Fixed dose combinations (FDCs)

Comment on the given proprietary preparation mentioning possible indications,

dose and route of administration, justification for inclusion of such ingredients,
special precaution if any and your general comment on the combination.

List of FDCs

1. Tablet Levodopa 100mg/ 250mg + Carbidopa 10mg/ 25mg

2. Tablet Sulfamethoxazole 400mg + Trimethoprim 80mg
3. Tablet Sulfadoxine 500mg + Pyrimethamine 25mg
4. Tablet Isoniazid 75mg + Rifampicin 150 mg + Pyrazinamide 400 mg+
Ethambutol 275 mg
5. Tablet Ethinylestradiol 0.03mg +Levonorgestrel 0.15mg
6. Injection Lignocaine 2% + Adrenaline 1:200000
7. Oral Rehydration Salt (ORS) – Sodium Chloride 3.5gm + Potassium
Chloride 1.5gm + Sodium Citrate Dihydrate 2.9gm + Glucose 20gm.
8. Ointment Benzoic acid 6% + Salicylic acid 3%
9. Tablet Propranolol Hcl 40mg + Dihydrallazine Sulphate 25mg +
Hydrochlorthiazide 20mg
10. Tablet Atenolol 50mg + Nifedipine (SR) 20mg
11. Tablet Enalapril 10mg + Hydrochlorthiazide 25mg
12. Tablet Folic Acid 750 microgram + Vitamin B12 7.5 microgram + Ferrous
fumarate 200mg
13. Tablet Norfloxacin 400mg + Tinidazole 600mg
14. Tablet Ibuprofen 400mg + Paracetamol 325mg
15. Tablet Amoxycillin 250/ 500mg + Clavulanic acid 125mg
 1. Tablet Levodopa 100mg/ 250mg + Carbidopa 10mg/ 25mg

Indication:

Parkinsonism

Dose and route:

Started with 1 tablet three times a day orally. Dosage increased slowly over a
period of weeks depending on the response of the patient.

Justification:

1. L-dopa is a prodrug while carbidopa is a peripheral dopa decarboxylase

inhibitor.
2. If l-dopa is used alone, more than 95% of it is converted in peripheral tissues to
dopamine by the peripheral dopa decarboxylase, therefore only 1 to 2 % of l-
dopa is available to cross the blood brain barrier and reach the brain striatal
region to produce its beneficial effect.
3. The peripherally produced dopamine is responsible for certain side effects –
tachycardia, palpitations, nausea, vomiting.
4. Carbidopa by inhibiting peripheral dopa decarboxylase, prevents peripheral
conversion of l-dopa to dopamine and therefore permits more amount of l-dopa
to enter the brain and thus increases the therapeutic effect of l-dopa.

The FDC of both drugs have following advantages:

1. Effective dose of l-dopa is reduced by 75%

2. Side effects like nausea, vomiting, tachycardia, palpitations are prevented. This
permits more rapid increase in dosage to optimum levels and also improves
patient compliance
3. Pyridoxine does not antagonise the effects of l-dopa
4. Control of symptoms is smoother and “on-off” effect is minimised
5. Degree of improvement is higher. Some patients not responding adequately to
l-dopa alone also improves.

Contraindications:

1. H/o hypersensitivity to l-dopa &/or carbidopa

2. Presence of cardiovascular and psychiatric disorders.

General comments:

Clinical documentation justifies the use of this FDC and it is included in WHO list
of essential drugs.
 2. Tablet Sulfamethoxazole 400mg + Trimethoprim 80mg

Indications, dose and route:

Given orally used to treat;

1. Acute urinary tract infections due to E. Coli, proteus – 2 tablets twice a day
for 10-14 days.
2. Acute respiratory tract infections caused by gram positive cocci and H.
Influenzae - 2 tablets twice a day for 7-10 days.
3. Typhoid 2 tablets twice a day, continued for 7 days after fever comes down
(3+7 = 10 days)
4. Gonorrhoea - 2 tablets twice a day for 5 days.
5. Bacterial diarrhoeas and dysentery due to E. Coli, Shigella, Compylobacter
- 2 tablets twice a day for 5 days.
6. Pneumocystis carini infection in AIDS patient.

Justification:

Each drug is bacteriostatic but combination is bactericidal. Therapeutic effect is

greater than the sum of the effect of each drug. They form supraadditive
synergistic combination due to sequential blockade.

PABA Folic acid (DHFA) Folinic acid

Prevented by Prevented by
sulfamethoxazole trimethoprim by
by inhibiting folic inhibiting dihydrofolate
acid synthetase reductase
Other advantage is that bacterial resistance develops slowly to the combination.

Precaution:

Should NOT be prescribed to patients with H/O hypersensitivity reactions to sulfa

drugs &/or trimethoprim.

Contraindications:

Pregnancy

General comments:

1. Compliance is improved
2. Cost is less than the sum of the individual drugs
3. Clinical documentation justifies the use of the combination
4. This FDC is included in WHO list of essential drugs
 3. Tablet Sulfadoxine 500mg + Pyrimethamine 25mg

Indications:

To treat acute attack of malaria especially chloroquine resistant falciparum

malaria.

Dose and route:

2-3 tablets single dose orally for adults

Justification:

Sulfadoxine has some inhibitory effect on the erythrocytic phase, specially of

P.falciparum. However, it forms supraadditive synergistic combination with
pyrimethamine due to sequential blockade

PABA Folic acid (DHFA) Folinic acid

Prevented by Prevented by
sulfadoxine by
Pyrimethamine by
inhibiting folic acid
inhibiting dihydrofolate
synthetase
reductase
Precaution:

Should NOT be prescribed to patient with H/O hypersensitivity reactions to

sulfonamides &/ or pyrimethamine

Contraindication:

Pregnancy

General comment:

1. Cost is less than the sum of the individual drugs

2. Clinical documentation justifies the use of the combination
3. This FDC is included in WHO list of essential drugs.
 4. Tablet Isoniazid 75mg + Rifampicin 150 mg + Pyrazinamide
400 mg+ Ethambutol 275 mg

Indication: To treat PulmonaryTuberculosis ( Newly diagnosed case) for

giving first intensive phase of treatment

Dose and route:

2-5tablets daily orally for 2 months in intensive phase of treatment as per

weight of patient as mentioned in RNTCP guidelines of 2016

Justification:

Due to combination of all 4 drugs in one tablet, compliance of patient and

adherence to treatment increases, chance of development of resistance in bacilli
to anti TB drugs is reduced

Contraindication:

1. Hepatic diseases
2. Renal failure
3. Sensitivity to Isoniazid &/ or thiacetazone

General comments: This FDC is rational & justifiable and is included in WHO
list of essential drugs and also in RNTCP guidelines in India.
 5. Tablet Ethinylestradiol 0.03mg +Levonorgestrel 0.15mg

Indication:

For contraception in females

Dose and route:

Taken orally. 1 tablet is taken daily for 21 days starting on 5th day of
menstruation. The next course is started after a gap of 7 days. Calendar packs with 21
active and 7 blank pills are available.

Justification:

Ethinylestradiol; mainly responsible for inhibiting ovulation

Levonorgestrel;

1) Ensures prompt bleeding on withdrawal and reduces the risk of endometrial

carcinoma

2) Helps in contraception by inhibiting ovulation and by making the cervical

mucus thick, viscid and hostile to sperms.

Contraindications:

1. Thromboembolic disorders or H/O it.

2. Moderate to severe hypertension
3. Active liver disease or H/O jaundice during past pregnancy
4. Suspected/ overt malignancy of genitals/ breasts

General comments:

This FDC is justifiable and is included in WHO list of essential drugs

 6. Injection Lignocaine 2% + Adrenaline 1:200000

Indication:

For infiltration and nerve block anaesthesia

Route:

For infiltration anaesthesia – the local anaesthetic solution is infiltrated under

the skin in the area of operation – block sensory nerve endings

For nerve block anaesthesia – the local anaesthetic solution is injected around
nerve trunks or plexuses.

Justification:

Adrenaline by constricting blood vessels, slows the absorption of the local

anaesthetic from the site of administration and thus;

a) Prolongs the duration of action of the local anaesthetic

b) Decreases the systemic toxicity of the local anaesthetic

Precautions:

1. Lignocaine containing adrenaline injection should NOT be used to treat

ventricular tachycardia.
2. Lignocaine containing adrenaline injection should NOT be injected in tissues/
sites supplied by end arteries. e.g. fingers, toes, penis, ears and nose. To do so
will result in ischaemic necrosis and gangrene because of adrenaline induced
vasoconstriction of end arteries.
3. Lignocaine containing adrenaline injection should NOT be used in patients
with myocardial diseases (ischaemia), arrhythmias, hypertension and
hyperthyroidism.

General comments:

Combination of lignocaine with adrenaline is rational and this FDC is included in

WHO list of essential drugs.
 7. Oral Rehydration Salt (ORS) – Sodium Chloride 3.5gm + Potassium
Chloride 1.5gm + Sodium Citrate Dihydrate 2.9gm + Glucose 20gm

Indication:

To correct dehydration in case of diarrhoeas, cholera. Helps to restore and

maintain hydration, electrolyte and pH balance.

Dose and route:

Content of packet dissolved in a litre of water. ORS solution taken orally at 1/2
to 1 hourly intervals, initially 5 - 7.5% body weight volume equivalent is given in 2-4
hours. Subsequently taken in amounts and at intervals sufficient to cover the rate of
loss in stools.

Justification:

1. Sodium chloride, Potassium chloride are used to correct the Na+, K+ and Cl-
loss respectively
2. Glucose is added as it facilitates Na+ reabsorption (Glucose-Na+ Cotransport
system is functional). Glucose also provides nutrition.
3. Sodium citrate is used to correct acidosis.

Precaution:

Excessive glucose should not be used as it can produce osmotic diarrhoea.

General comments:

This FDC is justifiable and is included in WHO list of essential drugs.

 8. Ointment Benzoic acid 6% + Salicylic acid 3%

Indication:

To treat ring worm, tinea pedis, tinea versicolor and other dermatomycoses.

Route:

Ointment applied locally to the affected part twice or thrice a day or as

required. Called Whitfield’s ointment

Justification:

1. Benzoic acid has antifungal activity – is fungistatic

2. Salicylic acid is comparatively a weak antifungal agent but has keratolytic
properties. By its keratolytic action it helps to remove hyperkeratotic skin
tissue and thus promotes the penetration of benzoic acid into the lesion and
ensures better contact of benzoic acid with fungus

Side effects:

Patients may complain of irritation and burning sensation at site of application.

General comments:

This FDC is justifiable and is included in WHO list of essential drugs.

 9. Tablet Propranolol Hcl 40mg + Dihydrallazine Sulphate 25mg +
Hydrochlorthiazide 20mg

Indication, dose and route:

Moderate to severe hypertension. Given orally, start with one tablet once a day or
twice a day and gradually increase upto 5 tablets daily until control is achieved.

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 act as additive antihypertensive effect.

Hydralazine induced;

1. Salt and water retention is counteracted by hydrochlorthiazide

2. Tachycardia and palpitation by propranolol.

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

affecting blood pressure are reduced viz. Cardiac output by propranolol, peripheral
resistance by Hydralazine, and plasma volume by hydrochlorthiazide.

However, using these 3 drugs in a FDC has the following disadvantage:

1. It is not possible to alter the dose of any one drug independent of the other.
2. Contraindication/ allergy to one component contraindicates the whole
preparation.
Hence using 3 drugs in a FDC is NOT justifiable.

General comments:

The 3 drugs should be prescribed and taken separately and should not be used
as FDC.
 10. Tablet Atenolol 50mg + Nifedipine (SR) 20mg

Indication:

1. Moderate to severe hypertension

2. Exertional angina

Dose and route:

Given orally, 1 tablet daily; increased to 2 tablets daily if required

Justification:

This combination of cardioselective β1 receptor blocker Atenolol and 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 decreases myocardial oxygen
requirement by acting through different mechanisms viz. Atenolol decreases
heart rate and force of contraction by blocking cardiac β1 receptors, Nifedipine
decreases afterload by dilating arterioles
3. Further Atenolol counteracts Nifedipine induced reflex tachycardia and
palpitations.

However, using the 2 drugs in FDC has following disadvantages:

1. It is not possible to alter the dose of one drug independent of the other
2. History of hypersensitivity to one of the drug contraindicates the FDC
3. Contraindication to any one drug contraindicates the FDC.
Hence using the two drugs in a FDC is NOT justifiable.

General comments:

The drugs should be prescribed and taken separately and should not be used in
a FDC
 11. Tablet Enalapril 10mg + Hydrochlorthiazide 25mg

Indication:

1. Moderate to severe hypertension

2. Congestive cardiac failure

Dose and route:

1 tablet daily increasing to 2 tablets daily if required, orally

Justification:

Advantages of using both drugs are:

1. They produce an additive effect

2. Thiazide induced hypokalemia is counteracted by Enalapril

However, using the two drugs in FDC 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 a 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 FDC is used.
3. Enalapril is preferred in patients having associated diabetes mellitus, gout
while hydrochlorthiazide is to be avoided. Therefore such FDC cannot be
used in patients having associated diabetes mellitus and gout.

Contraindications:

1. Pregnancy
2. Bilateral renal artery stenosis
3. Persistent cough

General comments:

The 2 drugs should be prescribed and taken separately and not used as FDC.
 12. Tablet Folic Acid 750 microgram + Vitamin B12 7.5 microgram +
Ferrous fumarate 200mg

Indications:

To treat anaemias due to Folic acid, Vit B12 and Iron deficiency

Dose and route:

1 tablet three times a day after food, orally.

Justification:

Using all 3 drugs in a FDC is NOT justifiable as-

1. It is rare for a person to suffer from Folic acid, Vit B12 and Iron deficiency
at the same time.
2. If the person for example is suffering from iron deficiency anaemia, then
simultaneous administration of folic acid and Vit B12 is of no use. It only
leads to wastage of drugs and unnecessarily increases the cost of treatment.
3. If the person for example is suffering from Vit B12 deficiency, then
simultaneous administration of folic acid can prove harmful. Folic acid, by
diverting Vit B12 for erythropoiesis, reduces the availability of Vit B12 for
nervous tissue and thus aggravates peripheral neuritis.

Side effects:

Constipation or GI upset due to ferrous fumarate.

General comments:

Depending on the cause of anaemia, a single specific drug should only be used
and such type of shotgun therapy using multiple haematinics in FDC should be
avoided. Hence using such FDC is not rational. Not justified and cannot be
recommended.
 13. Tablet Norfloxacin 400mg + Tinidazole 600mg

Indications, dose and route:Diarrhoea or dysentery of bacterial, amoebic or of mixed

origin. 1 tablet twice daily for 5 days orally

Justification:This is FDC of an antibacterial drug Norfloxacin with antiamoebic drug

Tinidazole.

Using both drugs in FDC is NOT justifiable as:

1. Only occasionally a patient suffers from both bacterial and amoebic

dysenteries at the same time.
2. If the patient is suffering from bacterial dysentery, only then Norfloxacin is
useful and simultaneous administration of Tinidazole leads to wastage of
tinidazole and unnecessarily increases the cost of treatment. Similarly, if the
patient is suffering from amoebic dysentery, only then tinidazole is useful
and simultaneous administration of Norfloxacin leads to wastage of
Norfloxacin and unnecessarily increases the cost of treatment.
3. History of hypersensitivity to Norfloxacin or Tinidazole contraindicates the
FDC
4. Norfloxacin is avoided in children because of risk of arthropathy, therefore
this FDC cannot be used in children.
5. Both drugs share common adverse effects e.g. GI distress and CNS effects –
headache, dizziness. Therefore unnecessary use of both drugs in FDC
subjects the patient to an increased risk of these adverse effects.

Contraindications:

1. History of hypersensitivity to Norfloxacin/ or Tinidazole

2. Pregnancy

Special precautions:

1. Patients predisposed to seizures, having neurological disorders

2. Avoid alcohol (as Disulfiram like reaction to tinidazole will occur)

General comments:

In the occasional adult patient suffering from both bacillary and amoebic dysentery
this FDC may be used. However, its routine use for every case of pure amoebic or
bacillary dysentery is NOT rational and hence not recommended.
 14. Tablet ibuprofen 400mg + Paracetamol 325mg

Indications:

1. Rheumatoid arthritis
2. Osteoarthritis
3. Ankylosing spondylitis
4. Musculoskeletal disorders
5. To relieve postoperative, postpartum pain, toothache

Dose and route:1 tablet three times a day orally after meals to avoid GIT side effects
or as required.

Justification:This is a FDC of an analgesic, anti-inflammatory drug ibuprofen with an

analgesic antipyretic drug paracetamol.

Using both drugs in FDC is NOT justified as-

1. In the above stated conditions, in majority of patients ibuprofen alone in

adequate dosage will relieve the pain and inflammation.
2. In an occasional patient, if pain is not adequately relieved by ibuprofen
alone then paracetamol can be prescribed and taken separately to provide
extra pain relief.
3. Therefore, in majority of patients giving both drugs in FDC leads to
wastage of paracetamol and unnecessarily increases the cost of treatment.

Contraindications:

1. History of hypersensitivity to ibuprofen/ or paracetamol.

2. Acute peptic ulcer

Special precautions:

1. Bronchial asthma
2. Renal, hepatic or bleeding disorders
3. Those receiving coumarin anticoagulants
4. Pregnancy

General comments:

1. Contraindications to one component e.g. hypersensitivity to ibuprofen or

paracetamol contraindicates the whole preparation.
2. This FDC is NOT rational and hence not justifiable.
 15. Tablet Amoxycillin 250/ 500mg + Clavulanic acid 125mg
Indications: For impirical therapy of:

a. Skin and soft tissue infections, intra-abdominal and gynaecological

sepsis, urinary, biliary and respiratory tract infections: specially for
hospital acquired infections

b. Gonorrhoea (including PPNG)

Dose and route: Oral – 1 to 2 tablets TDS just before meal

Justification:

Clavulanic acid permeates the outer layers of the cell wall of bacteria and
inhibits the periplasmically located β-lactamase. Addition of clavulanic acid to
amoxicillin re-establishes the activity of amoxicillin against β-lactamase
producing resistant Staph. Aureus, H.influenzae, N.gonorrhoeae, E. coli,
Proteus, Kleibsiella, Salmonella, Shigella.

Contraindications:

History of allergy to any one of the ingredient, or with history of allergy

to penicillin antibiotics.

Special precautions:

a. Glandular fever

b. In patient on contraceptive pills

c. Liver or kidney disease

General comments:

This FDC is justifiable and it is included in WHO list of essential

medicines.