Protamine Sulfate

Class: Antiheparin Agents
CAS Number: 9009-65-8

• 
  

  Possible severe hypotension, cardiovascular collapse, noncardiogenic pulmonary edema, catastrophic pulmonary vasoconstriction, and pulmonary hypertension with rapid IV injection, high doses, repeated doses, or previous exposure to protamine or protamine-containing drugs (e.g., insulin).¹⁰⁰ Other possible risk factors include known sensitivity to fish, vasectomy, severe left ventricular dysfunction, and abnormal pulmonary hemodynamics.¹⁰⁰ Weigh risk against anticipated benefit of protamine therapy in patients with risk factors.¹⁰⁰ Administer only when facilities and equipment for treatment of such reactions are readily available.¹⁰⁰ (See Sensitivity Reactions under Cautions.)

  
  


• 
  

  Protamine should not be used for bleeding that occurs without prior exposure to heparin.¹⁰⁰

  
  

Introduction

Heparin antagonist; prepared from the sperm or mature testes of salmon or related species.¹⁰⁰

Uses for Protamine Sulfate

Heparin Overdosage

Treatment of severe heparin overdosage.^{100 116}

Do not use for minor bleeding during heparin therapy.¹²³ (See Boxed Warning.) Heparin withdrawal usually corrects minor overdosage or bleeding within a few hours.¹²³

Heparin Neutralization during Extracorporeal Circulation

Neutralization of heparin administered during extracorporeal circulation† in arterial and cardiac surgery or dialysis procedures.^{100 122}

Heparin Neutralization in Pregnant Women Near Delivery

Neutralization of anticoagulant effect of heparin to reduce risk of bleeding near delivery† in pregnant women receiving heparin therapy who go into spontaneous labor.¹²⁵

Low Molecular Weight Heparin Overdosage

Has been used for treatment of low molecular weight (LMW) heparin (e.g., dalteparin, enoxaparin, tinzaparin) overdosage†.^{114 115 121} However, neutralization of an LMW heparin is not complete even with multiple doses of protamine.^{114 115 121} (See Actions.)

Protamine Sulfate Dosage and Administration

General

Heparin Overdosage

• 
  

  With severe heparin overdosage, discontinue heparin and administer protamine sulfate immediately.^a Blood transfusions may be required for massive blood loss.^{100 a}

  
  


• 
  

  Dose of protamine sulfate determined by dose of heparin received, route of administration, time elapsed since heparin was given, and blood coagulation studies.^{100 116 117} Generally, 1 mg of protamine sulfate will neutralize no less than 100 units of heparin sodium.^{100 117}

  
  


• 
  

  Blood heparin concentrations decrease rapidly after IV administration of heparin; dose of protamine sulfate required in the treatment of IV heparin overdosage also decreases rapidly as time elapses.¹⁰⁰

  
  


• 
  

  Monitor therapeutic response through coagulation studies (aPTT, activated coagulation time [ACT], heparin titration test with protamine, plasma thrombin time).^{100 117 a}

  
  


• 
  

  Additional doses of protamine sulfate may be required in patients with heparin rebound (e.g., as may occur during extracorporeal circulation† in arterial and cardiac surgery or dialysis procedures) if indicated by coagulation studies.^{100 119 123 a} (See Effects on Hemostasis under Cautions.)

  
  

Low Molecular Weight Heparin Overdosage†

• 
  

  Dose of protamine sulfate determined by dose of LMW heparin received, the time elapsed since the drug was given, and blood coagulation studies.^{114 115 121}

  
  


• 
  

  Following higher doses of protamine sulfate, aPTT may remain more prolonged than would be the case following treatment of heparin overdosage since anti-factor X_a activity is never completely neutralized.^{114 115} A maximum of about 60–75% or 60% of anti-factor X_a activity is neutralized with protamine sulfate administration for overdosage of dalteparin or enoxaparin, respectively.^{114 115}

  
  

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by very slow IV injection.¹⁰⁰ (See Sensitivity Reactions under Cautions.)

Has been administered by continuous IV infusion†.¹¹⁷

Dilution

May be administered without further dilution at a concentration of 10 mg/mL.¹⁰⁰ However, if more dilute infusion solution is desired, further dilution in 5% dextrose or 0.9% sodium chloride injection recommended.¹⁰⁰ Contains no preservatives; discard unused portion.¹⁰⁰

Rate of Administration

Administer by very slow IV injection over 10 minutes.^{100 116}

Dosage

Available as protamine sulfate; dosage expressed in terms of the salt.¹⁰⁰

Adults

Heparin Overdosage

IV

Severe bleeding occurring a few minutes after IV injection of heparin: 1 mg for every 100 units of heparin sodium administered.^{100 116 117}

Severe bleeding occurring 30 minutes after IV injection of heparin: 0.5 mg for every 100 units of heparin sodium administered.¹⁰⁰

Severe bleeding occurring ≥2 hours after IV injection of heparin: 0.25–0.375 mg for every 100 units of heparin sodium administered.^a

Severe bleeding occurring after sub-Q injection of heparin: Some clinicians recommend 1–1.5 mg for every 100 units of heparin sodium; prolonged infusion may be required to neutralize sub-Q heparin dose.^a A loading dose of 25–50 mg by slow IV infusion suggested by some clinicians,^a with remainder of calculated dose administered by continuous IV infusion† over 8–16 hours or expected duration of absorption of heparin.^a

Heparin Neutralization During Extracorporeal Circulation†

IV

1.5 mg for every 100 units of heparin sodium administered.^a Alternatively, determine dosage by using sequential ACT determinations and a dose-response curve which correlates results with amount of heparin remaining in body.^a

Low Molecular Weight Heparin Overdosage†

IV

Severe bleeding within 8 hours of administration of an LMW heparin: 1 mg for every 100 anti-factor X_a units of LMW heparin (e.g., enoxaparin sodium, dalteparin sodium, tinzaparin sodium) administered (e.g., 1 mg of enoxaparin sodium has an anti-factor X_a activity of approximately 100 units).^{114 115 117} If aPTT measured 2–4 hours after first infusion of protamine sulfate remains prolonged or if bleeding continues, may administer a second dose of 0.5 mg protamine sulfate for every 100 anti-factor X_a units of LMW heparin administered.^{114 115 117 121}

Severe bleeding >8 hours after administration of an LMW heparin: 0.5 mg for every 100 anti-factor X_a units of LMW heparin administered.^{114 117}

Protamine sulfate administration may not be required if >12 hours has elapsed since administration of enoxaparin.¹¹⁴

Prescribing Limits

Adults

Heparin Overdosage

IV

Maximum 50 mg administered in any 10-minute period, unless larger dose clearly needed.^{100 116} (See Sensitivity Reactions under Cautions.)

Cautions for Protamine Sulfate

Contraindications

• 
  

  Known hypersensitivity to protamine sulfate.¹⁰⁰

  
  

Warnings/Precautions

Warnings

Effects on Hemostasis

Heparin rebound (hyperheparinemia) with bleeding reported (e.g., after cardiac surgery, dialysis procedure).^{100 123}

Heparin rebound usually occurs several hours after heparin has been adequately neutralized by protamine sulfate but has been reported 0.5–18 hours following cardiopulmonary bypass procedure†.^{100 123}

Precise cause unknown; may result from release of heparin from protamine-heparin complex or from extravascular compartments.^{119 123} (See Metabolism under Pharmacokinetics.)

Monitor patients closely following cardiac surgery; administer additional doses of protamine sulfate if indicated by coagulation studies.^{100 117 119 123}

Sensitivity Reactions

Severe hypotension and potentially fatal anaphylactoid reactions reported, particularly with large doses or too-rapid administration.^{100 109 110 111 112 113 114 115 116 121 122 123} Take particular care to avoid overdosage with protamine.^{114 115 121} (See Boxed Warning.)

Patients at increased risk for development of antiprotamine antibodies and hypersensitivity reactions include infertile or vasectomized men,^{100 101 102 103 104 105 106 107 108 117 123} those with previous exposure to protamine-containing preparations (e.g., protamine-containing insulin, previous protamine sulfate therapy),^{10 100 109 110 112 113} or those with known hypersensitivity to fish.^{8 100 113} (See Introduction.)

Severe reactions to IV protamine can occur in absence of local or systemic allergic reactions to sub-Q protamine-containing insulin.¹⁰⁰ Fatal anaphylaxis reported in at least 1 patient with no prior history of allergies.¹⁰⁰

Minimize these adverse effects by administering drug slowly.^{100 117 123} (See IV Administration under Dosage and Administration.) Administer only when medical facilities equipped to provide resuscitation and treat shock available.¹⁰⁰ Patients at risk for protamine allergy can be pretreated with corticosteroids and antihistamines.¹¹⁷ (See Actions.)

Specific Populations

Pregnancy

Category C.¹⁰⁰

Lactation

Not known whether protamine sulfate is distributed into milk.¹⁰⁰ Use caution.¹⁰⁰

Pediatric Use

Safety and efficacy not established in children.¹⁰⁰

Common Adverse Effects

Decreased BP or hypotension,^{100 117 123} bradycardia,^{100 117} skin reactions (e.g., flushing, feeling of warmth, urticaria, edema),^{120 123} dyspnea,¹⁰⁰ nausea,¹⁰⁰ vomiting,¹⁰⁰ lassitude,¹⁰⁰ back pain.¹⁰⁰

Interactions for Protamine Sulfate

Specific Drugs

Drug	Interaction
Heparin	Neutralization of anticoagulant activity of heparin100 117 123
Insulin	Prolongs absorption of insulin123
LMW heparins	Incomplete neutralization of anticoagulant activity of LMW heparin114 115 117 121

Protamine Sulfate Pharmacokinetics

Absorption

Onset

Neutralization of heparin occurs <5 minutes after IV administration.¹⁰⁰

Duration

Variable duration presumably results from release of heparin from protamine-heparin complex or extravascular compartments.^{118 119 120 123} (See Metabolism under Pharmacokinetics.)

Distribution

Not known whether protamine sulfate is distributed into milk.¹⁰⁰ (See Lactation under Cautions.)

Elimination

Metabolism

Metabolic fate of the protamine-heparin complex has not been elucidated; however, protamine-heparin complex may be partially metabolized or attacked by fibrinolysin, freeing heparin.¹⁰⁰ (See Effects on Hemostasis under Cautions.)

Half-life

Without heparin in healthy individuals: Median 7.4 minutes.^{117 118}

Following cardiopulmonary bypass procedure† with heparin: Median 4.5 minutes.¹¹⁹

Stability

Storage

Parenteral

Solution for Injection

20–25°C; do not freeze.¹⁰⁰

Compatibility

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

Drug Compatibility

Incompatible with some anti-infective agents, including some cephalosporins and penicillins.¹⁰⁰

Admixture CompatibilityHID

Compatible

Cimetidine HCl

Ranitidine HCl

Verapamil HCl

ActionsActions

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  Neutralization of anticoagulant activity of heparin by complexing with heparin to form a stable salt.^{100 117 123 124} Protamine-heparin complex has no anticoagulant activity.^{100 117 123 124}

  
  


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  Does not bind to the low molecular weight fragments within LMW heparin preparations¹¹⁷ resulting in incomplete neutralization of anti-factor X_a activity when protamine is used to treat overdosage of LMW heparins.^{114 115 117 121}

  
  


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  Has weak anticoagulant activity as a result of inhibition of platelet aggregation and interaction of many proteins, including fibrinogen,^{100 120 123} and inhibition of thromboplastin generation and activity, which prevents conversion of prothrombin to thrombin.^a

  
  


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  Reduces systolic and diastolic BP, increases pulmonary artery pressure, and decreases heart rate and systemic vascular resistance.^{123 124}

  
  


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  Vasoactive effects associated with release of vasoactive mediators (e.g., histamine, bradykinin, thromboxane, nitric oxide), complement activation, and antibody production.^{120 122 123}

  
  

Advice to Patients

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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.¹⁰⁰

  
  


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  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.¹⁰⁰

  
  


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  Importance of informing patients of other important precautionary information.¹⁰⁰ (See Cautions.)

  
  

Preparations

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

Protamine Sulfate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV use only	10 mg/mL	Protamine Sulfate Injection (preservative-free; available as single-dose vials)	Abraxis

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 July 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

8. Caplan SN, Berkman EM. Protamine sulfate and fish allergy. N Engl J Med. 1976; 295:172. [IDIS 64060] [PubMed 1272338]

10. Lakin JD, Blocker TJ, Strong DM et al. Anaphylaxis to protamine sulfate mediated by a complement-dependent IgG antibody. J Allergy Clin Immunol. 1978; 61:102-7. [IDIS 100356] [PubMed 621346]

100. APP. Protamine sulfate injection prescribing information. Schaumberg, IL; 2008 Jan.

101. Lake CL, Arnold WP, Epstein RM. Vasectomy and health. JAMA. 1985; 253:1723. [PubMed 3974049]

102. Watson RA, Ansbacher R, Barry M et al. Allergic reaction to protamine: a late complication of elective vasectomy? Urology. 1983; 22:493-5.

103. Alexander NJ, Anderson DJ. Vasectomy: consequences of autoimmunity to sperm antigens. Fertil Steril. 1979; 32:253-60. [PubMed 114428]

104. Samuel T, Kolk AHJ, Rümke P. Studies on the immunogenicity of protamines in humans and experimental animals by means of a micro-complement fixation test. Clin Exp Immunol. 1978; 33:252-60. [PubMed 102475]

105. Hellema HWJ, Rümke P. Sperm autoantibodies as a consequence of vasectomy. I. Within 1 year post-operation. Clin Exp Immunol. 1978; 31:18-29. [PubMed 639346]

106. Samuel T. Antibodies reacting with salmon and human protamines in sera from infertile men and from vasectomized men and monkeys. Clin Exp Immunol. 1977; 30:181-7. [PubMed 414865]

107. Samuel T, Kolk AHJ, Rümke P et al. Autoimmunity to sperm antigens in vasectomized men. Clin Exp Immunol. 1975; 21:65-74. [PubMed 1102162]

108. Samuel T, Linnet L, Rümke P. Post-vasectomy antoimmunity to protamines in relation to the formation of granulomas and sperm agglutinating antibodies. Clin Exp Immunol. 1978; 33:261-9. [PubMed 102476]

109. Sharath MD, Metzger WJ, Richerson HB et al. Protamine-induced fatal anaphylaxis: prevalence of antiprotamine immunoglobulin E antibody. J Thorac Cardiovasc Surg. 1985; 90:86-90. [IDIS 201797] [PubMed 3892171]

110. Weiler JM, Freiman P, Sharath MD et al. Serious adverse reactions to protamine sulfate: are alternatives needed? J Allergy Clin Immunol. 1985; 75:297-303.

111. Olinger GN, Becker RM, Bonchek LI. Noncardiogenic pulmonary edema and peripheral vascular collapse following cardiopulmonary bypass: rare protamine reaction? Ann Thorac Surg. 1980; 29:20-5.

112. Holland CL, Singh AK, McMaster PR et al. Adverse reactions to protamine sulfate following cardiac surgery. Clin Cardiol. 1984; 7:157-62. [PubMed 6705300]

113. Stewart WJ, McSweeney SM, Kellett MA et al. Increased risk of severe protamine reactions in NPH insulin-dependent diabetics undergoing cardiac catheterization. Circulation. 1984; 70:788-92. [IDIS 192617] [PubMed 6488493]

114. Aventis Pharmaceuticals. Lovenox (enoxaparin sodium) injection prescribing information. Bridgewater, NJ; 2007 Oct

115. Eisai. Fragmin (dalteparin sodium) injection prescribing information. Woodcliff, NJ; 2007 Apr.

116. APP Pharmaceuticals. Heparin sodium injection prescribing information. Schaumburg, IL; 2007 Dec.

117. Hirsh J, Bauer KA, Donati MB et al. Parenteral anticoagulants: American College of Chest Physicians evidenced-based clinical practice guidelines (8th ed). Chest. 2008; 133 (Suppl):141S-59S. [PubMed 18574264]

118. Butterworth J, Lin YA, Prielipp R et al. The pharmacokinetics and cardiovascular effects of a single intravenous dose of protamine in normal volunteers. Anesth Analg. 2002; 94:514-22. [PubMed 11867368]

119. Butterworth J, Lin YA, Prielipp RC et al. Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass. Ann Thorac Surg. 2002; 74:1589-95. [PubMed 12440613]

120. Jaques LB. Protamine-antagonist to heparin. Can Med Assoc J. 1973; 108:1291-5. [PubMed 4122234]

121. Celgene. Innohep (tinzaparin sodium) injection prescribing information. Boulder, CO; 2008 Apr.

122. Pretorius M, Scholl FG, McFarlane JA et al. A pilot study indicating that bradykinin β₂ receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass. Clin Pharmacol Ther. 2005; 78:477-85. [PubMed 16321614]

123. Lindblad B. Protamine sulphate: A review of its effects: hypersensitivity and toxicity. Eur J Vasc Surg. 1989; 3:195-201. [PubMed 2663545]

124. Carr JA, Silverman N. The heparin-protamine interaction. J Cardiovasc Surg. 1999; 40:659-66.

125. Bates SM, Greer I, Pabinger I et al. Venous thromboembolism, thrombophilia, antithrombotic therapy and pregnancy: American College of Chest Physicians evidenced-based clinical practice guidelines (8th ed). Chest. 2008; 133(Suppl):844S-86S.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1432-3.

a. AHFS Drug Information 2010. McEvoy GK, ed. Protamine. Bethesda, MD: American Society of Health-System Pharmacists; 2010:1601-3.

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• Heparin Overdose

Hydrocodone and Acetaminophen Oral Solution

Generic Name: hydrocodone bitartrate and acetaminophen

Dosage Form: oral solution
Unknown Title

Hydrocodone Bitartrate and Acetaminophen Oral Solution (7.5mg/325mg per 15 mL)

Rx

HEPATOTOXICITY

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product.

DESCRIPTION

Hydrocodone bitartrate and acetaminophen is supplied in liquid form for oral administration.

WARNING: May be habit-forming (see PRECAUTIONS, Information for Patients, and DRUG ABUSE AND DEPENDENCE).

Hydrocodone bitartrate is an opioid analgesic and antitussive and occurs as fine, white crystals or as a crystalline powder. It is affected by light. The chemical name is 4,5α-epoxy-3-methoxy-17- methylmorphinan-6-one tartrate (1:1) hydrate (2:5). It has the following structural formula:

Acetaminophen, 4’-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:

Hydrocodone Bitartrate and Acetaminophen oral solution contains:

Per         Per                                                                                    5mL       15 mL

Hydrocodone Bitartrate .......................................... 2.5 mg    7.5 mg

WARNING: May be habit-forming.

Acetaminophen ...................................................... 108 mg   325 mg

Alcohol ...................................................................... 7%         7%

In addition, the liquid contains the following inactive ingredients: citric acid anhydrous, ethyl maltol, glycerin, methylparaben, propylene glycol, propylparaben, purified water, saccharin sodium, sorbitol solution, sucrose, with D&C Red #33 and FD&C Red #40 as coloring and natural and artificial flavoring.

CLINICAL PHARMACOLOGY

Hydrocodone is a semisynthetic narcotic analgesic and antitussive with multiple actions qualitatively similar to those of codeine. Most of these involve the central nervous system and smooth muscle. The precise mechanism of action of hydrocodone and other opiates is not known, although it is believed to relate to the existence of opiate receptors in the central nervous system. In addition to analgesia, narcotics may produce drowsiness, changes in mood and mental clouding.

The analgesic action of acetaminophen involves peripheral influences, but the specific mechanism is as yet undetermined. Antipyretic activity is mediated through hypothalamic heat regulating centers. Acetaminophen inhibits prostaglandin synthetase. Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.

Pharmacokinetics

The behavior of the individual components is described below.

Hydrocodone

Following a 10 mg oral dose of hydrocodone administered to five adult male subjects, the mean peak concentration was 23.6 ± 5.2 ng/mL. Maximum serum levels were achieved at 1.3 ± 0.3 hours and the half-life was determined to be 3.8 ± 0.3 hours. Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation and 6-keto reduction to the corresponding 6-α- and 6-β-hydroxymetabolites. See OVERDOSAGE for toxicity information.

Acetaminophen

Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug. See OVERDOSAGE for toxicity information.

INDICATIONS AND USAGE

Hydrocodone bitartrate and acetaminophen oral solution is indicated for the relief of moderate to moderately severe pain.

CONTRAINDICATIONS

This product should not be administered to patients who have previously exhibited hypersensitivity to hydrocodone, acetaminophen, or any other component of this product.

Patients known to be hypersensitive to other opioids may exhibit cross-sensitivity to hydrocodone.

WARNINGS

Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products.

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.

Hypersensitivity/Anaphylaxis

There have been postmarketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue Hydrocodone Bitartrate and Acetaminophen Oral Solution immediately and seek medical care if they experience these symptoms. Do not prescribe Hydrocodone Bitartrate and Acetaminophen Oral Solution for patients with acetaminophen allergy.

Respiratory Depression

At high doses or in sensitive patients, hydrocodone may produce dose-related respiratory depression by acting directly on the brain stem respiratory center. Hydrocodone also affects the center that controls respiratory rhythm, and may produce irregular and periodic breathing.

Infants may have increased sensitivity to the respiratory depressant effects of opioids (see PRECAUTIONS, Pediatric Use). If use of Hydrocodone bitartrate and acetaminophen oral solution in such patients is contemplated, it should be administered cautiously, in substantially reduced initial doses, by personnel experienced in administering opioids to infants, and with intensive monitoring.

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions, which may obscure the clinical course of patients with head injuries.

Acute Abdominal Conditions

The administration of narcotics may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Misuse, Abuse and Diversion of Opioids

Hydrocodone bitartrate oral solution contains hydrocodone, an opioid agonist, and is a Schedule III controlled substance. Opioid agonists have the potential for being abused and are sought by abusers and people with addiction disorders, and are subject to diversion.

Hydrocodone bitartrate oral solution can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing hydrocodone bitartrate and acetaminophen oral solution in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion (see DRUG ABUSE AND DEPENDENCE).

PRECAUTIONS

General

Special Risk Patients

As with any narcotic analgesic agent, hydrocodone bitartrate and acetaminophen oral solution should be used with caution in elderly or debilitated patients, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison’s disease, prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind.

Cough Reflex

Hydrocodone suppresses the cough reflex; as with all narcotics, caution should be exercised when hydrocodone bitartrate and acetaminophen oral solution is used postoperatively and in patients with pulmonary disease.

Information for Patients

Hydrocodone, like all narcotics, may impair mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while taking this product.

Alcohol and other CNS depressants may produce an additive CNS depression when taken with this combination product, and should be avoided. Hydrocodone may be habit-forming.

Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

Physicians should instruct patients and caregivers to read the patient information leaflet, which appears as the last section of the labeling.

Do not take Hydrocodone Bitartrate and Acetaminophen Oral Solution if you are allergic to any of its ingredients.

If you develop signs of allergy such as rash or difficulty breathing stop taking Hydrocodone Bitartrate and Acetaminophen Oral Solution and contact your healthcare provider immediately.

Do not take more than 4,000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose.

Laboratory Tests

In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests.

Drug Interactions

Patients receiving narcotics, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with hydrocodone bitartrate and acetaminophen oral solution may exhibit an additive CNS depression. When combined therapy is contemplated, the dose of one or both agents should be reduced.

The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone.

Drug/Laboratory Test Interactions

Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleactic acid.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No adequate studies have been conducted in animals to determine whether hydrocodone has a potential for carcinogenesis, mutagenesis, or impairment of fertility.

Hydrocodone has not demonstrated mutagenic potential using the Ames Salmonella-Microsomal Activation test, the Basc test on Drosophila germ cells, and the Micronucleus test on mouse bone marrow.

No adequate studies have been conducted in animals to determine whether acetaminophen has a potential for carcinogenesis, mutagenesis, or impairment of fertility.

Acetaminophen has not demonstrated mutagenic potential using the Ames Salmonella-Microsomal Activation test, the Basc test on Drosophila germ cells, and the Micronucleus test on mouse bone marrow.

Pregnancy

Teratogenic Effects

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Hydrocodone Bitartrate and Acetaminophen oral solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting and fever. These signs usually appear during the first few days of life. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.

Labor and Delivery

Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see OVERDOSAGE). The effect of hydrocodone, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers

Acetaminophen is excreted in breast milk in small amounts, but the significance of its effects on nursing infants is not known. It is not known whether hydrocodone is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from hydrocodone and acetaminophen, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in the pediatric population below the age of two years have not been established. Use of hydrocodone bitartrate and acetaminophen oral solution in the pediatric population is supported by the evidence from adequate and well controlled studies of hydrocodone and acetaminophen combination products in adults with additional data which support the development of metabolic pathways in children two years of age and over (see DOSAGE AND ADMINISTRATION for pediatric dosage information).

Geriatric Use

Clinical Studies of hydrocodone bitartrate and acetaminophen oral solution 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.

Hydrocodone and the major metabolites of acetaminophen are known to be substantially excreted by the kidney. Thus the risk of toxic reactions may be greater in patients with impaired renal function due to the accumulation of the parent compound and/or metabolites in the plasma. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hydrocodone may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of hydrocodone bitartrate and acetaminophen oral solution and observed closely.

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Boca Pharmacal, Inc. at 1-800-354-8460, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Potential effects of high dosage are also listed in the OVERDOSE section.

Cardio-Renal: Bradycardia, cardiac arrest, circulatory collapse, renal toxicity, renal tubular necrosis, hypotension.

Central Nervous System/Psychiatric: Anxiety, dizziness, drowsiness, dysphoria, euphoria, fear, general malaise, impairment of mental and physical performance, lethargy, lightheadedness, mental clouding, mood changes, psychological dependence, sedation, somnolence progressing to stupor or coma.

Endocrine: Hypoglycemic coma.

Gastrointestinal System: Abdominal pain, constipation, gastric distress, heartburn, hepatic necrosis, hepatitis, occult blood loss, nausea, peptic ulcer, and vomiting.

Genitourinary System: Spasm of vesical sphincters, ureteral spasm, and urinary retention.

Hematologic: Agranulocytosis, hemolytic anemia, iron deficiency anemia, prolonged bleeding time, thrombocytopenia.

Hypersensitivity: Allergic reactions.

Musculoskeletal: Skeletal muscle flaccidity.

Respiratory Depression: Acute airway obstruction, apnea, dose-related respiratory depression (see OVERDOSAGE), shortness of breath.

Special Senses: Cases of hearing impairment or permanent loss have been reported predominantly in patients with chronic overdose.

Skin: Cold and clammy skin, diaphoresis, pruritus, rash.

DRUG ABUSE AND DEPENDENCE

Misuse Abuse and Diversion of Opioids

Hydrocodone bitartrate oral solution contains hydrocodone, and opioid agonist, and is a Schedule III controlled substance. Hydrocodone bitartrate oral solution, and other opioids used in analgesia can be abused and are subject to criminal diversion.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease utilizing a multidisciplinary approach, but relapse is common.

“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physical dependence usually assumes clinically significant dimensions only after several weeks of continued opiod use, although a mild degree of physical dependence may develop after a few days of opioid therapy. Tolerance, in which increasingly large doses are required in order to produce the same degree of analgesia, is manifested initially by a shortened duration of analgesic effect, and subsequently by decreases in the intensity of analgesia. The rate of development of tolerance varies among patients. Physicians should be aware that abuse of opioids can occur in the absence of true addiction and is characterized by misuse for nonmedical purposes, often in combination with other psychoactive substances. Hydrocodone bitartrate and acetaminophen oral solution like other opioids, may be diverted for non-medical use. Record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

OVERDOSAGE

Following an acute overdosage, toxicity may result from hydrocodone or acetaminophen.

Signs and Symptoms:

Hydrocodone: Serious overdose with hydrocodone is characterized by respiratory depressIon (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis). extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur.

Acetaminophen: In acetaminophen overdosage:

dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.

Treatment

A single or multiple drug overdose with hydrocodone and acetaminophen is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered.

For hydrocodone overdose, primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The narcotic antagonist naloxone hydrochloride is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to narcotics, including hydrocodone. Since the duration of action of hydrocodone may exceed that of the antagonist, the patient should be kept under continued surveillance, and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression.

Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease absorption if acetaminophen is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose-dependent and occurs in the course of intoxication.

DOSAGE AND ADMINISTRATION

Dosage should be adjusted according to severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related.

The usual adult dosage is one tablespoonful every 4 to 6 hours as needed for pain. The total daily dosage for adults should not exceed 6 tablespoonfuls.

The usual dosages for children are given by the table on the next page, and are to be given every 4 to 6 hours as needed for pain. These dosages correspond to an average individual dose of 0.27 mL/kg of hydrocodone bitartrate and acetaminophen oral solution (providing 0.135 mg/kg of hydrocodone bitartrate and 5.85 mg/kg of acetaminophen). Dosing should be based on the weight whenever possible.

The total daily dosage for children should not exceed 6 doses per day.

It is of utmost importance that the dose of hydrocodone bitartrate and acetaminophen oral solution be administered accurately. A household teaspoon or tablespoon is not an adequate measuring device, especially when one-half or three-fourths of a teaspoonful is to be measured. Given the inexactitude of the household spoon measure and the possibility of using a tablespoon instead of a teaspoon, which could lead to overdosage, it is strongly recommended that caregivers obtain and use a calibrated measuring device. Health care providers should recommend a dropper that can measure and deliver the prescribed dose accurately, and instruct caregivers to use extreme caution in measuring the dosage.

HOW SUPPLIED

Hydrocodone bitartrate and acetaminophen oral solution, is a red-colored, tropical fruit punch flavored liquid containing hydrocodone bitartrate (WARNING: may be habit-forming) 7.5 mg and acetaminophen 325 mg per 15 mL, with 7% alcohol. It is supplied in containers of

16 oz (473 mL) NDC 64376-640-16 and

4 oz (118 mL) NDC 64376-640-40.

STORAGE: Store at 20° - 25°C (68° - 77°F) [see USP Controlled Room Temperature].

PHARMACIST: Dispense in a tight, light-resistant container with a child-resistant closure. Dispense the Patient Information Leaflet with the drug product.

A Schedule CIII Narcotic.

Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-1088.

Manufactured for:

Boca Pharmacal, Inc.

Coral Springs, FL 33065

www.bocapharmacal.com

1-800-354-8460

Rev. 06/11

Summary

Hydrocodone bitartrate and acetaminophen oral solution is used to relieve moderate to moderately severe pain. You should not take hydrocodone bitartrate and acetaminophen oral solution if you are allergic to hydrocodone or acetaminophen. The most common side effects of hydrocodone bitartrate and acetaminophen oral solution are abdominal pain, dizziness, drowsiness, lightheadedness, nausea, shortness of breath, unusual tiredness, and vomiting. Take this medicine as directed by your doctor. Do not take more of it, do not take more often, and do not take for a longer time than your doctor ordered.

Uses

Hydrocodone bitartrate and acetaminophen oral solution is an analgesic used to relieve moderate to moderately severe pain. Hydrocodone bitartrate and acetaminophen oral solution is a combination product containing hydrocodone (hye-droe-KO-done) bitartrate and acetaminophen (a-seat-a-MIN-oh-fen). Hydrocodone is a narcotic pain reliever and a cough suppressant.

Acetaminophen is a non-narcotic pain reliever and fever reducer. A narcotic analgesic and acetaminophen used together may provide better pain relief than either product used alone. If you have any questions, please call your doctor or pharmacist.

General Cautions:

• Do not take this drug if you have allergies or unusual reactions to narcotic pain relievers or acetaminophen because it is likely that you may also be allergic to hydrocodone bitartrate and acetaminophen oral solution.


• This product may inhibit your mental and physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while you are taking this product.


• This medicine may not be right for you. Check with your doctor or pharmacist if you:

• are pregnant

• are nursing

• are taking other medications:

narcotic pain relievers; allergy medicines; antidepressant medicines; acetaminophen-containing medicines or other medicines that cause central nervous system depression, including alcohol.

• have other medical problems: a history of drug or alcohol abuse; recent head injury; emphysema, asthma, or other chronic lung disease; liver disease; kidney disease; underactive thyroid, Addison’s disease, enlarged prostate or difficulty urinating

Proper Use

Take this medicine as directed by your doctor. Do not share it with anyone else. This medicine can cause drug dependence and has the potential for abuse. 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 you think that this medicine is not working properly after taking it for some time, do not increase the dose. Check with your doctor or pharmacist.

Dosing

The dose of this medication will be different for different patients. Follow the directions provided by your doctor.

The following information includes only the average doses of this medication. If your dose is different, do not change doses unless your doctor tells you to do so.

It is very important that hydrocodone bitartrate and acetaminophen oral solution be dosed accurately. A household teaspoon or tablespoon is not an adequate measuring device, especially when one-half or three-fourths of a teaspoonful is to be measured.

Since a household teaspoon is not accurate and can be mixed-up with a tablespoon which can cause overdosage), it is strongly recommended that you obtain and use a proper measuring device. Ask your doctor or pharmacist for help to find a dropper that can measure the needed dose properly and ask for help if you do not understand how to use the dropper.

Missed Dose

• To avoid a possible overdose, it is important that you do not take more than a single dosage at one time, or that you don’t take doses at intervals less than 4 hours apart.


• If you miss taking a dose of hydrocodone bitartrate and acetaminophen oral solution, take it as soon as you remember. However, make sure to wait at least 4 hours before taking your next dose.


• If you missed taking a dose and it is almost time for your next dose, skip the missed dose and take your medicine as scheduled.


• Do not double the prescribed dose.

Possible Side Effects

Side effects you may experience include abdominal pain, constipation, difficulty urinating, dizziness and drowsiness, fear, fuzzy thinking, general feeling of discomfort or illness, lightheadedness, mood changes, nausea, nervousness, rash, shortness of breath, slower reactions, unusual tiredness, and vomiting. Call your doctor if these effects continue or are bothersome. Side effects not listed above may sometimes occur. If you notice any other effects, check with your doctor.

Storage

• Keep out of reach of children.


• Store at room temperature (protect from heat, do not refrigerate).


• Keep in original labeled bottle.


• Discard medicines that are old or no longer needed.


• Even a single overdose of this medicine may be a life-threatening situation. If you suspect that you or someone else may have taken more than the prescribed dose of this medicine, contact your local poison control center or emergency room immediately. This medicine was prescribed for your particular condition. Do not use it for another condition or give the drug to others.


• This leaflet provides a summary of information about hydrocodone bitartrate and acetaminophen oral solution. If you have any questions or concerns, or want more information about hydrocodone bitartrate and acetaminophen oral solution, contact your doctor or pharmacist. Your pharmacist also has a longer leaflet about hydrocodone bitartrate and acetaminophen oral solution that is written for health professionals that you can ask to read.

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

Manufactured for:

Boca Pharmacal, Inc.

Coral Springs, FL 33065

www.bocapharmacal.com

1-800-354-8460

Rev. 06/11

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

[Rev 7]

HYDROCODONE BITARTRATE AND ACETAMINOPHEN  hydrocodone bitartrate, acetaminophen  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 64376-640 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ACETAMINOPHEN (ACETAMINOPHEN) ACETAMINOPHEN 325 mg  in 15 mL HYDROCODONE BITARTRATE (HYDROCODONE) HYDROCODONE BITARTRATE 7.5  mg  in 15 mL

Inactive Ingredients Ingredient Name Strength GLYCERIN   METHYLPARABEN   PROPYLENE GLYCOL   PROPYLPARABEN   FD&C RED NO. 40   ANHYDROUS CITRIC ACID   ETHYL MALTOL   D&C RED NO. 33   SACCHARIN SODIUM   SORBITOL   SUCROSE   WATER

Product Characteristics Color RED Score      Shape Size Flavor FRUIT PUNCH (Tropical) Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 64376-640-40 118 mL In 1 BOTTLE None 2 64376-640-16 473 mL In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA040894	07/27/2011

Labeler - Boca Pharmacal, Inc. (170266089)

Registrant - Boca Pharmacal, Inc (170266089)

Establishment
Name	Address	ID/FEI	Operations
Sovereign Pharmaceuticals		623168267	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Mallinckrodt Inc.		097722284	API MANUFACTURE

Revised: 07/2011Boca Pharmacal, Inc.

More Hydrocodone and Acetaminophen Oral Solution resources

• Hydrocodone and Acetaminophen Oral Solution Side Effects (in more detail)
• Hydrocodone and Acetaminophen Oral Solution Dosage
• Hydrocodone and Acetaminophen Oral Solution Use in Pregnancy & Breastfeeding
• Drug Images
• Hydrocodone and Acetaminophen Oral Solution Drug Interactions
• Hydrocodone and Acetaminophen Oral Solution Support Group
• 370 Reviews for Hydrocodone and Acetaminophen - Add your own review/rating

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• Back Pain
• Cough
• Pain
• Rheumatoid Arthritis

Trifluridine Drops

Pronunciation: trye-FLURE-i-deen
Generic Name: Trifluridine
Brand Name: Viroptic

Trifluridine Drops are used for:

Treating herpes eye infection.

Trifluridine Drops are an antiviral. It works by killing sensitive viruses.

Do NOT use Trifluridine Drops if:

• you are allergic to any ingredient in Trifluridine Drops

Contact your doctor or health care provider right away if any of these apply to you.

Before using Trifluridine Drops:

Some medical conditions may interact with Trifluridine Drops. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances

Some MEDICINES MAY INTERACT with Trifluridine Drops. Because little, if any, of Trifluridine Drops are absorbed into the blood, the risk of it interacting with another medicine is low.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Trifluridine Drops may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Trifluridine Drops:

Use Trifluridine Drops as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• To use Trifluridine Drops, first, wash your hands. Tilt your head back. Using your index finger, pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close your eyes. Immediately use your finger to apply pressure to the inside corner of the eye for 1 to 2 minutes. Do not blink. Remove excess medicine around your eye with a clean tissue, being careful not to touch your eye. Wash your hands to remove any medicine that may be on them. To prevent germs from contaminating your medicine, do not touch the applicator tip to any surface, including your eye. Keep the container tightly closed.


• Contact your doctor for instructions on using your contact lenses while using Trifluridine Drops.


• To clear up your infection completely, continue using Trifluridine Drops for the full course of treatment even if you feel better in a few days.


• If you miss a dose of Trifluridine Drops, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Trifluridine Drops.

Important safety information:

• Do not exceed the recommended dose or use Trifluridine Drops for longer than prescribed without checking with your doctor.


• If your condition does not improve within 7 days or if it becomes worse, check with your doctor.


• Do not use Trifluridine Drops for other eye problems without first checking with your doctor.


• It is important to use Trifluridine Drops for the full course of treatment. Failure to do so may decrease the effectiveness of Trifluridine Drops and increase the risk that the virus will no longer be sensitive to Trifluridine Drops and will not be able to be treated by this or certain other antivirals in the future.


• Use Trifluridine Drops with extreme caution in CHILDREN younger than 6 years of age. Safety and effectiveness in this age group have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, discuss with your doctor the benefits and risks of using Trifluridine Drops during pregnancy. It is unknown if Trifluridine Drops are excreted in breast milk. If you are or will be breast-feeding while you are using Trifluridine Drops, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Trifluridine Drops:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Temporary burning or stinging.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); new or worsening eye irritation or pain; red or bloodshot eyes; swelling of the eye or eyelid; vision changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Trifluridine side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Trifluridine Drops:

Store Trifluridine Drops in the refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze. Keep Trifluridine Drops out of the reach of children and away from pets.

General information:

• If you have any questions about Trifluridine Drops, please talk with your doctor, pharmacist, or other health care provider.


• Trifluridine Drops are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Trifluridine Drops. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Trifluridine resources

• Trifluridine Side Effects (in more detail)
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• 0 Reviews for Trifluridine - Add your own review/rating

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• Herpetic Keratitis

Fibrogammin P

CSL Behring

FIBROGAMMIN P 250 IU

Powder and solvent for injection or infusion

Read all of this leaflet carefully before you start using this medicine.

Keep this leaflet. You may need to read it again. If you have further questions, please ask your doctor or your haemophilia nurse. This medicine has been prescribed for you personally and you should not pass it on to others. It may harm them, even if their symptoms are the same as yours.

In This Leaflet:

1. What Fibrogammin P is and what it is used for

2. Before you use Fibrogammin P

3. How to use Fibrogammin P

4. Possible side effects

5. Storing Fibrogammin P

6. Further information

What Fibrogammin P Is And What It Is Used For

Fibrogammin P (Factor XIII) is a product made from human plasma (this is the liquid part of the blood). It is used to prevent or stop the bleeding that you might get because of a lack of factor XIII in your blood, a condition that you have had from birth. Factor XIII is needed for the formation of blood clots which help bleeding to stop and helps slow healing wounds to heal more quickly.

Before You Use Fibrogammin P

Do not use Fibrogammin P

• If you are allergic to any of the ingredients (see section 6). If you are unsure about this, ask your doctor.

Take special care with Fibrogammin P

• If you experience any signs of an allergic reaction to Fibrogammin P (for example a rash, tight chest, wheezing or feeling dizzy), stop injecting the product immediately and contact your doctor.


• You should visit your doctor or haemophilia treatment centre regularly to ensure that your dose is correct. The doctor may wish to carry out some tests to make sure that you are getting the right amount.


• If your bleeding is not being controlled with Fibrogammin P, tell your doctor immediately. You may have developed an inhibitor (an antibody which can cancel out the effects of factor XIII) and your doctor may wish to carry out more tests to confirm this.


• If you have ever had a blood clot (thrombosis), you should ask your doctor for advice.

Taking or using other medicines

There are no medicines that are known to react with Fibrogammin P. However, if you are taking another medicine and are concerned, please ask your doctor or haemophilia nurse.

Pregnancy and breast-feeding

If you are pregnant or planning a family soon, or if you are breast-feeding, ask your doctor for advice before using this product.

Driving and using machines

Fibrogammin P does not affect your ability to drive or use machines.

Important information about some of the ingredients of Fibrogammin P

Fibrogammin P contains up to 17 mg sodium per vial. Please take this into account if you are on a sodium (salt) controlled diet as you may need to cut down on the salt in your diet.

Fibrogammin P contains up to 24 mg glucose per vial. Please take this into account if you have diabetes.

Important safety information related to infections

When medicines are made from human blood, steps are taken to stop infections (e.g. HIV and Hepatitis) being passed on to the patient. This includes:

• Careful selection of the blood donors


• Testing of each donation for signs of infection


• Steps in the manufacture which can kill or remove viruses

However, there is still a small chance of an infection being passed on to the patient. This may include a new virus or infection. Therefore, every time Fibrogammin P is used, it is important to note the name and batch number of the medicine (found on the carton).

How To Use Fibrogammin P

The amount of factor XIII you need will depend on several factors, such as your weight, the severity of your condition, the site and severity of bleeding or the need to prevent bleeding during an operation or investigation.

Fibrogammin P is given by injection or infusion into a vein.

If you have been prescribed Fibrogammin P to use at home, your doctor or haemophilia centre nurse will make sure that you are shown how to inject it and how much to use.

If you are in any doubt about injecting Fibrogammin P, go back to your doctor or haemophilia centre for more advice and training before attempting to treat yourself.

Follow the directions given to you by your doctor or haemophilia nurse. You can also use the directions given below as a guide.

Directions for preparing and administering Fibrogammin P

• Wash your hands thoroughly using soap and warm water.


• Warm the Fibrogammin P powder vial and the liquid (Water for Injections) ampoule to room or body temperature without opening either container. You can do this by leaving them to stand at room temperature for about an hour after taking them out of the fridge or, if you need them quickly by holding them in your hands for a few minutes.
  
  DO NOT expose the containers to direct heat or stand them on a radiator. They must not be heated above body temperature (37º C).


• Hold the water ampoule upright and shake it to move any liquid from the ampoule tip. Break off the ampoule tip with your thumb and index finger. Draw the water up into a sterile syringe with a sterile needle attached.


• Remove the cap from the powder vial and clean the rubber stopper with antiseptic solution. Allow to dry. Inject the water through the rubber stopper into the powder vial and swirl gently to dissolve. The solution should be clear or slightly cloudy, but should not contain particles.


• Once you have made up the solution, it should be used immediately. If this is not possible it should be used up within 8 hours. The solution should be put back in the fridge during this time.


• The solution should be injected at a maximum rate of 4 ml per minute.


• Any unused solution should be left in the vial or syringe. Dispose of all ampoules, vials, needles, syringes and antiseptic swabs in a ‘Sharps box’ or as you have been told. Do not throw them away with your household rubbish.

If you use more Fibrogammin P than you should

No symptoms of overdose with Fibrogammin P have been reported. However, if you accidentally inject a large overdose, then you should tell your doctor or haemophilia centre immediately.

If you forget to use Fibrogammin P

Inject your normal dose as soon as you remember and then continue as instructed by your doctor or haemophilia nurse.

Fibrogammin P Side Effects

Like all medicines, Fibrogammin P can cause side effects, although not everybody gets them.

Rare side effects (affect less than 1 in 1,000 people):

• Fever


• Rash, itchy swellings on the skin (hives)


• Low blood pressure which could make you feel faint or dizzy


• Difficulty breathing

Fibrogammin P could increase your risk of a thrombosis.

Symptoms of a thrombosis include:

• Unusual pain or swelling in your legs


• Sudden sharp pain in your chest


• Sudden difficulty breathing


• An unusual, severe or long-lasting headache


• Dizziness or fainting

If you have any of these symptoms, stop your injection immediately and contact your doctor.

If you notice that your Fibrogammin P is less effective than usual, contact your doctor or haemophilia centre immediately.

Storing Fibrogammin P

Store in a fridge at 2 °C to 8 °C, in the original packaging. Do not freeze.

Keep out of the reach and sight of children.

Do not use Fibrogammin P after the expiry date on the carton.

Further Information

What Fibrogammin P contains

The active substance is:

• 250 International Units (IU) human plasma coagulation factor XIII

Other ingredients are:

• human albumin


• glucose


• sodium chloride


• traces of sodium hydroxide or hydrochloric acid may also be present, (used for pH adjustment).

Bottles of product and liquid may appear partly empty but this is normal and does not mean that there is the wrong amount of powder or solution.

Marketing Authorisation Holder and Manufacturer

CSL Behring GmbH

Emil-von-Behring-Strasse 76

35041 Marburg

Germany

This leaflet was last approved on: 07/2010

For further information contact

CSL Behring UK Limited

Hayworth House

Market Place

Haywards Heath

West Sussex

RH16 1DB

UK

Telephone number:01444 447 405

Tylenol Allergy Multi-Symptom

Generic Name: acetaminophen, chlorpheniramine, and phenylephrine (a SEET a MIN oh fen, KLOR fen EER a meen, FEN ill EFF rin)

Brand Names: Alka-Seltzer Plus Cold, Allergy Relief Multi-Symptom, Comtrex Flu Therapy, Comtrex Severe Cold & Sinus, Contac Cold+Flu, Dristan Cold Multi Symptom Formula, Protid, Robitussin Nighttime Nasal Relief, Sinus Congestion & Pain Nighttime, Tylenol Allergy Multi-Symptom, Tylenol Children's Plus Cold, Tylenol Sinus Congestion and Pain Cool Burst Day Night, Tylenol Sinus Congestion Nighttime

What is Tylenol Allergy Multi-Symptom (acetaminophen, chlorpheniramine, and phenylephrine)?

Acetaminophen is a pain reliever and fever reducer.

Chlorpheniramine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of acetaminophen, chlorpheniramine, and phenylephrine is used to treat headache, fever, body aches, runny or stuffy nose, sneezing, itching, watery eyes, and sinus congestion caused by allergies, the common cold, or the flu.

Acetaminophen, chlorpheniramine, and phenylephrine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Tylenol Allergy Multi-Symptom (acetaminophen, chlorpheniramine, and phenylephrine)?

Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death. Do not take this medication without a doctor's advice if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You should not use this medicine if you have severe constipation, a blockage in your stomach or intestines, or if you are unable to urinate. Do not use this medicine if you have untreated or uncontrolled diseases such as glaucoma, asthma or COPD, high blood pressure, heart disease, coronary artery disease, or overactive thyroid. Avoid drinking alcohol. It may increase your risk of liver damage while taking acetaminophen and can increase certain side effects of chlorpheniramine. Do not use this medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects. Ask a doctor or pharmacist before using any other cold, allergy, pain, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose.

What should I discuss with my healthcare provider before taking Tylenol Allergy Multi-Symptom (acetaminophen, chlorpheniramine, and phenylephrine)?

You should not use this medicine if you have severe constipation, a blockage in your stomach or intestines, or if you are unable to urinate. Do not take this medication without a doctor's advice if you have ever had alcoholic liver disease (cirrhosis) or if you drink more than 3 alcoholic beverages per day. You may not be able to take medicine that contains acetaminophen. Do not use this medicine if you have untreated or uncontrolled diseases such as glaucoma, asthma or COPD, high blood pressure, heart disease, coronary artery disease, or overactive thyroid. Do not use this medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you have:

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  liver disease, cirrhosis, or a history of alcoholism;

  
  


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  a blockage in your digestive tract (stomach or intestines);

  
  


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  diabetes;

  
  


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  kidney disease;

  
  


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  epilepsy or other seizure disorder;

  
  


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  cough with mucus, or cough caused by smoking, emphysema, or chronic bronchitis;

  
  


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  enlarged prostate or urination problems;

  
  


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  low blood pressure;

  
  


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  pheochromocytoma (an adrenal gland tumor); or

  
  


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  if you take potassium (Cytra, Epiklor, K-Lyte, K-Phos, Kaon, Klor-Con, Polycitra, Urocit-K).

  
  

It is not known whether acetaminophen, chlorpheniramine, and phenylephrine will harm an unborn baby. Do not use this medicine without your doctor's advice if you are pregnant. This medication may pass into breast milk and may harm a nursing baby. Antihistamines and decongestants may also slow breast milk production. Do not use this medicine without your doctor's advice if you are breast-feeding a baby.

How should I take Tylenol Allergy Multi-Symptom (acetaminophen, chlorpheniramine, and phenylephrine)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. This medicine is usually taken only for a short time until your symptoms clear up.

Do not take more of this medication than is recommended. An overdose of acetaminophen can damage your liver or cause death.

Measure liquid medicine with a special dose-measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Drop the effervescent tablets into a glass of water (at least 4 ounces, or one-half cup). Stir this mixture and drink all of it right away.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children.

Do not take for longer than 7 days in a row. Stop taking the medicine and call your doctor if you still have a fever after 3 days of use, you still have pain after 7 days (or 5 days if treating a child), if your symptoms get worse, or if you have a skin rash, ongoing headache, or any redness or swelling.

If you need surgery or medical tests, tell the surgeon or doctor ahead of time if you have taken this medicine within the past few days. Store at room temperature away from moisture and heat. Do not allow liquid medicine to freeze.

What happens if I miss a dose?

Since this medicine is taken when needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1 800 222 1222. An overdose of acetaminophen can be fatal.

The first signs of an acetaminophen overdose include loss of appetite, nausea, vomiting, stomach pain, sweating, and confusion or weakness. Later symptoms may include pain in your upper stomach, dark urine, and yellowing of your skin or the whites of your eyes.

Overdose symptoms may also include severe forms of some of the side effects listed in this medication guide.

What should I avoid while taking Tylenol Allergy Multi-Symptom (acetaminophen, chlorpheniramine, and phenylephrine)?

Ask a doctor or pharmacist before using any other cold, allergy, pain, or sleep medication. Acetaminophen (sometimes abbreviated as APAP) is contained in many combination medicines. Taking certain products together can cause you to get too much acetaminophen which can lead to a fatal overdose. Check the label to see if a medicine contains acetaminophen or APAP. Avoid drinking alcohol. It may increase your risk of liver damage while taking acetaminophen, and can increase certain side effects of chlorpheniramine. This medicine may cause blurred vision or impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

Tylenol Allergy Multi-Symptom (acetaminophen, chlorpheniramine, and phenylephrine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as:

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  chest pain, rapid pulse, fast or uneven heart rate;

  
  


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  confusion, hallucinations, severe nervousness;

  
  


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  tremor, seizure (convulsions);

  
  


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  easy bruising or bleeding, unusual weakness;

  
  


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  urinating less than usual or not at all;

  
  


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  nausea, pain in your upper stomach, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of your skin or eyes); or

  
  


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  dangerously high blood pressure (severe headache, blurred vision, buzzing in your ears, anxiety, chest pain, shortness of breath, uneven heartbeats, seizure).

  
  

Less serious side effects may include:

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  dizziness, drowsiness;

  
  


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  mild headache;

  
  


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  dry mouth, nose, or throat;

  
  


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  constipation;

  
  


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  blurred vision;

  
  


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  feeling nervous; or

  
  


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  sleep problems (insomnia);

  
  

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 Tylenol Allergy Multi-Symptom (acetaminophen, chlorpheniramine, and phenylephrine)?

Ask a doctor or pharmacist before using this medicine if you regularly use other medicines that make you sleepy (such as narcotic pain medication, sedatives, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety). They can add to sleepiness caused by chlorpheniramine.

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

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  leflunomide (Arava);

  
  


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  topiramate (Topamax);

  
  


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  zonisamide (Zonegran);

  
  


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  an antibiotic, antifungal medicine, sulfa drug, or tuberculosis medicine;

  
  


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  an antidepressant;

  
  


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  birth control pills or hormone replacement therapy;

  
  


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  bladder or urinary medications;

  
  


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  blood pressure medication;

  
  


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  a bronchodilator;

  
  


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  cancer medicine;

  
  


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  cholesterol-lowering medications such as Lipitor, Niaspan, Zocor, Vytorin, and others;

  
  


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  gout or arthritis medications (including gold injections);

  
  


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  HIV/AIDS medication;

  
  


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  medication for nausea and vomiting, stomach ulcers, or irritable bowel syndrome;

  
  


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  medicines to treat psychiatric disorders;

  
  


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  an NSAID such as Advil, Aleve, Arthrotec, Cataflam, Celebrex, Indocin, Motrin, Naprosyn, Treximet, Voltaren, others; or

  
  


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  seizure medication.

  
  

This list is not complete and other drugs may interact with acetaminophen, chlorpheniramine, and phenylephrine. 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 Tylenol Allergy Multi-Symptom resources

• Tylenol Allergy Multi-Symptom Side Effects (in more detail)
• Tylenol Allergy Multi-Symptom Use in Pregnancy & Breastfeeding
• Tylenol Allergy Multi-Symptom Drug Interactions
• 0 Reviews for Tylenol Allergy Multi-Symptom - Add your own review/rating

• Tylenol Allergy Multi-Symptom MedFacts Consumer Leaflet (Wolters Kluwer)


• Alka-Seltzer Plus Cold MedFacts Consumer Leaflet (Wolters Kluwer)


• Dryphen MedFacts Consumer Leaflet (Wolters Kluwer)


• Protid Controlled-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Tylenol Allergy Multi-Symptom with other medications

• Cold Symptoms
• Sinus Symptoms

Where can I get more information?

• Your pharmacist can provide more information about acetaminophen, chlorpheniramine, and phenylephrine.

See also: Tylenol Allergy Multi-Symptom side effects (in more detail)