Off-label use Unlicensed use Zuzana Baťová State Institute for Drug Control, Bratislava, Slovakia

Off-label use means all uses of a marketed drug not detailed in the summary of the product characteristics including therapeutic indication, use in age- subsets, appropriate strength (dosage), pharmaceutical form and route of administration.

Unlicensed use means all uses of a drug that has never received a European Marketing Authorisation as a medicinal for human use in either adults or children

European legislation does not require member states to prohibit the prescription or administration of medicines outside their authorised indications Medicines prescribed outside the term of marketing authorisation may be dispensed by pharmacists and administrated

Art.5 of Directive 2001/83 EC “A Member State may, in accordance with legislation in force and to fulfill special needs, exclude from the provisions of this Directive medicinal products supplied in response to a bona fide unsolicited order, formulated in accordance with the specifications of an authorized health-care professional and for use by an individual patient under his direct personal responsibility.”

Off- label/unlicensed use can occurs: drugs under development and undergoing authorized clinical trials, variations in marketing authorisation of the drug that have already been submitted but not approved or have been refused medicines that no longer have a relevant marketing authorization in individual Member State, because it has been suspended, revoked, not renewed, compassionate use

Frequency, examples in general 10-80%; higher rates younger vs older patients and hospital vs community settings oncology, < 50% pediatric (oncology), neonatology geriatric pregnant women

Avastin (bevacizumab) approved indication: treatment of adult patients with metastatic carcinoma of the colon or rectum, breast cancer, lung cancer off label use: to treat wet age-related macular degeneration (authorised product Lucentis (bevacizumab))

Neurontin (gabapentin) approved indication: to relieve peripheral neuropathic pain and as adjunctive therapy in the treatment of partial seizures. off-label use: bipolar disorder, insomnia, depression, restless leg syndrom bendamustin off label use: multiple myeloma, Mantle cell lymphoma

off-label promotion strictly prohibited (art. 87 Directive 2001/83/EC) The promotion of off-label use, regardless if by companies or governments, is never acceptable patients vs physicians vs budget-holders vs pharmaceutical industry

Misuse Drug abuse

Misuse Drug misuse is defined as the use of a substance/drug for a purpose not consistent with legal or medical guidelines (WHO, 2006). When a person takes a legal prescription medication for a purpose other than the reason it was prescribed, or when that person takes a drug not prescribed to him or her.

drug/substance abuse maladaptive pattern of substance use manifested by recurrent and significant adverse consequences related to the repeated use of substances (use of ilegal drugs/substance)

Criteria for a Diagnosis of Substance Dependence A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period: 1. Tolerance, as defined by either of the following: A) A need for markedly increased amounts of the substance to achieve intoxication or desired effect. B) Markedly diminished effect with continued use of the same amount of the substance. 2. Withdrawal, as manifested by either of the following: A) The characteristic withdrawal syndrome for the substance B) The same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms. 3. The substance is often taken in larger amounts or over a longer period than was intended. 4. There is a persistent desire or unsuccessful efforts to cut down or control substance use. 5. A great deal of time is spent in activities necessary to obtain the substance, use the substance (e.g., chain-smoking), or recover from its effects. 6. Important social, occupational, or recreational activities are given up or reduced because of substance use. 7. The substance use is continued despite knowledge of having a persistent or recurrent physical or mental health problem that is likely to have been caused or exacerbated by the substance

Drugs with high abuse potential Theraputic agents: benzodiazepines barbiturates other hypnotics and sedatives opiate analgesics and analogues Non-therapeutic agents (“streets” drugs) cannabis cocaine amfetamines LSD, psylocibin, phencyclidine and other hallucionegs solvents alcohol

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