A combination drug is most simply defined as a chemical composition of at least two drugs combined in a single dosage form, typically as a tablet or capsule to be administered orally, an elixir or tincture (sublingual), an injectable suspension (intramuscular administration or intravenous therapy), or a suppository (rectal). A legitimate combination drug that exceeds rigorous laboratory quality standards and is approved for medical use is a safe option for treating multiple symptoms or diseases amongst various patients within a large population–and this includes combinations of over-the-counter medicine and/or of prescription drugs. When medications are paired with supplements^{[disambiguation needed]}, consumers can be certain of accurate dosing and ingredient labeling, as well as product quality as it would be regulated and manufactured as a medication and must meet rigorous standards of pharmaceutical quality.

A polypill is specifically formulated as a pill containing four or more active ingredients, frequently requiring custom preparation at a compounding pharmacy in order to meet the personalized specifications deemed necessary by a patient's medical prescription. Such specificities may include uncommon, unconventional, or unavailable dosage, dosage form, a modified release mechanism, and necessity for a particular speed of onset and/or duration of action. Polypills can encompass four or more of any combination of approved prescription drugs and over the counter drugs, and may also include nutritional supplements, amino acids, enzymes, hormones, vitamins and/or essential minerals.

Fixed-dose combination drugs were initially developed to target a single disease, as with antiretroviral FDCs indicated for treating AIDS and HIV. Combination drug treatment conceptually emphasizes simplified treatment plans, reduced pill burden and increased patient compliance by offering accessible and affordable ingredients, generally generic drugs with established therapeutic efficacy, and the ability to treat a variety of symptoms and conditions amongst a large patient population with varying treatment needs.

The combination drugs listed below are universally available by prescription only, but specific circumstances regarding a given combination's legal accessibility, or any specific regulation pertinent to ingredient quality, quantities, production standards, sourcing, etc. will vary by jurisdictions, and include:

Combination drugs for sale over the counter (OTC) exist around the world, constituting doses that are tolerable to a mainstream consumer population. In the United States, items containing ephedrine, pseudoephedrine, or phenylpropanolamine can be purchased without a prescription, albeit under strict oversight and from behind the pharmacy counter, per the U.S. Federal drug law titled the Combat Methamphetamine Epidemic Act of 2005. The following combination drugs are accessible OTC in nearly all locations:

Most of the combination drugs which have been discontinued since the twentieth century were simultaneously indicated and utilized for treatment of various conditions, with medical use justified as part of a multifaceted, comprehensive approach to patient health care and medical treatment. Substituted amphetamines (stimulants) simultaneously functioned as appetite suppressant, antidepressant, and eugeroic agents, also increasing mental alertness and concentration and physical stamina, while a GABAergic depressant (e.g. a barbiturate, benzodiazepine, antipsychotic, or quinazolone) offered tranquilizing, muscle relaxant, sedative properties to ease overstimulation, paranoia, anxiety without eliminating the stimulant's therapeutic benefits. Patients are empowered with the capability of alleviating symptoms of multiple medical conditions with the ingestion of a single dosage form, reducing the patient's pill burden and consistently showing improved medication compliance scores. The American Association of Orthodontists asserts that fixed-dose combinations "limit clinicians' ability to customize dosing regimens."

Scientists formulating combination drugs face challenges in the development stages of multi-drug formulations such as compatibility issues among active ingredients and excipients affecting solubility and dissolution. For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed.

Obsessive-compulsive disorder, social anxiety, and anxiety are all commonly likely to comorbidity with tics; as such, polypharmacy necessitates secondary or even tertiary solutions to treat these aspects of the umbrella term: OCD alone is often resolved clomipramine (a tricyclic antidepressant) anxietys with use of individual benzodiazepines or SSRIs for the former two conditions, and fluvoxamine or clomipramine first-line treatments for OCD and related disorders, such as hoarding or compulsive decluttering. But, where Attention-Deficit Hyperactivity Disorder, depression, or insomnia become a primary concern to the patient, it is only through polypharmacy (in this case, adding another antidepressant or a "booster, alongside a hypnotic soporific agent, and/or psychostimulants to both treat ADHD and counteract the sleep inertia, grogginess or hangover caused by the other evening medications).