Paclitaxel

Paclitaxel is a taxane that disrupts the normal behaviour of microtubules, the protein filaments that form the cell’s internal scaffold and move chromosomes during cell division. The active substance is the same in every product, but it is supplied in two forms that behave differently in the body and must not be exchanged for one another:

• Conventional paclitaxel is a solvent-based concentrate (macrogolglycerol ricinoleate and ethanol) that is diluted and infused over 3 or 24 hours. It is authorised nationally in EU member states.
• Albumin-bound paclitaxel (nab-paclitaxel) is a powder in which paclitaxel is bound to human albumin in nanoparticles; it is reconstituted and infused over 30 minutes. It is authorised centrally as Abraxane, and generics carry their own names (Pazenir, Naveruclif, Apexelsin).

Mechanism of Action

• Microtubule stabilisation: paclitaxel promotes the assembly of microtubules from tubulin dimers and prevents their depolymerisation. It binds the β subunit of tubulin and locks the building blocks in place, so the microtubule network can no longer reorganise as the cell needs in interphase and in mitosis.
• Effect on cell division: paclitaxel produces abnormal arrays (bundles) of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. Chromosomes depend on the shortening and lengthening of microtubules to separate, so dividing cancer cells are blocked and die.
• Apoptosis: laboratory research suggests that paclitaxel also triggers programmed cell death by binding Bcl-2, a protein that normally stops apoptosis.
• Solvent-based formulation: the excipient macrogolglycerol ricinoleate (polyoxyethylated castor oil) can cause severe hypersensitivity reactions, probably mediated by histamine. This is why premedication is required with conventional paclitaxel.
• Albumin-bound formulation: nanoparticles of about 130 nm hold paclitaxel in a non-crystalline, amorphous state. After intravenous injection they dissociate rapidly into soluble albumin-bound paclitaxel complexes of about 10 nm. Albumin carries plasma components across the vessel wall (caveolar transcytosis), and in vitro the albumin in Abraxane increased the transport of paclitaxel across endothelial cells. It is hypothesised that this uses the gp-60 albumin receptor, and that the albumin-binding protein SPARC (secreted protein acidic and rich in cysteine) concentrates paclitaxel in tumour tissue.

Pharmacokinetics

• Albumin-bound, exposure: after 30- and 180-minute infusions of 80 to 375 mg/m², exposure (AUC) rose linearly from 2,653 to 16,736 ng·h/mL for doses from 80 to 300 mg/m². Variability of AUC within the same patient was 19% (12 patients given 260 mg/m²), and there was no accumulation over repeated courses.
• Albumin-bound versus solvent-based: in a comparison of 260 mg/m² over 30 minutes with 175 mg/m² of solvent-based paclitaxel over 3 hours, plasma clearance was 43% larger and the volume of distribution 53% higher with the albumin-bound product. Terminal half-lives did not differ.
• Albumin-bound, distribution: paclitaxel is evenly distributed between blood cells and plasma and is 94% bound to plasma proteins. The free fraction was higher with Abraxane (6.2%) than with solvent-based paclitaxel (2.3%), giving more unbound drug at a similar total exposure, possibly because paclitaxel is not trapped in solvent micelles. The total volume of distribution is about 1,741 L, which indicates extensive distribution outside the blood vessels and binding to tissues.
• Conventional, distribution: after intravenous administration plasma concentrations fall in two phases. The steady-state volume of distribution ranged from 198 to 688 L/m². In vitro, 89–98% of the drug binds to plasma proteins, and cimetidine, ranitidine, dexamethasone and diphenhydramine did not change this.
• Conventional, dose dependence: with 3-hour infusions the kinetics are non-linear. A 30% dose increase from 135 to 175 mg/m² raised Cmax by 75% and AUC by 81%. Differences between patients in exposure were small, and there was no accumulation over repeated courses.
• Metabolism (both formulations): hepatic. CYP2C8 forms the main metabolite, 6α-hydroxypaclitaxel; CYP3A4 forms 3’-p-hydroxypaclitaxel, and both enzymes together form 6α,3’-p-dihydroxypaclitaxel. After a radiolabelled dose, about 26%, 2% and 6% of the radioactivity was recovered in faeces as these three metabolites. Clearance is determined mainly by CYP2C8- and CYP3A4-mediated metabolism followed by biliary excretion.
• Elimination, conventional: across studies of 135 and 175 mg/m² given over 3 or 24 hours, the mean terminal half-life ranged from 3.0 to 52.7 hours and total body clearance from 11.6 to 24.0 L/h/m²; clearance appeared to fall at high plasma concentrations. Only 1.3–12.6% of the dose was recovered unchanged in urine, so elimination is mainly non-renal, probably through hepatic metabolism and biliary clearance.
• Special populations: the effect of hepatic or renal impairment on conventional paclitaxel given as a 3-hour infusion has not been studied formally. One patient on haemodialysis had pharmacokinetics within the range of patients not on dialysis. In 19 patients with AIDS-related Kaposi’s sarcoma given 100 mg/m² over 3 hours, clearance averaged 20.6 L/h/m², volume of distribution 291 L/m² and terminal half-life 23.7 hours.

The two formulations have different indications. The albumin-bound indications follow the centrally authorised Abraxane SmPC. The conventional indications follow the Spanish SmPC of one nationally authorised product (Paclitaxel Hospira); paclitaxel concentrates are authorised nationally, so the wording and scope can differ between member states and the national SmPC applies.

Albumin-Bound Paclitaxel (Abraxane and Other Albumin-Bound Products)

• Metastatic breast cancer: as monotherapy in adults who have failed first-line treatment for metastatic disease and for whom standard anthracycline-containing therapy is not indicated.
• Metastatic adenocarcinoma of the pancreas: first-line treatment in adults, in combination with gemcitabine.
• Non-small cell lung cancer: first-line treatment in adults who are not candidates for potentially curative surgery and/or radiation therapy, in combination with carboplatin.

Conventional Paclitaxel (Solvent-Based Concentrate)

• Ovarian carcinoma, first line: in combination with cisplatin, in patients with advanced carcinoma of the ovary or residual disease (more than 1 cm) after initial laparotomy.
• Ovarian carcinoma, second line: metastatic carcinoma of the ovary after failure of standard platinum-based therapy.
• Breast carcinoma, adjuvant: node-positive breast carcinoma after anthracycline and cyclophosphamide (AC) therapy. Adjuvant paclitaxel can be considered an alternative to continuing AC.
• Breast carcinoma, metastatic or locally advanced: initial treatment, either in combination with an anthracycline where anthracycline therapy is indicated, or in combination with trastuzumab in patients whose tumours overexpress HER2 at the 3+ level by immunohistochemistry and for whom an anthracycline is not indicated. As a single agent, it is used in metastatic breast carcinoma after failure of, or when patients are not candidates for, standard anthracycline therapy.
• Advanced non-small cell lung carcinoma: in combination with cisplatin, in patients who are not candidates for potentially curative surgery and/or radiotherapy.
• AIDS-related Kaposi’s sarcoma: advanced disease after failure of previous liposomal anthracycline therapy. The efficacy data supporting this indication are limited.

Albumin-Bound Paclitaxel

• Hypersensitivity to paclitaxel or to any excipient.
• Breast-feeding.
• Baseline neutrophil count below 1,500 cells/mm³.

Conventional Paclitaxel

• Hypersensitivity to paclitaxel or to any excipient, including macrogolglycerol ricinoleate.
• Pregnancy and breast-feeding.
• Baseline neutrophil count below 1,500/mm³ (below 1,000/mm³ in Kaposi’s sarcoma) or platelet count below 100,000/mm³ (below 75,000/mm³ in Kaposi’s sarcoma).
• Kaposi’s sarcoma with severe, uncontrolled concurrent infection.

The two formulations have somewhat different side-effect profiles, so they are listed separately. For both, the main effects are bone marrow suppression (especially neutropenia), peripheral neuropathy, joint and muscle pain, hair loss, nausea, vomiting and diarrhoea. Conventional paclitaxel also causes hypersensitivity reactions linked to its solvent, which is why premedication is required.

Albumin-Bound Paclitaxel

The list below follows the SmPC table for monotherapy at any dose in any indication (789 patients) and post-marketing reports. Some entries come only from post-marketing reports: severe hypersensitivity, cystoid macular oedema, tumour lysis syndrome, multiple cranial nerve palsies, vocal cord paralysis, Stevens-Johnson syndrome, toxic epidermal necrolysis, palmar-plantar erythrodysaesthesia syndrome and scleroderma.

Very common (≥1/10): bone marrow suppression, neutropenia, thrombocytopenia, anaemia, leukopenia, lymphopenia; anorexia; peripheral neuropathy, neuropathy, hypoaesthesia, paraesthesia; diarrhoea, vomiting, nausea, constipation, stomatitis; alopecia, rash; arthralgia, myalgia; fatigue, asthenia, pyrexia.

Common (≥1/100 to <1/10): infection, urinary tract infection, upper respiratory tract infection, folliculitis, candidiasis, sinusitis; febrile neutropenia; dehydration, decreased appetite, hypokalaemia; depression, insomnia, anxiety; sensory and motor peripheral neuropathy, dizziness, ataxia, headache, sensory disturbance, somnolence, dysgeusia; blurred vision, increased lacrimation, dry eye, keratoconjunctivitis sicca, madarosis (loss of eyelashes or eyebrows); vertigo; arrhythmia, tachycardia, supraventricular tachycardia; hypertension, lymphoedema, flushing, hot flush; interstitial pneumonitis, dyspnoea, epistaxis, pharyngolaryngeal pain, cough, rhinitis, rhinorrhoea; gastro-oesophageal reflux, dyspepsia, abdominal pain and distension, oral hypoaesthesia; pruritus, dry skin, nail disorders and nail discolouration, erythema, skin hyperpigmentation, onycholysis; back pain, pain in extremity, bone pain, muscle cramps; malaise, lethargy, weakness, peripheral oedema, mucosal inflammation, pain, rigors, oedema, reduced performance status, chest pain, influenza-like illness, hyperpyrexia; weight loss, raised alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase and alkaline phosphatase, lower haematocrit and red blood cell count, raised body temperature.

Uncommon (≥1/1,000 to <1/100): sepsis, neutropenic sepsis, pneumonia, oral candidiasis, nasopharyngitis, cellulitis, herpes simplex, herpes zoster, viral and fungal infections, catheter-related and injection-site infection; tumour necrosis, metastatic pain; hypersensitivity; hypophosphataemia, fluid retention, hypoalbuminaemia, polydipsia, hyperglycaemia, hypocalcaemia, hypoglycaemia, hyponatraemia; nervousness; polyneuropathy, areflexia, hyporeflexia, syncope, postural dizziness, dyskinesia, neuralgia, neuropathic pain, tremor, sensory loss; reduced visual acuity, abnormal vision, visual disturbance, eye irritation, eye pain, eye pruritus, conjunctivitis, keratitis; tinnitus, ear pain; hypotension, orthostatic hypotension, peripheral coldness; pulmonary embolism, pulmonary thromboembolism, pleural effusion, exertional dyspnoea, sinus and nasal congestion, nasal dryness, decreased breath sounds, productive cough, allergic rhinitis, hoarseness, wheezing; rectal haemorrhage, dysphagia, flatulence, glossodynia, dry mouth, gingival pain, soft faeces, oesophagitis, lower abdominal pain, mouth ulceration, oral pain; hepatomegaly; photosensitivity reaction, urticaria, skin pain, generalised pruritus, skin and pigmentation disorders, hyperhidrosis, onychomadesis, erythematous, generalised, macular, papular and maculo-papular rash, dermatitis, night sweats, vitiligo, hypotrichosis, nail bed tenderness, nail pain, skin lesions, facial swelling; chest wall pain, muscular weakness, neck pain, groin pain, muscle spasms, musculoskeletal pain, limb discomfort; haematuria, dysuria, pollakiuria, nocturia, polyuria, urinary incontinence; breast pain; chest discomfort, gait disturbance, swelling, injection-site reaction; raised blood pressure, weight gain, raised lactate dehydrogenase, creatinine, glucose, phosphorus and bilirubin, lower blood potassium; contusion.

Rare (≥1/10,000 to <1/1,000): pancytopenia; severe hypersensitivity; cystoid macular oedema; cardiac arrest, congestive heart failure, left ventricular dysfunction, atrioventricular block, bradycardia; thrombosis; extravasation; radiation recall phenomenon and radiation pneumonitis.

Very rare (<1/10,000): Stevens-Johnson syndrome, toxic epidermal necrolysis.

Not known: tumour lysis syndrome, multiple cranial nerve palsies, vocal cord paralysis, palmar-plantar erythrodysaesthesia syndrome (in some patients previously exposed to capecitabine), scleroderma.

Combination use changes the picture only in part. With gemcitabine (421 patients), the very common reactions also included dehydration, decreased appetite, hypokalaemia, depression, insomnia, dizziness, headache, dysgeusia, dyspnoea, epistaxis, cough, abdominal pain, pain in extremity, chills, peripheral oedema, weight loss and raised alanine aminotransferase. In that trial, laboratory tests showed anaemia in 97% of patients, neutropenia in 73% (grade 3–4 in 38%) and thrombocytopenia in 74%. With carboplatin (514 patients), the very common reactions were the same blood, nerve, gastrointestinal, skin and muscle reactions plus decreased appetite, dyspnoea and peripheral oedema.

In the breast cancer study of 260 mg/m² every 3 weeks (229 patients), neutropenia occurred in 79% (grade 4 in 9%), leukopenia in 71%, anaemia in 46%, peripheral neuropathy in 68% (grade 3 in 10%, none grade 4), arthralgia in 32% (severe in 6%), myalgia in 24% (severe in 7%), asthenia or fatigue in 40%, nausea in 29%, diarrhoea in 25% and alopecia in more than 80%.

Serious reactions that need prompt action are severe neutropenia, febrile neutropenia and sepsis (sepsis occurred in 5% of patients given gemcitabine with albumin-bound paclitaxel, and 5 of 22 cases were fatal), pneumonitis (1% with monotherapy, 4% with gemcitabine; 2 of 17 cases were fatal), severe hypersensitivity including anaphylaxis, severe peripheral neuropathy and severe skin reactions.

Conventional Paclitaxel

The frequencies below come from the Spanish SmPC: 812 patients with solid tumours given single-agent paclitaxel as 3-hour infusions, plus post-marketing reports. Other national SmPCs may differ in detail.

Very common (≥1/10): infection (mainly urinary tract and upper respiratory tract, with some reports of fatal outcome); myelosuppression, neutropenia, anaemia, thrombocytopenia, leukopenia, bleeding; minor hypersensitivity reactions (mainly flushing and rash); neurotoxicity (mainly peripheral neuropathy, which can persist for more than 6 months after treatment stops); hypotension; nausea, vomiting, diarrhoea; mucositis; alopecia; arthralgia, myalgia.

Common (≥1/100 to <1/10): bradycardia; mild and transient nail and skin changes; injection-site reactions (localised oedema, pain, erythema and induration; extravasation can occasionally lead to cellulitis, skin fibrosis and skin necrosis); marked rises in aspartate aminotransferase and alkaline phosphatase.

Uncommon (≥1/1,000 to <1/100): septic shock; significant hypersensitivity reactions needing treatment (hypotension, angioedema, respiratory distress and generalised urticaria, with chills, back pain, chest pain, tachycardia, abdominal pain, limb pain, sweating and hypertension); cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy, atrioventricular block and syncope, myocardial infarction; hypertension, thrombosis, thrombophlebitis; marked rise in bilirubin.

Rare (≥1/10,000 to <1/1,000): pneumonia, sepsis, peritonitis; febrile neutropenia; anaphylactic reactions; dehydration; motor neuropathy with distal weakness; cardiac failure; dyspnoea, pleural effusion, interstitial pneumonia, pulmonary fibrosis, pulmonary embolism, respiratory failure; intestinal obstruction, intestinal perforation, ischaemic colitis, pancreatitis; pruritus, rash, erythema; asthenia, pyrexia, oedema, malaise; raised serum creatinine.

Very rare (<1/10,000): pseudomembranous colitis; acute myeloid leukaemia, myelodysplastic syndrome; anaphylactic shock; anorexia; confusional state; autonomic neuropathy (paralytic ileus, orthostatic hypotension), grand mal seizures, convulsions, encephalopathy, dizziness, headache, ataxia; optic nerve or visual disturbances (scintillating scotomata), particularly at doses above those recommended; ototoxicity, hearing loss, tinnitus, vertigo; atrial fibrillation, supraventricular tachycardia; shock; cough; mesenteric thrombosis, oesophagitis, constipation, ascites, neutropenic colitis; hepatic necrosis and hepatic encephalopathy (both with fatal outcomes); Stevens-Johnson syndrome, epidermal necrosis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (hands and feet should be protected from the sun).

Not known: bronchospasm; tumour lysis syndrome; macular oedema, photopsia, vitreous floaters; phlebitis; palmar-plantar erythrodysaesthesia syndrome; systemic lupus erythematosus, scleroderma.

Key figures from the same database: severe neutropenia (below 500 cells/mm³) in 28% of patients (not linked to fever, and lasting 7 days or longer in only 1%), thrombocytopenia in 11%, anaemia in 64% (severe in 6%), arthralgia or myalgia in 60% (severe in 13%), alopecia in 87%, minor hypersensitivity reactions in 34% and significant hypersensitivity in under 1%. With cisplatin, neurotoxicity occurred in 85% of patients (15% severe) after 175 mg/m² over 3 hours, against 25% peripheral neuropathy (3% severe) after 135 mg/m² over 24 hours. Disseminated intravascular coagulation, often with sepsis or multi-organ failure, has been reported.

In combination, paclitaxel with cisplatin as first-line ovarian treatment caused more neurotoxicity, arthralgia or myalgia and hypersensitivity, and less myelosuppression, than cyclophosphamide with cisplatin. With doxorubicin, neutropenia, anaemia, peripheral neuropathy, arthralgia or myalgia, asthenia, fever and diarrhoea were more frequent and more severe than with the FAC regimen, while nausea and vomiting were less frequent. With trastuzumab, cardiac failure (8% versus 1%) and infection (46% versus 27%) were more frequent than with paclitaxel alone, and cardiac dysfunction was more frequent and severe in patients previously treated with anthracyclines. Radiation pneumonitis has been reported with concurrent radiotherapy.

In AIDS-related Kaposi’s sarcoma, bone marrow suppression was the main dose-dependent toxicity: severe neutropenia in 20% of patients in the first cycle and 39% overall, febrile neutropenia in 14%, thrombocytopenia in 50% (severe in 9%) and anaemia in 61% (severe in 10%). Three patients (2.8%) died of sepsis related to paclitaxel. Raised bilirubin (28%), alkaline phosphatase (43%) and aspartate aminotransferase (44%) occurred in patients with normal liver function at baseline, most of whom were also taking protease inhibitors.

Paclitaxel is metabolised by CYP2C8 and CYP3A4, so medicines that inhibit or induce these enzymes change its exposure. No pharmacokinetic interaction study with such medicines is available, and the cautions apply to both formulations.

• CYP2C8 or CYP3A4 inhibitors: use caution, because higher paclitaxel exposure may increase toxicity. The SmPCs name ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir and nelfinavir; the conventional SmPC also names deferasirox and trimethoprim.
• CYP2C8 or CYP3A4 inducers: not recommended, because lower paclitaxel exposure may reduce efficacy. Named examples are rifampicin, carbamazepine, phenytoin, efavirenz and nevirapine; the conventional SmPC adds St John’s wort.
• Food and herbal products: grapefruit products inhibit CYP3A4 and may raise paclitaxel levels, so use caution. St John’s wort induces CYP3A4 and may lower them. Echinacea should be avoided.
• Cisplatin (conventional paclitaxel): give paclitaxel before cisplatin. When paclitaxel followed cisplatin, patients had marked myelosuppression and paclitaxel clearance fell by about 20%. In gynaecological cancers, paclitaxel with cisplatin may carry a higher risk of kidney problems than cisplatin alone.
• Doxorubicin (conventional paclitaxel): give paclitaxel 24 hours after doxorubicin. Elimination of doxorubicin and its active metabolites can fall when the two are given close together; paclitaxel given immediately after doxorubicin raised total doxorubicin exposure by 30%. Deeper neutropenia and stomatitis occurred when paclitaxel was given before doxorubicin with infusion times longer than recommended (24 hours and 48 hours).
• Premedication (conventional paclitaxel): cimetidine premedication does not change paclitaxel clearance.
• Gemcitabine and carboplatin (albumin-bound paclitaxel): paclitaxel and gemcitabine do not share a metabolic pathway, but a pharmacokinetic interaction has not been evaluated in humans. No clinically relevant pharmacokinetic interaction was found with carboplatin. Albumin-bound paclitaxel should not be used with other anticancer agents beyond its indications: monotherapy for breast cancer, with gemcitabine for pancreatic cancer, or with carboplatin for lung cancer.
• Alcohol in the conventional concentrate: the ethanol it contains can affect the action of other medicines.

Paclitaxel must be given only under the supervision of a physician experienced in cytotoxic chemotherapy. For albumin-bound paclitaxel, this means a qualified oncologist in a unit specialised in giving cytotoxic agents. Facilities to treat serious hypersensitivity reactions must be available. The two formulations are dosed and prepared differently and are described separately below; the albumin-bound generics have their own SmPCs, and where a detail differs from Abraxane, the individual SmPC applies.

Albumin-Bound Paclitaxel: Doses

• Metastatic breast cancer: 260 mg/m² intravenously over 30 minutes every 3 weeks.
• Pancreatic adenocarcinoma: 125 mg/m² over 30 minutes on days 1, 8 and 15 of each 28-day cycle, with gemcitabine 1,000 mg/m² over 30 minutes immediately afterwards on the same days.
• Non-small cell lung cancer: 100 mg/m² over 30 minutes on days 1, 8 and 15 of each 21-day cycle, with carboplatin AUC = 6 mg·min/mL on day 1 only of each 21-day cycle, starting immediately after the albumin-bound paclitaxel infusion.
• Method: the reconstituted dispersion is infused through an infusion set with a 15 µm filter, and the line is flushed with sodium chloride 9 mg/mL (0.9%) solution afterwards so that the whole dose is delivered. Reconstitution follows section 6.6 of the SmPC.

Albumin-Bound Paclitaxel: Dose Adjustments

• Breast cancer: for severe neutropenia (below 500 cells/mm³ for a week or longer) or severe sensory neuropathy, reduce to 220 mg/m² for later courses, and to 180 mg/m² if it recurs. Do not give a dose until neutrophils have recovered to above 1,500 cells/mm³. For grade 3 sensory neuropathy, withhold treatment until it falls to grade 1 or 2, then reduce the dose for all later courses.
• Pancreatic cancer, dose levels: full dose is 125 mg/m² with gemcitabine 1,000 mg/m²; first reduction 100 mg/m² with 800 mg/m²; second reduction 75 mg/m² with 600 mg/m². A further reduction means stopping treatment.
• Pancreatic cancer, blood counts: on day 1, delay doses until recovery if neutrophils are below 1,500 cells/mm³ or platelets below 100,000 cells/mm³. On day 8, reduce both medicines by one dose level if neutrophils are 500 to below 1,000 cells/mm³ or platelets 50,000 to below 75,000 cells/mm³, and withhold doses if neutrophils are below 500 or platelets below 50,000. The SmPC sets out the rules for day 15.
• Pancreatic cancer, other toxicity: for grade 3 or 4 febrile neutropenia, withhold both medicines until the fever resolves and neutrophils are at least 1,500, then resume at the next lower dose level. For grade 3 or 4 peripheral neuropathy, withhold albumin-bound paclitaxel until it improves to grade 1 or below and resume at the next lower level (gemcitabine is unchanged). For grade 2 or 3 skin toxicity, reduce to the next lower level and stop if it persists. For grade 3 mucositis or diarrhoea, withhold until grade 1 or below, then resume at the next lower level.
• Lung cancer: do not give the day 1 dose until neutrophils are at least 1,500 cells/mm³ and platelets at least 100,000 cells/mm³. Each weekly dose needs neutrophils of at least 500 cells/mm³ and platelets above 50,000 cells/mm³; otherwise withhold it until counts recover. The first reduction is to 75 mg/m² with carboplatin AUC 4.5, the second to 50 mg/m² with AUC 3.0, and a third means stopping. Reductions are triggered by a neutrophil nadir below 500 cells/mm³ with fever above 38 °C, a delayed next cycle because of persistent neutropenia, or a nadir below 500 cells/mm³ lasting more than a week. A platelet nadir below 50,000 cells/mm³ allows one reduction (75 mg/m², AUC 4.5), and a second means stopping.
• Lung cancer, other toxicity: for grade 2 or 3 skin toxicity, grade 3 diarrhoea or mucositis, grade 3 or higher peripheral neuropathy, or any other grade 3 or 4 non-haematological toxicity, interrupt treatment until it improves to grade 1 or below (grade 2 or below for the other toxicities), then restart at the reduced levels above. Stop for grade 4 skin toxicity, diarrhoea or mucositis. On day 1, albumin-bound paclitaxel and carboplatin are reduced together; on days 8 or 15 only albumin-bound paclitaxel is reduced, and carboplatin is reduced in the next cycle.

Albumin-Bound Paclitaxel: Special Populations

• Hepatic impairment: no adjustment for mild impairment (bilirubin above 1 to 1.5 × the upper limit of normal and AST up to 10 × the upper limit). With moderate to severe impairment (bilirubin above 1.5 to 5 × the upper limit and AST up to 10 × the upper limit), a 20% dose reduction is recommended in breast and lung cancer, and the dose can be raised again if tolerated for at least two cycles. There are insufficient data for pancreatic cancer with moderate to severe impairment, or for any patient with bilirubin above 5 × the upper limit or AST above 10 × the upper limit.
• Renal impairment: no adjustment for mild to moderate impairment (creatinine clearance 30 to below 90 mL/min). There are insufficient data for severe impairment or end-stage renal disease (below 30 mL/min).
• Elderly: no additional dose reduction beyond those for all patients. In pancreatic cancer, patients aged 75 or older had more serious reactions and treatment stops, so they should be assessed carefully before treatment. In lung cancer, myelosuppression, peripheral neuropathy and arthralgia were more frequent from age 65, and experience with the carboplatin combination from age 75 is limited. In breast cancer, patients aged 65 or older had more epistaxis, diarrhoea, dehydration, fatigue and peripheral oedema, and modelling suggests they may be more susceptible to neutropenia in the first cycle.
• Children and adolescents: safety and efficacy under 18 years have not been established, no posology can be recommended, and there is no relevant use in these indications.

Conventional Paclitaxel: Premedication and Administration

• All patients receive a corticosteroid, an antihistamine and an H2 antagonist before each dose to prevent severe hypersensitivity. Examples: dexamethasone 20 mg by mouth (about 12 and 6 hours before) or intravenously (30–60 minutes before), or 8–20 mg in Kaposi’s sarcoma; diphenhydramine 50 mg intravenously, or an equivalent antihistamine such as chlorphenamine 10 mg intravenously, 30–60 minutes before; and cimetidine 300 mg or ranitidine 50 mg intravenously 30–60 minutes before.
• The concentrate must be diluted before use (SmPC section 6.6) and is given by intravenous infusion only, through an in-line filter with a microporous membrane of 0.22 µm or less.
• Because of the risk of extravasation, the infusion site should be watched closely for infiltration.

Conventional Paclitaxel: Doses

• Ovarian cancer, first line: with cisplatin, paclitaxel 175 mg/m² intravenously over 3 hours followed by cisplatin 75 mg/m² every 3 weeks, or paclitaxel 135 mg/m² over 24 hours followed by cisplatin 75 mg/m², with 3 weeks between cycles.
• Ovarian cancer, second line: 175 mg/m² over 3 hours every 3 weeks.
• Adjuvant breast cancer: 175 mg/m² over 3 hours every 3 weeks for four cycles, after AC therapy.
• Metastatic or locally advanced breast cancer, first line: with doxorubicin (50 mg/m²), paclitaxel 220 mg/m² over 3 hours every 3 weeks, given 24 hours after doxorubicin. With trastuzumab, 175 mg/m² over 3 hours every 3 weeks; the infusion can start the day after the first trastuzumab dose, or immediately after later trastuzumab doses if the previous dose was well tolerated.
• Breast cancer, second line: 175 mg/m² over 3 hours every 3 weeks.
• Advanced non-small cell lung cancer: 175 mg/m² over 3 hours followed by cisplatin 80 mg/m², every 3 weeks.
• AIDS-related Kaposi’s sarcoma: 100 mg/m² as a 3-hour intravenous infusion every 2 weeks.

Conventional Paclitaxel: Dose Adjustments and Special Populations

• Later doses are given according to each patient’s tolerance. Treatment is not restarted until neutrophils are at least 1,500/mm³ (1,000/mm³ in Kaposi’s sarcoma) and platelets at least 100,000/mm³ (75,000/mm³ in Kaposi’s sarcoma).
• After severe neutropenia (below 500/mm³ for 7 days or longer) or severe peripheral neuropathy, later doses are reduced by 20% (25% in Kaposi’s sarcoma).
• Hepatic impairment: the available data are not adequate to recommend dose changes in mild or moderate impairment. Patients with severe hepatic impairment must not be treated.
• Children and adolescents: safety and efficacy under 18 years have not been established.

Conventional and Albumin-Bound Paclitaxel Are Not Interchangeable

The Abraxane SmPC states that albumin-bound paclitaxel may have substantially different pharmacological properties from other paclitaxel formulations and must not be substituted for or with them. The two differ in dose (for example 260 mg/m² every 3 weeks for albumin-bound paclitaxel in metastatic breast cancer, against 175 mg/m² for conventional paclitaxel), in infusion time (30 minutes against 3 or 24 hours), in indications, and in premedication, which is mandatory for conventional paclitaxel. The formulation named on the prescription must be checked against the pack before the infusion is prepared.

Hypersensitivity Reactions

• Conventional paclitaxel: significant reactions (dyspnoea and hypotension needing treatment, angioedema, generalised urticaria) occurred in under 1% of patients after proper premedication. Rare severe reactions, and very rarely anaphylaxis with fatal outcome, have been reported. They are probably histamine-mediated, and the excipient macrogolglycerol ricinoleate can cause them. If a severe reaction occurs, stop the infusion immediately, start symptomatic treatment and do not give paclitaxel again.
• Albumin-bound paclitaxel: rare severe hypersensitivity reactions, including very rare anaphylaxis with fatal outcome, have been reported. Stop the medicine immediately, treat symptoms and do not rechallenge with paclitaxel.

Bone Marrow Suppression and Infection

• Blood counts: neutropenia is the dose-limiting toxicity of both formulations, with the neutrophil nadir at a median of 11 days with conventional paclitaxel. Blood counts must be checked often, and treatment is not repeated until neutrophils and platelets have recovered (see the dose adjustment rules above). Most Kaposi’s sarcoma patients in the conventional-paclitaxel study received G-CSF.
• Fever and sepsis: with albumin-bound paclitaxel plus gemcitabine, sepsis occurred in 5% of patients, with biliary obstruction or a biliary stent as important contributing factors. A patient who becomes febrile, whatever the neutrophil count, should start broad-spectrum antibiotics. For febrile neutropenia, withhold albumin-bound paclitaxel and gemcitabine until the fever resolves and neutrophils are at least 1,500 cells/mm³, then resume at reduced dose levels.

Peripheral Neuropathy

• Albumin-bound paclitaxel: sensory neuropathy is frequent, though severe symptoms are less common. Grade 1 or 2 neuropathy does not generally need a dose reduction; grade 3 or higher requires withholding treatment and a lower dose afterwards (see the dose adjustment rules above).
• Conventional paclitaxel: neuropathy is frequent, severe symptoms are rare, and a 20% dose reduction is advised in severe cases. Severe neurotoxicity was more common when a 3-hour infusion was followed by cisplatin in lung and ovarian cancer. Neuropathy can appear after the first cycle, worsen with later cycles and persist for more than 6 months; neuropathy from earlier treatment is not a contraindication.

Heart and Blood Pressure (Conventional Paclitaxel)

Severe cardiac conduction abnormalities have rarely been reported; patients who develop significant conduction disturbances need appropriate treatment and monitoring during later paclitaxel therapy. Hypotension, hypertension and bradycardia occur during infusion, usually without symptoms or need for treatment, so vital signs should be monitored, especially in the first hour. Serious cardiovascular events were more frequent in lung cancer than in breast or ovarian cancer. Before paclitaxel is combined with doxorubicin or trastuzumab for first-line metastatic breast cancer, cardiac function is assessed (history, examination, ECG, echocardiogram and/or MUGA scan) and then monitored, for example every three months, and every 1–2 cycles if treatment continues despite worsening function. The cumulative anthracycline dose should be considered.

Liver Impairment

Paclitaxel toxicity can be greater in hepatic impairment, especially grade III–IV myelosuppression. With conventional paclitaxel, there was no evidence of more toxicity in moderate impairment with 3-hour infusions, but longer infusions in moderate to severe impairment can increase myelosuppression, so patients must be monitored closely; severe hepatic impairment is a reason not to treat, and there are no data in severe cholestasis. Albumin-bound paclitaxel should be used with caution in hepatic impairment (see the dose rules above).

Lung, Bowel and Eye Reactions

• Pneumonitis: with albumin-bound paclitaxel it occurred in 1% of patients on monotherapy and 4% with gemcitabine. Watch for signs and symptoms; after infection has been ruled out and pneumonitis diagnosed, stop albumin-bound paclitaxel and gemcitabine permanently and treat promptly. With conventional paclitaxel, combination with radiotherapy for lung cancer, in any sequence, can contribute to interstitial pneumonitis.
• Pseudomembranous colitis: rarely reported with conventional paclitaxel, including in patients not taking antibiotics. Consider it in severe or persistent diarrhoea during or soon after treatment.
• Cystoid macular oedema: reduced visual acuity has been reported with paclitaxel and other taxanes. Patients whose vision deteriorates need an immediate full eye examination, and conventional paclitaxel is stopped if the diagnosis is confirmed.

Extravasation and Intra-Arterial Administration (Conventional Paclitaxel)

Extravasation can cause local oedema, pain, erythema, induration, skin discolouration and, occasionally, cellulitis, fibrosis or necrosis. No specific treatment is known. Skin reactions have rarely recurred at an old extravasation site after a later infusion elsewhere. Intra-arterial administration must be avoided, because it caused severe tissue reactions in animal studies.

Pregnancy, Breastfeeding and Fertility

• Albumin-bound paclitaxel: women of childbearing potential should use effective contraception during treatment and for at least six months after the last dose, and have a pregnancy test before starting. Men with female partners of reproductive potential should use effective contraception and avoid fathering a child during treatment and for at least three months after the last dose. The medicine should not be used in pregnancy, or in women of childbearing potential not using effective contraception, unless the mother’s condition requires it; paclitaxel is suspected to cause serious birth defects. Breast-feeding is contraindicated and must stop for the duration of therapy. Fertility may be compromised in men and women, and men should seek advice on sperm conservation before treatment because infertility may be irreversible.
• Conventional paclitaxel: the SmPC lists pregnancy and breast-feeding as contraindications, and section 4.6 adds that paclitaxel should not be used in pregnancy unless the woman’s clinical condition requires it. Paclitaxel was teratogenic, embryotoxic and mutagenic in several experiments. Women of childbearing potential should use effective contraception during treatment and for at least 7 months after the last dose, and men with female partners of childbearing potential for at least 4 months. Paclitaxel has been found in breast milk, so mothers should not breastfeed during treatment and for 2 weeks after the last dose. Men should seek advice on sperm cryopreservation, and fertility preservation should be discussed with women before treatment.

Excipients (Conventional Paclitaxel)

The concentrate contains macrogolglycerol ricinoleate, which can cause severe allergic reactions. It also contains 49.7% ethanol, about 21 g per dose, which is harmful in alcohol dependence. The alcohol content should be considered in pregnant or breast-feeding women, in children and in high-risk groups such as patients with liver disease or epilepsy. It can affect the action of other medicines and can reduce the ability to drive or use machines.

Effect on Driving

Albumin-bound paclitaxel has a minor to moderate influence on the ability to drive and use machines. Tiredness (very common) and dizziness (common) can interfere, and patients who feel tired or dizzy should not drive or use machines. The alcohol in conventional paclitaxel can also reduce the ability to drive or use machines.

• Albumin-bound paclitaxel: keep unopened vials in the outer carton to protect them from light. The medicine needs no special temperature conditions, and neither freezing nor refrigeration affects its stability. Storage after reconstitution is described under Shelf Life.
• Conventional paclitaxel: do not store above 25 °C, and keep the vial in the original package to protect it from light. Freezing does not alter the quality. A refrigerated vial may form a precipitate that dissolves again at room temperature with little or no shaking; if the solution stays cloudy or an insoluble precipitate remains, the vial must be discarded.

Neither product needs a refrigerated cold chain.

• Albumin-bound paclitaxel, unopened vial: 3 years.
• Albumin-bound paclitaxel, reconstituted dispersion: chemical and physical stability in the vial has been shown for 24 hours at 2–8 °C in the original carton, protected from light. In the infusion bag it is 24 hours at 2–8 °C followed by 4 hours at 25 °C, protected from light. From a microbiological point of view, the product should be used immediately unless reconstitution and filling of the bags rule out microbial contamination; otherwise the user is responsible for in-use times and conditions.
• Conventional paclitaxel, unopened vial: 2 years. After the vial is opened and before dilution, it remains stable for up to 28 days below 25 °C, protected from light, after multiple needle insertions and withdrawals. After dilution, chemical and physical stability has been shown for 72 hours at 25 °C under normal light, and the diluted solution must not be frozen.

Prescription only (Rx), on the prescription of a specialist experienced in cancer chemotherapy. Both formulations are cytotoxic infusions given in a hospital or specialised oncology unit, so they are supplied to the hospital or clinic that administers them. The order must name the formulation: conventional paclitaxel (6 mg/mL concentrate for solution for infusion) and albumin-bound paclitaxel (100 mg powder for dispersion for infusion) are different medicines with different doses and must not be substituted for one another. Neither needs a refrigerated cold chain; conventional paclitaxel should not be kept above 25 °C, and both are protected from light.