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F. No. 04-146/2007-DC
Government of India
Directorate General of Health Services
Central Drugs Standard Control Organization
(FDC Division)
FDA Bhawan, Kotla road,
New Delhi
Dated: 12 0EC 2018
To
All State/UT Drugs Controllers
Subject:- Consideration of the directions of Hon’ble Supreme Court of India in the
case of 294 FDCs in respect of FDCs which require further generation of
data —reg.
Sir,
The office of Drugs Controller General (India) received complaints from Consumer
Associations in year 2007 regarding Fixed Dose Combinations (FDC) not approved by
DCG(|) but marketed in the country. As a part of follow up action of complaints, the office of
DCG(!) prepared a list of 294 FDCs and directions were issued to all State/UT Drugs
Controllers to withdraw these 294 FDCs which were licensed without approval of DCG(I).
The manufacturers association, however, got stay from the Hon’ble High Court of Madras on
the directions issued in the matter.
The matter was then placed in DTAB in the 56" meeting dated 16.01.2008. A Sub-
Committee was constituted by DTAB to examine these FDCs. Accordingly the Sub-
Committee examined these FDCs and submitted its report to the DTAB. DTAB in its meeting
held on 16.02.2015 agreed with the recommendations of Sub-Committee of DTAB. The
Hon'ble Supreme Court as per its judgement dated 15.12.2017 has accepted the
recommendations of DTAB.
As per the recommendations of DTAB, there are 49 FDCs which require further generation
of data in terms of safety and efficacy by conducting clinical trial. The details of these 49
FDCs along with the detailed recommendations of DTAB Sub-Committee are annexed
herewith as Annexure A.
You are requested to direct all concerned manufacturers of the above mentioned 49 FDCs
under your jurisdiction to submit the Clinical Trial protocol/PMS data for obtaining NOC from
this Directorate for further generation of data in terms of safety and efficacy as mentioned
under Annexure A, so that final action can be taken on these FDCs. The study protocols are
required to be submitted in hard copy as well as soft copy(i.e. in CD form) latest by
01.04.2019.
It may be communicated that in case of non-submission, this Directorate reserves the right
to make its decision on the basis of information available before it in light of the judgement of
the Hon’ble Supreme Court.
aii faithfully,
(Dr. S. EsWara Reddy)
Drugs Controller General (India)
Copy for information and necessary action to:-
1. Web site of CDSCO.
2. CDSCO Zonal and Sub-Zonal offices.
3. All Drugs manufacturer association with the request to publicise it widely amongst
their members for submitting the protocol.Annexure-A
S.No. Name of FDC Recommendation of Experts
Aceclofenac+ Committee observed that there are no published data on safety and efficacy of the above mentioned
Paracetamol+ FDCs. Further, muscle reluxant like Chlorzoxazone is generally given for short term use while
Chlorzoxazone paracetamol, diclofenac etc. are administered for longer time period in case of arthritis patients.
Clinical opinion was sought from the clinicians attending the meeting. Although clinician opined in
favour of the above three drugs FDCs based on their experience and information received from the
pharmaceuticals companies, it was concluded that documented evidence in support of clinical safety
and efficacy is necessary. After detailed deliberation, committee recommended that these FDCs can
be considered only for short term use in acute musculoskeletal pain associated with spasms subject to
the condition that statistically powered clinical trials comparing 3 drugs FDC with 2-drug combination of
Chlorzoxazone + Paracetamol is required to be conducted within one year from the date of final
decision on marketing of these FDCs .
Aceclofenac+ 3 drug combination of Serratiopeptidase + Paracetamol + Aceclofenac
Paracetamol+
Serratiopeptidase
/ Diclofenac / Ibuprofen /
Nimesulide needs to be demonstrated to be superior in efficacy than Serratiopeptidase/NSAID +
Paracetamol (2 drug FDC). Since the published data on efficacy of 3 drug FDCs are not available
Clinical opinion was sought from the clinicians attending the meeting. Although the clinicians especially
the practicing Orthopedic surgeons supported the usefulness of serratiopeptidase, it was concluded
that documented evidence complementing the positive clinical experience is necessary. After detailed
deliberation, committee recommended that these FDCs can be considered only for short term use in
acute pain subject to condition that clinical trial data needs to be generated in adequately powered
study comparing 3 drug FDC with 2-drug combination of Serratiopeptidase/NSAID+ Paracetamol
within one year from the date of final decision on marketing of these FDCs .
Further, Dr Y K Gupta and Dr Nilima Kshirsagar suggested that for serratiopeptidase there needs to
be data available substantiating its absorption. This could be in form of documented evidence, and in
absence of same, the industry has to conduct a Study to prove that orally administered
Aceclofenac+ Committee observed that there are no published data on safety and efficacy. Further, muscle reluxant
Paracetamol+ Tizanidine is given for short term use while paracetamol, diclofenac etc. are administered for longer
Tizanidine time period in case of arthritis patients. Although clinician opined in favour of the above three drugs
FDCs based on their experience and information received from the pharmaceuticals companies, it was
concluded that documented evidence in support of clinical safety and efficacy is necessary. After
detailed deliberation, committee recommended that these FDCs can be considered only for short term
use in acute musculoskeletal pain associated with spasms subject to the condition that statistically
powered Clinical trials comparing 3 drugs FDC with 2-drug combination of Tizanidine + Paracetamol is
required to be conducted within one year from the date of final decision on marketing of these FDCs.
Aceclofenac+ Although clinician opined in favour of the above three drugs FDCs based on their experience and
Paracetamol+ information received from the pharmaceuticals companies, it was concluded that documented
Tramadol evidence in support of clinical safety and efficacy is necessary. After detailed deliberation, committee
recommended that this FDCs can be considered only for short term use in acute pain subject to
condition that statistically powered clinical trials comparing 3 drugs FDC with 2-drug combination of
Aceclofenac + Paracetamol is required to be conducted within one year from the date of final decision
on marketing of these FDCs.
Alprazolam+ The committee observed that FDC of Alprazolam + Melatonin (S. No. 31 as per DCG(I) List)is for the
Melatonin treatment of insomnia. However, there is no rationality and scientific evidence available in support of
the formulation. The specialist Dr. Deshpende, (Psychiatrist) from RML Hospital, New Delhi stated that
the combination is not rational for treatment of insomnia/sleep disorders as alprazolam is anxiolytic
drug and it is not used for treatment of insomnia/sleep disorders. Dr Rehan, also agreed with the
opinion of Dr. Deshpande since the evidence are not adequate.
After detailed deliberation the committee opined that clinical trial may be carried out to prove that the
combination is useful in withdrawal of benzodiazepine and also to prove that the combination is useful
in treatment of chronic insomnia.
Alprazolam+ The committee opined that the FDCs may be considered only for acute anxiety disorders. However
Propranolol pharmacokinetics study is required to be carried out to prove that there is no drug-drug interaction
between the individual drugs in the formulation before considering it for the said indication.
Amoxicillin+ FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
Cloxacillin+ Lactic than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
acid bacillus Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.Annexure-A
S.No. Name of FDC Recommendation of Experts
8 Amoxicillin+ The above FDCs were discussed on following lines:
Serratiopeptidase+ |1. Whether Serratiopeptidase is absorbed when taken orally?
Lactobacillus 2. Serratiopeptidase is an enzyme which is known to be degraded in gastrointestinal tract.
Sporogenes
However, one report published in 1994 by Moriya N et al. in Biotechnol App! Biochem 1994
Aug;20(Pt1):101-8 titled “Intestinal absorption of Serratiopeptidase (TSP) in rats” indicates that orally
administered TSP was absorbed from the intestinal tract and transferred into the circulation in an
enzymically active form. However, the cautionary note in this study is that this study was conducted in
rats and no active absorption has been demonstrated in humans.
An article published in 1986 by Koyama A et al. in Jpn J Antibiot. 1986 Mar; 39(3):761-71 titled
“Augmentation by serrapeptase of tissue permeation by cefotiam” shows that there is an improved
penetration of cephalosporin into the tissues. In spite of this, there is no evidence of superiority of the
FDC over Amoxicillin when used alone. Therefore, there is insufficient evidence for adding
Serratiopeptidase to antibiotic. Committee opined that above formulations shall not be permitted
unless clinical evidence is generated.
) Amoxycillin+ FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
Clavulanic acid+ —_|than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Lactic acid bacillus {Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
10 Amoxycillin+ The above FDCs were discussed on following lines:
Cloxacillin+ Lactic |1. Whether Serratiopeptidase is absorbed when taken orally?
acid bacillus+ 2. Serratiopeptidase is an enzyme which is known to be degraded in gastrointestinal tract.
Serrapeptase
However, one report published in 1994 by Moriya N et al. in Biotechnol App! Biochem 1994
Aug;20(Pt1):101-8 titled “Intestinal absorption of Serratiopeptidase (TSP) in rats” indicates that orally
administered TSP was absorbed from the intestinal tract and transferred into the circulation in an
enzymically active form. However, the cautionary note in this study is that this study was conducted in
rats and no active absorption has been demonstrated in humans.
An article published in 1986 by Koyama A et al. in Jpn J Antibiot. 1986 Mar; 39(3):761-71 titled
“Augmentation by serrapeptase of tissue permeation by cefotiam” shows that there is an improved
penetration of cephalosporin into the tissues. In spite of this, there is no evidence of superiority of the
FDC over Amoxicillin when used alone. Therefore, there is insufficient evidence for adding
Serratiopeptidase to antibiotic. Committee opined that above formulations shall not be permitted
11 Amoxycillin+ Lactic
acid bacillus FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
12. |Amoxycillin+ FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
Lactobacillus than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
acidophilus+ Further committee recommended that a PMS data on incidence of prevention of diarrhea and
Flucloxacillin opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
Sodium also be submitted in this regard. If not, phase IV trial is required to be conducted.
1S Amoxycillin+ The above FDCs were discussed on following lines:
Serratiopeptidase |1. Whether Serratiopeptidase is absorbed when taken orally?
2. Serratiopeptidase is an enzyme which is known to be degraded in gastrointestinal tract.
However, one report published in 1994 by Moriya N et al. in Biotechnol App! Biochem 1994
Aug;20(Pt1):101-8 titled “Intestinal absorption of Serratiopeptidase (TSP) in rats” indicates that orally
administered TSP was absorbed from the intestinal tract and transferred into the circulation in an
enzymically active form. However, the cautionary note in this study is that this study was conducted in
rats and no active absorption has been demonstrated in humans.
An article published in 1986 by Koyama A et al. in Jpn J Antibiot. 1986 Mar; 39(3):761-71 titled
‘Augmentation by serrapeptase of tissue permeation by cefotiam” shows that there is an improved
penetration of cephalosporin into the tissues. In spite of this, there is no evidence of superiority of the
FDC over Amoxicillin when used alone. Therefore, there is insufficient evidence for adding
Serratiopeptidase to antibiotic. Committee opined that above formulations shall not be permittedAnnexure-A
S.No. Name of FDC Recommendation of Experts
14. |Ampicillin+
Cloxacillint Lactic |FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
acid bacillus than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
15 = |Ampicillin+ Lactic
acid bacillus FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
16 Calcium Dr. S. K. Acharya, the expert from AIIMS, New Delhi opined that there is no documented evidence in
dobesilate+ support of safety and efficacy for these combination products. After detailed deliberation, committee
Decusate sodium recommended that well designed clinical trials in adequate number of patients need to be conducted.
Clinical trial protocol should be developed in consultation with the experts.
17 Calcium Dr. S. K. Acharya, the expert from AIIMS, New Delhi opined that there is no documented evidence in
dobesilate+ support of safety and efficacy for these combination products. After detailed deliberation, committee
Lignocaine recommended that well designed clinical trials in adequate number of patients need to be conducted.
Clinical trial protocol should be developed in consultation with the experts.
18 Calcium This is a three drug combination with specific indication for symptomatic relief from painful itching
dobesilate+ hemorrhoids and inflammation. There is only one study available w.r.t. local application of calcium
Lignocaine+ Dobesilate in symptomatic relief of hemorrhoids. Calcium Dobesilate for oral has been approved by
Hydrocortisone DCG(I) however the topical use of Calcium Dobesilate is not approved. There is no published study
also for safety and efficacy of Calcium Dobesilate + Lignocaine + Hydrocortisone. FDC is not
approved anywhere except Ethiopia. However, there is one study where the 3 drug combination is
available with dexamethasone which is also a steroid and is published in journal GEN 1995; 49(4) 296-
302. The traceability of journal as on date could not be identified. Although the journal is pub med
indexed, however the full form of the journal could not be traced. This study is on 40 subjects, which is
inadequate. The study results shows 2 arms study, one arm with calcium Dobesilate and other without
calcium Dobesilate and it had no significant difference (i.e. 88% vs. 85.5% only). The concluding line
of abstract available says that both the formulation were innocuous.
With the above information the committee felt that the
1. Calcium Dobesilate is not approved as topical by DCG(I)
2. There is no evidence of increase enhanced efficacy by addition of Calcium Dobesilate
3. The only study available is inadequate to arrive at a statistical significance.
Therefore, there is no significant evidence to justify the rationality of the FDC and hence a properly
designed Clinical Trial is required in a statistical significant number of subjects.
19 Calcium Dr. S. K. Acharya, the expert from AIIMS, New Delhi opined that there is no documented evidence in
Dobesilate+ support of safety and efficacy for these combination products. After detailed deliberation, committee
Troxerutin recommended that well designed clinical trials in adequate number of patients need to be conducted.
Clinical trial protocol should be developed in consultation with the experts.
20 Cefadroxyl+ Lactic
acid bacillus FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
21 Cefadroxyl+ The committee discussed at length for the benefits of Probenecid with Cephalosporins and also noted
Probenecid from literature that this combination can reduce dose of Probenecid if combined with Cephalosporins.
Probenecid has many side effects like kidney stones, polyuria etc.
The committee opined that this FDC is rational, however a good scientific pharmacokinetic study must
be done to find out dose determination for Probenecid + Cephalosporins in infections where it is
indicated for skin and soft tissue infection, UTI, URTI since the dose titration & subsequent reduction
is also of equal importance.Annexure-A
S.No. Name of FDC Recommendation of Experts
22 Cefdinir+ Lactic FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
acid bacillus than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
23 Cefixime+ Lactic FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
acid bacillus than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
24 Cefixime+
Lactobacillus+ FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
Dicloxacillin than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
25 Cefpodoxime
prozetil+ Lactic FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
acid bacillus than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
26 Cefpodoxime+ FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
Cloxacillin+ than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Lactobacillus Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
27 Cefprozil+
Lactobacillus FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
28 Cefuroxime+ The above FDCs were discussed on following lines:
Serratiopeptidase 1. Whether Serratiopeptidase is absorbed when taken orally?
2. Serratiopeptidase is an enzyme which is known to be degraded in gastrointestinal tract.
However, one report published in 1994 by Moriya N et al. in Biotechnol App! Biochem 1994
Aug;20(Pt1):101-8 titled “Intestinal absorption of Serratiopeptidase (TSP) in rats” indicates that orally
administered TSP was absorbed from the intestinal tract and transferred into the circulation in an
enzymically active form. However, the cautionary note in this study is that this study was conducted in
rats and no active absorption has been demonstrated in humans.
An article published in 1986 by Koyama A et al. in Jpn J Antibiot. 1986 Mar; 39(3):761-71 titled
“Augmentation by serrapeptase of tissue permeation by cefotiam” shows that there is an improved
penetration of cephalosporin into the tissues. In spite of this, there is no evidence of superiority of the
FDC over Amoxicillin when used alone. Therefore, there is insufficient evidence for adding
Serratiopeptidase to antibiotic. Committee opined that above formulations shall not be permitted
29 Cepodoxime+ FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
Cloxacillin+ Lactic than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
acid bacillus Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.Annexure-A
S.No. Name of FDC Recommendation of Experts
30 Chlorzoxazone+ Committee observed that there are no published data on safety and efficacy of the above mentioned
Paracetamol + FDCs. Further, muscle reluxant like Chlorzoxazone is generally given for short term use while
Diclofenac paracetamol, diclofenac etc. are administered for longer time period in case of arthritis patients.
Clinical opinion was sought from the clinicians attending the meeting. Although clinician opined in
favour of the above three drugs FDCs based on their experience and information received from the
pharmaceuticals companies, it was concluded that documented evidence in support of clinical safety
and efficacy is necessary. After detailed deliberation, committee recommended that these FDCs can
be considered only for short term use in acute musculoskeletal pain associated with spasms subject to
the condition that statistically powered clinical trials comparing 3 drugs FDC with 2-drug combination of
Chlorzoxazone + Paracetamol is required to be conducted within one year from the date of final
decision on marketing of these FDCs .
31 Chlorzoxazone+ Committee observed that there are no published data on safety and efficacy of the above mentioned
Paracetamol+ FDCs. Further, muscle reluxant like Chlorzoxazone is generally given for short term use while
Ibuprofen paracetamol, diclofenac etc. are administered for longer time period in case of arthritis patients.
Clinical opinion was sought from the clinicians attending the meeting. Although clinician opined in
favour of the above three drugs FDCs based on their experience and information received from the
pharmaceuticals companies, it was concluded that documented evidence in support of clinical safety
and efficacy is necessary. After detailed deliberation, committee recommended that these FDCs can
be considered only for short term use in acute musculoskeletal pain associated with spasms subject to
the condition that statistically powered clinical trials comparing 3 drugs FDC with 2-drug combination of
Chlorzoxazone + Paracetamol is required to be conducted within one year from the date of final
decision on marketing of these FDCs .
32 Chlorzoxazone+ Committee observed that there are no published data on safety and efficacy of the above mentioned
Paracetamol+ FDCs. Further, muscle reluxant like Chlorzoxazone is generally given for short term use while
Nimesulide paracetamol, diclofenac etc. are administered for longer time period in case of arthritis patients.
Clinical opinion was sought from the clinicians attending the meeting. Although clinician opined in
favour of the above three drugs FDCs based on their experience and information received from the
pharmaceuticals companies, it was concluded that documented evidence in support of clinical safety
and efficacy is necessary. After detailed deliberation, committee recommended that these FDCs can
be considered only for short term use in acute musculoskeletal pain associated with spasms subject to
the condition that statistically powered clinical trials comparing 3 drugs FDC with 2-drug combination of
Chlorzoxazone + Paracetamol is required to be conducted within one year from the date of final
decision on marketing of these FDCs. Additional study to establish hepatic safety needs to be done
within six months from the date of final decision on marketing of this FDC since all the 3 ingredients
are potentially hepatotoxic.
33 Diclofenac+ 3 drug combination of Serratiopeptidase + Paracetamol + Aceclofenac / Diclofenac
Paracetamol+
Serratiopeptidase
/ Ibuprofen /
Nimesulide needs to be demonstrated to be superior in efficacy than Serratiopeptidase/NSAID +
Paracetamol (2 drug FDC). Since the published data on efficacy of 3 drug FDCs are not available
Clinical opinion was sought from the clinicians attending the meeting. Although the clinicians especially
the practicing Orthopedic surgeons supported the usefulness of serratiopeptidase, it was concluded
that documented evidence complementing the positive clinical experience is necessary. After detailed
deliberation, committee recommended that these FDCs can be considered only for short term use in
acute pain subject to condition that clinical trial data needs to be generated in adequately powered
study comparing 3 drug FDC with 2-drug combination of Serratiopeptidase/NSAID+ Paracetamol
within one year from the date of final decision on marketing of these FDCs .
Further, Dr Y K Gupta and Dr Nilima Kshirsagar suggested that for serratiopeptidase there needs to
be data available substantiating its absorption. This could be in form of documented evidence, and in
absence of same, the industry has to conduct a Study to prove that orally administered
34 Diclofenac+ Committee observed that there are no published data on safety and efficacy. Further, muscle reluxant
paracetamol+ Tizanidine is given for short term use while paracetamol, diclofenac etc. are administered for longer
Tizanidine time period in case of arthritis patients. Although clinician opined in favour of the above three drugs
FDCs based on their experience and information received from the pharmaceuticals companies, it was
concluded that documented evidence in support of clinical safety and efficacy is necessary. After
detailed deliberation, committee recommended that these FDCs can be considered only for short term
use in acute musculoskeletal pain associated with spasms subject to the condition that statistically
powered Clinical trials comparing 3 drugs FDC with 2-drug combination of Tizanidine + Paracetamol is
required to be conducted within one year from the date of final decision on marketing of these FDCs.
35 Dicyclomine+ This FDC was stated to be indicated as antispasmodic analgesic whenever there is a risk of gastric
Diclofenac spasm. Committee opined that a three drugs vs. two drugs Clinical Trial is required to be conducted in
Sodium+ a significant number of subjects before considering further.
ParacetamolAnnexure-A
S.No. Name of FDC Recommendation of Experts
36 Dicyclomine+ Dr. S. K. Acharya, the expert from AIIMS, New Delhi opined that there is no documented evidence in
Ranitidine support of safety and efficacy for these combination products. After detailed deliberation, committee
recommended that well designed clinical trials in adequate number of patients need to be conducted.
Clinical trial protocol should be developed in consultation with the experts.
37 Domperidone+ The rationality of the FDC was considered. The FDC of the analgesic and prokinetic /antiemetic
Paracetamol cannot be considered rational for general purpose of any kind of pain except migraine. Migraine is a
specific pain that is frequently associated with nausea and vomiting and therefore sometime antiemetic
is required. It was discussed that combining Domperidone with Analgesic may lead to unnecessary
exposure of Domperidone to patients. The committee felt that a clinical trial is required to be carried
out in this regard and if the manufacturer has evidence of clinical trial, same may also be considered.
38 Domperidone+ The rationale for the FDC was considered. Tramadol is an opoid analgesic and is combined with
Paracetamol+ Paracetamol in cases of severe to moderate pain. Although, Paracetamol and Tramadol have been
Tramadol used for moderate to severe pain with higher efficacy, evidence for use of the FDC in migraine is
lacking.
The clinical evidence is lacking regarding the reduction in incidence of nausea/vomiting when the
combination is used in migraine. Accordingly, a clinical trial is required to be carried out. Committee
therefore felt that evidence needs to be generated to demonstrate:
1. Superiority of combination of Tramadol + Paracetamol + Domperidone vs Tramadol! +Paracetamol
on recommended dose in migraine patients.
2. Beneficial effect of the Domperidone in the combination in all migraine patients.
3. Specific advantages of combining three drugs in this FDC.
However, if the manufacturer has evidence of clinical trial to support the above points, same may also
be considered.
39 Doxycycline+
Lactobacillus FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
40 Drotaverine+ The FDC was discussed in detail. Committee opined that the majority of the conditions of pain may not
Nimesulide require antispasmodic. In some visceral pain where there is requirement of anti-spasmodic, an anti-
inflammatory may not be required. Further, the combination of Drotaverine + Nimesulide has not been
shown to offer any enhanced efficacy. Although there is one study JIMA, 1999, Sept.97(9):398-400
which has shown enhanced efficacy of Diclofenac + Pitofenone fenperivanum.
The members opined that above combinations may likely to be misused in larger situations and will
increase the probability of side effects of individual drugs. Committee also noted that Nimesulide has
been banned because of adverse risk profile in children. In adults, the drug is under focus
pharmacovigilance. Therefore the only indication of Dysmennorhea and colic pain were discussed in
detail and members opined that sequential need basis treatment is appropriate wherever required. If
and when the firm produce a data of increased therapeutic benefit of FDC through literature or by way
of generating data, the combination can be reconsidered.
All members agreed that this combination is not rational for all pain. Committee also opined that
above FDCs can be considered only for one indication i.e. dysmennorhea. However, the data of
superior efficacy should be generated.
a1 Drotaverine+ The FDC was discussed in detail. Committee opined that the majority of the conditions of pain may not
Paracetamol require antispasmodic. In some visceral pain where there is requirement of anti-spasmodic, an anti-
inflammatory may not be required. Further, the combination of Drotaverine + Nimesulide has not been
shown to offer any enhanced efficacy. Although there is one study JIMA, 1999, Sept.97(9):398-400
which has shown enhanced efficacy of Diclofenac + Pitofenone fenperivanum.
The members opined that above combinations may likely to be misused in larger situations and will
increase the probability of side effects of individual drugs. Committee also noted that Nimesulide has
been banned because of adverse risk profile in children. In adults, the drug is under focus
pharmacovigilance. Therefore the only indication of Dysmennorhea and colic pain were discussed in
detail and members opined that sequential need basis treatment is appropriate wherever required. If
and when the firm produce a data of increased therapeutic benefit of FDC through literature or by way
of generating data, the combination can be reconsidered.
All members agreed that this combination is not rational for all pain. Committee also opined that
above FDCs can be considered only for one indication i.e. dysmennorhea. However, the data of
superior efficacy should be generated.Annexure-A
S.No. Name of FDC Recommendation of Experts
42 Ibuprofen+ 3 drug combination of Serratiopeptidase + Paracetamol + Aceclofenac
Paracetamol+
Serratiopeptidase
/ Diclofenac / Ibuprofen /
Nimesulide needs to be demonstrated to be superior in efficacy than Serratiopeptidase/NSAID +
Paracetamol (2 drug FDC). Since the published data on efficacy of 3 drug FDCs are not available
clinical opinion was sought from the clinicians attending the meeting. Although the clinicians especially
the practicing Orthopedic surgeons supported the usefulness of serratiopeptidase, it was concluded
that documented evidence complementing the positive clinical experience is necessary. After detailed
deliberation, committee recommended that these FDCs can be considered only for short term use in
acute pain subject to condition that clinical trial data needs to be generated in adequately powered
study comparing 3 drug FDC with 2-drug combination of Serratiopeptidase/NSAID+ Paracetamol
within one year from the date of final decision on marketing of these FDCs .
Further, Dr Y K Gupta and Dr Nilima Kshirsagar suggested that for serratiopeptidase there needs to
be data available substantiating its absorption. This could be in form of documented evidence, and in
absence of same, the industry has to conduct a study to prove that orally administered
43 Lincomycin+ FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
Lactobacillus than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
44 Nimesulide+ 3 drug combination of Serratiopeptidase + Paracetamol + Aceclofenac
Paracetamol+
Serratiopeptidase
/ Diclofenac / Ibuprofen /
Nimesulide needs to be demonstrated to be superior in efficacy than Serratiopeptidase/NSAID +
Paracetamol (2 drug FDC). Since the published data on efficacy of 3 drug FDCs are not available
clinical opinion was sought from the clinicians attending the meeting. Although the clinicians especially
the practicing Orthopedic surgeons supported the usefulness of serratiopeptidase, it was concluded
that documented evidence complementing the positive clinical experience is necessary. After detailed
deliberation, committee recommended that these FDCs can be considered only for short term use in
acute pain subject to condition that clinical trial data needs to be generated in adequately powered
study comparing 3 drug FDC with 2-drug combination of Serratiopeptidase/NSAID+ Paracetamol
within one year from the date of final decision on marketing of these FDCs .
Further, Dr Y K Gupta and Dr Nilima Kshirsagar suggested that for serratiopeptidase there needs to
be data available substantiating its absorption. This could be in form of documented evidence, and in
absence of same, the industry has to conduct a study to prove that orally administered
45 Ofloxacin+ Lactic FDC of Antibiotics with Lactobacillus is not irrational however Lactic Acid Bacillus should be not less
acid bacillus than 5 billion daily dose for adults. A cautionary note for pregnant/lactation women should be added.
Further committee recommended that a PMS data on incidence of prevention of diarrhea and
opportunistic infections (clostridium) be generated in 2 years of time. However, published data may
also be submitted in this regard. If not, phase IV trial is required to be conducted.
46 Ondansetron+ Dr. S. K. Acharya, the expert from AIIMS, New Delhi opined that there is no documented evidence in
Ranitidine support of safety and efficacy for these combination products. After detailed deliberation, committee
recommended that well designed clinical trials in adequate number of patients need to be conducted.
Clinical trial protocol should be developed in consultation with the experts.
47 Propranolol+ The committee opined that the FDCs may be considered only for acute anxiety disorders. However
Diazepam pharmacokinetics study is required to be carried out to prove that there is no drug-drug interaction
between the individual drugs in the formulation before considering it for the said indication.
48 Tizanidine+ Committee observed that there are no published data on safety and efficacy. Further, muscle reluxant
Nimesulide+ Tizanidine is given for short term use while paracetamol, diclofenac etc. are administered for longer
Paracetamol time period in case of arthritis patients. Although clinician opined in favour of the above three drugs
FDCs based on their experience and information received from the pharmaceuticals companies, it was
concluded that documented evidence in support of clinical safety and efficacy is necessary. After
detailed deliberation, committee recommended that these FDCs can be considered only for short term
use in acute musculoskeletal pain associated with spasms subject to the condition that statistically
powered Clinical trials comparing 3 drugs FDC with 2-drug combination of Tizanidine + Paracetamol is
required to be conducted within one year from the date of final decision on marketing of these FDCs.
49 Torsemide+ The representative from the association informed that it is used as congestive heart failure and liver
Spironolactone cirrhosis. The committee opined that the FDC seems to be rational. However, it needs to be justified.
Torsemide is a better drug than furosemide. Potassium loss is taken care by Spironolactone in this
FDC. The committee suggested that PSUR need to be generated with the FDC.