Side Effects of Klonopin (clonazepam)

Klonopin (clonazepam) is an anti-anxiety medication in the benzodiazepine family, used for short-term relief of symptoms of anxiety, to treat panic disorder, and to treat certain types of seizures, specifically petit mal seizures, akinetic seizures, and myoclonus, as well as Lennox-Gastaut syndrome. 

Klonopin may be used alone or together with other medications for these seizure disorders. Klonopin and other benzodiazepines act by enhancing the effects of gamma-aminobutyric acid (GABA) in the brain. 

GABA is a neurotransmitter (a chemical that nerve cells use to communicate with each other) that inhibits brain activity. It is believed that excessive activity in the brain may lead to anxiety or other psychiatric disorders. 

Common side effects of Klonopin include

• sedation,
• dizziness,
• depression,
• loss of orientation,
• headache,
• weakness,
• unsteadiness,
• sleep disturbance,
• lack of inhibition,
• fatigue,
• amnesia,
• confusion,
• changes in sexual desire,
• rash, and 
• irritability.

Serious side effects of Klonopin include

• respiratory depression,
• fainting,
• enlarged liver,
• withdrawal symptoms (if stopped suddenly),
• increased heart rate,
• low blood pressure,
• blood disorders, and
• increased risk of suicidal thinking and behavior. 

Drug interactions of Klonopin include other drugs that slow the brain's processes, such as alcohol, barbiturates, and narcotics, because Klonopin, like all other benzodiazepines, accentuates the effects of these drugs and leads to increased sedation. 

Klonopin and other benzodiazepines have been associated with fetal damage, including congenital malformations, when taken by pregnant women in their first trimester. Klonopin is best avoided in the first trimester and probably throughout pregnancy. 

Benzodiazepines are secreted in breast milk. Mothers who are breastfeeding should not take Klonopin.

The most common side effects associated with clonazepam are sedation, which is reported in approximately half of patients. Dizziness is reported in one-third of patients.

Other common side effects include:

• A feeling of depression,
• Loss of orientation,
• Headache,
• Weakness,
• Unsteadiness, and
• Sleep disturbance
• Lack of inhibition
• Fatigue
• Amnesia
• Confusion
• Changes in sexual desire
• Rash
• Irritability

Other serious side effects of clonazepam include:

• Respiratory depression
• Fainting
• Enlarged liver
• Withdrawal symptoms (if stopped suddenly)
• Increased heart rate
• Low blood pressure
• Blood disorders

Other serious adverse reactions:

• Antiepileptic medications have been associated with an increased risk of suicidal thinking and behavior. Anyone considering the use of antiepileptic drugs must balance this risk of suicide with the clinical need for the antiepileptic drug. Patients who begin antiepileptic therapy should be closely observed for clinical worsening, suicidal thoughts or unusual changes in behavior.

The adverse experiences for Klonopin are provided separately for patients with seizure disorders and with panic disorder.

Seizure Disorders

The most frequently occurring side effects of Klonopin are referable to CNS depression. Experience in treatment of seizures has shown that drowsiness has occurred in approximately 50% of patients and ataxia in approximately 30%.

In some cases, these may diminish with time; behavior problems have been noted in approximately 25% of patients. Others, listed by system, including those identified during postapproval use of Klonopin are:

• Cardiovascular: Palpitations
• Dermatologic: Hair loss, hirsutism, skin rash, ankle and facial edema
• Gastrointestinal: Anorexia, coated tongue, constipation, diarrhea, dry mouth, encopresis, gastritis, increased appetite, nausea, sore gums
• Genitourinary: Dysuria, enuresis, nocturia, urinary retention
• Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia
• Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase
• Musculoskeletal: Muscle weakness, pains
• Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight loss or gain
• Neurologic: Abnormal eye movements, aphonia, choreiform movements, coma, diplopia dysarthria, dysdiadochokinesis, ‘‘glassy-eyed’’ appearance, headache, hemiparesis, hypotonia, nystagmus, respiratory depression, slurred speech, tremor, vertigo
• Psychiatric: Confusion, depression, amnesia, hysteria, increased libido, insomnia, psychosis (the behavior effects are more likely to occur in patients with a history of psychiatric disturbances. The following paradoxical reactions have been observed:
  • irritability,
  • aggression,
  • agitation,
  • nervousness,
  • hostility,
  • anxiety,
  • sleep disturbances,
  • nightmares,
  • abnormal dreams,
  • hallucinations.
• Respiratory: Chest congestion, rhinorrhea, shortness of breath, hypersecretion in upper respiratory passages

Panic Disorder

• Adverse events during exposure to Klonopin were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing.
• Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories.
• In the tables and tabulations that follow, CIGY dictionary terminology has been used to classify reported adverse events, except in certain cases in which redundant terms were collapsed into more meaningful terms, as noted below.
• The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Findings Observed In Short-Term, Placebo-Controlled Trials

Adverse Events Associated With Discontinuation Of Treatment

Overall, the incidence of discontinuation due to adverse events was 17% in Klonopin compared to 9% for placebo in the combined data of two 6- to 9-week trials. The most common events (≥1%) associated with discontinuation and a dropout rate twice or greater for Klonopin than that of placebo included the following:

Table 2 Most Common Adverse Events (≥1%) Associated with Discontinuation of Treatment

Adverse Events Occurring At An Incidence Of 1% Or More Among Klonopin-Treated Patients

• Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy of panic disorder from a pool of two 6- to 9-week trials.
• Events reported in 1% or more of patients treated with Klonopin (doses ranging from 0.5 to 4 mg/day) and for which the incidence was greater than that in placebo-treated patients are included.
• The prescriber should be aware that the figures in Table 3 cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials.
• Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators.
• The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence in the population studied.

Table 3 Treatment-Emergent Adverse Event Incidence in 6- to 9-Week Placebo-Controlled Clinical Trials*

Commonly Observed Adverse Events

Table 4 Incidence of Most Commonly Observed Adverse Events* in Acute Therapy in Pool of 6- to 9-Week Trials

Treatment-Emergent Depressive Symptoms

• In the pool of two short-term placebo-controlled trials, adverse events classified under the preferred term “depression” were reported in 7% of Klonopin-treated patients compared to 1% of placebo-treated patients, without any clear pattern of dose relatedness.
• In these same trials, adverse events classified under the preferred term “depression” were reported as leading to discontinuation in 4% of Klonopin-treated patients compared to 1% of placebo-treated patients.
• While these findings are noteworthy, Hamilton Depression Rating Scale (HAM-D) data collected in these trials revealed a larger decline in HAM-D scores in the clonazepam group than the placebo group suggesting that clonazepamtreated patients were not experiencing a worsening or emergence of clinical depression.

Other Adverse Events Observed During The Premarketing Evaluation Of Klonopin In Panic Disorder

Following is a list of modified CIGY terms that reflect treatment-emergent adverse events reported by patients treated with Klonopin at multiple doses during clinical trials.

All reported events are included except those already listed in Table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and events reported only once and which did not have a substantial probability of being acutely life-threatening.

It is important to emphasize that, although the events occurred during treatment with Klonopin, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency.

These adverse events were reported infrequently, which is defined as occurring in 1/100 to 1/1000 patients.

• Body as a Whole: weight increase, accident, weight decrease, wound, edema, fever, shivering, abrasions, ankle edema, edema foot, edema periorbital, injury, malaise, pain, cellulitis, inflammation localized
• Cardiovascular Disorders: chest pain, hypotension postural
• Central and Peripheral Nervous System Disorders: migraine, paresthesia, drunkenness, feeling of enuresis, paresis, tremor, burning skin, falling, head fullness, hoarseness, hyperactivity, hypoesthesia, tongue thick, twitching
• Gastrointestinal System Disorders: abdominal discomfort, gastrointestinal inflammation, stomach upset, toothache, flatulence, pyrosis, saliva increased, tooth disorder, bowel movements frequent, pain pelvic, dyspepsia, hemorrhoids
• Hearing and Vestibular Disorders: vertigo, otitis, earache, motion sickness
• Heart Rate and Rhythm Disorders: palpitation
• Metabolic and Nutritional Disorders: thirst, gout
• Musculoskeletal System Disorders: back pain, fracture traumatic, sprains and strains, pain leg, pain nape, cramps muscle, cramps leg, pain ankle, pain shoulder, tendinitis, arthralgia, hypertonia, lumbago, pain feet, pain jaw, pain knee, swelling knee Platelet, Bleeding and Clotting Disorders: bleeding dermal
• Psychiatric Disorders: insomnia, organic disinhibition, anxiety, depersonalization, dreaming excessive, libido loss, appetite increased, libido increased, reactions decreased, aggression, apathy, disturbance in attention, excitement, anger, hunger abnormal, illusion, nightmares, sleep disorder, suicide ideation, yawning
• Reproductive Disorders, Female: breast pain, menstrual irregularity
• Reproductive Disorders, Male: ejaculation decreased
• Resistance Mechanism Disorders: infection mycotic, infection viral, infection streptococcal, herpes simplex infection, infectious mononucleosis, moniliasis
• Respiratory System Disorders: sneezing excessive, asthmatic attack, dyspnea, nosebleed, pneumonia, pleurisy
• Skin and Appendages Disorders: acne flare, alopecia, xeroderma, dermatitis contact, flushing, pruritus, pustular reaction, skin burns, skin disorder
• Special Senses Other, Disorders: taste loss
• Urinary System Disorders: dysuria, cystitis, polyuria, urinary incontinence, bladder dysfunction, urinary retention, urinary tract bleeding, urine discoloration Vascular (Extracardiac) Disorders: thrombophlebitis leg
• Vision Disorders: eye irritation, visual disturbance, diplopia, eye twitching, styes, visual field defect, xerophthalmia

Effect Of Concomitant Use Of Benzodiazepines And Opioids

• The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration.
• Benzodiazepines interact at GABAA sites, and opioids interact primarily at mu receptors.
• When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.
• Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.

Effect Of Clonazepam On The Pharmacokinetics Of Other Drugs

• Clonazepam does not appear to alter the pharmacokinetics of carbamazepine or phenobarbital.
• Clonazepam has the potential to influence concentrations of phenytoin.
• Monitoring of phenytoin concentration is recommended when clonazepam is co-administrated with phenytoin. The effect of clonazepam on the metabolism of other drugs has not been investigated.

Effect Of Other Drugs On The Pharmacokinetics Of Clonazepam

• Literature reports suggest that ranitidine, an agent that decreases stomach acidity, does not greatly alter clonazepam pharmacokinetics.
• In a study in which the 2 mg clonazepam orally disintegrating tablet was administered with and without propantheline (an anticholinergic agent with multiple effects on the GI tract) to healthy volunteers, the AUC of clonazepam was 10% lower and the Cmax of clonazepam was 20% lower when the orally disintegrating tablet was given with propantheline compared to when it was given alone.
• The selective serotonin reuptake inhibitors sertraline (weak CYP3A4 inducer) and fluoxetine (CYP2D6 inhibitor), and the anti-epileptic drug felbamate (CYP2C19 inhibitor and CYP3A4 inducer) do not affect the pharmacokinetics of clonazepam.
• Cytochrome P- 450 inducers, such as phenytoin, carbamazepine, lamotrigine, and phenobarbital induce clonazepam metabolism, causing an approximately 38% decrease in plasma clonazepam levels.
• Although clinical studies have not been performed, based on the involvement of the cytochrome P-450 3A family in clonazepam metabolism, inhibitors of this enzyme system, notably oral antifungal agents (e.g., fluconazole), should be used cautiously in patients receiving clonazepam because they may impair the metabolism of clonazepam leading to exaggerated concentrations and effects.

Pharmacodynamic Interactions

• The CNS-depressant action of the benzodiazepine class of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and by other anticonvulsant drugs.

Drug Abuse And Dependence

Controlled Substance Class

• Clonazepam is a Schedule IV controlled substance.

Physical And Psychological Dependence

• Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (e.g., convulsions, psychosis, hallucinations, behavioral disorder, mood changes, tremor, abdominal and muscle cramps) have occurred following abrupt discontinuance of clonazepam.
• The more severe withdrawal symptoms have usually been limited to those patients who received excessive doses over an extended period of time.
• Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months.
• Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving clonazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.
• Following the short-term treatment of patients with panic disorder in Studies 1 and 2, patients were gradually withdrawn during a 7-week downward-titration (discontinuance) period.
• Overall, the discontinuance period was associated with good tolerability and a very modest clinical deterioration, without evidence of a significant rebound phenomenon.
• However, there are not sufficient data from adequate and well-controlled long-term clonazepam studies in patients with panic disorder to accurately estimate the risks of withdrawal symptoms and dependence that may be associated with such use.