Each ml contains :
Paclitaxel 6 mg
- As first-line chemotherapy for the treatment of ovarian cancer in patients with advanced ovarian cancer or tumor residue (> 1 cm) after laparotomy, combined with cisplatin.
- For second-line chemotherapy in metastatic ovarian cancer patients who have failed conventional therapy with platinum containing compounds.
- Adjuvant therapy for node-positive breast cancer, given sequentially with a combination of standard chemotherapy.
- Treatment after relapse within 6 months after adjuvant therapy. Prior therapy should include anthracycline unless it is clinically contraindicated.
- Second-line therapy after failure with combination chemotherapy for metastatic disease.
Prior therapy should include anthracycline unless clinically contraindicated.
- For treatment of advanced or metastatic breast cancer in combination with trastuzumab in patients overexpressing HER2 at levels 3+ as determined by immunohistochemistry or FISH+.
Non small cell lung cancer at an advanced stage
The combination of paclitaxel with cisplatin is given for the treatment of non-small cell lung cancer in patients who are potentially incompatible with curative surgery and/or radiation therapy.
Kaposi’s second line of sarcosm therapy related to AIDS.
- Severe hypersensitivity to paclitaxel, macrogol glycerol ricinoleate (polyoxyl castor oil) or other excipients.
- Paclitaxel is contraindicated in pregnancy and lactation.
- Paclitaxel should not be given to patients with an initial neutrophil count < 1500/mm3.
DOSAGE AND ADMINISTRATIONS :
Before starting treatment using paclitaxcel, all patients should be pre-medicated by administering corticosteroids, antihistamines, and H2 receptor antagonists.
|Premedication||Dose||Administration prior to Paclitaxel|
|Dexamethasone||20 mg oral atau IV||Oral : around 12 and 6 hours
IV : 30 – 60 minutes
|Dipenhydramine**||50 mg IV||30 – 60 minutes|
|Cimetidine||300 mg IV||30 – 60 minutes|
|Or Ranitidine||50 mg||30 – 60 minutes|
* 8 – 20 mg for Kaposi’s sarcoma patients
** or an antihistamine equivalent to chlorpheniramine
Paclitaxel should be administered using a micro porous filter with a pore size of ≤ 0.22 μm (in line filter).
Only for the treatment of intravenous infusion after dilution.
Although other dosing regimens are currently being evaluated, combination therapy with Paclitaxel and Cisplatin is recommended for the first-line treatment of ovarian cancer.
Depending on the duration of the infusion, two dosing regimens are recommended for treatment with paclitaxel : intravenous administration of 175 mg/m2 of the body area for 3 hours, followed by cisplatin 75 mg/m2, or paclitaxel 135 mg/m2 as an infusion for 24 hours, followed by cisplatin 75mg/m2. A 3 week interval without treatment is recommended during therapy.
Second line :
The recommended dose of paclitaxel is 175 mg/m2 of body area, given by infusion for 3 hours at 3 week intervals between programs.
The recommended dose of paclitaxel is 175 mg/m2 of body area, given by infusion for 3 hours at 3 week intervals between programs.
Non-small cell lung cancer
The recommended dose of paclitaxel is 175 mg/m2 of body area, given by infusion for 3 hours and continued with 80 mg/m2 of cisplatin, with 3 week intervals between programs.
Kaposi sarcosm therapy related to AIDS
The recommended Paclitaxel dose is 100 mg/m2 IV. Given as an intravenous infusion 3 hours every 2 weeks.
Dosage Adjustments during treatment :
The next dose of paclitaxel depends on the tolerance level of each individual. The paclitaxel treatment program can be repeated only if the neutrophil count is at least 1,500/mm3 and platelets of 100,000/mm3. In patients presenting severe neutropenia (neutrophils < 500/mm3 for one week or more) or severe peripheral neuropathy during paclitaxel therapy, the dose should be reduced by 20% at subsequent therapy).
Method of administration
As with other cytotoxic compounds, full care must be taken when handling paclitaxel. Paclitaxel dilution should be carried out in a room designed under aseptic conditions and carried out by specially trained medical personnel.
Protective gloves are recommended.
Contact with skin or mucous membranes should be avoided. If contact with skin occurs, wash immediately with soap and water. After direct contact, tingling, burning and redness of the skin have been reported. In case of contamination of the eyes, flush immediately with water and medical attention is required. Pregnant women should be kept away from handling paclitaxel. Dyspnea, thoracic pain, burning in the throat and nausea have been reported after inhalation of cytotoxic compounds. Guidelines for handling and disposal of cytotoxic compounds must be observed.
The use of a chemo-dispensing pin or other device is not recommended because it can cause the stopper to come off, thereby eliminating the sterility of the paclitaxel solution.
Intravenous infusion preparation
Prior to infusion, Paclihope should be dissolved under aseptic conditions in an injection of 0.9% sodium chloride or 5% glucose or 5% glucose and 0.9% sodium chloride solution or 5% glucose in Ringer’s injection to a final concentration of 0.3 – 1.2 mg/ml. The chemical and physical stability of the reconstituted solution showed that at 25ºC the solution was stable for up to 72 hours.
The visible coating in the solution after dilution is from the solvent and cannot be removed by filtering. Paclihope infusions must use a filter (in-line filter) with a micro-porous membrane with a pore size of ≤ 0.22 µm. In tests using the in-line filter infusion system, there was no significant decrease in efficiency.
Sediment formation has been observed, mostly toward the end of the 24-hour paclitaxel infusion. This precipitate may be an indication that the diluted solution is very saturated. Paclitaxel should be used immediately after reconstitution to reduce the risk of deposition. Excessive handling, vibration or shock should be avoided.
Infusion sets should be rinsed carefully before use. The solution should be checked for signs of deposition on the infusion; if there is sedimentation, the infusion should be stopped.
To reduce patient contamination of DEHP, which can be separated from PVC infusion bags, equipment or other medical devices, Paclihope should be stored in bottles that do not contain PVC (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and given via a polyethylene infusion tube. The use of a filter with a short PVC inlet or outlet pipe does not result in a significant release of DEHP.
Paclihope and Paclihope already reconstituted solution should not be exposed to contact with containers or medical devices made or mengadung PVC with excipients Macrogol glycerol ricinoleate which may cause the dissolution of the plasticizer di-(2-ethoxyhexy) Phtalate (DEHP).
The amount dissolved depends on the time and concentration. This applies to the preparation and storage and administration of paclitaxel solution. Paclitaxel should be administered using a polyethylene infusion tube.
WARNING AND PRECAUTIONS :
- Paclitaxel can only be administered by specially trained doctors with experience in the use of therapy tumors.
- Adequate emergency equipment must be on hand because anaphylactic reactions can occur.
- Patients previously had to undergo treatment with corticosteroids, antihistamines, and H2 receptor antagonists.
- Paclitaxel should be given before cisplatin when used in combination.
- Severe hypersensitivity reactions characterized by dyspnea and hypotension requiring therapy. Angioedema and full body urticaria can occur in patients taking paclitaxel despite premedication. This reaction can result in the release of histamine. In case of hypersensitivity reactions, pacitaxel infusion should be stopped immediately and given symptomatic therapy. Repeat therapy with paclitaxel is contraindicated in these patients.
- Myelosuppression (especially neutropenia) is a dose-limiting reaction. Hematological parameters must be monitored periodically. Therapy can only be continued after the blood count is sufficiently improved and the neutrophils are at least 1,500/mm3 and the platelets are at least 100,000/mm3.
- Severe cardiac impulse conduction disorders rarely occur after administration of paclitaxel as a single compound. If there is severe impaired cardiac impulse conduction during paclitaxel therapy, adequate treatment should be initiated and cardiac function should be monitored routinely during the next paclitaxel therapy program.
- Hypotension, hypertension and bradycardia were observed during paclitaxel therapy in asymptomatic patients and did not require therapy.
- Vital sign examination is recommended as often as possible, especially during the first hour of paclitaxel infusion. Severe cardiovascular effects were observed more frequently in non-small cell lung cancer patients than in patients with breast or ovarian cancer.
- Patients who are recommended combination therapy should undergo an initial cardiac examination including history, clinical examination, ECG, echocardiography and/or MUGA scan. Heart function should be monitored regularly during therapy (e.g., every 3 months). Monitoring can help identify patients who have a disorder sudden heart. Patients with asymptomatic heart disease benefit from regular monitoring (e.g., every 6 – 8 months). In patients with a decreased left ventricular asymptomatic ejection fraction, clinicians should assess whether the risks outweigh the benefits of therapy.
- Peripheral neuropathy generally occurs during therapy with Paclitaxel, but severe symptoms are rare. In cases of severe peripheral neuropathy, it is recommended to reduce the dosage by 20% on subsequent therapy.
- In non-small cell lung cancer and ovarian cancer patients receiving first-line therapy, 3 hours of intravenous paclitaxel combined with cisplatin, neurotoxicity was more common than in patients who were given paclitaxel or cyclophosphamide alone with cisplatin.
- Increased toxicity after 3 hours of paclitaxel administration in patients with mild hepatic dysfunction has not been proven, but data on patients with severe cholestasis at the onset of therapy are not available. Increased bone marrow depression can occur in patients with moderate to severe liver disorders, if a long-term infusion of paclitaxel is given. Paclitaxel cannot be given to patients with severe liver problems.
- Since Paclihope contains ethanol, attention should be paid to possible effects on the central nervous system or other effects.
- Intra-arterial use of paclitaxel should be absolutely avoided because in animal studies it causes severe tissue reactions.
- Pseudomembranous colitis is rare; in some cases the patient did not receive concurrent therapy with antibiotics. This should be borne in mind in the differential diagnosis of severe or persistent diarrhea occurring during or a short time after paclitaxel therapy. If Paclitaxel use is combined with pulmonary radiation therapy, regardless of the order of therapy, use of paclitaxel may cause interstitial pneumonitis.
Pregnancy and breast feeding
Paclitaxel has shown embryotoxic and fetotoxic effects in rabbits and has been shown to reduce fertility in mice.
Data on the use of paclitaxel in pregnant women are not available. Like other cytotoxic compounds, the use of paclitaxel during pregnancy may cause potential harm to the fetus and therefore paclitaxel is contraindicated during pregnancy. Patients undergoing paclitaxel therapy are advised to use effective contraceptives. If women become pregnant during paclitaxel therapy, they should immediately notify the treating doctor.
It is not known whether paclitaxel is secreted in breast milk. Paclitaxel is contraindicated during breastfeeding, breastfeeding should be discontinued before paclitaxel therapy.
Effects on ability to drive and use machines
Paclihope does not affect ability to drive and operate machinery. However, it should be considered that Paclihope contains ethanol (see WARNINGS AND PRECAUTIONS).
ADVERSE EFFECTS :
Unless otherwise indicated, the frequency and severity of side effects were generally the same in patients receiving paclitaxel for the treatment of ovarian cancer, breast cancer, and non small cell lung cancer (NSCLC). There is no relationship between the patient’s age and the side effects that occur.
Significant hypersensitivity reactions with possibly fatal outcomes (defined as hypotension requiring therapy, angioedema, respiratory distress, requiring bronchodilator therapy or general urticaria) occurred in the patient and minor hypersensitivity reactions. These minor reactions, especially redness and rash, do not require therapeutic intervention nor do they prevent continuation of paclitaxel therapy.
Injection site reactions during intravenous administration can cause localized edema, pain, erythema and induration; sometimes, extravasation can cause cellulitis. Skin peeling and/or peeling has been reported, sometimes associated with extravasation. Skin discoloration may also occur. Recurrence of skin reactions at the site of the previous extravasation after administration of paclitaxel at different sites is reported to be rare. The specific treatment for extra-vasation reactions is currently unknown.
In patients receiving first-line chemotherapy for ovarian cancer treatment, neurotoxicity, arthralgia/myalgia and hypersensitivity reactions after 3 hours of paclitaxel infusion followed by cisplatin were more common and more seen than patients who received cyclophosphamide followed by cipslatin. After 3 hours of paclitaxel infusion followed by cisplatin, myelosuppression was less frequent and no more severe than in patients receiving cyclophosphamide and cisplatin treatment.
Unless otherwise indicated, the following data on adverse events relate to administration of a single Paclitaxel as a 3-hour infusion for the treatment of patients with metastatic tumor growths.
- Infection and investment :
Very common : Infection, 2 cases with the recommended dose and infusion regimen have been reported to be fatal.
- Blood and lymphatic system disorders :
Very common : Myelosuppression is a serious side effect that is very common with Paclitaxel therapy. Severe neutropenia (< 500/mm3) occurs, but is not accompanied by fever.
Thrombocytopenia and anemia. Myelosuppression is less common and less severe when paclitaxel is given as an infusion for more than 3 hours than for 24 hours. In first-line ovarian cancer therapy, the recommended 24-hour paclitaxel/cisplatin regimen produces greater myelosuppression compared to single-agent paclitaxel or paclitaxel followed by cisplatin, when administered at a dose of 175 mg/m2 as a 3-hour infusion.
- Benign and malignant tumors (including cysts and polyps) :
Very rare : Acute myeloid leukemia, myelodysplastic syndrome.
- Immune system disorders :
Very common : Mild hypersensitivity reactions (especially redness and skin rash) for which no treatment or discontinuation of Paclitaxel therapy is required.
Uncommon : Severe hypersensitivity reaction which is possibly fatal and requires therapy (hypotension, angioedema, severe dyspnea requiring bronchodilation or respiratory distress, urticaria).
- Nervous system disorders :
Very common : Neurotoxicity, especially peripheral neuropathy, was seen to be more common and more severe with Paclitaxel 175 mg/m2 as a 3-hour infusion than in Paclitaxel 135 mg/m2 as a 24 hour infusion when combined with Cisplatin. In non-small cell lung cancer and ovarian cancer patients who received Paclitaxel followed by Cisplatin as an infusion for 3 hours, there was an increase in cases of severe neurotoxicity.
Common : Peripheral neuropathy may develop in the first cycle of treatment and get worse with increasing doses of Paclitaxel. In some cases, Paclitaxel therapy needs to be stopped. Symptoms of neuropathy usually develop and/or disappear within a few months of stopping Paclitaxel therapy. Preexisting neuropathy resulting from previous treatment is not contraindicated.
Very rarely: autonomic neuropathy (resulting in ileus paralysis and orthostatic hypotension), grand mal seizures, encephalopathy, motor neuropathy producing distal mild weakness.
- Heart and blood vessel disorders :
Very common : Hypotension, bradycardia and ECG abnormalities.
Uncommon : Severe cardiovascular symptoms such as asymptomatic ventricular tachycardia, tachycardia with bigeminal pulses, atrioventricular block and syncope may be associated with paclitaxel therapy. This symptom is more commonly seen in patients with non-small cell lung cancer (see WARNINGS AND PRECAUTIONS).
Very rarely : Hypertension, severe thrombotic symptoms (thrombophlebitis and thrombosis of the upper limb), hypotension with septic shock, cardiomyopathy, tachycardia with fever, myocardial infarction, cardiac insufficiency which usually occurs in patients who have previously undergone different chemotherapy (especially anthracycline).
- Respiratory, thoracic and mediastinal disorders :
Rarely : radiation-induced pneumonitis is observed in patients in radiation therapy.
- Indigestion :
Very common : Side effects on digestion are generally mild to moderate. Nausea, vomiting, diarrhea, mucosal inflammation.
Rarely : pseudomembranous colitis
- Liver and bile disorders :
Common : Significant increase in AST (SGOT) levels up to five times normal and alkaline phosphatase or bilirubin levels
Uncommon : elevated bilirubin levels
Very rare : Necrosysepatic and encephalopathic
- Skin and subcutaneous tissue disorders :
Very common : Alopecia
Very rare : Steven-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis
- Musculoskeletal and connective tissue disorders
Very common : Arthralgia, myalgia
- Common disorders and injection sites :
Rarely : Reactions at the injection site (edema, pain, erythema and crusting, extravasation which can sometimes cause cellulitis). Scaly and/or peeling skin has been reported, with some cases associated with extravation. Discoloration of the skin may occur. In rare cases there is a “recall phenomenon” of recurrent local skin infections at sites where extravasation has occurred after paclitaxel infusion at different sites. The specific therapy for the treatment of this phenomenon is still unknown.
DRUG INTERACTIONS :
- Premedication with cimetidine has no effect on paclitaxel clearance.
- In first-line treatment of ovarian cancer, the recommended treatment regimen is to give paclitaxel before cisplatin. When paclitaxel was given before cisplatin, the safety profile of paclitaxel was almost the same when used as a single drug. Administration of paclitaxel after cisplatin caused an increase in myelotoxicity and a 20% decrease in paclitaxel clearance.
- Paclitaxel metabolism is catalyzed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. CYP2C8 which helps the metabolism of 6α-hydroxyPaclitaxel is the main stage of metabolism in humans. Based on data to date, there is no clinically relevant interaction between paclitaxel and other CYP2C8 substrates. Shared use ketoconazole (which is a strong inhibitor of CYP3A4) does not inhibit paclitaxel elimination in patients. Therefore, no dose adjustment is required in combination therapy of Paclitaxel and ketoconazole. Since data on Paclitaxel and other CYP3A4 inhibitor substrates are limited, special care should be taken when using Paclitaxel in combination with compounds known to be CYP3A4 substrates or inhibitors.
- Further data on potential drug interactions between paclitaxel and other CYP3A4 substrates/inhibitors are limited. Therefore, caution should be exercised when administering paclitaxel together with drugs known to inhibit CYP2C8 or 3 A4 (e.g., erythromycin, fluoxetine, gemfibrozil) or induce (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine).
- Patients taking multiple drugs concurrently suggested that clearance of the paclitaxel system was significantly lower in the presence of elfinavir and ritonavir, but not indinavir. Insufficient information is available on interactions with other protease inhibitors.
- Consequently, paclitaxel should be administered with caution in patients receiving protease inhibitors as concomitant therapy.
There is no specific antidote for Paclitaxel overdose. Early symptoms of a Paclitaxel overdose include bone marrow depression, peripheral neuropathy and mucositis.
PRESENTATION AND REGISTRATION NUMBER :
Paclihope 30. Box, 1 vial @ 5 ml – Reg. No. DKI2055000143A1
ON MEDICAL PRESCRIPTION ONLY
STORE AT 2°C – 8°C (REFRIGERATOR TEMPERATURE), PROTECT FROM LIGHT
STORE IN ORIGINAL PACKAGE
Manufactured by :
GLENMARK GENERICS S.A., Calle 9, No. 593, Parque Industrial Pilar (B1629MAX) Pilar, Buenos Aires, Argentina
T +54 0230-4529555 www.glenmarkpharma.com
Imported by :
Solo – Indonesia