Adverse Drug Withdrawal Events

It is important to be aware of possible adverse drug withdrawal events (ADWE). These events may be caused by physiological withdrawal reaction, but it is also possible that the underlying disease is worsened. An example of ADWE is delirium or seizures that may occur after abrupt discontinuing of benzodiazepines or alcohol. 

There is an increased risk of adverse drug reactions and adverse drug withdrawal events in old age... 

The number on the outside of the case is required to be numeric or alphanumeric, not the name of the patient. Patient names are not permitted to be publicly disclosed in the context of a MedWatch report according to 21 CFR 21.63(f). The initial report is the first reported information received by the company about an individual s adverse drug experience. There must be a prompt attempt to obtain follow-up information about each initial report. The attempt(s) are made according to the company s written procedures. If the written safety procedures are not followed, the safety reports are not appropriately submitted, or the safety records are not appropriately kept, FDA has the authority under Section 80 of Part 315 to withdraw the market NDA. The follow-up report is the format for submitting additional information about an experience. Each case regards only one individual unless the experience is both temporally and clinically unrelated to a second event experienced by the same person taking the same drug product. 

Approximately 10% of new chemical entities (NCEs) show serious adverse drug reactions (ADRs) after market launch. Such events usually result in new black box warnings by the US Food and Drug Administration (FDA), label change or market withdrawal. The most common causes for these actions are hepatic toxicity, hematologic toxicity and cardiovascular toxicity [2], Reasons for such ADRs, which are identified only after NCEs are launched on the market, include the narrow spectrum of clinical disorders and participating patient profiles in clinical studies as well as the fact that serious ADRs are often rare and that the number of patient exposures required to identify such occurrences sometimes may range over a few millions [3],... 

Intracavernosal alprostadil was effective and well tolerated in the treatment of erectile dysfunction, according to the results of a 6-month study (funded by Pharmacia Upjohn) in 848 men (mean age 52 years) with at least a 4-month history of erectile dysfunction (12). This is provided that the individual dose is established by titration and patients receive training in injection techniques and periodic supervision during treatment. An initial dose was established for each patient and the patients then administered the alprostadil themselves at home. Of 727 evaluable patients, 682 (94%) had at least one erectile response after the injection of alprostadil, and 88% of injections lead to a satisfactory sexual response. The most commonly reported adverse event was penile pain, reported by 44% of patients, but only after 8% of injections. In just over half of the patients who had penile pain, the condition was reported as mild. Prolonged erection, penile fibrosis, and priapism occurred in 8,4, and 0.9% of patients respectively. Treatment was withdrawn because of medical events in 4% of patients, and drug-related events accounted for treatment withdrawal in 2% of patients. 

In a placebo-controlled study of 1142 hypercholestero-lemic patients treated with pravastatin for 8-16 weeks, the numbers of adverse drug experiences were similar in the treated and untreated individuals (1). Rash was the only adverse clinical event that was different (4.0 versus 1.1%). However, in the same patients withdrawal of therapy during follow-up was thought to be necessary in 3.2% of those given pravastatin alone. Myopathy was observed in one instance only, and increases in creatine kinase activity in those taking pravastatin did not differ significantly from controls. There were marked persistent increases in transaminases in 1.1%, with no cases of symptomatic hepatitis. Pravastatin is believed to have a particularly low potential for nervous system-related adverse effects, as it has not been shown to enter the cerebrospinal fluid, and clinical experience suggests that muscle toxicity occurs less often with pravastatin than with lovastatin (2). 

There are two different kinds of life-threatening adverse events associated with drug withdrawal physical risks and emotional risks. The most common physical risks are seizures and blood pressure spikes. The most common emotional risks are violence against self and others and manic or psychotic reactions. 

Gerety, M.B. Cornell, J.E. Plichta, D.T. Eimer, M. Adverse events related to drugs and drug withdrawal in nursing home residents. J. Am. Geriatr. Soc. 1993, 41, 1326-1332. 

In 110 children with ascariasis or trichuriasis the efficacy of a single dose of albendazole 400 mg has been compared with that of nitazoxanide 100 mg bd for 3 days in children aged 1-3 years and 200 mg bd for 3 days in children aged 4-11 years (16). Nitazoxanide cured 89 and 89% of the cases of ascariasis and trichuriasis respectively. Albendazole cured 91 and 58% of the cases of ascariasis and trichuriasis respectively. Abdominal pain (n — 9), nausea (n = 1), diarrhea (n — 2), and headache (n — 1) were reported as mild adverse effects in 105 patients who took nitazoxanide, and abdominal pain (n — 1), nausea (n = 1), and vomiting (n — 1) were reported as adverse effects in 54 patients who took albendazole. AU the adverse events were mild and transient and drug withdrawal was not necessary. 

The effect of sildenafil on arterial pressure has been tested in 16 hypertensive men taking amlodipine 5-10 mg/day (23). Sildenafil did not affect amlodipine pharmacokinetics, but caused a further additive fall in blood pressure. Adverse events with the combination of sildenafil and amlodipine, headache, dyspepsia, and nausea, did not require drug withdrawal. 

Rheumatoid arthritis Double-blind randomized controlled trial 24 weeks Leflunomide 100 mg/day for 2 days, then 10 mg/day (n = 130) versus placebo (n = 133), both with methotrexate 10-25 mg/day American College of Rheumatology 20 rates at 24 weeks leflunomide -i- methotrexate 46% versus placebo -i- methotrexate 20% similar drug withdrawal and adverse events rates (18)... 

In patients with mucoviscidosis treated with pefloxacin the most common adverse event was arthropathy, and the symptoms disappeared 3 days to 3 months after drug withdrawal (6). 

In an open, non-comparative, multicenter study in immunocompromised patients with proven or probable invasive aspergillosis, 116 patients were treated with intravenous voriconazole 6 mg/kg bd twice and then 3 mg/kg bd for 6-27 days, followed by 200 mg bd orally for up to 24 weeks voriconazole was given as primary therapy in 60 (7). There were good responses in 56 16 had a complete response and 40 a partial response there was a stable response in 24 patients. There were adverse events in 91% of the patients who received at least one dose of voriconazole, but only 15% were attributed to the drug. The most common adverse events attributed to voriconazole were skin rash (8.7%), reversible visual disturbances (11%), and raised liver function tests (15%). There was evidence of a concentration-dependent incidence of adverse events six of seven patients with voriconazole plasma concentrations over 10 pg/ml developed adverse events requiring drug withdrawal. 

CV safety issues are a major cause of drug attrition in both the nonclinical and clinical phases of drug discovery and development, and an estimated 45% of drug withdrawals during the postmarketing phase are atttibuted to adverse CV events, such as myocardial infarction, arrhythmia, and cardiac arrest (Laverty et al., 2011 Pierson et al., 2013). 

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