Paclitaxel

Mitosis-inhibiting cytostatic (from the group of taxanes) which is mainly extracted from the Pacific yew(Taxus brevifolia).

Approved for the therapy of:

• Ovarian cancer: Paclitaxel is indicated for the first-line chemotherapy of ovarian cancer in patients with advanced ovarian cancer or a residual tumour (>1 cm) after previous laparotomy in combination with cisplatin.
• For second-line chemotherapy of ovarian cancer after failure of standard therapy with platinum-containing drugs.
• Breast cancer: Paclitaxel is indicated for the adjuvant therapy of patients with nodal-positive breast cancer following anthracycline/cyclophosphamide therapy.
• Paclitaxel is indicated for the initial treatment of patients with locally advanced or metastatic breast cancer either in combination with an anthracycline in patients for whom anthracycline therapy is indicated or in combination with trastuzumab if HER2 is classified as 3+ according to immunohistochemical determination and if anthracycline-containing therapy is not indicated.
• As a monotherapy, paclitaxel is indicated for the treatment of metastatic breast cancer in patients for whom standard therapy with anthracyclines has been unsuccessful or for whom therapy with an anthracycline is not indicated.
• Advanced non-small cell lung cancer: Paclitaxel in combination with cisplatin is indicated for the treatment of non-small cell lung cancer (NSCLC) in patients for whom potentially curative surgery and/or radiotherapy is not indicated.
• AIDS-associated Kaposi's sarcoma: Paclitaxel is indicated for the treatment of patients with AIDS-associated advanced Kaposi's sarcoma (KS) in whom previous liposomal anthracycline therapy has failed.

The data situation is not very meaningful. It can be assumed that paclitaxel causes serious damage to the unborn child if it is used during pregnancy. Paclitaxel showed both embryotoxic and fetotoxic properties in rabbits and reduced fertility in rats. Like other cytotoxic drugs, paclitaxel can cause fetal damage when used in pregnant women. Therefore, paclitaxel should not be used during pregnancy unless clearly necessary. Paclitaxel should also not be used in women of childbearing age who do not use effective contraception, unless it is absolutely necessary to treat the mother with paclitaxel.

Women of childbearing age should use a reliable contraceptive method during and up to 6 months after treatment with paclitaxel.

Note: Male patients treated with paclitaxel are advised not to conceive a child during and up to 6 months after treatment.

The frequency of adverse reactions (see alsoMedDRA) were assessed according to the criteria "very common (≥1/10); common (≥1/100,<1/10);occasional (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000)".

Immunologic UAWs:

• Anaphylactic reactions: Rare are severe hypersensitivity reaction with potentially lethal outcome (defined as hypotension requiring treatment, angioedema, dyspnea requiring bronchodilator treatment, or generalized urticaria); furthermore, abdominal pain, pain in extremities, diaphoresis, and hypertension.
• Mild hypersensitivity reactions are common (in about 1/3 of patients). These reactions consist of transient exanthemas usually not requiring treatment.

Hematologic UAWs:

• Bone marrow suppression: most common serious adverse reaction. Severe neutropenia (<500 cells/mm3) without febrile episodes occurred in 28% of patients. Only 1% of patients had severe neutropenia for ≥7 days.

Thrombocytopenia was reported in 11% of patients. Three percent of patients had a platelet nadir <50,000/mm3 at least once during the study. Anemia was observed in 64% of patients but was severe (Hb <5 mmol/l) in only 6%. The incidence and severity of anemia depended on the baseline hemoglobin level.

Neurotoxicity (common): mainly peripheral neuropathy which occurred mainly in combination with cisplatin. Rarely, motor neuropathy (with resulting minor distal weakness)Very rarely, grand mal seizures, autonomic neuropathy (resulting in paralytic ileus and orthostatic hypotension), encephalopathy, convulsions, dizziness, ataxia, headache

Arthralgia or myalgia were observed in 60% of patients; they were classified as severe in 13% of patients.

DIK: Disseminated intravascular coagulation (DIK), often associated with sepsis or multiorgan failure, has been reported.

Infections and Infestations:

• Infections (mainly urinary and upper respiratory) are very common, with reports of lethal cases (septic shock). Rare are sepsis, peritonitis, pneumonia. Febrile neutropenia
• Very rare: Pseudomembranous colitis.

Acute myeloid leukemia, myelodysplastic syndrome occur very rarely.

Eye disorders:

• Optic nerve disorders and/ or visual disturbances (flicker scotoma) are very rare, especially in patients who received higher than recommended doses.
• Not known: macular edema, photopsia, vitreous opacities.

Diseases of the ear and labyrinth:

• Very rare hearing loss, ototoxicity, tinnitus, vertigo.

Cardiac side effects

• Frequent: bradycardia; occasionally reported myocardial infarction, AV block and syncope, cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy
• Rarely: heart failure.
• Very rarely atrial fibrillation or supraventricular tachycardia.

Vascular disorders:

• Occasional: thrombosis, hypertension, thrombophlebitis.

Respiratory tract, chest and abdomen:

• Rare: respiratory failure, pulmonary embolism, pulmonary fibrosis, interstitial pneumonia, dyspnea, pleural effusion

Gastrointestinal Tract Disorders:

• Very common: diarrhea, vomiting, nausea,
• Rarely: obstruction in the colon, colon perforation, ischemic colitis, pancreatitis.
• Very rare: mesenteric thrombosis, neutropenic colitis, ascites, esophagitis, constipation

Skin and subcutaneous tissue disorders:

• Very common are hair loss: alopecia was observed in 87% of patients and occurred abruptly. Most patients who experience alopecia are expected to have marked hair loss of ≥ 50%.
• Transient onycholysis is common.

• Common: injection site reactions (including localized edema, pain, erythema, induration; occasionally extravasation may result in localized inflammation, skin fibrosis and necrosis). Injection site reactions: during intravenous use may result in localized edema, pain, erythema, induration. Depigmentation of the skin may also occur. Recurrence of skin reactions at the site of a previous extravasation when paclitaxel is injected at a different site(a so-called "recall") has been reported sporadically only. In some cases, reactions were delayed for up to 10 days.

• Very rarely, Stevens-Johnson syndrome has been reported, erythema multiforme, urticaria. During treatment, patients should protect hands and feet from sunlight.

Laboratory Tests:

• Frequently AST, SGOT, alkaline phosphatase elevation ↑↑↑↑↑
• Occasionally: bilirubin ↑↑
• Rarely increase in blood creatinine level.

Combinations:

• (Paclitaxel + Trastuzumab): the following events were observed more frequently:: heart failure (8% vs. 1%), infection (46% vs. 27%), chills (42% vs. 4%), fever (47% vs. 23%), cough (42% vs. 22%), rash (39% vs. 18%), arthralgia (37% vs. 21%), tachycardia (12%vs. 4%), diarrhea (45%vs. 30%), hypertension (11%vs. 3%), nosebleeds (18%vs. 4%), acne (11%vs. 3%), herpes simplex (12%vs. 3%), unintentional injuries (13%vs. 3%), insomnia (25% vs. 13%), rhinitis (22% vs. 5%), sinusitis (21% vs. 7%), and injection site reactions (7% vs. 1%).
• (Paclitaxel +Doxorubicin ) cardiac contraction abnormality (≥20% reduction in left ventricular ejection fraction) observed in 15% of patients vs 10% with standard FAC dosing regimen. When trastuzumab was used in combination with paclitaxel in patients previously treated with anthracyclines, the incidence and severity of cardiac dysfunction increased compared with paclitaxel monotherapy(NYHA Class I/II 10% vs 0%; NYHA Class III/IV 2% vs 1%) and was rarely associated with deaths (see Trastuzumab SmPC). Except in these rare cases, all patients responded to appropriate medical treatment.
• Radiation pneumonitis has been reported in patients who received concurrent radiotherapy.
• AIDS-associated Kaposi's sarcoma: In addition to the previously listed UAWs, neutropenia occurred as the most important hematologic toxicity. During the first cycle of treatment, severe neutropenia (<500 cells/mm3) occurred in 20% of patients. Over the entire treatment period, severe neutropenia was observed in 39% of patients. Neutropenia lasted 47 days in 41% of patients and between 30 - 35 days in 8% of patients. In all patients followed up, neutropenia resolved within 35 days. The incidence of grade 4 neutropenia lasting at least 7 days was 22%.
• Neutropenic fever associated with paclitaxel occurred in 14%of patients and 1.3%of treatment cycles. During paclitaxel use, 3 septic incidents (2.8%)with fatal outcome occurred in association with the drug.

Taxol®

The metabolism of paclitaxel is partly catalysed by the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution is therefore required when paclitaxel is used in combination with other drugs that inhibit either CYP2C8 or CYP3A4 (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir and nelfinavir) as the toxicity of paclitaxel may be increased due to the higher exposure to paclitaxel. The use of paclitaxel together with other drugs that induce either CYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended as efficacy may be impaired due to lower paclitaxel exposure.

Studies in patients with Kaposi's sarcoma who received extensive concomitant medication suggest that the systemic clearance of paclitaxel was significantly reduced in the presence of nelfinavir and ritonavir, but not in the presence of indinavir. There is insufficient information on interactions with other protease inhibitors. Consequently, paclitaxel should be used with caution in patients receiving protease inhibitors as concomitant medication.

1. Marks DH et al (2018) Evaluation of Prevention Interventions for Taxane-Induced Dermatologic Adverse Events: A Systematic Review. JAMA Dermatol 154:1465-1472.
2. Picard M (2017) Management of Hypersensitivity Reactions to Taxanes. Immunol Allergy Clin North Am 37:679-693.
3. Sibaud V et al (2016) Dermatological adverse events with taxane chemotherapy. Eur J Dermatol 26:427-443.