Tolvaptan

Class: Vasopressin Antagonists
ATC Class: C03XA01
Chemical Name: N - [4 - [(7 - chloro - 2,3,4,5 - tetrahydro - 5 - hydroxy - 1H - 1 - benzazepin - 1 - yl)carbonyl] - 3 - methylphenyl] - 2 - methyl - benzamide
Molecular Formula: C₂₆H₂₅ClN₂O₃
CAS Number: 150683-30-0
Brands: Samsca

• 
  

  Initiate or reinitiate tolvaptan only in a hospital setting, where serum sodium concentrations and therapeutic response can be monitored closely.¹

  
  


• 
  

  Too rapid a correction of hyponatremia (e.g., increases in serum sodium concentration of >12 mEq/L over 24 hours) may cause osmotic demyelination syndrome, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death.¹

  
  


• 
  

  Slower rates of correction may be advisable in susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease.¹ (See Overly Rapid Correction of Serum Sodium Concentration under Cautions.)

  
  

REMS:

FDA approved a REMS for tolvaptan to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of tolvaptan and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Selective, nonpeptide antagonist of arginine vasopressin (antidiuretic hormone) V₂ receptors; benzazepine derivative.^{1 2 3 4 5}

Uses for Tolvaptan

Euvolemic or Hypervolemic Hyponatremia

Treatment of clinically important euvolemic or hypervolemic hyponatremia (serum sodium concentration of <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including cases in patients with heart failure, cirrhosis, or SIADH.^{1 2 6 9}

Not indicated for the treatment of hypovolemic hyponatremia.¹

Do not use in patients who require urgent intervention to raise serum sodium concentrations to prevent or treat serious neurologic manifestations.¹

Use of tolvaptan to increase serum sodium concentrations has not been established to provide symptomatic benefit to patients.¹

Tolvaptan Dosage and Administration

General

• 
  

  Avoid fluid restriction during first 24 hours of therapy.¹ Advise patients that they may continue drinking fluids in response to thirst.¹

  
  


• 
  

  Following discontinuance of drug, advise patients to resume fluid restriction and monitor patients for changes in serum sodium concentration and fluid status.¹

  
  

Administration

Initiate or reinitiate tolvaptan only in a hospital setting, where serum sodium concentrations and therapeutic response can be monitored closely; too rapid a correction of hyponatremia may cause serious neurologic sequelae (e.g., osmotic demyelination syndrome).¹ (See Boxed Warning and see Overly Rapid Correction of Serum Sodium Concentration under Cautions.)

Oral Administration

Administer orally without regard to meals.¹

Dosage

Adults

Euvolemic or Hypervolemic Hyponatremia

Oral

Initially, 15 mg once daily; dosage may be increased at intervals of ≥24 hours to 30 mg once daily and subsequently up to 60 mg once daily as needed to achieve the desired serum sodium concentration.¹

Frequently monitor serum electrolytes and fluid status during initiation and titration of therapy.¹

Discontinue or interrupt therapy if serum sodium concentrations increase too rapidly or manifestations of hypovolemia occur.¹ (See Overly Rapid Correction of Serum Sodium Concentration and also Dehydration and Hypovolemia under Cautions.)

Prescribing Limits

Adults

Euvolemic or Hypervolemic Hyponatremia

Oral

Maximum: 60 mg once daily.¹ Doses >60 mg do not further increase aquaresis or serum sodium concentrations.¹

Special Populations

Dosage adjustment based on gender, race, or cardiac function not necessary.¹

Hepatic Impairment

Dosage adjustment not necessary.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not necessary in patients with mild to severe renal impairment (Cl_cr of 10–79 mL/minute); not studied in patients with Cl_cr of <10 mL/minute or in patients undergoing dialysis.¹ (See Renal Impairment under Cautions.)

Anuric patients not expected to benefit from therapy.¹ (See Contraindications under Cautions.)

Geriatric Patients

Dosage adjustment not necessary.¹ (See Geriatric Use under Cautions.)

Cautions for Tolvaptan

Contraindications

• 
  

  Patients requiring urgent intervention to acutely raise serum sodium concentrations; drug not studied in these patients.¹

  
  


• 
  

  Patients unable to sense or appropriately respond to thirst.¹ Individuals unable to autoregulate fluid balance at substantially increased risk for overly rapid correction of serum sodium concentrations, hypernatremia, and hypovolemia.¹ (See Overly Rapid Correction of Serum Sodium Concentration and see Dehydration and Hypovolemia under Cautions.)

  
  


• 
  

  Hypovolemic hyponatremia.¹ Risks associated with worsening hypovolemia, including complications such as hypotension and renal failure, outweigh possible benefits of therapy.¹ (See Dehydration and Hypovolemia under Cautions.)

  
  


• 
  

  Concomitant use of potent CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin).¹ (See CYP3A Inhibitors under Interactions.)

  
  


• 
  

  Anuria.¹ Anuric patients not expected to obtain clinical benefit from therapy.¹

  
  

Warnings/Precautions

Overly Rapid Correction of Serum Sodium Concentration

Initiate or reinitiate tolvaptan only in a hospital setting, where serum sodium concentrations and therapeutic response can be monitored closely.¹ (See Boxed Warning.)

Increases in serum sodium of >12 mEq/L over 24 hours may cause osmotic demyelination syndrome, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death.¹ Slower rates of correction may be advisable in susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease.¹ Patients with SIADH or very low baseline serum sodium concentrations may be at increased risk for too rapid a correction of serum sodium concentration.¹

Monitor serum sodium concentrations and neurologic status, especially during initiation and following titration of therapy; if serum sodium concentrations increase too rapidly, discontinue or interrupt tolvaptan and consider administration of hypotonic fluid.¹

Avoid fluid restriction during the first 24 hours of therapy; may increase the risk of overly rapid correction of serum sodium concentration.¹

Because of the risk of osmotic demyelination syndrome, FDA required and approved a Risk Evaluation and Mitigation Strategy (REMS) for tolvaptan.¹² Goals are to educate health-care providers on risk of overly rapid correction of serum sodium concentrations and need for initiating therapy in a hospital and to inform patients of the serious risks associated with the use of the drug, particularly the risk of osmotic demyelination syndrome.¹² (See Advice to Patients.)

GI Bleeding in Patients with Cirrhosis

GI bleeding reported in patients with cirrhosis; use tolvaptan in patients with cirrhosis only when the need for treatment outweighs this risk.¹

Dehydration and Hypovolemia

Dehydration and hypovolemia may occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted.¹

If clinically important signs or symptoms of hypovolemia occur, discontinue or interrupt tolvaptan and provide supportive care, including careful management of vital signs, fluid balance, and electrolytes.¹

Fluid restriction during therapy may increase risk of dehydration and hypovolemia.¹ Patients should continue drinking fluids in response to thirst; use is contraindicated in patients unable to sense or appropriately respond to thirst and in those with hypovolemic hyponatremia.¹ (See Contraindications under Cautions.)

Concomitant Use with Hypertonic Sodium Chloride

No experience with concomitant use of hypertonic sodium chloride injection; concomitant use with hypertonic sodium chloride not recommended.¹

Hyperkalemia

Acute reduction of extracellular fluid volume may occur, resulting in increased serum potassium concentrations.¹

Monitor serum potassium concentrations after initiation of therapy in patients with a serum potassium concentration of >5 mEq/L and in those receiving drugs known to increase serum potassium concentrations (e.g., angiotensin II receptor antagonists, ACE inihibitors, potassium-sparing diuretics).^{1 11} (See Drugs Increasing Serum Potassium Concentration under Interactions.)

Specific Populations

Pregnancy

Category C.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 11}

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹ Dosage adjustment based on age not necessary.¹

Hepatic Impairment

Moderate or severe hepatic impairment does not appear to have clinically important effects on exposure to drug.¹ Dosage adjustment based on hepatic function not necessary.¹

Risk of GI bleeding in patients with cirrhosis; use only when need for treatment outweighs this risk.¹

Renal Impairment

Exposure and response to drug similar in patients with Cl_cr of 10–79 mL/minute and in those without renal impairment; no dosage adjustment necessary in patients with mild to severe renal impairment (Cl_cr of 10–79 mL/minute).¹

Exposure and response to drug not studied in patients with Cl_cr <10 mL/minute or in those undergoing chronic dialysis.¹

Anuric patients not expected to benefit from therapy.¹ (See Contraindications under Cautions.)

Common Adverse Effects

Thirst,^{1 2 3} dry mouth,^{1 2 3} pollakiuria or polyuria,¹ asthenia,¹ constipation,^{1 2} hyperglycemia,^{1 2} pyrexia,¹ anorexia.¹

Interactions for Tolvaptan

Mainly, if not exclusively, metabolized by CYP3A; weak inhibitor of CYP3A.¹ Substrate and inhibitor of P-glycoprotein transport system.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Pharmacokinetic interaction (marked increase in exposure to tolvaptan).^{1 11} Insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use; concomitant use is contraindicated.¹ (See Contraindications under Cautions.)

Moderate CYP3A inhibitors: Effect on tolvaptan exposure not studied; substantial increase in exposure to tolvaptan expected.¹ Avoid concomitant use.¹

CYP3A inducers: Potential pharmacokinetic interaction (decreased plasma tolvaptan concentrations) with concomitant use of potent CYP3A inducers.^{1 11} Avoid concomitant use with CYP3A inducers.^{1 11} If used concomitantly with CYP3A inducers, expected clinical effects of tolvaptan may not be observed at recommended dosage; monitor patient response and adjust dosage accordingly.^{1 11}

Drugs Affecting the P-glycoprotein Transport System

Inhibitors of the P-glycoprotein transport system: Potential pharmacokinetic interaction (increased tolvaptan concentrations);^{1 11} may require reduction of tolvaptan dosage based on clinical response.¹

Drugs Increasing Serum Potassium Concentration

Potential pharmacologic interaction (increased incidence of hyperkalemia) with concomitant use of angiotensin II receptor antagonists, ACE inihibitors, or potassium-sparing diuretics; however, formal drug interaction studies not performed.¹ Monitor serum potassium concentrations during concomitant use with drugs known to increase serum potassium concentrations.^{1 11} (See Hyperkalemia under Cautions.)

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Amiodarone	No clinically important effects on pharmacokinetics of amiodarone or its active metabolite, desethylamiodarone;1 7 no apparent increase in tolvaptan concentrations7
Angiotensin II receptor antagonists	Possible increased risk of hyperkalemia1 11	Monitor serum potassium concentrations1 11
ACE inihibitors	Possible increased risk of hyperkalemia1 11	Monitor serum potassium concentrations1 11
Anticonvulsants (e.g., barbiturates, carbamazepine, phenytoin)	Decreased plasma tolvaptan concentrations (effects similar to those of rifampin) expected1 11	Avoid concomitant use1 11 If used with barbiturates, carbamazepine, or phenytoin, expected clinical effects of tolvaptan may not be observed at recommended dosage; monitor patient response and adjust dosage accordingly1 11
Antimycobacterials (e.g., rifabutin, rifampin, rifapentine)	Decreased plasma tolvaptan concentrations1 11 Rifampin: Reduced plasma tolvaptan concentrations by 85%1 11	Avoid concomitant use1 11 If used with rifabutin, rifampin, or rifapentine, expected clinical effects of tolvaptan may not be observed at recommended dosage; monitor patient response and adjust dosage accordingly1 11
Aprepitant	Substantial increase in exposure to tolvaptan expected1	Avoid concomitant use1
Clarithromycin	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Cyclosporine	Possible increased tolvaptan concentrations1 11	Reduction of tolvaptan dosage may be required based on clinical response1
Digoxin	Increased exposure to digoxin; no clinically important effects on exposure to tolvaptan1
Diltiazem	Substantial increase in exposure to tolvaptan expected1	Avoid concomitant use1
Diuretics, potassium-sparing	Possible increased risk of hyperkalemia1 11	Monitor serum potassium concentrations1 11
Erythromycin	Substantial increase in exposure to tolvaptan expected1	Avoid concomitant use1
Fluconazole	Substantial increase in exposure to tolvaptan expected1	Avoid concomitant use1
Furosemide	No apparent clinically important effects on furosemide pharmacokinetics or tolvaptan exposure1 8 24-hour urine output is greater with tolvaptan than with furosemide, but is not substantially greater with combined tolvaptan/furosemide use than with tolvaptan alone1 8
Grapefruit juice	Increased exposure to tolvaptan1
Hydrochlorothiazide	No apparent clinically important effects on hydrochlorothiazide pharmacokinetics or tolvaptan exposure1 8 24-hour urine output is greater with tolvaptan than with hydrochlorothiazide, but is not substantially greater with combined tolvaptan/hydrochlorothiazide use than with tolvaptan alone1 8
Indinavir	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Itraconazole	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Ketoconazole	Ketoconazole 200 mg daily: Fivefold increase in tolvaptan exposure observed1 Ketoconazole 400 mg daily: Even greater increase in tolvaptan exposure expected1	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Lovastatin	Increased exposure to lovastatin and its active metabolite, lovastatin-β hydroxyacid; not considered clinically important1 No clinically important effects on exposure to tolvaptan1
Nefazodone	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Nelfinavir	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Ritonavir	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
St. John’s wort (Hypericum perforatum)	Decreased plasma tolvaptan concentrations (effects similar to those of rifampin) expected1 11	Avoid concomitant use1 11 If used concomitantly, expected clinical effects of tolvaptan may not be observed at recommended dosage; monitor patient response and adjust dosage accordingly1 11
Saquinavir	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Telithromycin	Marked increase in tolvaptan exposure (effects similar to those of ketoconazole) expected1 11	Concomitant use contraindicated; insufficient experience available to determine dosage adjustment necessary to allow safe concomitant use1
Verapamil	Substantial increase in exposure to tolvaptan expected1	Avoid concomitant use1
Warfarin	No apparent clinically important effects on pharmacokinetics of warfarin1

Tolvaptan Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability unknown; at least 40% of dose absorbed as tolvaptan or metabolites.¹

Peak plasma concentrations observed 2–4 hours following a dose.¹

AUC increases proportionally with dose; however, at doses ≥60 mg, peak plasma concentrations increase less than proportionally with dose.¹

Onset

Onset of aquaretic and sodium-increasing effects occurs within 2–4 hours following a single 60-mg dose in healthy individuals.¹

Peak effects (increases in serum sodium concentrations and urinary excretion rate of about 6 mEq/L and 9 mL/minute, respectively) observed 4–8 hours following a 60-mg dose.^{1 11}

Duration

About 60% of peak effect on serum sodium concentrations sustained at 24 hours following a dose; however, urinary excretion rate no longer elevated at this time.¹

Food

Food does not affect bioavailability.¹

Special Populations

Increasing age does not affect plasma tolvaptan concentrations.¹

Exposure to drug similar in patients with Cl_cr of 10–79 mL/minute and in those without renal impairment; exposure to drug not studied in patients with Cl_cr of <10 mL/minute or in those undergoing chronic dialysis.¹

Moderate or severe hepatic impairment does not have clinically important effects on exposure to drug.¹

Patients with CHF do not have a clinically important increase in exposure to drug.¹

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

99%.¹

Special Populations

Moderate or severe hepatic impairment increases volume of distribution; not considered clinically important.¹

CHF increases volume of distribution; not considered clinically important.¹

Elimination

Metabolism

Mainly, if not exclusively, metabolized in the liver by CYP3A.^{1 6} Substrate of the P-glycoprotein transport system.¹ Metabolites have little or no V₂-receptor antagonist activity.¹

Elimination Route

Following administration of radiolabeled tolvaptan, approximately 40 and 59% of radioactivity recovered in urine and feces, respectively; <1% of tolvaptan dose is excreted unchanged in urine, about 19% is excreted unchanged in feces, and about 80% is metabolized.¹¹ Tolvaptan eliminated entirely (about 99%) by nonrenal mechanisms.^{1 11}

Half-life

Terminal-phase half-life is approximately 12 hours.¹

Special Populations

In patients with hyponatremia of any origin, clearance of drug is reduced.¹

Moderate or severe hepatic impairment decreases clearance; not considered clinically important.¹

CHF decreases clearance; not considered clinically important.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions

• 
  

  Selective arginine vasopressin (antidiuretic hormone) V₂ receptor antagonist.^{1 2 3 4 5}

  
  


• 
  

  Affinity for V₂ receptors 29 times that for V_1A receptors.^{1 4 5}

  
  


• 
  

  Does not appear to have any affinity for V_1B receptors.⁵

  
  


• 
  

  Antagonizes effects of vasopressin at V₂ receptors of distal nephron, resulting in increased free water clearance, decreased urine osmolality, and increased serum sodium concentrations.^{1 2 4}

  
  


• 
  

  Urinary sodium and potassium excretion and plasma potassium concentrations not substantially altered; plasma concentrations of endogenous arginine vasopressin may increase.^{1 2 4}

  
  


• 
  

  Does not appear to have a clinically important effect on the QT_c interval.¹

  
  

Advice to Patients

• 
  

  Under the REMS program approved by FDA, medication guide must be dispensed with every prescription for the drug.¹² (See Overly Rapid Correction of Serum Sodium Concentration under Cautions.) Importance of reviewing this information with the patient.¹ Importance of reading the medication guide before initiating therapy and each time the prescription is refilled.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.¹ Importance of informing clinicians if receiving drugs that are moderate or potent inhibitors of CYP3A or inhibitors of the P-glycoprotein transport system (see Interactions).¹

  
  


• 
  

  Potential for too rapid an increase in serum sodium concentration, which may result in serious neurologic sequelae.¹ Importance of informing clinician if any signs or symptoms suggestive of osmotic demyelination syndrome (e.g., difficulty speaking or swallowing, drowsiness, confusion, mood changes, weakness or involuntary movements in the extremities, seizures) occur.¹ Importance of patients not stopping or restarting tolvaptan therapy on their own initiative.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Necessity of advising women to avoid breast-feeding during tolvaptan therapy.¹

  
  


• 
  

  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.

Tolvaptan

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	15 mg	Samsca	Otsuka
		30 mg	Samsca	Otsuka

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 October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Otsuka America Pharmaceutical, Inc. Samsca (tolvaptan) tablets prescribing information. Rockville, MD; 2009 May.

2. Schrier RW, Gross P, Gheorghiade M et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006; 355:2099-112. [PubMed 17105757]

3. Konstam MA, Gheorghiade M, Burnett JC et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007; 297:1319-31. [PubMed 17384437]

4. Farmakis D, Filippatos G, Kremastinos DT et al. Vasopressin and vasopressin antagonists in heart failure and hyponatremia. Curr Heart Fail Rep. 2008; 5:91-6. [PubMed 18765079]

5. Miyazaki T, Fujiki H, Yamamura Y et al. Tolvaptan, an orally active vasopressin V(2)-receptor antagonist - pharmacology and clinical trials. Cardiovasc Drug Rev. 2007; 25:1-13. [PubMed 17445084]

6. . Tolvaptan (Samsca) for hyponatremia. Med Lett Drugs Ther. 2009; 51:95-6. [PubMed 20224525]

7. Shoaf SE, Elizari MV, Wang Z et al. Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias. J Cardiovasc Pharmacol Ther. 2005; 10:165-71. [PubMed 16211205]

8. Shoaf SE, Bramer SL, Bricmont P et al. Pharmacokinetic and pharmacodynamic interaction between tolvaptan, a non-peptide AVP antagonist, and furosemide or hydrochlorothiazide. J Cardiovasc Pharmacol. 2007; 50:213-22. [PubMed 17703139]

9. Berl T, Quittnat-Pelletier F, Verbalis JG et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol. 2010; 21:705-12. [PubMed 20185637]

10. Merck & Co., Inc. Mevacor (lovastatin) tablets prescribing information. Whitehouse Station, NJ; 2010 May.

11. Otsuka America Pharmaceutical, Inc., Rockville, MD: Personal communication.

12. Otsuka Pharmaceutical. Proposed risk evaluation and mitigation strategy (REMS): NDA 22-275 Samsca (tolvaptan). Rockville, MD; 2009 May 19. Available from FDA website. Accessed 2010 Dec 21.

More Tolvaptan resources

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

• Tolvaptan MedFacts Consumer Leaflet (Wolters Kluwer)


• Tolvaptan Professional Patient Advice (Wolters Kluwer)


• tolvaptan Advanced Consumer (Micromedex) - Includes Dosage Information


• Samsca Prescribing Information (FDA)


• Samsca Consumer Overview

Compare Tolvaptan with other medications

• Euvolemic Hyponatremia
• Hyponatremia

Slow Release Iron

Generic Name: ferrous sulfate (FARE us SUL fate)

Brand Names: Feosol, Fer-Gen-Sol, Fer-In-Sol, Fer-in-Sol, Fer-Iron, Feratab, FeroSul, Ferra T.D. Caps, Ferro-Bob, Lydia E. Pinkham, MyKidz Iron 10, Slow Fe, Slow Release Iron

What is Slow Release Iron (ferrous sulfate)?

Ferrous sulfate is a type of iron. You normally get iron from the foods you eat. In your body, iron becomes a part of your hemoglobin (HEEM o glo bin) and myoglobin (MY o glo bin). Hemoglobin carries oxygen through your blood to tissues and organs. Myoglobin helps your muscle cells store oxygen.

Ferrous sulfate is used to treat iron deficiency anemia (a lack of red blood cells caused by having too little iron in the body).

Ferrous sulfate may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Slow Release Iron (ferrous sulfate)?

Ask a doctor or pharmacist if it is safe for you to take this medication if you have iron overload syndrome, hemolytic anemia (a lack of red blood cells), porphyria (a genetic enzyme disorder that causes symptoms affecting the skin or nervous system), thalassemia (a genetic disorder of red blood cells), if you are an alcoholic, or if you receive regular blood transfusions.

Avoid taking any other multivitamin or mineral product within 2 hours before or after you take ferrous sulfate. Taking similar mineral products together at the same time can result in a mineral overdose or serious side effects. Seek emergency medical attention if you think you have used too much of this medicine, or if anyone has accidentally swallowed it. An overdose of iron can be fatal, especially in a young child.

Overdose symptoms may include nausea, severe stomach pain, bloody diarrhea, coughing up blood or vomit that looks like coffee grounds, shallow breathing, weak and rapid pulse, pale skin, blue lips, and seizure (convulsions).

Take ferrous sulfate on an empty stomach, at least 1 hour before or 2 hours after a meal. Avoid taking antacids or antibiotics within 2 hours before or after taking ferrous sulfate.

Ferrous sulfate is only part of a complete program of treatment that may also include a special diet. It is very important to follow the diet plan created for you by your doctor or nutrition counselor. You should become very familiar with the list of foods you should eat to make sure you get enough iron from both your diet and your medication.

What should I discuss before taking Slow Release Iron (ferrous sulfate)?

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

• 
  

  iron overload syndrome;

  
  


• 
  

  hemolytic anemia (a lack of red blood cells);

  
  


• 
  

  porphyria (a genetic enzyme disorder that causes symptoms affecting the skin or nervous system);

  
  


• 
  

  thalassemia (a genetic disorder of red blood cells);

  
  


• 
  

  if you are an alcoholic; or

  
  


• 
  

  if you receive regular blood transfusions.

  
  

It is not known whether this medication could be harmful to an unborn baby. Tell your doctor if you become pregnant during treatment. It is not known whether ferrous sulfate 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 ferrous sulfate to a child without the advice of a doctor.

How should I take Slow Release Iron (ferrous sulfate)?

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.

Take ferrous sulfate on an empty stomach, at least 1 hour before or 2 hours after a meal. Avoid taking antacids or antibiotics within 2 hours before or after taking ferrous sulfate . Take this medication with a full glass of water. Do not crush, chew, break, or open an extended-release tablet or capsule. Swallow the pill whole. Breaking or opening the pill may cause too much of the drug to be released at one time. Shake the oral suspension (liquid) well just before you measure a dose. Measure the liquid with a special dose-measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Ferrous sulfate can stain your teeth, but this effect is temporary. To prevent tooth staining, mix the liquid form of ferrous sulfate with water or fruit juice (not with milk) and drink the mixture through a straw. You may also clean your teeth with baking soda once per week to treat any tooth staining.

Ferrous sulfate is only part of a complete program of treatment that may also include a special diet. It is very important to follow the diet plan created for you by your doctor or nutrition counselor. You should become very familiar with the list of foods you should eat to make sure you get enough iron from both your diet and your medication.

Store at room temperature, away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222, especially if a child has accidentally swallowed it. An overdose of ferrous sulfate can be fatal to a child.

Overdose symptoms may include nausea, severe stomach pain, bloody diarrhea, coughing up blood or vomit that looks like coffee grounds, shallow breathing, weak and rapid pulse, pale skin, blue lips, and seizure (convulsions).

What should I avoid while taking Slow Release Iron (ferrous sulfate)?

Avoid taking any other multivitamin or mineral product within 2 hours before or after you take ferrous sulfate. Taking similar mineral products together at the same time can result in a mineral overdose or serious side effects.

Avoid taking an antibiotic medicine within 2 hours before or after you take ferrous sulfate. This is especially important if you are taking an antibiotic such as ciprofloxacin (Cipro), demeclocycline (Declomycin), doxycycline (Adoxa, Doryx, Oracea, Vibramycin), levofloxacin (Levaquin), lomefloxacin (Maxaquin), minocycline (Dynacin, Minocin, Solodyn, Vectrin), norfloxacin (Noroxin), ofloxacin (Floxin), or tetracycline (Brodspec, Panmycin, Sumycin, Tetracap).

Certain foods can also make it harder for your body to absorb ferrous sulfate. Avoid taking this medication within 1 hour before or 2 hours after eating fish, meat, liver, and whole grain or "fortified" breads or cereals.

Avoid using antacids without your doctor's advice. Use only the type of antacid your doctor recommends. Some antacids can make it harder for your body to absorb ferrous sulfate.

Slow Release Iron (ferrous sulfate) 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.

Less serious side effects may include:

• 
  

  constipation;

  
  


• 
  

  upset stomach;

  
  


• 
  

  black or dark-colored stools; or

  
  


• 
  

  temporary staining of the teeth.

  
  

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 Slow Release Iron (ferrous sulfate)?

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

• 
  

  acetohydroxamic acid (Lithostat);

  
  


• 
  

  chloramphenicol;

  
  


• 
  

  cimetidine (Tagamet);

  
  


• 
  

  etidronate (Didronel);

  
  


• 
  

  dimercaprol (an injection used to treat poisoning by arsenic, lead, or mercury);

  
  


• 
  

  levodopa (Larodopa, Dopar, Sinemet);

  
  


• 
  

  methyldopa (Aldomet); or

  
  


• 
  

  penicillamine (Cuprimine).

  
  

This list is not complete and other drugs may interact with ferrous sulfate. 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 Slow Release Iron resources

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

• FeoSol MedFacts Consumer Leaflet (Wolters Kluwer)


• Feosol MedFacts Consumer Leaflet (Wolters Kluwer)


• Feosol Advanced Consumer (Micromedex) - Includes Dosage Information


• Fer-Gen-Sol Drops MedFacts Consumer Leaflet (Wolters Kluwer)


• Slow Fe Controlled-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Slow Release Iron with other medications

• Anemia Associated with Chronic Renal Failure
• Iron Deficiency Anemia
• Vitamin/Mineral Supplementation and Deficiency
• Vitamin/Mineral Supplementation during Pregnancy/Lactation

Where can I get more information?

• Your pharmacist can provide more information about ferrous sulfate.

See also: Slow Release Iron side effects (in more detail)

Tenuate

Pronunciation: dye-eth-il-PROE-pee-on
Generic Name: Diethylpropion
Brand Name: Tenuate

Tenuate is used for:

Short-term weight reduction in the management of obesity as part of a diet plan, exercise, and behavior therapy.

Tenuate is an appetite suppressant. It works by acting on the appetite center in the brain to cause a temporary reduction in hunger or craving for food.

Do NOT use Tenuate if:

• you are allergic to any ingredient in Tenuate


• you are currently taking guanadrel, guanethidine, furazolidone, or other weight loss medicines


• you are currently taking or have taken a monoamine oxidase (MAO) inhibitor (eg, phenelzine) within the last 14 days


• you have a history of heart disease, atherosclerosis, brain or spinal cord disorders, high blood pressure in the lungs, severe or uncontrolled high blood pressure, an overactive thyroid, glaucoma, a highly nervous state or agitation, or a history of substance abuse

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

Before using Tenuate:

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

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


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


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


• if you have kidney problems, diabetes, high blood pressure, blood vessel disease, irregular heartbeat or other heart problems, or a history of seizures


• if you have used weight loss medicines within the last year

Some MEDICINES MAY INTERACT with Tenuate. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Furazolidone, MAO inhibitors (eg, phenelzine), general anesthetics (eg, thiopental), or tramadol because side effects such as elevated blood pressure, slow or irregular heartbeat, elevated body temperature, or an increased risk of seizures may occur


• Serotonin reuptake inhibitors (eg, fluoxetine) because the actions and side effects of these medicines may be increased


• Guanethidine and methyldopa because the effectiveness of these medicines may be decreased


• Phenothiazines (eg, thioridazine) because the effectiveness of Tenuate may be decreased

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

How to use Tenuate:

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

• Take Tenuate 1 hour before meals. If desired, take it at least 4 to 6 hours before bedtime to avoid night hunger, or as directed by your doctor.


• If you miss a dose of Tenuate, take it as soon as possible. If it is after 4 pm, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

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

Important safety information:

• Tenuate may cause drowsiness, dizziness, or blurred vision. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Tenuate.


• Avoid drinking alcohol or taking other medications that cause drowsiness (eg, sedatives, tranquilizers) while taking Tenuate. Tenuate will add to the effects of alcohol and other depressants. Ask your pharmacist if you have questions about which medicines are depressants.


• Do not use Tenuate with any other weight loss medicines, including over-the-counter, prescription, or herbal/natural supplements.


• Before you have any medical or dental treatments, emergency care, or surgery, tell the doctor or dentist that you are taking Tenuate.


• It is dangerous and illegal to use Tenuate to improve athletic skills, mental alertness, or to stay awake.


• Diabetes patients - Tenuate may affect your blood sugar level. Your doctor may need to adjust the dose of diabetes medicine you are taking.


• Use Tenuate with caution in the ELDERLY because they may be more sensitive to its effects.


• Tenuate is not recommended for CHILDREN younger than 16 years of age. Safety and effectiveness in this age group have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you plan on becoming pregnant, discuss with your doctor the benefits and risks of using Tenuate during pregnancy. Tenuate is excreted in breast milk. If you are or will be breast-feeding while you are using Tenuate, check with your doctor or pharmacist to discuss the risks to your baby.

Tenuate may be habit-forming and has the potential for abuse. Stopping Tenuate suddenly can cause symptoms of WITHDRAWAL, including extreme tiredness, depression, and sleep changes. Do not stop taking Tenuate suddenly. If you feel that your medicine is not working any more, talk with your doctor. Do not take more medicine or use it for a longer period of time than prescribed.

Possible side effects of Tenuate:

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

Anxiety; bad taste in mouth; change in sex drive; constipation; depression; diarrhea; difficulty moving; dizziness; drowsiness; dry mouth; enlargement of breasts; exaggerated sense of well-being; general body discomfort; hair loss; headache; increased pupil size; increased urination; jitteriness; menstrual upset; nausea; nervousness; restlessness; sleeplessness; stomach upset; tremor; vomiting.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bizarre behavior; blurred vision; chest pain; chills; fainting; fast or irregular heartbeat; fever; impotence; painful urination; pounding in the chest; seizures; shortness of breath; sore throat; swelling of the legs and feet; unusual bruising.

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

See also: Tenuate side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include aggressiveness; changes in heartbeat; confusion; diarrhea; excessive sweating; fainting; hallucinations; large pupil size; nausea; pounding in the chest; panic states; rapid breathing; restlessness; stomach cramps; tremor; vomiting.

Proper storage of Tenuate:

Store Tenuate at room temperature, below 86 degrees F (30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Tenuate out of the reach of children and away from pets.

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Tenuate resources

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

• Tenuate Consumer Overview


• Tenuate Advanced Consumer (Micromedex) - Includes Dosage Information


• Diethylpropion Prescribing Information (FDA)


• Diethylpropion Hydrochloride Monograph (AHFS DI)

Compare Tenuate with other medications

• Obesity

Protelos

1. Name Of The Medicinal Product

PROTELOS 2 g granules for oral suspension

2. Qualitative And Quantitative Composition

Each sachet contains 2 g of strontium ranelate.

Excipient: Each sachet also contains 20 mg of aspartame (E951).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Granules for oral suspension

Yellow granules

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of osteoporosis in postmenopausal women to reduce the risk of vertebral and hip fractures (see section 5.1).

4.2 Posology And Method Of Administration

Posology

The recommended dose is one 2 g sachet once daily by oral administration.

Due to the nature of the treated disease, strontium ranelate is intended for long-term use.

The absorption of strontium ranelate is reduced by food, milk and derivative products and therefore, PROTELOS should be administered in-between meals. Given the slow absorption, PROTELOS should be taken at bedtime, preferably at least two hours after eating (see sections 4.5 and 5.2).

Patients treated with strontium ranelate should receive vitamin D and calcium supplements if dietary intake is inadequate.

Elderly population

The efficacy and safety of strontium ranelate have been established in a broad age range (up to 100 years at inclusion) of postmenopausal women with osteoporosis. No dose adjustment is required in relation to age.

Renal impairment

Strontium ranelate is not recommended for patients with severe renal impairment (creatinine clearance below 30 ml/min) (see sections 4.4 and 5.2). No dose adjustment is required in patients with mild-to-moderate renal impairment (30-70 ml/min creatinine clearance) (see section 5.2).

Hepatic impairment

As strontium ranelate is not metabolised, no dose adjustment is required in patients with hepatic impairment.

Paediatric population

The safety and efficacy of PROTELOS in children aged below 18 years have not been established. No data are available.

Method of administration

For oral use.

The granules in the sachets must be taken as a suspension in a glass containing a minimum of 30 ml (approximately one third of a standard glass) of water.

Although in-use studies have demonstrated that strontium ranelate is stable in suspension for 24 hours after preparation, the suspension should be drunk immediately after being prepared.

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

Use in patients with renal impairment

In the absence of bone safety data in patients with severe renal impairment treated with strontium ranelate, PROTELOS is not recommended in patients with a creatinine clearance below 30 ml/min (see section 5.2). In accordance with good medical practice, periodic assessment of renal function is recommended in patients with chronic renal impairment. Continuation of treatment with PROTELOS in patients developing severe renal impairment should be considered on an individual basis.

Venous thromboembolism

In phase III placebo-controlled studies, strontium ranelate treatment was associated with an increase in the annual incidence of venous thromboembolism (VTE), including pulmonary embolism (see section 4.8). The cause of this finding is unknown. PROTELOS should be used with caution in patients at increased risk of VTE, including patients with a past history of VTE. When treating patients at risk, or developing risk of VTE, particular attention should be given to possible signs and symptoms of VTE and adequate preventive measures taken.

Skin reactions

Cases of severe hypersensitivity syndromes, including, in particular, drug rash with eosinophilia and systemic symptoms (DRESS), sometimes fatal, have been reported with the use of PROTELOS (see section 4.8). The DRESS syndrome is characterised by rash, fever, eosinophilia and systemic involvement (e.g. adenopathy, hepatitis, interstitial nephropathy, interstitial lung disease). Time to onset was usually around 3-6 weeks and the outcome in most cases favourable upon discontinuation of PROTELOS and after initiation of corticosteroid therapy. Recovery could be slow and recurrences of the syndrome have been reported in some cases after discontinuation of corticosteroid therapy.

Patients should be informed to stop PROTELOS immediately and permanently when a rash occurs and to seek medical advice. Patients who have stopped treatment due to hypersensitivity reactions or other serious allergic reactions should not re-start therapy with PROTELOS.

Interaction with laboratory test

Strontium interferes with colorimetric methods for the determination of blood and urinary calcium concentrations. Therefore, in medical practice, inductively coupled plasma atomic emission spectrometry or atomic absorption spectrometry methods should be used to ensure an accurate assessment of blood and urinary calcium concentrations.

Excipient

PROTELOS contains a source of phenylalanine, which may be harmful for people with phenylketonuria.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Food, milk and derivative products, and medicinal products containing calcium may reduce the bioavailability of strontium ranelate by approximately 60-70%. Therefore, administration of PROTELOS and such products should be separated by at least two hours (see section 5.2).

As divalent cations can form complexes with oral tetracycline and quinolone antibiotics at the gastro-intestinal level and thereby reduce their absorption, simultaneous administration of strontium ranelate with these medicinal products is not recommended. As a precautionary measure, PROTELOS treatment should be suspended during treatment with oral tetracycline or quinolone antibiotics.

An in vivo clinical interaction study showed that the administration of aluminium and magnesium hydroxides either two hours before or together with strontium ranelate caused a slight decrease in the absorption of strontium ranelate (20-25% AUC decrease), while absorption was almost unaffected when the antacid was given two hours after strontium ranelate. It is therefore preferable to take antacids at least two hours after PROTELOS. However, when this dosing regimen is impractical due to the recommended administration of PROTELOS at bedtime, concomitant intake remains acceptable.

No interaction was observed with oral supplementation of vitamin D.

No evidence of clinical interactions or relevant increase of blood strontium levels with medicinal products expected to be commonly prescribed concomitantly with PROTELOS in the target population were found during clinical trials. These included: nonsteroidal anti-inflammatory agents (including acetylsalicylic acid), anilides (such as paracetamol), H₂ blockers and proton pump inhibitors, diuretics, digoxin and cardiac glycosides, organic nitrates and other vasodilators for cardiac diseases, calcium channel blockers, beta blockers, ACE inhibitors, angiotensin II antagonists, selective beta-2 adrenoceptor agonists, oral anticoagulants, platelet aggregation inhibitors, statins, fibrates and benzodiazepine derivatives.

4.6 Pregnancy And Lactation

Pregnancy

PROTELOS is only intended for use in postmenopausal women. There are no data from the use of strontium ranelate in pregnant women.

At high doses, animal studies have shown reversible bone effects in the offspring of rats and rabbits treated during pregnancy (see section 5.3). If PROTELOS is used inadvertently during pregnancy, treatment must be stopped.

Breastfeeding

Physico-chemical data suggest excretion of Strontium ranelate in human milk. PROTELOS should not be used during breast-feeding.

Fertility

No effects were observed on males and females fertility in animal studies.

4.7 Effects On Ability To Drive And Use Machines

Strontium ranelate has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

PROTELOS has been studied in clinical trials involving nearly 8,000 participants. Long-term safety has been evaluated in postmenopausal women with osteoporosis treated for up to 60 months with strontium ranelate 2 g/day (n=3,352) or placebo (n=3,317) in phase III studies. Mean age was 75 years at inclusion and 23% of the patients enrolled were 80 to 100 years of age.

There were no differences in the nature of adverse reactions between treatment groups regardless of whether patients were aged below or above 80 at inclusion.

Overall incidence rates for adverse reactions with strontium ranelate did not differ from placebo and adverse reactions were usually mild and transient. The most common adverse reactions consisted of nausea and diarrhoea, which were generally reported at the beginning of treatment with no noticeable difference between groups afterwards. Discontinuation of therapy was mainly due to nausea (1.3% and 2.2% in the placebo and strontium ranelate groups respectively).

In phase III studies, the annual incidence of venous thromboembolism (VTE) observed over 5 years was approximately 0.7%, with a relative risk of 1.4 (95% CI = [1.0 ; 2.0]) in strontium ranelate treated patients as compared to placebo (see section 4.4).

The following adverse reactions have been reported during clinical studies and/or post marketing use with Strontium ranelate.

Adverse reactions, defined as adverse events considered at least possibly attributable to strontium ranelate treatment in phase III studies are listed below using the following convention (frequencies versus placebo): very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

System Organ Class (SOC) Frequency category Adverse Reaction	Percentage of Patients Experiencing the adverse reaction
Treatment
Strontium ranelate (n=3352)	Placebo (n=3317)
Psychiatric disorders
Frequency unknown:a
Confusional state	-	-
Insomnia	-	-
Nervous system disorders
Common:
Headache	3.3%	2.7%
Disturbances in consciousness	2.6%	2.1%
Memory loss	2.5%	2.0%
Uncommon:
Seizures	0.4%	0.1%
Vascular disorders
Common:
Venous thromboembolism (VTE)	2.7%	1.9%
Respiratory, thoracic and mediastinal disorders
Frequency unknown:a
Bronchial hyperreactivity	-	-
Gastrointestinal disorders
Common:
Nausea	7.1%	4.6%
Diarrhoea	7.0%	5.0%
Loose stools	1.0%	0.2%
Frequency unknown:a
Vomiting	-	-
Abdominal pain	-	-
Oral mucosal irritation (stomatitis and/or mouth ulceration)	-	-
Gastrooesophageal reflux	-	-
Dyspepsia	-	-
Constipation	-	-
Flatulence	-	-
Hepatobiliary disorders
Frequency unknown:a
Serum transaminase increased (in association with hypersensitivity skin reactions)	-	-
Hepatitis	-	-
Skin and subcutaneous tissue disorders
Common:
Dermatitis	2.3%	2.0%
Eczema	1.8%	1.4%
Frequency unknown:a
Hypersensitivity skin reactions (rash, pruritus, urticaria, angioedema)	-	-
Severe hypersensitivity syndromes including Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS (see Section 4.4)	-	-
Alopecia	-	-
Musculoskeletal and connective tissue disorders
Frequency unknown:a
Musculoskeletal pain (muscle spasm, myalgia, bone pain, arthralgia and pain in extremity)	-	-
General disorders and administration site conditions
Frequency unknown:a
Peripheral oedema	-	-
Pyrexia (in association with hypersensitivity skin reactions)	-	-
Blood and Lymphatic disorders
Frequency unknown:a
Bone marrow failure	-	-
Eosinophilia (in association with hypersensitivity skin reactions)	-	-
Lymphadenopathy (in association with hypersensitivity skin reactions)	-	-
Investigations
Common:
Blood Creatine phosphokinase (CPK) increasedb	1.4%	0.6%

^a Post-marketing experience

^b Musculo-skeletal fraction > 3 times the upper limit of the normal range. In most cases, these values spontaneously reverted to normal without change in treatment.

4.9 Overdose

Good tolerance was shown in a clinical study investigating the repeated administration of 4 g strontium ranelate per day over 25 days in healthy postmenopausal women. Single administration of doses up to 11 g in healthy young male volunteers did not cause any particular symptoms.

Following episodes of overdoses during clinical trials (up to 4 g/day for a maximal duration of 147 days), no clinically relevant events were observed.

Administration of milk or antacids may be helpful to reduce the absorption of the active substance. In the event of substantial overdose, vomiting may be considered to remove unabsorbed active substance.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs for the treatment of bone diseases - Other drugs affecting bone structure and mineralisation, ATC code: M05BX03

Mechanism of action

In vitro, strontium ranelate:

- increases bone formation in bone tissue culture as well as osteoblast precursor replication and collagen synthesis in bone cell culture;

- reduces bone resorption by decreasing osteoclast differentiation and resorbing activity.

This results in a rebalance of bone turnover in favour of bone formation.

The activity of strontium ranelate was studied in various non-clinical models. In particular, in intact rats, strontium ranelate increases trabecular bone mass, trabeculae number and thickness; this results in an improvement of bone strength.

In bone tissue of treated animals and humans, strontium is mainly adsorbed onto the crystal surface and only slightly substitutes for calcium in the apatite crystal of newly formed bone. Strontium ranelate does not modify the bone crystal characteristics. In iliac crest bone biopsies obtained after up to 60 months of treatment with strontium ranelate 2 g/day in phase III trials, no deleterious effects on bone quality or mineralisation were observed.

The combined effects of strontium distribution in bone (see section 5.2) and increased X-ray absorption of strontium as compared to calcium, leads to an amplification of bone mineral density (BMD) measurement by dual-photon X-ray absorptiometry (DXA). Available data indicate that these factors account for approximately 50% of the measured change in BMD over 3 years of treatment with PROTELOS 2 g/day. This should be taken into account when interpreting BMD changes during treatment with PROTELOS. In phase III studies, which demonstrated the anti-fracture efficacy of PROTELOS treatment, measured mean BMD increased from baseline with PROTELOS by approximately 4% per year at the lumbar spine and 2% per year at the femoral neck, reaching 13% to 15% and 5% to 6% respectively after 3 years, depending on the study.

In phase III studies, as compared to placebo, biochemical markers of bone formation (bone-specific alkaline phosphatase and C-terminal propeptide of type I procollagen) increased and those of bone resorption (serum C-telopeptide and urinary N-telopeptide cross links) decreased from the third month of treatment up to 3 years.

Secondary to the pharmacological effects of strontium ranelate, slight decreases in calcium and parathyroid hormone (PTH) serum concentrations, increases in blood phosphorus concentrations and in total alkaline phosphatase activity were observed, with no observed clinical consequences.

Clinical efficacy

Osteoporosis is defined as BMD of the spine or hip 2.5 SD or more below the mean value of a normal young population. A number of risk factors are associated with postmenopausal osteoporosis including low bone mass, low bone mineral density, early menopause, a history of smoking and a family history of osteoporosis. The clinical consequence of osteoporosis is fractures. The risk of fractures is increased with the number of risk factors.

Treatment of postmenopausal osteoporosis:

The anti-fracture studies program of PROTELOS was made up of two placebo-controlled phase III studies: SOTI study and TROPOS study. SOTI involved 1,649 postmenopausal women with established osteoporosis (low lumbar BMD and prevalent vertebral fracture) and a mean age of 70 years. TROPOS involved 5,091 postmenopausal women with osteoporosis (low femoral neck BMD and prevalent fracture in more than half of them) and a mean age of 77 years. Together, SOTI and TROPOS enrolled 1,556 patients over 80 years at inclusion (23.1% of the study population). In addition to their treatment (2 g/day strontium ranelate or placebo), the patients received adapted calcium and vitamin D supplements throughout both studies.

PROTELOS reduced the relative risk of new vertebral fracture by 41% over 3 years in the SOTI study (table 1). The effect was significant from the first year. Similar benefits were demonstrated in women with multiple fractures at baseline. With respect to clinical vertebral fractures (defined as fractures associated with back pain and/or a body height loss of at least 1 cm), the relative risk was reduced by 38%. PROTELOS also decreased the number of patients with a body height loss of at least 1 cm as compared to placebo. Quality of life assessment on the QUALIOST specific scale as well as the General Health perception score of the SF-36 general scale indicated benefit of PROTELOS, compared with placebo.

Efficacy of PROTELOS to reduce the risk of new vertebral fracture was confirmed in the TROPOS study, including for osteoporotic patients without fragility fracture at baseline.

Table 1: Incidence of patients with vertebral fracture and relative risk reduction
	Placebo	PROTELOS	Relative Risk Reduction vs. placebo (95%CI), p value
SOTI	N=723	N=719
New vertebral fracture over 3 years	32.8%	20.9%	41% (27-52), p<0.001
New vertebral fracture over the 1st year	11.8%	6.1%	49% (26-64), p<0.001
New clinical vertebral fracture over 3 years	17.4%	11.3%	38% (17-53), p<0.001
TROPOS	N=1823	N=1817
New vertebral fracture over 3 years	20.0%	12.5%	39% (27-49), p<0.001

In patients over 80 years of age at inclusion, a pooled analysis of SOTI and TROPOS studies showed that PROTELOS reduced the relative risk of experiencing new vertebral fractures by 32% over 3 years (incidence of 19.1% with strontium ranelate vs. 26.5% with placebo).

In an a-posteriori analysis of patients from the pooled SOTI and TROPOS studies with baseline lumbar spine and / or femoral neck BMD in the osteopenic range and without prevalent fracture but with at least one additional risk factor for fracture (N=176), PROTELOS reduced the risk of a first vertebral fracture by 72% over 3 years (incidence of vertebral fracture 3.6% with strontium ranelate vs. 12.0% with placebo).

An a-posteriori analysis was performed on a subgroup of patients from the TROPOS study of particular medical interest and at high-risk of fracture [defined by a femoral neck BMD T-score

Table 2: Incidence of patients with hip fracture and relative risk reduction in patients with BMD
	Placebo	PROTELOS	Relative Risk Reduction vs. placebo (95%CI), p value
TROPOS	N=995	N=982
Hip fracture over 3 years	6.4%	4.3%	36% (0-59), p=0.046

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with PROTELOS in all subsets of the paediatric population in osteoporosis (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic Properties

Strontium ranelate is made up of 2 atoms of stable strontium and 1 molecule of ranelic acid, the organic part permitting the best compromise in terms of molecular weight, pharmacokinetics and acceptability of the medicinal product. The pharmacokinetics of strontium and ranelic acid have been assessed in healthy young men and healthy postmenopausal women, as well as during long-term exposure in postmenopausal osteoporotic women including elderly women.

Due to its high polarity, the absorption, distribution and binding to plasma proteins of ranelic acid are low. There is no accumulation of ranelic acid and no evidence of metabolism in animals and humans. Absorbed ranelic acid is rapidly eliminated unchanged via the kidneys.

Absorption

The absolute bioavailability of strontium is about 25% (range 19-27%) after an oral dose of 2 g strontium ranelate. Maximum plasma concentrations are reached 3-5 hours after a single dose of 2 g. Steady state is reached after 2 weeks of treatment. Intake of strontium ranelate with calcium or food reduces the bioavailability of strontium by approximately 60-70%, compared with administration 3 hours after a meal. Due to the relatively slow absorption of strontium, food and calcium intake should be avoided both before and after administration of PROTELOS. Oral supplementation with vitamin D has no effect on strontium exposure.

Distribution

Strontium has a volume of distribution of about 1 l/kg. The binding of strontium to human plasma proteins is low (25%) and strontium has a high affinity for bone tissue. Measurement of strontium concentration in iliac crest bone biopsies from patients treated for up to 60 months with strontium ranelate 2 g/day indicate that bone strontium concentrations may reach a plateau after about 3 years of treatment. There are no data in patients to demonstrate elimination kinetics of strontium from bone off-therapy.

Biotransformation

As a divalent cation, strontium is not metabolised. Strontium ranelate does not inhibit cytochrome P450 enzymes.

Elimination

The elimination of strontium is time and dose independent. The effective half-life of strontium is about 60 hours. Strontium excretion occurs via the kidneys and the gastrointestinal tract. Its plasma clearance is about 12 ml/min (CV 22%) and its renal clearance about 7 ml/min (CV 28%).

Pharmacokinetics in special clinical situations

Elderly

Population pharmacokinetic data showed no relationship between age and apparent clearance of strontium in the target population.

Patients with renal impairment

In patients with mild-to-moderate renal impairment (30-70 ml/min creatinine clearance), strontium clearance decreases as creatinine clearance decreases (approximately 30% decrease over the creatinine clearance range 30 to 70 ml/min) and thereby induces an increase in strontium plasma levels. In phase III studies, 85% of the patients had a creatinine clearance between 30 and 70 ml/min and 6% below 30 ml/min at inclusion, and the mean creatinine clearance was about 50 ml/min. No dosage adjustment is therefore required in patients with mild-to-moderate renal impairment.

There is no pharmacokinetic data in patients with severe renal impairment (creatinine clearance below 30 ml/min).

Patients with hepatic impairment

There is no pharmacokinetic data in patients with hepatic impairment. Due to the pharmacokinetic properties of strontium, no effect is expected.

5.3 Preclinical Safety Data

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential.

Chronic oral administration of strontium ranelate at high doses in rodents induced bone and tooth abnormalities, mainly consisting of spontaneous fractures and delayed mineralisation. These effects were reported at bone strontium levels 2-3 times higher than long-term clinical bone strontium levels and were reversible after cessation of treatment.

Developmental toxicity studies in rats and rabbits resulted in bone and tooth abnormalities (e.g. bent long bones and wavy ribs) in the offspring. In rats, these effects were reversible 8 weeks after cessation of treatment.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Aspartame (E951)

Maltodextrin

Mannitol (E421)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

- 3 years

- Once reconstituted in water, the suspension is stable for 24 hours. However, it is recommended to drink the suspension immediately after preparation (see section 4.2)

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Paper/polyethylene/aluminium/polyethylene sachets.

Pack sizes

Boxes containing 7, 14, 28, 56, 84 or 100 sachets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

LES LABORATOIRES SERVIER

50, rue Carnot

92284 Suresnes cedex

France

8. Marketing Authorisation Number(S)

EU/1/04/288/001

EU/1/04/288/002

EU/1/04/288/003

EU/1/04/288/004

EU/1/04/288/005

EU/1/04/288/006

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 21/09/2004

Date of renewal: 21/09/2009

10. Date Of Revision Of The Text

09/2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu