OFF-LABEL DRUG USE

Off-label drug use (OLDU) simply means “unapproved use of approved drugs”. This term can
be used to mean any of the following.

 It involves using currently available and marketed medications, but for indications
that have not been approved. (e.g. paclitaxel is approved to treat breast and ovarian
cancer, but physicians use it to treat pancreatic cancer, an off-label use).

 It also applies to the use of a marketed medication in a patient population where the
drug was not studied and approved. (e.g. use of cetirizine in children below two years)

 It also means use of a drug in a dosage form or administering it using a route that has
not been approved. For example, use of injectable colchicine in management of gout.

 OLDU also involves administration of drugs in doses and dosages that have not been
approved, this includes under-dosage and over-dosage. For example, administration
of over 30 mg/day of metoclopramide in management of nausea and vomiting.

 OLDU is common in areas of medicine in which the patient population is less likely to
be included in clinical trials. e.g. paediatric, pregnant, psychiatric etc.

Off-label drug use is not illegal, neither is it incorrect nor investigational if based on sound
scientific evidence, expert medical judgment or published literature. OLDU is considered as
legal unless it violates ethical guidelines or other safety regulations.

However, off-label drug use can put people at risk of receiving ineffective or even harmful
treatment. To avoid these risks, it is suggested that doctors only prescribe drugs off-label
when they have solid evidence that the benefits outweigh the risks.

Some drugs are used more frequently off-label than for their original approved indications.
A good example are the tricyclic antidepressants (e.g. amitriptyline) that are currently used
more frequently off-label to treat neuropathic pain than they are for depression, their
original approved indication.

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Factors that motivate off-label drug use

1. Absence of an approved drug to treat a certain condition encourages off-label drug

use. (e.g. nocturnal enuresis has no approved drug, so desmopressin and imipramine
are being used off-label to manage the condition).

2. Some drugs were not studied and approved for specific populations (e.g. pregnant,
paediatric, geriaric etc), so they are used off-label in these populations, for example,
use of loratadine in paediatrics.

3. Sometimes the drugs that have gained approval for a particular condition have not
been effective for a particular person, so healthcare providers decide to use another
drug that has not been approved for that condition. (e.g. use of levofloxacin off-label
to treat acne vulgaris when approved doxycycline fails).

4. In other instances, the drugs that have been approved for a certain condition are too
expensive or otherwise inaccessible, this intimates physicians to prescribe
alternative off-label drugs that are less expensive and readily available. (for example,
use of cheap levofloxacin off-label to treat acne instead of expensive approved
isotretinoin)

5. Presence of life-threatening or terminal medical condition that intimates logical and

available treatment, whether approved or not. (e.g. use of paclitaxel for breast cancer
before its approval in 1972)

6. If one medication from a class of drugs has approval, physicians commonly use other
medications in same class without specific approval for that use for the same
indication. (e.g. paclitaxel is approved for treatment of ovarian cancer, but use of
docetaxel from the same class to treat ovarian cancer is off-label).

7. If the pathologic or physiologic features of two conditions are similar, physicians may
use a medication approved for one of those conditions for both (e.g. diabetes and
metabolic syndrome, anxiety and post-traumatic stress disorder).

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Reasons why manufacturers don’t apply for approval of off-label drug indications

1. Approval for medication use is crazy costly and time-consuming.

As such, generic medications may not have the requisite funding foundations needed
to pursue approval studies, so drug proprietors may never seek approval for a new
drug indication.

2. To add additional indications for an already approved medication requires the

proprietor to file a supplemental drug application and even if eventually approved,
revenues for new indication may not offset the expense and effort of obtaining
approval.

3. Most often, the number of people with the disease for which the drug is being used
off-label is small, so potential sales generated after approval may not generate enough
revenue to justify the cost of the studies required for approval.

4. Sometimes, there is a similar drug on the market that already has the disease as a
labeled indication, and the manufacturer assumes that its own drug also will be used
as a treatment for the disease because the two drugs have similar effects.

5. In other instances, off-label use of the drug may be so common that obtaining
approval for the indication would not make much of a difference in the use of the drug
and the revenue that is generated. (e.g. use of amitriptyline for insomnia and
neuropathic pain).

6. Sometimes, a combination ingredient product has been approved, but a manufacturer

markets only a single ingredient from this product. For example, the combination of
oral colchicine and probenecid is an FDA-approved drug. However, oral colchicine ,
as a single active ingredient, is an unapproved drug.

The opposite of this is when two ingredients are approved separately, but are being
marketed in combination as an unapproved drug. For example a combination of
sildenafil and dapoxetine.

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EXAMPLES OF OFF-LABEL DRUG USES

DRUG OFF-LABEL INDICATION

Acetylcysteine  Keratoconjuctivitis Sicca

 Prevention of contrast-media nephrotoxicity

Alendronate  Hypercalcemia of malignancy

Amiodarone  Supraventricular tachycardia

Amitriptyline  Bulimia
 Fibromyalgia
 Insomnia
 Irritable bowel syndrome
 Migraine prophylaxis
 Neuropathic pain

Amoxicillin  Chlamydial infection in pregnant women

 Lyme disease
 Otitis media in children

Aspirin  Anti-thrombosis in atrial fibrillation

 Colorectal cancer prophylaxis
 Coronary disease prophylaxis in diabetes

Atenolol  Alcohol withdrawal syndrome

 Hypertension in children
 Migraine prophylaxis
 Supraventricular arrhythmias
 Thyrotoxicosis

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Azathioprine  Atopic dermatitis
 Crohn Disease
 Lupus nephritis
 Psoriasis
 Thrombocytopenic purpura
 Ulcerative colitis

Celecoxib  Fibromatosis
 Familial adenomatous polyposis

Citalopram  Alcoholism
 Binge-eating disorder
 Fibromyalgia
 Generalized anxiety disorder
 Hot flashes
 Irritable bowel syndrome
 Obsessive Compulsive Disorder
 Panic disorder
 Pathologic gambling
 Premenstrual dysphoric disorder
 Stuttering

Clomipramine  Insomnia
 Major depressive disorder
 Premature ejaculation

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Clonazepam  Anxiety
 Burning mouth syndrome
 Essential tremor
 Hiccups
 Myoclonic jerks
 Neuropathic pain
 REM sleep behavior disorder
 Restless leg syndrome
 Sedation
 Tardive dyskinesia

Cyproheptadine  Decreased appetite due to disease

 Drug-induced sexual dysfunction
 Migraine headache prophylaxis
 Serotonin syndrome
 Spinal cord spasticity

Desmopressin  Nocturnal enuresis

Dexamethasone  Altitude sickness

 Chemotherapy-induced nausea and vomiting
 Post-operative nausea
 Spinal cord compression

Diphenhydramine  Insomnia
 Chemotherapy emesis

Donepezil  Fronto-temporal dementia

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Doxorubicin  Refractory multiple myeloma

Duloxetine  Anxiety

Erythromycin  Chancroid
 Gastroparesis
 Granuloma inguinale

Erythropoietin  Anemia of chronic disease

Fentanyl  Analgesia*

Finasteride  Female hirsutism

Fluoxetine  Borderline personality disorder

 Diabetic neuropathy
 Fibromyalgia
 Hot flashes
 Migraines
 Premature ejaculation
 Raynaud phenomenon

Furosemide (nebulized)  Dyspnea

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Gabapentin  Cocaine withdrawal
 Diabetic neuropathy
 Fibromyalgia
 Headache
 Hiccups
 Hot flashes-cancer related
 Insomnia
 Restless leg syndrome
 Tremors in multiple sclerosis

Haloperidol  Hiccups
 Intravenous formulation for psychosis

Halothane  Intra-operative uterine contraction

 Status asthmaticus

Imipramine  Enuresis in children

Indomethacin  Closure of patent Ductus arteriosus

Infliximab  Alopecia
 Atomic dermatitis
 Pityriasis
 Vasculitis

Isoflurane  Intra-operative uterine contraction

 Seizure
 Status asthmaticus
 Status epilepticus

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Ketamine  Neuropathic pain
 Resistant depression
 Severe pain

Lidocaine  Post-herpetic neuralgia

 Premature ventricular beats during cardiac arrest

Linezolid  Infective endocarditis

Lisinopril  Coronary artery disease

 Diabetic nephropathy

Lorazepam  Chemotherapy-induced Nausea and vomiting

 Chronic insomnia
 Sedation in ICU
 Skeletal muscle spasms

Magnesium sulphate  Premature labour

Methotrexate  Ectopic pregnancy

 Myasthenia gravis

Methylphenidate  Depression
 Fatigue

Metoclopramide  Hiccups
 Post-operative nausea and vomiting

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Metoprolol  Acute tachyarrhythmia
 Atrial fibrillation
 Migraine prophylaxis

Midazolam  Hiccups
 Muscle spasms
 Seizures

Modafinil  Depression

Montelukast  COPD

Morphine  Cough
 Diarrhea
 Dyspnea
 Paediatric pain

Octreotide  AIDS-related diarrhea

 Chemotherapy-related diarrhea
 Chylothorax
 Dumping syndrome
 Esophageal variceal bleeding
 GI or pancreatic fistula
 High fistula output
 Ileostomy-related diarrhea
 Nausea and vomiting due to bowel obstruction
 Secretory diarrhea

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Olanzapine  Anxiety
 Chemotherapy-associated nausea and vomiting
 Dementia
 Depression
 Obsessive Compulsive Disorder
 Post-traumatic Stress Disorder
 Substance abuse

Omeprazole  Reflux related laryngitis

Ondansetron  Cholestatic pruritus

 Nausea and vomiting not associated with
chemotherapy, radiotherapy or post-op.
 Rosacea
 Spinal opioid-induced pruritus
 Uremic pruritus

Pethidine  Post anesthetic shivering

Phenobarbital  Terminal restlessness

Prazosin  Benign Prostatic Hypertrophy

 Nightmares in PTSD
 Raynaud’s phenomenon
 Sleep disruption in PTSD

Propofol  Intracranial hypertension

 Post-operative nausea

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Propranolol  Aggressive behavior
 Esophageal variceal bleeding
 Migraine prophylaxis
 Panic disorder

Quetiapine  Anxiety
 Dementia
 Nausea and vomiting
 Obsessive Compulsive Disorder
 Post-traumatic Stress Disorder
 Substance abuse

Ranitidine  Itching
 Sweating
 Stress ulcer prophylaxis

Risperidone  Anxiety
 Dementia
 Obsessive Compulsive Disorder
 Post-traumatic Stress Disorder
 Substance abuse
 Tourette syndrome

Rituximab  Alopecia
 Atomic dermatitis
 Pityriasis
 Vasculitis
 Idiopathic thrombocytopenic purpura

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Salbutamol  Hyperkalemia

Sertraline  Bipolar Disorder

 Pruritus

Sildenafil  Hypertension in children

 Sexual dysfunction symptoms in women

Spironolactone  Acne vulgaris in females

 Hirsutism in females

Sulfamethoxazole-Trimethoprim  Sinusitis

Trazodone  Aggressive behavior

 Alcohol withdrawal
 Cocaine withdrawal
 Insomnia in elderly
 Prevention of migraine

Valproate  Neuropathic pain

Venlafaxine  Bipolar Disorder

 Hot flashes due to hormonal chemotherapy
 Neuropathic pain
 Post-traumatic stress disorder

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 Warfarin  Antiphospholid Antibody syndrome
 Cardio-embolic stroke
 Cryptogenic stroke
 Hypertensive heart disease
 Patent Foramen Ovale with DVT
 Rheumatic Valve Disease
 Systolic Left Ventricular Dysfunction

NB

 It is important to note that fentanyl is indicated for general anesthesia, but not analgesia.
 Other off-label drug uses exist and keep emerging every single day. You can send other left out off-
label drug uses to miyingoivan@gmail.com.

REFERENCES

1. Drugs & Therapy Bulletin: Volume 23, No.4, April 2009

2. https://doi.org/10.1136/bmj.j603: BMJ 2017;356:j603

3. Journal of Pharmacology and Pharmacotherapeutics: Wolters Kluwer

4. Pharmacy and Therapeutics: Off-label drug information: C. Lee Ventola, MS

5. Ten Common Questions (and Their Answers) About Off-label Drug Use:
https://www.ncbi.nlm.nih.gov

AUTHOR:

MIYINGO IVAN
BPHARM, MPS

© 2020

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