VIT-0910 STUDY: COUNTRY-SPECIFIC ADDENDUM FOR THE NETHERLANDS

Transcription

1 VIT-0910 STUDY: COUNTRY-SPECIFIC ADDENDUM FOR THE NETHERLANDS Investigational Medicinal Products 1. Paragraph 8.1: The protocol states that all drugs will need to be provided from commercial stock. However, the combination of Vincristine and Irinotecan is a standard combination for patients that relapsed after standard chemotherapy, and used in international RMS trials with proven efficacy. The randomization will try to answer the question whether the addition of Temozolomide to the combination of Vincristine and Irinotecan will be efficacious, safe and tolerable. Therefore, Temozolomide is considered to be the investigational medicinal product (IMP) in this study, and will be provided as study medication. The Erasmus Medical Center pharmacy will buy Temozolomide from commercial stock and re-label the drug as study medication and arrange the drug-distribution to the other Dutch participating centers. The Go4Children Foundation will financially support this, hence there is no company-support for this part of the trial. 2. Paragraph 9.4.2: Cefixime is advised to prevent Irinotecan associated diarrhea. Whereas Cefixime and its alternative Cefpodoxime are registered in most participating countries in the VI(T)-0910 study, in the Netherlands neither Cefixime, nor Cefpodoxime are registered. Therefore Cefixime will be considered as investigational medicinal product (IMP) in this study, and will be provided as study medication. The Erasmus Medical Center pharmacy will buy Cefixime from commercial stock and re-label the drug as study medication and arrange the drugdistribution to the other Dutch participating centers. The Go4Children Foundation will financially support this; hence there is no company-support for this part of the trial. Product characteristics temozolomide Storage and Handling Temozolomide is a registered compound in the Netherlands and will be dealt with according to the SPC. Drug order procedure Temozolomide will be distributed free of charge to the sites after re-labeling and QP-release by the trial pharmacy of Erasmus MC, which will be done in accordance with the ICH GCP, GMP, EU and National legislation guidelines. The first drug shipment to a site will be issued after release of a Investigational Product Authority To Ship Form, which authorizes Erasmus MC to ship drug to the site once the Dutch representative of the overall sponsor (Dr J.H.M. Merks, AMC) on behalf of the sponsor has agreed that all regulatory documents are in place. Requests for drug shipment can be made by the site using a Shipment Request Form. Further details of the drug ordering procedure are specified in the Procedure Manual. Drug accountability It is the responsibility of the Investigator to ensure that the investigational product (temozolomide) is only dispensed to study subjects. The investigational product must be dispensed only from official study sites by authorized personnel according to local regulations. The lot numbers, dosing dates and the used vial number for each dosing must be recorded on drug accountability pages. VIT-0910 study Dutch addendum - version 1.0 Page 1 of 5

2 It is the responsibility of the Investigator to ensure that a current record of investigational product disposition is maintained at each study site where investigational product is inventoried and disposed. Records or logs must comply with applicable regulations and guidelines, and should include: Amount received and placed in storage area. Amount currently in storage area. Label ID number or batch number and use date or expiry date. Dates and initials of person responsible for each investigational product inventory entry/movement. Amount dispensed to and returned for each subject, including unique subject identifiers. Amount transferred to another area/site for dispensing or storage. Non-study disposition (e.g., lost, wasted, broken). Amount returned to Sponsor. Amount destroyed at study site, if applicable. Used or partially used investigational products will be destroyed on site, as well as unused vials, according to hospital procedures. It is the Investigator s responsibility to ensure that arrangements have been made for disposal and written authorization has been granted by the sponsor, and that procedures for proper disposal have been established according to applicable regulations, guidelines, and institutional procedures. Appropriate records of the disposal must be maintained. Anticipated Toxicity See protocol pages Product characteristics cefixime Cefixime is an orally active cephalosporin antibiotic which has marked in vitro bactericidal activity against a wide variety of Gram-positive and Gram-negative organisms. Cefixime prophylaxis in this trial is used to prevent the occurrence of irinotecan associated diarrhea (see page 23). It is a safe and feasible way to help optimize use of protracted irinotecan in children, and can improve both dose intensity and drug exposure. It does not interfere with the pharmacokinetics of irinotecan [Furman 2006, Pappo 2007, Wagner 2007]. Route of Administration: Oral. Absorption of Cefixime is not significantly modified by the presence of food. The recommended dosage for children is 8 mg/kg/day administered as a single dose (max 400 mg). Cefixime is well tolerated and can be given once daily, starting up to 2 days before chemotherapy administration and continuing throughout day 7. Dosage In Renal Impairment: Cefixime may be administered in the presence of impaired renal function. Normal dose and schedule may be given in patients with creatinine clearances of 20 ml/min or greater. In patients whose creatinine clearance is less than 20 ml/min, it is recommended that a dose of 200 mg once daily should not be exceeded. The dose and regimen for patients who are maintained on chronic ambulatory peritoneal dialysis or haemodialysis should follow the same recommendation as that for patients with creatinine clearances of less than 20 ml/min. Contraindications: Patients with known hypersensitivity to cephalosporin antibiotics. Cefixime should be given with caution to patients who have shown hypersensitivity to other drugs. VIT-0910 study Dutch addendum - version 1.0 Page 2 of 5

3 Cephalosporins should be given with caution to penicillin-sensitive patients, as there is some evidence of partial cross-allergenicity between the penicillins and cephalosporins. Patients have had severe reactions (including anaphylaxis) to both classes of drugs. If an allergic effect occurs with Cefixime, the drug should be discontinued and the patient treated with appropriate agents if necessary. Cefixime should be administered with caution in patients with markedly impaired renal function (See Dosage in Renal Impairment ). Interaction with other medicinal products and other forms of interaction: A false positive direct Coombs test has been reported during treatment with cephalosporin antibiotics, therefore it should be recognised that a positive Coombs test may be due to the drug. In common with other cephalosporins, increases in prothrombin times have been noted in a few patients. Care should therefore be taken in patients receiving anticoagulation therapy. Pregnancy and lactation: Reproduction studies have been performed in mice and rats at doses up to 400 times the human dose and have revealed no evidence of impaired fertility or harm to the foetus due to cefixime. In the rabbit, at doses up to 4 times the human dose, there was no evidence of a teratogenic effect; there was a high incidence of abortion and maternal death which is an expected consequence of the known sensitivity of rabbits to antibiotic-induced changes in the population of the microflora of the intestine. There are no adequate and well-controlled studies in pregnant women. Cefixime should therefore not be used in pregnancy or in nursing mothers unless considered essential by the physician. Effects on ability to drive and use machines: None. Undesirable effects: Cefixime is generally well tolerated. The majority of adverse reactions observed in clinical trials were mild and self-limiting in nature. Gastrointestinal Disturbances: The most frequent side effects seen with Cefixime are diarrhoea and stool changes; diarrhoea has been more commonly associated with higher doses. Some cases of moderate to severe diarrhoea have been reported; this has occasionally warranted cessation of therapy. Cefixime should be discontinued if marked diarrhoea occurs. Other gastrointestinal side effects seen less frequently are nausea, abdominal pain, dyspepsia, vomiting and flatulence. Pseudomembranous colitis has been reported. Central Nervous System: Headache and dizziness. Hypersensitivity Reactions: Allergies in the form of rash, pruritus, drug fever and arthralgia have been observed, including rare cases of urticaria or angioedema. These reactions usually subsided upon discontinuation of therapy. Rarely, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Haematological and Clinical Chemistry: Thrombocytosis, thrombocytopenia, leucopenia, hypereosinophilia, neutropenia and agranulocytosis have been reported. These reactions were infrequent and reversible. Mild transient changes in liver and renal function tests have been observed. Hepatic Disorders: Transient rises in liver transaminases, alkaline phosphatase and jaundice can also occur. Miscellaneous: Other possible reactions include genital pruritus and vaginitis. Overdose:There is no experience with overdoses with Cefixime. Adverse reactions seen at dose levels up to 2 g Cefixime in normal subjects did not differ from the profile seen in patients treated at the recommended doses. Gastric lavage may be VIT-0910 study Dutch addendum - version 1.0 Page 3 of 5

4 indicated in overdosage. No specific antidote exists. Cefixime is not removed from the circulation in significant quantities by dialysis. PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties Cefixime is an oral third generation cephalosporin which has marked in vitro bactericidal activity against a wide variety of Gram-positive and Gram-negative organisms. Clinical efficacy has been demonstrated in infections caused by commonly occurring pathogens including Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Proteus mirabilis, Klebsiella species, Haemophilus influenzae (beta-lactamase positive and negative), Branhamella catarrhalis (beta-lactamase positive and negative) and Enterobacter species. It is highly stable in the presence of beta-lactamase enzymes. Most strains of enterococci (Streptococcus faecalis, group D Streptococci) and Staphylococci (including coagulase positive and negative strains and methicillin-resistant strains) are resistant to cefixime. In addition, most strains of Pseudomonas, Bacteroides fragilis, Listeria monocytogenes and Clostridia are resistant to cefixime. Pharmacokinetic properties The absolute oral bioavailability of cefixime is in the range of 22-54%. Absorption is not significantly modified by the presence of food. Cefixime may therefore be given without regard to meals. From in vitro studies, serum or urine concentrations of 1 mcg/ml or greater were considered to be adequate for most common pathogens against which cefixime is active. Typically, the peak serum levels following the recommended adult or paediatric doses are between 1.5 and 3 mcg/ml. Little or no accumulation of cefixime occurs following multiple dosing. Cefixime is predominantly eliminated as unchanged drug in the urine. Glomerular filtration is considered the predominant mechanism. Metabolites of cefixime have not been isolated from human serum or urine. Serum protein binding is well characterised for human and animal sera; cefixime is almost exclusively bound to the albumin fraction, the mean free fraction being approximately 30%. Protein binding of cefixime is only concentration dependent in human serum at very high concentrations which are not seen following clinical dosing. Transfer of 14C-labelled cefixime from lactating rats to their nursing offspring through breast milk was quantitatively small (approximately 1.5% of the mothers' body content of cefixime in the pup). No data are available on secretion of cefixime in human breast milk. Placetal transfer of cefixime was small in pregnant rats dosed with labelled cefixime. Storage and Handling Shelf life 2 years unopened. 2 weeks after reconstitution. Special precautions for storage Do not store unreconstituted product above 25 C. Bottled product: To reconstitute, add 33 ml of water (50 ml bottle) or 66 ml of water (100 ml bottle) in two portions shaking after each addition. After reconstitution, the suspension may be stored at room temperature (below 25º C) for 14 days without significant loss of potency. VIT-0910 study Dutch addendum - version 1.0 Page 4 of 5

5 Do not freeze. Keep bottles tightly closed and shake well before use. Discard any unused portion after 14 days. Dilution of the suspension is not recommended. Nature and contents of container Type III amber glass screw necked bottle with child resistant push/turn closure with white polyethylene cap with polyethylene film seal on expanded low density polyethylene. Bottles are supplied with a single ended transparent polypropylene (plastic) spoon capable of measuring 3.75 and 5.0ml of the suspension. Pack sizes of 50 and 100 ml. Special precautions for disposal and other handling None stated. Drug order procedure Cefixime will be distributed free of charge to the sites after re-labeling and QP-release by the trial pharmacy of Erasmus MC, which will be done in accordance with the ICH GCP, GMP, EU and National legislation guidelines. The first drug shipment to a site will be issued after release of a Investigational Product Authority To Ship Form, which authorizes Erasmus MC to ship drug to the site once the Dutch representative of the overall sponsor (Dr J.H.M. Merks, AMC) on behalf of the sponsor has agreed that all regulatory documents are in place. Requests for drug shipment can be made by the site using a Shipment Request Form. Further details of the drug ordering procedure are specified in the Procedure Manual. Drug accountability It is the responsibility of the Investigator to ensure that the investigational product (cefixime) is only dispensed to study subjects. The investigational product must be dispensed only from official study sites by authorized personnel according to local regulations. The lot number and the dosing start date for each dosing schedule must be recorded on drug accountability pages. It is the responsibility of the Investigator to ensure that a current record of investigational product disposition is maintained at each study site where investigational product is inventoried and disposed. Records or logs must comply with applicable regulations and guidelines, and should include: Amount received and placed in storage area. Amount currently in storage area. Label ID number or batch number and use date or expiry date. Dates and initials of person responsible for each investigational product inventory entry/movement. Amount dispensed to and returned for each subject, including unique subject identifiers. Amount transferred to another area/site for dispensing or storage. Non-study disposition (e.g., lost, wasted, broken). Amount returned to Sponsor. Amount destroyed at study site, if applicable. Used or partially used investigational products will be destroyed on site, as well as unused bottles, according to hospital procedures. It is the Investigator s responsibility to ensure that arrangements have been made for disposal and written authorization has been granted by the sponsor, and that procedures for proper disposal have been established according to applicable regulations, guidelines, and institutional procedures. Appropriate records of the disposal must be maintained. VIT-0910 study Dutch addendum - version 1.0 Page 5 of 5