Objectives: To evaluate Rytmonorm in children with ventricular and supraventricular tachycardia

Transcription

1 Synopsis Sponsor: BASF Pharma Clinical Research and Development Cardiology/Nephrology Department Title: Efficacy and tolerability of Rytmonorm 0 mg sugar-coated tablets in children: Results of a multicenter trial Name of Active Ingredient: Rytmonorm (propafenone) Investigators: On file Study Site: sites in Germany Publication based on study: Not applicable Study Period: Not available Objectives: To evaluate Rytmonorm in children with ventricular and supraventricular tachycardia Methodology: In a multicenter study involving study sites based throughout the Federal Republic of Germany, a total of 35 children aged between day and.8 years (mean age 5.7 years) with ventricular and supraventricular tachycardia of various causes were treated with Rytmonorm 0 mg sugar-coated tablets and followed up. The trial protocol proposed a titration period - with documentation of all cross analysis procedures - followed by weekly follow-ups until the end of week 4; then another 2 months of follow-up. At treatment follow-up in Months 2 and 3, the visit intervals were chosen to suit local conditions. Where parenteral administration of Rytmonorm was necessary initially, it did not affect assessibility of subsequent oral Rytmonorm therapy. In 4 cases, antiarrhythmic therapy

2 was initiated with an intravenous dose of Rytmonorm at a dose level of to 2.5 mg/kg body weight. The protocol specified 3 times daily dosing with oral Rytmonorm. Based on prior experience, the initial dose was set at 2 22 mg/kg daily. In PSVT, atrial fibrillation/flutter and VT, response to treatment was rated on the basis of the following criteria depending on the incidence and duration of the episodes: Incidence: more frequent, unchanged, less frequent, resolved Duration: longer, unchanged, shorter In SVPBs and VPBs, incidence was rated on the basis of the following criteria depending on reduction in the number of VPBs: Very good Good Unsatisfactory = 80-00% reduction = 50 - < 80% reduction = < 50% reduction LOWN classification was used in addition to rate treatment response in VPB patients who underwent Holter monitoring. Special attention was paid to documenting all observed side effects and findings outside normal limits (e.g. lab values). Number of Subjects: 35 children Diagnosis and Main Criteria for Inclusion: Children with ventricular and supraventricular tachycardia of various causes Baseline Demographics and Other Relevant Characteristics: Table shows gender and age distribution, the children's weights with lower and upper limits, and the s administered. Diagnosed rhythm disorders are given in Table 2. Secondary cardiac diagnoses are listed in Table 3. 2

3 Table. Age,, Weight and Dose Distribution in the Total Population Age Male Female Min Max Min Max day year > year 5 years >5 years 0 years >0 years Table 2. Rhythm Disorders Diagnostic groups ) Ventricular premature beats 2) PSVT, SVT, SV tachyarrhythmia, atrial flutter 3) VT, paroxysmal VT, AV node tachycardia 4) SVPBs 5) LGL syndrome Number of patients (multiple mentions) Note: This distribution attempt is tentative as overlaps and combinations of different types of arrhythmia did not allow clear cut grouping of the cases in question. Table 3. Secondary Cardiac Diagnoses Diagnoses Rashkind procedure, Mustard OP (correction of transposition of the great arteries) Cardiomyopathy Ventricular septal defect + resection of infundibular pulmonary stenosis Myocarditis Valvular aortic stenosis Tetralogy of Fallot (operated) Number of Patients 3 Table 4 shows age, gender and weight distribution and minimum and maximum daily s administered to the 5 children diagnosed with VPBs. 3

4 Table 4. Age,, Weight and Dose Distribution of the Children in Group Age Male Female Min Max Min Max day year > year 5 years >5 years 0 years >0 years Table 5 shows age, gender and weight distribution as well as minimum and maximum daily s administered to the 6 children diagnosed with paroxysmal supraventricular tachycardia, supraventricular tachycardia, supraventricular tachyarrhythmia and atrial flutter. Table 5. Age, Weight and Dose Distribution of the Children in Group 2 Age Male Female Min Max Min Max day year > year 5 years >5 years 0 years >0 years Table 6 shows age, gender and weight distribution as well as maximum and minimum daily s administered to the 9 children diagnosed with ventricular tachycardia, paroxysmal ventricular tachycardia and AV node tachycardia. Table 6. Age,, Weight and Dose Distribution of the Children in Group 3 Age Male Female Min Max Min Max day year >5 years 0 years

5 Table 7 shows age, gender and weight distribution as well as maximum and minimum daily s administered to the 4 children diagnosed with supraventricular premature beats. Table 7. Age,, Weight and Dose Distribution of the Children in Group 4 Age Male Female Min Max Min Max day year >5 years 0 years Table 8 shows age, gender and weight distribution as well as maximum and minimum daily s administered to the 3 children diagnosed with LGL syndrome. Table 8. Age,, Weight and Dose Distribution of the Children in Group 5 Age Male Female Min Max Min Max day year >5 years 0 years Summary of Results: Efficacy Results The results of Rytmonorm therapy in this population of 35 patients are summarized by main diagnosis (Table 2) and commented below. Group : Treatment response in the 5 patients with VPBs at Week 4 of treatment can be summarized as follows. Response to treatment was described as very good in 2 cases and good in 2 cases. Response to Rytmonorm 0 mg sugar-coated tablets was unsatisfactory in one patient and treatment was discontinued at 6 weeks (this patient had fenoterol cardiomyopathy). 5

6 At Month 3, a "very good" treatment response rating was given for 3 patients. No information was provided for one patient with a good response in the previous rating. Holter monitoring was performed in 5 patients in this group. All patients had been classified as having Lown Grade III arrhythmia prior to treatment. After 4 weeks of Rytmonorm therapy, 3 were moved down to Grade 0, and 2 were moved down to Grade I. Group 2: Treatment response in the 6 patients in Group 2 at 4 weeks can be summarized as follows. Arrhythmia did not recur in cases. Arrhythmia episodes were less frequent and of shorter duration in 2 patients. In one patient, arrhythmia disappeared after 3 weeks of Rytmonorm treatment but recurred in Week 4. Rytmonorm therapy was discontinued after 7 weeks in this patient and after 4 and 0 days in another 2 patients due to unsatisfactory response. At 3 months, 9 of the above-mentioned patients were still arrhythmia-free. The other 2 patients experienced recurrence of arrhythmia, but the episodes were less frequent and shorter than prior to Rytmonorm treatment. In the remaining 2 patients whose arrhythmia episodes had become less frequent and shorter, the situation remained unchanged. Group 3: Treatment response in the 9 patients in Group 3 at Week 4 of treatment can be summarized as follows. 7 patients were arrhythmia-free. In one patient, the arrhythmia was less frequent and the episodes shorter. In another patient, treatment had to be discontinued on the first day due to block development. At 3 months, 6 patients were arrhythmia-free. The patient whose arrhythmia episodes had become less frequent and shorter no longer had arrhythmia. In another 2 patients whose arrhythmia had disappeared, the condition recurred. However, the episodes were less frequent and shorter in one of those patients. In the other, the episodes were the same as before Rytmonorm treatment. 6

7 Group 4: Treatment response in the 4 patients in Group 4 at Week 4 of treatment can be summarized as follows: Treatment response was rated "very good" in all 4 cases. At Month 3, evaluation of treatment response still yielded very good outcomes in 3 patients, but one patient who had previously had a very good response was now found to have a good response. Group 5: Treatment response in the 3 patients in Group 5 at Week 4 of treatment can be summarized as follows: Arrhythmia episodes were shorter in 2 cases; in one case, they had ceased. In the 2 cases, the effect of Rytmonorm on the number of VPBs was described as good. At Month 3, arrhythmia had ceased in one patient who was said in the previous rating to have had shorter episodes, moreover the effect on the number of VPBs, previously rated good, was now rated as very good. The condition of the other 2 patients remained unchanged from the end of Week 4. Safety Results In the population of 35 children described here, Rytmonorm therapy had to be discontinued due to unsatisfactory response in only 4 cases. Adverse reactions during Rytmonorm therapy occurred in 8 patients. Table 9 shows all data in relation to the observed side effects. 7

8 Table 9. Adverse Drug Reactions Type of side Patient No. effect 4/ Increased AV block, Bradycardia Duration (in days) Severity Countermeasure 7 Not stated Treatment discontinued Rytmonormrelated Not stated 5/4 AV block 3 st degree Treatment discontinued Not stated 0/2 Headache, dizziness 3/ All ECG intervals prolonged 5/ Vomiting, dyspepsia -- Mild Dose reduction Probable -- Not stated None Yes 7 Mild None Probable 7/2 Onset of WPW syndrome when dose increased 4 hours Moderate Treatment discontinued Yes 7/3 Bradycardia Cyanosis 2 hours 2 hours Moderate Moderate Dose reduction -- Yes Bradycardia was the cause 3/3 Loss of appetite, nausea, vomiting 4 Moderate None Probable The tolerability of Rytmonorm 0 mg sugar-coated tablets was rated "good" by all investigators except in those patients where treatment had to be discontinued. The medicinal products listed in Table 0 were prescribed as concomitant medication during Rytmonorm therapy. No interactions were observed. Nor were food interactions observed. 8

9 Table 0: Concomitant Medication During the Study Product Daily dose, route of administration Number of patients Penicillin Refobacin Digoxin Dociton Methylated digoxin Vitamin D Lenoxin Verapamil Aldactone Lasix Aspirin junior Firobrol suppositories Esberitox Eupatol syrup Mucosolvan solution Prospan 50,000 V i.v. 4 times daily 0 mg i.v. b.i.d. 0. mg p.o. b.i.d. 00 mg p.o mg/day p.o. mg p.o. t.i.d. drop b.i.d. 2 drops b.i.d. (= mg/day) 0.0 mg/kg p.o. (4 drops t.i.d.) 500 M/day 0.7 ml = mg p.o. mg i.v. 8 times daily 50 mg 20 mg once daily 00 mg t.i.d. Conclusions: In terms of kg of body weight, an average oral dose of 2.30 mg/kg body weight in 3-4 divided doses proved to be therapeutically effective in this multicenter study. This initial dose can be reduced by about 20% in many cases and used as a maintenance dose once a definite improvement in the arrhythmia has been ascertained. As shown in this study, the adverse reaction rate is relatively low. Doses in excess of the recommended therapeutic dose may prolong ECG intervals; whereby PR prolongation and QRS widening are key parameters in monitoring Rytmonorm dosage. 9

10 In summary, based on existing experience in children, it can be concluded that Rytmonorm is a highly effective antiarrhythmic agent with a relatively wide therapeutic range, and is suitably well tolerated. It suppresses ventricular and supraventricular cardiac rhythm disorders and causes relatively few side effects. Date of Synopsis: Prepared on 07 Dec 20 for submission to EMA in accordance with Article 45 of Regulation (EC) No 90/2006. Date of original study report: 20 July