pjs
★    

India,
2015-07-30 08:55
(2271 d 18:47 ago)

Posting: # 15173
Views: 10,002
 

 Nitrofurantoin BE study [Regulatives / Guidelines]

Dear all,

we are developing Nitrofurantoin oral suspension for EMA submission.

As per OGD SD fed study is required. As per RLD (Furadantin oral suspension) Furadantin should be given with food to improve drug absorption and, in some patients, tolerance.

In literature there has been mention of the food effect. BA is reported to enhance by 20% to 400% when taken with food.

For other dosage form (capsule) of the Nitrofurantoin both fed and fasting studies have been submitted in the published UKPAR. The innovator Smpc suggest “The dose should be taken with food or milk.”

Now in the Smpc of the innovator of oral suspension (Furadantin) in pososlogy there is no specific mention of the drug intake with food. The statements included are “Gastrointestinal reactions may be minimised by taking the drug with food or milk, or by adjustment of dosage.” And “Increased absorption with food or agents delaying gastric emptying.” As per PIL “Nitrofurantoin Oral Suspension should be taken with food or milk.”

For generic submission in EMA which study should be conducted fasting or fed or both?

Regards,
PJS
drgunasakaran1
★★  
avatar

2015-08-02 14:56
(2268 d 12:46 ago)

@ pjs
Posting: # 15178
Views: 8,377
 

 Nitrofurantoin BE study

Dear Mr PJS,

» Now in the Smpc of the innovator of oral suspension (Furadantin) in pososlogy there is no specific mention of the drug intake with food. The statements included are “Gastrointestinal reactions may be minimised by taking the drug with food or milk, or by adjustment of dosage.” And “Increased absorption with food or agents delaying gastric emptying.” As per PIL “Nitrofurantoin Oral Suspension should be taken with food or milk.”
»
» For generic submission in EMA which study should be conducted fasting or fed or both?

EMA's Guideline on the Investigation of Bioequivalence states that "For products where the SmPC recommends intake of the reference medicinal product only in fed state, the bioequivalence study should generally be conducted under fed conditions."
Since SmPC of Furadantin states that “Gastrointestinal reactions may be minimised by taking the drug with food or milk, or by adjustment of dosage", I feel that you can conduct the study under fed conditions providing the above SmPC justification".

Dr S Gunasakaran MBBS MD
Disclaimer: The replies/posts are my personal opinions and it does not represent my company views on the same.
pjs
★    

India,
2015-08-03 10:06
(2267 d 17:36 ago)

@ drgunasakaran1
Posting: # 15180
Views: 8,302
 

 Nitrofurantoin BE study

Dr.S.Gunasakaran,


Thanks for the response.

I also think the study should be conducted under fed condition. However for capsule of the same innovator, generic company has conducted both fed and fasted study UKPAR.

Guideline also states “SmPC recommends intake of the reference medicinal product on an empty stomach or irrespective of food intake, the bioequivalence study should hence be conducted under fasting conditions. For products where the SmPC recommends intake of the reference medicinal product only in fed state, the bioequivalence study should generally be conducted under fed conditions.” Also Gastrointestinal reactions may also be minimised by adjustment of dosage and concomitant food intake is not necessary. As there is no mention that the product should be taken only with food i am confused.

Also as per the steps taken for assessment section in the mentioned UKPAR, the approval process has taken longer duration than usual for national submission. There could so many possible reasons for this delay in the approval but one of the reason could be deficiency regarding the type of the study fasting/fed conducted initially by applicant and opposite study required by the regulatory agency.

Regards,
PJS
pjs
★    

India,
2015-08-07 04:10
(2263 d 23:32 ago)

@ pjs
Posting: # 15190
Views: 8,017
 

 Nitrofurantoin BE study

Dear all,

I have another question regarding the study design.

As per BE guideline, “A statistical evaluation of tmax is not required. However, if rapid release is claimed to be clinically relevant and of importance for onset of action or is related to adverse events, there should be no apparent difference in median tmax and its variability between test and reference product.”

Now nitrofurantoin is indicated for the treatment of and prophylaxis against acute or recurrent, uncomplicated lower urinary tract infections or pyelitis either spontaneous or following surgical procedures. SMPC

As per my understanding rapid release is not clinically relevant in this case (generally applied for analgesic drugs) and statistical evaluation of tmax is not required.

Now what if this test is performed and apparent difference is cited for tmax. But BE criteria Cmax and AUC fulfilled? This will lead to deficiency from the agency.

Please suggest statistical evaluation of tmax is required in this BE study or not.

Regards,
PJS
pjs
★    

India,
2015-08-27 15:36
(2243 d 12:06 ago)

@ pjs
Posting: # 15359
Views: 7,812
 

 Nitrofurantoin BE study

Dear all,

Apologies for the consecutive post.

» Please suggest statistical evaluation of tmax is required in this BE study or not.

Pls share your views for the mentioned.

How to decide what is clinically relevant and what is not?

What is the usual practice? to keep the Statistical evalution of Tmax or not?

What justification can be given if statistically significant diff is found between Tmax of test and ref but BE criteria is fulfilled in terms of Cmax nad AUC.

Regards,
PJS
Dr_Dan
★★  

2015-08-28 09:15
(2242 d 18:27 ago)

@ pjs
Posting: # 15361
Views: 7,603
 

 Nitrofurantoin BE study

Dear PJS
You already gave the answer yourself to your question regarding the possible request of statistical evaluation of tmax: rapid release is not clinically relevant in this case and statistical evaluation of tmax is not required. Why be so afraid? tmax is no primary parameter and of course you have to present descriptive statistics but nothing more. Orally administered Nitrofurantoin is readily absorbed in the upper gastrointestinal tract and if there are significant differences in tmax between your formulation and the originator you may fail to demonstrate BE for Cmax.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
pjs
★    

India,
2015-08-28 10:37
(2242 d 17:05 ago)

@ Dr_Dan
Posting: # 15362
Views: 7,637
 

 Nitrofurantoin BE study

Dear Dr_Dan,

Many thanks for your suggestion.

As a sponsor we have recieved some BE protocols of diff products from the CRO for review. The usual practice of the CRO is that they analyse median difference of Tmax by nonparametric Wilcoxon test for all the Products. As per my understanding this evaluation is only necessary in case of clinical relevance and should not be included in all the protocols. But i am confused what to consider clinically relevant and what not. I think analgesic drugs fall under this catgory but what about other class of drugs?

I am afarid if the sample size is small in the study, then smaller diff between test and ref product Tmax may come as statistically significant although BE criteria may be fulfilled for AUC and Cmax (is this possible or if there is statistically significant diff between Tmax then Cmax must fail BE criteria).

Regards
PJS
Dr_Dan
★★  

2015-08-31 18:19
(2239 d 09:23 ago)

@ pjs
Posting: # 15369
Views: 7,326
 

 Nitrofurantoin BE study

Dear PJS
Tmax is a secondary endpoint and undergoes only descriptive statistics.
Don´t try to answer questions nobody asked. So keep the study protocol as simple as it needs to be and if a authority raises questions regarding tmax you can still make up your mind. Without knowing the study outcome it is useless to discuss whether differences are clinically relevant and/or statistically significant.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
AB661
☆    

India,
2021-06-15 09:38
(124 d 18:04 ago)

@ Dr_Dan
Posting: # 22412
Views: 1,020
 

 Nitrofurantoin BE study

Dear All,

OGD BE recommendation recently updated. As per New guidance there are two studies ( fasting & Fed) need to be performed. Earlier only fasting study recommended. In current guidance for Dose of Suspension for BE study not mentioned. Whether BE Study to be performed with 25 mg ( 5mL) or 100 mg ( 20 mL ) ?



With regards
AB661
Relaxation
★    

Germany,
2021-06-15 12:10
(124 d 15:32 ago)

@ AB661
Posting: # 22413
Views: 981
 

 Nitrofurantoin BE study

Hi.

For the interested, the current (draft:-)) version of PSG_009175 is dated May 2021.

»Whether BE Study to be performed with 25 mg ( 5mL) or 100 mg ( 20 mL ) ?

For both, fasted and fed trial given in the product-specific BE guidance:
Strength: 25 mg; 5 mL

Best regards.
AB661
☆    

India,
2021-06-16 08:13
(123 d 19:29 ago)

@ Relaxation
Posting: # 22415
Views: 933
 

 Nitrofurantoin BE study

Dear Sir,

In Current recommendation only strength is mentioned. Dose is not mentioned. Nitrofurantoin have low plasma concentration. Considering sensitivity of bioanalytical method dose should be mentioned.

With regards
AB
Relaxation
★    

Germany,
2021-06-16 12:59
(123 d 14:43 ago)

@ AB661
Posting: # 22417
Views: 914
 

 Nitrofurantoin BE study

Hi AB661.

You are right. I was to quick and as they stated "Strength: 25 mg; 5 mL" and not "Strength: 25 mg/5 mL" this appeared to me as a dose recommendation. Should have checked the SmPC :-(

I personally would search for the standard highest dose (which is 100 mg here according to the SmPC, right), but you may want to check initially whether exposure is proportional to dose, discuss which dose actually is needed to have sufficient concentrations with the analytical method (or if the method can be improved rather than discuss supra-therapeutic doses) and which dose is acceptable in healthy subjects for safety reasons.

Best regards!
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