Sargramostim

Class: Hematopoietic Agents
VA Class: BL400
Molecular Formula: C₆₃₉H₁₀₀₂O₁₉₆S₈
CAS Number: 123774-72-1
Brands: Leukine

Introduction

Biosynthetic hematopoietic agent that affects the proliferation and differentiation of a variety of hematopoietic progenitor cells; a yeast-derived (Saccharomyces cerevisiae) recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF).^{1 5 131 132}

Uses for Sargramostim

Autologous and Allogeneic Bone Marrow Transplantation

Acceleration of myeloid recovery in adults with non-Hodgkin’s lymphoma, acute lymphocytic (lymphoblastic) leukemia (ALL), or Hodgkin’s disease undergoing cytotoxic chemotherapy and autologous bone marrow transplantation (BMT).^{1 5 7 8 12 55 75 77 78 91 96 173 174 196}

Acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLA-matched related donors.^{1 5 21 112 173} Also has been used to accelerate myeloid recovery in patients receiving allogeneic BMT from unrelated donors†.²¹

Designated an orphan drug by FDA for use in BMT patients for the management of neutropenia associated with BMT and for the promotion of early engraftment.²²²

Peripheral Blood Progenitor Cell Transplantation

Mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis.¹

Acceleration of myeloid engraftment following autologous peripheral blood progenitor cell (PBPC) transplantation.¹

Bone Marrow Transplantation Failure or Engraftment Delay

Prolongation of survival in adults who have undergone allogeneic or autologous BMT and in whom engraftment is delayed or has failed.^{1 18 19} Designated an orphan drug by FDA for use in BMT patients for the treatment of delayed or failed engraftment.²²²

Has been used in a limited number of patients to reduce the period of severe myelosuppression and the risk of infectious complications in patients with delayed engraftment following PBPC transplantation†.¹⁹

Leukemias

Acceleration of neutrophil recovery and reduction of the incidence of severe and life-threatening infections following induction chemotherapy in adults ≥55 years of age with acute myelogenous leukemia (AML);^{1 220} safety and efficacy not established in individuals <55 years of age.¹

Designated an orphan drug by FDA for use in patients with AML to reduce neutropenia and leukopenia and to increase survival.²²²

Use of biosynthetic GM-CSFs in patients with acute leukemia has been controversial, since results of in vitro studies indicate that certain leukemic cell lines have receptors for GM-CSF and that these drugs may have a stimulatory effect on leukemic blast cells in vitro.^{49 52 54 96 203} Some experts state that use of sargramostim in the treatment of myeloid leukemias should be considered investigational and undertaken with caution.^{49 51 88 96 201}

Myelodysplastic Syndromes and Aplastic Anemia

Has been used to increase leukocyte counts in adults with myelodysplastic syndrome† (MDS) classified as refractory anemia (RA), refractory anemia with excess blasts (RAEB), or refractory anemia with excess blasts in transformation (RAEB-T);^{5 43 44 45 47 48 77 91 129 150 151 171 172} however, it is unclear whether sargramostim will alter (either increase or decrease) the rate of progression to AML or alter the usually fatal outcome of the disease.^{5 10 43 44 45 47 129 150 151 172 189} Generally should be used under protocol conditions.^{201 206}

Has been used with some success to increase leukocyte counts in a limited number of adults and adolescents ≥15 years of age with moderate to severe aplastic anemia†.^{129 134} Generally should be used under protocol conditions.^{201 206}

Neutropenia Associated with HIV Infection and Antiretroviral Therapy

Treatment to correct or minimize HIV-associated neutropenia† or drug-induced neutropenia (e.g., neutropenia associated with use of zidovudine, interferon alfa, and/or cytotoxic chemotherapy) in HIV-infected patients†.^{5 34 35 36 37 38 39 96 111 136 138 149 158 159 160 161 189 217 218 219 229 231}

Congenital, Cyclic, and Idiopathic Neutropenias

Has been used with variable success in an effort to increase neutrophil counts in patients with various primary neutropenias, including congenital neutropenia†,^{59 186} acquired idiopathic neutropenia†,⁶³ and glycogen storage disease type Ib†.⁹⁷ Filgrastim may be more effective than sargramostim and other biosynthetic GM-CSFs, since filgrastim results in more consistent increases in neutrophil counts and does not cause eosinophilia.^{5 58 59 77 101}

Chemotherapy-induced Neutropenia

Treatment to increase neutrophil counts and decrease the risk of infectious complications† in patients with malignancies receiving myelosuppressive antineoplastic therapy.^{5 23 24 26 27 28 29 30 31 33 75 81 87 96 109 110 114 115 120 144 162 163 164 165 166 167 169 184 187 198 199} Has been used prophylactically in a limited number of children with refractory solid tumors receiving myelosuppressive therapy†.³⁰

Filgrastim has been used more extensively to date than biosynthetic GM-CSFs in patients with chemotherapy-induced neutropenia;^{96 168} intermittent low-grade fevers reported in a large proportion of patients receiving GM-CSF therapy^{5 29 71 95 108 201} but not in those receiving filgrastim therapy.²⁰¹

Sargramostim Dosage and Administration

Administration

Administer by IV infusion^{1 5 30 95 103} or sub-Q injection.^{1 5 34 59 67 95 104} Sub-Q injection is most convenient for self-administration and especially useful for prolonged maintenance therapy.²⁰¹

Do not administer sargramostim within 24 hours before or after radiation therapy or chemotherapy.¹

Intended for use under the guidance and supervision of a clinician; may be self-administered if clinician determines that patient and/or caregiver is competent to safely administer drug after appropriate instruction.¹ (See Advice to Patients.)

IV Administration

For drug compatibility information, see Compatibility under Stability.

IV infusion using an in-line filter is not recommended.^{1 206} Adsorption of the drug could occur.^{1 206}

Reconstitution

Reconstitute vials containing 250 mcg of sargramostim powder with 1 mL of sterile or bacteriostatic water for injection to provide a solution containing 250 mcg/mL.¹ Direct diluent at the side of the vial and gently swirl contents to avoid foaming.¹ Avoid shaking or excessive agitation of vial.¹ Use care to eliminate air bubbles from the needle hub of the syringe containing the diluent to ensure the correct final concentration.¹

Commercially available vials of sargramostim lyophilized powder for injection are for single use only.¹ Do not reenter or reuse vials.¹

Dilution

For IV infusion, dilute sargramostim injection or further dilute reconstituted solutions of sargramostim powder for injection in 0.9% sodium chloride injection.¹

If sargramostim is diluted to a final concentration of <10 mcg/mL, add albumin human to minimize adsorption of the drug to drug delivery system components.¹ Add 1 mg of albumin human per 1 mL of 0.9% sodium chloride injection (e.g., dilute 1 mL of 5% albumin human in 50 mL of 0.9% sodium chloride injection).¹

Rate of Administration

Patients undergoing BMT: Administer by IV infusion over 2 hours.^{1 5 8 21}

For mobilization of hematopoietic progenitor cells or for acceleration of myeloid engraftment following autologous PBPC transplantation: Administer by continuous IV infusion over 24 hours.¹

For BMT failure or engraftment delay: Administer by IV infusion over 2 hours.^{1 5 18 19}

Patients with AML: Administer by IV infusion over 4 hours.¹

Sub-Q Administration

For sub-Q injection, administer sargramostim injection or reconstituted solutions without further dilution.¹

Reconstitution

Reconstitute vials containing 250 mcg of sargramostim powder for injection with 1 mL of sterile or bacteriostatic water for injection to provide a solution containing 250 mcg/mL.¹ Direct diluent at the side of the vial and gently swirl contents to avoid foaming.¹ Avoid shaking or excessive agitation of vial.¹ Use care to eliminate air bubbles from the needle hub of the syringe containing the diluent to ensure the correct final concentration.¹

Commercially available vials of sargramostim lyophilized powder for injection are for single use only.¹ Do not reenter or reuse vials.¹

Dosage

If a severe adverse reaction occurs, reduce dosage by 50% or temporarily discontinue therapy until the reaction abates.¹

Discontinue therapy if blast cells appear on the leukocyte differential or if disease progression occurs.^{1 5}

Temporarily discontinue therapy or reduce dosage by 50% if the ANC is >20,000/mm³ or if the platelet count is >500,000/mm³.¹ Base decision to interrupt therapy or reduce dosage on the clinical condition of the patient.¹

Pediatric Patients

Neutropenia Associated with HIV Infection and Antiretroviral Therapy†

IV or Sub-Q

Adolescents: Dosage of 250 mcg/m² administered by IV infusion or sub-Q injection once daily for 2–4 weeks has been used.²¹⁸

Adults

Autologous or Allogeneic Bone Marrow Transplantation

IV

250 mcg/m² once daily, administered by IV infusion over 2 hours.^{1 5 8 21} Initiate therapy 2–4 hours after infusion of bone marrow (but no sooner than 24 hours after the last course of radiation therapy or the last dose of chemotherapy).^{1 5 8 21} Do not initiate therapy until the posttransplantation ANC is <500/mm³.¹ Continue until the ANC is >1500/mm³ for 3 consecutive days.¹

Peripheral Blood Progenitor Cell Transplantation

Mobilization of Hematopoietic Progenitor Cells

IV or Sub-Q

250 mcg/m² daily, administered by continuous IV infusion over 24 hours or by sub-Q injection once daily.¹ Continue therapy throughout the period of PBPC collection.¹ Usually, initiate PBPC collection by day 5 of therapy and perform daily until protocol-specified targets are achieved.¹

Reduce dosage by 50% if the leukocyte count increases to >50,000/mm³.¹

Administration Following Reinfusion of PBPC Collection

IV or Sub-Q

To accelerate myeloid engraftment following autologous PBPC transplantation, 250 mcg/m² daily, administered by continuous IV infusion over 24 hours or by sub-Q injection once daily.¹ Initiate immediately following infusion of PBPC and continue until the ANC is >1500/mm³ for 3 consecutive days.¹

Bone Marrow Transplantation Failure or Engraftment Delay

IV

Initially, 250 mcg/m² administered by IV infusion over 2 hours once daily^{1 5 18 19} for 14 consecutive days.^{1 5 19} Discontinue for 7 consecutive days.^{1 5 19}

If engraftment has not occurred after this 7-day interval, administer a second course of therapy.^{1 5} For the second course of therapy, administer 250 mcg/m² by IV infusion over 2 hours once daily for 14 consecutive days.^{1 5} Discontinue for 7 consecutive days.^{1 5}

If engraftment has not occurred after this 7-day interval, administer a third course of therapy.^{1 5} For the third course of therapy, administer 500 mcg/m² by IV infusion over 2 hours once daily for 14 consecutive days.^{1 5}

Leukemias

Acute Myelogenous Leukemia

IV

Initially, 250 mcg/m² administered by IV infusion over 4 hours once daily.¹ Initiate therapy on approximately day 11 or 4 days following completion of induction therapy;¹ use only if the bone marrow is hypoplastic with <5% blast cells on day 10.¹ If a second cycle of induction chemotherapy is necessary, administer sargramostim therapy approximately 4 days after completion of chemotherapy;¹ use only if the bone marrow is hypoplastic with <5% blast cells.¹ Continue sargramostim until the ANC is >1500/mm³ for 3 consecutive days or for a maximum of 42 days.¹

Temporarily discontinue therapy or reduce dosage by 50% if the ANC is >20,000/mm³.¹

Discontinue therapy immediately if leukemia regrowth occurs.¹

Myelodysplastic Syndromes† andAplastic Anemia†

Myelodysplastic Syndromes†

IV

Dosages of 15–500 mcg/m² once daily, administered by IV infusion over 1–12 hours, have been used.^{44 129 172} Alternatively, dosages of 30–500 mcg/m² daily, administered by continuous IV infusion over 24 hours, have been used.^{47 48}

Aplastic Anemia†

IV

Dosages of 15–480 mcg/m² once daily, administered by IV infusion over 1–12 hours, have been used.¹²⁹ Alternatively, dosages of 120–500 mcg/m² daily, administered by continuous IV infusion over 24 hours, have been used.¹³⁴

Neutropenia Associated with HIV Infection and Antiretroviral Therapy†

IV or Sub-Q

Dosage of 250 mcg/m² administered by IV infusion or sub-Q injection once daily for 2–4 weeks has been used.²¹⁸

Prescribing Limits

Adults

Bone Marrow Transplantation Failure or Engraftment Delay

IV

Maximum 3 courses of therapy (500 mcg/m² daily during the third course) recommended.^{1 5}

Leukemias

Acute Myelogenous Leukemia

IV

Maximum 250 mcg/m² once daily for 42 days.¹

Cautions for Sargramostim

Contraindications

• 
  

  Excessive (i.e., ≥10%) leukemic myeloid blasts in the bone marrow or peripheral blood.^{1 5}

  
  


• 
  

  Known hypersensitivity to sargramostim, any ingredient in the formulation, or yeast-derived products.¹

  
  


• 
  

  Concomitant use of chemotherapy or radiation therapy.¹

  
  

Warnings/Precautions

Warnings

Fluid Retention

Possible edema, capillary leak syndrome, and pleural and/or pericardial effusion.^{1 5 8} Possible precipitation or aggravation of fluid retention, especially in patients with preexisting pleural and pericardial effusions.¹

Monitor body weight and hydration status during therapy.²⁰¹

Use with caution in patients with preexisting fluid retention, pulmonary infiltrates, or CHF.^{1 5}

Respiratory Effects

Possible sequestration of granulocytes in the pulmonary circulation; dyspnea reported occasionally.¹

Use with caution in patients with preexisting lung disease and/or hypoxia.^{1 5}

Give special attention to respiratory symptoms that develop during or immediately following administration.¹ If dyspnea develops during administration, decrease the IV infusion rate by 50%;^{1 5} administer oxygen to provide symptomatic relief if necessary.^{5 106 108} If respiratory symptoms worsen despite reduction in the infusion rate, discontinue the infusion.¹ Subsequent doses may be administered according to the usual dosage schedule with careful monitoring.¹

Cardiovascular Effects

Possible transient, reversible supraventricular arrhythmia.¹

Use with caution in patients with preexisting cardiac disease.¹

Increased incidence of syncope with or without hypotension reported with edetate disodium (EDTA)-containing sargramostim injection (formulation no longer commercially available in the US).^{232 233 234} (See Preparations.) A similar increase in such adverse effects not observed with commercially available sargramostim lyophilized powder for injection (without EDTA).^{232 233 234}

Sensitivity Reactions

Serious allergic or anaphylactic reactions reported rarely.¹

Discontinue sargramostim and initiate appropriate therapy if such reactions occur.¹

General Precautions

First-dose Reaction

Syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia reported following the first dose of sargramostim in each treatment cycle.¹ Manifestations usually resolve with symptomatic treatment and generally do not recur with subsequent doses in the same treatment cycle.¹

If a first-dose reaction occurs, provide symptomatic treatment (e.g., oxygen, IV fluids, acetaminophen or NSAIA).^{106 108}

Chemotherapy and Radiation Therapy

Safety and efficacy of concomitant radiation therapy or myelosuppressive antineoplastic agents not established.¹ Do not administer sargramostim within 24 hours of radiation therapy or a dose of a myelosuppressive antineoplastic agent.¹ (See Interactions.)

Patients who previously received extensive radiation therapy or were exposed to multiple myelotoxic agents (e.g., alkylating agents, anthracycline antibiotics, antimetabolites) may have a limited response to sargramostim therapy following autologous BMT.^{1 93 122}

Patients Receiving Purged Bone Marrow

Is effective in accelerating myeloid recovery following BMT when the marrow is purged by anti-B lymphocyte monoclonal antibodies.¹ Patients receiving chemically purged marrow may not respond to sargramostim if the chemical agents cause a clinically important decrease in the number of responsive hematopoietic progenitors;¹ if the purging process preserves a sufficient number of progenitors (>1.2 × 10⁴ per kg), sargramostim may provide a beneficial effect on myeloid engraftment.¹

Excessive Hematologic Effects

Possible rapid rise in leukocyte count.^{1 134} Marked leukocytosis (leukocyte count ≥100,000/mm³) reported occasionally.⁴⁷ Various effects on platelet counts reported in patients receiving biosynthetic GM-CSFs.^{5 11 24 29 36 94 108 109 122 129}

Monitor CBC and platelet counts twice weekly during therapy to avoid potential complications of excessive leukocytosis and/or thrombocytosis.^{1 5 95} Temporarily discontinue therapy or reduce dosage by 50% if the ANC is >20,000/mm³ or if the platelet count is >500,000/mm³.¹

Effect on Malignant Cells

The possibility that sargramostim could act as a growth factor for any tumor type, particularly myeloid malignancies, has not been excluded.^{1 54 72}

Caution recommended in patients with any malignancy with myeloid characteristics.^{1 43 44 45 47 49 51 88 96 129 215 216} Discontinue therapy if disease progression is detected in patients with non-Hodgkin’s lymphoma, ALL, or Hodgkin’s disease.¹

Has been used in patients with MDS† or AML without evidence of increased relapse rates;^{1 43 44 45 47 48 49 52 54 91 96 129 220} however, regrowth of leukemic cells and an increase in leukemic blasts have occurred in a few patients with AML who were receiving the drug.⁵⁴

When used for mobilization of hematopoietic progenitor cells, possible release of tumor cells from the marrow and subsequent collection in the leukapheresis product; effect of reinfusion of tumor cells not well studied and limited data available to date are inconclusive.¹

Laboratory Monitoring

Perform CBC and platelet counts prior to initiation of therapy and routinely (e.g., twice weekly) during therapy.^{1 5 95}

Immunogenicity

Development of anti-GM-CSF antibodies reported occasionally in patients receiving sargramostim.^{1 100 212} Consider the possibility that formation of anti-GM-CSF antibodies during sargramostim therapy theoretically could result in drug-induced neutropenia, neutralization of endogenous GM-CSF activity, or decreased effectiveness of sargramostim.^{1 87 100}

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether sargramostim is distributed into milk; use only if clearly needed.^{1 193}

Pediatric Use

Safety and efficacy not established.^{1 5 30 42 59} However, no unusual adverse effects reported during use in children 4 months to 18 years of age (at daily dosages of 60–1000 mcg/m² IV or 4–1500 mcg/m² sub-Q).^{1 5 30 42 59} Some evidence that children may tolerate higher dosages of biosynthetic GM-CSF compared with adults in the treatment of chemotherapy-induced neutropenia†.^{5 30 82}

Avoid administration of solutions containing benzyl alcohol (sargramostim injection, sargramostim powder reconstituted with bacteriostatic water for injection) in neonates.¹ Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) have been associated with toxicity in neonates.^{224 225 226 227 228}

Geriatric Use

Experience in patients ≥65 years of age limited to those with AML.¹ Analysis of general trends in safety and efficacy demonstrate a response in geriatric patients similar to that in younger adults.^{76 1} The possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.¹

Hepatic Impairment

Possible increased concentrations of serum bilirubin and hepatic enzymes.^{1 21 44}

Monitor hepatic function every other week during therapy in patients with hepatic impairment.^{1 206}

Renal Impairment

Possible increased S_cr.^{1 21 44}

Monitor renal function every other week during therapy in patients with renal impairment.^{1 206}

Common Adverse Effects

Fever, asthenia, chills, headache, nausea, diarrhea, myalgia, bone pain.^{1 5 47 55 73 87 112 134 172}

Interactions for Sargramostim

Specific Drugs

Drug	Interaction	Comments
Antineoplastic agents	Sensitivity of rapidly dividing cells to cytotoxic chemotherapy may be increased1	Safety and efficacy of concomitant administration not established.1 Administration of sargramostim within 24 hours of administration of chemotherapy is not recommended1
Didanosine	No evidence of synergism against HIV133 200
Myeloproliferative agents (e.g., corticosteroids, lithium)	Possible additive myeloproliferative effects1	Use with caution1
Zalcitabine	No evidence of synergism against HIV133 200
Zidovudine	Possible pharmacologic and/or pharmacokinetic interaction resulting in additive or synergistic antiretroviral effect3 5 35 39 133 135 136 137 149 157 158 161 200

Sargramostim Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations are attained during or immediately after completion of an IV infusion.¹

Rapidly absorbed following sub-Q injection,^{1 67 104} with peak serum concentrations generally attained within 1–4 hours.^{1 67 104}

Duration

In patients with sargramostim-associated leukocytosis or thrombocytosis, excessive blood cell counts usually return to normal or baseline levels within 2–10 days following interruption of therapy.^{1 11 43 44 47 87 91 94 121 129}

Distribution

Extent

Murine GM-CSF is distributed into various tissues including liver, spleen, and kidney in mice.¹⁰²

Not known whether sargramostim distributes into CSF¹⁹³ or milk or crosses the placenta in humans.^{1 193}

Elimination

Metabolism

Not known whether sargramostim is metabolized.¹⁹³

Elimination Route

Elimination route not known.¹⁹³

Half-life

Terminal elimination half-life is approximately 60 minutes following IV infusion over 2 hours.¹

Following sub-Q administration, terminal elimination half-life is approximately 162 minutes.¹

Stability

Storage

Parenteral

Powder and Solution

2–8°C;^{1 206} do not freeze.¹

Use solutions reconstituted with sterile water for injection within 6 hours.^{1 206} Use solutions reconstituted with bacteriostatic water for injection within 20 days.^{1 206} Administer previously reconstituted solution mixed with freshly reconstituted solution within 6 hours following mixing.¹

Compatibility

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

Parenteral

Drug Compatibility

Y-Site CompatibilityHID

Compatible
Amikacin sulfate
Aminophylline
Aztreonam
Bleomycin sulfate
Butorphanol tartrate
Calcium gluconate
Carboplatin
Carmustine
Cefazolin sodium
Cefepime HCl
Cefotaxime sodium
Ceftizoxime sodium
Ceftriaxone sodium
Cefuroxime sodium
Cimetidine HCl
Cisplatin
Clindamycin phosphate
Co-trimoxazole
Cyclophosphamide
Cyclosporine
Cytarabine
Dacarbazine
Dactinomycin
Dexamethasone sodium phosphate
Diphenhydramine HCl
Dopamine HCl
Doxorubicin HCl
Doxycycline hyclate
Droperidol
Etoposide
Famotidine
Fentanyl citrate
Floxuridine
Fluconazole
Fluorouracil
Furosemide
Gentamicin sulfate
Granisetron HCl
Heparin sodium
Idarubicin HCl
Ifosfamide
Immune globulin intravenous
Magnesium sulfate
Mannitol
Meperidine HCl
Mesna
Methotrexate sodium
Metoclopramide HCl
Metronidazole
Mitoxantrone HCl
Pentostatin
Piperacillin sodium–tazobactam sodium
Potassium chloride
Prochlorperazine edisylate
Promethazine HCl
Ranitidine HCl
Teniposide
Ticarcillin disodium–clavulanate potassium
Vinblastine sulfate
Vincristine sulfate
Zidovudine
Incompatible
Acyclovir sodium
Ampicillin sodium
Ampicillin sodium–sulbactam sodium
Chlorpromazine HCl
Ganciclovir sodium
Haloperidol lactate
Hydrocortisone sodium phosphate
Hydrocortisone sodium succinate
Hydromorphone HCl
Hydroxyzine HCl
Imipenem–cilastatin sodium
Lorazepam
Methylprednisolone sodium succinate
Mitomycin
Morphine sulfate
Nalbuphine HCl
Ondansetron HCl
Sodium bicarbonate
Tobramycin sulfate
Variable
Amphotericin B
Amsacrine
Ceftazidime
Vancomycin HCl

ActionsActions

• 
  

  Exerts the pharmacologic effects usually produced by endogenous human GM-CSF.^{1 5 11 85 86 95 132}

  
  


• 
  

  Influences leucopoiesis;^{1 5 85 95} affects the proliferation and differentiation of a variety of hematopoietic progenitor cells,^{1 5 131 132} principally in the granulocyte-macrophage lineage.^{1 11 78 83 84 85 86 87 90 91 132}

  
  


• 
  

  Acts directly on various progenitor target cells^{5 98 150 203} by binding to GM-CSF-specific receptors on their cell surfaces.^{1 5 78 83 84 87 88 91 105 140 141 142}

  
  


• 
  

  Induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways.^{1 11 78 83 84 85 86 87 90 91 132 150 151} Also stimulates the proliferation of eosinophils, megakaryocytes, erythroid progenitors, and mast-cell precursors.^{1 11 46 83 84 85 87 90 132 150}

  
  


• 
  

  Alters the kinetics of myeloid progenitor cells within the bone marrow.^{5 82 94 198 203 204} Causes rapid entry of cells into the cell cycle and decreases the cell cycle time.^{5 82 94 198 203 204}

  
  


• 
  

  Produces a dose-dependent^{11 32 78 84 87 91 122} and biphasic increase in the leukocyte count.^{24 93 122}

  
  


• 
  

  Enhances certain functions of normal mature neutrophils, eosinophils, basophils, and macrophages^{78 79 83 85 119 150} (e.g., oxidative metabolism of neutrophils, phagocytosis, eosinophil cytotoxicity, antibody-dependent cellular cytotoxicity, chemotax

CHAMPIX 0.5 mg film-coated tablets; CHAMPIX 1 mg film-coated tablets

1. Name Of The Medicinal Product

CHAMPIX ^®

CHAMPIX ^®

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 0.5 mg of varenicline (as tartrate).

Each film-coated tablet contains 1 mg of varenicline (as tartrate).

Excipient(s):

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

0.5 mg film-coated tablets: White, capsular-shaped, biconvex tablets debossed with “Pfizer” on one side and “CHX 0.5” on the other side.

1 mg film-coated tablets: Light blue, capsular-shaped, biconvex tablets debossed with “Pfizer” on one side and “CHX 1.0” on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

CHAMPIX is indicated for smoking cessation in adults.

4.2 Posology And Method Of Administration

Posology

The recommended dose is 1 mg varenicline twice daily following a 1-week titration as follows:

Days 1 – 3:	0.5 mg once daily
Days 4 – 7:	0.5 mg twice daily
Day 8 – End of treatment:	1 mg twice daily

The patient should set a date to stop smoking. Champix dosing should usually start at 1-2 weeks before this date (see section 5.1).

Patients who cannot tolerate adverse reactions of CHAMPIX may have the dose lowered temporarily or permanently to 0.5 mg twice daily.

Patients should be treated with CHAMPIX for 12 weeks.

For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment with CHAMPIX at 1 mg twice daily may be considered (see section 5.1).

No data are available on the efficacy of an additional 12 weeks course of treatment for patients who do not succeed in stopping smoking during initial therapy or who relapse after treatment.

Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided with additional advice and support.

In smoking cessation therapy, risk for relapse to smoking is elevated in the period immediately following the end of treatment. In patients with a high risk of relapse, dose tapering may be considered (see section 4.4).

Special populations

Patients with renal insufficiency

No dosage adjustment is necessary for patients with mild (estimated creatinine clearance > 50 ml/min and

For patients with moderate renal impairment who experience adverse reactions that are not tolerable, dosing may be reduced to 1 mg once daily.

For patients with severe renal impairment (estimated creatinine clearance < 30 ml/min), the recommended dose of CHAMPIX is 1 mg once daily. Dosing should begin at 0.5 mg once daily for the first 3 days then increased to 1 mg once daily. Based on insufficient clinical experience with CHAMPIX in patients with end stage renal disease, treatment is not recommended in this patient population (see section 5.2).

Patients with hepatic impairment

No dosage adjustment is necessary for patients with hepatic impairment (see section 5.2).

Dosing in elderly patients

No dosage adjustment is necessary for elderly patients (see section 5.2). Because elderly patients are more likely to have decreased renal function, prescribers should consider the renal status of an elderly patient.

Paediatric population

The safety and efficacy of CHAMPIX in children or adolescents below 18 years have not yet been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Method of administration

CHAMPIX is for oral use and the tablets should be swallowed whole with water.

CHAMPIX can be taken with or without food

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Effect of smoking cessation: Physiological changes resulting from smoking cessation, with or without treatment with CHAMPIX, may alter the pharmacokinetics or pharmacodynamics of some medicinal products, for which dosage adjustment may be necessary (examples include theophylline, warfarin and insulin). As smoking induces CYP1A2, smoking cessation may result in an increase of plasma levels of CYP1A2 substrates.

Neuropsychiatric symptoms

Changes in behaviour or thinking, anxiety, psychosis, mood swings, aggressive behaviour, depression, suicidal ideation and behaviour and suicide attempts have been reported in patients attempting to quit smoking with CHAMPIX in the post-marketing experience. Not all patients had stopped smoking at the time of onset of symptoms and not all patients had known pre-existing psychiatric illness. Clinicians should be aware of the possible emergence of significant depressive symptomatology in patients undergoing a smoking cessation attempt, and should advise patients accordingly. Champix should be discontinued immediately if agitation, depressed mood or changes in behaviour or thinking that are of concern for the doctor, the patient, family or caregivers are observed, or if the patient develops suicidal ideation or suicidal behaviour. In many post-marketing cases, resolution of symptoms after discontinuation of varenicline was reported, although in some cases the symptoms persisted; therefore, ongoing follow up should be provided until symptoms resolve.

Depressed mood, rarely including suicidal ideation and suicide attempt, may be a symptom of nicotine withdrawal. In addition, smoking cessation, with or without pharmacotherapy, has been associated with exacerbation of underlying psychiatric illness (e.g. depression).

Cardiovascular events

In a trial of patients with stable cardiovascular disease (CVD) certain cardiovascular events were reported more frequently in patients treated with CHAMPIX (see section 5.1). Patients taking CHAMPIX should be instructed to notify their doctor of new or worsening cardiovascular symptoms and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction.

History of psychiatric illness

The safety and efficacy of Champix in patients with serious psychiatric illness such as schizophrenia, bipolar disorder and major depressive disorder has not been established. Care should be taken with patients with a history of psychiatric illness and patients should be advised accordingly.

Epilepsy

There is no clinical experience with CHAMPIX in patients with epilepsy.

Treatment discontinuation

At the end of treatment, discontinuation of CHAMPIX was associated with an increase in irritability, urge to smoke, depression, and/or insomnia in up to 3% of patients. The prescriber should inform the patient accordingly and discuss or consider the need for dose tapering.

Hypersensitivity reactions

There have been post-marketing reports of hypersensitivity reactions including angioedema in patients treated with varenicline. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), neck (throat and larynx) and extremities. There were rare reports of life-threatening angioedema requiring urgent medical attention due to respiratory compromise. Patients experiencing these symptoms should discontinue treatment with varenicline and contact a health care provider immediately.

Cutaneous reactions

There have also been post-marketing reports of rare but severe cutaneous reactions, including Stevens-Johnson Syndrome and Erythema Multiforme in patients using varenicline. As these skin reactions can be life threatening, patients should discontinue treatment at the first sign of rash or skin reaction and contact a healthcare provider immediately.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Based on varenicline characteristics and clinical experience to date, CHAMPIX has no clinically meaningful drug interactions. No dosage adjustment of CHAMPIX or co-administered medicinal products listed below is recommended.

In vitro studies indicate that varenicline is unlikely to alter the pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes.

Furthermore since metabolism of varenicline represents less than 10% of its clearance, active substances known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of varenicline (see section 5.2) and therefore a dose adjustment of CHAMPIX would not be required.

In vitro studies demonstrate that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, active substances that are cleared by renal secretion (e.g. metformin - see below) are unlikely to be affected by varenicline.

Metformin: Varenicline did not affect the pharmacokinetics of metformin. Metformin had no effect on varenicline pharmacokinetics.

Cimetidine: Co-administration of cimetidine, with varenicline increased the systemic exposure of varenicline by 29% due to a reduction in varenicline renal clearance. No dosage adjustment is recommended based on concomitant cimetidine administration in subjects with normal renal function or in patients with mild to moderate renal impairment. In patients with severe renal impairment, the concomitant use of cimetidine and varenicline should be avoided.

Digoxin: Varenicline did not alter the steady-state pharmacokinetics of digoxin.

Warfarin: Varenicline did not alter the pharmacokinetics of warfarin. Prothrombin time (INR) was not affected by varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics (see section 4.4).

Alcohol: There is limited clinical data on any potential interaction between alcohol and varenicline

Use with other therapies for smoking cessation:

Bupropion: Varenicline did not alter the steady-state pharmacokinetics of bupropion.

Nicotine replacement therapy (NRT): When varenicline and transdermal NRT were co-administered to smokers for 12 days, there was a statistically significant decrease in average systolic blood pressure (mean 2.6 mmHg) measured on the final day of the study. In this study, the incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue was greater for the combination than for NRT alone.

Safety and efficacy of CHAMPIX in combination with other smoking cessation therapies have not been studied.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of CHAMPIX in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. CHAMPIX should not be used during pregnancy.

Breastfeeding

It is unknown whether varenicline is excreted in human breast milk. Animal studies suggest that varenicline is excreted in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with CHAMPIX should be made taking into account the benefit of breast-feeding to the child and the benefit of CHAMPIX therapy to the woman.

Fertility

There are no clinical data on the effects of varenicline on fertility.

Non-clinical data revealed no hazard for humans based on standard male and female fertility studies in the rat (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

CHAMPIX may have minor or moderate influence on the ability to drive and use machines.

CHAMPIX may cause dizziness and somnolence and therefore may influence the ability to drive and use machines. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medicinal product affects their ability to perform these activities.

4.8 Undesirable Effects

Summary of the safety profile

Smoking cessation with or without treatment is associated with various symptoms. For example, dysphoric or depressed mood; insomnia, irritability, frustration or anger; anxiety; difficulty concentrating; restlessness; decreased heart rate; increased appetite or weight gain have been reported in patients attempting to stop smoking. No attempt has been made in either the design or the analysis of the CHAMPIX studies to distinguish between adverse reactions associated with study drug treatment or those possibly associated with nicotine withdrawal.

Clinical trials included approximately 4,000 patients treated with CHAMPIX for up to 1 year (average exposure 84 days). In general, when adverse reactions occurred, onset was in the first week of therapy; severity was generally mild to moderate and there were no differences by age, race or gender with regard to the incidence of adverse reactions.

In patients treated with the recommended dose of 1mg BID following an initial titration period the adverse event most commonly reported was nausea (28.6%). In the majority of cases nausea occurred early in the treatment period, was mild to moderate in severity and seldom resulted in discontinuation.

The treatment discontinuation rate due to adverse reactions was 11.4% for varenicline compared with 9.7% for placebo. In this group, the discontinuation rates for the most common adverse reactions in varenicline treated patients were as follows: nausea (2.7% vs. 0.6% for placebo), headache (0.6% vs. 1.0% for placebo), insomnia (1.3% vs. 1.2% for placebo), and abnormal dreams (0.2% vs. 0.2% for placebo).

Tabulated summary of adverse reactions

In the table below all adverse reactions, which occurred at an incidence greater than placebo are listed by system organ class and frequency (very common (

System Organ Class	Adverse Drug Reactions
Infections and infestations
Uncommon	Bronchitis, nasopharyngitis, sinusitis, fungal infection, viral infection,.
Metabolism and nutrition disorders
Common	Increased appetite
Uncommon	Anorexia, decreased appetite, polydipsia
Psychiatric disorders
Very common	Abnormal dreams, insomnia
Uncommon	Panic reaction, dysphoria, bradyphrenia, thinking abnormal, restlessness, mood swings, depression*, anxiety*, hallucinations*, libido increased, libido decreased
Not Known	Suicidal ideation, psychosis, aggression, abnormal behaviour
Nervous system disorders
Very common	Headache
Common	Somnolence, dizziness, dysgeusia
Uncommon	Hypertonia, dysarthria, tremor, coordination abnormal, ,lethargy, hypoaesthesia, hypogeusia
Rare	Cerebrovascular accident
Eye disorders
Uncommon	Scotoma, scleral discolouration, eye pain, mydriasis, photophobia, myopia, lacrimation increased
Ear and labyrinth disorders
Uncommon	Tinnitus
Cardiac disorders
Uncommon	Atrial fibrillation, palpitations, electrocardiogram ST segment depression, electrocardiogram T wave amplitude decreased, heart rate increased
Not Known	Myocardial infaction
Vascular Disorders
Uncommon	Blood pressure increased
Respiratory, thoracic and mediastinal disorders
Uncommon	Dyspnoea, cough, respiratory tract congestion, hoarseness, pharyngolaryngeal pain, throat irritation, sinus congestion, post nasal drip, rhinorrhoea, snoring
Gastrointestinal disorders
Very common	Nausea
Common	Vomiting, constipation, diarrhoea, abdominal distension, stomach discomfort, dyspepsia, flatulence, dry mouth
Uncommon	Haematemesis, haematochezia, gastritis, gastrooesophageal reflux disease, abdominal pain, change of bowel habit, abnormal faeces, eructation, aphthous stomatitis, gingival pain, tongue coated
Skin and subcutaneous tissue disorders
Uncommon Not Known	Rash generalised, erythema, pruritus, acne, hyperhidrosis, night sweats Severe cutaneous reactions, including Stevens Johnson Syndrome and Erythema Multiforme, angioedema
Musculoskeletal and connective tissue disorders
Uncommon	Joint stiffness, muscle spasms, chest wall pain, costochondritis
Renal and urinary disorders
Uncommon	Glycosuria, nocturia, polyuria
Reproductive system and breast disorders
Uncommon	Menorrhagia, vaginal discharge, sexual dysfunction
General disorders and administration site conditions
Common	Fatigue
Uncommon	Chest discomfort, chest pain, pyrexia, feeling cold, asthenia, circadian rhythm sleep disorder, malaise, cyst
Investigations
Uncommon	Liver function test abnormal, platelet count decreased, semen abnormal, C-reactive protein increased, blood calcium decreased, weight increased

* frequencies are estimated from a post-marketing, observational cohort study

4.9 Overdose

No cases of overdose were reported in pre-marketing clinical trials.

In case of overdose, standard supportive measures should be instituted as required.

Varenicline has been shown to be dialyzed in patients with end stage renal disease (see section 5.2), however, there is no experience in dialysis following overdose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: OTHER NERVOUS SYSTEM DRUGS; Drugs used in nicotine dependence, ATC code: N07BA03

Mechanism of action

Varenicline binds with high affinity and selectivity at the α4β2 neuronal nicotinic acetylcholine receptors, where it acts as a partial agonist - a compound that has both agonist activity, with lower intrinsic efficacy than nicotine, and antagonist activities in the presence of nicotine.

Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to the α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Nicotine competes for the same human α4β2 nAChR binding site for which varenicline has higher affinity. Therefore, varenicline can effectively block nicotine's ability to fully activate α4β2 receptors and the mesolimbic dopamine system, the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds more potently to the α4β2 receptor subtype (Ki=0.15 nM) than to other common nicotinic receptors (α3β4 Ki=84 nM, α7 Ki= 620 nM, α1βγδ Ki= 3,400 nM), or to non-nicotinic receptors and transporters (Ki > 1μM, except to 5-HT3 receptors: Ki=350 nM).

Pharmacodynamic effects

The efficacy of CHAMPIX in smoking cessation is a result of varenicline's partial agonist activity at the α4β2 nicotinic receptor where its binding produces an effect sufficient to alleviate symptoms of craving and withdrawal (agonist activity), while simultaneously resulting in a reduction of the rewarding and reinforcing effects of smoking by preventing nicotine binding to α4β2 receptors (antagonist activity).

Clinical efficacy and safety

The efficacy of CHAMPIX in smoking cessation was demonstrated in 3 clinical trials involving chronic cigarette smokers (

Comparative Clinical Studies

Two identical double-blind clinical trials prospectively compared the efficacy of CHAMPIX (1 mg twice daily), sustained release bupropion (150 mg twice daily) and placebo in smoking cessation. In these 52-week duration studies, patients received treatment for 12 weeks, followed by a 40-week non-treatment phase.

The primary endpoint of the two studies was the carbon monoxide (CO) confirmed, 4-week continuous quit rate (4W-CQR) from week 9 through week 12. The primary endpoint for CHAMPIX demonstrated statistical superiority to bupropion and placebo.

After the 40 week non-treatment phase, a key secondary endpoint for both studies was the Continuous Abstinence Rate (CA) at week 52. CA was defined as the proportion of all subjects treated who did not smoke (not even a puff of a cigarette) from Week 9 through Week 52 and did not have an exhaled CO measurement of> 10 ppm. The 4W-CQR (weeks 9 through 12) and CA rate (weeks 9 through 52) from studies 1 and 2 are included in the following table:

	Study 1 (n=1022)	Study 2 (n=1023)
4W CQR	CA Wk 9-52	4W CQR	CA Wk 9-52
CHAMPIX	44.4%	22.1%	44.0%	23.0%
Bupropion	29.5%	16.4%	30.0%	15.0%
Placebo	17.7%	8.4%	17.7%	10.3%
Odds ratio CHAMPIX vs placebo	3.91 p<0.0001	3.13 p<0.0001	3.85 p<0.0001	2.66 p<0.0001
Odds ratio CHAMPIX vs bupropion	1.96 p<0.0001	1.45 p=0.0640	1.89 p<0.0001	1.72 p=0.0062

Patient reported craving, withdrawal and reinforcing effects of smoking

Across both Studies 1 and 2 during active treatment, craving and withdrawal were significantly reduced in patients randomized to CHAMPIX in comparison with placebo. CHAMPIX also significantly reduced reinforcing effects of smoking that can perpetuate smoking behaviour in patients who smoke during treatment compared with placebo. The effect of varenicline on craving, withdrawal and reinforcing effects of smoking were not measured during the non-treatment long-term follow-up phase.

Maintenance of Abstinence Study

The third study assessed the benefit of an additional 12 weeks of CHAMPIX therapy on the maintenance of abstinence. Patients in this study (n=1,927) received open-label CHAMPIX 1 mg twice daily for 12 weeks. Patients who stopped smoking by Week 12 were then randomized to receive either CHAMPIX (1 mg twice daily) or placebo for an additional 12 weeks for a total study duration of 52 weeks.

The primary study endpoint was the CO-confirmed continuous abstinence rate from week 13 through week 24 in the double-blind treatment phase. A key secondary endpoint was the continuous abstinence (CA) rate for week 13 through week 52.

This study showed the benefit of an additional 12-week treatment with CHAMPIX 1 mg twice daily for the maintenance of smoking cessation compared to placebo. The odds of maintaining abstinence at week 24, following an additional 12 weeks of treatment with CHAMPIX, were 2.47 times those for placebo (p<0.0001). Superiority to placebo for CA was maintained through week 52 (Odds Ratio=1.35, p=0.0126).

The key results are summarised in the following table:

	CHAMPIX n=602	Placebo n=604	Difference (95% CI)	Odds ratio (95% CI)
CA wk 13-24	70.6%	49.8%	20.8% (15.4%, 26.2%)	2.47 (1.95, 3.15)
CA wk 13-52	44.0%	37.1%	6.9% (1.4%,12.5%)	1.35 (1.07, 1.70)

There is currently limited clinical experience with the use of CHAMPIX among black people to determine clinical efficacy.

Flexible quit date between weeks 1 and 5

The efficacy and safety of varenicline has been evaluated in smokers who had the flexibility of quitting between weeks 1 and 5 of treatment. In this 24-week study, patients received treatment for 12 weeks followed by a 12 week non-treatment follow up phase. The 4 week (week 9-12) CQR for varenicline and placebo was 53.9% and 19.4%, respectively (difference=34.5%, 95% CI: 27.0% - 42.0%) and the CA week 9-24 was 35.2% (varenicline) vs 12.7% (placebo) (difference=22.5%, 95% CI: 15.8% - 29.1%). Patients who are not willing or able to set the target quit date within 1-2 weeks, could be offered to start treatment and then choose their own quit date within 5 weeks.

Subjects with Cardiovascular Disease

CHAMPIX was evaluated in a randomised, double-blind, placebo-controlled study of subjects with stable, cardiovascular disease (other than, or in addition to, hypertension) that had been diagnosed for more than 2 months. Subjects were randomized to CHAMPIX 1 mg twice daily (n=353) or placebo (n=350) for 12 weeks and then were followed for 40 weeks post-treatment. The 4 week CQR for varenicline and placebo was 47.3% and 14.3%, respectively and the CA week 9-52 was 19.8% (varenicline) vs 7.4% (placebo).

Deaths and serious cardiovascular events were adjudicated by a blinded, committee. The following adjudicated events occurred with a frequency

Subjects with mild-moderate chronic obstructive pulmonary disease (COPD)

The efficacy and safety of CHAMPIX (1 mg twice daily) for smoking cessation in subjects with mild-moderate COPD was demonstrated in a randomised double-blind placebo-controlled clinical trial. In this 52-week duration study, patients received treatment for 12 weeks, followed by a 40-week non-treatment follow-up phase. The primary endpoint of the study was the CO-confirmed, 4-week Continuous Quit Rate (4W CQR) from week 9 through week 12 and a key secondary endpoint was the Continuous Abstinence (CA) from Week 9 through Week 52. The safety profile of varenicline was comparable to what was reported in other trials in the general population, including pulmonary safety. The results for the 4W CQR (weeks 9 through 12) and CA rate (weeks 9 through 52) are shown in the following table:

	4W CQR	CA Wk 9-52
CHAMPIX, (n = 248)	42.3%	18.5%
Placebo, (n = 251)	8.8%	5.6%
Odds ratio (CHAMPIX vs Placebo)	8.40 p<0.0001	4.04 p<0.0001

5.2 Pharmacokinetic Properties

Absorption: Maximum plasma concentrations of varenicline occur typically within 3-4 hours after oral administration. Following administration of multiple oral doses to healthy volunteers, steady-state conditions were reached within 4 days. Absorption is virtually complete after oral administration and systemic availability is high. Oral bioavailability of varenicline is unaffected by food or time-of-day dosing.

Distribution: Varenicline distributes into tissues, including the brain. Apparent volume of distribution averaged 415 litres (%CV= 50) at steady-state. Plasma protein binding of varenicline is low (< 20%) and independent of both age and renal function. In rodents, varenicline is transferred through the placenta and excreted in milk.

Biotransformation: Varenicline undergoes minimal metabolism with 92% excreted unchanged in the urine and less than 10% excreted as metabolites. Minor metabolites in urine include varenicline N-carbamoylglucuronide and hydroxyvarenicline. In circulation, varenicline comprises 91% of drug-related material. Minor circulating metabolites include varenicline N-carbamoylglucuronide and N-glucosylvarenicline.

In vitro studies demonstrate that varenicline does not inhibit cytochrome P450 enzymes (IC50 > 6,400 ng/ml). The P450 enzymes tested for inhibition were: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, varenicline was shown to not induce the activity of cytochrome P450 enzymes 1A2 and 3A4. Therefore, varenicline is unlikely to alter the pharmacokinetics of compounds that are primarily metabolised by cytochrome P450 enzymes.

Elimination: The elimination half-life of varenicline is approximately 24 hours. Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion via the organic cationic transporter, OCT2. (see section 4.5).

Linearity/Non linearity: Varenicline exhibits linear kinetics when given as single (0.1 to 3 mg) or repeated (1 to 3 mg/day) doses.

Pharmacokinetics in special patient populations: There are no clinically meaningful differences in varenicline pharmacokinetics due to age, race, gender, smoking status, or use of concomitant medicinal products, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.

Patients with hepatic impairment: Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic impairment. (see section 4.2).

Renal Insufficiency: Varenicline pharmacokinetics were unchanged in subjects with mild renal impairment (estimated creatinine clearance > 50 ml/min and

Elderly: The pharmacokinetics of varenicline in elderly patients with normal renal function (aged 65-75 years) is similar to that of younger adult subjects (see section 4.2). For elderly patients with reduced renal function please refer to section 4.2.

Paediatric population:

Adolescents: When 22 adolescents aged 12 to 17 years (inclusive) received a single 0.5 mg and 1 mg dose of varenicline the pharmacokinetics of varenicline was approximately dose proportional between the 0.5 mg and 1 mg doses. Systemic exposure, as assessed by AUC (0-inf), and renal clearance of varenicline were comparable to adults. An increase of 30% in C_max and a shorter elimination half-life (10.9 hr) were observed in adolescents compared with adults (see section 4.2).

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, fertility and embryo-foetal development. In male rats dosed for 2 years with varenicline, there was a dose-related increase in the incidence of hibernoma (tumour of the brown fat). In the offspring of pregnant rats treated with varenicline there were decreases in fertility and increases in the auditory startle response (see section 4.6). These effects were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Nonclinical data indicate varenicline has reinforcing properties albeit with lower potency than nicotine. In clinical studies in humans, varenicline showed low abuse potential.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core Tablet

Cellulose, Microcrystalline

Calcium Hydrogen Phosphate Anhydrous

Croscarmellose Sodium

Silica, Colloidal Anhydrous

Magnesium Stearate

Film Coating

Hypromellose

Titanium Dioxide (E171)

Macrogols

Triacetin

1mg tablet also contains Indigo Carmine Aluminium Lake E132 excipient in its film coating.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions

6.5 Nature And Contents Of Container

Treatment initiation packs

PCTFE / PVC blisters with aluminium foil backing containing one clear blister of 11 x 0.5 mg film-coated tablets and a second clear blister of 14 x 1 mg film-coated tablets in secondary heat sealed card packaging.

PCTFE / PVC blisters with aluminium foil backing containing one clear blister of 11 x 0.5 mg film-coated tablets and a second clear blister containing 14 x 1 mg film-coated tablets in a carton.

PCTFE / PVC / blisters with aluminium foil backing containing one clear blister of 11 x 0.5 mg and 14 x 1 mg film-coated tablets and a second clear blister of 28 x 1 mg film-coated tablets in secondary heat sealed card packaging.

Maintenance packs

PCTFE / PVC blisters with aluminium foil backing in a pack containing 28 x 0.5 mg film-coated tablets in secondary heat sealed card packaging.

PCTFE / PVC blisters with aluminium foil backing in a pack containing 56 x 0.5 mg film-coated tablets in secondary heat sealed card packaging.

High-density polyethylene (HDPE) blue white tablet container with polypropylene child resistant closure and an aluminium foil / polyethylene induction seal containing 56 x 0.5 mg film-coated tablets

PCTFE / PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tablets in secondary heat sealed card packaging.

PCTFE / PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tablets in secondary heat sealed card packaging.

PCTFE / PVC blisters with aluminium foil backing in a pack containing 28 x 1 mg film-coated tablets in a carton.

PCTFE / PVC blisters with aluminium foil backing in a pack containing 56 x 1 mg film-coated tablets in a carton.

PCTFE / PVC blisters with aluminium foil backing in a pack containing 112 x 1 mg film-coated tablets in a carton.

PCTFE / PVC blisters with aluminium foil backing in a pack containing 140 x 1 mg film-coated tablets in a carton.

High-density polyethylene (HDPE) blue white tablet container with polypropylene child resistant closure and an aluminium foil / polyethylene induction seal contai

Geneye Extra

Generic Name: tetrahydrozoline ophthalmic (TE tra hye DROZ oh leen)

Brand Names: Altazine, Geneye Extra, Geneyes, Opti-Clear, Optigene 3, Redness Relief, Redness Relief Original, Visine, Visine Maximum Redness Relief, Vision Clear

What is Geneye Extra (tetrahydrozoline ophthalmic)?

Tetrahydrozoline ophthalmic narrows the blood vessels (veins and arteries) in your eyes.

Tetrahydrozoline ophthalmic (for the eyes) is used to relieve redness, burning, irritation, and dryness of the eyes caused by wind, sun, and other minor irritants.

Tetrahydrozoline ophthalmic may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Geneye Extra (tetrahydrozoline ophthalmic)?

Do not use tetrahydrozoline ophthalmic without medical advice if you have glaucoma. Do not use this medication while wearing contact lenses. Tetrahydrozoline ophthalmic may contain a preservative that can discolor soft contact lenses. Wait at least 15 minutes after using tetrahydrozoline ophthalmic before putting your contact lenses in. Do not allow the tip of the dropper to touch any surface, including your eyes or hands. If the dropper becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye. Do not use tetrahydrozoline ophthalmic more often than recommended, or use it for longer than 48 to 72 hours without medical advice. Long-term use of this medication may damage the blood vessels in the eyes. Call your doctor if your symptoms do not improve or if they get worse.

What should I discuss with my healthcare provider before using Geneye Extra (tetrahydrozoline ophthalmic)?

Do not use tetrahydrozoline ophthalmic without medical advice if you have glaucoma.

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

• 
  

  heart disease or coronary artery disease;

  
  


• 
  

  high blood pressure;

  
  


• 
  

  diabetes; or

  
  


• 
  

  a thyroid disorder.

  
  

FDA pregnancy category C. It is not known whether tetrahydrozoline ophthalmic will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether tetrahydrozoline nasal passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Do not give this medication to a child without a doctor's advice.

How should I use Geneye Extra (tetrahydrozoline ophthalmic)?

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.

Do not use tetrahydrozoline ophthalmic more often than recommended, or use it for longer than 48 to 72 hours without medical advice. Long-term use of this medication may damage the blood vessels in the eyes. Call your doctor if your symptoms do not improve or if they get worse. Do not use this medication while you are wearing contact lenses. This medication may contain a preservative that can be absorbed by soft contact lenses. Wait at least 15 minutes after using tetrahydrozoline before putting your contact lenses in. Wash your hands before and after using the eye drops.

To apply the eye drops:

• 
  

  Tilt your head back slightly and pull down your lower eyelid to create a small pocket. Hold the dropper above the eye with the tip down. Look up and away from the dropper as you squeeze out a drop, then close your eye.

  
  


• 
  

  Gently press your finger to the inside corner of the eye (near your nose) for about 1 minute to keep the liquid from draining into your tear duct.

  
  


• 
  

  Do not allow the dropper tip to touch any surface, including the eyes or hands. If the dropper becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye.

  
  

Do not allow the tip of the dropper to touch any surface, including your eyes or hands. If the dropper becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye.

Do not use the eye drops if the liquid has changed colors or has particles in it.

Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.

What happens if I miss a dose?

Since tetrahydrozoline ophthalmic is used on an as needed basis, you are not likely to miss a dose.

What happens if I overdose?

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

What should I avoid while using Geneye Extra (tetrahydrozoline ophthalmic)?

Do not use other eye medications during treatment with tetrahydrozoline ophthalmic unless your doctor tells you to.

Geneye Extra (tetrahydrozoline ophthalmic) 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 tetrahydrozoline ophthalmic and call your doctor at once if you have a serious side effect such as:

• 
  

  severe burning, stinging, swelling, or other irritation after using the eye drops;

  
  


• 
  

  fast or pounding heartbeats; or

  
  


• 
  

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

  
  

Less serious side effects may include:

• 
  

  burning, stinging, pain, or increased redness of the eye;

  
  


• 
  

  tearing or blurred vision;

  
  


• 
  

  nausea;

  
  


• 
  

  nervousness, dizziness, drowsiness;

  
  


• 
  

  sleep problems (insomnia); or

  
  


• 
  

  headache.

  
  

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 Geneye Extra (tetrahydrozoline ophthalmic)?

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

• 
  

  an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate); or

  
  


• 
  

  a beta blocker such as atenolol (Tenormin, Tenoretic), carvedilol (Coreg), labetalol (Normodyne, Trandate), metoprolol (Dutoprol, Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), sotalol (Betapace), and others.

  
  

This list is not complete and other drugs may interact with tetrahydrozoline ophthalmic. 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 Geneye Extra resources

• Geneye Extra Side Effects (in more detail)
• Geneye Extra Use in Pregnancy & Breastfeeding
• Geneye Extra Drug Interactions
• Geneye Extra Support Group
• 0 Reviews for Geneye Extra - Add your own review/rating

• Clarinex Monograph (AHFS DI)


• Visine Eye Drops MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Geneye Extra with other medications

• Eye Dryness/Redness

Where can I get more information?

• Your pharmacist can provide more information about tetrahydrozoline ophthalmic.

See also: Geneye Extra side effects (in more detail)