Paclex^®

PACLEX^® is contraindicated in patients with:

– severe hypersensitivity reactions to paclitaxel, macrogolglycerol ricinoleate (polyoxyl castor oil)

– baseline neutrophils <1.5 × 10⁹/l (<1 × 10⁹/l for KS patients) or platelets <100 × 10⁹/l (<75 × 10⁹/l for KS patients).

– concurrent, serious, uncontrolled infections

– severe hepatic impairment

and contraindicated during lactation

PACLEX^® should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Patients must be pretreated with corticosteroids, antihistamines and H antagonists. PACLEX^® should be given before cisplatin when used in combination. Significant hypersensitivity reactions, as characterised by dyspnoea and hypotension requiring treatment, angioedema, and generalised urticaria. Fatal hypersensitivity reactions have occurred in patients despite premedication. In the case of severe hypersensitivity reactions, paclitaxel infusion should be discontinued immediately, symptomatic therapy should be initiated and the patient should not be challenged with paclitaxel.

Bone marrow suppression, primarily neutropenia, is the dose­limiting toxicity. Frequent monitoring of blood counts should be instituted. Patients should not be retreated until the neutrophil count is ≥1.5 × 10⁹/l (≥1 × 10⁹/l for KS patients) and the platelets recover to ≥100 × 10⁹/l (≥75 × 10⁹/l for KS patients). Severe cardiac conduction abnormalities have been reported rarely with single agent paclitaxel. If patients develop significant conduction abnormalities during paclitaxel administration, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel. Hypotension, hypertension, and bradycardia have been observed during paclitaxel administration; patients are usually asymptomatic and generally do not require treatment. Frequent vital signs monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Severe cardiovascular events were observed more frequently in patients with nonsmall cell lung cancer than in those with breast or ovarian carcinoma. When paclitaxel is used in combination with doxorubicin or trastuzumab for initial treatment of metastatic breast cancer,attention should be placed on the monitoring of cardiac function. When patients are candidates for treatment with paclitaxel in these combinations, they should undergo baseline cardiac assessment including history, physical examination, electrocardiogram (ECG), echocardiogram, and/or multigated acquisition (MUGA) scan. Cardiac function should be further monitored during treatment (e.g., every three months). Monitoring may help to identify patients who develop cardiac dysfunction and treating physicians should carefully assess the cumulative dose (mg/m²) of anthracycline administered when making decisions regarding frequency of ventricular function assessment. When testing indicates deterioration in cardiac function, even asymptomatic, treating physicians should carefully assess the clinical benefits of further therapy against the potential for producing cardiac damage, including potentially irreversible damage. If further treatment is administered, monitoring of cardiac function should be more frequent (e.g., every 1­2 cycles). Peripheral neuropathy: The occurrence of peripheral neuropathy is frequent; the development of severe symptoms is rare. In severe cases, a dose reduction of 20% (25% for KS patients) is recommended for all subsequent courses of paclitaxel. In non­small cell lung cancer patients the administration of paclitaxel in combination with cisplatin resulted in a greater incidence of severe neurotoxicity than administration of single agent paclitaxel. In first line ovarian cancer patients, administration of paclitaxel as a 3-hour infusion combined with cisplatin resulted in a greater incidence of severe neurotoxicity than administration of a combination of cyclophosphamide and cisplatin. Impaired hepatic function: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III­IV myelosuppression. There is no evidence that the toxicity of paclitaxel is increased when given as a 3-hour infusion to patients with mildly abnormal liver function. No data are available for patients with severe baseline cholestasis. When paclitaxel is given as a longer infusion, increased myelosuppression may be seen in patients with moderate to severe hepatic impairment. Patients should be monitored closely for the development of profound myelosuppression. Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments. Patients with severe hepatic impairment must not be treated with paclitaxel. Ethanol: This product contains ethanol (alcohol) This may be harmful to patients suffering from alcoholism. It should also be taken into account when considering using this medicine in children and high-risk groups such as those with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the effects of other medicines. Intra­arterial: Special care should be taken to avoid intra­arterial administration of paclitaxel. Pseudomembranous colitis has also been reported, rarely, including cases in patients who have not received concurrent antibiotic treatment. This reaction should be considered in the differential diagnosis of severe or persistent cases of diarrhea occurring during or shortly after treatment with paclitaxel. A combination of pulmonary radiotherapy and paclitaxel treatment (irrespective of the order of the treatments) may promote the development of interstitial pneumonitis. Paclitaxel has been shown to be a teratogen, embryotoxic and a mutagen in several experimental systems. Therefore, female and male patients of reproductive age must take contraceptive measures for themselves and/or their sexual partners during and for at least 6 months after therapy. Male patients are advised to seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with paclitaxel. In KS patients, severe mucositis is rare. If severe reactions occur, the paclitaxel dose should be reduced by 25%. There have been reports of reduced visual acuity due to cystoid macular oedema (CME) during treatment with paclitaxel as well as with other taxanes. Patients with visual impairment during paclitaxel treatment should seek a prompt and complete ophthalmologic examination. Discontinue paclitaxel treatment if a CME diagnosis is confirmed. Clinicians should consider whether the benefits of restarting paclitaxel treatment after CME resolution are expected to exceed the risks of further therapy.

Pre­medication: All patients must be given pre­medication consisting of corticosteroids, antihistamines and H ­receptor antagonists prior to paclitaxel administration, in order to prevent severe hypersensitivity reactions. Paclitaxel should be administered using an in­line filter with a microporous membrane of ≤0.22 microns. Given the possibility of extravasation, it is advisable to monitor closely the infusion site for possible infiltration during administration. First­line treatment of ovarian cancer: Although alternative medication regimens for paclitaxel are under investigation at present, a combination therapy of paclitaxel and cisplatin is recommended. Depending on the duration of infusion, two different dosages are recommended for paclitaxel treatment: 175 mg/m² of paclitaxel is administered as an intravenous infusion over a period of three hours followed thereafter by 75 mg/m² of cisplatin and the therapy is repeated at 3-week intervals, or 135 mg/m² of paclitaxel is administered as an intravenous infusion over a period of 24 hours followed thereafter by 75 mg/m² of cisplatin and the therapy is repeated at 3-week intervals. Second­line treatment of ovarian cancer: The recommended dose of paclitaxel is 175 mg/m² administered over 3 hours,

with a 3-week interval between courses. Adjuvant chemotherapy in breast carcinoma: The recommended dose of paclitaxel is 175 mg/m² administered over a period of 3 hours every 3 weeks for four courses, following AC therapy. First­line chemotherapy of breast carcinoma: When used in combination with doxorubicin (50 mg/m²), paclitaxel should be administered 24 hours after doxorubicin. The recommended dose of paclitaxel is 220 mg/m² administered intravenously over a period of 3 hours, with a 3-week interval between courses. When used in combination with trastuzumab, the recommended dose of paclitaxel is 175 mg/m² administered intravenously over a period of 3 hours, with a 3-week interval between courses. Paclitaxel infusion may be started the day following the first dose of trastuzumab or immediately after the subsequent doses of trastuzumab if the preceding dose of trastuzumab was well tolerated. Second­line chemotherapy of breast carcinoma: The recommended dose of paclitaxel is 175 mg/m² administered over a period of 3 hours, with a 3-week interval between courses. Advanced non­small cell lung cancer: The recommended dose of paclitaxel is 175 mg/m² administered over 3 hours followed by 80 mg/m² of cisplatin, with a 3-week interval between courses. Treatment of AIDS related KS: The recommended dose of paclitaxel is 100 mg/m² administered as 3-hour intravenous infusion every two weeks. Dose adjustment: Subsequent doses of paclitaxel should be administered according to individual patient tolerance. Paclitaxel should not be re­administered until the neutrophil count is ≥1.5 ×10⁹/l (≥1 × 10⁹/l for KS patients) and the platelet count is ≥100 × 10⁹ /l (≥75 × 10⁹/l for KS patients). Patients who experience severe neutropenia (neutrophil count <0.5 ×10⁹/l for a minimum of 7 days) or severe peripheral neuropathy, should receive a dose reduction of 20% for subsequent courses (25% for KS patients).
Patients with hepatic impairment: Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments. Patients with severe hepatic impairment must not be treated with paclitaxel. Paediatric use: Paclitaxel is not recommended for use in children below 18 years due to lack of data on safety and efficacy.

Like all medicines, PACLEX^® can cause side effects, although not everybody gets them.

Very common (occurs in more than 1 out of 10 a user):

– Infections (mainly urinary tract and upper respiratory tract infections), with reported cases of fatal outcome – Myelosuppression, neutropenia, anemia, thrombocytopenia, leucopenia, bleeding – Minor hypersensitivity reactions (mainly flushing and rash) – Neurotoxicity (mainly: peripheral neuropathy). – Hypotension. – Nausea, vomiting, diarrhea. – Alopecia. – Arthralgia, myalgia. – Mucosal inflammation

Common (may affect up to 1 in 10 people):

– Bradycardia – Transient and mild nail and skin changes – Administration site reactions (including swelling, pain, redness, induration, thickening of the skin (skin fibrosis), – death of skin tissue (skin necrosis) – Raised liver enzyme levels indicating hepatic function impairment.

Uncommon (may affect up to 1 in 100 people):

– Septic shock – Significant hypersensitivity reactions requiring therapy (e.g., hypotension, angioneurotic oedema, respiratory distress, generalized urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, pain in extremity, diaphoresis, and hypertension) – Cardiomyopathy, asymptomatic ventricular tachycardia, tachycardia with bigeminy, atrio­ventricular block and syncope, myocardial infarction. – Hypertension, thrombosis, thrombophlebitis – Raised level of bilirubin

Rare (may affect up to 1 in 1,000 people):

– Pneumonia, peritonitis, sepsis – Febrile neutropenia – Anaphylactic reactions – Dehydration – Motor neuropathy (with resultant minor distal weakness) – Motor neuropathy (with resultant minor distal weakness)
 – Cardiac failure – Dyspnoea, pleural effusion, interstitial pneumonia, lung fibrosis, pulmonary embolism, respiratory failure – Bowel obstruction, bowel perforation, ischaemic colitis, pancreatitis –  Pruritus, rash, erythema – Asthenia, pyrexia, oedema, malaise – Increase in blood creatinine
Very rare (occurs in less than 1 out of 10,000 users):
– Pseudomembranous colitis- Anaphylactic shock – Acute myeloid leukaemia, myelodysplastic syndrome – Anorexia – Confusional state – Autonomic neuropathy (resulting in paralytic ileus and orthostatic hypotension), grand mal seizures, convulsions, encephalopathy, dizziness, headache, ataxia – Optic nerve and/or visual disturbances (scintillating scotomata), particularly in patients who have received higher doses than recommended – Ototoxicity, hearing loss, tinnitus, vertigo –  Atrial fibrillation, supraventricular tachycardia – Shock – mesenteric thrombosis, neutropenic colitis, oesophagitis, constipation, ascites – Hepatic necrosis, hepatic encephalopathy (both with reported cases of fatal outcome) – Stevens­Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients on therapy should wear sun protection on hands and feet)
Not known (frequency cannot be estimated from the available data):
– Disseminated intravascular coagulation (DIC) – Bronchospasm – Tumour lysis syndrome – Macular oedema, photopsia, vitreous floaters – Phlebitis – Palmar­plantar erythrodysesthesia syndrome – Systemic lupus erythematosus, scleroderma
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Paclitaxel clearance is not affected by cimetidine premedication. Cisplatin: Paclitaxel is recommended to be administered before cisplatin. When given before cisplatin, the safety profile of paclitaxel is consistent with that reported for single agent use. Administration of paclitaxel after cisplatin treatment leads to greater myelosuppression and about a 20% decrease in paclitaxel clearance. Patients treated with paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynecological cancers. Doxorubicin: Since the elimination of doxorubicin and its active metabolites can be reduced when paclitaxel and doxorubicin are given closer in time, paclitaxel for initial treatment of metastatic breast cancer should be administered 24 hours after doxorubicin. Sequence effects characterized by more profound neutropenic and stomatitis episodes have been observed with combination use of paclitaxel and doxorubicin when paclitaxel was administered before doxorubicin and using longer than recommended infusion times (paclitaxel administered over 24 hours; doxorubicin over 48 hours). Active substances metabolized in the liver: The metabolism of paclitaxel is catalyzed, in part, by cytochrome P450

isoenzymes CYP2C8 and CYP3A4. Therefore, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of paclitaxel may be increased due to higher paclitaxel exposure. Administering paclitaxel concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin,

carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because efficacy may be compromised because of lower paclitaxel exposures.

PACLEX^® should not be used during pregnancy unless the clinical condition of the woman requires treatment with paclitaxel. Women of childbearing potential receiving paclitaxel should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur. Female and male patients of fertile age, and/or their partners should use contraception’s for at least 6 months after treatment with paclitaxel. Breast­feeding should be discontinued for the duration of therapy with paclitaxel.

– Keep the medicine in the box until it is consumed.
– store the medicine at temperatures below 30° C and stored away from light and moisture.
– Keep the medicine out of the reach and sight and reach of children.
– Chemical and physical in-use stability has been demonstrated for 28 days at 25°C following multiple needle entries and product withdrawal.
– The solution prepared for injection should be taken immediately. The maximum storage time of the prepared solution at room temperature (25° C) should not exceed 96 hours. Diluted solutions should not be refrigerated.