IXABEPILONE Drug Interactions: What You Need to Know

INTERACTIONS Strong CYP3A4 Inhibitors: Avoid strong CYP3A4 inhibitors. If coadministration cannot be avoided, reduce the dosage of IXEMPRA ( 2.5 , 7.1 ). Strong CYP3A4 Inducers: Avoid strong CYP3A4 inducers. If coadministration cannot be avoided, reduce the dosage of IXEMPRA ( 2.5 , 7.1 ).

7.1 Effect of Other Drugs on IXEMPRA Strong CYP3A4 Inhibitors The coadministration of IXEMPRA with a strong CYP3A4 inhibitor increased ixabepilone plasma concentration, which may increase the incidence and severity of adverse reactions of IXEMPRA. Avoid coadministration of IXEMPRA with strong CYP3A4 inhibitors. If the coadministration of IXEMPRA with strong CYP3A4 cannot be avoided, reduce the dose of IXEMPRA <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ), Clinical Pharmacology ( 12.3 ]</span>. Moderate or Weak CYP3A4 Inhibitors The coadministration of IXEMPRA with moderate or weak CYP3A4 inhibitors may increase the incidence and severity of adverse reactions of IXEMPRA. Monitor for adverse reactions and reduce the dose of IXEMPRA as recommended <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ), Adverse Reactions ( 6 )]</span>. Strong CYP3A4 Inducers The coadministration of IXEMPRA with a strong CYP3A4 inducer, decreased plasma concentrations of ixabepilone, which may decrease the efficacy of IXEMPRA <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Avoid the coadministration IXEMPRA with strong CYP3A4 inducers. If the coadministration of IXEMPRA with a strong CYP3A4 inducer cannot be avoided, increase the dose of IXEMPRA <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>.

Concomitant

Use of IXEMPRA and Capecitabine No clinically meaningful differences in the pharmacokinetics of ixabepilone and capecitabine were observed when IXEMPRA was administered in combination with capecitabine (1000 mg/m 2 ) [see Clinical Pharmacology ( 12.3 )].

7.2 Effect of Ixabepilone on Other Drugs Ixabepilone does not inhibit CYP enzymes at relevant clinical concentrations and is not expected to alter the plasma concentrations of other drugs <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>.

7.3 Capecitabine In patients with cancer who received ixabepilone (40 mg/m 2 ) in combination with capecitabine (1000 mg/m 2 ), ixabepilone Cmax decreased by 19%, capecitabine Cmax decreased by 27%, and 5-fluorouracil AUC increased by 14%, as compared to ixabepilone or capecitabine administered separately. The interaction is not clinically significant given that the combination treatment is supported by efficacy data.

IXEMPRA is contraindicated in patients who have: a neutrophil count <1500 cells/mm 3 or a platelet count <100,000 cells/mm 3 [see Warnings and Precautions ( 5.2 )]. a history of severe hypersensitivity to agents containing Cremophor ® EL or its derivatives (e.g., polyoxyethylated castor oil) [see Warnings and Precautions ( 5.4 )]. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Boxed Warning and Warnings and Precautions ( 5.3 )]. Baseline neutrophil count <1500 cells/mm 3 or a platelet count <100,000 cells/mm 3 ( 4 ). Hypersensitivity to drugs formulated with Cremophor ® EL ( 4 ). IXEMPRA in combination with capecitabine is contraindicated for use in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN.( 4 ).

AND PRECAUTIONS Peripheral Neuropathy: Monitor for symptoms of neuropathy (sensory and motor neuropathy).) Withhold, reduce, or discontinue IXEMPRA depending on severity. ( 2.3 , 5.1 ). Myelosuppression: Neutropenia, febrile neutropenia, and infections have occurred. Monitor blood cell counts before and during treatment with IXEMPRA. Withhold, reduce, or discontinue IXEMPRA depending on severity ( 2.3 , 5.2 ).

Increased

Toxicity in Patients with Hepatic Impairment: Grade 4 neutropenia, febrile neutropenia, and serious adverse reactions may occur in patients with hepatic impairment during treatment with IXEMPRA. Reduce dose depending on severity. ( 2.3 , 5.3 , 6.1 ).

Hypersensitivity

Reactions: Severe hypersensitivity reactions (including anaphylaxis) have occurred. Premedicate all patients before treatment with IXEMPRA. Withhold, reduce, or discontinue IXEMPRA depending on severity ( 2.1 , 2.3 , 5.4 ).

Cardiac Adverse

Reactions: Myocardial ischemia and ventricular dysfunction have occurred. Closely monitor patients with a history of cardiac disease during treatment with IXEMPRA. Consider discontinuation of IXEMPRA in patients who develop cardiac ischemia or impaired cardiac function ( 2.3 , 5.5 ). Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception ( 5.6 , 8.1 , 8.3)

Alcohol

Content: The alcohol content in a dose of IXEMPRA may affect the central nervous system. This may include impairment of a patient's ability to drive or use machines immediately after infusion. ( 5.7 ).

5.2 Myelosuppression Severe, life-threatening, or fatal myelosuppression can occur in patients treated with IXEMPRA. Myelosuppression is dose-dependent and primarily manifests as neutropenia. In clinical studies, grade 4 neutropenia (&lt;500 cells/mm 3 ) occurred in 36% of patients treated with IXEMPRA in combination with capecitabine and 23% of patients treated with single agent IXEMPRA monotherapy. Febrile neutropenia and infection with neutropenia were reported in 5% and 6% of patients treated with IXEMPRA in combination with capecitabine, respectively, and 3% and 5% of patients treated with IXEMPRA as a single agent, respectively. Neutropenia-related death occurred in 1.9% of 414 patients with normal hepatic function or mild hepatic impairment treated with IXEMPRA in combination with capecitabine. The rate of neutropenia-related deaths was higher (29%, 5 out of 17) in patients with AST or ALT &gt;2.5 x ULN or bilirubin &gt;1.5 x ULN <span class="opacity-50 text-xs">[see Boxed Warning, Contraindications ( 4 ), and Warnings and Precautions ( 5.3 )]</span> . Neutropenia-related death occurred in 0.4% of 240 patients treated with IXEMPRA as a single agent. No neutropenia-related deaths were reported in 24 patients with AST or ALT &gt;2.5 x ULN or bilirubin &gt;1.5 x ULN treated with IXEMPRA as a single agent. IXEMPRA is contraindicated for use in patients with a neutrophil count of &lt;1500 cells/mm 3 . <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Monitor patients receiving IXEMPRA for myelosuppression with frequent peripheral blood cell counts. Withhold, reduce, or discontinue IXEMPRA depending on the severity and persistence of myelosuppression <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> .

5.1 Peripheral Neuropathy Peripheral neuropathy (sensory and motor neuropathy) occurred in patients treated with IXEMPRA in combination with capecitabine and in patients treated with single agent IXEMPRA as shown in Table (see Table 3 ).

Table

3: Peripheral Neuropathy a Sensory and motor neuropathy combined. b 24% and 27% of patients in 046 and 081, respectively, had preexisting neuropathy (grade 1). IXEMPRA IXEMPRA as with capecitabine Single Agent Study 046 Study 081 Peripheral neuropathy (all grades) a,b 67% 63% Peripheral neuropathy (grades 3/4) a,b 23% 14% Discontinuation due to neuropathy 21% 6% Median number of cycles to onset of grade 3/4 neuropathy 4 4 Median time to improvement of grade 3/4 neuropathy to baseline or to grade 1 6.0 weeks 4.6 weeks In Studies 046 and 081, 80% and 87%, respectively, of patients with peripheral neuropathy who received IXEMPRA had improvement or no worsening of their neuropathy following dose reduction. For patients with grade 3 or 4 neuropathy in Studies 046 and 081, 76% and 79%, respectively, had documented improvement to baseline or grade 1, twelve weeks after onset. A pooled analysis of 1540 cancer patients treated with IXEMPRA indicated that patients with diabetes mellitus or preexisting peripheral neuropathy may be at increased risk of severe neuropathy. Patients with moderate to severe neuropathy (grade 2 or greater) were excluded from studies with IXEMPRA. Monitor patients for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Withhold, reduce, or discontinue IXEMPRA depending on the severity and persistence of peripheral neuropathy [ see Dosage and Administration ( 2.3 ) ].

5.3 Increased Toxicities in Patients with Hepatic Impairment Patients with baseline AST or ALT &gt;2.5 x ULN or bilirubin &gt;1.5 x ULN experienced greater toxicity than patients with baseline AST or ALT ≤2.5 x ULN or bilirubin ≤1.5 x ULN when treated with IXEMPRA at 40 mg/m 2 in combination with capecitabine or as single agent in breast cancer studies. In combination with capecitabine, the overall frequency of grade 3/4 adverse reactions, febrile neutropenia, serious adverse reactions, and toxicity-related deaths was increased oin patients with hepatic impairment. IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT &gt;2.5 x ULN or bilirubin &gt;1 x ULN due to increased risk of toxicity- and neutropenia-related death <span class="opacity-50 text-xs">[see Boxed Warning , Contraindications ( 4 ), and Warnings and Precautions ( 5.2 )]</span>. With IXEMPRA single agent therapy, grade 4 neutropenia, febrile neutropenia, and serious adverse reatcitons were increased in patients with hepatic impairment <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 ). Reduce the dose IXEMPRA based in the degree of hepatic impairment. Avoid use in patients with AST or ALT &gt;10 x ULN or bilirubin &gt;3 x ULN [see Dosage and Administration ( 2.4 )]</span>

5.4 Hypersensitivity Reactions IXEMPRA is contraindicated in patients with a history of a severe hypersensitivity reaction to agents containing Cremophor ® EL or its derivatives (eg, polyoxyethylated castor oil) [ see Contraindications ( 4 )] . Of the 1323 patients treated with IXEMPRA in clinical studies, 9 patients (1 %) had experienced severe hypersensitivity reactions (including anaphylaxis). Three of the 9 patients were able to be retreated. Patients who experience a hypersensitivity reaction in one cycle of IXEMPRA must be premedicated in subsequent cycles with a corticosteroid in addition to the H 1 and H 2 antagonists, and extension of the infusion time should be considered <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 ) and Contraindications ( 4 )]</span> Administer an H 1 and H 2 antagonist approximately 1 hour before IXEMPRA infusion and observe patients for hypersensitivity reaction occur, stop the infusion of IXEMPRA provide supportive treatment as clinically indicated (e.g.. epinephrine, corticosteriods).

5.5 Cardiac Adverse Reactions Cardiac adverse reactions (myocardial ischemia and ventricular dysfunction) occurred in patients receiving IXEMPRA in combination with capecitabine (1.9%) and as a single agent (0.3%). Supraventricular arrhythmias were observed in the combination arm (0.5%). Closely monitor patients with a history of cardiac disease during treatment with IXEMPRA. Consider discontinuation of IXEMPRA in patients who develop cardiac ischemia or impaired cardiac function <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span>.

5.6 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, IXEMPRA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of ixabepilone to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, and fetal abnormalities at maternal exposures below the human clinical exposure based on AUC. Advise females of reproductive potential and pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IXEMPRA and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IXEMPRA and for 4 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )]</span>.

5.7 Alcohol Content The alcohol content in a dose of IXEMPRA may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in IXEMPRA on the ability to drive or use machines immediately after the infusion. Each administration of IXEMPRA at the recommended dosage of 40 mg/m 2 delivers approximately 8.4 g/m 2 of ethanol. For a patient with a BSA of 2.0 m 2 , this would deliver approximately 16.8 grams of ethanol <span class="opacity-50 text-xs">[see Description ( 11 )]</span>.