KARNATAK INSTITUTE OF MEDICAL SCIENCES

HUBLI- 21
Department of Pharmacology

Fixed dose combinations (Irrational)

1.Tab Pertenso-N Propranolol hydrochloride 40 mg

HydralazineHCl 25 mg
Bendroflumethiazide 20 mg
2.Tab Betatrop Atenolol 50 mg
Nifedipine (SR) 20 mg
3.Tab Enapril-HT Enalapril 10 mg
Hydrochlorthiazide 25 mg
4.Tab Acezide Captopril 25 mg
Hydrochlorthiazide 25 mg
5.Tab Livogen Captabs Folic acid 750µg
Vit. B12 7.5µg
Ferrous fumarate 200 mg
6.Tab Ampiclox Ampicillin 250 mg
Cloxacillin 250 mg
7.Tab Enteroflox-T Norfloxacin 400 mg
Tinidazole 600 mg
8.Tab Imol Ibuprofen 400 mg
Paracetamol 325 mg
1) Tab. Pertenso -N :
Propranolol hydrochloride…….40 mg
Hydralazine HCl………………25 mg
Bendroflumethiazide………….20 mg

Indication, Dose and Route :

Moderate to severe hypertension. Given orally, start with one tablet once
or twice daily and gradually increase, until control is achieved.
(Max-five tablets per day).
Justification :
This is a combination of β blocker, an arteriolar dilator and a diuretic in
the treatment of moderate to severe hypertension, Combination of drugs
is used to-
1) Prevent side effects
2) To get additive antihypertensive effect.

Hydralazine induced –
1) Salt and water retention is counteracted by Bendroflumethiazide.
2) Tachycardia and palpitations are counteracted by propranolol.

Further the combination of 3 drugs is highly effective as 3 different

parameters affecting BP are reduced viz. cardiac output by propranolol,
peripheral resistance by Hydralazine, plasma volume by
Bendroflumethiazide.
Disadvantages:
However, using these 3 drugs in fixed dose combination has the
following disadvantages-
1) It is NOT possible to alter the dose of any one drug independent of the
other.

2) In case of contraindication to one component the whole preparation is

contraindicated. For instance, as Propranolol is contraindicated in
bronchial asthma, this fixed dose combination preparation cannot be used
in hypertensives having bronchial asthma.

Hence using the 3 drugs in a fixed dose combination is NOT justifiable.

General Comments:
The 3 drugs should be prescribed and taken separately and should NOT
be used in fixed dose combination.

***
2. Tab. Betatrop :
Atenolol…………. 50 mg
Nifedipine (SR) …..20 mg

Indications :
1) Moderate to Severe hypertension.
2) Exertional Angina.

Dose and Route :

Given orally, one tablet daily, increased to two tablets daily if
required.

Justification :
This combination of the cardioselective β1 receptor blocker Atenolol
and the calcium channel blocker, Nifedipine (an arteriolar dilator)
is used as it provides-
1) An additive antihypertensive effect- Atenolol decreases cardiac
output and Nifedipine decreases peripheral resistance.

2) An additive antianginal effect- the 2 drugs decrease myocardial oxygen

requirement by acting through different mechanisms i.e. Atenolol
decreases heart rate and force of contraction by blocking cardiac
β1 receptors.
Nifedipine decreases afterload by dilating arterioles. Further, Atenolol
counteracts nifedipine induced reflex tachycardia and palpitations.
 Disadvantages:
Using the 2 drugs in a fixed dose combination has following
disadvantages:
1) It is NOT possible to alter the dose of one drug independent of the
other.
2) H/O hypersensitivity to any one drug contraindicates the fixed dose
combination tablet.
3) Contraindication to any one drug contraindicates the fixed dose
combination tablet e.g Atenolol is contraindicated in Congestive
cardiac failure, sinus bradycardia, AV blocks, etc. Therefore, this fixed
dose combination tablet cannot be used in hypertensives and patients of
exertional angina having these associated diseases.

Hence using the 2 drugs in a fixed dose combination is NOT justifiable.

General Comments:
The two drugs should be prescribed and taken separately and should
be used in a fixed dose combination form.

***
3) Tab. Enapril - HT : Enalapril ……… 10 mg.
Hydrochlorthiazide ……. 25 mg.

Indication:
1) Moderate to severe hypertension.
2) Congestive Cardiac Failure.

Dose and Route:

Given orally one tablet daily, can be increased to two tablets once daily if
required.

Advantages of using both drugs are:

1) They produce additive effect.
2) Thiazide induced hypokalemia is counteracted by Enalapril.

However using the 2 drugs in fixed dose combination is NOT

justifiable as:

1) It is NOT possible to alter the dose of one drug independent of the other.

2) To avoid first dose severe hypotensive effect of Enalapril, it is usually

started in small doses of 2.5 mg or 5 mg daily and the thiazide diuretic is
usually stopped. The diuretic therapy is restarted later if required.
One cannot take this precaution if fixed dose combination tablet is used.
 3) Enalapril is preferred in hypertensive patients having associated diabetes
mellitus, gout while Hydrochlorothiazide is to be avoided. Therefore
such fixed dose combination tablet cannot be used in patients having
associated diseases like diabetes mellitus and gout.

Contraindications:
1) Pregnancy.
2) Patients with bilateral renal artery stenosis.
3) Patients suffer
4) ing from persistent cough, as it causes dry persistent cough in
approximately 15% of patients.

General Comments:
The two drugs should be prescribed and taken separately and NOT used as
fixed dose combination tablet.

***
 4) Tab. Acezide :
Captopril ………25 mg.
Hydrochlorthiazide …..25 mg.

Indication:
1) Moderate to severe hypertension
2) Congestive cardiac failure

Dose and Route:

One Tablet two to three times a day, orally.

Advantages of using both drugs are:

1) They produce additive effect and
2) Thiazide induced hypokalemia is counteracted by Captopril.

However using the 2 drugs in fixed dose combination is NOT

justifiable as:
1) It is NOT possible to alter the dose of one drug independent of the other.

2) To avoid first dose severe hypotensive effect of Captopril, it is usually

started in small doses of 6.25 mg two or three times a day and the diuretic
is usually stopped. The diuretic therapy is restarted later if required. One
cannot take this precaution if fixed dose combination tablet is used.
 3) Captopril is preferred in hypertensive patients having associated diabetes
mellitus, gout while Hydrochlorothiazide is to be avoided. Therefore
such fixed dose combination tablet cannot be used in patients having
associated diseases like diabetes mellitus and gout. It cannot be used in
patients with COPD and patient suffering from persistent cough.

Contraindications:
1) Pregnancy.
2) Patients with bilateral renal artery stenosis.
3) Patients suffering form persistent cough.

General Comments:
The two drugs should be prescribed and taken separately and NOT used as
fixed dose combination.

***
5) Tab. Livogen Captabs : Folic Acid ……… 750 ug
Vitamin B12 …….. 7.5 ug
Ferrous fumarate …… 200 mg
Indications:
To treat anaemias due to Folic acid, Vitamin B12 and Iron deficiency.
Dose and Route:
One tablet 3 times a day after food, orally.
Using all 3 drugs in a fixed dose combination is NOT justified as:
1) It is rare for a person to suffer from Folic acid, Vitamin B 12 and Iron
deficiency at the same time.

2) If the person is suffering from Iron deficiency anaemia only, then

simultaneous administration of Folic acid and Vitamin B 12 is of no use. It
leads to wastage of drugs and unnecessarily increases the cost of
treatment.

3) If the person is suffering from Vitamin B 12 deficiency only, then

simultaneous administration of Folic acid can prove harmful because
Folic acid diverts Vitamin B12 for erythropoiesis and reduces the
availability of Vitamin B12 for nervous tissue and thus aggravates
peripheral neuritis.
Side Effect:
Constipation or gastrointestinal upsets due to Iron fumarate.

General Comment:
 Depending on the cause of anaemia, a single specific drug should be used
and such type of shotgun therapy using multiple haematinics in fixed dose
combination should be avoided.

6) Cap. Amipiclox : Ampicillin …….250 mg

Cloxacillin …….250 mg

Indications:
Mixed bacterial infections (gram –ve bacilli and penicillinase producing
Staph. aureus), Surgical, Orthopaedic, Respiratory tract, Skin and soft tissue
infections.

Dose and Route:

One capsule four times a day, orally.

Ampicillin – it is effective against all organisms sensitive to Penicillin G i.e.

gram +ve and –ve cocci and gram +ve bacilli. In addition it is also effective
against gram –ve bacilli i.e. E coli, H. influenzae, Proteus, Salmonella and
Shigella. It is NOT effective against organisms which produce penicillinase
as it is destroyed by penicillinase.

Cloxacillin – It is a penicillinase resistant penicillin, effective against

penicillinase producing Staph. aureus. It is NOT effective against gram –ve
bacilli.
Routine use of both drugs in fixed dose combination is NOT
justified as:
1) If the causative organisms are Ampicillin – sensitive gram –ve bacilli and
non penicillinase producing Staph. aureus, then Ampicillin alone is
useful. Co-administration of Cloxacillin is NOT necessary and NOT
justifiable as it only leads to wastage of drug and increases cost of
treatment. Further, Cloxacillin itself induces penicillinase production and
its use should therefore be restricted only to treat penicillinase –
producing Staph. aureus infections.
2) If the causative organism is penicillinase producing, Staph. aureus then
Cloxacillin alone is useful. Co-administration of Ampicillin is NOT
necessary and NOT justifiable as it leads to wastage of drug and increases
the cost of treatment.

However, when it is proved that the infection is a mixed one due to

Ampicillin sensitive gram –ve bacilli and penicillinase producing
Staph. aureus, then the use of both the drugs is indicated. But in such a
situation, ideally, they should be prescribed and taken separately and their
use in fixed dose combination should be avoided.

Contraindication:
H/O hypersensitivity to penicillin.
General Comment:
Routine use of this fixed dose combination is NOT justifiable.

***
7) Tab. Enteroflox-T : Norfloxacin ……. 400 mg
Tinidazole ……. 600 mg

Indications, Dose and Route:

Diarrhoea or Dysentery of bacterial, amoebic or mixed origin. One tablet
twice daily for 5 days orally.

This is a fixed dose combination of an antibacterial drug Norfloxacin with

antiamoebic drug Tinidazole.

Using both drugs in a fixed dose combination is not justified as:

1) Only occasionally does a patient suffer from both bacterial and amoebic
dysenteries at the same time.

2) If the patient is suffering from bacterial dysentery only, then Norfloxacin

alone is useful and simultaneous administration of Tinidazole leads to
wastage. Tinidazole unnecessarily increases the cost of treatment and may
lead to ADR Similarly, if the patient is suffering from amoebic dysentery,
then Tinidazole alone is useful and simultaneous administration of
Norfloxacin leads to wastage of Norfloxacin and unnecessarily increases
the cost of treatment and may lead to ADR.

3) H/O hypersensitivity to either Norfloxacin or Tindazole contraindicates

the fixed dose combination preparation.
 4) Norfloxacin can not be judiciously used in children because of risk of
arthropathy. So this combination cannot be used in children.

5) Both drugs share common adverse effects such as gastro intestinal

distress and central nervous system effects like headache and dizziness.
So unnecessary use of both the drugs in a fixed dose combination puts the
patient to an increased risk of these adverse effects.

Contraindications:
1) H/O hypersensitivity to Norfloxacin and / or Tinidazole.
2) Pregnancy.
3) Children.

Special Precaution:
1) Patients predisposed to seizures, having neurological disorders.
2) Avoid alcohol as disulfiram like reaction to Tinidazole will occur.

General Comments:
Its routine use for case of pure amoebic or bacillary dysentery is NOT
rational and hence is NOT recommended.

***
8) Tab. Imol : Ibuprofen ……. 400 mg
Paracetamol ……. 325 mg

Indications:
1) Rheumatoid arthritis.
2) Osteoarthritis.
3) Ankylosing spondylitis.
4) Museculoskeletal disorders.
5) To relive postoperative pain, postpartum pain, toothache.

Dose and Route:

One tablet to be taken thrice daily orally after meals to avoid gastomtestinal
side effects or as required.

This fixed dose combination of an analgesic, anti inflammatory drug

Ibuprofen with an analgesic, antipyretic drug Paracetamol.

Using both drugs in a fixed dose combination is NOT justified as:

1) In the above stated conditions, in a majority of patients, Ibuprofen alone
in adequate dosage will relive the pain and inflammation.

2) In an occasional patient, if pain is not adequately relived by Ibuprofen

alone then, Paracetamol can be prescribed in adequate doses and taken
separately to provide extra pain relief.
 3) Therefore, in majority of patients, giving both drugs in fixed dose
combination lead to wastage of Paracetamol and unnecessarily increases
the cost of treatment and may lead to ADR.

Contraindications:
1) H/O hypersensitivity to Ibuprofen and / or Paracetemol.
2) Active peptic ulcer.

Special Precautions:
1) Bronchial asthma.
2) Renal, Hepatic or Bleeding disorders.
3) Those receiving Coumarin anticoagulants.
4) Pregnancy.

General Comments:
1) Contraindication to one component e.g. hypersensitivity to Ibuprofen or
Paracetamol contraindicates the whole preparation.
2) This fixed dose combination is NOT rational and hence NOT justifiable.

***
 Disadvantages:
Using the 2 drugs in a fixed dose combination has following disadvantages:

4) It is NOT possible to alter the dose of one drug independent of the other.
5) H/O hypersensitivity to any one drug contraindicates the fixed dose
combination tablet.
6) Contraindication to any one drug contraindicates the fixed dose
combination tablet e.g Atenolol is contraindicated in patients having
associated Congestive cardiac failure, sinus bradycardia, A V blocks.
Therefore, this fixed dose combination tablet cannot be used in
hypertensives and patients of exertional. Angina having these associated
diseases.

Hence using the 2 drugs in a fixed dose combination is NOT justifiable.

 General Comments:
The two drugs should be prescribed and taken separately and should be used
in a fixed dose combination form.
3) Tablet Enapril - HT : Enalapril - 10 mg.
Hydrochlorthiazide - 25 mg.

 Indication:
3) Moderate to sever hypertension.
4) Congestive Cardiac Failure.

 Dose and Route:

One Tablet daily, increasing to two tablets once daily if required, orally

 Advantages of using both drugs are:

3) The produce additive effect and
4) Thiazide induced hypokalemia is counteracted by Enalapril.

 However using the 2 drugs in fixed dose combination is NOT

justifiable as:

5) It is NOT possible to alter the dose of one drug independent of the other.
 6) To avoid first does severe hypertensive effect of Enalapril, it is usually
started in small doses of 2.5 mg or 5 mg daily and the thiazide diuretic is
usually stopped. The diuretic therapy is restarted later if required. One
cannot take this precaution if fixed dose combination tablet is used.

7) Enalapril is preferred in patients having associated diabetes mellitus, gout

while Hydrochlorothiazide is to be avoided. Therefore such fixed dose
combination tablet cannot be used patients having associated diseases like
diabetes mellitus and gout.

 Contraindications:
5) Pregnancy.
6) Patients with bilateral renal artery stenosis.
7) Patients suffering form persistent cough. Causes dry persistent cough is
apropos 15% of patients as its causes.

 General Comments:
The two drugs should be prescribed and taken separately and NOT used as
fixed dose combination tablets.
4) Tablet Acezide : Captopril - 25 mg.
Hydrochlorthiazide - 25 mg.

 Indication:
3) Moderate to severe hypertension
4) Congestive Cardiac Failure

 Dose and Route:

One Tablet two to three times a day, orally.

 Advantages of using both drugs are:

3) The produce additive effect and
4) Thiazide induced hypokalemia is counteracted by Captopril.
 However using the 2 drugs in fixed dose combination is NOT
justifiable as:
4) It is NOT possible to alter the dose of one drug independent of the other.

5) To avoid first does severe hypertensive effect of Captopril, it is usually

started in small doses of 6.25 mg two or three times a day and the diuretic
is usually stopped. The diuretic therapy is restarted later if required. One
cannot take this precaution if fixed dose combination tablet is used.

6) Captopril is preferred in patients having associated diabetes mellitus, gout

while Hydrochlorothiazide is to be avoided. Therefore such fixed dose
combination tablet cannot be used patients having associated diseases like
diabetes mellitus and gout. Cannot be use the patient with COPD and
patient suffering from persistent cough.

 Contraindications:
4) Pregnancy.
5) Patients with bilateral renal artery stenosis.
6) Patients suffering form persistent cough.

 General Comments:
The two drugs should be prescribed and taken separately and NOT used as
fixed dose combination.
5) Tablet Livogen Captabs : Folic Acid - 750 ug
Vitamin B12 - 7.5 ug
Ferrous Fumarate - 200 mg

 Indication:
To treat anaemias due to Folic acid, Vitamin B12 and Iron deficiency.

 Dose and Route:

One Tablet 3 times a day after food, orally.
 Using all 3 drugs in a fixed dose combination is NOT justified
as:
4) It is rare for a person to suffer from Folic acid, Vitamin B 12 and Iron
deficiency at the same time.

5) If the person is suffering from Iron deficiency anaemia only, then

simultaneous administration of Folic acid and Vitamin B 12 is of no use. It
leads to wastage of drugs and unnecessarily increases the cost of
treatment.

6) If the person is suffering from Vitamin B 12 deficiency only, then

simultaneous administration of Folic acid can prove harmful. Folic acid
by diverting Vitamin B12 for erythropoeises, reduces the availability of
Vitamin B12 for nervous tissue and thus aggravates peripheral neuritis.

 Side Effect:
Constipation or gastrointestinal upsets due to Iron fumarate.

 General Comment:
Depending on the cause of anaemia, a single specific drug should be used
and such type of shotgun therapy using multiple haematinics in fixed does
combination should be avoided.
6) Capsule Amipiclox : Ampicillin - 250 mg
Cloxacillin - 250 mg

 Indication:
 Mixed bacterial infections (gram –ve bacilli and penicillinase producing
Staph. aureus), Surgical, Othopaedic, Respiratory Tract, Skin and soft tissue
infections.

 Dose and Route:

One capsules four times a day, orally.

Ampicillin – it is effective against all organisms sensitive to Penicillin G i.e.

gram +ve and –ve cocci and gram +ve bacilli. In addition it is also effective
against gram –ve bacilli i.e. E coli, H. influenzae, Proteus, Salmonella and
Shigella. It is NOT effective against organisms which produce penicillinase
as it destroyed by penicillinase.

Cloxacillin – It is a penicillinase resistant penicillin, effective against

penicillinase producing Staph. aureus. It is NOT effective against gram –ve
bacilli.

 Routine use of both drugs in fixed dose combination is NOT

justified as:
3) if the causative organisms are Ampicillin – sensitive gram –ve bacilli and
non penicillinase producing Staph. aureus, then Ampicillin alone is
useful. Co-administration of Cloxacillin is NOT necessary and NOT
justifiable as it only leads to wastage of drug and increases cost treatment.
Further, Cloxacillin itself induces penicillinase production and its use
should therefore be restricted only to treat penicillinase – producing
Staph. aureus infections.
4) If the causative organism is penicillinase producing, Staph. aureus then
Cloxacillin alone is useful. Co-administration of Ampicillin is NOT
 necessary and NOT justifiable as it leads to wastage of drug and increases
the cost of treatment.
However, when it is proved that the infection is a mixed one due to
Ampicillin sensitive gram –ve bacilli and penicillinase producing Staph.
aureus, then the use of both the drugs is indicated. But in such a situation,
ideally, they should be prescribed and taken separately and their use in fixed
dose combination should be avoided.

 Contraindication:
H/O hypersensitivity to penicillin.

 General Comment:
Routine use of this fixed dose combination is NOT justifiable.

7) Tablet Enteroflox-T : Norfloxacin - 400 mg

 Tinidazole - 600 mg

 Indications, Dose and Route:

Diarrhoea or Dysentery of bacterial, amoebic or mixed origin. One tablet
twice daily for 5 days orally.

This is a fixed dose combination of an antibacterial drug Norfloxacin with

antiamoebic drug Tinidazole.

 Using both drugs in a fixed dose combination is not justified as:

6) Only occasionally does a patient suffer from both bacterial and amoebic
dysenteries at the same time.

7) If the patient is suffering from bacterial dysentery only, then Norfloxacin

alone is useful and simultaneous administration of Tinidazole leads to
wastage. Tinidazole unnecessarily increases the cost of treatment and may
lead to A.D.R. Similarly, if the patient is suffering from amoebic
dysentery, then Tinidazole alone is useful and simultaneous
administration of Norfloxacin leads to wastage of Norfloxacin and
unnecessarily increases the cost of treatment and may lead to ADR.

8) H/O hypersensitivity to either Norfloxacin or Tindazole contraindicates

the fixed dose combination preparation.

9) Norfloxacin can not be Judiously used in children because of risk of

arthropathy. So this combination cannot be used in children.
 10) Both drugs share common adverse effects such as gastro intestinal
distress and central nervous system effects like headache and dizziness.
So unnecessary use of both the drugs in a fixed dose combination puts the
patient to an increased risk of these adverse effects.

 Contraindications:
4) H/O hypersensitivity to Norfloxacin and / or Tinidazole.
5) Pregnancy.
6) Children.

 Special Precaution:
3) Patients predisposed to seizures, having neurological disorders.
4) Avoid alcohol as disulfiram like reaction to Tinidazole will occur.

 General Comments:
Its routine use for case of pure amoebic or bacillary dysentery is NOT
rational and hence is NOT recommended.
8) Tablet Imol : Ibuprolen - 400 mg.
Paracetamol - 325 mg.

 Indications:
6) Rheumatoid arthritis.
7) Osteoarthritis.
8) Ankylosing spondylitis.
9) Museculoskeletal disorders.
10) To relive postoperative pain, postpartum pain, toothache.

 Dose and Route:

One tablet to be taken thrice daily orally after meals to avoid gastomtestinal
side effects or as required.

This fixed dose combination of an analgesic, anti inflammatory drug

Ibuprofen with an analgesic, antipyretic drug Paracetamol.

 Using both drugs in a fixed dose combination is NOT justified

as:
4) In the above stated conditions, in a majority of patients, Ibuprofen alone
in adequate dosage will relive the pain and inflammation.
 5) In an occasional patient, if pain is not adequately relived by Ibuprofen
alone then in adequate doses, Paracetamol can be prescribed and taken
separately to provide extra pain relief.

6) Therefore, in majority of patients, giving both drugs in fixed dose

combination lead to wastage of Paracetamol and unnecessarily increases
the cost of treatment and may lead to ADR.

 Contraindications:
3) H/O hypersensitivity to Ibuprofen and / or Paracetemol.
4) Active peptic ulcer.

 Special Precautions:
5) Bronchial asthma.
6) Renal, Hepatic or Bleeding disorders.
7) Those receiving Coumarin anticoagulants.
8) Pregnancy.

 General Comments:
3) Contraindication to one component e.g. hypersensitivity to Ibuprofen or
Paracetamol contraindicates the whole preparation.
4) This fixed dose combination is NOT rational and hence NOT justifiable.