Overdoses have been observed, including one patient who received 133-fold the recommended therapeutic dose of BLINCYTO delivered over a short duration. Overdoses resulted in adverse reactions which were consistent with the reactions observed at the recommended therapeutic dose and included fever, tremors, and headache. In the event of overdose, interrupt the infusion, monitor the patient for signs of toxicity, and provide supportive care. Consider reinitiation of BLINCYTO at the correct therapeutic dose when all toxicities have resolved and no earlier than 12 hours after interruption of the infusion.
BLINCYTO is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation.
The following adverse reactions are discussed in greater detail in other sections of the label:
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.
The safety data described in this section reflect exposure to BLINCYTO in clinical trials in which 212 patients with relapsed or refractory ALL received up to 28 mcg/day. All patients received at least one dose of BLINCYTO. The median age of the study population was 37 years (range: 18 to 79 years), 63% were male, 79% were White, 3% were Asian, and 3% were Black or African American.
The most common adverse reactions (≥ 20%) were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), and constipation (20%).
Serious adverse reactions were reported in 65% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia, and headache.
Adverse reactions of Grade 3 or higher were reported in 80% of patients. Discontinuation of therapy due to adverse reactions occurred in 18% of patients treated with BLINCYTO. The adverse reactions reported most frequently as the reason for discontinuation of treatment included encephalopathy and sepsis. Fatal adverse events occurred in 15% of patients. The majority of these events were infections. No fatal adverse events occurred on treatment among patients in remission.
The adverse reactions with ≥ 10% incidence for any grade or ≥ 5% incidence for Grade 3 or higher are summarized in Table 2.
Table 2. Adverse Reactions With ≥ 10% Incidence for Any Grade or ≥ 5% Incidence for Grade 3 or
Higher (N = 212)
| Adverse Reaction | Any Grade1 (%) |
Grade 3 or Higher1 (%) |
| Blood and lymphatic system disorders | ||
| Febrile neutropenia | 25 | 23 |
| Anemia | 18 | 13 |
| Neutropenia | 16 | 15 |
| Thrombocytopenia | 11 | 8 |
| Leukopenia | 9 | 8 |
| Gastrointestinal disorders | ||
| Nausea | 25 | 0 |
| Constipation | 20 | < 1 |
| Diarrhea2 | 20 | 1 |
| Abdominal pain | 15 | 2 |
| Vomiting | 13 | 0 |
| General disorders and administration site conditions | ||
| Pyrexia | 62 | 7 |
| Peripheral edema | 25 | < 1 |
| Fatigue | 17 | 1 |
| Chills | 15 | 0 |
| Chest pain | 11 | 1 |
| Immune system disorders | ||
| Cytokine release syndrome | 11 | 1 |
| Infections and infestations | ||
| Other pathogen infections | 44 | 25 |
| Bacterial infections | 19 | 12 |
| Fungal infections | 15 | 7 |
| Viral infections | 13 | 4 |
| Pneumonia | 9 | 8 |
| Sepsis | 7 | 6 |
| Investigations | ||
| Increased alanine aminotransferase | 12 | 6 |
| Increased aspartate aminotransferase | 11 | 4 |
| Increased weight | 11 | 0 |
| Metabolism and nutrition disorders | ||
| Hypokalemia | 23 | 6 |
| Hypomagnesemia | 12 | 0 |
| Hyperglycemia | 11 | 7 |
| Decreased appetite | 10 | 3 |
| Hypophosphatemia | 6 | 5 |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 14 | 2 |
| Pain in extremity | 12 | 1 |
| Bone pain | 11 | 3 |
| Arthralgia | 10 | 2 |
| Nervous system disorders | ||
| Headache | 36 | 3 |
| Tremor3 | 20 | 1 |
| Dizziness | 14 | < 1 |
| Psychiatric disorders | ||
| Insomnia | 15 | 0 |
| Respiratory, thoracic, and mediastinal disorders | ||
| Cough | 19 | 0 |
| Dyspnea4 | 15 | 5 |
| Skin and subcutaneous tissue disorders | ||
| Rash5 | 21 | 2 |
| Vascular disorders | ||
| Hypotension | 11 | 2 |
| Hypertension | 8 | 5 |
|
1 Grading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 2 Diarrhea includes the following terms: colitis, diarrhea, enteritis, and neutropenic colitis. 3 Tremor includes the following terms: resting tremor and tremor. 4 Dyspnea includes the following terms: acute respiratory failure, bronchial hyperactivity, bronchospasm, dyspnea, dyspnea exertional, respiratory distress, respiratory failure, and wheezing. 5 Rash includes the following terms: erythema, rash, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, and vesicular rash. |
||
Additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were:
Blood and lymphatic system disorders: leukocytosis (2%), lymphopenia (1%)
Cardiac disorders: tachycardia (8%)
General disorders and administration site conditions: edema (5%)
Immune system disorders: cytokine storm (1%)
Investigations: decreased immunoglobulins (9%), increased blood bilirubin (8%), increased gammaglutamyl- transferase (6%), increased liver enzymes (1%)
Metabolism and nutrition disorders: tumor lysis syndrome (4%), hypoalbuminemia (4%)
Nervous system disorders: encephalopathy (5%), paresthesia (5%), aphasia (4%), convulsion (2%), memory impairment (2%), cognitive disorder (1%), speech disorder (< 1%)
Psychiatric disorders: confusion (7%), disorientation (3%)
Vascular disorders: capillary leak syndrome (< 1%).
Hypersensitivity reactions related to BLINCYTO treatment were hypersensitivity (1%) and bronchospasm (< 1%).
ImmunogenicityAs with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of BLINCYTO has been evaluated using either an electrochemiluminescence detection technology (ECL) or an enzyme-linked immunosorbent assay (ELISA) screening immunoassay for the detection of binding anti-blinatumomab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.
In clinical studies, less than 1% of patients treated with BLINCYTO tested positive for binding antiblinatumomab antibodies. All patients who tested positive for binding antibodies also tested positive for neutralizing anti-blinatumomab antibodies.
Anti-blinatumomab antibody formation may affect pharmacokinetics of BLINCYTO. No association was seen between antibody development and development of adverse events.
If formation of anti-blinatumomab antibodies with a clinically significant effect is suspected, contact Amgen at 1-800-77-AMGEN (1-800-772-6436) to discuss antibody testing.
The detection of anti-blinatumomab antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to blinatumomab with the incidence of antibodies to other products may be misleading.
BLINCYTO is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.
During the continuous intravenous infusion over 4 weeks, the pharmacodynamic response was characterized by T-cell activation and initial redistribution, reduction in peripheral B cells, and transient cytokine elevation.
Peripheral T cell redistribution (ie, T cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred after start of BLINCYTO infusion or dose escalation. T cell counts initially declined within 1 to 2 days and then returned to baseline levels within 7 to 14 days in majority patients. Increase of T cell counts above baseline (T cell expansion) was observed in few patients.
Peripheral B cell counts decreased to less than or equal to 10 cells/microliter during the first treatment cycle at doses ≥ 5 mcg/m2/day or ≥ 9 mcg/day in the majority of patients. No recovery of peripheral B-cell counts was observed during the 2-week BLINCYTO-free period between treatment cycles. Incomplete depletion of B cells occurred at doses of 0.5 mcg/m2/day and 1.5 mcg/m2/day and in a few patients at higher doses.
Cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, and IFN-γ were measured, and IL-6, IL10, and IFN-γ were elevated. The highest elevation of cytokines was observed in the first 2 days following start of BLINCYTO infusion. The elevated cytokine levels returned to baseline within 24 to 48 hours during the infusion. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial 48 hours of the first treatment cycle.
The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 90 mcg/m2/day (approximately equivalent to 9 to 162 mcg/day) in adult patients. Following continuous intravenous infusion, the steady-state serum concentration (Css) was achieved within a day and remained stable over time. The increase in mean Css values was approximately proportional to the dose in the range tested. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed/refractory ALL, the mean (SD) Css was 211 (258) pg/mL and 621 (502) pg/mL, respectively.
DistributionThe estimated mean (SD) volume of distribution based on terminal phase (Vz) was 4.52 (2.89) L with continuous intravenous infusion of blinatumomab.
MetabolismThe metabolic pathway of blinatumomab has not been characterized. Like other protein therapeutics, BLINCYTO is expected to be degraded into small peptides and amino acids via catabolic pathways.
EliminationThe estimated mean (SD) systemic clearance with continuous intravenous infusion in patients receiving blinatumomab in clinical studies was 2.92 (2.83) L/hour. The mean (SD) half-life was 2.11 (1.42) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses.
Body Weight, Body Surface Area, Gender, And AgeResults of population pharmacokinetic analyses indicate that age (18 to 80 years of age), gender, body weight (44 to 134 kg), and body surface area (1.39 to 2.57 m2) do not influence the pharmacokinetics of blinatumomab.
Renal ImpairmentNo formal pharmacokinetic studies of blinatumomab have been conducted in patients with renal impairment.
Pharmacokinetic analyses showed an approximately 2-fold difference in mean blinatumomab clearance values between patients with moderate renal impairment (CrCL ranging from 30 to 59 mL/min, N = 21) and normal renal function (CrCL more than 90 mL/min, N = 215). However, high interpatient variability was discerned (CV% up to 95.6%), and clearance values in renal impaired patients were essentially within the range observed in patients with normal renal function. There is no information available in patients with severe renal impairment (CrCL less than 30 mL/min) or patients on hemodialysis.
Risk Summary
There are no adequate and well-controlled studies of BLINCYTO in pregnant women. Based on its mechanism of action, BLINCYTO may cause fetal toxicity including B-cell lymphocytopenia when administered to a pregnant woman. BLINCYTO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data
Animal reproduction studies have not been conducted with blinatumomab. In embryo-fetal developmental toxicity studies, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis. The surrogate molecule crossed the placental barrier and did not cause embryo-fetal toxicity or teratogenicity. The expected depletions of B and T cells were observed in the pregnant mice, but hematological effects were not assessed in fetuses.
For injection: 35 mcg of lyophilized powder in a single-use vial for reconstitution.
Storage And HandlingEach BLINCYTO package (NDC 55513-160-01) contains:
Store BLINCYTO and IV Solution Stabilizer vials in the original package refrigerated at 2°C to 8°C (36°F to 46°F) and protect from light until time of use. Do not freeze.
Store and transport the prepared IV bag containing BLINCYTO solution for infusion at 2°C to 8°C (36°F to 46°F) conditions. Ship in packaging that has been validated to maintain temperature of the contents at 2°C to 8°C (36°F to 46°F). Do not freeze.
Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799. Revised: Dec 2014
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS Cytokine Release SyndromeCytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO.
Infusion reactions have occurred with the BLINCYTO infusion and may be clinically indistinguishable from manifestations of CRS.
Serious adverse events that may be associated with CRS included pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these events infrequently led to BLINCYTO discontinuation. Life-threatening or fatal CRS was infrequently reported in patients receiving BLINCYTO. In some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) have been reported in the setting of CRS.
Patients should be closely monitored for signs or symptoms of these events. Management of these events may require either temporary interruption or discontinuation of BLINCYTO.
Neurological ToxicitiesIn patients receiving BLINCYTO in clinical trials, neurological toxicities have occurred in approximately 50% of patients. The median time to onset of any neurological toxicity was 7 days. Grade 3 or higher (severe, life-threatening, or fatal) neurological toxicities following initiation of BLINCYTO administration occurred in approximately 15% of patients and included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The majority of events resolved following interruption of BLINCYTO, but some resulted in treatment discontinuation.
Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities, and interrupt or discontinue BLINCYTO as recommended.
InfectionsIn patients receiving BLINCYTO in clinical trials, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of patients, some of which were life-threatening or fatal. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with BLINCYTO. Monitor patients for signs and symptoms of infection and treat appropriately.
Tumor Lysis SyndromeTumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving BLINCYTO. Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used for the prevention of TLS during BLINCYTO treatment. Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of BLINCYTO.
Neutropenia And Febrile NeutropeniaNeutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO. Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion. Interrupt BLINCYTO if prolonged neutropenia occurs.
Effects On Ability To Drive And Use MachinesDue to the potential for neurologic events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness. Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
Elevated Liver EnzymesTreatment with BLINCYTO was associated with transient elevations in liver enzymes. Although the majority of these events were observed in the setting of CRS, some were observed outside of this setting. For these events, the median time to onset was 15 days. In patients receiving BLINCYTO in clinical trials, Grade 3 or greater elevations in liver enzymes occurred in approximately 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatment. Interrupt BLINCYTO if the transaminases rise to greater than 5 times the upper limit of normal or if bilirubin rises to more than 3 times the upper limit of normal.
LeukoencephalopathyCranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown.
Preparation And Administration ErrorsPreparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration strictly to minimize medication errors (including underdose and overdose).
Patient Counseling InformationSee FDA-approved Medication Guide.
Advise patients to contact a healthcare professional for any of the following:
Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. Patients should be advised that they may experience neurological events.
Inform patients that:
No carcinogenicity or genotoxicity studies have been conducted with blinatumomab.
No studies have been conducted to evaluate the effects of blinatumomab on fertility. A murine surrogate molecule had no adverse effects on male and female reproductive organs in a 13-week repeat-dose toxicity study in mice.
Use In Specific Populations Pregnancy Pregnancy Category CRisk Summary
There are no adequate and well-controlled studies of BLINCYTO in pregnant women. Based on its mechanism of action, BLINCYTO may cause fetal toxicity including B-cell lymphocytopenia when administered to a pregnant woman. BLINCYTO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data
Animal reproduction studies have not been conducted with blinatumomab. In embryo-fetal developmental toxicity studies, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis. The surrogate molecule crossed the placental barrier and did not cause embryo-fetal toxicity or teratogenicity. The expected depletions of B and T cells were observed in the pregnant mice, but hematological effects were not assessed in fetuses.
LactationIt is not known whether blinatumomab is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from blinatumomab, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric UseThere is limited experience in pediatric patients. BLINCYTO was evaluated in a dose-escalation study of 41 pediatric patients with relapsed or refractory B-precursor ALL. The median age was 6 years (range: 2 to 17 years). BLINCYTO was administered at doses of 5 to 30 mcg/m2/day. The recommended phase 2 regimen was 5 mcg/m2/day on Days 1-7 and 15 mcg/m2/day on Days 8-28 for cycle 1, and 15 mcg/m2/day on Days 1-28 for subsequent cycles. At a higher dose, a fatal cardiac failure event occurred in the setting of life-threatening cytokine release syndrome (CRS).
The steady-state concentrations of blinatumomab were comparable in adult and pediatric patients at the equivalent dose levels based on body surface area (BSA)-based regimens.
Geriatric UseOf the total number of patients with relapsed or refractory ALL, approximately 13% were 65 years of age and over. Generally, safety and efficacy were similar between elderly patients (≥ 65 years of age) and patients less than 65 years of age treated with BLINCYTO. Elderly patients experienced a higher rate of neurological toxicities, including cognitive disorder, encephalopathy, confusion, and serious infections.
Hepatic ImpairmentNo formal pharmacokinetic studies using BLINCYTO have been conducted in patients with hepatic impairment.
Renal ImpairmentNo formal pharmacokinetic studies using BLINCYTO have been conducted in patients with renal impairment. No dose adjustment is needed for patients with baseline creatinine clearance (CrCL) equal to or greater than 30 mL/min. There is no information available in patients with CrCL less than 30 mL/min or patients on hemodialysis.
Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and reinitiation (eg, if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
Do not flush the BLINCYTO infusion line especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof. Preparation and administration errors resulting in overdose have occurred.
DosageIf the interruption after an adverse event is no longer than 7 days, continue the same cycle to a total of 28 days of infusion inclusive of days before and after the interruption in that cycle. If an interruption due to an adverse event is longer than 7 days, start a new cycle.
| Toxicity | Grade* | Action |
| Cytokine Release Syndrome (CRS) | Grade 3 - | Withhold BLINCYTO until resolved, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur. |
| Grade 4 - | Discontinue BLINCYTO permanently. | |
| Neurological Toxicity | Seizure - | Discontinue BLINCYTO permanently if more than one seizure occurs. |
| Grade 3 - | Withhold BLINCYTO until no more than Grade 1 (mild) and for at least 3 days, then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur. If the toxicity occurred at 9 mcg/day, or if the toxicity takes more than 7 days to resolve, discontinue BLINCYTO permanently. | |
| Grade 4 - | Discontinue BLINCYTO permanently. | |
| Other Clinically Relevant Adverse Reactions | Grade 3 - | Withhold BLINCYTO until no more than Grade 1 (mild), then restart BLINCYTO at 9 mcg/day. Escalate to 28 mcg/day after 7 days if the toxicity does not recur. If the toxicity takes more than 14 days to resolve, discontinue BLINCYTO permanently. |
| Grade 4 - | Consider discontinuing BLINCYTO permanently. | |
| *Based on the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is severe, and Grade 4 is life-threatening. |
It is very important that the instructions for preparation (including admixing) and administration provided in this section are strictly followed to minimize medication errors (including underdose and overdose).
Call 1-800-77-AMGEN (1-800-772-6436) if you have questions about the reconstitution and preparation of BLINCYTO.
Gather SuppliesNOTE: 1 package BLINCYTO includes 1 vial of BLINCYTO and 1 vial of IV Solution Stabilizer.
Before preparation, ensure you have the following supplies ready:
The following supplies are also required, but not included in the package:
Aseptic technique must be strictly observed when preparing the solution for infusion since BLINCYTO vials do not contain antimicrobial preservatives. To prevent accidental contamination, prepare BLINCYTO according to aseptic standards, including but not limited to:
Specific admixing instructions are provided for each dose and infusion time. Verify the prescribed dose and infusion time of BLINCYTO and identify the appropriate dosing preparation section listed below. Follow the steps for reconstituting BLINCYTO and preparing the IV bag.
Preparation of BLINCYTO 9 mcg/day infused over 24 hours at a rate of 10 mL/h
Preparation of BLINCYTO 9 mcg/day infused over 48 hours at a rate of 5 mL/h
Preparation of BLINCYTO 28 mcg/day infused over 24 hours at a rate of 10 mL/h
Preparation of BLINCYTO 28 mcg/day infused over 48 hours at a rate of 5 mL/h
The information in Table 1 indicates the storage time for the reconstituted BLINCYTO vial and prepared IV bag containing BLINCYTO solution for infusion. Lyophilized BLINCYTO vial and IV Solution Stabilizer may be stored for a maximum of 8 hours at room temperature.
Table 1. Storage Time for Reconstituted BLINCYTO and IV Solution Stabilizer
| Maximum Storage Time of Reconstituted BLINCYTO Vial* | Maximum Storage Time of Prepared IV Bag Containing BLINCYTO Solution for Infusion | ||
| Room Temperature 23°C to 27°C (73°F to 81°F) |
Refrigerated 2°C to 8°C (36°F to 46°F) |
Room Temperature 23°C to 27°C (73°F to 81°F) |
Refrigerated 2°C to 8°C (36°F to 46°F) |
| 4 hours | 24 hours | 48 hours† | 8 days |
|
* While stored, protect BLINCYTO and IV Solution Stabilizer vials from light. † Storage time includes infusion time. If IV bag containing BLINCYTO solution for infusion is not administered within the time frames and temperatures indicated, it must be discarded; it should not be refrigerated again. |
Transient elevation of cytokines may suppress CYP450 enzyme activities.
