Dosage and Important Administration Instructions. Shake vial for 5 to 8 seconds

Transcription

1 STEP-BY-STEP GUIDE TIPRI (ciprofloxacin otic sspension) 6% Have all materials ready ne vial of TIPRI (enogh for doses) Two ml ler lock syringes wo 8-G T preparation needles wo 0-4G, T -3 inch blnt, flexible administration needles Alcohol pads PTINAL: Ice pack and drape to keep TIPRI vial cold Dosage and Important Administration Instrctions Shake vial for 5 to 8 seconds To keep the vial cold dring shaking, hold the TIPRI vial by the alminm seal to prevent to mix well ntil a visally homogenos sspension is obtained. TIPRI is for intratympanic administration only TIPRI is intended for single-patient se; discard nsed portion dminister TIPRI as a single intratympanic A administration of one (6 mg) dose into each affected ear, following sctioning of middle ear effsion 3 sspension with preparation needle Using an 8-G needle, withdraw of the sspension into the ml syringe. Always hold the vial by the alminm seal to prevent gelation. KEEP CLD dring preparation. If TIPRI thickens dring preparation, place the vial back in refrigeration. 4 Replace preparation needle with administration needle Replace the needle with a 0-4G, -3 inch blnt, flexible needle to be sed for administration. 5 Prime the syringe Prime the needle, leaving a dose of (0. cc). INDICATINS AND USAGE TIPRI (ciprofloxacin otic sspension) 6% is a floroqinolone antibacterial indicated for the treatment of pediatric patients with bilateral otitis media with effsion ndergoing tympanostomy tbe placement. IMPRTANT SAFETY INFRMATIN CNTRAINDICATINS TIPRI is contraindicated in patients with a history of hypersensitivity to ciprofloxacin, to other qinolones, or to any of the components of TIPRI. Please see accompanying fll Prescribing Information. 6 Prepare second syringe for bilateral administration only epeat Steps 3, 4, and 5 sing the same R vial to prepare a second syringe for the other ear and dispose of the vial Use a different syringe for each ear fter preparation, syringes can be kept A at room temperatre or in the refrigerator prior to administration Keep syringes on their side iscard syringes if not administered in D 3 hors WARNINGS AND PRECAUTINS Potential for Microbial vergrowth: TIPRI may reslt in overgrowth of nonssceptible bacteria and fngi. If sch infections occr, institte alternative therapy. ADVERSE REACTINS Adverse reactions (incidence at least 3%) that occrred in two Phase 3 trials with TIPRI vs sham were: nasopharyngitis (5% vs 4%), irritability (5% vs 3%), and rhinorrhea (3% vs %). USE IN SPECIFIC PPULATINS Pediatric Use: The safety and effectiveness of TIPRI in infants below six months of age have not been established. 07 tonomy, Inc. All rights reserved. TIPRI is a registered trademark of tonomy, Inc. -TI66

2 HIGHLIGHTS F PRESCRIBING INFRMATIN These highlights do not inclde all the information needed to se TIPRI safely and effectively. See fll prescribing information for TIPRI. TIPRI (ciprofloxacin otic sspension), for intratympanic or otic se Initial U.S. Approval: RECENT MAJR CHANGES Indications and Usage () 3/08 Dosage and Administration () 3/ INDICATINS AND USAGE TIPRI is a floroqinolone antibacterial indicated for the following conditions: The treatment of pediatric patients (age 6 months and older) with bilateral otitis media with effsion ndergoing tympanostomy tbe placement. () The treatment of acte otitis externa in patients 6 months of age and older de to Psedomonas aerginosa and Staphylococcs ares. () DSAGE AND ADMINISTRATIN TIPRI is for intratympanic or otic administration by a healthcare professional only. (.) TIPRI is intended for single-patient se with p to two doses available in each vial. (.) For bilateral otitis media with effsion, administer TIPRI as a single intratympanic administration of one (6 mg) dose into each affected ear, following sctioning of the middle ear effsion. (.) For acte otitis externa, administer TIPRI as a single 0. ml ( mg) administration to the affected ear(s). (.) See Fll Prescribing Information for directions for TIPRI dose preparation. (.) DSAGE FRMS AND STRENGTHS tic Sspension: Each TIPRI vial contains ml of 6% (60 mg/ml) ciprofloxacin otic sspension. (3) CNTRAINDICATINS TIPRI is contraindicated in patients with a history of hypersensitivity to ciprofloxacin, to qinolones, or to any component of TIPRI. (4) WARNINGS AND PRECAUTINS Potential for Microbial vergrowth: TIPRI may reslt in overgrowth of non-ssceptible bacteria and fngi. (5.) ADVERSE REACTINS titis Media with Effsion: The most freqently occrring adverse reactions (with an incidence rate greater than 3%) were nasopharyngitis and irritability. (6.) Acte titis Externa: The most freqently occrring adverse reactions (with an incidence rate of at least %) were: ear prrits, headache, otitis media and ear discomfort. (6.) To report SUSPECTED ADVERSE REACTINS, contact tonomy at or FDA at -800-FDA-088 or See 7 for PATIENT CUNSELING INFRMATIN Revised: 3/08 FULL PRESCRIBING INFRMATIN: CNTENTS* INDICATINS AND USAGE DSAGE AND ADMINISTRATIN. Dosage and Important Administration Instrctions. Preparation of TIPRI 3 DSAGE FRMS AND STRENGTHS 4 CNTRAINDICATINS 5 WARNINGS AND PRECAUTINS 5. Potential for Microbial vergrowth 6 ADVERSE REACTINS 6. Clinical Trials Experience 8 USE IN SPECIFIC PPULATINS 8. Pregnancy 8. Lactation 8.4 Pediatric Use 8.5 Geriatric Use DESCRIPTIN CLINICAL PHARMACLGY. Mechanism of Action.3 Pharmacokinetics.4 Microbiology 3 NNCLINICAL TXICLGY 3. Carcinogenesis, Mtagenesis, Impairment of Fertility 3. Animal Toxicology and/or Pharmacology 4 CLINICAL STUDIES 4. Bilateral titis Media with Effsion 4. Acte titis Externa 6 HW SUPPLIED/STRAGE AND HANDLING 7 PATIENT CUNSELING INFRMATIN *Sections or sbsections omitted from the fll prescribing information are not listed.

3 FULL PRESCRIBING INFRMATIN INDICATINS AND USAGE TIPRI is indicated for The treatment of pediatric patients (6 months of age and older) with bilateral otitis media with effsion ndergoing tympanostomy tbe placement. The treatment of acte otitis externa in patients 6 months of age and older de to Psedomonas aerginosa and Staphylococcs ares. DSAGE AND ADMINISTRATIN. Dosage and Important Administration Instrctions TIPRI is intended for single-patient se, discard nsed portion. For bilateral otitis media with effsion, administer TIPRI as a single intratympanic administration of one (6 mg) dose into each affected ear of pediatric patients (6 months of age and older), following sctioning of middle ear effsion. For acte otitis externa, administer TIPRI as a single 0. ml ( mg) administration to the external ear canal of each affected ear of patients aged 6 months and older.. Preparation of TIPRI Directions for TIPRI dose preparation and handling are presented in Figre. The directions differ for each indication. Follow the correct directions. TIPRI is for intratympanic or otic administration by a healthcare professional only. Figre : Preparation and dosing directions for Acte titis Externa and for titis Media with Effsion. Dosing directions differ for each indication. Follow the correct directions. Acte titis Externa titis Media with Effsion STEP Preparation for ACUTE TITIS EXTERNA Materials needed: vial of TIPRI (for single patient with nilateral or bilateral AE) STEP Preparation for TITIS MEDIA with EFFUSIN Materials needed: vial of TIPRI (for single patient, enogh for bilateral se) For each affected ear: ne ml ler lock syringe ne 8G-G preparation needle ne 0-4G,.5 inch blnt, flexible catheter or comparable administration needle Two ml ler lock syringes Two 8G-G preparation needles Two 0-4G, -3 inch blnt, flexible catheters or comparable administration needles Alcohol pads Alcohol pad ptional: ice pack and drape to keep TIPRI vial cold. ptional: ice pack and drape to keep TIPRI vial cold. Keep prodct cold dring preparation. If TIPRI thickens dring preparation, place the vial back in refrigeration. Keep prodct cold dring preparation. If TIPRI thickens dring preparation, place the vial back in refrigeration. STEP TIPRI Mixing To keep the vial cold dring shaking, hold the TIPRI vial by the alminm seal to prevent to mix well ntil a visally homogenos sspension is obtained. STEP TIPRI Mixing To keep the vial cold dring shaking, hold the TIPRI vial by the alminm seal to prevent to mix well ntil a visally homogenos sspension is obtained. R STEP 3 TIPRI Removal Using an 8-G needle, withdraw of the sspension into the ml syringe. STEP 4 Replace with the Administration Needle Replace the needle with a 0-4G, -3 inch blnt, flexible catheter to be sed for administration. Do not prime the syringe ntil after the administration needle has been attached. STEP 4 Replace with the Administration Needle Replace the needle with a 0-4G,.5 inch blnt, flexible catheter to be sed for administration. Do not prime the syringe ntil after the administration needle has been attached. Prime Primetoto STEP 5 Priming the Administration Needle for ACUTE TITIS EXTERNA Prime the needle leaving a dose of 0. ml (0. cc). Always hold the vial by the alminm seal to prevent gelation. Always hold the vial by the alminm seal to prevent gelation. STEP 3 TIPRI Removal Using an 8-G needle, withdraw of the sspension into the ml syringe. Prime Prime to to STEP 5 Priming the Administration Needle for TITIS MEDIA with EFFUSIN Prime the needle leaving a dose of (0. cc). Prime 0.tomL 0. ml 0. ml STEP 6 Preparing Second Dose for Bilateral Administration nly Repeat Steps 3, 4 and 5 to prepare a second syringe for the other ear and dispose of the vial. STEP 6 Preparing Second Dose for Bilateral Administration nly Repeat Steps 3, 4 and 5 to prepare a second syringe for the other ear and dispose of the vial. Use a different syringe for each ear. Use a different syringe for each ear. AFTER PREPARATIN Syringes can be kept at room temperatre or in the refrigerator prior to administration. Keep syringes on their side. Discard syringes if not administered in 3 hors. AFTER PREPARATIN Syringes can be kept at room temperatre or in the refrigerator prior to administration. Keep syringes on their side. Discard syringes if not administered in 3 hors.

4 3 DSAGE FRMS AND STRENGTHS tic Sspension: Each ml of TIPRI contains a white, preservative-free, sterile otic sspension consisting of 6% (60 mg/ml) ciprofloxacin in a single-patient se glass vial. 4 CNTRAINDICATINS TIPRI is contraindicated in patients with a history of hypersensitivity to ciprofloxacin, to other qinolones, or to any of the components of TIPRI. 5 WARNINGS AND PRECAUTINS 5. Potential for Microbial vergrowth TIPRI may reslt in overgrowth of non-ssceptible bacteria and fngi. If sch infections occr, institte alternative therapy. 6 ADVERSE REACTINS 6. Clinical Trials Experience Becase clinical stdies are condcted nder widely varying conditions, adverse reaction rates observed in the clinical stdies of a drg cannot be directly compared to rates in the clinical stdies of another drg and may not reflect the rates observed in practice. titis Media with Effsion In two randomized, sham-controlled Phase 3 clinical trials, 530 pediatric patients with bilateral otitis media with effsion ndergoing tympanostomy tbe placement were treated with TIPRI or sham administered intratympanically as a single dose ( to each ear). The median age of the pediatric patients enrolled in the clinical trials was.5 years; 6% of patients were 6 months throgh years of age and 38% of patients were greater than years of age. Adverse reactions that occrred in at least 3% of TIPRI patients and at an incidence greater than sham are presented in Table. Table : Adverse Reactions in Phase 3 titis Media with Effsion Trials Adverse Reactions TIPRI (N=357) (N=73) Nasopharyngitis 5% 4% Irritability 5% 3% Rhinorrhea 3% % Acte titis Externa In a single randomized, sham controlled Phase 3 clinical trial, 59 pediatric and adlt patients with acte otitis externa were treated with TIPRI or sham administered by a healthcare professional to the external ear canal as a single dose (0. ml to each affected ear). The median age of the patients enrolled in the clinical trial was 34 years; 6% were pediatric patients (age 3 to 7 years), 65% were adlts (age 8 to 64 years), and 8% were elderly patients (age 65 years and older). Adverse reactions that occrred in at least % of TIPRI patients and at an incidence greater than sham are presented in Table. Table : Adverse Reactions in Phase 3 Acte titis Externa Trial Adverse Reactions TIPRI (N=7) (N=3) Ear Prrits % % Headache % % titis Media % % Ear Discomfort % 0% 8 USE IN SPECIFIC PPULATINS 8. Pregnancy Risk Smmary Animal reprodction stdies have not been condcted with TIPRI. No adeqate and well-controlled stdies have been performed in pregnant women. Becase of the negligible systemic exposre associated with clinical administration of TIPRI, this prodct is expected to be of minimal risk for maternal and fetal toxicity when administered to pregnant women. 8. Lactation Risk Smmary Ciprofloxacin is excreted in hman milk with systemic administration. However, becase of the negligible systemic exposre after otic application, nrsing infants of mothers receiving TIPRI shold not be affected. 8.4 Pediatric Use The safety and effectiveness of TIPRI for the treatment of pediatric patients (6 months of age and older) with bilateral otitis media with effsion ndergoing tympanostomy tbe placement was established in 530 patients who participated in the Phase 3 trials. The median age of patients enrolled in the clinical trials was.5 years; 6% of patients were 6 months throgh years of age and 38% of patients were greater than years of age [see Adverse Reactions (6.) and Clinical Stdies (4)]. 3 The safety and effectiveness of TIPRI for the treatment of acte otitis externa was established in 67 pediatric patients (3 throgh 7 years of age) who participated in the Phase 3 trial; 57% of patients were 3 throgh years of age and 43% of patients were throgh 7 years of age. The safety and efficacy observed in the pediatric patients was no different from the older poplation. TIPRI is indicated for the treatment of acte otitis externa in pediatric patients 6 months of age and older. [see Indications and Usage (), Dosage and Administration (), Adverse Reactions (6.) and Clinical Stdies (4)]. The safety and effectiveness of TIPRI in infants below 6 months of age have not been established for the treatment of pediatric patients with bilateral otitis media with effsion ndergoing tympanostomy tbe placement and acte otitis externa. 8.5 Geriatric Use Clinical stdies of TIPRI did not inclde sfficient nmbers of patients aged 65 and over to determine whether they respond differently from yonger patients. ther reported clinical experience has not identified differences in responses between the elderly and yonger patients [see Adverse Reactions (6.) and Clinical Stdies (4)]. DESCRIPTIN TIPRI (ciprofloxacin otic sspension) 6% contains the synthetic floroqinolone antibacterial, ciprofloxacin. TIPRI is for intratympanic administration for otitis media with effsion and otic administration to the external ear canal for acte otitis externa. TIPRI is spplied as a white, preservative-free, sterile otic sspension of 6% (w/v) ciprofloxacin in a netral ph, bffered, isotonic soltion in a single-patient se glass vial containing ml. The glass vial is fitted with a stopper not made with natral rbber latex. The inactive ingredients are poloxamer 407, sodim chloride, tromethamine, hydrochloric acid and water for injection (WFI). The thermosensitive sspension exists as a liqid at room temperatre or below and gels when warmed [see How Spplied/Storage and Handling (6)]. Ciprofloxacin has the following nomenclatre: -cyclopropyl-6-floro-,4-dihydro-4-oxo-7-(-piperazinyl)-3-qinolinecarboxylic acid. Its empirical formla is C 7 H 8 FN 3 3 and its moleclar weight is Its chemical strctre is as follows: Figre : Strctre of Ciprofloxacin CLINICAL PHARMACLGY. Mechanism of Action Ciprofloxacin is a floroqinolone antibacterial [see Microbiology (.4)]..3 Pharmacokinetics The plasma concentration of ciprofloxacin following otic administration of TIPRI was not measred..4 Microbiology Mechanism of Action The bactericidal action of ciprofloxacin reslts from interference with the enzyme DNA gyrase, which is needed for the synthesis of bacterial DNA. Resistance Bacterial resistance to floroqinolones can develop throgh chromosomally- or plasmid-mediated mechanisms. In vitro stdies demonstrated cross-resistance between ciprofloxacin and some floroqinolones. There is generally no crossresistance between ciprofloxacin and other classes of antibacterial agents, sch as beta-lactams or aminoglycosides. Antimicrobial Activity Ciprofloxacin has been shown to be active against most isolates of the following bacteria: Gram-positive Bacteria Staphylococcs ares Streptococcs pnemoniae Gram-negative Bacteria Haemophils inflenzae Moraxella catarrhalis Psedomonas aerginosa

5 3 NNCLINICAL TXICLGY 3. Carcinogenesis, Mtagenesis, Impairment of Fertility Eight in vitro mtagenicity tests have been condcted with ciprofloxacin, and the test reslts are listed below: Salmonella/Microsome Test (Negative) Escherichia coli DNA Repair Assay (Negative) Mose Lymphoma Cell Forward Mtation Assay (Positive) Chinese Hamster V79 Cell HGPRT Test (Negative) Syrian Hamster Embryo Cell Transformation Assay (Negative) Saccharomyces cerevisiae Point Mtation Assay (Negative) Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative) Rat Hepatocyte DNA Repair Assay (Positive) Ths, of the 8 in vitro tests were positive, bt reslts of the following 3 in vivo test systems gave negative reslts: Rat Hepatocyte DNA Repair Assay Microncles Test (Mice) Dominant Lethal Test (Mice) Long-term carcinogenicity stdies in mice and rats have been completed for ciprofloxacin. After daily oral doses of 750 mg/kg in mice and 50 mg/kg in rats (for mice and rats respectively, approximately 300 and 00 times the maximm recommended clinical dose of ototopical ciprofloxacin based pon body srface area, assming total absorption of ciprofloxacin from the ear of a patient treated with TIPRI) were administered for p to years, there was no evidence that ciprofloxacin had any carcinogenic or tmorigenic effects in these species. Fertility stdies performed in rats at oral doses of ciprofloxacin p to 00 mg/kg/ day revealed no evidence of impairment. This wold be approximately 80 times the maximm recommended clinical dose of ototopical ciprofloxacin based pon body srface area, assming total absorption of ciprofloxacin from the ear of a patient treated with TIPRI. 3. Animal Toxicology and/or Pharmacology Ginea pigs dosed in the middle ear with TIPRI exhibited no drg-related strctral or fnctional changes of the cochlear hair cells. 4 CLINICAL STUDIES 4. Bilateral titis Media with Effsion Two randomized, mlticenter, sham-controlled clinical trials in 53 pediatric patients with bilateral otitis media with effsion ndergoing myringotomy with tympanostomy tbe placement evalated the safety and efficacy of TIPRI when administered intratympanically as a single dose (NCT and NCT 09494). The median age of patients enrolled in the clinical trials was.5 years; 6% of patients were 6 months throgh years of age and 38% of patients were greater than years of age. The efficacy endpoint for both trials was the cmlative proportion of stdy treatment failres throgh Day 5, defined as the occrrence of any of the following events: otorrhea as determined by a blinded assessor on or after 3 days post-srgery, otic or systemic antibacterial drg se for any reason any time post-srgery, as well as patients who missed visits or were lost-to-follow-p. Table 3 presents the reslts from each Phase 3 trial. Table 3: Cmlative Proportion of Treatment Failres Throgh Day 5 in Phase 3 Trials (titis Media with Effsion) TIPRI Treatment Failre 5% (44/79) Reason for Failre Trial (N=66) 45% (39/87) Difference ( TIPRI) TIPRI 0% % (8%, 3%) (38/78) Trial (N=66) 45% (40/88) torrhea 7% % 7% 7% tic antibacterial drgs Systemic antibacterial drgs Lost-to-follow-p and missed visit 6% 7% 5% 8% % 5% 3% 3% 0% % 6% 7% Difference ( TIPRI) 4% (%, 36%) the earliest occrring treatment failre event, and patients were classified as a treatment failre de only to that component for the remainder of the stdy P-vale <0.00 for Cochran-Mantel-Haenszel test (adjsted for age-grop) Administration of TIPRI did not lead to impairment in hearing fnction, middle ear fnction or tbe patency by Day Acte titis Externa ne randomized mlticenter, sham-controlled clinical trial in 6 pediatric and adlt patients with nilateral or bilateral acte otitis externa was designed to evalate the safety and efficacy of TIPRI when administered by a healthcare professional as a single dose to the external ear canal to patients aged 6 months and older (NCT ). The median age of patients enrolled in the clinical trials was 34 years; 6% of patients were 3 to 7 years of age, 65% of patients were 8 to 64 years of age, and 8% of patients were greater than 65 years of age. No patients less than 3 years of age were enrolled. The primary efficacy endpoint was the proportion of patients with clinical response at Day 8. Clinical response was defined as the complete absence of signs and symptoms of acte otitis externa (i.e., tenderness, erythema, edema, and otorrhea as determined by the blinded assessor), and no concomitant systemic or topical antibacterial drg (given in the stdy ear) was taken for any reason at or prior to the stdy visit. Table 4 contains the proportions of patients with clinical response at Day 8 in both the intent to treat (ITT) poplation which contains all sbjects who were randomized and did not have grop A streptococci cltred on Day and the microbiological ITT poplation which contains all ITT sbjects who had a positive cltre for S. ares or P. aerginosa on Day. Table 4: Proportion of Patients with Clinical Response at Stdy Day 8 (Acte titis Externa) Stdy Poplation TIPRI % Difference (TIPRI - ) Intention to Treat (ITT) 69% N=60 90/30 Microbiological ITT (Mic-ITT) 60% N=08 3/5 46% 60/30 34% 9/56 3. (0.66, 34.6) 5.7 (6.57, 43.3) p<0.00 from a Fisher s exact test. p=0.0 from a Fisher s exact test. ITT poplation = all patients who were randomized and did not have grop A streptococci cltred on Day. Mic-ITT poplation = all ITT patients who had a positive cltre for S. ares or P. aerginosa on Day. 6 HW SUPPLIED/STRAGE AND HANDLING TIPRI is a sterile, preservative-free, otic sspension of 6% (60 mg/ml, w/v) ciprofloxacin in a netral ph bffered, isotonic soltion containing poloxamer 407. Each TIPRI carton contains ml of 6% (60 mg/ml, w/v) ciprofloxacin in a ml single-patient se glass vial fitted with a stopper not made with natral rbber latex. (NDC ) TIPRI shold be stored at to 8 C (36 to 46 F) ntil prior to se to prevent thickening dring preparation. Protect from light. Store in the original carton ntil dose preparation. 7 PATIENT CUNSELING INFRMATIN Advise patients and their caregiver(s) that there may be drainage from the ear the first few days following ear tbe srgery, bt if the ear becomes painfl, or continos ear discharge is noted, or the patient develops a fever, advise patients and their caregiver(s) to conslt their physician. For acte otitis externa, advise patients and/or their caregivers that if the ear contines to be painfl, swollen or itchy after a week, they shold conslt their physician. Distribted by: tonomy, Inc. San Diego, CA 9 TIPRI is a registered trademark of tonomy. U.S. Patent Nos: 8,38,87, 9,05,048, 9,0,796, 9,33,068, 9,486,405, and 9,603,796 TI