**1.2 Off-label use of drugs**

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

'Drug repurposing' (or 'drug repositioning') is an effective way to find new targets or new indications of any drug that is already FDA approved and existing in the market. It is an excellent alternative over the *de novo* drug development process which is relatively time consuming and money involved procedure [4]. Since the data including drug efficacy, safety, bioavailability, route and formulation of administration, pharmacokinetic and pharmacodynamic (PK-PD) profile, toxicological data and associated adverse effects, are well known with already approved drugs. Thus, the evaluation process for drug candidates gets facilitated with drug repurposing and drug enters the clinical market for new therapeutic indications. Also, drug repurposing reduces the risk of development failure into the market, thus reducing the cost of the overall drug development process. At present, in the U.S approximately 30% of newly FDA approved drugs are repurposed only [5]. History witnessed numerous drug candidates that have been repurposed either opportunistic or serendipitous. Sildenafil is one of the blockbusters in the history of drug repurposing. Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, was introduced in the market in the 1980s by Pfizer for the treatment of coronary artery disease (CAD), hypertension and angina pectoris. During phase-1 trials of sildenafil, it was observed that the patients suffered from marked penile erection. In 1988, the drug was repurposed and approved by FDA for erectile dysfunction in the US market after the drug failed to prove its efficacy in phase-2 trials in angina patients [6]. Another big hit example is thalidomide. In 1957, the drug was developed by German pharmaceutical company named Grünentha for treatment of motion sickness in pregnant women. Soon the drug was withdrawn from the market as its use lead to serious birth defects (malformations of the limbs) and death in approximately 10,000 children in around 46 countries. Subsequently in 2006, the drug was re-approved by FDA for the treatment of multiple myeloma [4]. In the 1960s, amantadine was developed as an antiviral drug to treat influenza infections. After a few years, a patient who was suffering from Parkinson's disease (PD) had taken amantadine for her flu infection. It was seen that the patient was having improvement in her PD symptoms after taking amantadine. From there, it has been concluded that the drug can be used in treating neurological disorders. Years later, amantadine received FDA approval for treatment of PD [7].

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**1.1 Drug repurposing**

*Phases in drug development.*

**Figure 1.**

"Off-label drug use (OLDU)" defines to prescribe the drug beyond the conditions for which the drug is holding the license for its market authorization. More specifically, off-label means using a drug for indications, dosage form, dose strength, route of administration or in that patient age group which are not approved by FDA [8]. FDA approves a drug to market only if it shows to be effective and safe in preclinical as well as clinical studies, refers to as "on-label drug use". However, OLDU is being extensively practiced by physicians in situations: first, when two therapeutic conditions possessing same pathophysiology; second, to treat any life-threatening condition where no treatment is available and thereby provide off-label use may be proven helpful to patient; and third, drug has not been studies in specific group or patient age (pediatrics, pregnancy or geriatric). There are many examples of drugs which have been prescribed commonly as "off-label" drugs (**Table 1**) [9].
