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CINNARIZINE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cinnarizine is a piperazine derivative with antihistaminic, sedative, and calcium-channel blocking activity. Flunarizine is a difluorinated derivative of cinnarizine with a similar pharmacological profile.

Specific Substances

    A) CINNARIZINE
    1) Cinnarizinum
    2) 516-MD
    3) R-516
    4) R-1575
    5) 1-Benzhydryl-4-cinnamylpiperazine
    6) (E)-1-(Diphenylmethyl)-4-(3-phenylprop-2-enyl) piperazine
    7) Molecular Formula: C26-H28-N2
    8) CAS 298-57-7
    FLUNARIZINE
    1) R-14950
    2) trans-1-Cinnamyl-4-(4,4-difluorobenzhydryl)piperazine
    3) dihydrochloride
    4) Molecular Formula: C26-H26-F2-N2, 2HCl
    5) CAS 52468-60-7 (flunarizine)
    6) CAS 30484-77-6 (flunarizine hydrochloride)

Available Forms Sources

    A) FORMS
    1) Cinnarizine is available in Europe as 15 mg tablets, 25 mg tablets, 75 mg tablets, 75 mg capsules, and 75 mg/mL oral drops.
    2) Flunarizine is available in Mexico, Europe, and Asia as 5 mg capsules, 5.9 mg tablets, and 10 mg capsules.
    3) Cinnarizine and flunarizine are not currently available in the United States.
    B) USES
    1) Cinnarizine is used for the symptomatic treatment of nausea and vertigo, caused by Meniere's disease and other vestibular disorders, and for the prevention and treatment of motion sickness (JEF Reynolds , 1999). Cinnarizine has also been used in the management of various peripheral and cerebrovascular disorders.
    2) Flunarizine is used for migraine prophylaxis, for vertigo and vestibular disorders, and for peripheral and cerebrovascular disorders (JEF Reynolds , 1999). Flunarizine has also been considered as an adjunctive anti-epileptic agent in patients refractory to standard regimens.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) OVERDOSE -
    1) At the time of this review, there is no overdose information available. The following information is derived from adverse effects in humans at therapeutic dose.
    B) ADVERSE EFFECTS AT THERAPEUTIC DOSE -
    1) CNS effects, including drowsiness, headache, and extrapyramidal effects, are the primary adverse effects that may occur following therapeutic administration of cinnarizine and flunarizine.
    2) Blurred vision, tinnitus, weight gain, cholestasis, and impotence are rare occurrences that have been reported with cinnarizine and flunarizine therapy.
    0.2.7) NEUROLOGIC
    A) Somnolence, fatigue, headache, ataxia, and extrapyramidal effects, including dyskinesia and dystonia, may commonly occur with cinnarizine and flunarizine therapy.
    B) Insomnia is a rare occurrence that has been reported during flunarizine treatment.
    0.2.8) GASTROINTESTINAL
    A) Weight gain has been reported with therapeutic use of cinnarizine and flunarizine.
    B) Constipation and diarrhea may occur during cinnarizine or flunarizine therapy.
    0.2.18) PSYCHIATRIC
    A) Nightmares and hallucinations are rare occurrences reported with flunarizine therapy.
    0.2.20) REPRODUCTIVE
    A) Cinnarizine is in FDA pregnancy category C. At the time of this review, no data were available to assess the potential effects of this agent during lactation.

Laboratory Monitoring

    A) Serum cinnarizine and flunarizine levels are not clinically useful.
    B) Monitor liver function tests in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression.
    B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    D) Treatment is SYMPTOMATIC and SUPPORTIVE.

Range Of Toxicity

    A) The minimum lethal human dose to this agent has not been delineated. The maximum tolerated human exposure to this agent has not been delineated.

Clinical Effects

Gastrointestinal

    3.8.1) SUMMARY
    A) Weight gain has been reported with therapeutic use of cinnarizine and flunarizine.
    B) Constipation and diarrhea may occur during cinnarizine or flunarizine therapy.
    3.8.2) CLINICAL EFFECTS
    A) WEIGHT GAIN FINDING
    1) Weight gain was reported in four patients with cinnarizine therapy. The average weight increase was approximately 6 kilograms and was always associated with increased appetite and food intake (Navarro-Badenes et al, 1992).
    2) Weight gain occurred in several patients involved in a rising-dose flunarizine study (Handforth et al, 1995).
    3) During a clinical trial, weight gain was reported by 11 of 38 patients (28.9%) receiving cinnarizine therapy 75 mg three times daily for 6 weeks (Gananca et al, 1988).
    B) CONSTIPATION
    1) Constipation was reported as an adverse effect during cinnarizine and flunarizine therapy (Gananca et al, 1988; Holmes et al, 1984; Barber et al, 1980).
    C) DIARRHEA
    1) Diarrhea has been associated with therapeutic administration of cinnarizine and flunarizine (Holmes et al, 1984; Barber et al, 1980).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTASIS
    1) CASE REPORT - A 70-year-old male presented with a three-week history of progressive jaundice, weight loss, dark urine, and pale stools. The patient had been taking cinnarizine 15 mg three times daily three weeks prior to the onset of jaundice. Lab exams revealed a bilirubin concentration of 117 mcm/L, an ALT of 281 IU/L, and an AST 71 IU/L. A liver biopsy showed canalicular cholestasis. The patient's liver function returned to normal within 3 months after discontinuation of the cinnarizine (Moss et al, 1990).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) IMPOTENCE
    1) CASE REPORT - A 55-year-old male complained of erectile impotence three months after beginning cinnarizine therapy for treatment of postural vertigo. The patient's impotence disappeared within three days after cinnarizine withdrawal (Sempere et al, 1993).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) LICHENOID DERMATITIS
    1) CASE REPORT - A 72-year-old female began cinnarizine therapy and, 12 weeks later, developed lichen planus-like lesions on her lower extremities that progressively spread to her trunk. The lesions consisted of reddish-purple macules and papules, and many were bullous. The lesions disappeared within 4 weeks after treatment with griseofulvin and discontinuation of the cinnarizine. Rechallenge with cinnarizine, 150 mg daily for 2 days, caused severe itching and reactivation of the lesions. The patient's symptoms resolved within 2 weeks after drug cessation (Miyagawa et al, 1985).

Summary Of Exposure

    A) OVERDOSE -
    1) At the time of this review, there is no overdose information available. The following information is derived from adverse effects in humans at therapeutic dose.
    B) ADVERSE EFFECTS AT THERAPEUTIC DOSE -
    1) CNS effects, including drowsiness, headache, and extrapyramidal effects, are the primary adverse effects that may occur following therapeutic administration of cinnarizine and flunarizine.
    2) Blurred vision, tinnitus, weight gain, cholestasis, and impotence are rare occurrences that have been reported with cinnarizine and flunarizine therapy.

Heent

    3.4.3) EYES
    A) BLURRED VISION was reported in 3 patients following administration of 25 to 50 mg flunarizine (Handforth et al, 1995).
    3.4.4) EARS
    A) TINNITUS was reported in one patient 1 day after beginning combination therapy with cinnarizine and indomethacin. The tinnitus disappeared after discontinuation of cinnarizine (Narvaez et al, 1994). The database of the WHO International Programme for Drug Monitoring included other reports of tinnitus associated with cinnarizine therapy.
    3.4.6) THROAT
    A) DRY MOUTH was reported as an adverse effect following cinnarizine and flunarizine therapy (Barber et al, 1980; Towse, 1980; Holmes et al, 1984).

Neurologic

    3.7.1) SUMMARY
    A) Somnolence, fatigue, headache, ataxia, and extrapyramidal effects, including dyskinesia and dystonia, may commonly occur with cinnarizine and flunarizine therapy.
    B) Insomnia is a rare occurrence that has been reported during flunarizine treatment.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) Depression, somnolence, and fatigue are common occurrences following therapeutic administration of cinnarizine and flunarizine (Handforth et al, 1995; Gananca et al, 1988; Barber et al, 1980; Towse, 1980).
    B) HEADACHE
    1) Headache was reported as an adverse effect during cinnarizine therapy (Gananca et al, 1988; Barber et al, 1980; Towse, 1980).
    C) ATAXIA
    1) Ataxia was reported with high-dose flunarizine therapy (20 to 25 mg) (Handforth et al, 1995) and gait unsteadiness occurred in 3 patients following cinnarizine therapy (Towse, 1980).
    D) EXTRAPYRAMIDAL DISEASE
    1) Chronic administration of flunarizine or cinnarizine have been associated with development of Parkinsonism and exacerbation of existing Parkinson's disease (Marti-Masso & Poza, 1998; Mangone & Herskovitz, 1989) Masso et al, 1987). Symptoms are generally reversible upon discontinuation of the medication.
    2) CASE REPORT - A 32-year-old female developed a predominantly right-sided postural tremor in her upper limbs approximately 2 months after beginning flunarizine therapy, 10 mg/day, for migraine prophylaxis. The tremor completely resolved within one month after discontinuation of the flunarizine (Baldrati et al, 1987).
    3) CASE SERIES - Micheli et al (1987) reported the development of Parkinsonism, akathisia, and orofacial dyskinesia in several patients following long-term administration of cinnarizine or flunarizine. The medication period prior to the onset of symptoms ranged from approximately 3 days to 1.5 years. The majority of symptoms were reversible upon discontinuation of the medication.
    4) RISK FACTORS - Older patients and patients with a family history for essential tremors or Parkinson's disease may be at risk for developing cinnarizine- or flunarizine-related parkinsonism (Gimenez-Roldan & Mateo, 1991).
    E) INSOMNIA
    1) Volta et al (1990) described two patients experienced insomnia approximately a week after beginning flunarizine therapy for migraine prophylaxis. The insomnia resolved upon discontinuation of the flunarizine. Rechallenge of the flunarizine, in one patient, resulted in the reappearance of the insomnia.

Reproductive

    3.20.1) SUMMARY
    A) Cinnarizine is in FDA pregnancy category C. At the time of this review, no data were available to assess the potential effects of this agent during lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) CINNARIZINE - FDA pregnancy category C (Briggs et al, 1998).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of this agent during lactation.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum cinnarizine and flunarizine levels are not clinically useful.
    B) Monitor liver function tests in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum levels of cinnarizine and flunarizine are not clinically useful.
    2) Monitor liver function tests in symptomatic patients.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor for CNS depression.

Methods

    A) CHROMATOGRAPHY
    1) A high-performance liquid chromatographic method was used to determine the presence of cinnarizine in human plasma. The detection limit, using this method, was approximately 2 ng/mL of plasma (Nitsche & Mascher, 1982).
    2) Woestenborghs et al (1982) described using a gas chromatographic method to determine the presence of cinnarizine and flunarizine in human plasma. The detection limit of both compounds was 0.5 ng/mL.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Serum cinnarizine and flunarizine levels are not clinically useful.
    B) Monitor liver function tests in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression.
    B) ACTIVATED CHARCOAL -
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    C) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is SYMPTOMATIC and SUPPORTIVE.
    B) DRUG-INDUCED DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).

Range Of Toxicity

Summary

    A) The minimum lethal human dose to this agent has not been delineated. The maximum tolerated human exposure to this agent has not been delineated.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) CINNARIZINE -
    a) VERTIGO - The usual dose, in the United Kingdom, is 30 milligrams orally three times daily. In other European countries, the dose is 75 milligrams orally once or twice daily (JEF Reynolds , 1999).
    b) MOTION SICKNESS - 30 milligrams may be taken 2 hours before the start of travel and 15 milligrams every 8 hours during travel (JEF Reynolds , 1999).
    c) CEREBROVASCULAR DISORDERS - 75 milligrams orally one to three times daily (JEF Reynolds , 1999).
    d) PERIPHERAL VASCULAR DISORDERS - 75 milligrams orally two or three times daily (JEF Reynolds , 1999).
    2) FLUNARIZINE -
    a) The usual dose is 5 to 10 milligrams orally daily, preferably at bedtime (JEF Reynolds , 1999). Doses are usually expressed in terms of equivalent amounts of flunarizine.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) CINNARIZINE -
    1) LD50- (ORAL)MOUSE:
    a) >4500 mg/kg
    2) LD50- (ORAL)RAT:
    a) >6500 mg/kg
    B) FLUNARIZINE -
    1) LD50- (ORAL)MOUSE:
    a) 960 mg/kg (RTECS, 1999)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) CINNARIZINE -
    1) Cinnarizine is a long-acting, potent inhibitor of potassium chloride- depolarization-induced peripheral vasoconstriction, acting via selective inhibition of calcium influx into depolarized cells. The availability of free calcium ions for induction and maintenance of contraction in smooth muscle is then reduced (Schuermans et al, 1971; Verhaegen et al, 1974)
    2) Cinnarizine directly antagonizes the stimulated influx of extracellular calcium, modifying intracellular calcium adenosine triphosphate balance in erythrocytes, thus increasing their flexibility and decreasing whole blood viscosity. It has demonstrated some clinical efficacy in decreasing blood viscosity in patients with intermittent claudication, via augmented red blood cell deformability, and anti-vasoconstrictive effects (Towse, 1980; Barber et al, 1980).
    B) FLUNARIZINE -
    1) Flunarizine selectively blocks calcium entry into the cells when excess calcium is stimulated to enter the cells, thus preventing cell damage, in certain tissues, due to calcium overload (Holmes et al, 1984).
    2) Flunarizine does not appear to interfere with normal cellular calcium homeostasis, exert significant negative inotropic effects on normal heart muscle, and does not appear to influence the myogenic tone of blood vessels (Holmes et al, 1984).

Physicochemical

Physical Characteristics

    A) CINNARIZINE is a white or almost white powder that is insoluble in water, slightly soluble in alcohol and methyl alcohol, and soluble in acetone and dichloromethane (JEF Reynolds , 1999).

Molecular Weight

    A) CINNARIZINE - 368.5 (JEF Reynolds , 1999)
    B) FLUNARIZINE - 477.4 (JEF Reynolds , 1999).

References

General Bibliography

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