyclophosphamide; however, 99% of patients were prophylactically treated with phenytoin.

Renal: Creatinine was mild/moderately elevated in 17% of patients. BUN was increased in 2% of patients and to a severe degree in 1%. 13% of patients experienced dysuria, 11% oliguria, and 9% hematuria; all were mild/moderate except for 1% severe hematuria. Moderate renal insufficiency was reported in 2% of patients.
Skin: Mild/moderate rash (50%) and pruritus (29%) were reported; both conditions were predominantly mild. Alopecia was mild in 12% of patients and moderate in 3%.
Mild vesicular rash was reported in 8% of patients and mild/moderate maculopapular rash in 7%.

Metabolic: Hyperglycemia was observed in 57% of patients and was severe in 5%.
More than half of the patients experienced some electrolyte disturbance, usually a decrease, and none were considered serious. Hypomagnesemia was mild/moderate in 64% of patients; hypokalemia was mild/moderate in 57% and severe in 1%; hypocalcemia was mild/moderate in 40% and severe in 3%; hypophosphatemia was mild/moderate in 21%; hyponatremia was mild/moderate in 3%.

Other: Other events reported include: headache (mild/moderate 65%, severe 4%), abdominal pain (mild/moderate 61%, severe 2%), asthenia (mild/moderate 56%, severe 1%), unspecified pain (mild/moderate 40%, severe 1%), allergic reaction (mild/moderate 31%, severe 1%), injection site inflammation (mild/moderate 23%) or injection site pain (mild/moderate 17%), chest pain (mild/moderate 23%), back pain (mild/moderate 18%), myalgia (mild/moderate 17%), and arthralgia (mild/moderate 13%).

Post-Marketing Adverse Drug Reactions:
The following additional adverse events have been spontaneously reported during the post-marketing use of BUSULFEX: febrile neutropenia; tumor lysis syndrome; thrombotic micro-angiopathy (TMA); severe bacterial, viral (e.g., cytomegalovirus viraemia) and fungal infections; sepsis; and tooth hypoplasia. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il/

SYMPTOMS AND TREATMENT OF OVERDOSAGE
The principal toxic effect is profound bone marrow hypoplasia/aplasia and pancytopenia but the central nervous system, liver, lungs, and gastrointestinal tract may be affected.
There is no known antidote to busulfan overdosage, other than hematopoietic progenitor cell transplantation. The hematologic status should be closely monitored and vigorous supportive measures instituted as medically indicated. In the absence of hematopoietic progenitor cell transplantation, the recommended dosage for BUSULFEX (busulfan) would constitute an overdose of busulfan. Survival after a single 140 mg dose of Myleran® Tablets in an 18 kg, 4-year old child has been reported. Inadvertent administration of a greater than normal dose of oral busulfan (2.1 mg/kg; total dose of 23.3 mg/kg) occurred in a 2-year old child prior to a scheduled bone marrow transplant without sequelae. An acute dose of 2.4 g was fatal in a 10-year old boy. There has been one report that busulfan is dialyzable, thus dialysis should be considered in the case of an overdose. Busulfan is metabolized through conjugation with glutathione, thus administration of glutathione may be considered.