FDCs

2nd MBBS
Fixed Dose Combination:
Combination of two or more drugs in a
fixed dose ratio in a single pharmaceutical
formulation.
Examples:
Trimethoprim + sulfamethoxazole
(COTRIMOXAZOLE)
Levodopa+ carbidopa
(SYNDOPA 110)
 Rationality of FDCs
• Different mechanisms of action
• Pharmacokinetics must not be widely
different
• Should not have supraadditive toxicity
 ADVANTAGES
• Convenient
• Synergistic
• Minimisation of side effects
• Better patient compliance
• Reduced cost
Simplified packaging, fewer prescriptions,
and lesser dispensing time and cost.
• Certain combinations are synergistic .eg: OCP,
levodopa+ carbidopa

• Side effect of one component may be

counteracted by the other. eg: thiazide +
spironolactone, magnesium hydroxide+
aluminium hydroxide.

• Combined formulation ensures that a single drug

will not be administered. eg: Therapy for
Pulmonary TB, HIV.
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 DISADVANTAGES
• Dose of one drug cannot be altered without altering the
dose of other drug.
eg. atorvastatin 10 mg + amlodipine 5 mg
• Time course of action of the components may be
different: administering them at same intervals may be
inappropriate.
e.g. Pantoprazole(OD) + Domperidone(TDS)
• Patient may not actually need all the drugs present in
the combination subjecting the patient to additional side
effects
eg. Ibuprofen + paracetamol + caffeine.
• Confusion of therapeutic aims and false sense of
superiority of two drugs over one is fostered, specially in
antimicrobials.
• Adverse effects when occurs cannot be
ascribed to one particular component of
the combination.
eg. Isoniazid+Rifampicin
• Altered renal or hepatic function may
differentially affect the pharmacokinetics
of the components.
• Contraindication to one component
contraindicates the whole product.
• Irrational FDC’s increase the chance of
drug resistance.
eg. Ciprofloxacin+tinidazole
 NLEM FDC’s
1) Aluminium hydroxide +magnesium hydroxide
2) Amoxicillin+clavulanic acid
3) Trimethoprim+sulfamethoxazole
4) Levodopa + carbidopa
5) Artesunate +amodiaquine
6) Sulfadoxine+ pyrimethamine
7) Lamivudine+zidovudine
8) Lamivudine +stavudine
9) Lignocaine+ epinephrine
10) Acriflavin+glycerine
11) Ethinylestradiol + levonorgestrel
12) Ethinylestradiol + norethisterone
 BANNED FDCs in India

• Penicillins with sulfonamides (additive risk

of hypersensitivity)

• Tetracyclines with vitamin C (raises the

levels of tetracycline)

• More than one antihistamine in the same

preparation (same mechanism of action)
 Banned FDCs in India
• Salbutamol with centrally acting
antitussive (Their fixed dose combinations
with antitussives are not satisfactory
because of differences in time course of
action of the components and liability for
indiscriminate use)
• Vit B1, B6 and B12 combination (No
therapeutic advantage over individual
drugs)
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Examples of RATIONAL FDCs
Trimethoprim + Sulfamethoxazole
(COTRIMOXAZOLE)
Indication:
Acute uncomplicated UTI , chronic bronchitis, bacterial
diarrhoeas and dysentry, pneumocystis carinii pneumonia.

Why FDC: Sequential blockade of folate metabolism:

sulfamethoxazole reduces DHF levels so that DHFR
inhibitor(trimethoprim) can competitively inhibit DHFR easily.
Individually bacteriostatic, in combination bactericidal.
•t1/2 of trimethoprim (10h) and t1/2 of sulfamethoxazole (11 h) are
almost same.
•ratio of MIC for synergism in vitro is 1:20.
•aVd of Trimethoprim is 1 L/kg and that of Sufamethoxazole is
0.2L/kg.
•1(×5):20= 1: 4
•In practice 1:5 (160:800 mg) dose ratio is used to prevent
development of resistence.
 MOA

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Levodopa + carbidopa
Indication: Parkinson's disease
Why FDC: Levodopa when given alone ,only 1-3% reaches the brain.
Concomitant carbidopa increases it to 10%
•Carbidopa is peripheral dopa decarboxylase inhibitor- plasma t1/2 of
levodopa is prolonged. Allows more levodopa to enter brain.

•t1/2 of levodopa 1.7 hr and that of carbidopa 2 hr match closely.

•Systemic concentration of Dopamine is reduced- less nausea/vomiting,
postural hypotension.

•Incidence of On-Off phenomena are reduced by ensuring sustained

levels of levodopa in the brain.
 MOA

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 Amoxicillin + clavulanic acid
Indication: Skin and soft tissue infections, Gonorrhoea(PPNG), Community
acquired pneumonia.
Why FDC: Clavulanic acid - beta lactamase inhibitor and prevent hydrolysis of
amoxicillin.
•t1/2 of both Amoxycillin and Clavulinate is 1-1.5 hrs.
•aVd of both is 0.2 L/kg. Hence combined in standard doses.(500:125mg)

•Addition of clavulanic acid extends the antimicrobial spectrum of amoxicillin

against beta lactamase producing bacteria.
•Spectrum of amoxycillin and (amoxyclav): streptococci,clostridia, bacillus, H
influenzae, E coli, S typhi, B pertusis, proteus, salmonella, shigella ( PPNG, beta
lactamase producing anaerobes, Klebsiella etc)
 Imipenem + Cilastatin
Indication: LRTI, intra abdominal infections, complicated and
uncomplicated UTI,
Why FDC:
Imipenem is hydrolyzed by Renal dehydropeptidase I (renal brush border).
Cilastatin is a reversible inhibitor of dehydropeptidase I. Hence protects
imipenem from hydrolysis.

t½ of both is 1 hr.
Imipenem-cilastatin is admiistered 0.5 g i.v. 6 hourly (max 4 g/day).
Artemether+ Lumefantrine
Indication: uncomplicated falciparum malaria
Why FDC: The combination of artemether (an artemisinin derivative)
and lumefantrine in a 1:6 (80mg:480mg) ratio.
•Both artemether and lumefantrine are blood schizonticides
•complementary pharmacokinetics. t1/2 of artemether 2-3 hrs, that of
Lumefantrine is 3-6 days

•dissimilar modes of action hence provide synergistic anti-malarial

activity .

•The combination provides

– rapid clearance of parasitemia and most malaria-related
symptoms (artemether)
– prevention of recrudescence (lumefantrine)
 Lopinavir+Ritonavir
Indication: Antiretroviral therapy
Why FDC:In case of different Protease inhibitors ,
6–18 tablets are to be taken daily.Hence
compliance is often low.
•Combining them with a low and subtherapeutic
dose (100 mg) of ritonavir increases their
bioavailability.
• By reducing first pass metabolism, ritonavir
increases the bioavailability and by slowing
systemic metabolism decreases clearance of the
companion PI (Lopinavir).
• This ‘boosted PI regimen’ permits reduction in the
number/ frequency of tablets to be taken each day.
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 Magnesium hydroxide+ aluminium
hydroxide
Indication: Acid peptic disease (Antacid)
Why FDC:
(a) Fast (Mag. hydrox.) and slow (Alum. hydrox.) acting
components yield prompt as well as sustained effect.
(b) Mag. salts are laxative, while alum. salts are
constipating: combination may annul each other’s action
and bowel movement may be least affected.
(c) Gastric emptying is least affected; while alum. salts tend
to delay it, mag./cal. salts tend to hasten it.
(d) Dose of individual components is reduced; systemic
toxicity (dependent on fractional absorption) is minimized.

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 Benzoic acid + Salicylic acid
Indication: Superficial fungal infections
Why FDC:
•Benzoic acid :It has antifungal and antibacterial
property in slightly acidic medium

•Salicylic acid by its keratolytic action, helps to

remove the infected tissue and promotes the
penetration of benzoic acid into the lesion

•Whitfield’s ointment: benzoic acid 5% + salicylic acid

3%

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 Sufadoxine + Pyrimethamine
Indication: uncomplicated CQ resistant falciparum
malaria
Why FDC: Sulfadoxine 1500 mg + pyrimethamine 75 mg (3
tab) single dose
•supra-additive synergistic combination with pyrimethamine
due to sequential block.
•Though, both components are slow acting, the combination
acts faster.
•Potential to cause serious adverse effects (exfoliative
dermatitis, Stevens Johnson syndrome, etc.) due to the
sulfonamide.
Therefore, use is restricted to single dose treatment of
uncomplicated CQ-resistant falciparum malaria.
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 IRRATIONAL
FDCs

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 NORFLOXACIN+TINIDAZOLE

INDICATION: Gastroenteritis

Why irrational:
• Norfloxacin is effective against bacterial diarrhoea
Tinidazole is effective against intestinal amoebiasis
Both these conditions rarely coexist.
So, only one drug will be effective
• Increased cost
• More adverse effects
• Increased chances of developing resistance
 AMPICILLIN + CLOXACILLIN

INDICATION: Respiratory tract infections, skin and soft tissue

infections

WHY IRRATIONAL:
• Ampicillin – effective against Gram negative bacilli
Cloxacillin- Anti staphylococcal penicillin (Gram positive)
Both these infections rarely coexist
One of the drug would be useless
• Increased cost
• Increased adverse effects
• Increased chances of resistance
• Reduces the dose of effective drug to half, longer course of
therapy
 ENALAPRIL + LOSARTAN

INDICATION: Hypertension, CHF

WHY IRRATIONAL:
• Both drugs affect the same pathway- no added efficacy
• More adverse effects
Higher rates of hypotensive symptoms, hyperkalemia
 IBUPROFEN + PARACETAMOL

INDICATION: Mild to moderate pain

Migraine, backache, dental pain

WHY IRRATIONAL:
• Same mechanism of action- no synergism
• Increased risk of nephrotoxicity
• Adds to cost of therapy
 Expectorants + centrally acting
antitussives
EXAMPLE: Guaiphenesin + dextromethorpham
INDICATION: Cough

WHY IRRATIONAL:
• Antitussives are used for treatment of dry cough and
expectorants for cough with expectoration
Both the conditions do not coexist.
• Expectorants are a costlier way of treating a self resolving
condition.
• Expectorants in effective dose- not tolerated, produce adverse
effects
 NSAIDS + ANTISPASMODICS
Eg: Dicyclomine 20mg + Paracetamol 500mg [Tab
CYCLOPAM]

INDICATION: Spasmodic pain

WHY IRRATIONAL:
•Antipyretic drug promotes sweating- heat dissipation
•Anticholinergic antispasmodic- inhibits sweating
Combination- dangerous elevation of body temperature
 H2 Blocker + Domperidone

Indication: peptic ulcer disease, GERD

Why irrational:
• H2 blockers (ranitidine, famotidine): reduce gastric acid
production – symptomatic relief
• Peptic ulcer not always associated with vomiting- so
combination of domperidone is irrational
• GERD- domperidone less effective as compared to
metoclopramide

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 RECENTLY APPROVED FDCs
FDC INDICATION
Ezetimibe 10 mg + Simvastatin 40 mg Primary hypercholesterolemia

Glimepiride IP 0.5 mg + Metformin Type 2 diabetes mellitus( monotherapy is not

Hydrochloride ER 500 mg able to achieve glycemic control )

Pantoprazole 40 + Levosulpiride 75mg GERD (not respond to PPI alone)

Minoxidil IP 5 % + Finasteride IP 0.1% Androgenic alopecia in males

Mometasone Furoate IP 1 mg + Salicylic Acid Chronic plaque psoriasis

IP 50 mg ointment

Indacaterol Maleate 110 mcg COPD

Glycopyrronium Bromide 50 mcg