Phenylephrine Hydrochloride

Class: alpha-Adrenergic Agonists
VA Class: AU100
CAS Number: 61-76-7
Brands: Benadryl, Excedrin, Neo-Synephrine, Preparation H, Sudafed PE, Theraflu, Triaminic, Tylenol, Vicks

Introduction

Sympathomimetic amine that predominantly acts by a direct effect on α-adrenergic receptors.

Uses for Phenylephrine Hydrochloride

Shock

Used to produce vasoconstriction as an adjunct to correct hemodynamic imbalances in the treatment of shock that persists after adequate fluid volume replacement.^b (See Contraindications and also see Warnings under Cautions.)

Individual hemodynamic abnormalities must be identified and monitored so that therapy can be adjusted as necessary.^b

May be ineffective if severe peripheral vasoconstriction exists and may have a deleterious effect by causing further reductions in plasma volume and blood flow to vital organs.^b

Value of pressor therapy in shock, especially when due to septicemia, burns, trauma, or drug overdosage, is questionable;^b may be indicated if patient fails to respond to administration of fluids, a change in position or other measures directed to the specific cause of shock, such as anti-infectives in septicemia, epinephrine in anaphylactic shock, or specific antidotes and/or removal of the drug in cases of overdosage. Drugs which also stimulate the myocardium (e.g., norepinephrine, metaraminol) are usually preferred to phenylephrine, especially in shock caused by myocardial infarction, septicemia, or surgical complications.^b

Pressor therapy in overdosage of barbiturates or other sedatives is especially controversial; some clinicians have stated that the incidence of mortality may actually be increased when a pressor is given.^b

May be useful when cardiac stimulation is undesirable (as in the treatment of hypotension occurring during general anesthesia with cyclopropane, halothane, or other agents that sensitize the myocardium to arrhythmias).^b

May be used to treat hypotension or shock resulting from overdosage of or idiosyncratic reactions to certain drugs (e.g., adrenergic and ganglionic blocking agents, rauwolfia and veratrum alkaloids, phenothiazines).^b

May be useful to control shock following pheochromocytomectomy, but shock generally can be prevented by maintenance of adequate blood volume and/or preoperative administration of an α-adrenergic blocking agent.^b

Hypotension During Spinal Anesthesia

Has been used both for the prevention and treatment of hypotension resulting from spinal anesthesia, but some clinicians state that pure α-adrenergic agonists should not be used because they may further reduce cardiac output.^b

Routine prophylactic use of any vasopressor in spinal anesthesia has been questioned because hypotension does not always occur during spinal anesthesia and treatment can readily be instituted if necessary; it has been suggested that vasopressors be administered prophylactically only in those cases in which a substantial decrease in BP is expected.^b

Use of vasopressors to correct hypotension occurring during anesthesia in obstetrical patients is controversial; hypotension can usually be minimized by adequate hydration and changing the position of the patient so that the uterus does not compress the inferior vena cava; if a vasopressor is required, ephedrine is usually preferred.^b

Prolongation of Local Anesthesia

May be added to solutions of some local anesthetics to decrease the rate of vascular absorption of the anesthetic, thereby localizing anesthesia and prolonging the duration of anesthesia.^b

Decreases risk of systemic toxicity due to the local anesthetic.^b

Not as effective as epinephrine in prolonging local anesthesia but may be preferred when cardiostimulation is undesirable.^b

Paroxysmal Supraventricular Tachycardia

Administered IV to raise BP in order to terminate some attacks of paroxysmal supraventricular tachycardia, especially in patients who are also hypotensive or in shock.^b

Administration of an anticholinesterase drug having a short duration of action (e.g., edrophonium chloride) may be safer.^b

Nasal Congestion

Self-medication for temporary relief of nasal congestion associated with upper respiratory allergy (e.g., hay fever) or the common cold.^{114 124} However, efficacy of oral phenylephrine for this use has been questioned.^{115 125 126 127}

Self-medication for temporary relief of sinus congestion and pressure.^{114 124}

Used in fixed combination with other agents (e.g., acetaminophen, chlorpheniramine, dextromethorphan, diphenhydramine, guaifenesin, pheniramine) for temporary relief of nasal/sinus congestion and/or other symptoms (e.g., rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal itching, cough) associated with seasonal or perennial allergic rhinitis, other upper respiratory allergies, or the common cold.^{133 134 135 136 137 138 139}

Because of recent state and federal actions restricting OTC sale and purchase of preparations containing pseudoephedrine, ephedrine, or phenylpropanolamine (no longer commercially available in the US),^{109 110 111 112} some manufacturers have reformulated various OTC preparations by substituting phenylephrine for pseudoephedrine that was previously contained in these preparations.^{113 116}

Labeled and has been used for self-medication for temporary relief of nasal congestion associated with sinusitis;^{114 117} however, efficacy data are lacking and/or controversial.^{117 118 119} In October 2005, FDA issued a final rule to remove this indication from labeling of OTC nasal decongestants.¹¹⁷ Compliance date for preparations with annual sales <$25,000 was October 11, 2007; compliance date for all other preparations was April 11, 2007.¹¹⁷

Hemorrhoids

Anorectal preparations (e.g., creams, gels, ointments, suppositories) containing phenylephrine hydrochloride are used topically or rectally to provide temporary symptomatic relief of external or internal hemorrhoids.^{101 102 103 104 105 106 107 108}

When applied topically or rectally to the anorectal area, vasoconstrictors such as phenylephrine stimulate α-adrenergic receptors in the vascular beds¹⁰² with a resultant temporary constriction of arterioles and a modest and transient reduction in congestion (swelling) of hemorrhoidal tissues.^{101 102 108}

May relieve anorectal pruritus, discomfort, and irritation, possibly in part secondary to some weak local anesthetic action; the mechanism of this local anesthetic effect is unknown.^{102 108}

May relieve pruritus associated with histamine release.^{102 108}

If minor bleeding is present, a clinician should be consulted promptly for advice since anorectal bleeding may be a sign of conditions ranging in seriousness from simple abrasions to cancer.¹⁰⁸

Diagnosis of Heart Murmurs

IV phenylephrine has been used to increase BP as an aid in the diagnosis of heart murmurs†.^b

Phenylephrine Hydrochloride Dosage and Administration

General

• 
  

  Vasopressor therapy: Elevate BP to slightly less than the patient’s normal BP.^b

  
  


• 
  

  Previously normotensive patients: SBP should be maintained at 80–100 mm Hg.^b

  
  


• 
  

  Previously hypertensive patients: SBP should be maintained at 30–40 mm Hg below their usual BP.^b

  
  


• 
  

  Very severe hypotension: Maintenance of even lower BP may be desirable if blood or fluid volume replacement has not been completed.^b

  
  


• 
  

  Do not leave patients receiving the drug by IV infusion unattended; the infusion flow rate must be closely monitored; check BP frequently, especially during IV administration.^b

  
  


• 
  

  Continue therapy until adequate BP and tissue perfusion are maintained.^b

  
  


• 
  

  IV infusion discontinuance: Gradually slow the infusion rate and avoid abrupt withdrawal.^b

  
  


• 
  

  Observe patient carefully so that therapy may be resumed if the BP falls too rapidly.^b

  
  


• 
  

  Do not reinstate pressor therapy until the SBP falls to 70–80 mm Hg; some patients may require additional administration of IV fluids before discontinuation.^b

  
  

Administration

Parenteral Administration

Vasopressor therapy: Administer by IM, sub-Q, or slow IV injection or IV infusion; route of administration determined by the needs of the individual patient.^b

Patients who are in shock may require IV administration to ensure absorption.^b Usually administered by IV infusion as a dilute solution.^b

Direct IV injections are administered in treating paroxysmal atrial or nodal tachycardia or in emergencies requiring a strong, immediate pressor effect.^b

Emergencies: May be administered by direct IV injection.^b

Dilution

For convenience in administration by direct IV injection, 1 mL of the commercially available phenylephrine hydrochloride injection containing 10 mg/mL may be diluted with 9 mL of sterile water for injection to prepare a solution containing 1 mg/mL.^b

For IV infusion, phenylephrine may be diluted with 5% dextrose or 0.9% sodium chloride injection.^b

The concentration of phenylephrine and the infusion rate depend on the drug and fluid requirements of the individual patient. Infusion solutions are usually prepared by adding 10 mg of phenylephrine hydrochloride to 500 mL of diluent.

Oral Administration

Vasoconstrictor for nasal congestion: Administer orally alone^{114 124} or as a fixed-combination decongestant preparation.^b

Place orally dissolving strip(s) on the tongue, where it rapidly dissolves and then can be swallowed.¹²⁴

Topical and Rectal Administration

Vasoconstrictor for hemorrhoidal symptoms: Topical preparations are administered externally to the affected perianal area, and rectal preparations are administered externally to the affected perianal area and/or intrarectally.^{101 102 103 104 105 106 107 108}

Apply topical preparations labeled for external use only externally to the affected area and do not administer inside the rectum by either using fingers or any mechanical device or applicator.^{101 102 103 105 107}

Rectal preparations are labeled either for rectal use only (e.g., suppositories) or for external and/or intrarectal use only.^{101 102 104 106 107}

When a special applicator such as a pile pipe or other mechanical device is used to administer the drug intrarectally, attach the applicator to the tube of drug and then lubricate the applicator well and gently insert into the rectum;^{101 102 104} cleanse the applicator thoroughly after each use and store according to the manufacturer’s instructions.¹⁰⁴

Do not use such preparations if introduction of the applicator or device into the rectum causes additional pain; advise patients to consult a clinician promptly in such cases.^{101 102 104 107}

Remove wrapper from suppositories prior to insertion into the rectum.^{101 102 106 107}

Advise patients receiving the drug for the local management of hemorrhoids to cleanse the affected perianal area by patting with warm water and mild soap and rinsing thoroughly or with an appropriate cleansing wipe whenever practical.^{101 102 103 104 105 106 107}

Dry the area by patting or blotting with toilet tissue or a soft cloth before application of the drug.^{101 102 103 104 105 106 107}

Dosage

Because combinations and dosage strengths vary for fixed-combination preparations, consult manufacturer's product labeling for appropriate dosage of the specific preparation.

Pediatric Patients

Administer the lowest effective dosage for the shortest possible time; when possible, small doses should be injected initially and subsequent doses determined by pressor response.^b

Hypotension

Mild or Moderate

IM or Sub-Q

Children: 0.1 mg/kg or 3 mg/m² IM or sub-Q; may give additional IM or sub-Q doses in 1–2 hours if needed.^b

Hypotension During Spinal Anesthesia

Treatment

IM or Sub-Q

Children: 0.044–0.088 mg/kg IM or sub-Q to treat hypotension during spinal anesthesia.^b

Nasal Congestion

Oral

Self-medication in children 2–5 years of age: 2.5 mg every 4 hours.¹²⁴

Self-medication in children 6–11 years of age: 5 mg every 4 hours.¹²⁴

Self-medication in children ≥12 years of age: Usually, 10 mg every 4 hours.^{114 b}

May be administered in fixed combination with other drugs.^b

Discontinue therapy if symptoms persist for >7 days or are accompanied by fever or if nervousness, dizziness, or insomnia occurs.^{114 124}

Hemorrhoids

Temporary Relief

Topical or Rectal

Children ≥12 years of age: Self-medication with a cream, gel, ointment, or suppository containing 0.25% of the drug alone or in combination with other anorectal agents (e.g., protectants, local anesthetics, astringents, antipruritics, analgesics).^{101 102 103 104 105 106 107 108}

Administer at bedtime, in the morning, and after bowel movements^{102 103 104 105 106} up to 4 times daily.^{101 102 103 104 105 106 107 108}

Do not exceed the recommended dosage unless otherwise directed by a clinician.^{101 102 103 104 105 106 107 108}

Anorectal dosage for self-medication of hemorrhoids should not exceed 2 mg daily (i.e., 0.5 mg 4 times daily).¹⁰⁸

Adults

Administer the lowest effective dosage for the shortest possible time; when possible, small doses should be injected initially and subsequent doses determined by pressor response.^b

Hypotension

Mild or Moderate

IM or Sub-Q

Usually, 2–5 mg; doses range from 1–10 mg.^b

Initially, do not exceed 5 mg.^b

IV

Usually, 0.2 mg by slow IV injection; doses range from 0.1–0.5 mg.^b

Initial dose should not exceed 0.5 mg; doses may be given no more frequently than every 10–15 minutes.^b

Severe Hypotension or Shock

IV

Administer as a dilute solution.^b (See Parenteral Administration under Dosage and Administration.)

Usually administer at an initial rate of 0.1–0.18 mg/minute; after the BP stabilizes, 0.04–0.06 mg/minute is usually adequate.^b

Rate of infusion is adjusted to maintain the BP at the desired level.^b

To produce the desired pressor response, additional drug in increments of 10 mg or more may be added to the infusion solution and the rate of flow adjusted according to the response of the patient.^b

Hypotensive emergencies: May be given IV in an initial dose of 0.2 mg; any subsequent dose should not exceed the previous dose by 0.1–0.2 mg and a single dose should not exceed 0.5 mg.^b

Hypotension During Spinal Anesthesia

Prevention

IM or Sub-Q

Low spinal anesthesia: Usually, 2 mg.^b

High spinal anesthesia: 3 mg may be necessary.^b

Administer 3–4 minutes prior to the spinal anesthetic.^b

Prolongation of Spinal Anesthesia

IV

Usually, 2–5 mg are added to the anesthetic solution.^b

Vasoconstriction for Regional Anesthesia

IV

Optimally, the concentration of phenylephrine hydrochloride is 0.05 mg/mL (1:20,000).^b

Solutions may be prepared for regional anesthesia by adding 1 mg of phenylephrine hydrochloride to each 20 mL of local anesthetic solution.^b

Some pressor response can be expected when at least 2 mg is injected.^b

Paroxysmal Supraventricular Tachycardia

IV

Initially, administer rapidly (within 20–30 seconds) by direct IV injection with a dose not exceeding 0.5 mg; increase subsequent doses in increments of 0.1–0.2 mg, depending on the BP response of the patient. ^b

Do not raise SBP above 160 mm Hg.^b

Maximum single dose is 1 mg.^b

Nasal Congestion

Oral

Self-medication: Usually, 10 mg every 4 hours.^{114 b} May be administered in fixed combination with other drugs.^b

Discontinue therapy if symptoms persist for >7 days or are accompanied by fever or if nervousness, dizziness, or insomnia occurs.¹¹⁴

Hemorrhoids

Temporary Relief

Topical or Rectal

Self-medication as a cream, gel, ointment, or suppository containing 0.25% of the drug alone or in combination with other anorectal agents (e.g., protectants, local anesthetics, astringents, antipruritics, analgesics).^{101 102 103 104 105 106 107 108}

Administer at bedtime, in the morning, and after bowel movements^{102 103 104 105 106} up to 4 times daily.^{101 102 103 104 105 106 107 108}

Do not to exceed the recommended dosage unless otherwise directed by a clinician.^{101 102 103 104 105 106 107 108}

Anorectal dosage for self-medication of hemorrhoids should not exceed 2 mg daily (i.e., 0.5 mg 4 times daily).¹⁰⁸

Prescribing Limits

Pediatric Patients

Nasal Congestion

Oral

Self-medication in children 2–5 years of age: Maximum 15 mg in any 24-hour period.¹²⁴

Self-medication in children 6–11 years of age: Maximum 30 mg in any 24-hour period.¹²⁴

Self-medication in children ≥12 years of age: Maximum 60 mg in any 24-hour period.¹¹⁴

Hemorrhoids (Temporary Relief)

Topical or Rectal

Children ≥12 years of age: Anorectal dosage for self-medication of hemorrhoids should not exceed 2 mg daily (i.e., 0.5 mg 4 times daily).¹⁰⁸

Adults

Hypotension

Mild or Moderate

Sub-Q or IM

Initially, do not exceed 5 mg.^b

IV

Initial dose should not exceed 0.5 mg; repeat doses no more frequently than every 10–15 minutes.^b

Hypotension during Spinal Anesthesia (Prevention)

IM or Sub-Q

Hypotensive emergencies: May be given IV in an initial dose of 0.2 mg; any subsequent dose should not exceed the previous dose by 0.1–0.2 mg and a single dose should not exceed 0.5 mg.^b

Paroxysmal Supraventricular Tachycardia

IV

Maximum single dose is 1 mg.^b

Do not raise SBP above 160 mm Hg.^b

Nasal Congestion

Oral

Self-medication: Maximum 60 mg in any 24-hour period.¹¹⁴

Hemorrhoids (Temporary Relief)

Topical or Rectal

Anorectal dosage for self-medication of hemorrhoids should not exceed 2 mg daily (i.e., 0.5 mg 4 times daily).¹⁰⁸

Cautions for Phenylephrine Hydrochloride

Contraindications

• 
  

  Severe hypertension or ventricular tachycardia.^b

  
  


• 
  

  Peripheral or mesenteric vascular thrombosis, because ischemia may be increased and the area of infarction extended.^b

  
  


• 
  

  For use in fingers, toes, ears, nose, or genitalia in conjunction with local anesthetics.^b

  
  


• 
  

  Severe coronary disease or cardiovascular disease (including MI) in the view of some clinicians.^b

  
  


• 
  

  For self-medication of hemorrhoidal symptoms unless otherwise directed by a clinician: Cardiac disease, high BP, thyroid disease, diabetes mellitus, or difficulty in urination secondary to prostatic hyperplasia.^{101 102 103 104 105 106 107 108}

  
  


• 
  

  Known hypersensitivity to phenylephrine or to any ingredient in the respective formulation.^b

  
  

Warnings/Precautions

Warnings

Hypovolemia

Pressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes.^b

Correct blood volume depletion as fully as possible before administration.^b

May be used in an emergency as an adjunct to fluid volume replacement or as a temporary supportive measure to maintain coronary and cerebral artery perfusion until volume replacement therapy can be completed, but phenylephrine must not be used as sole therapy in hypovolemic patients.^b

Additional volume replacement also may be necessary during or after administration of epinephrine, especially if hypotension recurs.^b

Monitoring of central venous pressure or left ventricular filling pressure may be helpful in detecting and treating hypovolemia; in addition, monitoring of central venous or pulmonary arterial diastolic pressure is necessary to avoid overloading the cardiovascular system and precipitating CHF.^b

Severe vasoconstrictive effects may be most likely to occur in hypovolemic patients.^b

Hypoxia and Acidosis

Hypoxia and acidosis may reduce the effectiveness of phenylephrine and must be identified and corrected prior to or concurrently with administration of the drug.^b

Concomitant Diseases

Administer with extreme caution to geriatric or hyperthyroid patients or those with bradycardia, partial heart block, myocardial disease, or severe arteriosclerosis.^b

Administer parenterally with extreme caution if at all to hypertensive patients.^b

If administered to patients with acute pancreatitis or hepatitis, the drug may increase ischemia in the liver or pancreas.^b

Do not use for self-medication for nasal congestion in patients with thyroid disease, diabetes mellitus, hypertension, heart disease, or difficulty urinating because of prostatic hypertrophy without consulting a clinician.^{114 124}

MAO Inhibitors and Antihypertensive Agents

Avoid use for self-medication for nasal congestion if currently receiving or have recently received (i.e., within 2 weeks) an MAO inhibitor.^{114 124}

Consult a clinician before initiating self-medication with an anorectal preparation of the drug if they currently are receiving an antihypertensive agent or antidepressant (e.g., MAO inhibitor).^{101 102 103 104 105 106 107 108}

Sensitivity Reactions

Sulfite Reactions

Some formulations of phenylephrine hydrochloride injection contain sulfites which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.^b

Major Toxicities

Overdosage

Overdosage may cause hypertension, headache, seizures, cerebral hemorrhage, palpitation, paresthesia, or vomiting; headache may be a symptom of hypertension.^b

Hypertension may be relieved by administration of an α-adrenergic blocking agent (e.g., phentolamine).^b

General Precautions

Prolonged Administration

Prolonged administration of vasopressors has caused edema, hemorrhage, focal myocarditis, subpericardial hemorrhage, necrosis of the intestine, or hepatic and renal necrosis; these effects have generally occurred in patients with severe shock and it is not clear if the drug or the shock state itself was the cause.^b

Combination Preparations

When used in combination with other drugs (e.g., acetaminophen, chlorpheniramine, dextromethorphan, diphenhydramine, guaifenesin, pheniramine), consider the cautions, precautions, and contraindications associated with all ingredients in the formulation.^{133 134 135 136 137 138 139 b}

Prolonged use of the drug may result in plasma volume depletion which may result in perpetuation of the shock state or the recurrence of hypotension when phenylephrine is discontinued.^b

Systemic Effects

Injections may be followed by paresthesia in the extremities or a feeling of coolness in the skin.^b

Cardiac Effects

When ≥2 mg is injected during regional local anesthesia, a pressor response may occur.^b

Administration by rapid IV injection in the treatment of paroxysmal supraventricular tachycardia may result in overdosage with short paroxysms of ventricular tachycardia, ventricular extrasystoles, or a sensation of fullness in the head.^b

Can cause severe bradycardia and decreased cardiac output.^b

Decreased cardiac output may be especially harmful to elderly patients and/or those with initially poor cerebral or coronary circulation.^b

Reduced Vital Organ Blood Flow

Can cause severe peripheral and visceral vasoconstriction, reduced blood flow to vital organs, decreased renal perfusion, and probably reduced urine output and metabolic acidosis.

Extravasation

May cause necrosis or sloughing of tissue if extravasation occurs during IV administration or following sub-Q administration.^b

Anorectal Use

Based on observations with local use for nasal congestion, prolonged local use of excessive anorectal dosages of vasoconstrictors will likely lead to rebound vasodilation and congestion.¹⁰⁸

Less commonly, prolonged local use of excessive anorectal dosages of vasoconstrictors can lead to anxiety and paranoia.¹⁰⁸

Contact dermatitis has been reported following topical application of certain formulations of vasoconstrictors.¹⁰⁸

Possibility that topical anorectal application of vasoconstrictors if absorbed systemically in adequate amounts could interact with MAO inhibitors resulting in potentiated hypertensive effects should be considered.¹⁰⁸

For additional precautions associated with anorectal phenylephrine therapy, see Topical and Rectal Administration under Dosage and Administration.

Specific Populations

Pregnancy

Category C.¹³²

Administration in late pregnancy or labor may cause fetal anoxia and bradycardia by increasing contractility of the uterus and decreasing uterine blood flow.^{132 b}

If a vasopressor is used in conjunction with oxytocic drugs, the vasopressor effect is potentiated and may result in potentially serious adverse effects.^b (See Oxytocic Drugs under Interactions.)

Use during pregnancy only when clearly needed.^b Other pressors (e.g., ephedrine) usually preferred.¹³²

Lactation

Does not appear to be distributed to any great extent into breast milk.¹²¹ However, caution if used in nursing women.^b

Pediatric Use

Risk of overdosage and toxicity (including death) in children <2 years of age receiving OTC preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.^{128 129} Limited evidence of efficacy for these preparations in this age group; appropriate dosages not established.¹²⁸ Therefore, FDA recommends not to use such preparations in children <2 years of age; safety and efficacy in older children currently under evaluation. Because children 2–3 years of age also are at increased risk of overdosage and toxicity, some manufacturers of oral nonprescription cough and cold preparations recently agreed to voluntarily revise the product labeling to state that such preparations should not be used in children <4 years of age. During the transition period, some preparations on pharmacy shelves will have the new recommendation (“do not use in children <4 years of age”), while others will have the previous recommendation (“do not use in children <2 years of age”). FDA recommends that parents and caregivers adhere to dosage instructions and warnings on the product labeling that accompanies the preparation and consult a clinician about any concerns.

Geriatric Use

Administer with extreme caution to geriatric patients.^b

Common Adverse Effects

Systemic use: May cause restlessness, anxiety, nervousness, weakness, dizziness, precordial pain or discomfort, tremor, respiratory distress, pallor or blanching of the skin, or a pilomotor response.^b

Anorectal use: In recommended dosages for local effect in anorectal disorders (e.g., hemorrhoids), adverse systemic effects of vasoconstrictors such as phenylephrine generally are minimal.¹⁰⁸

Interactions for Phenylephrine Hydrochloride

Specific Drugs

Drug	Interaction	Comments
α-Adrenergic blocking agents (phentolamine mesylate, phenothiazine)	Vasopressor response to phenylephrine is decreased by prior administration of an α-adrenergic blocking agentb
β-Adrenergic blocking agents	Cardiostimulating effects of phenylephrine are blocked by prior administration of β-adrenergic blocking drugsb
Anesthetics, general (cyclopropane or halogenated hydrocarbon)	Cyclopropane or halogenated hydrocarbon general anesthetics increase cardiac irritability, may sensitize the myocardium to phenylephrine, and may result in arrhythmiasb	Use only with extreme caution or not at all with these general anestheticsb
Antidepressants, tricyclic	May potentiate the vasopressor effects of phenylephrineb
Atropine	Blocks the reflex bradycardia caused by phenylephrine and enhances the pressor response to phenylephrineb
Digoxin	Possibility that digoxin can sensitize the myocardium to the effects of sympathomimetic drugs should be consideredb
Ergot alkaloids	Excessive rise in BP may occur if phenylephrine is administered to patients receiving a parenteral injection of an ergot alkaloid such as ergonovine maleate132 b
Guanethidine	May potentiate the vasopressor effects of phenylephrineb
MAO inhibitors	Cardiac and pressor effects of phenylephrine are potentiated by prior administration of MAO inhibitors because metabolism of phenylephrine is reducedb The potentiation is greater following oral administration of phenylephrine than after parenteral administration of the drug because reduction of the metabolism of phenylephrine in the intestine results in increased absorption of the drugb	Avoid oral administration of phenylephrine in patients receiving an MAO inhibitor. Parenteral administration of phenylephrine to these patients, if unavoidable, should be undertaken with extreme caution and initial doses should be small Patients should consult a clinician before initiating anorectal phenylephrine therapy if they are receiving an MAO inhibitorb
Oxytocic drugs	The pressor effect of phenylephrine is potentiated132 b	If phenylephrine is used during labor and delivery to correct hypotension or is added to a local anesthetic solution, the obstetrician should be cautioned that some oxytocic drugs may cause severe persistent hypertension and that rupture of a cerebral blood vessel may occur during the postpartum period132 b
Phenothiazines	Phenothiazines have some α-adrenergic blocking effects; therefore, prior administration of a phenothiazine may reduce the pressor effect and duration of action of phenylephrineb
Sympathomimetic agents (epinephrine)	Combination products containing phenylephrine and a bronchodilator sympathomimetic agent should not be used concomitantly with epinephrine or other sympathomimetic agents because tachycardia or other serious arrhythmias may occurb

Phenylephrine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Completely absorbed following oral administration; undergoes extensive first-pass metabolism in the intestinal wall.^{121 122}

Bioavailability following oral administration is approximately 38% relative to IV administration.^{121 122} Because of extensive first-pass metabolism, considerable interindividual and possibly intraindividual variation in oral bioavailability exists.¹²¹

Peak serum concentrations occur at 0.75–2 hours following oral administration of 1- or 7.8-mg dose.^{121 122}

Given parenterally to achieve cardiovascular effects.^b

Onset

IV administration: Pressor effect occurs almost immediately.^b

IM administration: Pressor effect occurs within 10–15 minutes.^b

Oral administration: Nasal decongestion may occur within 15 or 20 minutes.^b

Duration

IV administration: Pressor effect persists for 15–20 minutes.^b

IM administration: Pressor effect persists for 30 minutes to 1–2 hours.^b

Oral administration: Nasal decongestion may persist for 2–4 hours.^b

Distribution

Extent

Undergoes rapid distribution into peripheral tissues; may be stored in certain organ compartments.¹²¹ Pharmacologic effects are terminated at least partially by uptake into tissues.^b

Penetration into the brain appears to be minimal.¹²¹

Not known if phenylephrine crosses the placenta.¹³²

Does not appear to be distributed to any great extent into breast milk.¹²¹

Elimination

Metabolism

Undergoes extensive metabolism in the intestinal wall (first-pass) and in the liver.^{121 122}

Principal routes of metabolism involve sulfate conjugation (principally in the intestinal wall) and oxidative deamination (by the enzyme MAO); glucuronidation also occurs to a lesser extent.^{121 122}

Elimination Route

Excreted in urine (80–86%) mainly as metabolites; unchanged drug accounts for 2.6 or 16% of an oral or IV dose, respectively.^{121 122}

Half-life

2–3 hours following oral or IV administration.^{121 122}

Special Populations

Clinical data regarding effects of renal or hepatic impairment on phenylephrine pharmacokinetics are limited.¹²¹

Because of extensive first-pass metabolism in the intestinal wall, hepatic impairment unlikely to result in major changes following oral administration; however, phenylephrine pharmacokinetics may be substantially altered following IV administration.¹²¹

Stability

Storage

Oral

Strips, orally dissolving

20–25°C.¹²⁴

Tablets

15–25°C in a dry place.¹¹⁴

Parenteral

Injection

Tight, light-resistant containers.^b

Up to 30°C protected from light.^b

Solutions diluted in 5% dextrose injection are stable for at least 48 hours at pH 3.5–7.5.^b

Stable for at least 48 hours when diluted to 0.02 mg/mL with 5% sodium bicarbonate injection.^b

Compatibility

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

Parenteral

Solution Compatibility^HID

Compatible
Dextran 6% in dextrose 5%
Dextran 6% in sodium chloride 0.9%
Dextrose–Ringer’s injection combinations
Dextrose–Ringer’s injection, lactated, combinations
Dextrose–saline combinations
Dextrose 2.5, 5 or, 10% in water
Fructose 10% in sodium chloride 0.9%
Fructose 10% in water
Invert sugar 5 and 10% in sodium chloride 0.9%
Invert sugar 5 and 10% in water
Ionosol products
Ringer’s injection
Ringer’s injection, lactated
Sodium bicarbonate 5%
Sodium chloride 0.45 or 0.9%
Sodium lactate (1/6) M

Drug Compatibility

Admixture CompatibilityHID

Compatible
Chloramphenicol sodium succinate
Chloramphenicol sodium succinate with sodium bicarbonate
Dobutamine HCl
Lidocaine HCl
Potassium chloride
Sodium bicarbonate
Sodium bicarbonate with chloramphenicol sodium succinate

Y-site CompatibilityHID

Compatible
Alcohol 10% in dextrose 5%
Amiodarone HCl
Argatroban
Bivalirudin

paclitaxel protein-bound

Generic Name: paclitaxel protein-bound (PAK li TAX el PRO teen-bound)

Brand Names: Abraxane

What is paclitaxel protein-bound?

Paclitaxel protein-bound is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Paclitaxel protein-bound is used in the treatment of breast cancer.

Paclitaxel protein-bound is usually given after other cancer medicines have been tried without successful treatment.

Paclitaxel protein-bound may also be used for purposes not listed in this medication guide.

What is the most important information I should know about paclitaxel protein-bound?

Do not use paclitaxel protein-bound if you are pregnant. It could harm the unborn baby. Use birth control to prevent pregnancy while you are receiving paclitaxel protein-bound, whether you are a man or a woman. Paclitaxel protein-bound use by either parent may cause birth defects. You should not use paclitaxel protein-bound if you are allergic to it, or if you have a low white blood cell count.

Before you receive this medication, tell your doctor if you have kidney disease, liver disease, heart disease, or bone marrow suppression.

To make sure this medication is helping your condition and not causing harmful effects, your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests. Do not miss any follow-up visits to your doctor.

Call your doctor at once if you have a serious side effect such as fever, chills, flu symptoms, mouth sores, easy bruising or bleeding, pale skin, feeling light-headed or short of breath, swelling or rapid weight gain, chest pain, sudden cough, rapid heart rate, or trouble breathing.

What should I discuss with my healthcare provider before receiving paclitaxel protein-bound?

You should not use paclitaxel protein-bound if you are allergic to it, or if you have a low white blood cell count.

To make sure you can safely receive paclitaxel protein-bound, tell your doctor if you have any of these other conditions:

• 
  

  kidney disease;

  
  


• 
  

  liver disease;

  
  


• 
  

  heart disease; or

  
  


• 
  

  bone marrow suppression.

  
  

FDA pregnancy category D. Do not use paclitaxel protein-bound if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment. Use birth control to prevent pregnancy while you are receiving paclitaxel protein-bound, whether you are a man or a woman. Paclitaxel protein-bound use by either parent may cause birth defects. It is not known whether paclitaxel protein-bound passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are receiving paclitaxel protein-bound.

How is paclitaxel protein-bound given?

Paclitaxel protein-bound is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. Paclitaxel protein-bound must be given slowly, and the IV infusion can take at least 30 minutes to complete.

Paclitaxel protein-bound is usually given once every 3 weeks. Follow your doctor's dosing instructions very carefully.

Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when paclitaxel protein-bound is injected.

To make sure this medication is helping your condition and not causing harmful effects, your blood will need to be tested often. Your cancer treatments may be delayed based on the results of these tests. Do not miss any follow-up visits to your doctor.

What happens if I miss a dose?

Call your doctor for instructions if you miss an appointment for your paclitaxel protein-bound injection.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include some of the serious side effects listed in this medication guide.

What should I avoid while using paclitaxel protein-bound?

Paclitaxel protein-bound can be harmful if it gets in your eyes, mouth, or nose, or on your skin. If skin contact occurs, wash the area with soap and water or rinse the eyes thoroughly with plain water.

Paclitaxel protein-bound 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 a serious side effect such as:

• 
  

  fever, chills, body aches, flu symptoms, sores in your mouth and throat;

  
  


• 
  

  easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

  
  


• 
  

  pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;

  
  


• 
  

  feeling like you might pass out;

  
  


• 
  

  swelling, rapid weight gain; or

  
  


• 
  

  chest pain, sudden cough, wheezing, trouble breathing, fast heart rate.

  
  

Less serious side effects may include:

• 
  

  numbness or tingly feeling;

  
  


• 
  

  muscle or joint pain;

  
  


• 
  

  nausea, vomiting;

  
  


• 
  

  diarrhea; or

  
  


• 
  

  hair loss.

  
  

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.

Paclitaxel protein-bound Dosing Information

Usual Adult Dose for Breast Cancer:

260 mg/m2 administered intravenously over 30 minutes every 3 weeks

What other drugs will affect paclitaxel protein-bound?

Tell your doctor about all other medicines you use, especially:

• 
  

  bosentan (Tracleer);

  
  


• 
  

  conivaptan (Vaprisol);

  
  


• 
  

  imatinib (Gleevec);

  
  


• 
  

  isoniazid (for treating tuberculosis);

  
  


• 
  

  montelukast (Singulair) or zafirlukast (Accolate);

  
  


• 
  

  rifampin (Rifater, Rifadin, Rifamate);

  
  


• 
  

  selegiline (Eldepryl, Emsam, Zelapar);

  
  


• 
  

  an antibiotic such as clarithromycin (Biaxin), dalfopristin/quinupristin (Synercid), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), or telithromycin (Ketek);

  
  


• 
  

  an antidepressant such as nefazodone or fluoxetine (Prozac);

  
  


• 
  

  antifungal medication such as clotrimazole (Mycelex Troche), itraconazole (Sporanox), ketoconazole (Extina, Ketozole, Nizoral, Xolegal), or voriconazole (Vfend);

  
  


• 
  

  a blood thinner such as warfarin (Coumadin);

  
  


• 
  

  cancer medication such as paclitaxel (Taxol) or tamoxifen (Soltamox);

  
  


• 
  

  heart or blood pressure medications such as amiodarone (Cordarone, Pacerone), carvedilol (Coreg), diltiazem (Cartia, Cardizem), felodipine (Plendil), losartan (Hyzaar, Cozaar), nifedipine (Nifedical, Procardia), torsemide (Demadex), verapamil (Calan, Covera, Isoptin, Verelan), and others;

  
  


• 
  

  HIV/AIDS medicine such as atazanavir (Reyataz), delavirdine (Rescriptor), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase), or ritonavir (Norvir);

  
  


• 
  

  seizure medications such as fosphenytoin (Cerebyx), or phenytoin (Dilantin);

  
  


• 
  

  oral diabetes medication such as glimepiride (Amaryl), glipizide (Glucotrol), nateglinide (Starlix), pioglitazone (Actos, Actoplus Met), repaglinide (Prandin), rosiglitazone (Avandia, Avandamet), or tolbutamide (Orinase); or

  
  


• 
  

  sulfa drugs (Bactrim, Gantanol, Gantrisin, Septra, SMX-TMP, and others).

  
  

This list is not complete and other drugs may interact with paclitaxel protein-bound. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More paclitaxel protein-bound resources

• Paclitaxel protein-bound Side Effects (in more detail)
• Paclitaxel protein-bound Dosage
• Paclitaxel protein-bound Use in Pregnancy & Breastfeeding
• Paclitaxel protein-bound Drug Interactions
• Paclitaxel protein-bound Support Group
• 1 Review for Paclitaxel protein-bound - Add your own review/rating

• paclitaxel protein-bound Intravenous Advanced Consumer (Micromedex) - Includes Dosage Information


• Abraxane Prescribing Information (FDA)


• Abraxane MedFacts Consumer Leaflet (Wolters Kluwer)


• Abraxane Consumer Overview

Compare paclitaxel protein-bound with other medications

• Breast Cancer
• Breast Cancer, Metastatic

Where can I get more information?

• Your doctor or pharmacist can provide more information about paclitaxel protein-bound.

See also: paclitaxel protein-bound side effects (in more detail)

Hyphed

Generic Name: hydrocodone, chlorpheniramine, and pseudoephedrine (Oral route)

hye-droe-KOE-done bye-TAR-trate, klor-fen-IR-a-meen MAL-ee-ate, soo-doe-e-FED-rin hye-droe-KLOR-ide

Commonly used brand name(s)

In the U.S.

• Hydron PSC


• Hyphed


• Notuss-Forte


• Zutripro

Available Dosage Forms:

• Liquid


• Tablet


• Suspension


• Solution


• Syrup


• Capsule

Therapeutic Class: Antitussive, Opioid/Antihistamine/Decongestant Combination

Pharmacologic Class: Chlorpheniramine

Chemical Class: Hydrocodone

Uses For Hyphed

Hydrocodone, chlorpheniramine, and pseudoephedrine combination is used to relieve cough and nasal congestion associated with the common cold and upper respiratory allergies in adults 18 years of age and older.

Hydrocodone is a narcotic antitussive (cough suppressant). It acts directly on the cough center in the brain to relieve cough. Chlorpheniramine is an antihistamine, which is used to relieve or prevent symptoms of an allergy. Pseudoephedrine is a decongestant, which decreases nasal congestion by narrowing the blood vessels and reducing blood flow to the nasal passage.

When hydrocodone is used for a long time, it may become habit-forming, causing mental or physical dependence. However, people who have continuing cough and nasal congestion should not let the fear of dependence keep them from using narcotics to relieve their cough. Mental dependence (addiction) is not likely to occur when narcotics are used for this purpose. Physical dependence may lead to withdrawal side effects if treatment is stopped suddenly. However, severe withdrawal side effects can usually be prevented by gradually reducing the dose over a period of time before treatment is stopped completely.

This medicine is available only with your doctor's prescription.

Before Using Hyphed

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Use of Zutripro™ is not indicated in children younger than 18 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of Zutripro™ in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require caution and an adjustment in the dose for patients receiving this medicine.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Clorgyline


• Dihydroergotamine


• Furazolidone


• Iproniazid


• Isocarboxazid


• Linezolid


• Moclobemide


• Naltrexone


• Nialamide


• Pargyline


• Phenelzine


• Procarbazine


• Rasagiline


• Selegiline


• Toloxatone


• Tranylcypromine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Adinazolam


• Alfentanil


• Alprazolam


• Amobarbital


• Anileridine


• Aprobarbital


• Bromazepam


• Brotizolam


• Buprenorphine


• Butabarbital


• Butalbital


• Butorphanol


• Carisoprodol


• Chloral Hydrate


• Chlordiazepoxide


• Chlorzoxazone


• Clobazam


• Clonazepam


• Clorazepate


• Codeine


• Dantrolene


• Dezocine


• Diazepam


• Estazolam


• Ethchlorvynol


• Fentanyl


• Flunitrazepam


• Flurazepam


• Fospropofol


• Guanethidine


• Halazepam


• Hydrocodone


• Hydromorphone


• Ketazolam


• Levorphanol


• Lorazepam


• Lormetazepam


• Medazepam


• Meperidine


• Mephenesin


• Mephobarbital


• Meprobamate


• Metaxalone


• Methocarbamol


• Methohexital


• Methyldopa


• Midazolam


• Midodrine


• Morphine


• Morphine Sulfate Liposome


• Nalbuphine


• Nitrazepam


• Nordazepam


• Opium


• Oxazepam


• Oxycodone


• Oxymorphone


• Pentazocine


• Pentobarbital


• Phenobarbital


• Prazepam


• Propoxyphene


• Quazepam


• Remifentanil


• Secobarbital


• Sodium Oxybate


• Sufentanil


• Tapentadol


• Temazepam


• Thiopental


• Triazolam

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Escitalopram

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Addison's disease (adrenal gland problem) or


• Asthma or


• Diabetes or


• Drug dependence, especially narcotic abuse or dependence, or history of or


• Enlarged prostate (BPH, prostatic hypertrophy) or


• Problems with passing urine or


• Thyroid disease—Use with caution. May increase risk for more serious side effects.

• Heart disease (e.g., coronary artery disease), severe or


• Hypertension (high blood pressure), severe or


• Narrow angle glaucoma or


• Urinary retention—Should not be used in patients with these conditions.

• Kidney disease, severe or


• Liver disease, severe—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Proper Use of hydrocodone, chlorpheniramine, and pseudoephedrine

This section provides information on the proper use of a number of products that contain hydrocodone, chlorpheniramine, and pseudoephedrine. It may not be specific to Hyphed. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. If too much of this medicine is taken for a long time, it may become habit-forming (causing mental or physical dependence) or cause an overdose.

Measure the oral liquid correctly using the marked measuring spoon, oral syringe, or medicine cup. The average household teaspoon may not hold the right amount of liquid. Ask your pharmacist for instructions for measuring the correct dose of this medicine.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (solution):
  
  • For relief of cough, sneezing, or runny or stuffy nose:
    
    • Adults—5 milliliters (mL) every 4 to 6 hours as needed. However, the dose is usually not more than 4 doses (20 mL) in 24 hours.
    
    
    • Children—Use is not recommended.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Hyphed

It is very important that your doctor check your progress while you are using this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it. If your symptoms do not improve or if they get worse, call your doctor.

Do not use this medicine if you have used an MAO inhibitor (MAOI) such as Eldepryl®, Marplan®, Nardil®, or Parnate® within the past 14 days.

Symptoms of an overdose include: extreme dizziness or weakness, shortness of breath, slow heartbeat or breathing, seizures, and cold, clammy skin. In case of an overdose, call your doctor right away.

This medicine may be habit-forming. If you feel that the medicine is not working as well, do not use more than your prescribed dose. Call your doctor for instructions.

This medicine may make you dizzy or drowsy. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that can make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds; sedatives, tranquilizers, or sleeping medicine; other prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of these medicines while you are using this medicine.

Using narcotics for a long time can cause severe constipation. To prevent this, your doctor may direct you to take laxatives, drink a lot of fluids, or increase the amount of fiber in your diet. Be sure to follow the directions carefully, because continuing constipation can lead to more serious problems.

Using this medicine while you are pregnant may cause neonatal withdrawal syndrome in your newborn babies. Tell your doctor right away if your child has the following symptoms: abnormal sleep pattern, diarrhea, fever, high-pitched cry, irritability, shakiness or tremor, vomiting, weight loss, or failure to gain weight.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Hyphed Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Fainting


• lightheadedness


• shakiness in the legs, arms, hands, or feet


• trembling or shaking of the hands or feet

Incidence not known

• Abdominal or stomach cramps or pain


• bloating


• blurred vision


• bulging soft spot on the head of an infant


• change in the ability to see colors, especially blue or yellow


• confusion


• constipation


• convulsions


• decrease in the frequency of urination


• decrease in the urine volume


• diarrhea


• difficult or troubled breathing


• difficulty in passing urine (dribbling)


• dizziness


• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position


• drowsiness


• fainting


• fast, slow, or irregular heartbeat


• headache


• irregular, fast or slow, or shallow breathing


• loss of appetite


• nervousness


• painful urination


• pale or blue lips, fingernails, or skin


• pounding in the ears


• shortness of breath


• sore throat


• spasm of the throat


• sweating


• tightness of the chest


• unusual tiredness or weakness


• vomiting

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Disturbed color perception


• double vision


• dry mouth


• false or unusual sense of well-being


• fear or nervousness


• halos around lights


• hyperventilation


• nausea


• night blindness


• overbright appearance of lights


• relaxed and calm


• restlessness


• sleepiness or unusual drowsiness


• sleeplessness


• trouble sleeping


• tunnel vision


• unable to sleep


• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness

Incidence not known

• Acid or sour stomach


• belching


• bigger, dilated, or enlarged pupils (black part of the eye)


• bloating


• change in color vision


• chills


• cold sweats


• coma


• continuing ringing or buzzing or other unexplained noise in the ears


• cool, pale skin


• darkened urine


• depression


• difficulty seeing at night


• feeling of constant movement of self or surroundings


• fever


• flushing or redness of the skin


• full feeling


• hearing loss


• heartburn


• hives or welts


• increased appetite


• increased hunger


• increased in sexual ability, desire, drive, or performance


• increased interest in sexual intercourse


• increased sensitivity of the eyes to sunlight


• increased sweating


• indigestion


• itching skin


• loss of appetite


• nightmares


• pains in the stomach, side, or abdomen, possibly radiating to the back


• pressure in the stomach


• seizures


• sensation of spinning


• skin rash


• slurred speech


• stomach discomfort or upset


• sugar in the urine


• swelling of the abdominal or stomach area


• swelling of the breasts or breast soreness in both females and males


• unusually warm skin


• watering of the eyes


• yellow eyes or skin

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Hyphed resources

• Hyphed Use in Pregnancy & Breastfeeding
• Hyphed Drug Interactions
• Hyphed Support Group
• 0 Reviews for Hyphed - Add your own review/rating

• Histinex PV Liquid MedFacts Consumer Leaflet (Wolters Kluwer)


• Tussend MedFacts Consumer Leaflet (Wolters Kluwer)


• Zutripro Prescribing Information (FDA)


• Zutripro Consumer Overview

Compare Hyphed with other medications

• Cough and Nasal Congestion

Calcium Folinate 3 mg / mL Injection

1. Name Of The Medicinal Product

Calcium Folinate 3 mg/mL Injection

2. Qualitative And Quantitative Composition

Each vial of 1 ml solution contains 3 mg/ml of folinic acid provided as calcium folinate.

For excipients, see 6.1.

3. Pharmaceutical Form

Solution for Injection

4. Clinical Particulars

4.1 Therapeutic Indications

Calcium folinate is indicated

a) to diminish the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy and overdose in adults and children. In cytotoxic therapy, this procedure is commonly known as “Calcium Folinate Rescue”;

4.2 Posology And Method Of Administration

For intravenous and intramuscular administration only. In the case of intravenous administration, no more than 160 mg of calcium folinate should be injected per minute due to the calcium content of the solution.

For intravenous infusion, calcium folinate may be diluted with 0.9% sodium chloride solution or 5% glucose solution before use. Refer also to sections 6.3 and 6.6.

Calcium folinate rescue in methotrexate therapy:

Since the calcium folinate rescue dosage regimen depends heavily on the posology and method of the intermediate- or high-dose methotrexate administration, the methotrexate protocol will dictate the dosage regimen of calcium folinate rescue. Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of calcium folinate.

The following guidelines may serve as an illustration of regimens used in adults, elderly and children:

Calcium folinate rescue has to be performed by parenteral administration in patients with malabsorption syndromes or other gastrointestinal disorders where enteral absorption is not assured. Dosages above 25-50 mg should be given parenterally due to saturable enteral absorption of calcium folinate.

Calcium folinate rescue is necessary when methotrexate is given at doses exceeding 500 mg/m² body surface and should be considered with doses of 100 mg – 500 mg/m² body surface.

Dosage and duration of calcium folinate rescue primarily depend on the type and dosage of methotrexate therapy, the occurrence of toxicity symptoms, and the individual excretion capacity for methotrexate. As a rule, the first dose of calcium folinate is 15 mg (6-12 mg/m²) to be given 12-24 hours (24 hours at the latest) after the beginning of methotrexate infusion. The same dose is given every 6 hours throughout a period of 72 hours. After several parenteral doses treatment can be switched over to the oral form.

In addition to calcium folinate administration, measures to ensure the prompt excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the calcium folinate rescue treatment. Renal function should be monitored through daily measurements of serum creatinine.

Forty-eight hours after the start of the methotrexate infusion, the residual methotrexate-level should be measured. If the residual methotrexate-level is>0.5 µmol/l, calcium folinate dosages should be adapted according to the following table:

Residual methotrexate blood level 48 hours after the start of the methotrexate administration:	Additional calcium folinate to be administered every 6 hours for 48 hours or until levels of methotrexate are lower than 0.05 µmol/l:
> 0.5 µmol/l	15 mg/m²
> 1.0 µmol/l	100 mg/m²
> 2.0 µmol/l	200 mg/m²

Antidote to the folic acid antagonists trimetrexate, trimethoprim, and pyrimethamine:

Trimetrexate toxicity:

• Prevention: Calcium folinate should be administered every day during treatment with trimetrexate and for 72 hours after the last dose of trimetrexate. Calcium folinate can be administered either by the intravenous route at a dose of 20 mg/m² for 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m², or by oral route with four doses of 20 mg/m² administered at equal time intervals. Daily doses of calcium folinate should be adjusted depending on the haematological toxicity of trimetrexate.

• Overdosage (possibly occurring with trimetrexate doses above 90 mg/m² without concomitant administration of calcium folinate): after stopping trimetrexate, calcium folinate 40 mg/m² IV every 6 hours for 3 days.

Trimethoprim toxicity:

• After stopping trimethoprim, 3-10 mg/day calcium folinate until recovery of a normal blood count.

Pyrimethamine toxicity:

• In case of high dose pyrimethamine or prolonged treatment with low doses, calcium folinate 5 to 50 mg/day should be simultaneously administered, based on the results of the peripheral blood counts.

4.3 Contraindications

• Known hypersensitivity to calcium folinate, or to any of the excipients.

• Pernicious anaemia or other anaemias due to vitamin B12 deficiency.

Regarding the use of calcium folinate with methotrexate during pregnancy and lactation, see section 4.6, “Pregnancy and Lactation” and the summaries of product characteristics for methotrexate - containing medicinal products.

4.4 Special Warnings And Precautions For Use

Calcium folinate should only be given by intramuscular or intravenous injection and must not be administered intrathecally. When folinic acid has been administered intrathecally following intrathecal overdose of methotrexate death has been reported.

General

Calcium folinate should be used with methotrexate only under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.

Calcium folinate treatment may mask pernicious anaemia and other anaemias resulting from vitamin B12 deficiency.

Many cytotoxic medicinal products – direct or indirect DNA synthesis inhibitors – lead to macrocytosis (hydroxycarbamide, cytarabine, mecaptopurine, thioguanine). Such macrocytosis should not be treated with folinic acid.

In epileptic patients treated with phenobarbital, phenytoin, primidone, and succinimides there is a risk to increase the frequency of seizures due to a decrease of plasma concentrations of anti-epileptic drugs. Clinical monitoring, possibly monitoring of the plasma concentrations and, if necessary, dose adaptation of the anti-epileptic drug during calcium folinate administration and after discontinuation is recommended (see also section 4.5 Interactions).

Calcium folinate/methotrexate

For specific details on reduction of methotrexate toxicity refer to the SPC of methotrexate.

Calcium folinate has no effect on non-haematological toxicities of methotrexate such as the nephrotoxicity resulting from methotrexate and/or metabolite precipitation in the kidney. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure and all toxicities associated with methotrexate (please refer to the SPC for methotrexate). The presence of preexisting- or methotrexate-induced renal insufficiency is potentially associated with delayed excretion of methotrexate and may increase the need for higher doses or more prolonged use of calcium folinate.

Excessive calcium folinate doses must be avoided since this might impair the antitumour activity of methotrexate, especially in CNS tumours where calcium folinate accumulates after repeated courses.

Resistance to methotrexate as a result of decreased membrane transport implies also resistance to folinic acid rescue as both medicinal products share the same transport system.

An accidental overdose with a folate antagonist, such as methotrexate, should be treated as a medical emergency. As the time interval between methotrexate administration and calcium folinate rescue increases, calcium folinate effectiveness in counteracting toxicity decreases.

The possibility that the patient is taking other medications that interact with methotrexate (eg, medications which may interfere with methotrexate elimination or binding to serum albumin) should always be considered when laboratory abnormalities or clinical toxicities are observed.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

When calcium folinate is given in conjunction with a folic acid antagonist (e.g. cotrimoxazole, pyrimethamine) the efficacy of the folic acid antagonist may either be reduced or completely neutralised.

Calcium folinate may diminish the effect of anti-epileptic substances: phenobarbital, primidone, phenytoin and succinimides, and may increase the frequency of seizures (a decrease of plasma levels of enzymatic inductor anticonvulsant drugs may be observed because the hepatic metabolism is increased as folates are one of the cofactors) (see also sections 4.4 and 4.8).

Concomitant administration of calcium folinate with 5-fluorouracil has been shown to enhance the efficacy and toxicity of 5-fluorouracil.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women. No formal animal reproductive toxicity studies with calcium folinate have been conducted. There are no indications that folic acid induces harmful effects if administered during pregnancy. During pregnancy, methotrexate should only be administered on strict indications, where the benefits of the drug to the mother should be weighed against possible hazards to the foetus. Should treatment with methotrexate or other folate antagonists take place despite pregnancy or lactation, there are no limitations as to the use of calcium folinate to diminish toxicity or counteract the effects.

Please refer also to the summaries of product characteristics for methotrexate-, other folate antagonists - containing medicinal products.

Lactation

It is not known whether calcium folinate is excreted into human breast milk. Calcium folinate can be used during breast feeding when considered necessary according to the therapeutic indications.

4.7 Effects On Ability To Drive And Use Machines

There is no evidence that calcium folinate has an effect on the ability to drive or use machines.

4.8 Undesirable Effects

Immune system disorders

Very rare (<0.01%): allergic reactions, including anaphylactoid reactions and urticaria.

Psychiatric disorders

Rare (0.01-0.1%): insomnia, agitation and depression after high doses.

Gastrointestinal disorders

Rare (0.01-0.1%): gastrointestinal disorders after high doses.

Neurological disorders

Rare (0.01-0.1%): increase in the frequency of attacks in epileptics (see also section 4.5 Interactions...).

General disorders and administration site conditions

Uncommon (0.1-1%): fever has been observed after administration of calcium folinate as solution for injection.

4.9 Overdose

There have been no reported sequelae in patients who have received significantly more calcium folinate than the recommended dosage. However, excessive amounts of calcium folinate may nullify the chemotherapeutic effect of folic acid antagonists.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment; ATC code: V03AF03

Calcium folinate is the calcium salt of 5-formyl tetrahydrofolic acid. It is an active metabolite of folinic acid and an essential coenzyme for nucleic acid synthesis in cytotoxic therapy.

Calcium folinate is frequently used to diminish the toxicity and counteract the action of folate antagonists, such as methotrexate. Calcium folinate and folate antagonists share the same membrane transport carrier and compete for transport into cells, stimulating folate antagonist efflux. It also protects cells from the effects of folate antagonist by repletion of the reduce folate pool. Calcium folinate serves as a pre-reduced source of H4 folate; it can therefore bypass folate antagonist blockage and provide a source for the various coenzyme forms of folic acid.

Finally intravenous calcium folinate can be administered for the prevention and treatment of folate deficiency when it cannot be prevented or corrected by the administration of folic acid by the oral route. This may be the case during total parenteral nutrition and severe malabsorption disorders. It is also indicated for the treatment of megaloblastic anaemia due to folic acid deficiency, when oral administration is not feasible.

5.2 Pharmacokinetic Properties

Absorption

Following intramuscular administration of the aqueous solution, systemic availability is comparable to an intravenous administration. However, lower peak serum levels (Cmax) are achieved.

Metabolism

Calcium folinate is a racemate where the L-form (L-5-formyl-tetrahydrofolate, L-5-formyl-THF), is the active enantiomer. The major metabolic product of folinic acid is 5-methyl-tetrahydrofolic acid (5-methyl-THF) which is predominantly produced in the liver and intestinal mucosa.

Distribution

The distribution volume of folinic acid is not known.

Peak serum levels of the parent substance (D/L-5-formyl-tetrahydrofolic acid, folinic acid) are reached 10 minutes after i.v. administration.

AUC for L-5-formyl-THF and 5-methyl-THF were 28.4±3.5 mg.min/l and 129±112 mg.min/l after a dose of 25 mg. The inactive D-isomer is present in higher concentration than L-5-formyltetrahydrofolate.

Elimination

The elimination half-life is 32 - 35 minutes for the active L-form and 352 - 485 minutes for the inactive D-form, respectively.

The total terminal half-life of the active metabolites is about 6 hours (after intravenous and intramuscular administration).

Excretion

80-90 % with the urine (5- and 10-formyl-tetrahydrofolates inactive metabolites), 5-8 % with the faeces.

5.3 Preclinical Safety Data

There are no preclinical data considered relevant to clinical safety beyond data included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride

Water for Injections

6.2 Incompatibilities

Incompatibilities have been reported between injectable forms of calcium folinate and injectable forms of droperidol, fluorouracil, foscarnet and methotrexate.

Droperidol

1. Droperidol 1.25 mg/0.5 ml with calcium folinate 5 mg/0.5 ml, immediate precipitation in direct admixture in syringe for 5 minutes at 25° C followed by 8 minutes of centrifugation.

2. Droperidol 2.5 mg/0.5 ml with calcium folinate 10 mg/0.5 ml, immediate precipitation when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections.

Fluorouracil

Calcium folinate must not be mixed in the same infusion as 5-fluorouracil because a precipitate may form. Fluorouracil 50 mg/ml with calcium folinate 20 mg/ml, with or without dextrose 5% in water, has been shown to be incompatible when mixed in different amounts and stored at 4°C, 23°C, or 32° C in polyvinyl chloride containers.

Foscarnet

Foscarnet 24 mg/ml with calcium folinate 20 mg/ml formation of a cloudy yellow solution reported.

6.3 Shelf Life

Product as packaged for sale: 24 months.

In use: From a microbial point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally mot be longer than 24 hours at 2 to 8°C.

6.4 Special Precautions For Storage

Store in a refrigerator (+2°C to +8°C).

Store ampoules in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

Clear 1ml Type I Glass Ampoules. Presented in packs of 5 ampoules.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Prior to administration, calcium folinate should be inspected visually. The solution for injection or infusion should be a clear and yellowish solution. If cloudy in appearance or particles are observed, the solution should be discarded. Calcium folinate solution for injection or infusion is intended only for single use. Any unused portion of the solution should be disposed of in accordance with the local requirements.

7. Marketing Authorisation Holder

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

UK

8. Marketing Authorisation Number(S)

PL 04515/0032

9. Date Of First Authorisation/Renewal Of The Authorisation

March 2003

10. Date Of Revision Of The Text

December 2007