Book on hepatitis from page 258 to 265

Book on hepatitis from page 258 to 265

258  Hepatology 2012
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262  Hepatology 2012
15. Management of Adverse Drug Reactions
Martin Schaefer and Stefan Mauss
Introduction
Good adherence is a key factor for success in the treatment of hepatitis C. However,
almost all patients on treatment with interferon and ribavirin will experience adverse
events that can threaten good adherence. Therefore, proactive clinical management
is crucial to avoid suboptimal therapy and treatment discontinuations.
The most common adverse events in patients on treatment with pegylated
interferon plus ribavirin are flu-like symptoms, myalgia, sleep disturbances,
asthenia, gastrointestinal disorders and depressive episodes (Table 1).
Table 1. Incidence of most reported IFN α-induced psychiatric side effects. Data
from Outpatient Department, Essen-Mitte Clinics, Essen.
Psychiatric side effects  Incidence
Fatigue
Sleep disturbances
Irritability
Cognitive disturbances with impairments of concentration and memory
Depressive episodes
Mild
Moderate
Severe
Delirium, psychosis
Suicidal syndrome
50-80%
45-65%
60-85%
45-60%
20-60%
30-60%
20-30%
5-10%
1-6%
<1%
For most adverse events, clinical trials with dose adjustment have not been done,
and because of this, recommendations in this review are necessarily partially based
on clinical experience.
Flu-like symptoms, fever, arthralgia and myalgia
Flu-like symptoms, fever, arthralgia and myalgia appear a few hours after the PEG-IFN injection and may last for up to three days. One common approach is the use of
Management of Adverse Drug Reactions  263
paracetamol or other NSAIDs immediately before or after the injection of
interferon. Flu-like symptoms usually diminish spontaneously over the first weeks
of treatment (Figure 1).
Low platelets are a contraindication for the use of acetylsalicylic acid, diclofenac
or ibuprofen because of the inhibition of platelet aggregation. High doses of
paracetamol may result in liver toxicity. Doses exceeding 2 g/day of paracetamol
are not recommended.
Figure 1. Time course of interferon-associated adverse events.
Gastrointestinal disorders
Nausea can be mitigated by prokinetic agents such as metoclopramide or
domperidone taken before the ribavirin. This may also positively influence the
frequently observed loss of appetite.
Dry mouth has been reported as a result of inhibition of saliva production, a
frequent complication of ribavirin, which may continue after discontinuation of
therapy.
Weight loss
The average weight loss in interferon-based controlled studies is around 6-10% for a
treatment period of 48 weeks (Seyam 2004). This may be predominantly due to loss
of appetite and reduction in calorie intake. The weight loss is rapidly reversible
upon discontinuation of therapy.
Asthenia and fatigue
Asthenia and fatigue are frequent complaints of patients that usually increase slowly
in intensity over the first couple weeks of therapy (Figure 1). In patients with
marked anemia these symptoms can be improved by raising low hemoglobin with
264  Hepatology 2012
the use of erythropoietin, reduction of ribavirin or red blood cell transfusion
(Pockros 2004). Asthenia is also reported by patients without marked anemia. In
these patients hypothyroidism may be the explanation. Symptomatic treatment of
asthenia and fatigue in patients without an underlying complication such as anemia,
depression or hypothyroidism is difficult.
Chronic fatigue has been successfully treated in individual cases with
antidepressants or tryptophan (Sammut 2002; Schaefer 2008). A first prospective
randomised controlled trial showed superior effects of the 5-HT3 receptor
antagonist ondansetron compared to placebo (Piche 2005). However, currently
available data does not offer specific treatment recommendations.
Cough and dyspnea
Cough while on therapy is frequently reported and is most probably due to edema of
the mucosa of the respiratory system. Therefore, advanced, not well-controlled
asthma bronchiale may be a contraindication for hepatitis C therapy. Dyspnea is
another frequent complaint with a more complex etiology involving mucosa
swelling, anemia and asthenia.
Disorders of the thyroid gland
Hypothyroidism while on interferon-based therapy is reported with an incidence of
3-10% (Bini 2004, Tran 2005). Hyperthyroidism is less frequently observed with an
incidence of 1-3% (Bini 2004, Tran 2005). Interferon-induced thyroiditis or the
induction of thyroid antibodies is reported as an underlying mechanism.
Hypothyroidism is treated via substitution of thyroid hormone whereas clinical
symptomatic hyperthyroidism may be treated with ß-blockers or carbimazole.
Premature termination of interferon-based therapy is usually not necessary. About
half of the cases of hypothyroidism are reversible upon discontinuation of
interferon-based therapy, although some cases may need prolonged periods of
thyroid hormone replacement therapy.
Psychiatric adverse events
Incidence and profile of psychiatric adverse events
The most commonly emerging IFN α-induced psychiatric adverse events are
outlined in Table 1. However, data on the frequency of psychiatric side effects
differs depending on the design of the trial. Most hepatological trials are only
monitored for depression as a single symptom without using depression scales or
diagnostic instruments, leading to an underreporting of mild to moderate depressive
episodes. Most psychiatric trials used self-rating scales (e.g., SDS-scale, BDI-Scale)
or monitor patients via expert rating scales (Hamilton Depression Scale [HAMDS]
or Montgomery Asperg Depression Scale [MADRS]) to detect depressive
syndromes and treatment-related mood changes even if total scores do not fulfil
DSM-IV criteria for major depression. Regarding these more sensitive psychiatric
rating methods, over 50% of patients suffer from sleep disorders, chronic fatigue,
irritability or cognitive disturbances (Schaefer 2007,  Schaefer 2002,  Dieperink
2000, Renault 1987). Anxiety occurs in 30-45%, especially during the first 2 months
Management of Adverse Drug Reactions  265
of treatment. Mild depression with symptoms like reduced self-esteem, anhedonia,
loss of interest, rumination, a diminished libido and spontaneous crying can be
observed in 30-60% of the patients. 20-30% of treated patients develop moderate to
severe depressive episodes (Bonnaccorso 2002,  Dieperink 2000,  Renault 1987,
Schaefer 2002, Malaguarnera 2002). Major depression has been reported in 15-55%
(Schäfer 2007). Suicidal ideation is seen in 5-6% of patients, while suicide attempts
have been reported in single cases (Janssen 1994, Sockalingam 2010). Mania has
been reported as a sporadically appearing side effect. Contrary to assumptions,
patients with pre-existing psychiatric disturbances do not appear to have a greater
risk for development of depression or attempting suicide (Schaefer 2007, Schaefer
2003, Pariante 2002). However, patients with intravenous drug abuse not stabilized
in a substitution treatment program (e.g., methadone) seem more likely to
discontinue treatment in the first three months compared to controls (Schaefer 2003,
Mauss 2004, Schaefer 2007).
Antidepressants frequently used in trials are selective serotonin re-uptake
inhibitors (SSRIs) such as citalopram, escitalopram, paroxetine or sertraline. The
introduction of SSRIs and other current antidepressants has markedly improved the
adverse event profile of antidepressants. Therefore, depending on the major
symptoms, current sedating or activating antidepressants, especially SSRIs, are
treatment of choice for interferon-induced depressive mood disorders (Table 2). In
patients with predominantly agitation and aggression, other strategies, e.g., modern
antipsychotics, may be added.
The efficacy of antidepressants for the treatment of interferon α-induced
depression has been shown in several open uncontrolled cohorts (Farah 2002,
Gleason 2002, Kraus 2001, Schramm 2000, Hauser 2002, Gleason 2005). In a first
prospective randomized controlled trial an improvement of depressive symptoms
after treatment of IFN-associated depression was shown with citalopram compared
to placebo (Kraus 2008). In particular because of the favourable adverse event
profile, SSRIs seem to be most appropriate for treatment of IFN α-associated
depressive symptoms. However, antidepressants with different receptor profiles
(i.e., mirtazapine) and classic antidepressants (i.e., nortriptyline) are also effective
(Kraus 2001, Valentine 1995). Nevertheless, tricyclic antidepressants should be
used as second choice because of pharmacological interactions, anticholinergic side
effects, a higher risk for development of delirium, and liver or myocardial toxicity.
To reduce early occurring adverse events of SSRIs (headache, nausea, agitation),
treatment with antidepressants should be started at a low dose with subsequent dose
increase depending on the effect and tolerability. In general, a therapeutically
relevant antidepressive effect cannot be expected before day 8-14 of treatment. In
case of non-response, the dose can be escalated. Treatment adherence should be
assessed by monitoring serum levels before patients are switched to a different
antidepressant.
Benzodiazepines can be given for a short period in case of severe sleep
disturbances, irritability or depression. However, benzodiazepines should be
avoided in patients with a history of IV drug or alcohol over-use because of their
potential to induce addiction.
In the case of psychotic symptoms, antipsychotics (e.g., risperidone, olanzapine)
can be used at low doses, but patients should be monitored carefully by a