Elimite

Generic Name: permethrin topical (per METH rin)

Brand Names: Elimite, Lice Bedding Spray, Nix Complete Lice Treatment System, Nix Cream Rinse, Nix Lice Control, RID Home Lice Control Spray for Surfaces

What is Elimite (permethrin topical)?

Permethrin is an anti-parasite medication.

Permethrin topical (for the skin) is used to treat head lice and scabies.

Permethrin topical may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Elimite (permethrin topical)?

Use this medication exactly as directed on the label, or as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended.

Do not take this medication by mouth. It is for use only on the skin, hair, fabrics, or other surfaces. Do not apply permethrin topical to open cuts or wounds. Do not use this medication if you are allergic to permethrin or to chrysanthemums. For the most complete treatment of lice or scabies and to prevent reinfection, you must treat your environment (clothing, bedding, pillows, furniture, hats, hair brushes and accessories, etc) at the same time you treat your body.

Avoid sexual or intimate contact with others until your lice or scabies infection has cleared up. Avoid sharing hair brushes, combs, hair accessories, hats, clothing, bed linens, and other articles of personal use. Lice and scabies infections are highly contagious.

What should I discuss with my healthcare provider before using Elimite (permethrin topical)?

Do not use this medication if you are allergic to permethrin or to chrysanthemums. FDA pregnancy category B. Permethrin topical is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Permethrin can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Do not use this medication on an infant younger than 2 months without the advice of a doctor.

How should I use Elimite (permethrin topical)?

Do not take this medication by mouth. It is for use only on the skin, hair, fabrics, or other surfaces.

Use this medication exactly as directed on the label, or as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended.

You may need to shake the medication before each use. Follow the directions on the medicine label. Do not apply permethrin topical to open cuts or wounds.

To treat scabies:

• 
  

  Make sure your skin is clean and dry. Apply a thin layer of permethrin topical to all body parts from the neck down to the soles of the feet. Rub in completely. Leave the medication on for 8 to 14 hours, then wash it off completely.

  
  


• When using permethrin topical on an infant, also apply the medication to the scalp, temples, and forehead. Avoid applying close to the eyes, nose, mouth, or genitals.


• 
  

  If your condition does not clear up within 14 days after applying permethrin topical, use another application.

  
  

To treat head lice:

• 
  

  When using the shampoo, apply it to dry hair only. Cover all hair completely and leave the shampoo in for 10 minutes. Then work into a lather using warm water and rinse out thoroughly.

  
  


• 
  

  When using the cream rinse, wash your hair using shampoo only (no conditioner or 2-in-1 shampoo). Rinse thoroughly and towel dry the hair, leaving it damp. Apply enough of the cream rinse to completely saturate all hair. Leave the cream rinse in your hair for 10 minutes.

  
  


• Use a towel or washcloth to protect your eyes while the medication is left in your hair.


• 
  

  Use a second application if lice are still seen 7 days after your first treatment.

  
  


• 
  

  You may also use a nit comb to remove lice eggs from the hair. Your hair should be slightly damp while using a nit comb. Work on only one section of hair at a time, combing through 1- to 2-inch strands from the scalp to the ends.

  
  


• 
  

  Rinse the nit comb often during use. Place removed nits into a sealed plastic bag and throw it into the trash to prevent re-infestation.

  
  


• 
  

  Check the scalp again daily to make sure all nits have been removed.

  
  

To treat pubic lice (crabs):

• 
  

  Wash and dry the treatment area. Apply permethrin topical to all pubic hair and any surrounding hairs on the thighs and around the anus.

  
  


• 
  

  Avoid getting this medication inside the rectum or vagina.

  
  


• 
  

  Leave the medication in for 10 minutes. Then work into a lather using warm water and rinse out thoroughly.

  
  


• 
  

  You may also use a nit comb to remove lice eggs from pubic hair (hair should be slightly damp).

  
  


• 
  

  All sexual partners should also be treated to prevent re-infestation of crabs.

  
  

To prevent reinfection, wash all clothing, hats, bed clothes, bed linens, and towels in hot water and dry in high heat. Dry-clean any non-washable clothing. Hair brushes, combs, and hair accessories should be soaked in hot water for at least 10 minutes.

Use permethrin surface spray to disinfect non-washable items such as:

• 
  

  furniture;

  
  


• 
  

  mattresses and pillows;

  
  


• 
  

  stuffed toys;

  
  


• 
  

  hats, gloves, and scarves;

  
  


• 
  

  headphones or headbands;

  
  


• 
  

  the inside of a bike helmet; or

  
  


• 
  

  seats and carpets inside your car.

  
  

Stuffed toys or pillows that cannot be washed should be sealed in air-tight plastic bags for 4 weeks.

Vacuum all rugs and carpets and throw away the vacuum cleaner bag.

For the most complete treatment of lice or scabies, you must treat your environment (clothing, bedding, etc) at the same time you treat your body. Store permethrin topical at room temperature away from moisture and heat.

What happens if I miss a dose?

Since permethrin topical is usually needed only once, you are not likely to be on a dosing schedule. Wait at least 7 days before using a second application.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Symptoms of a permethrin topical overdose are unknown.

What should I avoid while using Elimite (permethrin topical)?

Avoid getting this medication in your mouth or eyes. If it does get into any of these areas, rinse with water.

Do not use other medicated skin products unless your doctor has told you to.

Avoid sexual or intimate contact with others until your lice or scabies infection has cleared up. Avoid sharing hair brushes, combs, hair accessories, hats, clothing, bed linens, and other articles of personal use. Lice and scabies infections are highly contagious.

Elimite (permethrin topical) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have severe burning, stinging, redness, or swelling after applying permethrin topical.

Less serious side effects may include:

• 
  

  itching or mild skin rash;

  
  


• 
  

  mild burning, stinging, or redness; or

  
  


• 
  

  numbness or tingling where the medication was applied.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Elimite (permethrin topical)?

It is not likely that other drugs you take orally or inject will have an effect on topically applied permethrin. But many drugs can interact with each other. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Elimite resources

• Elimite Side Effects (in more detail)
• Elimite Use in Pregnancy & Breastfeeding
• Elimite Support Group
• 1 Review for Elimite - Add your own review/rating

• Elimite Prescribing Information (FDA)


• Elimite Topical Advanced Consumer (Micromedex) - Includes Dosage Information


• Elimite Cream MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Elimite with other medications

• Head Lice
• Lice
• Scabies

Where can I get more information?

• Your pharmacist has additional information about permethrin topical written for health professionals that you may read.

See also: Elimite side effects (in more detail)

fluphenazine decanoate

Class: Phenothiazines
Note: This monograph also contains information on fluphenazine hydrochloride
VA Class: CN701
CAS Number: 5002-47-1
Brands: Prolixin

Special Alerts:

[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.

The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.

BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .

[Posted 06/16/2008] FDA notified healthcare professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis. In April 2005, FDA notified healthcare professionals that patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death. Since issuing that notification, FDA has reviewed additional information that indicates the risk is also associated with conventional antipsychotics. Antipsychotics are not indicated for the treatment of dementia-related psychosis. The prescribing information for all antipsychotic drugs will now include the same information about this risk in a BOXED WARNING and the WARNINGS section. For more information visit the FDA website at: , and .

Introduction

Phenothiazine antipsychotic agent.^{a b c d f g i}

Uses for fluphenazine decanoate

Psychotic Disorders

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Symptomatic management of psychotic disorders (i.e., schizophrenia).^{a b c f g i}

The long-acting decanoate ester is used mainly for maintenance therapy in patients with chronic schizophrenic disorder who cannot be relied on to take oral antipsychotic drugs; do not use for acute management of severely agitated patients.^{a b}

Mental Retardation

Efficacy not established for management of behavioral complications in mental retardation.^{a b c f g i}

fluphenazine decanoate Dosage and Administration

General

• 
  

  Use shorter-acting fluphenazine hydrochloride formulations in patients with acute schizophrenic reactions so that dosage can be readily adjusted according to patient’s tolerance and therapeutic response.^{a b}

  
  

Administration

Administer fluphenazine hydrochloride orally or IM.^{a b c f g i}

Administer fluphenazine decanoate IM or sub-Q.^{a b} If used outside of psychiatric institutions, administer under direction of clinician experienced in use of psychotropic drugs, particularly phenothiazine derivatives.^b

Avoid skin contact with elixir, oral concentrate solution, or injection since contact dermatitis rarely occurs.^{a d}

Oral Administration

Fluphenazine hydrochloride: Administer orally every 6–8 hours initially; maintenance therapy can often be administered as a single daily dose.^{a c f g}

When oral concentrate solution is used, dilute dose with at least 60 mL of suitable diluent (e.g., water; uncaffeinated soft drinks [e.g., Seven-Up]; carbonated orange beverage; sodium chloride; milk; V-8; or pineapple, apricot, prune, orange, tomato, or grapefruit juice) just before administration.^{a f} (See Compatibility under Stability.)

IM or Sub-Q Administration

Fluphenazine hydrochloride: Administer IM every 6–8 hours.^{a f}

Fluphenazine decanoate: Administer IM or sub-Q using a dry syringe and needle of at least 21 gauge; use of a wet needle or syringe may cause solution to become cloudy.^b

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as fluphenazine hydrochloride or fluphenazine decanoate; dosage expressed in terms of the salt.^{b c f g i}

Carefully adjust dosage according to individual requirements and response, using lowest possible effective dosage.^{a c f g}

Because of risk of adverse reactions associated with cumulative effects of phenothiazines, periodically evaluate patients with a history of long-term therapy with fluphenazine and/or other antipsychotic agents to determine whether maintenance dosage may be decreased or drug therapy discontinued.^a

Conversion from oral fluphenazine hydrochloride to long-acting decanoate injection may be indicated for psychotic patients stabilized on a fixed daily oral dosage.^{a c f g} In patients without a history of therapy with phenothiazines, administer shorter-acting form for several weeks prior to instituting therapy with fluphenazine decanoate in order to determine patient’s approximate dosage requirements and susceptibility to adverse effects.^{a b}

Precise formula for converting therapy from fluphenazine hydrochloride to fluphenazine decanoate not established.^a An approximate conversion ratio of 12.5 mg every 3 weeks of fluphenazine decanoate for every 10 mg daily of fluphenazine hydrochloride has been used.^a

Adults

Psychotic Disorders

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Oral

Fluphenazine hydrochloride: Initially, 2.5–10 mg daily given in divided doses every 6–8 hours.^{a c f g} Dosage may be gradually increased, if necessary, until desired clinical effects are obtained.^{a c f g}

Optimum therapeutic effect often occurs with oral fluphenazine hydrochloride dosages <20 mg daily.^{a c f g} Dosages up to 40 mg may be required in severely disturbed patients, but safety of prolonged administration of such dosages not established.^{a c f g} Use dosages >20 mg daily with caution.^a

After maximum response attained, reduce fluphenazine hydrochloride dosage gradually to maintenance dosage of 1–5 mg daily, often as a single dose.^{a c f g} To avoid recurrence of psychotic symptoms, continued therapy is required following optimum therapeutic response.^a

IM

Fluphenazine hydrochloride: Generally, IM dose is approximately one-third to one-half the oral dose.^{a i}

Usual initial fluphenazine hydrochloride dose is 1.25 mg.^{a i} Depending on severity and duration of symptoms, initial total IM dosage may range from 2.5–10 mg daily given in divided doses every 6–8 hours; may gradually increase dosage if necessary, until symptoms are controlled.^{a i}

Use fluphenazine hydrochloride dosages >10 mg daily with caution.^{a i}

After symptoms are controlled, oral therapy generally should replace parenteral therapy.^{a i}

IM or Sub-Q

Fluphenazine decanoate: In patients with chronic schizophrenic disorder, usual initial dose is 12.5–25 mg.^{a b}

Carefully adjust subsequent fluphenazine decanoate dose and dosage interval according to patient tolerance and response;^{a b} if doses >50 mg are deemed necessary, increase the next and succeeding doses cautiously in increments of 12.5 mg, but do not exceed 100 mg.^{a b}

When administered as maintenance therapy, a single fluphenazine decanoate injection may be effective in controlling schizophrenic symptoms for up to 4 weeks or longer; response may persist for up to 6 weeks in some patients.^{a b}

Prescribing Limits

Adults

Psychotic Disorders

Oral

Fluphenazine hydrochloride: Safety of prolonged administration of dosages up to 40 mg daily not established.^{a f g} Use dosages >20 mg daily with caution.^a

IM

Fluphenazine hydrochloride: Use dosages >10 mg daily with caution.^{a i}

IM or Sub-Q

Fluphenazine decanoate: Do not exceed 100 mg.^b

Special Populations

Geriatric Patients

Fluphenazine hydrochloride: Initially 1–2.5 mg orally daily.^{a c f g} Increase dosage more gradually in debilitated, emaciated, or geriatric patients.^a

Cautions for fluphenazine decanoate

Contraindications

• 
  

  Suspected or established subcortical brain damage.^{b c f g i}

  
  


• 
  

  Comatose or severely depressed states.^{b c f g i}

  
  


• 
  

  Blood dyscrasia or liver damage.^{b c f g i}

  
  


• 
  

  Concomitant therapy with large doses of hypnotics.^{b c f g i}

  
  


• 
  

  Known hypersensitivity to fluphenazine^{b c f g i} or other phenothiazine derivatives (unless potential benefits outweigh possible risks).^d

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, may develop in patients receiving antipsychotic agents, including fluphenazine.^{b c f g i} Consider discontinuance.^{b c f g i}

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, may occur in patients receiving antipsychotic agents, including fluphenazine.^{b c f g i}

Sensitivity Reactions

Hypersensitivity

Skin disorders (e.g., pruritus, erythema, urticaria, seborrhea, photosensitivity, eczema, exfoliative dermatitis) reported with phenothiazine derivatives.^{b c f g i} Contact dermatitis reported rarely.^a

Consider possibility of anaphylactoid reactions.^{b c f g i}

Cross-sensitivity

Possible cross-sensitivity with other phenothiazines; use with caution in patients who have developed cholestatic jaundice, dermatoses, or other allergic reactions to phenothiazine derivatives.^{b c f g i}

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Use phenothiazines with caution in debilitated patients, patients with renal or hepatic disease, patients with glaucoma or prostatic hypertrophy, and patients exposed to organophosphate insecticides.^{b c d f g i}

Use phenothiazines with caution in patients with hypocalcemia, since susceptibility to dystonic reactions may be increased.^d

Abrupt Withdrawal

Gastritis, nausea, vomiting, dizziness, and tremulousness reported after abrupt discontinuance of high-dose therapy; minimize symptoms by continuing concomitant antiparkinsonian agents for several weeks after phenothiazine is withdrawn.^{b c f g i}

Cardiovascular Effects

Hypotension occurs rarely.^{a b f g i} Patients with pheochromocytoma, cerebral or vascular insufficiency, or severe cardiac reserve deficiency (e.g., mitral insufficiency), or psychotic patients receiving large doses of phenothiazines who are undergoing surgery may be especially prone to hypotensive effects;^{a b c f g i} closely monitor such patients during therapy.^{a b c f g i}

Hypertension and fluctuations in BP may occur.^{a b c f g i}

Nervous System Effects

Possible risk of seizures; phenothiazines may lower seizure threshold.^d Use with caution in patients with a history of seizures or EEG abnormalities or in those receiving anticonvulsant agents.^{b c d f g i} Maintain adequate anticonvulsant therapy.^d

Drowsiness or lethargy possible; may necessitate dosage reduction.^{b c f g i}

Because of CNS depressant effects of phenothiazines, use with caution in patients with chronic respiratory disorders (e.g., severe asthma, emphysema, acute respiratory tract infections).^d

Neurologic reactions from phenothiazine therapy may be similar to CNS manifestations accompanying certain disorders (e.g., Reye’s syndrome, encephalopathy, meningitis, tetanus); diagnosis of these disorders may be obscured or disease-associated manifestations may be incorrectly diagnosed as drug induced.^d

Antiemetic effect of phenothiazines may mask signs of overdosage of toxic drugs (e.g., antineoplastic agents) or may obscure cause of vomiting in various disorders (e.g., intestinal obstruction, Reye’s syndrome, brain tumor).^d

Phenothiazines depress hypothalamic mechanism for body temperature regulation; use caution in patients exposed to extreme heat or cold.^{b c f g i}

Extrapyramidal symptoms occur frequently and are usually reversible; persistent reactions can usually be controlled by concomitant therapy with an antiparkinsonian drug and subsequent dosage reduction.^{a b c f g i}

Autonomic reactions (e.g., nausea, appetite loss, salivation, polyuria, perspiration, dry mouth, headache, constipation) may occur.^{a b c f g i}

Hematologic Effects

Blood dyscrasias, including leukopenia, agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura, eosinophilia, and pancytopenia reported with phenothiazine derivatives.^{b c d f g i} Perform hematologic evaluations periodically.^{b c d f g i}

If manifestations of blood dyscrasias (e.g., sore throat, fever, weakness) occur, discontinue until possibility of adverse hematologic effect is ruled out; if evidence of cellular depression (i.e., decreased leukocyte and differential counts) occurs, discontinue and institute appropriate therapy.^{b c d f g i}

Hepatic Effects

Liver damage, manifested by cholestatic jaundice may occur, particularly during first months of therapy;^{b c f g i} discontinue immediately if liver damage occurs.^d

Consider possibility of liver damage in patients receiving prolonged therapy.^{b c f g i} Monitor hepatic function periodically.^{b c f g i}

Ocular Effects

Consider possibility of pigmentary retinopathy and lenticular and corneal deposits in patients receiving prolonged therapy.^{b c d f g i} Periodic ophthalmic examinations recommended in patients receiving prolonged phenothiazine therapy with moderate to high dosages.^d

Endocrine Effects

Elevated prolactin concentrations, which persist during chronic administration, possible.^{b c d f g i}

Galactorrhea, amenorrhea, gynecomastia, and impotence reported.^{b c f g i}

Pulmonary Effects

Clinicians should be alert to possible development of “silent pneumonias” in patients receiving phenothiazines, including fluphenazine.^{b c f g i}

Use with caution in patients with chronic respiratory disorders (e.g., severe asthma, emphysema, acute respiratory tract infections).^d

Specific Populations

Pregnancy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Category C.^e

Lactation

Phenothiazines are distributed into milk.^{d e} Women receiving phenothiazines should not breast-feed.^d

Pediatric Use

Insufficient experience with fluphenazine hydrochloride to establish safety and efficacy.^{a c f g i}

Safety and efficacy of fluphenazine decanoate not established in children <12 years of age.^{a b}

Geriatric Use

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Geriatric patients appear to be particularly sensitive to adverse CNS (e.g., tardive dyskinesia, parkinsonian manifestations, akathisia, sedation), anticholinergic, and cardiovascular (e.g., orthostatic hypotension) effects of antipsychotic agents.^d (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use phenothiazines with caution in patients with hepatic disease.^d Monitor hepatic function periodically.^{b c f g i}

Renal Impairment

Use phenothiazines with caution in patients with renal disease.^d Monitor renal function periodically; if BUN becomes abnormal, discontinue therapy.^{b c f g i}

Common Adverse Effects

Extrapyramidal reactions (e.g., pseudo-parkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, hyperreflexia), drowsiness, lethargy, weight gain.^{a b c d f g i}

Interactions for fluphenazine decanoate

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Anticonvulsants	Phenothiazines may lower seizure threshold, but CNS depressant effects do not potentiate anticonvulsant activity of anticonvulsantsd	Dosage adjustment of anticonvulsant may be necessary to maintain seizure control during concomitant used
Atropine	Possible potentiated effects of atropine in some patients receiving fluphenazine because of added anticholinergic effectsb c f g i
CNS depressants (e.g., alcohol, analgesics, antihistamines, barbiturates, general anesthetics, opiates)	Possible additive effects or potentiated action of other CNS depressantsb c d f g i	Use concomitantly with caution to avoid excessive sedation or CNS depressionb c d During surgery in patients receiving high fluphenazine dosages, may need to reduce dosages of anesthetics or other CNS depressantsb c f g i
Epinephrine	Reversal of epinephrine actionb c f g i	Do not use epinephrine for phenothiazine-induced hypotension; further lowering of BP may resultb c f g i
Lithium	An acute encephalopathic syndrome reported occasionally, especially when high serum lithium concentrations presentd	Observe patients receiving combined therapy for evidence of adverse neurologic effects; promptly discontinue if such signs or symptoms appeard
Test for phenylketonuria (PKU)	False-positive test results may occur during phenothiazine used
Tests for pregnancy	False-positive results reported in some patients receiving phenothiazinesb c d f g i
Tests for urobilinogen, amylase, uroporphyrins, porphobilinogens, 5-hydroxyindolacetic acid	Urinary metabolites of phenothiazines may cause urine to darken and result in false-positive test resultsd

fluphenazine decanoate Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from GI tract and from parenteral sites.^a Peak serum concentrations were attained within 1.5–2 or 0.5 hours after IM or oral administration, respectively, of fluphenazine hydrochloride.^a

Onset

Fluphenazine hydrochloride: Usually occurs within 1 hour following oral or IM administration.^a

Fluphenazine decanoate: Within 24–72 hours.^{a b}

Duration

Fluphenazine hydrochloride: 6–8 hours following oral or IM administration.^a

Fluphenazine decanoate: Usually 1–6 weeks (average: 2 weeks).^a

Distribution

Extent

Not fully elucidated; reportedly crosses blood-brain barrier.^a

Phenothiazines cross the placenta and are distributed into milk.^e

Elimination

Metabolism

Metabolic fate not fully elucidated.^a

Elimination Route

Excreted in feces and urine as unchanged drug, fluphenazine sulfoxide, and 7-hydroxyfluphenazine following IM administration of fluphenazine decanoate in 1 patient studied; also excreted in urine as metabolite conjugates.^a

Half-life

Fluphenazine hydrochloride: 14.7–15.3 hours following IM or oral administration.^a

Fluphenazine decanoate: 6.8–9.6 days following IM administration.^a

Stability

Storage

Oral

Tablets

15–30°C.^c Protect from light.^c Avoid excessive heat.^c

Elixir

Tightly closed containers at 15–30°C, unless otherwise specified by manufacturer; ^{a d g} avoid freezing.^g Protect from light.^{a g}

Solution, concentrate

Tightly closed containers at <40°C, preferably 15–30°C, unless otherwise specified by manufacturer;^{a d f} avoid freezing.^{d f} Protect from light.^{a f}

Parenteral

Injection

Fluphenazine decanoate: 15–30°C.^b Avoid freezing and excessive heat.^b Protect from light.^b

Fluphenazine hydrochloride: 15–30°C.^{d i} Avoid freezing.^a Protect from light.^{a i}

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Oral

Do not mix oral concentrate solution with beverages containing caffeine (e.g., coffee, cola), tannic acid (e.g., tea), or pectinates (e.g., apple juice), since physical incompatibility may result.^{a f} (See Oral Administration under Dosage and Administration.)

Parenteral

Drug Compatibility (for Fluphenazine Hydrochloride)

Syringe Compatibilityh

Compatible
Benztropine mesylate
Diphenhydramine HCl
Hydroxyzine HCl

ActionsActions

• 
  

  Precise mechanism(s) of antipsychotic action not determined but may be principally related to antidopaminergic effects.^d

  
  


• 
  

  Exhibits weak anticholinergic and sedative effects and strong extrapyramidal effects; has weak antiemetic activity.^a

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Risk of drowsiness and impairment of mental and physical abilities required for driving a car or operating heavy machinery.^{a b c f g i}

  
  


• 
  

  Importance of avoiding alcohol during fluphenazine therapy.^{a b c f g i}

  
  


• 
  

  Importance of clinicians informing patients in whom chronic use is contemplated of risk of tardive dyskinesia, taking into account clinical circumstances and competency of patient to understand information provided.^{a b c f g i}

  
  


• 
  

  Importance of clinicians informing patients of risk of extrapyramidal reactions and providing reassurance that these reactions usually can be controlled by administration of antiparkinsonian drugs (e.g., benztropine) and by subsequent dosage reduction.^{b c f g i}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{a b c f g i}

  
  


• 
  

  Importance of avoiding exposure to temperature extremes.^{b c d f g i}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{a b c f g i}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{a b c f g i} (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Fluphenazine Decanoate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection	25 mg/mL	Fluphenazine Decanoate Injection (with benzyl alcohol 1.2% in sesame oil)	Abraxis, Apotex, Bedford, Sicor
			Prolixin Decanoate (with benzyl alcohol 1.2% in sesame oil)	Sandoz

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Fluphenazine Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Elixir	2.5 mg/5 mL	Fluphenazine Hydrochloride Elixir	Pharmaceutical Associates, Teva
	Solution, concentrate	5 mg/mL	Fluphenazine Hydrochloride Concentrate	Pharmaceutical Associates, Teva
	Tablets	1 mg*	Fluphenazine Hydrochloride Tablets	Mylan, Par, Sandoz, UDL
		2.5 mg*	Fluphenazine Hydrochloride Tablets	Mylan, Par, Sandoz, UDL
		5 mg*	Fluphenazine Hydrochloride Tablets	Mylan, Par, Sandoz, UDL
		10 mg*	Fluphenazine Hydrochloride Tablets	Mylan, Par, Sandoz, UDL
Parenteral	Injection, for IM use only	2.5 mg/mL	Fluphenazine Hydrochloride Injection (with parabens)	Abraxis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Fluphenazine Decanoate 25MG/ML Solution (APP PHARMACEUTICAL): 5/$69.99 or 10/$130

Fluphenazine HCl 1MG Tablets (SANDOZ): 90/$17.99 or 180/$23.98

Fluphenazine HCl 10MG Tablets (SANDOZ): 60/$24.99 or 180/$74.98

Fluphenazine HCl 2.5MG Tablets (MYLAN): 60/$15.99 or 180/$38.98

Fluphenazine HCl 5MG Tablets (SANDOZ): 60/$18.99 or 180/$45.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions March 15, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

a. AHFS drug information 2004. McEvoy GK, ed. Fluphenazine. Bethesda, MD: American Society of Health-System Pharmacists; 2004:2314-5.

b. Gensia Sicor Pharmaceuticals, Inc. Fluphenazine decanoate injection prescribing information. Irvine, CA; 1998 Aug.

c. Par Pharmaceutical, Inc. Fluphenazine hydrochloride tablets prescribing information. Spring Valley, NY; 2003 Jul.

d. AHFS drug information 2004. McEvoy GK, ed. Phenothiazines general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2004: 2301-11.

e. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 6th ed. Baltimore, MD: Williams & Wilkins; 2002:574-5.

f. Pharmaceutical Associates, Inc. Fluphenazine hydrochloride oral solution prescribing information. Greenville, SC; 2000 Oct.

g. Pharmaceutical Associates, Inc. Fluphenazine hydrochloride elixir prescribing information. Greenville, SC; 2002 Nov.

h. Trissel LA. Handbook on injectable drugs. 12th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2003:622-3.

i. American Pharmaceutical Partners. Fluphenazine hydrochloride injection prescribing information. Schaumburg, IL; 2002 Jul.

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Verapamil Extended Release Capsules

Dosage Form: capsule, extended release

Verapamil Extended Release Capsules Description

Verapamil hydrochloride extended-release is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Verapamil hydrochloride extended-release is available for oral administration as a 120 mg hard gelatin capsule, a 180 mg hard gelatin capsule and a 240 mg hard gelatin capsule. These bead filled capsules provide an extended-release of the drug in the gastrointestinal tract. The structural formula of verapamil hydrochloride is given below:

C27H38N2O4 • HCl               M.W. 491.07

Chemical name: (±)-5-[(3,4-Dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile monohydrochloride.

Verapamil hydrochloride, USP is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform and methanol. Verapamil hydrochloride is not structurally related to other cardioactive drugs.

In addition to verapamil hydrochloride, the verapamil hydrochloride extended-release capsule contains the following inactive ingredients: ammonium hydroxide, dibutyl sebacate, diethyl phthalate, ethylcellulose, fumed silica, hypromellose, maltodextrin, methacrylic acid copolymer, oleic acid, polyethylene glycol, povidone, silicon dioxide, sodium lauryl sulfate, sugar spheres and talc.

In addition, each of the empty gelatin capsules contain the following: FD&C Green No. 3, gelatin, and titanium dioxide. In addition the 180 mg capsule contains D&C yellow No. 10.

The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol, and shellac glaze.

Verapamil Extended Release Capsules - Clinical Pharmacology

Verapamil hydrochloride extended-release is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) which exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells.

Normal sinus rhythm is usually not affected by verapamil hydrochloride. However in patients with sick sinus syndrome, verapamil hydrochloride may interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block.

Atrioventricular block can occur in patients without preexisting conduction defects. (See WARNINGS.) Verapamil hydrochloride does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. Verapamil hydrochloride may shorten the antegrade effective refractory period of accessory bypass tracts.

Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil. (See WARNINGS.)

Verapamil hydrochloride has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man.

Mechanism of Action

Essential Hypertension

Verapamil hydrochloride exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/minute is uncommon).

Verapamil hydrochloride regularly reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral resistance (afterload) against which the heart works.

Pharmacokinetics and Metabolism

With the immediate-release formulations, more than 90% of the orally administered dose is absorbed, and peak plasma concentrations of verapamil are observed 1 to 2 hours after dosing. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, the absolute bioavailability ranges from 20% to 35%. Chronic oral administration of the highest recommended dose (120 mg every 6 hours) resulted in plasma verapamil levels ranging from 125 to 400 ng/mL with higher values reported occasionally. A nonlinear correlation between the verapamil hydrochloride dose administered and verapamil plasma levels does exist.

During initial dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the PR interval. However, during chronic administration this relationship may disappear. The quantitative relationship between plasma verapamil concentrations and blood pressure reduction has not been fully characterized.

In a multiple dose pharmacokinetic study, peak concentrations for a single daily dose of verapamil hydrochloride extended-release 240 mg were approximately 65% of those obtained with an 80 mg t.i.d. dose of the conventional immediate-release tablets, and the 24-hour post-dose concentrations were approximately 30% higher. At a total daily dose of 240 mg, verapamil hydrochloride extended-release was shown to have a similar extent of verapamil bioavailability based on the AUC-24 as that obtained with the conventional immediate-release tablets. In this same study verapamil hydrochloride extended-release doses of 120 mg, 240 mg and 360 mg once daily were compared after multiple doses. The ratios of the verapamil and norverapamil AUCs for verapamil hydrochloride extended-release 120 mg, 240 mg and 360 mg once daily doses are 1 (565 ng•hr/mL):3 (1660 ng•hr/mL):5 (2729 ng•hr/mL) and 1 (621 ng•hr/mL):3 (1614 ng•hr/mL):4 (2535 ng•hr/mL), respectively, indicating that the AUC increased non-proportionately with increasing doses.

Food does not affect the extent or rate of the absorption of verapamil from the verapamil hydrochloride extended-release capsule. The verapamil hydrochloride extended-release 240 mg capsule when administered with food had a Cmax of 77 ng/mL which occurred 9 hours after dosing, and an AUC(0-inf) of 1387 ng•hr/mL. Verapamil hydrochloride extended-release 240 mg under fasting conditions had a Cmax of 77 ng/mL which occurred 9.8 hours after dosing, and an AUC(0-inf) of 1541 ng•hr/mL.

The bioequivalence of verapamil hydrochloride extended-release 240 mg, administered as the beads sprinkled on applesauce and as the intact capsule, was demonstrated in a single-dose, cross-over study in 32 healthy adults. Comparative ratios (sprinkled/intact) of verapamil were 0.95, 1.02, and 1.01 for Cmax, Tmax, and AUC(0-inf) respectively. When the contents of the verapamil hydrochloride extended-release capsule were administered by sprinkling onto one tablespoonful of applesauce, the rate and extent of verapamil absorption were found to be bioequivalent to the same dose when administered as an intact capsule. Similar results were observed with norverapamil.

The time to reach maximum verapamil concentrations (Tmax) with verapamil hydrochloride extended-release has been found to be approximately 7 to 9 hours in each of the single dose (fasting), single dose (fed), the multiple dose (steady-state) studies, and dose proportionality pharmacokinetic studies. Similarly the apparent half-life (t1/2) has been found to be approximately 12 hours independent of dose. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly.

In healthy man, orally administered verapamil hydrochloride undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The biologic activity of norverapamil appears to be approximately 20% that of verapamil.

Approximately 70% of an administered dose of verapamil hydrochloride is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours (see PRECAUTIONS), the volume of distribution is increased, and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one-third of the oral daily dose required for patients with normal liver function.

After 4 weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil.

In ten healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg), resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg/dL) compared with placebo. (See PRECAUTIONS: Drug Interactions.)

The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ± 97.24 mg•hr/dL).

Verapamil AUCs were positively correlated (r=0.71) to increased ethanol blood AUC values.

Geriatric Use

The pharmacokinetics of verapamil GITS were studied after 5 consecutive nights of dosing 180 mg in 30 healthy young (19 to 43 years) vs. 30 healthy elderly (65 to 80 years) male and female subjects. Older subjects had significantly higher mean verapamil Cmax, Cmin and AUC(0-24h) compared to younger subjects. Older subjects had mean AUCs that were approximately 1.7 to 2 times higher than those of younger subjects as well as a longer average verapamil t1/2 (approximately 20 hr vs. 13 hr).

Hemodynamics and Myocardial Metabolism

Verapamil hydrochloride reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with IHSS and those with coronary heart disease has also been observed with verapamil hydrochloride therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil hydrochloride is countered by reduction of afterload and cardiac index is usually not reduced. In patients with severe left ventricular dysfunction however, (e.g., pulmonary wedge pressure above 20 mm Hg or ejection fraction lower than 30%), or in patients on beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur. (See PRECAUTIONS: Drug Interactions.)

Pulmonary Function

Verapamil hydrochloride does not induce bronchoconstriction and hence, does not impair ventilatory function.

Indications and Usage for Verapamil Extended Release Capsules

Verapamil hydrochloride extended-release capsules are indicated for the management of essential hypertension.

Contraindications

Verapamil hydrochloride extended-release capsules are contraindicated in:

1. Severe left ventricular dysfunction. (See WARNINGS.)


2. Hypotension (less than 90 mm Hg systolic pressure) or cardiogenic shock.


3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker).


4. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).


5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). (See WARNINGS.)


6. Patients with known hypersensitivity to verapamil hydrochloride.

Warnings

Heart Failure

Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30% or moderate to severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker. (See PRECAUTIONS: Drug Interactions.) Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (note interactions with digoxin under: PRECAUTIONS).

Hypotension

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension.

Elevated Liver Enzymes

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT, and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine)

Some patients with paroxysmal and/or chronic atrial flutter or atrial fibrillation and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated. (See CONTRAINDICATIONS.)

Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.

Atrioventricular Block

The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed.

Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil hydrochloride and institution of appropriate therapy depending upon the clinical situation.

Patients with Hypertrophic Cardiomyopathy (IHSS)

In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mm Hg) capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see PRECAUTIONS: Drug Interactions) preceded the severe hypotension in three of the eight patients (two of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.

Precautions

THE CONTENTS OF THE VERAPAMIL HYDROCHLORIDE EXTENDED-RELEASE CAPSULE SHOULD NOT BE CRUSHED OR CHEWED. VERAPAMIL HYDROCHLORIDE EXTENDED-RELEASE CAPSULES ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO APPLESAUCE. (See DOSAGE AND ADMINISTRATION.)

General

Use in Patients with Impaired Hepatic Function

Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate-release verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE) should be carried out.

Use in Patients with Attenuated (Decreased) Neuromuscular Transmission

It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent, vecuronium and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.

Use in Patients with Impaired Renal Function

About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage. (See OVERDOSAGE.)

Information for Patients

When the sprinkle method of administration is prescribed, details of the proper technique should be explained to the patient. (See DOSAGE AND ADMINISTRATION.)

Drug-Drug Interactions

Drug Interactions

Effects of other drugs on verapamil pharmacokinetics

In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450, CYP3A4, CYP1A2, and CYP2C. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (e.g.,  rifampin) have caused a lowering of plasma levels of verapamil. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class of antibiotics.

Beta-Blockers

Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. The combination of extended-release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excess bradycardia and AV block, including complete heart block, when the combination has been used for the treatment of hypertension.

For hypertensive patients, the risk of combined therapy may outweigh the potential benefits. The combination should be used only with caution and close monitoring.

Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.

A decrease in metoprolol clearance has been reported when verapamil and metoprolol were administered together. A similar effect has not been observed when verapamil and atenolol are given together.

Clonidine

Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine.

Digitalis

Consider reducing digoxin dose when verapamil and digoxin are to be given together. Monitor digoxin level periodically during therapy. Chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin pharmacokinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. If digoxin toxicity is suspected, suspend or discontinue digoxin therapy.

In previous clinical trials with other verapamil formulations related to the control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients, and asymptomatic hypotension occurred in 5% of patients.

Antihypertensive Agents

Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta-blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin.

Antiarrhythmic Agents

Disopyramide

Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.

Flecainide

A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.

Quinidine

In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided.

The electrophysiological effects of quinidine and verapamil on AV conduction were studied in eight patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.

Nitrates

Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.

Alcohol

Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.)

Other

Aspirin

In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone.

Cimetidine

The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged.

Grapefruit Juice

Grapefruit juice may significantly increase concentrations of verapamil. Grapefruit juice given to nine healthy volunteers increased S- and R-verapamil AUC(0-12) by 36% and 28%, respectively. Steady-state Cmax and Cmin of S-verapamil increased by 57% and 16.7%, respectively with grapefruit juice compared to control. Similarly, Cmax and Cmin of R-verapamil increased by 40% and 13%, respectively. Grapefruit juice did not affect half-life, nor was there a significant change in AUC(0-12) ratio R/S compared to control. Grapefruit juice did not cause a significant difference in the PK of norverapamil. This increase in verapamil plasma concentration is not expected to have any clinical consequences.

Lithium

Pharmacokinetic and pharmacodynamic interactions between oral verapamil and lithium have been reported. The former may result in a lowering of serum lithium levels in patients receiving chronic stable oral lithium therapy. The latter may result in an increased sensitivity to the effects of lithium. Patients receiving both drugs must be monitored carefully.

Carbamazepine

Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.

Rifampin

Therapy with rifampin may markedly reduce oral verapamil bioavailability.

Phenobarbital

Phenobarbital therapy may increase verapamil clearance.

Cyclosporine

Verapamil therapy may increase serum levels of cyclosporine.

Inhalation Anesthetics

Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should be titrated carefully to avoid excessive cardiovascular depression.

Neuromuscular Blocking Agents

Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

Carcinogenesis, Mutagenesis, Impairment of Fertility

An 18-month toxicity study in rats, at a low multiple (6-fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for 2 years at doses of 10, 35, and 120 mg/kg per day or approximately 1x, 3.5x, and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day).

Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.

Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.

Pregnancy

Teratatogenic Effects. Pregnancy Category C

Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the maximum recommended human daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.

Labor and Delivery

It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil hydrochloride in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Nursing Mothers

Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.

Pediatric Use

Safety and efficacy of verapamil in children below the age of 18 years have not been established.

Geriatric Use

Clinical studies of verapamil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism.)

Verapamil is highly metabolized by the liver, and about 70% of the administered dose is excreted as metabolites in the urine. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered. (See PRECAUTIONS: General.) In general, lower initial doses of verapamil hydrochloride extended-release capsules may be warranted in the elderly. (See DOSAGE AND ADMINISTRATION.)

Animal Pharmacology and/or Animal Toxicology

In chronic animal toxicology studies verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not the rat. Development of cataracts due to verapamil has not been reported in man.

Adverse Reactions

Serious adverse reactions are uncommon when verapamil hydrochloride therapy is initiated with upward dose titration within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil.

In clinical trials involving 285 hypertensive patients on verapamil hydrochloride extended-release for greater than one week the following adverse reactions were reported in greater than 1% of the patients:

Constipation	7.4%
Headache	5.3%
Dizziness	4.2%
Lethargy	3.2%
Dyspepsia	2.5%
Rash	1.4%
Ankle Edema	1.4%
Sleep Disturbance	1.4%
Myalgia	1.1%

In clinical trials of other formulations of verapamil hydrochloride (N=4,954) the following reactions have occurred at rates greater than 1%:

Constipation	7.3%
CHF/Pulmonary Edema	1.8%
Dizziness	3.3%
Fatigue	1.7%
Nausea	2.7%
Bradycardia (HR<50/min)	1.4%
Hypotension	2.5%
AV block-total 1º, 2º, 3º	1.2%
2º and 3º	0.8%
Edema	1.9%
Headache	2.2%
Flushing	0.6%
Rash	1.2%
Elevated Liver Enzymes (See WARNINGS.)

In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial flutter, ventricular rate below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.

The following reactions, reported in 1% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope.

Digestive System: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia.

Hemic and Lymphatic: ecchymosis or bruising.

Nervous System: cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence.

Respiratory: dyspnea.

Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson Syndrome, erythema multiforme.

Special Senses: blurred vision, tinnitus.

Urogenital: gynecomastia, impotence, increased urination, spotty menstruation.

Treatment of Acute Cardiovascular Adverse Reactions

The frequency of cardiovascular adverse reactions which require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately, e.g., intravenously administered isoproterenol hydrochloride, levarterenol bitartrate, atropine (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine, metaraminol bitartrate or methoxamine) should be used to maintain blood pressure, and isoproterenol and levarterenol should be avoided. If further support is necessary, inotropic agents (dopamine or dobutamine) may be administered.

Actual treatment and dosage should depend on the severity and the clinical situation and the judgment and experience of the treating physician.

Overdosage

There is no specific antidote for verapamil overdosage; treatment should be supportive. Delayed pharmacodynamic consequences may occur with extended-release formulations, and patients should be observed for at least 48 hours, preferably under continuous hospital care. Reported effects include hypotension, bradycardia, cardiac conduction defects, arrhythmias, hyperglycemia, and decreased mental status. In addition, there have been literature reports of noncardiogenic pulmonary edema in patients taking large overdoses of verapamil (up to approximately 9 g).

In acute overdosage, gastrointestinal decontamination with cathartics and whole bowel irrigation should be considered. Calcium, inotropes (i.e., isoproterenol, dopamine, and glucagon), atropine, vasopressors (i.e., norepinephrine, and epinephrine), and cardiac pacing have been used with variable results to reverse hypotension and myocardial depression. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Calcium chloride is preferred to calcium gluconate since it provides 3 times more calcium per volume. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. Verapamil cannot be removed by hemodialysis.

Verapamil Extended Release Capsules Dosage and Administration

Essential Hypertension

The dose of verapamil hydrochloride extended-release capsules should be individualized by titration. The usual daily dose of extended-release verapamil hydrochloride capsules in clinical trials has been 240 mg given by mouth once daily in the morning. However, initial doses of 120 mg a day may be warranted in patients who may have an increased response to verapamil (e.g., elderly, small people, etc.). Upward titration should be based on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of verapamil hydrochloride extended-release capsules are evident within the first week of therapy.

If adequate response is not obtained with 120 mg of verapamil hydrochloride extended-release capsules, the dose may be titrated upward in the following manner:

1. 180 mg in the morning,


2. 240 mg in the morning,


3. 360 mg in the morning,


4. 480 mg in the morning.

Verapamil extended-release capsules are for once a day administration. When switching from immediate-release verapamil to verapamil hydrochloride extended-release capsules, the same total daily dose of verapamil hydrochloride extended-release capsules can be used.

As with immediate-release verapamil, dosages of verapamil hydrochloride extended-release capsules should be individualized and titration may be needed in some patients.

Sprinkling the Capsule Contents on Food

Verapamil hydrochloride extended-release bead filled capsules may also be administered by carefully opening the capsule and sprinkling the beads on a spoonful of applesauce. The applesauce should be swallowed immediately without chewing and followed with a glass of cool water to ensure complete swallowing of the beads. The applesauce used should not be hot, and it should be soft enough to be swallowed without chewing.

Any bead/applesauce mixture should be used immediately and not stored for future use. Subdividing the contents of a verapamil hydrochloride extended-release capsule is not recommended.

HOW SUPPLIED:

Verapamil Hydrochloride Extended-release Capsules, are available in 120 mg capsules.

The 120 mg capsule is a bluish green opaque cap/white opaque body, hard-shell gelatin capsule filled with white to off-white beads. The capsule is radially printed with MYLAN over 6320 in black ink on both the cap and the body. They are available as follows:

NDC 51079-917-20 - Unit dose blister packages of 100 (10 cards of 10 capsules each).

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Brief digressions above 25°C while not detrimental, should be avoided.

Avoid excessive heat.

Protect from moisture.

Call your doctor for medical advice about side effects. You may report side effects to Mylan Pharmaceuticals Inc. at 1-877-446-3769 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Manufactured by:

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Distributed by:

UDL Laboratories, Inc.

Rockford, IL 61103

S-7049 R6

4/11

PRINCIPAL DISPLAY PANEL - 120 mg

NDC  51079-917-20

VERAPAMIL

HYDROCHLORIDE

EXTENDED-RELEASE

CAPSULES

120 mg

100 Capsules (10 x 10)

Each capsule contains:

Verapamil

hydrochloride, USP 120 mg

Usual Adult Dosage: See

accompanying prescribing

information.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room

Temperature.]

Brief digressions above 25°C

while not detrimental, should be

avoided. Avoid excessive heat.

Protect from light and moisture.

Manufactured by:

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505

Rx only

S-7050 R2

Packaged and Distributed by:

UDL LABORATORIES, INC.

ROCKFORD, IL 61103

This unit dose package is not child resistant.

For institutional use only.

Keep this and all drugs out of the reach of children.

This container provides light-resistance.

See window for lot number and expiration date.

VERAPAMIL HYDROCHLORIDE  verapamil hydrochloride  capsule, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 51079-917 Route of Administration