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RANOLAZINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ranolazine is a piperazine derivative anti-anginal agent.

Specific Substances

    1) Ranolazine hydrochloride
    2) CVT-303
    3) KEG-1295
    4) RS-43285
    5) RS-43285-193
    6) CAS 95635-55-5 (ranolazine)
    7) CAS 95635-56-6 (ranolazine hydrochloride)
    1.2.1) MOLECULAR FORMULA
    1) C24-H33-N3-O4 (Prod Info RANEXA(TM) extended-release tablets, 2006)

Available Forms Sources

    A) FORMS
    1) Ranolazine is available as 500 mg and 1000 mg extended-release tablets for oral administration (Prod Info RANEXA(R) oral extended release tablets, 2013).
    B) USES
    1) Ranolazine is indicated for the treatment of chronic angina in patients who have not adequately responded to treatment with other antianginal drugs (Prod Info RANEXA(R) oral extended release tablets, 2013).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ranolazine is used in the treatment of chronic angina.
    B) PHARMACOLOGY: Ranolazine is a cardioselective antiischemic agent (piperazine derivative) that modulates myocardial metabolism by partially inhibiting fatty acid oxidation, thereby increasing glucose oxidation and generating more adenosine triphosphate (ATP) per molecule of oxygen consumed. The antianginal and antiischemic action of ranolazine is not dependent upon heart rate or blood pressure reduction and does not increase myocardial workload.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Commonly reported adverse effects with therapeutic administration include: dizziness, headache, constipation, and nausea. Dose-dependent QT interval prolongation may occur with ranolazine therapy.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited data. Anticipated effects following ranolazine overdose include: dizziness, nausea/vomiting, dose-dependent QT interval prolongation, diplopia, paresthesia, and confusion.
    2) SEVERE TOXICITY: Limited data. Significant QT prolongation may develop, however, there is limited experience with high doses (greater than 1000 mg twice daily) or exposure. While the clinical significance of this effect is unknown with ranolazine, other drugs with this potential have been associated with torsades de pointes-type dysrhythmias and sudden death. Syncope with prolonged loss of consciousness may develop secondary to torsades do pointes. Cardiac dysrhythmias and significant alterations in CNS function may develop.
    0.2.20) REPRODUCTIVE
    A) There are no available data on the use of ranolazine in pregnant or breastfeeding women. Studies in rats and rabbits demonstrated no evidence of fetal or pup harm after the maternal administration of ranolazine. The developmental and health benefits of breastfeeding should be considered against the mother's clinical need for ranolazine and the potential adverse effects on the breastfed infant.

Laboratory Monitoring

    A) Serum ranolazine levels are not clinically useful in managing overdose.
    B) Institute continuous ECG monitoring and obtain an ECG; QT interval prolongation may occur.
    C) Monitor vital signs and neuro status.
    D) Monitor serum electrolytes (including magnesium and calcium) and renal function.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Obtain a baseline ECG and institute continuous cardiac monitoring. Monitor vital signs and neurologic status. IV fluids may be indicated to treat nausea and vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Limited experience. Treatment is symptomatic and supportive. Monitor ECG and institute continuous cardiac monitoring to assess for QT prolongation and potential torsades de pointes-type dysrhythmias and cardiac instability or alterations in perfusion. Monitor oxygenation and neurologic function. Seizure activity was reported in an adolescent following an intentional ingestion of ranolazine (amount unknown); intubation was required. Hypotension and QTc prolongation were also observed and resolved with supportive care.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal may be indicated if the patient is alert and able to protect their airway.
    2) HOSPITAL: Administer activated charcoal, if the ingestion is relatively recent and the patient is alert and able to protect their airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following mild to moderate toxicity. However, patients with severe toxicity may develop cardiac toxicity or alterations in CNS function (ie, seizures) that may require intubation.
    E) ANTIDOTE
    1) There is no known antidote.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be of value due to high protein binding (62%) of ranolazine.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic adult with an inadvertent minor exposure may be monitored at home. Due to limited experience, a child with more than a minor exposure (500 mg) should be observed in a healthcare center.
    2) OBSERVATION CRITERIA: Patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. A patient with an inadvertent significant ingestion (1500 mg or more) should be monitored until symptoms resolve. Patients may be discharged to home, if they remain asymptomatic after treatment and cardiac monitoring remains normal. EXTENDED RELEASE FORMULATION: Observe patients for 7 to 12 hours (peak plasma concentration is reached between 2 and 5 hours).
    3) ADMISSION CRITERIA: Patients with persistent symptoms despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Contact a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    H) PHARMACOKINETICS
    1) EXTENDED RELEASE: Following oral administration of ranolazine, peak plasma concentration is reached between 2 to 5 hours. Bioavailability of ranolazine extended-release tablets compared to that from a ranolazine solution is 76%. It is approximately 62% bound to plasma proteins. Ranolazine is rapidly and extensively metabolized in the liver and intestines. After a single oral dose of ranolazine solution, approximately 75% of the dose is excreted in the urine and approximately 25% is excreted in the feces. After dosing to steady state with 500 to 1500 mg twice daily, the apparent terminal half-lives ranged from 6 to 22 hours.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose for ranolazine has not been established. Nausea, constipation, headache, dizziness, asthenia, and syncope were reported in several patients following ranolazine therapy, up to 1500 mg twice daily. High oral doses have produced dizziness, nausea, and vomiting; high intravenous doses have resulted in paresthesia, confusion, syncope and diplopia. In overdose, severe tremor, unsteady gait, dysphasia and hallucinations have been reported.
    B) THERAPEUTIC DOSE: ADULT: ORAL: 500 mg twice daily; Maximum dose: 1000 mg twice daily. PEDIATRIC: Safety and efficacy have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Ranolazine is used in the treatment of chronic angina.
    B) PHARMACOLOGY: Ranolazine is a cardioselective antiischemic agent (piperazine derivative) that modulates myocardial metabolism by partially inhibiting fatty acid oxidation, thereby increasing glucose oxidation and generating more adenosine triphosphate (ATP) per molecule of oxygen consumed. The antianginal and antiischemic action of ranolazine is not dependent upon heart rate or blood pressure reduction and does not increase myocardial workload.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Commonly reported adverse effects with therapeutic administration include: dizziness, headache, constipation, and nausea. Dose-dependent QT interval prolongation may occur with ranolazine therapy.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited data. Anticipated effects following ranolazine overdose include: dizziness, nausea/vomiting, dose-dependent QT interval prolongation, diplopia, paresthesia, and confusion.
    2) SEVERE TOXICITY: Limited data. Significant QT prolongation may develop, however, there is limited experience with high doses (greater than 1000 mg twice daily) or exposure. While the clinical significance of this effect is unknown with ranolazine, other drugs with this potential have been associated with torsades de pointes-type dysrhythmias and sudden death. Syncope with prolonged loss of consciousness may develop secondary to torsades do pointes. Cardiac dysrhythmias and significant alterations in CNS function may develop.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) Ranolazine has been associated with dose-dependent QT interval prolongation. While the clinical significance of this direct relationship with ranolazine is unknown, other drugs with this potential have been associated with torsades de pointes-type dysrhythmias and sudden death (Prod Info RANEXA(R) oral extended-release tablets, 2016; Prod Info Ranexa(R) extended-release oral tablets, 2011).
    b) During a large phase III clinical trial, involving 823 patients, the average QTc increase was 6.1 and 9.2 milliseconds, at a ranolazine dose of 750 and 1000 mg twice daily, respectively (Chaitman, 2004).
    c) The relationship between ranolazine levels and QTc is linear over a concentration range up to 4 times greater than the peak concentrations of ranolazine at a dose of 1000 mg twice daily; ranolazine doses of greater than 1000 mg twice daily should be avoided (Prod Info RANEXA(TM) extended-release tablets, 2006; Chaitman, 2004).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 15-year-old boy with attention-deficit/hyperactivity disorder developed a new onset of seizures after intentionally ingesting an unknown amount of ranolazine that belonged to a family member. He told his parents and they contacted emergency medical services. He had a witnessed generalized tonic-clonic seizure followed by 2 seizures in route to the hospital. At the time of arrival, hypotension was present and he was treated with 4 boluses of normal saline (500 mL) and a norepinephrine infusion was started. Intubation was performed to protect his airway. Laboratory studies including liver function were normal; a toxicology screen was negative. Based on a pill count, there was no evidence of an additional ingestion of his routine medications (ie, risperidone, clonidine, and venlafaxine). An initial ECG showed a prolonged QTc of 483. No further seizures were reported. The patient was gradually weaned off norepinephrine and he was successfully extubated. Neurologic function was intact and the patient denied ingesting any other medications. His QTc normalized over 3 days (Akil et al, 2015).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 15-year-old boy with attention-deficit/hyperactivity disorder developed a new onset of seizures after intentionally ingesting an unknown amount of ranolazine that belonged to a family member. He told his parents and they contacted emergency medical services. He had a witnessed generalized tonic-clonic seizure followed by 2 seizures in route to the hospital. At the time of arrival, hypotension was present and he was treated with 4 boluses of normal saline (500 mL) and a norepinephrine infusion was started. Intubation was performed to protect his airway. Laboratory studies including liver function were normal; a toxicology screen was negative. Based on a pill count, there was no evidence of an additional ingestion of his routine medications (ie, risperidone, clonidine, and venlafaxine). An initial ECG showed a prolonged QTc of 483. No further seizures were reported. The patient was gradually weaned off norepinephrine and he was successfully extubated. Neurologic function was intact and the patient denied ingesting any other medications. His QTc normalized over 3 days (Akil et al, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness is one of the most common adverse events reported with ranolazine therapy and appears to be dose-related (Prod Info RANEXA(R) oral extended-release tablets, 2016).
    b) Dizziness was reported in 4% (n=279), 6% (n=556), and 11.8% (n=187) of patients who received ranolazine 750 mg twice daily, 1000 mg twice daily, and 1500 mg twice daily, respectively (Prod Info RANEXA(TM) extended-release tablets, 2006; Chaitman, 2004).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) One of the most frequently reported adverse events occurring more often with ranolazine than placebo during clinical trials was headache (5.5%) (Prod Info RANEXA(R) oral extended-release tablets, 2016) .
    C) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 15-year-old boy with attention-deficit/hyperactivity disorder developed a new onset of seizures after intentionally ingesting an unknown amount of ranolazine that belonged to a family member. He told his parents and they contacted emergency medical services. He had a witnessed generalized tonic-clonic seizure followed by 2 seizures in route to the hospital. At the time of arrival, hypotension was present and he was treated with 4 boluses of normal saline (500 mL) and a norepinephrine infusion was started. The patient was intubated to protect his airway. Laboratory studies including liver function were normal; a toxicology screen was negative. Based on a pill count, there was no evidence of an additional ingestion of his routine medications (ie, risperidone, clonidine, and venlafaxine). An initial ECG showed a prolonged QTc of 483. No further seizures were reported. The patient was gradually weaned off norepinephrine and he was successfully extubated. Neurologic function was intact and the patient denied ingesting any other medication. His QTc normalized over 3 days (Akil et al, 2015).
    D) SYNCOPE
    1) WITH THERAPEUTIC USE
    a) Of 1387 patients enrolled in 2 separate randomized, placebo-controlled trials, 4 experienced syncope. All 4 patients were receiving ranolazine 1000 mg twice daily (Prod Info RANEXA(TM) extended-release tablets, 2006).
    b) In one study (n=193), syncope occurred in 3 patients receiving ranolazine 1500 mg twice daily (Chaitman et al, 2004a).
    E) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) During clinical trials, asthenia was reported in 5.9% of the patients (n=187) who received ranolazine 1500 mg twice daily for 1 week, and in 4.7% of the patients (n=275) who received ranolazine 1000 mg twice daily for 12 weeks (Chaitman, 2004).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) One of the most frequently reported adverse events occurring more often with ranolazine than placebo during clinical trials was nausea (4.4%) (Prod Info RANEXA(R) oral extended-release tablets, 2016). The incidence of nausea increased to 6% in patients aged 75 years and older (Prod Info RANEXA(TM) extended-release tablets, 2006). The incidence of nausea in ranolazine-treated patients appears to be dose-dependent (Chaitman, 2004).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation is one the most common adverse events reported with ranolazine therapy (Prod Info RANEXA(R) oral extended-release tablets, 2016).
    b) During phase III clinical trials, constipation was reported in 8% of patients (n=835) who received ranolazine during clinical trials as compared with 2% of patients (n=552) who received a placebo. The incidence of constipation increased to 19% in ranolazine-treated patients aged 75 years and older (Prod Info RANEXA(TM) extended-release tablets, 2006). The incidence of constipation in ranolazine-treated patients appears to be dose-dependent (Chaitman, 2004).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC LIVER DISEASE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 63-year-old woman with a history of hypertension and unstable angina and bing treated with bisoprolol, amlodipine and atorvastatin was started on ranolazine (375 mg twice daily). Approximately 3 months later she developed insomnia, malaise and increases in her liver enzymes. AST/ALT 97/201 Units/L (normal, 1 to 35 Units/L), alkaline phosphatase 150 Units/L (normal, 30 to 120 Units/L) and total bilirubin 0.55 mg/dL. Diagnostic and serology testing were negative. Ranolazine was discontinued and the patient clinically improved. At 2 month followup, liver enzymes returned to normal (Sancho-del-Val et al, 2013).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FUNCTION TESTS ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Small, reversible elevations in serum creatinine of 0.1 mg/dL in the absence of renal toxicity have been observed in clinical studies. No change in BUN was reported. It is believed that the elevated serum creatinine levels may be due to a blockage of creatinine's tubular secretion by ranolazine creatinine (Prod Info RANEXA(R) oral extended-release tablets, 2016).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Transient eosinophilia and was infrequently reported with ranolazine therapy (Prod Info RANEXA(R) oral extended-release tablets, 2016). There was no evidence of red cell destruction or gastrointestinal blood loss eosinophilia (Chaitman, 2004).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) ENDOCRINE FINDING
    1) WITH THERAPEUTIC USE
    a) HEMOGLOBIN A1C: Ranolazine has produced small reductions in hemoglobin A1c (Prod Info Ranexa(R) extended-release oral tablets, 2011).

Reproductive

    3.20.1) SUMMARY
    A) There are no available data on the use of ranolazine in pregnant or breastfeeding women. Studies in rats and rabbits demonstrated no evidence of fetal or pup harm after the maternal administration of ranolazine. The developmental and health benefits of breastfeeding should be considered against the mother's clinical need for ranolazine and the potential adverse effects on the breastfed infant.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS, RABBITS: Studies in rats showed decreased fetal weight and reduced ossification at doses 4 times the maximum recommended human dose (MRHD). No adverse fetal effects were noted in rats or rabbits to ranolazine at exposures equivalent to the MRHD (Prod Info RANEXA(R) oral extended-release tablets, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) There are no adequate well-controlled clinical studies of ranolazine in pregnant women (Prod Info RANEXA(R) oral extended-release tablets, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether ranolazine is excreted into human breast milk. The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for ranolazine as well as the potential adverse effects in the breastfeeding infant (Prod Info RANEXA(R) oral extended-release tablets, 2016).
    B) ANIMAL STUDIES
    1) Ranolazine is present in rat milk. However, no adverse effects were noted in the pups of mothers administered the equivalent of the maximum recommended human dose of the drug (based on AUC) from gestation day 6 through postnatal day 20. At maternally toxic doses, increased mortality rates and decreased body weight in both male and female pups and increased motor activity in female pups were observed (Prod Info RANEXA(R) oral extended-release tablets, 2016).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility in humans from ranolazine exposure (Prod Info RANEXA(R) oral extended-release tablets, 2016).
    B) ANIMAL STUDIES
    1) In male and female rats, the oral administration of ranolazine at doses 3- or 5-fold higher than the maximum recommended human dose (on an AUC basis) had no effect on fertility (Prod Info RANEXA(R) oral extended-release tablets, 2016).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) TUMOR PROMOTION
    1) Intraperitoneal administration of ranolazine, 30 mg/kg twice daily for 30 days, in APC (min/+) mice resulted in approximately 70% more visible tumors on the mucosal surface of the intestinal tract than the control group (p < 0.01). The average tumor diameter was also slightly greater in the mice who received 10 mg/kg and 30 mg/kg of ranolazine as compared with the control group (0.76 +/- 0.03 mm, 0.77 +/- 0.03 mm, and 0.72 +/- 0.03 mm, respectively).
    a) APC (min/+) mice have a heterozygous, dominant mutation in the tumor suppressor gene adenomatous polyposis coli (APC) and can spontaneously develop intestinal adenomas that can progress to carcinomas. It is speculated that, although there is no evidence that ranolazine is carcinogenic, it may have a stimulatory effect on tumor development due to its ability to promote efficient ATP synthesis and reduce lactate production in ischemic environments. The results of this study indicate that ranolazine administration promoted the development of pre-existing neoplastic lesions in the APC (min/+) mice (Suckow et al, 2004).
    B) LACK OF EFFECT
    1) MICE/RATS - Ranolazine did not appear to be carcinogenic following 21 to 24 month studies conducted in mice and rats. The highest oral doses used during these carcinogenicity studies were 150 mg/kg/day for 21 months in rats (900 mg/m(2)/day; equivalent to 0.8 times the maximum recommended human dose of 2 grams on a mg/m(2) basis) and 50 mg/kg/day for 24 months in mice (150 mg/m(2)/day; equivalent to 0.1 times the maximum recommended human dose of 2 grams on a mg/m(2) basis) (Prod Info RANEXA(TM) extended-release tablets, 2006).

Genotoxicity

    A) Ranolazine did not appear to be mutagenic in the following assays: Ames bacterial mutation assay, Saccharomyces assay for mitotic gene conversion, chromosomal aberrations assay in Chinese hamster ovary (CHO) cells, mammalian CHO/HGPRT gene mutation assay, and mouse and rat bone marrow micronucleus assays (Prod Info RANEXA(TM) extended-release tablets, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum ranolazine levels are not clinically useful in managing overdose.
    B) Institute continuous ECG monitoring and obtain an ECG; QT interval prolongation may occur.
    C) Monitor vital signs and neuro status.
    D) Monitor serum electrolytes (including magnesium and calcium) and renal function.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with persistent symptoms despite adequate treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic adult with an inadvertent minor exposure may be monitored at home. Due to limited experience, a child with more than a minor exposure (500 mg) should be observed in a healthcare center.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. A patient with an inadvertent significant ingestion (1500 mg or more) should be monitored until symptoms resolve. Patients may be discharged to home, if they remain asymptomatic after treatment and cardiac monitoring remains normal. EXTENDED-RELEASE FORMULATION: Observe patients for 7 to 12 hours (peak plasma concentration is reached between 2 and 5 hours) (Prod Info RANEXA(R) oral extended-release tablets, 2016).

Monitoring

    A) Serum ranolazine levels are not clinically useful in managing overdose.
    B) Institute continuous ECG monitoring and obtain an ECG; QT interval prolongation may occur.
    C) Monitor vital signs and neuro status.
    D) Monitor serum electrolytes (including magnesium and calcium) and renal function.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) 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) 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).
    6.5.3) TREATMENT
    A) SUPPORT
    1) In case of ranolazine overdose, treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Institute continuous ECG monitoring and obtain an ECG. QT interval prolongation may develop following overdose.
    2) Monitor vital signs, oxygenation and neurologic status.
    3) Monitor serum electrolytes (including calcium and magnesium) and liver and renal function as indicated.
    4) Serum ranolazine levels are not clinically useful in managing overdose.
    C) SEIZURE
    1) Limited data. Seizure activity and hypotension developed in an adolescent following an intentional ingestion of ranolazine.
    a) CASE REPORT: A 15-year-old boy with attention-deficit/hyperactivity disorder developed a new onset of seizures and hypotension after intentionally ingesting an unknown amount of ranolazine. He had a witnessed tonic-clonic seizure and was intubated to protect his airway. Hypotension was treated with several fluid boluses of normal saline and a norepinephrine infusion. An initial ECG also showed a prolonged QTc of 483. Following supportive care all symptoms resolved (Akil et al, 2015).
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    8) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).
    D) HYPOTENSIVE EPISODE
    1) Limited data. Seizure activity and hypotension developed in an adolescent following an intentional ingestion of ranolazine.
    a) CASE REPORT: A 15-year-old boy with attention-deficit/hyperactivity disorder developed a new onset of seizures and hypotension after intentionally ingesting an unknown amount of ranolazine. He had a witnessed tonic-clonic seizure and was intubated to protect his airway. Hypotension was treated with several fluid boluses of normal saline and a norepinephrine infusion. An initial ECG also showed a prolonged QTc of 483. Following supportive care all symptoms resolved (Akil et al, 2015).
    2) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    3) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    4) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Enhanced Elimination

    A) LACK OF EFFECT
    1) HEMODIALYSIS: Due to ranolazine's protein binding (62%), complete clearance of ranolazine via hemodialysis is unlikely (Prod Info RANEXA(R) oral extended-release tablets, 2016)..

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose for ranolazine has not been established. Nausea, constipation, headache, dizziness, asthenia, and syncope were reported in several patients following ranolazine therapy, up to 1500 mg twice daily. High oral doses have produced dizziness, nausea, and vomiting; high intravenous doses have resulted in paresthesia, confusion, syncope and diplopia. In overdose, severe tremor, unsteady gait, dysphasia and hallucinations have been reported.
    B) THERAPEUTIC DOSE: ADULT: ORAL: 500 mg twice daily; Maximum dose: 1000 mg twice daily. PEDIATRIC: Safety and efficacy have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) EXTENDED RELEASE: The initial recommended dose is 500 mg twice daily and may be increased to a maximum of 1000 mg twice daily. Extended-release tablets should be swallowed whole and NOT crushed, broken, or chewed (Prod Info RANEXA(R) oral extended release tablets, 2013).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of ranolazine in the pediatric population have not been established (Prod Info RANEXA(R) oral extended release tablets, 2013).

Maximum Tolerated Exposure

    A) SUMMARY
    1) High oral doses have produced dizziness, nausea, and vomiting; high intravenous doses have resulted in paresthesia, confusion, syncope and diplopia. In overdose, severe tremor, unsteady gait, dysphasia and hallucinations have been reported (Prod Info RANEXA(R) oral extended-release tablets, 2016).
    2) During phase III clinical trials, nausea, constipation, headache, dizziness, asthenia, and syncope were reported in several patients who received up to 1500 mg twice daily of ranolazine (Chaitman, 2004).
    B) CASE REPORT
    1) A 15-year-old boy with attention-deficit/hyperactivity disorder developed a new onset of seizures after intentionally ingesting an unknown amount of ranolazine that belonged to a family member. He told his parents and they contacted emergency medical services. He had a witnessed generalized tonic-clonic seizure and followed by 2 seizures in route to the hospital. At the time of arrival, hypotension was present and he was treated with 4 boluses of normal saline (500 mL) and a norepinephrine infusion was started. Intubation was performed to protect his airway. Laboratory studies including liver function were normal; a toxicology screen was negative. Based on a pill count, there was no evidence of an additional ingestion of his routine medications (ie, risperidone, clonidine, and venlafaxine). An initial ECG showed a prolonged QTc of 483. No further seizures were reported. The patient was gradually weaned off norepinephrine and he was successfully extubated. Neurologic function was intact and the patient denied ingesting any other medications. His QTc normalized over 3 days (Akil et al, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ranolazine is a cardioselective anti-ischemic agent (piperazine derivative) that modulates myocardial metabolism by partially inhibiting fatty acid oxidation, thereby increasing glucose oxidation and generating more adenosine triphosphate (ATP) per molecule of oxygen consumed (i.e., cardiac muscle cell substrate utilization is shifted towards carbohydrates and away from fatty acids) (Chaitman et al, 2004; Singh & Wadhani, 2004; McCormack et al, 1996; Anon, 1996; Hayashida et al, 1994; Thadani et al, 1994; Black et al, 1994; Allely et al, 1993; Cocco et al, 1992; Boddeke et al, 1989). The anti-anginal and anti-ischemic action of ranolazine is not dependent upon heart rate or blood pressure reduction and does not increase myocardial workload (Prod Info Ranexa(R) oral extended release tablets, 2012).
    B) Unlike beta-blockers and calcium antagonists, ranolazine lacks effects on hemodynamics, contractile and conduction parameters (Singh & Wadhani, 2004; McCormack et al, 1996; Clarke et al, 1993; Allely & Alps, 1988; Chierchia & Fragasso, 1993).
    C) Ranolazine has renal transplant preservation potential (storage/reperfusion; porcine model) (Lodge et al, 1990).
    D) In vitro studies have shown that ranolazine may be effective in preventing the development of torsades de pointes induced by class III antiarrhythmic compounds (ie, dofetilide, ibutilide, sotalol) by suppressing early afterdepolarizations (EADs) and triggered activity in Purkinje fibers and myocardial cells (Singh & Wadhani, 2004).

Physicochemical

Physical Characteristics

    A) Ranolazine is a white to off-white solid. It is soluble in dichloromethane and methanol; sparingly soluble in tetrahydrofuran, ethanol, acetonitrile, and acetone; slightly soluble in ethyl acetate, isopropanol, toluene, and ethyl ether; and very slightly soluble in water (Prod Info RANEXA(TM) extended-release tablets, 2006).

Molecular Weight

    A) 427.54 g/mole (Prod Info RANEXA(TM) extended-release tablets, 2006)

References

General Bibliography

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    41) Product Information: RANEXA(R) oral extended release tablets, ranolazine oral extended release tablets. Gilead Sciences, Inc. (per FDA), Foster City, CA, 2013.
    42) Product Information: RANEXA(R) oral extended-release tablets, ranolazine oral extended-release tablets. Gilead Sciences, Inc. (per FDA), Foster City, CA, 2016.
    43) Product Information: RANEXA(TM) extended-release tablets, ranolazine extended-release tablets. CV Therapeutics, Inc, Palo Alto, CA, 2006.
    44) Product Information: Ranexa(R) extended-release oral tablets, ranolazine extended-release oral tablets. Gilead Sciences, Inc. (per FDA), Foster City, CA, 2011.
    45) Product Information: Ranexa(R) oral extended release tablets, ranolazine oral extended release tablets. Gilead Sciences, Inc. (per DailyMed), Foster City, CA, 2012.
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    48) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    49) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
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