June 29, 2016
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Adcetris

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Adcetris




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Peripheral Neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the relapsed classical HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS].

Anaphylaxis And Infusion Reactions

Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.

Hematologic Toxicities

Prolonged ( ≥ 1 week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with treatment with ADCETRIS. Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent ADCETRIS doses [see DOSAGE AND ADMINISTRATION].

Serious Infections And Opportunistic Infections

Serious infections and opportunistic infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Patients should be closely monitored during treatment for the emergence of possible bacterial, fungal, or viral infections.

Tumor Lysis Syndrome

Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Increased Toxicity In The Presence Of Severe Renal Impairment

The frequency of ≥ Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Due to higher MMAE exposure, ≥ Grade 3 adverse reactions may be more frequent in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment [creatinine clearance (CLcr) < 30 mL/min] [see Use in Specific Populations].

Increased Toxicity In The Presence Of Moderate Or Severe Hepatic Impairment

The frequency of ≥ Grade 3 adverse reactions and deaths was greater in patients with moderate and severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations].

Hepatotoxicity

Serious cases of hepatotoxicity, including fatal outcomes, have occurred in patients receiving ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin. Cases have occurred after the first dose of ADCETRIS or after ADCETRIS rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin.

Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

Progressive Multifocal Leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Pulmonary Toxicity

Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

Serious Dermatologic Reactions

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Gastrointestinal Complications

Fatal and serious gastrointestinal (GI) complications including perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus have been reported in ADCETRIS-treated patients. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.

Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of ADCETRIS in pregnant women. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to the clinical dose of 1.8 mg/kg every three weeks.

Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS. If ADCETRIS is used during pregnancy or if the patient becomes pregnant during ADCETRIS treatment, the patient should be apprised of the potential risk to the fetus [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.

MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule disrupting agent. MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.

Fertility studies with brentuximab vedotin or MMAE have not been conducted. However, results of repeat-dose toxicity studies in rats indicate the potential for brentuximab vedotin to impair male reproductive function and fertility. In a 4-week repeat-dose toxicity study in rats with weekly dosing at 0.5, 5, or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed. Effects in animals were seen mainly at 5 and 10 mg/kg of brentuximab vedotin. These doses are approximately 3 and 6-fold the human recommended dose of 1.8 mg/kg, respectively, based on body weight.

Use In Specific Populations

Pregnancy

Risk Summary

ADCETRIS can cause fetal harm based on the findings from animal studies and the drug's mechanism of action [see CLINICAL PHARMACOLOGY]. In animal reproduction studies, administration of brentuximab vedotin to pregnant rats during organogenesis at doses similar to the clinical dose of 1.8 mg/kg every three weeks caused embryo-fetal toxicities, including congenital malformations [see Data]. Consider the benefits and risks of ADCETRIS and possible risks to the fetus when prescribing ADCETRIS to a pregnant woman.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

Animal Data

In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption ( ≥ 99%), post-implantation loss ( ≥ 99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with classical HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Lactation

Risk Summary

There is no information regarding the presence of brentuximab vedotin in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant from ADCETRIS, including cytopenias and neurologic or gastrointestinal toxicities, advise patients that breastfeeding is not recommended during ADCETRIS treatment.

Females And Males Of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating ADCETRIS therapy.

Contraception

Females

Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS. Advise females to immediately report pregnancy [see Use in Specific Populations].

Males

ADCETRIS may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS [see Nonclinical Toxicology].

Infertility

Males

Based on findings in rats, male fertility may be compromised by treatment with ADCETRIS [see Nonclinical Toxicology].

Pediatric Use

Safety and effectiveness of ADCETRIS have not been established in pediatric patients.

Geriatric Use

Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Renal Impairment

Avoid the use of ADCETRIS in patients with severe renal impairment (CLcr < 30 mL/min) [See WARNINGS AND PRECAUTIONS].

The kidney is a route of excretion for monomethyl auristatin E (MMAE). The pharmacokinetics and safety of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (CLcr > 50–80 mL/min; n=4), moderate (CLcr 30–50 mL/min; n=3) and severe (CLcr < 30 mL/min; n=3) renal impairment. In patients with severe renal impairment, the rate of Grade 3 or worse adverse reactions was 3/3 (100%) compared to 3/8 (38%) in patients with normal renal function. Additionally, the AUC of MMAE (component of ADCETRIS) was approximately 2-fold higher in patients with severe renal impairment compared to patients with normal renal function. Due to higher MMAE exposure, ≥ Grade 3 adverse reactions may be more frequent in patients with severe renal impairment compared to patients with normal renal function.

Hepatic Impairment

Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment [See WARNINGS AND PRECAUTIONS].

The liver is a route of clearance for MMAE. The pharmacokinetics and safety of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (Child-Pugh A; n=1), moderate (Child-Pugh B; n=5) and severe (Child-Pugh C; n=1) hepatic impairment. In patients with moderate and severe hepatic impairment, the rate of ≥ Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal hepatic function. Additionally, the AUC of MMAE was approximately 2.2-fold higher in patients with hepatic impairment compared to patients with normal hepatic function.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 4/1/2016

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