PACLITAXEL Drug Interactions: What You Need to Know

Drug Interactions: In a Phase I trial using escalating doses of paclitaxel (110 to 200 mg/m 2 ) and cisplatin (50 or 75 mg/m 2 ) given as sequential infusions, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence (i.e., paclitaxel before cisplatin). Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when paclitaxel was administered following cisplatin. The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering paclitaxel concomitantly with known substrates or inhibitors of the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when paclitaxel is concomitantly administered with known substrates (e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4. (See CLINICAL PHARMACOLOGY section.) Caution should also be exercised when paclitaxel is concomitantly administered with known substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., rifampin) of CYP2C8. (See CLINICAL PHARMACOLOGY . ) Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, have not been evaluated in clinical trials. Reports in the literature suggest that plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination. Hematology: Paclitaxel therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm 3 . In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving paclitaxel. Patients should not be retreated with subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm 3 and platelets recover to a level >100,000 cells/mm 3 . In the case of severe neutropenia (<500 cells/mm 3 for seven days or more) during a course of paclitaxel therapy, a 20% reduction in dose for subsequent courses of therapy is recommended. For patients with advanced HIV disease and poor-risk AIDS-related Kaposi's sarcoma, paclitaxel, at the recommended dose for this disease, can be initiated and repeated if the neutrophil count is at least 1,000 cells/mm 3 .

Hypersensitivity

Reactions: Patients with a history of severe hypersensitivity reactions to products containing Polyoxyl 35 Castor Oil, NF (e.g., cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with paclitaxel. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with paclitaxel should be premedicated with corticosteroids (such as dexamethasone), diphenhydramine and H 2 antagonists (such as cimetidine or ranitidine). Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with paclitaxel. Cardiovascular: Hypotension, bradycardia, and hypertension have been observed during administration of Paclitaxel Injection, USP, but generally do not require treatment. Occasionally paclitaxel infusions must be interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities. (See WARNINGS section.) When paclitaxel is used in combination with doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is recommended. (See ADVERSE REACTIONS . )

Nervous

System: Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of paclitaxel. Paclitaxel contains Dehydrated Alcohol USP, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol. (See PRECAUTIONS: Pediatric Use section.) Hepatic: There is limited evidence that the myelotoxicity of Paclitaxel may be exacerbated in patients with serum total bilirubin >2 times ULN (See CLINICAL PHARMACOLOGY ). Extreme caution should be exercised when administering Paclitaxel to such patients, with dose reduction as recommended in DOSAGE AND ADMINISTRATION , TABLE 17 .

Injection Site

Reaction: Injection site reactions, including reactions secondary to extravasation, were usually mild and consisted of erythema, tenderness, skin discoloration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e., “recall”, has been reported. More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been reported. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days. A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is contraindicated in patients with:

• Baseline neutrophil counts of < 1,500 cells/mm 3 [see Warnings and Precautions (5.1) ]
• A history of severe hypersensitivity reactions to paclitaxel protein-bound particles for injectable suspension (albumin-bound) [see Warnings and Precautions (5.5) ]
• Neutrophil counts of < 1,500 cells/mm 3 . ( 4 )
• Severe hypersensitivity reactions to paclitaxel protein-bound particles for injectable suspension (albumin-bound). ( 4 )

AND PRECAUTIONS Sensory neuropathy occurs frequently and may require dose reduction or treatment interruption. ( 5.2 ) Sepsis occurred in patients with or without neutropenia who received paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine; interrupt paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine until sepsis resolves, and if neutropenia, until neutrophils are at least 1500 cells/mm 3 , then resume treatment at reduced dose levels. ( 5.3 ) Pneumonitis occurred with the use of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine; permanently discontinue treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine. ( 5.4 ) Severe hypersensitivity reactions with fatal outcome have been reported. Do not re-challenge with this drug. ( 4 , 5.5 ) Exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, consider dose reduction and closely monitor patients with hepatic impairment. ( 2.5 , 5.6 ) Paclitaxel protein-bound particles for injectable suspension (albumin-bound) contains albumin derived from human blood, which has a theoretical risk of viral transmission. ( 5.7 ) Paclitaxel protein-bound particles for injectable suspension (albumin-bound) can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.8 , 8.1 , 8.3 )

5.1 Severe Myelosuppression Severe myelosuppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of paclitaxel protein-bound particles for injectable suspension (albumin-bound). In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer. Monitor for severe neutropenia and thrombocytopenia by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer paclitaxel protein-bound particles for injectable suspension (albumin-bound) to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm 3 <span class="opacity-50 text-xs">[see Contraindications ( 4 ) ]</span> . In the case of severe neutropenia (&lt;500 cells/mm 3 for seven days or more) during a course of paclitaxel protein-bound particles for injectable suspension (albumin-bound) therapy, reduce the dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of paclitaxel protein-bound particles for injectable suspension (albumin-bound) after ANC recovers to a level &gt;1,500 cells/mm 3 and platelets recover to a level &gt;100,000 cells/mm 3 . In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly paclitaxel protein-bound particles for injectable suspension (albumin-bound) and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm 3 and platelet count of at least 100,000 cells/mm 3 on Day 1 or to an ANC of at least 500 cells/mm 3 and platelet count of at least 50,000 cells/mm 3 on Days 8 or 15 of the cycle <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 ) ]</span>. In patients with adenocarcinoma of the pancreas, withhold paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine if the ANC is less than 500 cells/mm 3 or platelets are less than 50,000 cells/mm 3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm 3 or platelet count is less than 100,000 cells/mm 3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.6 ) ]</span>.

5.2 Severe Neuropathy Sensory neuropathy is dose- and schedule-dependent [ see Adverse Reactions (6.1) ]. If ≥ Grade 3 sensory neuropathy develops, withhold paclitaxel protein-bound particles for injectable suspension (albumin-bound) treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of paclitaxel protein-bound particles for injectable suspension (albumin-bound) <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span> .

5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span> .

5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving paclitaxel protein-bound particles for injectable suspension (albumin-bound) in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and gemcitabine.

5.5 Severe Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Do not rechallenge patients who experience a severe hypersensitivity reaction to paclitaxel protein-bound particles for injectable suspension (albumin-bound) with this drug. <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . Cross-hypersensitivity between paclitaxel protein-bound particles for injectable suspension (albumin-bound) and other taxane products has been reported and may include severe reactions such as anaphylaxis. Closely monitor patients with a previous history of hypersensitivity to other taxanes during initiation of paclitaxel protein-bound particles for injectable suspension (albumin-bound) therapy.

5.6 Use in Patients with Hepatic Impairment The exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment. Closely monitor patients with hepatic impairment for severe myelosuppression. Paclitaxel protein-bound particles for injectable suspension (albumin-bound) is not recommended in patients who have total bilirubin &gt;5 x ULN or AST &gt;10 x ULN. In addition, paclitaxel protein-bound particles for injectable suspension (albumin-bound) is not recommended in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total bilirubin &gt;1.5 x ULN and AST ≤10 x ULN). Reduce the starting dose for patients with moderate or severe hepatic impairment <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 ) , Use in Specific Populations ( 8.7 ) , Clinical Pharmacology ( 12.3 ) ]</span> .

5.7 Albumin (Human) Paclitaxel protein-bound particles for injectable suspension (albumin-bound) contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

5.8 Embryo-Fetal Toxicity Based on mechanism of action and findings in animals, paclitaxel protein-bound particles for injectable suspension (albumin-bound) can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and for at least six months after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) , Clinical Pharmacology (12.1) ]</span>. Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with paclitaxel protein-bound particles for injectable suspension (albumin-bound) and for at least three months after the last dose of paclitaxel protein-bound particles for injectable suspension (albumin-bound) <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) , Nonclinical Toxicology (13.1) ]</span>.