Phytonadione

Class: Vitamin K Activity
VA Class: VT702
CAS Number: 84-80-0
Brands: AquaMEPHYTON, Mephyton

• IV and IM Administration


• 
  

  Severe hypersensitivity reactions, including fatal anaphlaxis, have occurred during and immediately after IV or IM injection of phytonadione injection.^b

  
  


• 
  

  Such severe reactions have occurred despite employing measures to prevent hypersensitivity reactions, including dilution of the injection and administration by slow infusion.^b

  
  


• 
  

  These severe reactions are consistent with hypersensitivity or anaphylaxis, including shock and cardiac and/or respiratory arrest and have occurred after initial administration.^b

  
  


• 
  

  Restrict IV and IM administration to those situations where sub-Q administration is not feasible and the serious risk associated with IV or IM administration is considered justified.^b

  
  

.

Introduction

A fat-soluble naphthoquinone derivative; identical to naturally occurring vitamin K₁.^c

Uses for Phytonadione

Prophylaxis and treatment of coagulation disorders due to faulty formation of factors II, VII, IX and X caused by vitamin K deficiency or interference with vitamin K activity.^a

More effective and is preferred to other vitamin K preparations in the presence of impending or actual hemorrhage.^c

Anticoagulant-induced Hypoprothrombinemia

Drug of choice for the treatment of moderate or severe hemorrhage caused by overdosage of coumarin or indandione derivatives.^{a c}

Withdrawal of oral anticoagulant alone usually corrects excessively prolonged prothrombin time or minor hemorrhage.^c

Not effective against anticoagulant action of heparins, argatroban, bivalirudin, fondaparinux, or lepirudin.^c

Hemorrhagic Disease of the Newborn

Prophylaxis and treatment of hemorrhagic disease of the newborn.^{b c f 34 135 136 137}

AAP recommends routine IM administration to infants at birth to prevent hemorrhagic disease of the newborn.^{34 135 136 137 f}

Treatment of vitamin K deficiency in infants who are breast-fed or receiving prolonged hyperalimentation.^c

Drug-induced Hypoprothrombinemia

Treatment of hypoprothrombinemia secondary to drug therapy (e.g., salicylates, broad-spectrum anti-infectives, quinine, quinidine, sulfonamides) when it is definitely caused by interference with vitamin K activity.^{a b c}

Discontinuance or dosage reduction of drug interfering with coagulation attempted first, if possible, as alternative to phytonadione.^c

Other Causes of Hypoprothrombinemia

Treatment of hypoprothrombinemia secondary to obstructive jaundice or biliary fistulas; bile salts must be administered concomitantly with oral therapy.^a

Ineffective in the treatment of hereditary hypoprothrombinemia.^c

Vitamin K Deficiency

Treatment of vitamin K deficiency (e.g., in patients receiving prolonged hyperalimentation, as well as in the presence of malabsorption syndromes such as sprue, celiac disease, ulcerative colitis, regional enteritis, cystic fibrosis, prolonged diarrhea, obstructive jaundice, internal biliary fistula, dysentery, after extensive bowel resection).^c

Dietary Requirements

Prevention of vitamin K deficiency and vitamin K-responsive hypothrombinemia.^{121 c}

Adequate intake of vitamin K usually can be accomplished through consumption of foodstuffs.^{121 c}

Spinach, collards, broccoli, iceberg lettuce, and plant oils are the major contributors of vitamin K in the diet of US adults and children.^{121 c}

National Academies (formerly National Academy of Sciences; NAS) unable to establish accurate Recommended Dietary Allowances (RDAs) or Dietary Reference Intakes (DRIs) for vitamin K due to lack of adequate data.¹²¹

Adequate Intake (AI) for adults, adolescents, and children ≥1 year of age is based on reported vitamin K dietary intake in apparently healthy population groups (Third National Health and Nutrition Examination Survey [NHANES III]).¹²¹

Dietary intakes slightly lower in women than men.¹²¹

AI established for infants ≤6 months of age based on observed mean vitamin K intake of infants fed principally human milk.¹²¹

AI for infants 7–12 months of age set based on the AI for younger infants.¹²¹

Phytonadione Dosage and Administration

General

• 
  

  Restrict IV or IM administration to situations when sub-Q is not possible.^a

  
  


• 
  

  Monitor prothrombin time regularly as dictated by clinical condition.^b

  
  


• 
  

  If possible, discontinue or reduce dosage of drugs interfering with the coagulation mechanism as an alternative or adjunct to phytonadione therapy.^c

  
  


• 
  

  Diagnosis of vitamin K deficiency may be based on tests for vitamin K-dependent clotting factors (e.g., prothrombin time, which is sensitive to the levels of factors II, VII, and X) or on a therapeutic trial of phytonadione.^c

  
  

Administration

Administer orally or parenterally.^{a b}

Parental therapy: Sub-Q preferred because of hypersensitivity risk with IV or IM administration.^a (See Boxed Warning.)

Route of administration depends on the severity of the prothrombin deficiency and the risks associated with administration by each route.^c

Oral Administration

Avoid oral route when the clinical disorder would prevent proper absorption.^b

Patients with decreased bile secretion: Give bile salts (e.g., ox bile extract 300 mg or dehydrocholic acid 500 mg) with each oral dose of phytonadione to ensure absorption.^{b c}

The parenteral preparation has also been administered orally† to neonates.^{34 35 37 102 103 104 105 136}

IV, IM, or Sub-Q Administration

Because of the possibility of severe hypersensitivity reactions, IV or IM administration is indicated only when the serious risk involved is considered justified and other routes of administration are not feasible.^b (See Boxed Warning.)

Parenteral administration is indicated in patients unable to retain or absorb the drug from the GI tract.^c

Sub-Q or IM administration may be contraindicated in hypoprothrombinemia because of the possibility of inducing hemorrhage or hematoma at the site of injection.^c

Dilution

Dilute for infusion with preservative-free 5% dextrose, 0.9% sodium chloride, or 5% dextrose in 0.9% sodium chloride injection; other diluents should not be used.^c

Administer IV immediately after dilution, and any unused portion of the dilution and the unused contents of the ampul should be discarded.^c The infusion container must be protected from light at all times.^c (See Storage under Stability.)

Rate of Administration

Inject IV very slowly, at a rate ≤1 mg/minute.^b (See Boxed Warning.)

Dosage

Dose, frequency of administration, and duration of treatment depend on the severity of the prothrombin deficiency and the response of the patient.^c

Pediatric Patients

Hemorrhagic Disease of the Newborn

Prophylaxis

IM

AAP recommends a single IM dose of 0.5–1 mg within 1 hour of delivery.^{34 113 135 136 c f}

Oral

Alternatively, 1–2 mg orally† (can use injection formulation) immediately after delivery.^{135 136 137} Several oral doses, administered over a period of up to 3 months, may be required (e.g., at 1–2 weeks and 4 weeks of age in breast-fed infants, repeatedly if diarrhea occurs in breast-fed infants).^{135 136 137 f}

Treatment

Empiric administration should not replace proper laboratory evaluation of the coagulation mechanism.^b

A prompt response (shortening of the prothrombin time in 2–4 hours) following phytonadione usually is diagnostic of hemorrhagic disease of the newborn, and failure to respond indicates another diagnosis or coagulation disorder.^b

IM or Sub-Q

1 mg sub-Q or IM.^b Higher doses may be necessary if the mother has been receiving oral anticoagulants.^b

Dietary and Replacement Requirements

Healthy Infants ≤6 Months of Age

Oral

2 mcg daily.¹²¹

Healthy Infants 7–12 Months of Age

Oral

2.5 mcg daily.¹²¹

Healthy Children 1–3 Years of Age

Oral

30 mcg daily.¹²¹

Healthy Children 4–8 Years of Age

Oral

55 mcg daily.¹²¹

Healthy Children 9–13 Years of Age

Oral

60 mcg daily.¹²¹

Healthy Children 14–18 Years of Age

Oral

75 mcg daily.¹²¹

Adults

Anticoagulant-induced Hypoprothrombinemia

Oral

Usual initial dosage: 2.5–10 mg.^a Initial doses up to 25 mg have been used.^a

Subsequent frequency and dosage should be determined by prothrombin time response and/or clinical condition.^a

Dose may be repeated in 12–48 hours.^a

Rarely, larger doses (e.g., 50 mg) may be required; however, administer lowest effective dosage so that refractoriness to further anticoagulant therapy is minimized and prothrombin time is not decreased below the effective anticoagulant level.^{a c}

IV, IM, or Sub-Q

Usual initial dosage: 2.5–10 mg.^b Initial doses up to 25 mg have been used.^b

Subsequent frequency and dosage should be determined by prothrombin time response and/or clinical condition.^b

Dose may be repeated in 6–8 hours.^b

Rarely, larger doses (e.g., 50 mg) may be required; however, administer lowest effective dosage so that refractoriness to further anticoagulant therapy is minimized and prothrombin time is not decreased below the effective anticoagulant level.^{b c}

Hypoprothrombinemia from Other Causes

Oral

Usual initial dosage: 2.5–25 mg, depending on deficiency, severity, and response.^a Rarely, larger doses (e.g., 50 mg) may be required.^a

Determine subsequent frequency and dosage by prothrombin time response and/or clinical condition in addition to reduction or discontinuance of drug (if drug therapy causing hypoprothrombinemia).^a

IV, IM, or Sub-Q

Usual initial dosage: 2.5–25 mg, depending on deficiency severity and response.^a Rarely, larger doses (e.g., 50 mg) may be required.^a

Determine subsequent frequency and dosage by prothrombin time response and/or clinical condition in addition to reduction or discontinuance of interfering drug (if drug therapy causing hypoprothrombinemia).^a

Dietary and Replacement Requirements

Healthy Men ≥ 19 Years of Age

Oral

120 mcg daily.¹²¹

Healthy Women ≥19 Years of Age

Oral

90 mcg daily.¹²¹

Limited data suggest that the vitamin K status in pregnant women does not differ from that in nonpregnant women.¹²¹ Therefore, NAS states that the AI of vitamin K does not need to be increased during pregnancy (i.e., pregnant women can receive the usual AI appropriate for their age).¹²¹

Available evidence indicates that the vitamin K status of lactating women is comparable to that of nonlactating women.¹²¹ Vitamin K is not distributed in clinically important amounts into milk, and the AI for lactating women does not differ from that for nonlactating women.¹²¹

Special Populations

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.^a

Cautions for Phytonadione

Contraindications

• 
  

  Known hypersensitivity to phytonadione or any ingredient in the formulation.^a

  
  

Warnings/Precautions

Warnings

IV or IM Administration

Restrict IV and IM administration to those situations where sub-Q administration is not feasible and the risk of anaphylaxis associated with IV or IM administration is considered justified.^b (See Boxed Warning.)

Delayed Coagulant Effect

Coagulant effect is not immediate after parenteral administration; measurable improvement in prothrombin time generally occurs after a minimum of 1–2 hours.^b

Whole blood or component therapy may also be necessary for severe bleeding.^b

Heparins and Other Non-coumarin/Indandione Coagulants

Does not counteract the anticoagulant effect of heparins, argatroban, bivalirudin, fondaparinux, or lepirudin.^b

Anticoagulant-induced Hypoprothrombinemia

Use minimum effective dosage when treating anticoagulant-induced hypoprothrombinemia to avoid subsequent anticoagulant refractoriness; monitor prothrombin time regularly according to clinical conditions.^b

When used to treat excessive anticoagulant-induced hypoprothrombinemia and continued anticoagulant therapy is indicated, clotting hazards that existed prior to anticoagulant therapy should be considered.^b Phytonadione is not a clotting agent, but excessive dosage may restore conditions originally underlying the thromboembolic phenomena.^b

Hepatic Disease

Repeated large doses are not indicated in liver disease if the response to initial therapy with the vitamin is unsatisfactory.^b

Lack of response may indicate the condition is inherently unresponsive to phytonadione.^b

Sensitivity Reactions

Hypersensitivity Reactions

Serious and fatal hypersensitivity reactions, including anaphylaxis, after IV or IM administration.^b (See Boxed Warning.)

Pruritic Plaques

Infrequently, usually after repeated injection, erythematous, indurated, pruritic plaques reported; rarely, progression to persistent sclerodermalike lesions.^b Also, may resemble erythema perstans.^b

General Precautions

Light-Sensitivity

Rapidly degraded by light; protect phytonadione injection from light.^b Store in closed original carton until use.^b (See Stability.)

Specific Populations

Pregnancy

Category C.^{a g}

Lactation

Distributes into milk, but amount is too low to protect against hermorrhagic disease of newborn.^{c g} Caution if used in nursing women,^{a b} but maternal use considered compatible with breast-feeding.^g

Pediatric Use

Oral administration: Safety and efficacy of oral phytonadione not established.^{a b}

Severe hemolytic anemia, hyperbilirubinemia, and jaundice reported rarely in neonates, particularly premature neonates, following large doses (10–20 mg).^{a c} However, the incidence of these adverse effects is much less with phytonadione than with other vitamin K preparations.^c

Phytonadione injection contains 9 mg/mL of benzyl alcohol as a preservative.¹¹³ Administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.^{113 114 115 116 117 118 119 120} Toxicity appears to have resulted from administration of large amounts (i.e., 100–400 mg/kg daily) of benzyl alcohol in these neonates.^{114 115 116 117 118 119 120}

Whenever possible use of drugs or diluents preserved with benzyl alcohol should be avoided in neonates;^{114 116} however, AAP states that the small amount of the preservative in commercially available injection should not proscribe its use when indicated in neonates¹¹⁴ and the manufacturers state that there is no evidence that the amount of benzyl alcohol contained in the injections is associated with toxicity when the drug is used as recommended.¹¹³

Geriatric Use

Response in patients≥65 years of age does not appear to differ from that in younger adults; however, select dosage with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.^a

Common Adverse Effects

Parenteral Administration: Pain, swelling, and tenderness at the injection site, transient “flushing sensations,“ “peculiar” sensations of taste.^b

Fatal anaphylactic reaction reported after IV and IM administration.^b (See Boxed Warning.)

Interactions for Phytonadione

Specific Drugs

Drug	Interaction	Comments
Anticoagulants, oral (coumarins and indandiones)	Vitamin K1 is a pharmacologic antagonistc	Avoid concomitant use; only use concomitant phytonadione for treatment of excessive hypoprothrombinemiac Consider alternate to prothrombin-depressing anticoagulant (e.g., heparins) if neccesaryb
Orlistat	Possible decreased GI absorption of fat-soluble vitamins, inlcuding phytonadione (vitamin K1)122	Separate oral administration of orlistat and phytonadione by ≥2 hours 122 124 128 130

Phytonadione Pharmacokinetics

Absorption

Abosorbed from the GI tract only in the presence of bile salts.^c

Onset

Oral administration: blood coagulation factors increase in 6–10 hours.^c

Parenteral administration: blood coagulation factors increase within 1–2 hours.^c

Parenteral administration: bleeding usually controlled within 3–6 hours, and a normal prothrombin time often obtained within 12–14 hours.^c

Distribution

Extent

May be concentrated in the liver for a short time after absorption; only small amounts are stored in body tissues.^c

Appears to cross the placenta to a limited extent.^c

Distributes into milk.^{34 35 102 107 108 109 110 111 g}

Elimination

Route of excretion of vitamin K is not known.^c High fecal concentrations of vitamin K probably result from bacterial synthesis in the intestine.^c

Stability

Storage

Oral

Tablets

Tight, light resistant, original container at 25°C (may be exposed to 15–30°C).^a

Always protect from light.^a

Parenteral

Injection

Protect from light.^b Store in carton to protect from light until used.^b

Infusion solutions should be protected from light by wrapping the container with aluminum foil or other opaque material.^c

Use immediately after dilution; discard unused portion of ampul and dilution.^c

Compatibility

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

Parenteral

Solution Compatibility^HID

Compatible
Amino acids 4.25%, dextrose 25%
Dextran 6% in dextrose 5%
Dextran 6% in sodium chloride 0.9%
Dextrose 2½, 5, or 10% in water
Dextrose–Ringer’s injection combinations
Dextrose–Ringer’s injection, lactated, combinations
Dextrose–saline combinations
Fat emulsion 10%, IV
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 chloride 0.45 or 0.9%
Sodium lactate (1/6) M
Incompatible
Amino acids 2%, dextrose 12.5%
Dextran 12%

Drug Compatibility

Admixture CompatibilityHID

Compatible
Amikacin sulfate
Chloramphenicol sodium succinate
Cimetidine HCl
Sodium bicarbonate
Incompatible
Ranitidine HCl

Y-site CompatibilityHID

Compatible
Ampicillin sodium
Epinephrine HCl
Famotidine
Heparin sodium
Hydrocortisone sodium succinate
Potassium chloride
Vitamin B complex with C
Incompatible
Dobutamine HCl

ActionsActions

• 
  

  Same activity as naturally occurring vitamin K₁, which is required for the synthesis of blood coagulation factors II (prothrombin), VII (proconvertin), IX (Christmas factor or plasma thromboplastin component), and X (Stuart-Prower factor) in the liver.^c

  
  


• 
  

  Involved in carboxylation of the preformed, inactive precursors of these coagulation factors, resulting γ-carboxyglutamyl residues are required for the calcium-dependent phospholipid binding exhibited by active vitamin K-dependent clotting factors.^c

  
  


• 
  

  Reverses the inhibitory effect of coumarin and indandione derivatives on the synthesis of these factors.^c

  
  

Advice to Patients

• 
  

  Importance of advising patients receiving coumarin or indandione anticoagulants

  
  

  to avoid vitamin K supplementation or foods high in vitamin K (e.g., spinach, collards, broccoli, iceberg lettuce, plant oils).

  
  


• 
  

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

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^c

  
  


• 
  

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

  
  

Preparations

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

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

Phytonadione

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	5 mg	Mephyton (scored)	Merck
Parenteral	Injection	2 mg/mL*	AquaMEPHYTON (with polyoxyethylated fatty acid derivative, dextrose, and benzyl alcohol 0.9%)	Merck
			Phytonadione Injection	Hospira, IMS
		10 mg/mL*	AquaMEPHYTON (with polyoxyethylated fatty acid derivative, dextrose, and benzyl alcohol 0.9%)	Merck
			Phytonadione Injection	Hospira

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 August 2007. 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

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35. American Academy of Pediatrics Committee on Nutrition. Vitamin K supplementation for infants receiving milk substitute infant formulas and for those with fat malabsorption. Pediatrics. 1971; 48:483-7. [PubMed 5109893]

37. Vest M. Vitamin K in medical practice—pediatrics. Vitam Horm. 1966; 24:649-63. [PubMed 5340884]

100. Shearer MJ, Barkhan P, Webster GR. Absorption and excretion of an oral dose of titrated vitamin K₁ in man. Br J Haematol. 1970; 18:297-308. [PubMed 5491582]

101. Hollander D. Intestinal absorption of vitamins A, E, D, and K. J Lab Clin Med. 1981; 97:449-62. [PubMed 7205056]

102. Lane PA, Hathaway WE. Vitamin K in infancy. J Pediatr. 1985; 106:351-9. [IDIS 197121] [PubMed 3973772]

103. Sann L, Leclercq M, Bourgeois J et al. Pharmacokinetics of vitamin K₁ in newborn infants. Pediatr Res. 1983; 17:155A.

104. Dunn PM. Vitamin K₁ for all newborn babies. Lancet. 1982; 2:770. [IDIS 158995] [PubMed 6125839]

105. Shoskes M. “Solubilized” vitamin K₁ (phytonadione) in neonatal hypoprothrombinemia. J Pediatr. 1961; 58:27-31.

106. Hemorrhage in the newborn infant. In: Behrman RE, Vaughn RC III, eds. Nelson textbook of pediatrics. 12th ed. Philadelphia: WB Saunders Company; 1983:389-90.

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108. Haroon Y, Shearer MJ, Rahim S et al. The content of phylloquinone (vitamin K₁) in human milk, cow’s milk and infant formula foods determined by high-performance liquid chromatography. J Nutr. 1982; 112:1105-17. [PubMed 7086539]

109. O’Connor ME, Livingstone DS, Hannah J et al. Vitamin K deficiency and breast feeding. Am J Dis Child. 1983; 137:601-2. [IDIS 170978] [PubMed 6846298]

110. Sutherland JM, Glueck HI, Gleser G. Hemorrhagic disease of the newborn: breast feeding as a necessary factor in the pathogenesis. Am J Dis Child. 1967; 113:524-33. [PubMed 6071586]

111. Keenan WJ, Jewett T, Glueck HI. Role of feeding and vitamin K in hypoprothrombinemia of the newborn. Am J Dis Child. 1971; 121:271-7. [PubMed 5108035]

112. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press; 1998. (Prepublication copy uncorrected proofs.)

113. Merck. AquaMEPHYTON (phytonadione) injection aqueous colloidal solution of vitamin K₁ prescribing information (dated 1997 Sep). In: Physicians’ desk reference. 56th ed. Montvale, NJ: Medical Economics Company Inc; 2002:2042-3

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115. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12(2):10-1. [PubMed 7188569]

116. Anon. Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982; 31:290-1. [IDIS 150868] [PubMed 6810084]

117. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307:1384-8. [IDIS 160823] [PubMed 7133084]

118. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol. 1984; 1:288-92. [PubMed 6440575]

119. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol. 1984; 148:344-6. [IDIS 181207] [PubMed 6695984]

120. Food and Drug Administration. Parenteral drug products containing benzyl alcohol or other antimicrobial preservatives; intent and request for information. [Docket No. 85N-0043] Fed Regist. 1985; 50:20233-5.

121. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; 2002:162-98. (Prepublication copy uncorrected proofs.)

122. Roche Laboratories Inc. Xenical (orlistat) capsules prescribing information. Nutley, NJ; 1999 April.

123. Sjöström L, Rissanen A, Andersen T et al. Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet. 1998; 352:167-72. [IDIS 407969] [PubMed 9683204]

124. Davidson MH, Hauptman J, DiGirolamo M et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat. JAMA. 1999; 281:235-42. [IDIS 417495] [PubMed 9918478]

125. Hollander PA, Elbein SC, Hirsch IB et al. Role of orlistat in the treatment of obese patients with type 2 diabetes: a 1-year randomized double-blind study. Diabetes Care. 1998; 21:1288-94. [IDIS 411429] [PubMed 9702435]

126. Melia AT, Koss-Twardy SG, Zhi J. The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers. J Clin Pharmacol. 1996; 36:647-53. [IDIS 370479] [PubMed 8844448]

127. Zhi J, Melia AT, Koss-Twardy SG et al. The effect of orlistat, an inhibitor of dietary fat absorption, on the pharmacokinetics of β-carotene in healthy volunteers. J Clin Pharmacol. 1996; 36:152-9. [IDIS 364805] [PubMed 8852391]

128. Roche Laboratories Inc. Xenical (orlistat) capsules patient information. Nutley, NJ; 1999 April.

129. James WP, Avenell A, Broom J et al. A one-year trial to assess the value of orlistat in the management of obesity. Int J Obes Relat Metab Disord. 1997; 21(Suppl 3):S24-30. [PubMed 9225173]

130. Roche Laboratories Inc, Nutley, NJ: Personal communication on Orlistat 56:40.

131. Anon. Practice parameter: management issues for women with epilepsy (summary statement). Neurology. 1998; 51:944-8. [PubMed 9781510]

132. American College of Obstetricians and Gynecologists. ACOG educational bulletin No. 231: seizure disorders in pregnancy. Dec 1996.

133. Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy. Drugs. 1999; 57:535-44. [PubMed 10235691]

134. Merck. Mephyton (phytonadione) tablets vitamin K₁ prescribing information (dated 1998 Aug). In: Physicians’ desk reference. 56th ed. Montevale, NJ: Medical Economics Company Inc; 2002:2129-30.

135. American Academy of Pediatrics Vitamin K ad hoc task force. Controversies concerning vitamin K and the newborn. Pediatrics. 1993; 91:1001-3. [IDIS 313728] [PubMed 8474790]

136. Buck ML. Vitamin K for the prevention of bleeding in newborns. Pediatric Pharmacotherapy. 2001. From the web site ().

137. American Academy of Pediatrics Committee on Nutrition. Pediatric nutrition handbook. 4th ed. Elk Groove Village, IL: American Academy of Pediatrics; 1998:14,277-8.

a. Merck. Mephyton (phytonadione) vitamin K₁ tablets prescribing information. Whitehouse Station, NJ; 2002 Feb.

b. Merck. AquaMEPHYTON (phytonadione) injection aqueous colloidal solution of vitamin K₁ prescribing information.Whitehouse Station, NJ; 2002 Feb.

c. AHFS drug information 2004. McEvoy GK, ed. Phytonadione. Bethesda, MD: American Society of Health-System Pharmacists; 2004:3525-27.

d. Schilling McCann JA, Publisher. Pharmacists drug handbook. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins and American Society of Health-System Pharmacists; 2003.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1347-50.

f. American Academy of Pediatrics. Nutritional needs of preterm infant. In: Pediatric nutrition handbook. 5th ed. 2004.

g. Briggs GG, Freeman RK, Yaffe SJ. Phytonadione. In: Drugs in pregnancy and lactation. 6th ed. Baltimore: Lippincott Williams & Wilkins; 1128-1131.

More Phytonadione resources

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• Aquamephyton Concise Consumer Information (Cerner Multum)


• Mephyton Advanced Consumer (Micromedex) - Includes Dosage Information


• Mephyton Prescribing Information (FDA)


• Mephyton MedFacts Consumer Leaflet (Wolters Kluwer)


• Vitamin K1 Prescribing Information (FDA)

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• Hypoprothrombinemia, Anticoagulant Induced
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Sans-Acne Topical

Generic Name: erythromycin (Topical route)

e-rith-roe-MYE-sin

Commonly used brand name(s)

In the U.S.

• A/T/S


• Akne-Mycin


• Emcin


• Emgel


• Ery


• Erycette


• Eryderm


• Erygel


• Theramycin Z

In Canada

• Sans-Acne


• Staticin

Available Dosage Forms:

• Pad


• Gel/Jelly


• Ointment


• Solution


• Swab


• Lotion

Therapeutic Class: Antiacne

Chemical Class: Macrolide

Uses For Sans-Acne

Erythromycin belongs to the family of medicines called antibiotics. Erythromycin topical preparations are used on the skin to help control acne. They may be used alone or with one or more other medicines that are applied to the skin or taken by mouth for acne. They may also be used for other problems, such as skin infections, as determined by your doctor.

Erythromycin is available only with your doctor's prescription.

Before Using Sans-Acne

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

Erythromycin topical solution has been tested in children 12 years of age and older and, in effective doses, has not been shown to cause different side effects or problems than it does in adults.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults. Although there is no specific information comparing use of topical erythromycin in the elderly with use in other age groups, this medicine is not expected to cause different side effects or problems in older people than it does in younger adults.

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 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.

• Clindamycin

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. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Proper Use of erythromycin

This section provides information on the proper use of a number of products that contain erythromycin. It may not be specific to Sans-Acne. Please read with care.

Before applying this medicine, thoroughly wash the affected area with warm water and soap, rinse well, and pat dry. After washing or shaving, it is best to wait 30 minutes before applying the pledget (swab), topical gel, or topical liquid form. The alcohol in them may irritate freshly washed or shaved skin.

For patients using the pledget (swab), topical gel, or topical liquid form of erythromycin:

• These forms contain alcohol and are flammable. Do not use near heat, near open flame, or while smoking.


• It is important that you do not use this medicine more often than your doctor ordered. It may cause your skin to become too dry or irritated.


• Also, you should avoid washing the acne-affected areas too often. This may dry your skin and make your acne worse. Washing with a mild, bland soap 2 or 3 times a day should be enough, unless you have oily skin. If you have any questions about this, check with your doctor.


• To use:
  
  • The topical liquid form of this medicine may come in a bottle with an applicator tip, which may be used to apply the medicine directly to the skin. Use the applicator with a dabbing motion instead of a rolling motion (not like a roll-on deodorant, for example). If the medicine does not come in an applicator bottle, you may moisten a pad with the medicine and then rub the pad over the whole affected area. Or you may also apply this medicine with your fingertips. Be sure to wash the medicine off your hands afterward.
  
  
  • Apply a thin film of medicine, using enough to cover the affected area lightly. You should apply the medicine to the whole area usually affected by acne, not just to the pimples themselves. This will help keep new pimples from breaking out.
  
  
  • The pledget (swab) form should be rubbed over the whole affected area. You may use extra pledgets (swabs), if needed, to cover larger areas.
  
  
  • Since these medicines contain alcohol, they may sting or burn. Therefore, do not get these medicines in the eyes, nose, mouth, or on other mucous membranes. Spread the medicine away from these areas when applying. If these medicines do get in the eyes, wash them out immediately, but carefully, with large amounts of cool tap water. If your eyes still burn or are painful, check with your doctor.
  
  

This medicine will not cure your acne. However, to help keep your acne under control, keep using this medicine for the full time of treatment, even if your symptoms begin to clear up after a few days. You may have to continue using this medicine every day for months or even longer in some cases. If you stop using this medicine too soon, your symptoms may return. It is important that you do not miss any doses.

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 acne:
  
  • For gel dosage form:
    
    • Adults—Apply to the affected area(s) of the skin two times a day, morning and evening.
    
    
    • Children—Dose must be determined by your doctor.
    
    
  
  
  • For ointment dosage form:
    
    • Adults, teenagers, and children—Apply to the affected area(s) of the skin two times a day, morning and evening.
    
    
  
  
  • For pledgets dosage form:
    
    • Adults, teenagers, and children—Apply to the affected area(s) of the skin two times a day.
    
    
  
  
  • For topical solution dosage form:
    
    • Adults, teenagers, and children 12 years of age and over—Apply to the affected area(s) of the skin two times a day, morning and evening.
    
    
    • Children up to 12 years of age—Dose must be determined by your doctor.
    
    
  
  

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.

Precautions While Using Sans-Acne

If your acne does not improve within 3 to 4 weeks, or if it becomes worse, check with your health care professional. However, treatment of acne may take up to 8 to 12 weeks before you see full improvement.

For patients using the pledget (swab), topical gel, or topical liquid form of erythromycin:

• If your doctor has ordered another medicine to be applied to the skin along with this medicine, it is best to wait at least 1 hour before you apply the second medicine. This may help keep your skin from becoming too irritated. Also, if the medicines are used too close together, they may not work properly.


• After application of this medicine to the skin, mild stinging or burning may be expected and may last up to a few minutes or more.


• This medicine may also cause the skin to become unusually dry, even with normal use. If this occurs, check with your doctor.


• You may continue to use cosmetics (make-up) while you are using this medicine for acne. However, it is best to use only ``water-base'' cosmetics. Also, it is best not to use cosmetics too heavily or too often. They may make your acne worse. If you have any questions about this, check with your doctor.

Sans-Acne 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.

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:

For erythromycin ointmentLess common

• Peeling


• redness

For erythromycin pledget (swab), topical gel, or topical liquid form More common

• Dry or scaly skin


• irritation


• itching


• stinging or burning feeling

Less common

• Peeling


• redness

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 Sans-Acne Topical resources

• Sans-Acne Topical Use in Pregnancy & Breastfeeding
• Sans-Acne Topical Support Group
• 1 Review for Sans-Acne Topical - Add your own review/rating

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MicardisPlus 80 mg / 25 mg Tablets

MicardisPlus

80 mg/25 mg tablets

telmisartan/hydrochlorothiazide

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

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What MicardisPlus is and what it is used for


• 2. Before you take MicardisPlus


• 3. How to take MicardisPlus


• 4. Possible side effects


• 5. How to store MicardisPlus


• 6. Further information

What Micardisplus Is And What It Is Used For

MicardisPlus is a combination of two active substances, telmisartan and hydrochlorothiazide in one tablet. Both substances help to control high blood pressure.

• Telmisartan belongs to a group of medicines called angiotensin II receptor antagonists. Angiotensin-II is a substance produced in your body which causes your blood vessels to narrow, thus increasing your blood pressure. Telmisartan blocks the effect of angiotensin II so that the blood vessels relax, and your blood pressure is lowered.


• Hydrochlorothiazide belongs to a group of medicines called thiazide diuretics, which cause your urine output to increase leading to a lowering of your blood pressure.

High blood pressure, if not treated, can damage blood vessels in several organs, which could lead sometimes to heart attack, heart or kidney failure, stroke, or blindness. There are usually no symptoms of high blood pressure before damage occurs. Thus it is important to regularly measure blood pressure to verify if it is within the normal range.

MicardisPlus is used to treat high blood pressure (essential hypertension) in patients whose blood pressure is not controlled enough when either telmisartan or hydrochlorothiazide is used alone.

Before You Take Micardisplus

Do not take MicardisPlus

• if you are allergic (hypersensitive) to telmisartan or any other ingredients included in MicardisPlus tablets (see “Further Information” for a list of other ingredients).


• if you are allergic (hypersensitive) to hydrochlorothiazide or to any other sulfonamide-derived medicines.


• if you are more than 3 months pregnant. (It is also better to avoid MicardisPlus in early pregnancy – see pregnancy section.)


• if you have severe liver problems such as cholestasis or biliary obstruction (problems with drainage of the bile from the gall bladder), or any other severe liver disease.


• if you have severe kidney disease.


• if your doctor determines that you have low potassium levels or high calcium levels in your blood that do not get better with treatment.

If any of the above applies to you, tell your doctor or pharmacist before taking MicardisPlus.

Take special care with MicardisPlus

Please tell your doctor if you are suffering or have ever suffered from any of the following conditions or illnesses:

• Low blood pressure (hypotension), likely to occur if you are dehydrated (excessive loss of body water) or have salt deficiency due to diuretic therapy (water tablets), low-salt diet, diarrhoea, vomiting, or haemodialysis.


• Kidney disease or kidney transplant.


• Renal artery stenosis (narrowing of the blood vessels to one or both kidneys).


• Liver disease.


• Heart trouble.


• Diabetes.


• Gout.


• Raised aldosterone levels (water and salt retention in the body along with imbalance of various blood minerals).


• Lupus erythematosus (also called “lupus” or “SLE”) a disease where the body’s immune system attacks the body.

You must tell your doctor if you think you are (or might become) pregnant. MicardisPlus is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).

Treatment with hydrochlorothiazide may cause electrolyte imbalance in your body. Typical symptoms of fluid or electrolyte imbalance include dry mouth, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, nausea (feeling sick), vomiting, tired muscles, and an abnormally fast heart rate (faster than 100 beats per minute). If you experience any of these you should tell your doctor.

You should also tell your doctor, if you experience an increased sensitivity of the skin to the sun with symptoms of sunburn (such as redness, itching, swelling, blistering) occurring more quickly than normal.

In case of surgery or anaesthetics, you should tell your doctor that you are taking MicardisPlus.

The use of MicardisPlus in children and adolescents up to the age of 18 years is not recommended.

As with all other angiotensin II receptor antagonists, telmisartan may be less effective in lowering the blood pressure in black patients.

Taking other medicines:

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Your doctor may need to change the dose of these other medications or take other precautions. In some cases you may have to stop taking one of the medicines. This applies especially to the medicines listed below taken at the same time with MicardisPlus:

• Lithium containing medicines to treat some types of depression.


• Medicines associated with low blood potassium (hypokalaemia) such as other diuretics, (‘water tablets’), laxatives (e.g. castor oil), corticosteroids (e.g. prednisone), ACTH (a hormone), amphotericin (an antifungal medicine), carbenoxolone (used to treat mouth ulcers), penicillin G sodium (an antibiotic), and salicylic acid and derivatives.


• Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, ACE inhibitors that may increase blood potassium levels.


• Heart medicines (e.g. digoxin) or medicines to control the rhythm of your heart (e.g. quinidine, disopyramide).


• Medicines used for mental disorders (e.g. thioridazine, chlorpromazine, levomepromazine).


• Other medicines used to treat high blood pressure, steroids, painkillers, medicines to treat cancer, gout, or arthritis, and vitamin D supplements.

MicardisPlus may increase the blood pressure lowering effect of other medicines and you should consult with your doctor if you need to adjust the dose of your other medicine while taking MicardisPlus.

As with other blood pressure lowering medicines, the effect of MicardisPlus may be reduced when you take NSAIDs (non steroidal anti-inflammatory medicines, e.g. aspirin or ibuprofen).

Taking MicardisPlus with food and drink

You can take MicardisPlus tablets with or without food.

Pregnancy and breast-feeding

Pregnancy

You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking MicardisPlus before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of MicardisPlus. MicardisPlus is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. MicardisPlus is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.

Driving and using machines

No information is available on the effect of MicardisPlus on the ability to drive or operate machinery. Some people feel dizzy or tired when they are treated for high blood pressure. If you feel dizzy or tired, do not drive or operate machinery.

Important information about some of the ingredients of MicardisPlus

MicardisPlus contains milk sugar (lactose) and sorbitol.

If you are intolerant to some sugars, consult your doctor before taking MicardisPlus.

How To Take Micardisplus

Always take MicardisPlus exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

The usual dose of MicardisPlus is one tablet a day. Try to take the tablet at the same time each day. You can take MicardisPlus with or without food. The tablets should be swallowed with some water or other non-alcoholic drink. It is important that you take MicardisPlus every day until your doctor tells you otherwise.

If your liver is not working properly, the usual dose should not exceed 40 mg/12.5 mg once a day.

If you take more MicardisPlus than you should

If you accidentally take too many tablets, contact your doctor, pharmacist, or your nearest hospital emergency department immediately.

If you forget to take MicardisPlus

If you forget to take a dose, do not worry. Take it as soon as you remember then carry on as before. If you do not take your tablet on one day, take your normal dose on the next day. Do not take a double dose to make up for forgotten individual doses.

If you have further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

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

These side effects may occur with certain frequencies, which are defined as follows:

• very common: affects more than 1 user in 10


• common: affects 1 to 10 users in 100


• uncommon: affects 1 to 10 users in 1,000


• rare: affects 1 to 10 users in 10,000


• very rare: affects less than 1 user in 10,000


• not known: frequency cannot be estimated from the available data.

Common side effects may include:

Dizziness

Uncommon side effects may include:

Decreased blood potassium levels; anxiety; fainting (syncope); sensation of tingling, pins and needles (paraesthesia); feeling of spinning (vertigo); fast heart beat (tachycardia), heart rhythm disorders, low blood pressure, a sudden fall in blood pressure when you stand up; shortness of breath (dyspnoea); symptoms of an upset stomach such as diarrhoea; dry mouth, flatulence; back pain, muscle spasm, muscle pain; erectile dysfunction (inability to get or keep an erection); chest pain, increased blood uric acid levels.

Rare side effects may include:

Inflammation of the lung (bronchitis); feeling sad (depression); difficulty falling asleep (insomnia); impaired vision; difficulty breathing; abdominal pain, constipation, bloating (dyspepsia), feeling sick; abnormal liver function; rapid swelling of the skin and mucosa (angioedema), redness of the skin (erythema); allergic reactions such as itching or rash; increased sweating, hives (urticaria); joint pain (arthralgia) and pain in extremities, muscle cramps; flu-like-illness; pain; increased levels of uric acid, low levels of sodium, increased levels of creatinine, hepatic enzymes or creatine phosphokinase in the blood.

Side effects of unknown frequency may include:

Sore throat, inflamed sinuses; inflammation of the stomach (gastritis)

Telmisartan

In patients taking telmisartan alone the following additional side effects have been reported:

Side effects of unknown frequency may include:

Upper respiratory tract infection (e.g. sore throat, inflamed sinuses, common cold), urinary tract infections; increase in certain white blood cells (eosinophilia), deficiency in red blood cells (anaemia), low platelet count (thrombocytopenia); serious allergic reaction (e.g. hypersensitivity, anaphylactic reaction, drug rash); high potassium levels; slow heart rate (bradycardia); upset stomach; eczema (a skin disorder); inflammation of the tendons; kidney impairment including acute kidney failure; weakness; decreased haemoglobin (a blood protein), sepsis* (often called “blood poisoning”, is a severe infection with whole-body inflammatory response which can lead to death).

*In a long-term study involving more than 20,000 patients, more patients treated with telmisartan experienced sepsis compared with patients who received no telmisartan. The event may have happened by chance or could be related to a mechanism currently not known.

Hydrochlorothiazide

In patients taking hydrochlorothiazide alone the following additional side effects have been reported:

Side effects of unknown frequency may include:

Inflammation of the salivary gland; decreases in the number of cells in the blood, including low red and white blood cell count, low platelet count (thrombocytopenia); serious allergic reactions (e.g. hypersensitivity, anaphylactic reaction), inflammation of blood vessels (vasculitis necrotising), decreased or loss of appetite; restlessness, weakness, light-headedness; blurred or yellowing of vision; inflamed pancreas, upset stomach; yellowing of the skin or eyes (jaundice); skin disorders such as inflamed blood vessels in the skin; increased sensitivity to sunlight, or blistering and peeling of the top layer of skin (toxic epidermal necrolysis); kidney inflammation or impaired kidney function; fever; impaired electrolyte balance, high blood cholesterol levels, decreased blood volume, glucose in the urine (glycosuria),
increased levels of glucose, or fat in the blood.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How To Store Micardisplus

Keep out of the reach and sight of children.

Do not use MicardisPlus after the expiry date which is stated on the carton after “EXP”. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions. You should store your medicine in the original package in order to protect the tablets from moisture.

Occasionally, the outer layer of the blister pack separates from the inner layer between the blister pockets. You do not need to take any action need be taken if this happens.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What MicardisPlus contains

The active substances are telmisartan and hydrochlorothiazide. Each tablet contains 80 mg telmisartan and 25 mg hydrochlorothiazide.

The other ingredients are lactose monohydrate, magnesium stearate, maize starch, meglumine, microcrystalline cellulose, povidone, yellow iron oxide (E172), sodium hydroxide, sodium starch glycollate (type A), sorbitol (E420).

What MicardisPlus looks like and contents of the pack

MicardisPlus 80 mg/25 mg tablets are yellow and white, oval-shaped, two-layer tablets engraved with the company logo and the code ‘H9’.

MicardisPlus is available in blister packs containing 14, 28, 56, or 98 tablets, or unit dose blister packs containing 28 x 1, 30 x 1 or 90 x 1 tablets.

Not all pack sizes may be available in your country.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH

Binger Str. 173

D-55216 Ingelheim am Rhein

Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG

Binger Str. 173

D-55216 Ingelheim am Rhein

Germany

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

United Kingdom

Boehringer Ingelheim Ltd.

Tel:+44 1344 424 600

This leaflet was last approved in 04/2010.

Detailed information on this medicine is available on the European Medicines Agency (EMA) web site: http://www.ema.europa.eu/.

70709-06

Pegvisomant

Class: Somatotropin Antagonists
VA Class: HS701
Brands: Somavert

Introduction

Selective, competitive somatotropin receptor antagonist; biosynthetic analog of human growth hormone (somatotropin).^{1 3 5 6 7}

Uses for Pegvisomant

Acromegaly

Treatment of acromegaly in patients who have had inadequate responses to or are not candidates for surgical resection, pituitary irradiation, and/or other medical therapies (e.g., bromocriptine mesylate, octreotide).^{1 3 4 4}

Improves certain manifestations of acromegaly (decreases in ring size and a composite measure of soft tissue swelling, arthralgia, headache, excessive perspiration, and fatigue).^{1 3 6}

Pegvisomant Dosage and Administration

General

• 
  

  The goal of therapy in patients with acromegaly is to reduce serum insulin growth factor-I (IGF-I) concentrations to normal levels.^{1 3 4} Monitor serum IGF-I concentrations at least semiannually after such concentrations have normalized.^{1 10}

  
  

Administration

Sub-Q Administration

Administer by sub-Q injection into the upper arm, upper thigh, abdomen, or buttocks.^{1 2}

Reconstitution

Reconstitute by adding 1 mL of the manufacturer-supplied diluent (sterile water for injection) to a vial labeled as containing 10, 15, or 20 mg of pegvisomant protein to provide a solution containing 10, 15, or 20 mg/mL, respectively.^{1 2} Roll vial gently between the palms until powder is completely dissolved and a clear solution is attained;^{1 2} discard any unused diluent.^{2 10} Do not shake vial since denaturation of the protein may occur.^{1 2 10}

Dosage

Dosage of pegvisomant is expressed in terms of pegvisomant protein.¹ Each mg of pegvisomant protein contains approximately 1 unit of activity.^{1 10}

Adults

Acromegaly

Sub-Q

Loading dose: 40 mg; administer under medical supervision.^{1 2 6} Subsequently, self-inject 10 mg once daily.^{1 2 6}

Adjust dosage in 5-mg increments (or 5-mg decrements, if serum IGF-I concentrations are below normal) at intervals of no less than 4–6 weeks until the desired effect on serum IGF-I concentrations is observed or a maximum dosage of 30 mg daily is reached.^{1 5 6}

Not known if an increased dosage would be of benefit in patients who continue to have symptoms after achieving normal IGF-I levels.¹

Prescribing Limits

Adults

Acromegaly

Sub-Q

Maximum daily dosage 30 mg.^{1 5 6}

Special Populations

No special population recommendations at this time.^{1 10}

Cautions for Pegvisomant

Contraindications

• 
  

  Known hypersensitivity to pegvisomant or any ingredient in the formulation.¹ Vial stopper contains natural rubber latex,^{1 2} which may cause sensitivity reactions in susceptible individuals.^{8 9}

  
  

Warnings/Precautions

General Precautions

Hepatic Effects

Elevations in serum aminotransferase (transaminase) concentrations (i.e., AST [SGOT], ALT [SGPT]) >3 times but not >10 times the ULN^{1 3} reported.¹

Perform periodic liver function tests (i.e., serum aminotransferase, total bilirubin, and alkaline phosphatase concentrations) prior to and during therapy (i.e., monthly for first 6 months, every 3 months for the next 6 months, then every 6 months for the next year) in patients with normal liver function at baseline.¹ In patients who develop certain abnormalities in liver function tests (elevations 3–5 times the ULN without signs or symptoms of hepatotoxicity or an increase in total bilirubin) during therapy, continue the drug with caution.¹ Monitor liver function tests weekly, and perform a comprehensive hepatic examination to investigate possible alternative causes of liver dysfunction.¹

If serum aminotransferase elevations ≥3 times the ULN occur in conjunction with any increase in total bilirubin concentration or if liver function test elevations of ≥5 times the ULN occur (with or without manifestations of hepatitis or liver injury), discontinue therapy immediately.¹ In addition, undertake a thorough examination of hepatic function in such patients, including serial liver function tests to determine if and when liver dysfunction resolves.¹ If liver function test results normalize, consider cautious reinitiation of pegvisomant therapy, with frequent monitoring of liver function tests.¹

In patients who develop manifestations suggestive of hepatitis or other liver injury (e.g., jaundice, bilirubinuria, fatigue, nausea, vomiting, upper right quadrant pain, ascites, unexplained edema, easy bruising), a comprehensive hepatic examination should be performed and the drug discontinued if liver injury is confirmed.^{1 2}

For information about initiation of treatment in patients with hepatic impairment, see Hepatic Impairment under Cautions.

Tumor Growth

Progressive tumor growth occurred in 2 patients with underlying somatotropin-secreting pituitary tumors receiving pegvisomant in clinical trials.^{1 5}

Carefully monitor patients who have pituitary growth hormone-secreting neoplasms with periodic imaging scans of the sella turcica.^{1 10}

Endocrine and Metabolic Effects

Monitor patients with acromegaly and diabetes mellitus carefully for hypoglycemia and reduce dosage of insulin and/or antidiabetic drugs as necessary.¹

Functional growth hormone deficiency may occur despite the presence of elevated serum growth hormone concentrations.¹ Monitor patients for signs and symptoms of growth hormone deficiency.¹ Adjust dosage using serum IGF-I concentrations to maintain such concentrations within the age-adjusted normal range.¹

Specific Populations

Pregnancy

Category B.

Lactation

Not known whether pegvisomant is distributed in milk.¹ Use with caution.¹

Pediatric Use

Safety and efficacy not established in children.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently from younger adults.¹

Hepatic Impairment

Use with caution in patients with preexisting mild hepatic impairment (elevations in serum aminotransferase, total bilirubin, or alkaline phosphatase concentrations not >3 times the ULN).¹ Monitor liver function tests frequently (monthly for at least 1 year after initiation of therapy, then every 6 months for the next year) during therapy in such patients.¹ Do not initiate therapy in patients with liver function test elevations >3 times the ULN until a comprehensive examination establishes the cause of liver dysfunction.¹ Determine if cholelithiasis or choledocholithiasis is present, particularly in patients with a history of prior therapy with somatostatin analogs.^{1 10} If therapy is implemented in these patients, monitor liver function tests and clinical symptoms very closely.¹ (See Hepatic Effects under Cautions.)

Common Adverse Effects

Abnormal liver function test results,¹ accidental injury,^{1 5} back pain,^{1 5} chest pain,¹ diarrhea,^{1 3 5} dizziness,¹ flu syndrome,^{1 5} hypertension,¹ infection, ^{1 5} injection site reaction,^{1 3 5} nausea,^{1 3} pain, ^{1 3 5} paresthesia,¹ peripheral edema,¹ sinusitis.^{1 5}

Interactions for Pegvisomant

Specific Drugs or Laboratory Tests

Drug or Test	Interaction	Comments
Antidiabetic agents	Improved insulin sensitivity and glucose tolerance resulting from reduction in IGF-I concentrations1 6 10 11	Adjust dosage of concurrent antidiabetic therapy as necessary in patients with acromegaly and diabetes mellitus1 10
Opiate agonists	Decreased efficacy (higher serum concentrations of pegvisomant needed to produce appropriate suppression of IGF-I)1 10	Increased dosage of pegvisomant may be required1 10
Test, growth hormone concentrations	Pegvisomant cross-reacts with endogenous growth hormone, causing overestimation of endogenous growth hormone concentrations1 10 Even when accurately measured, growth hormone concentrations usually increase during pegvisomant therapy1 6 11	Monitor treatment and adjust dosage based on serum IGF-I concentrations1

Pegvisomant Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations usually attained 33–77 hours after administration.¹ The relative bioavailability of a 20-mg sub-Q dose was 57% compared with a 10-mg IV dose.¹

Onset

Reduction in serum IGF-I concentrations and increase in GH concentrations by week 2 of therapy.¹

Duration

Serum GH concentrations remained stable during 18 months of therapy.^{1 5}

Distribution

Extent

Mean apparent volume of distribution is 7L, suggesting that the drug does not distribute extensively into tissues.¹

Elimination

Elimination Route

<1% of an administered dose is recovered in urine over 96 hours.¹ Elimination route not determined in humans.¹

Half-life

Mean serum half-life approximately 6 days.¹

Stability

Storage

Parenteral

Powder for Sub-Q Injection

2–8°C; protect from freezing.¹ Use within 6 hours following reconstitution.¹

ActionsActions

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  Binds to somatotropin receptors and competitively blocks binding of endogenous growth hormone, thereby interfering with signal transduction and the subsequent production of insulin-like growth factor I (IGF-I).^{1 3 6 7} IGF-I mediates most of the somatotropic effects of growth hormone.^{1 3 6 7}

  
  


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  Produces a rapid decrease in serum IGF-I and other growth hormone-responsive serum proteins (e.g., IGF binding protein-3 [IGFBP-3], acid labile subunit of IGFBP-3) in patients with acromegaly.^{1 3 5 6}

  
  

Advice to Patients

• 
  

  Importance of patients understanding instructions for proper storage, preparation, and injection technique.²

  
  


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  Importance of omitting missed dose and administering next dose at regularly scheduled time.²

  
  


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  Importance of monitoring for signs and symptoms of functional growth hormone deficiency.^{1 2} Importance of obtaining periodic determinations of serum insulin growth factor-I (IGF-I) concentrations in order to achieve and maintain therapeutic response.^{1 2}

  
  


• 
  

  Importance of obtaining serial monitoring of liver function tests and of discontinuing therapy and reporting signs or symptoms of possible liver dysfunction (e.g., jaundice, dark urine, light stools, loss of appetite, nausea, fatigue, abdominal pain) to clinicians immediately.^{1 2}

  
  


• 
  

  Importance of alerting clinician about allergy to latex.^{1 2}

  
  


• 
  

  Importance of informing clinicians of concomitant conditions (e.g., diabetes mellitus, history of or current liver dysfunction) and existing or contemplated concomitant therapy, including prescription and OTC drugs (particularly insulin, other antidiabetic agents, or opiate agonists).^{1 2 10} (See Specific Drugs under Interactions.)

  
  


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  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 2}

  
  


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  Importance of informing patients of other important precautionary information.¹ (See Cautions).

  
  

Preparations

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

Pegvisomant

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for subcutaneous use	10 mg (as protein)	Somavert (with 10 mL sterile water for injection diluent; may contain natural latex components in packaging)	Pfizer
		15 mg (as protein)	Somavert (with 10 mL sterile water for injection diluent; may contain natural latex components in packaging)	Pfizer
		20 mg (as protein)	Somavert (with 10 mL sterile water for injection diluent; may contain natural latex components in packaging)	Pfizer

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 September 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer. Somavert (pegvisomant) for injection prescribing information. Kalamazoo, MI; 2003 Jun.

2. Pfizer. Somavert (pegvisomant) for injection patient information. Kalamazoo, MI; 2003 Jun.

3. Trainer PJ, Drake WM, Katznelson L et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med. 2000; 342:1171-7. [IDIS 444363] [PubMed 10770982]

4. Utiger RD. Treatment of acromegaly. N Engl J Med. 2000; 342:1210-1. [IDIS 444364] [PubMed 10770989]

5. van der Lely AJ, Hutson RK, Trainer PJ et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet. 2001; 358:1754-9. [PubMed 11734231]

6. Pfizer. Somavert (pegvisomant) for injection general review. Kalamazoo, MI; 2003 Mar.

7. Friend KE. Cancer and the potential place for growth hormone receptor antagonist therapy. Growth Horm IGF Res. 2001; 11(Suppl A):S121-3.

8. Food and Drug Administration. Amended economic impact analysis of final rule requiring use of labeling on natural rubber containing devices; 21 CFR Part 801. Final rule. (Docket no. 96N-0119). Fed Regist. 1998; 63:50660-704.

9. Food and Drug Administration. Latex-containing devices; user labeling. 21 CFR Part 801. Proposed rule. (Docket No. 96N-0119). Fed Regist. 1996; 61:32617-21.

10. Pfizer, New York, NY: Personal communication.

11. Parkinson C, Drake WM, Roberts ME et al. A comparison of the effects of pegvisomant and octreotide on glucose, insulin, gastrin, cholecystokinin, and pancreatic polypeptide responses to oral glucose and a standard mixed meal. J Endocrinol Metab. 2002; 87:1797-1804.

More Pegvisomant resources

• Pegvisomant Side Effects (in more detail)
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• Pegvisomant Drug Interactions
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• Pegvisomant MedFacts Consumer Leaflet (Wolters Kluwer)


• Pegvisomant Professional Patient Advice (Wolters Kluwer)


• pegvisomant Subcutaneous Advanced Consumer (Micromedex) - Includes Dosage Information


• Somavert Prescribing Information (FDA)


• Somavert Consumer Overview

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