Loratadine 10mg Tablets

1. Name Of The Medicinal Product

LORATADINE 10mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 10mg Loratadine.

For excipients, see section 6.1

3. Pharmaceutical Form

Tablet.

White, or almost white 8mm round, flat tablets, with the letter “L” on one side and a central division line on the reverse.

4. Clinical Particulars

4.1 Therapeutic Indications

Loratadine Tablets are indicated for the symptomatic treatment of allergic rhinitis and chronic idiopathic urticaria.

4.2 Posology And Method Of Administration

Adults and children over 12 years of age:

10 mg once daily. The tablet may be taken without regard to mealtime.

Children 2 to 12 years of age with:

Body weight more than 30 kg: 10 mg once daily.

Body weight 30 kg or less: These tablets are not suitable in children with a body weight less than 30 kg.

Efficacy and safety of Loratadine Tablets in children under 2 years of age has not been established.

Patients with severe liver impairment should be administered a lower initial dose because they may have reduced clearance of loratadine. An initial dose of 10 mg every other day is recommended for adults and children weighing more than 30 kg, and for children weighing 30 kg or less, 5 ml (5 mg) every other day is recommended.

No dosage adjustments are required in the elderly or in patients with renal insufficiency.

For oral administration.

4.3 Contraindications

Loratadine tablets are contraindicated in patients who are hypersensitive to the active substance or to any of the excipients in the formulation.

4.4 Special Warnings And Precautions For Use

Loratadine Tablets should be administered with caution in patients with severe liver impairment (see 4.2).

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The administration of Loratadine Tablets should be discontinued at least 48 hours before skin tests since antihistamines may prevent or reduce otherwise positive reactions to dermal reactivity index.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

When administered concomitantly with alcohol, Loratadine Tablets have no potentiating effects as measured by psychomotor performance studies.

Potential interaction may occur with all known inhibitors of CYP3A4 or CYP2D6 resulting in elevated levels of loratadine (see Section 5.2), which may cause an increase in adverse events.

4.6 Pregnancy And Lactation

Loratadine was not teratogenic in animal studies. The safe use of loratadine during pregnancy has not been established. The use of Loratadine Tablets during pregnancy is, therefore, not recommended.

Loratadine is excreted in breast milk, therefore the use of loratadine is not recommended in breast-feeding women.

4.7 Effects On Ability To Drive And Use Machines

In clinical trials that assessed driving ability, no impairment occurred in patients receiving loratadine. However, patients should be informed that very rarely some people experienced drowsiness, which may affect their ability to drive or use machines.

4.8 Undesirable Effects

In clinical trials in a paediatric population children aged 2 through 12 years, common adverse reactions reported in excess of placebo were headache (2.7%), nervousness (2.3%), and fatigue (1%).

In clinical trials involving adults and adolescents in a range of indications including AR and CIU, at the recommended dose of 10 mg daily, adverse reactions with loratadine were reported in 2% of patients in excess of those treated with placebo. The most frequent adverse reactions reported in excess of placebo were somnolence (1.2%), headache (0.6%), increased appetite (0.5%) and insomnia (0.1%). Other adverse reactions reported very rarely during the post-marketing period are listed in the following table.

Immune disorders	Anaphylaxis
Nervous system disorders	Dizziness
Cardiac disorders	Tachycardia, palpitation
Gastrointestinal disorders	Nausea, dry mouth, gastritis
Hepato-biliary disorders	Abnormal hepatic function
Skin and subcutaneous tissue disorders	Rash, alopecia
General disorders and administration site conditions	Fatigue

4.9 Overdose

Overdosage with loratadine increased the occurrence of anticholinergic symptoms. Somnolence, tachycardia, and headache have been reported with overdoses.

In the event of overdose, general symptomatic and supportive measures are to be instituted and maintained for as long as necessary. Administration of activated charcoal as a slurry with water may be attempted. Gastric lavage may be considered. Loratadine is not removed by haemodialysis and it is not known if loratadine is removed by peritoneal dialysis. Medical monitoring of the patient is to be continued after emergency treatment.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antihistamines – H₁ antagonist, ATC code: R06A X13.

Loratadine, the active ingredient in Loratadine Tablets, is a tricyclic antihistamine with selective, peripheral H₁-receptor activity.

Loratadine has no clinically significant sedative or anticholinergic properties in the majority of the population and when used at the recommended dosage.

During long-term treatment there were no clinically significant changes in vital signs, laboratory test values, physical examinations or electrocardiograms.

Loratadine has no significant H₂-receptor activity. It does not inhibit norepinephrine uptake and has practically no influence on cardiovascular function or on intrinsic cardiac pacemaker activity.

5.2 Pharmacokinetic Properties

After oral administration, loratadine is rapidly and well absorbed and undergoes extensive first pass metabolism, mainly by CYP3A4 and CYP2D6. The major metabolite-desloratadine (DL)-, is pharmacologically active and responsible for a large part of the clinical effect. Loratadine and DL achieve maximum plasma concentrations (T_max) between 1-1.5 hours and 1.5-3.7 hours after administration respectively.

Increase in plasma concentrations of loratadine has been reported after concomitant use with ketoconazole, erythromycin, and cimetidine in controlled trials, but without clinically significant changes (including electrocardiographic).

Loratadine is highly bound (97% to 99%) and its active metabolite moderately bound (73% to 76%) to plasma proteins.

In healthy subjects, plasma distribution half-lives of loratadine and its active metabolite are approximately 1 and 2 hours, respectively. The mean elimination half-lives in healthy adult subjects were 8.4 hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92 hours) for the major active metabolite.

Approximately 40% of the dose is excreted in the urine and 42% in the faeces over a 10 day period and mainly in the form of conjugated metabolites. Approximately 27% of the dose is eliminated in the urine during the first 24 hours. Less than 1% of the active substance is excreted unchanged in active form, as loratadine or DL.

The bioavailability parameters of loratadine and of the active metabolite are dose proportional.

The pharmacokinetic profile of loratadine and its metabolites is comparable in healthy adult volunteers and in healthy geriatric volunteers.

Concomitant ingestion of food can delay slightly the absorption of loratadine but without influencing the clinical effect.

In patients with chronic renal impairment, both the AUC and peak plasma levels (C_max) increased for loratadine and its metabolite as compared to the AUCs and peak plasma levels (C_max) of patients with normal renal function. The mean elimination half-lives of loratadine and its metabolite were not significantly different from that observed in normal subjects. Haemodialysis does not have an effect on the pharmacokinetics of loratadine or its active metabolite in subjects with chronic renal impairment.

In patients with chronic alcoholic liver disease, the AUC and peak plasma levels (C_max) of loratadine were double while the pharmacokinetic profile of the active metabolite was not significantly changed from that in patients with normal liver function. The elimination half-lives for loratadine and its metabolite were 24 hours and 37 hours, respectively, and increased with increasing severity of liver disease.

Loratadine and its active metabolite are excreted in the breast milk of lactating women.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

In reproductive toxicity studies, no teratogenic effects were observed. However, prolonged parturition and reduced viability of offspring were observed in rats at plasma levels (AUC) 10 times higher than those achieved with clinical doses.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate,

microcrystalline cellulose (E460),

maize starch,

magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

No special precautions for storage.

6.5 Nature And Contents Of Container

Transparent glassclear or white opaque

PVC/aluminium blister packs in cardboard outer box.

Pack sizes: 7, 10, 14, 15, 20, 28, 30, 50, 56, 60, 100

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

Administrative Data

7. Marketing Authorisation Holder

Actavis UK Limited (Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

United Kingdom

8. Marketing Authorisation Number(S)

PL 0142/0479

9. Date Of First Authorisation/Renewal Of The Authorisation

11 October 2001

10. Date Of Revision Of The Text

26/03/2011

LEGAL STATUS

P

Actemra

Generic Name: Tocilizumab
Class: Disease-modifying Antirheumatic Agents
Chemical Name: Immunoglobulin G1, anti-(human interleukin 6 receptor) (human-mouse monoclonal MRA heavy chain), disulfide with human-mouse monoclonal MRA k-chain, dimer
Molecular Formula: C₆₄₂₈H₉₉₇₆N₁₇₂₀O₂₀₁₈S₄₂
CAS Number: 375823-41-9

• Serious Infections


• 
  

  Serious, sometimes fatal infections including tuberculosis (pulmonary or extrapulmonary disease), bacterial and viral infections, invasive fungal infections (may be disseminated), and other opportunistic infections reported.¹ (See Infectious Complications under Cautions.)

  
  


• 
  

  Carefully consider risks and benefits prior to initiating tocilizumab therapy in patients with chronic or recurring infections.¹

  
  


• 
  

  Evaluate patients for latent tuberculosis infection prior to and periodically during tocilizumab therapy; if indicated, initiate appropriate antimycobacterial regimen prior to initiating tocilizumab therapy.¹

  
  


• 
  

  Closely monitor patients for infection, including active tuberculosis in those with a negative tuberculin skin test, during and after treatment.¹ If serious infection develops, discontinue tocilizumab until infection is controlled.¹

  
  

REMS:

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

Introduction

Biologic response modifier and a disease-modifying antirheumatic drug (DMARD); a recombinant humanized IgG₁ monoclonal antibody specific for interleukin-6 (IL-6) receptor.^{1 3 4 5 6 9 10 11 13}

Uses for Actemra

Rheumatoid Arthritis in Adults

Used to manage moderately to severely active rheumatoid arthritis in adults who have had an inadequate response to one or more tumor necrosis factor (TNF; TNF-α) blocking agents.¹

Can be used alone or in combination with methotrexate or other nonbiologic DMARDs (e.g., hydroxychloroquine, leflunomide, minocycline, sulfasalazine⁷ ).^{1 3 4 5 6}

Do not use concomitantly with other biologic DMARDs, such as TNF blocking agents (e.g., adalimumab, certolizumab, etanercept, golimumab, infliximab), interleukin-1 (IL-1) receptor antagonists (e.g., anakinra), anti-CD20 monoclonal antibodies (e.g., rituximab), and selective costimulation modulators (e.g., abatacept); concomitant use has not been studied and there is a possibility of increased immunosuppression and increased risk of infection.¹

Actemra Dosage and Administration

General

• 
  

  Do not initiate tocilizumab therapy in patients with ANC <2000/mm³, platelet count <100,000/mm³, or ALT or AST concentration >1.5 times the ULN.¹

  
  

Concomitant Therapy

• 
  

  Methotrexate, other nonbiologic DMARDs, NSAIAs, and corticosteroids may be continued in patients with rheumatoid arthritis.¹

  
  


• 
  

  Do not use concomitantly with other biologic DMARDs.¹ (See Rheumatoid Arthritis in Adults under Uses.)

  
  

REMS Program

• 
  

  FDA has approved a Risk Evaluation and Mitigation Strategy (REMS) for tocilizumab.¹⁴

  
  


• 
  

  The REMS program consists of a medication guide that must be provided to patients (see Advice to Patients) and a communication plan that includes initial and/or periodic communications targeting selected groups of clinicians.¹⁴

  
  


• 
  

  The goals are to inform patients and health care providers about the serious risks associated with the drug (see Cautions: Warnings/Precautions).¹⁴

  
  

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion once every 4 weeks.¹

Tocilizumab injection concentrate must be diluted prior to IV administration.¹

Allow tocilizumab infusion solutions to reach room temperature prior to administration.¹ (See Storage under Stability.)

Do not infuse tocilizumab simultaneously through the same IV line with other drugs.¹

Dilution

Dilute tocilizumab injection concentrate in 0.9% sodium chloride injection to provide a total volume of 100 mL (i.e., remove a volume of diluent equal to the total required volume of the injection concentrate from a 100-mL bag or bottle of 0.9% sodium chloride injection prior to adding the injection concentrate).¹ Slowly add the total required volume of tocilizumab injection concentrate to the diluent; gently invert bag or bottle to mix the solution.¹

Tocilizumab infusion solutions are compatible with polypropylene, polyethylene, and polyvinyl chloride infusion bags and polypropylene, polyethylene, and glass infusion bottles.¹

Discard any unused portion remaining in the vial since the injection concentrate contains no preservative.¹

Rate of Administration

Infuse dose over 60 minutes; do not administer by rapid IV injection (e.g., IV push or bolus).¹

Dosage

Adults

Rheumatoid Arthritis

IV

Initially, 4 mg/kg once every 4 weeks; may increase to 8 mg/kg once every 4 weeks based on clinical response.¹ Doses >800 mg are not recommended (see Special Populations under Pharmacokinetics).¹

Dosage Modification or Discontinuance for Toxicity

IV

If a serious infection, an opportunistic infection, or sepsis develops, discontinue tocilizumab until the infection is controlled.¹

If certain dose-related laboratory changes (i.e., elevated ALT or AST concentrations, neutropenia, thrombocytopenia) occur in patients receiving tocilizumab 8 mg/kg every 4 weeks, reduce tocilizumab dosage to 4 mg/kg every 4 weeks or temporarily interrupt or discontinue therapy (see tables).¹

Table 1. Recommended Dosage Adjustment Based on Changes in Liver Enzyme Laboratory Value

ALT or AST Value	Recommendation
>1 to 3 times ULN	Modify dosage of concomitant DMARDs if appropriate1
	For persistent increases within this range, reduce tocilizumab dosage to 4 mg/kg every 4 weeks or interrupt tocilizumab therapy until ALT/AST values have returned to normal1
>3 to 5 times ULN (confirmed by repeat testing)	Interrupt tocilizumab therapy until ALT/AST values are <3 times ULN and follow recommendations for ALT/AST values of >1 to 3 times ULN1
	For persistent increases of >3 times ULN, discontinue tocilizumab1
>5 times ULN	Discontinue tocilizumab1

Table 2. Recommended Dosage Adjustment Based on Absolute Neutrophil Count (ANC)

ANC (cells/mm3 )	Recommendation
>1000	Maintain current dosage1
500–1000	Interrupt tocilizumab therapy1
	When ANC is >1000/mm3, resume tocilizumab at 4 mg/kg every 4 weeks and increase to 8 mg/kg every 4 weeks as clinically indicated1
<500	Discontinue tocilizumab1

Table 3. Recommended Dosage Adjustment Based on Platelet Count

Platelet Count (cells/mm3)	Recommendation
50,0000–100,000	Interrupt tocilizumab therapy1
	When platelet count is >100,000/mm3, resume tocilizumab at 4 mg/kg every 4 weeks and increase to 8 mg/kg every 4 weeks as clinically indicated1
<50,000	Discontinue tocilizumab1

Prescribing Limits

Adults

Rheumatoid Arthritis

IV

Maximum 800 mg per dose.¹

Special Populations

Hepatic Impairment

Use is not recommended.¹

Renal Impairment

Dosage adjustment not necessary in patients with mild renal impairment; not evaluated in moderate or severe renal impairment.¹

Geriatric Patients

Manufacturer makes no specific dosage recommendations.¹

Cautions for Actemra

Contraindications

• 
  

  Manufacturer states none known.¹

  
  

Warnings/Precautions

Warnings

Infectious Complications

Serious, sometimes fatal infections (including bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic infections) reported, particularly in patients receiving concomitant therapy with other immunosuppressive agents (e.g., methotrexate, corticosteroids).¹ Opportunistic infections include tuberculosis, cryptococcal infection, aspergillosis, candidiasis, and pneumocystosis.¹ Infections may be disseminated.¹

Do not initiate tocilizumab in patients with active infections, including localized infections.¹ Consider potential risks and benefits of the drug prior to initiating therapy in patients with a history of chronic, recurring, serious, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who have resided or traveled in regions where tuberculosis or mycoses are endemic.¹

Closely monitor patients during and after treatment with tocilizumab for the development of signs or symptoms of infection.¹ If new infection occurs during therapy, perform thorough diagnostic evaluation (appropriate for immunocompromised patient), initiate appropriate anti-infective therapy, and closely monitor patient.¹ If serious infection, opportunistic infection, or sepsis develops, discontinue tocilizumab until the infection is controlled.¹

Evaluate all patients for latent tuberculosis and for risk factors for tuberculosis prior to and periodically during therapy.¹ When indicated, initiate an appropriate antimycobacterial regimen for the treatment of latent tuberculosis infection prior to tocilizumab therapy.¹ Consider initiation of antimycobacterial therapy prior to initiation of tocilizumab in individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed and in individuals with a negative test for latent tuberculosis who have risk factors for tuberculosis.¹ Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy.¹

Monitor all patients, including those with a negative test for latent tuberculosis, for active tuberculosis.¹

Viral reactivation can occur in patients receiving immunosuppressive therapies.¹ Herpes zoster exacerbation reported in patients receiving tocilizumab.¹

GI Perforation

GI perforation reported, usually as a complication of diverticulitis and most commonly in patients receiving concomitant therapy with NSAIAs, corticosteroids, or methotrexate.¹ The relative contribution of these agents versus tocilizumab to the occurrence of GI perforation remains to be determined.¹

Caution is advised if tocilizumab is used in patients at risk for GI perforation.¹

Promptly evaluate patients with new-onset abdominal symptoms for evidence of GI perforation.¹

Hematologic Effects

Possible neutropenia or thrombocytopenia.¹

Reduction in neutrophil count to <1000/mm³ reported in 1.8 or 3.4% of patients receiving tocilizumab 4 or 8 mg/kg every 4 weeks, respectively, in conjunction with nonbiologic DMARD therapy for 24 weeks; approximately one-half of cases occurred during first 8 weeks of therapy.¹ Decreases in neutrophil count to <1000/mm³ did not appear to be associated with serious infection.¹

Monitor neutrophil and platelet counts every 4–8 weeks in patients receiving tocilizumab.¹ Dosage adjustment or discontinuance may be necessary.¹ (See Dosage Modification or Discontinuance for Toxicity under Dosage and Administration.)

Hepatic Effects

Elevated transaminase concentrations may occur.¹ In clinical trials, changes were reversible following reduction of the tocilizumab or concomitant DMARD dosage or interruption of tocilizumab therapy and were not associated with clinical evidence of hepatic injury.¹

Incidence and magnitude of transaminase elevations were increased with concomitant use of hepatotoxic drugs (e.g., methotrexate).¹

Monitor serum ALT and AST every 4–8 weeks in patients receiving tocilizumab.¹ Monitor other liver function tests when clinically indicated.¹ Dosage adjustment or discontinuance of tocilizumab or concomitantly administered DMARDs may be necessary.¹ (See Dosage Modification or Discontinuance for Toxicity under Dosage and Administration.)

Effects on Serum Lipids

Increased serum concentrations of total cholesterol, triglycerides, LDL-cholesterol, and/or HDL-cholesterol reported.¹

Monitor lipoprotein concentrations 4–8 weeks after initiation of tocilizumab therapy and approximately every 24 weeks thereafter.¹ Manage lipid disorders as clinically appropriate.¹

Malignancies

Immunosuppressive therapy may increase the risk of malignancies.¹ Whether treatment with tocilizumab affects development of malignancies remains to be determined.¹ Malignancies were reported in clinical trials.¹

Sensitivity Reactions

Serious hypersensitivity reactions, including fatal anaphylaxis, reported;^{1 15} anaphylactic and anaphylactoid reactions generally have occurred during the second to fourth infusions of the drug.¹

Have appropriate agents and equipment available for immediate use in case a serious hypersensitivity reaction occurs.¹ If a serious hypersensitivity reaction occurs, immediately stop the drug infusion, provide appropriate supportive care, and permanently discontinue the drug.¹⁵

Nervous System Effects

Effect of tocilizumab on demyelinating disorders remains to be determined.¹ Multiple sclerosis and chronic inflammatory demyelinating polyneuropathy reported rarely in patients receiving tocilizumab.¹

Monitor patients receiving tocilizumab for signs and symptoms suggestive of a demyelinating disorder.¹ Exercise caution when considering tocilizumab therapy in patients with preexisting or recent-onset demyelinating disorders.¹

Immunization

Do not administer live vaccines to patients receiving tocilizumab.¹ Administer all age-appropriate vaccines, except for live vaccines, prior to initiation of tocilizumab therapy.¹

Information not available regarding immune response to vaccines in patients receiving tocilizumab or regarding secondary transmission of infection from individuals receiving live vaccines to patients receiving tocilizumab.¹

Laboratory Monitoring

Monitor neutrophil counts, platelet counts, and serum ALT and AST concentrations every 4–8 weeks during tocilizumab therapy.¹ Monitor other liver function tests when clinically indicated.¹ Monitor lipoprotein concentrations 4–8 weeks after initiation of therapy and approximately every 24 weeks thereafter.¹

Immunogenicity

Antibodies to tocilizumab detected in sera of about 2% of tocilizumab-treated patients; about 11% of these patients experienced hypersensitivity reactions resulting in drug discontinuance.¹ Neutralizing antibodies detected in about 1% of patients receiving the drug.¹

Specific Populations

Pregnancy

Category C.¹

Pregnancy registry at 877-311-8972.¹

Lactation

Not known whether tocilizumab is distributed into milk or is absorbed systemically following ingestion.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children.¹

Geriatric Use

Geriatric patients in general may have a higher incidence of infections than younger adults.¹ In clinical trials of tocilizumab, serious infections reported more frequently in patients ≥65 years of age than in younger adults.¹ Use tocilizumab with caution in this age group.¹

Hepatic Impairment

Safety and efficacy not established in patients with hepatic impairment, including those with serologic evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.¹ Use in patients with active hepatic disease or hepatic impairment is not recommended.¹

Renal Impairment

Not evaluated in patients with moderate to severe renal impairment.¹

Common Adverse Effects

Upper respiratory tract infection,^{1 3 4 5} nasopharyngitis,^{1 3 4} headache,^{1 3 4 5} hypertension,^{1 3 4 5} increased ALT concentrations.^{1 3 4 5}

Interactions for Actemra

May alter expression of CYP isoenzymes including 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4; effects on CYP2C8 or transporters (e.g., P-glycoprotein) not elucidated.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Possible increased metabolism of drugs metabolized by CYP isoenzymes.¹ Because IL-6 may down-regulate CYP isoenzymes, inhibition of IL-6 by tocilizumab in rheumatoid arthritis patients may restore CYP enzyme activity to higher levels.¹ Effects on CYP enzyme activity may persist for several weeks after drug discontinuance.¹

Drugs metabolized by CYP isoenzymes that have a low therapeutic index and require individualized dosing: Carefully monitor therapeutic effect and serum concentrations following initiation or discontinuance of tocilizumab; adjust dosage as needed.¹

Other CYP3A4 substrates: Caution advised when a reduction in efficacy would be undesirable.¹

Specific Drugs

Drug	Interaction	Comments
Contraceptives, oral	Possible increased metabolism of oral contraceptive1	Caution advised1
Corticosteroids	Concomitant use does not appear to affect clearance of tocilizumab1
Cyclosporine	Possible increased metabolism of cyclosporine1	Carefully monitor therapeutic effect and serum concentrations of cyclosporine following initiation or discontinuance of tocilizumab; adjust dosage as needed1
Dextromethorphan	Reduction in exposure to dextromethorphan and dextrorphan following initiation of tocilizumab reported in rheumatoid arthritis patients receiving dextromethorphan1 (In rheumatoid arthritis patients not receiving tocilizumab, systemic exposure to dextromethorphan is similar to, but exposure to dextrorphan is decreased, compared with values in healthy individuals1 )
DMARDs, biologic (e.g., TNF blocking agents)	Possible increased immunosuppression and increased risk of infection; concomitant use not studied1	Concomitant use not recommended1
HMG CoA reductase inhibitors (statins)	Statins metabolized by CYP isoenzymes (e.g., atorvastatin, lovastatin): Possible increased metabolism of the statin1 Simvastatin: Reduction in exposure to simvastatin and simvastatin acid following initiation of tocilizumab reported in rheumatoid arthritis patients receiving simvastatin (values were similar to or slightly higher than values observed after simvastatin administration in healthy individuals); exposure to simvastatin and simvastatin acid increased following discontinuance of tocilizumab1 (Systemic exposure to simvastatin and simvastatin acid is increased in rheumatoid arthritis patients not receiving tocilizumab compared with healthy individuals)1	Caution advised1 When selecting simvastatin dosages for patients with rheumatoid arthritis, consider the potential for altered systemic exposure to the drug following initiation or discontinuance of tocilizumab1
Methotrexate	Concomitant use does not appear to affect clearance of tocilizumab or exposure to methotrexate1
NSAIAs	Concomitant use does not appear to affect clearance of tocilizumab1
Omeprazole	Reduction in exposure to omeprazole following initiation of tocilizumab reported in rheumatoid arthritis patients receiving omeprazole (values were slightly higher than values observed after omeprazole administration in healthy individuals)1 (Systemic exposure to omeprazole is increased in rheumatoid arthritis patients not receiving tocilizumab compared with healthy individuals1 )
Theophylline	Possible increased metabolism of theophylline1	Carefully monitor therapeutic effect and serum concentrations of theophylline following initiation or discontinuance of tocilizumab; adjust dosage as needed1
Vaccines, live		Avoid live vaccines (see Immunization under Cautions)1
Warfarin	Possible increased metabolism of warfarin1	Carefully monitor therapeutic effect of warfarin following initiation or discontinuance of tocilizumab; adjust dosage as needed1

Actemra Pharmacokinetics

Absorption

Plasma Concentrations

Increase in dosage from 4 mg/kg to 8 mg/kg every 4 weeks associated with greater-than-proportional increases in AUC and trough plasma concentrations.¹

Distribution

Extent

Not known whether tocilizumab is distributed into milk.¹

Elimination

Half-life

Steady-state half-life: Up to 11 days at dosage of 4 mg/kg every 4 weeks; up to 13 days at dosage of 8 mg/kg every 4 weeks.¹

Clearance decreases as dose increases.¹ At low tocilizumab concentrations, concentration-dependent nonlinear clearance plays a major role in determining total drug clearance; at higher concentrations, nonlinear pathway is saturated and clearance is determined mainly by linear clearance.¹

Special Populations

As body size increases, linear clearance increases.¹ Following a weight-based dose of 8 mg/kg, systemic drug exposure is substantially greater in individuals weighing >100 kg than in those weighing <60 kg.¹

Pharmacokinetics not formally studied in renal or hepatic impairment.¹ Population pharmacokinetic data indicate that mild renal impairment (Cl_cr ≥50 mL/minute but <80 mL/minute) does not alter pharmacokinetics.¹

Stability

Storage

Parenteral

Injection Concentrate

2–8°C; do not freeze.¹ Protect vials from light.¹

Following dilution, 2–8°C or room temperature for up to 24 hours.¹ Protect from light.¹

Compatibility

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

Parenteral

Solution Compatibility

Compatible
Sodium chloride 0.9%

Actions

• 
  

  Binds specifically to both soluble and membrane-bound IL-6 receptors and inhibits IL-6-mediated signaling through these receptors, thereby resulting in a reduction in inflammatory mediator production.^{1 3 4 5 9 10}

  
  


• 
  

  IL-6, a pleiotropic proinflammatory cytokine, is produced by various cell types (e.g., T-cells, B-lymphocytes, monocytes, fibroblasts, synoviocytes, endothelial cells) and has a broad spectrum of biologic activities,^{1 3 4 5 9 10 12} including involvement in T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, stimulation of hematopoietic precursor cell proliferation and differentiation, and induction of osteoclast differentiation and activation.^{1 4 5 9 10 12}

  
  


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  IL-6 is overexpressed in synovial tissue in patients with rheumatoid arthritis and is thought to contribute to synovial proliferation and joint destruction in patients with the disease.^{4 9 10 12} Elevated levels of IL-6 in serum and synovial fluid correlate with clinical and laboratory measures of disease activity in patients with rheumatoid arthritis.^{3 5 9 10 12}

  
  

Advice to Patients

• 
  

  A copy of the manufacturer’s patient information (medication guide) for tocilizumab must be provided to all patients.¹ (See REMS Program under Dosage and Administration.) Importance of advising patients about potential benefits and risks of tocilizumab.¹ Importance of patients reading the medication guide prior to initiation of therapy and each time they receive an infusion of the drug.¹

  
  


• 
  

  Risk of increased susceptibility to infection.¹ Importance of informing clinicians immediately if any signs or symptoms suggestive of infection (e.g., fever; sweating; cough; dyspnea; diarrhea; burning or pain upon urination; warm, red, or painful skin) develop.¹

  
  


• 
  

  Risk of GI perforation.¹ Importance of informing clinician immediately if severe, persistent abdominal pain occurs.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., biologic antirheumatic drugs, immunizations) and OTC drugs, as well as any other illnesses (e.g., history of tuberculosis; concomitant, chronic, or recurring infections).¹

  
  


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  Importance of periodic laboratory monitoring.¹

  
  


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

  
  


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

  
  

Preparations

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

Tocilizumab (recombinant)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection concentrate, for IV infusion	20 mg/mL	Actemra	Genentech

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. Genentech. Actemra (tocilizumab) injection prescribing information. South San Francisco, CA; 2011 Jan.

2. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38:727-35. [PubMed 7779114]

3. Jones G, Sebba A, Gu J et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010; 69:88-96. [PubMed 19297346]

4. Smolen JS, Beaulieu A, Rubbert-Roth A et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008; 371:987-97. [PubMed 18358926]

5. Genovese MC, McKay JD, Nasonov EL et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008; 58:2968-80. [PubMed 18821691]

6. Emery P, Keystone E, Tony HP et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008; 67:1516-23. [PubMed 18625622]

7. Saag KG, Teng GG, Patkar NM et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008; 59:762-84. [PubMed 18512708]

8. Hoffmann-LaRoche Inc. FDA arthritis advisory committee briefing document for tocilizumab biologic license application 125276. Nutley, NJ; 2008 Jul 29.

9. Plushner SL. Tocilizumab: an interleukin-6 receptor inhibitor for the treatment of rheumatoid arthritis. Ann Pharmacother. 2008; 42:1660-8. [PubMed 18957621]

10. Sebba A. Tocilizumab: the first interleukin-6-receptor inhibitor. Am J Health Syst Pharm. 2008; 65:1413-8. [PubMed 18653811]

11. . Drugs for rheumatoid arthritis. Treat Guidel Med Lett. 2009; 7:37-46; quiz 47-8. [PubMed 19390497]

12. Park JY, Pillinger MH. Interleukin-6 in the pathogenesis of rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2007; 65 Suppl 1:S4-10. [PubMed 17708744]

13. Marti L, Golmia R, Golmia AP et al. Alterations in cytokine profile and dendritic cells subsets in peripheral blood of rheumatoid arthritis patients before and after biologic therapy. Ann N Y Acad Sci. 2009; 1173:334-42. [PubMed 19758170]

14. Actemra (tocilizumab) risk evaluation and mitigation strategy (REMS). From FDA website. Accessed 2010 Mar 18.

15. Barron H. Dear healthcare professional letter regarding important safety information regarding tocilizumab (Actemra/Roactemra). South San Francisco, CA; 2010 Sep.

16. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38:727-35. [PubMed 7779114]

17. Felson DT, Anderson JJ, Boers M et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum. 1993; 36:729-40. [PubMed 8507213]

18. Felson DT, Anderson JJ, Lange MLM et al. Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent. Arthritis Rheum. 1998; 41:1564-70. [IDIS 411264] [PubMed 9751088]

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Mifeprex

Pronunciation: MIF-eh-pri-stone
Generic Name: Mifepristone
Brand Name: Mifeprex

Serious and sometimes fatal infections or bleeding may rarely occur following any abortion, including those resulting from the use of Mifeprex. Read the Medication Guide and Patient Agreement that come with Mifeprex, and ask your doctor any questions that you may have. Make sure you are given clear instructions and understand whom to call and what to do in case of an emergency, including going to the nearest emergency room if your doctor is not available. Contact your doctor immediately or, if unavailable, seek emergency medical care if you experience persistent fever, severe abdominal pain, fast heartbeat, prolonged heavy vaginal bleeding, or fainting. If Mifeprex does not work within 2 days, your doctor may give you another medicine called misoprostol. If you experience stomach pain or discomfort, weakness, nausea, vomiting, or diarrhea more than 24 hours after taking misoprostol, contact your doctor immediately or seek emergency medical care. If you go to an emergency room or another health care provider, take the Medication Guide with you so that they will know that you are taking Mifeprex. If Mifeprex does not cause a complete abortion, surgery may be necessary. Talk with your doctor for more information.

Mifeprex is used for:

Ending pregnancy in women who have been pregnant for 49 days (7 weeks) or less. It may be used with other medicines. If Mifeprex does not work, surgery to end the pregnancy may be necessary.

Mifeprex is a synthetic steroid. It works by blocking a hormone (progesterone) necessary for pregnancy to continue.

Do NOT use Mifeprex if:

• you are allergic to any ingredient in Mifeprex, misoprostol, or similar medicines


• you are taking blood thinners (eg, warfarin, heparin) or corticosteroids (eg, prednisone, dexamethasone)


• you have an intrauterine device (IUD) in place


• you have a pregnancy outside the uterus (ectopic pregnancy)


• you have adrenal gland problems (chronic adrenal failure) or Addison disease


• you have bleeding problems or certain blood problems (eg, porphyria)


• you have an undiagnosed growth in the abdomen


• you are unable to follow-up with your heath care provider or you are unable to get emergency medical care for any serious problems that might occur within several weeks after taking Mifeprex


• you do not understand the effects of Mifeprex, the follow-up treatment procedures, or you are unable to comply with the instructions given by your health care provider

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

Before using Mifeprex:

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

• if you 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 breathing, heart, liver, lung, or kidney problems; diabetes; anemia; or high blood pressure


• if you will be undergoing general anesthesia


• if you are older than 35 years of age and you also smoke 10 or more cigarettes per day

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

• St. John's wort because the effectiveness of Mifeprex may be decreased


• Anticoagulants (eg, warfarin) or corticosteroids (eg, hydrocortisone) because the risk of side effects, including excessive bleeding, may be increased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Mifeprex 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 Mifeprex:

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

• Mifeprex comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Mifeprex refilled.


• Mifeprex is supplied by your health care provider and is not available at a pharmacy.


• Mifeprex requires 3 visits to your health care provider.


• On day 1 at your health care provider's office, you will read the Medication Guide and discuss the benefits and risks of using Mifeprex to end your pregnancy. If you decide Mifeprex is right for you, sign the Patient Agreement. After your physical exam, you will take 3 tablets of Mifeprex.


• On day 3 at your health care provider's office, if you are still pregnant, you will take 2 misoprostol tablets. Misoprostol may cause cramps, nausea, diarrhea, and other symptoms. Your health care provider may give you other medicines for these symptoms.


• Around day 14 at your health care provider's office, you will return for an important follow-up visit. You must return about 14 days after you have taken Mifeprex to be sure the pregnancy has ended. If the pregnancy has not ended, there is a chance of birth defects. Your health care provider will discuss with you your choices, including surgical abortion.


• Avoid drinking grapefruit juice while taking Mifeprex.


• You must follow the dosing schedule as directed by your doctor. If you miss an appointment, contact your doctor immediately.

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

Important safety information:

• Mifeprex may cause dizziness. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Mifeprex. Using Mifeprex alone, with certain other medicines, or with alcohol may lessen your ability to drive or to perform other potentially dangerous tasks.


• Make sure that your health care provider gives you clear instructions and a telephone number that you can call in case of an emergency, or if you have any problems or concerns.


• If you are using an IUD, it should be removed before treatment with Mifeprex begins.


• Mifeprex should not be used if your pregnancy is outside the womb (ectopic pregnancy). It will not cause an abortion in this case. In fact, it may cause very serious internal or external bleeding.


• You can become pregnant again immediately after using Mifeprex. To avoid pregnancy, start using birth control as soon as your pregnancy ends and before you start having sexual intercourse again.


• Before you have any medical or dental treatments, emergency care, laboratory tests, or surgery, tell the doctor or dentist that you are using Mifeprex.


• LAB TESTS, including human chorionic gonadotropin (hCG) levels and ultrasonographic scan, and health care provider's appointments will be required to monitor your progress. Be sure to keep all doctor and lab appointments.


• Mifeprex is not recommended for use in CHILDREN. Safety and effectiveness have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Mifeprex usually causes fetal death. In the unlikely event you have an ongoing pregnancy after treatment, birth defects may result. It is unknown if Mifeprex is excreted in breast milk. Because the effects of Mifeprex on infants are unknown, contact your doctor if you are breast-feeding to determine if you should discard your breast milk for a few days following treatment.

Possible side effects of Mifeprex:

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:

Abdominal (menstrual-like) pain and/or cramping; anxiety; back pain; chills/shaking; diarrhea; dizziness; headache; indigestion; nausea; tiredness; vaginal bleeding or discharge; 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); fainting; fast heartbeat; fever (100.4 degrees F or higher); heavy vaginal bleeding (enough to soak through 2 thick full-size sanitary pads per hour for 2 straight hours, or if you are concerned about heavy bleeding); infection; pelvic pain; severe abdominal pain; vaginal discomfort, itching, or unusual discharge.

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: Mifeprex side effects (in more detail)

If OVERDOSE is suspected:

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

Proper storage of Mifeprex:

Store Mifeprex at room temperature, between 59 and 77 degrees F (15 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Mifeprex out of the reach of children and away from pets.

General information:

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


• Mifeprex 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 Mifeprex. 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.

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Votubia 5mg Tablets

1. Name Of The Medicinal Product

2. Qualitative And Quantitative Composition

Each tablet contains 5 mg everolimus.

Excipients

Each tablet contains 149 mg lactose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet.

White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other.

4. Clinical Particulars

4.1 Therapeutic Indications

Votubia is indicated for the treatment of patients aged 3 years and older with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) who require therapeutic intervention but are not amenable to surgery.

The evidence is based on analysis of change in SEGA volume. Further clinical benefit, such as improvement in disease-related symptoms, has not been demonstrated.

4.2 Posology And Method Of Administration

Treatment with Votubia should be initiated by a physician experienced in the treatment of patients with TSC and therapeutic drug monitoring.

Posology

Careful titration may be required to obtain the optimal therapeutic effect. Doses that will be tolerated and effective vary between patients. Concomitant antiepileptic therapy may affect the metabolism of everolimus and may contribute to this variance (see section 4.5).

The recommended starting dose of Votubia for treatment of patients with SEGA is according to Table 1.

Table 1 Recommended starting dose of Votubia for treatment of patients with SEGA

Body Surface Area (BSA)	Starting daily dose
2	2.5 mg
1.3 to 2.1 m2	5 mg
2	7.5 mg

Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after commencing treatment. Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml. If concentrations are below 5 ng/ml, the daily dose may be increased by 2.5 mg every 2 weeks, subject to tolerability. The dose of Votubia should be reduced if trough concentrations>15 ng/ml are observed.

SEGA volume should be evaluated approximately 3 months after commencing Votubia therapy, with subsequent dose adjustments taking changes in SEGA volume, corresponding trough concentration, and tolerability into consideration.

Management of severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of therapy (see section 4.4). If dose reduction is required for patients receiving 2.5 mg daily, alternate day dosing should be considered.

If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next dose.

Therapeutic drug monitoring

Therapeutic drug monitoring of everolimus blood concentrations is required for patients treated for SEGA using a validated assay. Trough concentrations should be assessed approximately 2 weeks after the initial dose, after any change in dose or after initiation of or change in co-administration of CYP3A4 inducers or inhibitors (see sections 4.4 and 4.5).

Special populations

Paediatric population

The safety and efficacy of Votubia in children aged 0 to less than 3 years have not been established. No data are available.

The potential for growth/developmental delays with long-term treatment is unknown (see section 5.3).

Dosing recommendations for paediatric patients aged 3 years and older with SEGA are consistent with those for the adult SEGA population.

The safety and efficacy of Votubia in paediatric cancer patients have not been established. No data are available.

Elderly patients (

No dose adjustment is required (see section 5.2).

Renal impairment

No dose adjustment is required (see section 5.2).

Hepatic impairment

Dose should be reduced by approximately 50% to maintain target trough concentrations of 5 to 15 ng/ml.

Patients with severe hepatic impairment (Child-Pugh class C):

Everolimus has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) and is not recommended for use in this patient population (see sections 4.4 and 5.2).

Method of administration

Votubia must be administered orally once daily at the same time every day, consistently either with or without food (see section 5.2). Votubia tablets are to be swallowed whole with a glass of water. The tablets must not be chewed or crushed. For patients unable to swallow tablets, Votubia tablet(s) can be dispersed completely in a glass with approximately 30 ml of water by gently stirring, immediately prior to drinking. After the dispersion has been swallowed, any residue must be re-dispersed in the same volume of water and swallowed (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Non-infectious pneumonitis

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. Non-infectious pneumonitis (including interstitial lung disease) was described very commonly in patients taking everolimus in the advanced renal cell carcinoma (RCC) setting (see section 4.8). Some cases were severe and on rare occasions, a fatal outcome was observed. A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnoea, and in whom infectious, neoplastic and other non-medicinal causes have been excluded by means of appropriate investigations. Patients should be advised to report promptly any new or worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue Votubia therapy without dose adjustments. If symptoms are moderate, consideration should be given to interruption of therapy until symptoms improve. The use of corticosteroids may be indicated. Votubia may be reinitiated at a daily dose approximately 50% lower than the dose previously administered.

For cases where symptoms of non-infectious pneumonitis are severe, Votubia therapy should be discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve. Votubia may be reinitiated at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances.

Infections

Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoal infections, including infections with opportunistic pathogens (see section 4.8). Localised and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus, have been described in patients taking everolimus in the oncology setting. Some of these infections have been severe (e.g. leading to respiratory or hepatic failure) and occasionally fatal.

Physicians and patients should be aware of the increased risk of infection with Votubia. Pre-existing infections should be treated appropriately and should have resolved fully before starting treatment with Votubia. While taking Votubia, be vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Votubia.

If a diagnosis of invasive systemic fungal infection is made, Votubia treatment should be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy.

Hypersensitivity reactions

Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus (see section 4.3).

Oral ulceration

Mouth ulcers, stomatitis and oral mucositis have been observed in patients treated with Votubia (see section 4.8). In such cases topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed (see section 4.5).

Renal failure events

Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with everolimus (see section 4.8). Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.

Laboratory tests and monitoring

Renal function

Elevations of serum creatinine, usually mild, and proteinuria have been reported in clinical trials (see section 4.8). Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein or serum creatinine, is recommended prior to the start of Votubia therapy and periodically thereafter.

Blood glucose and lipids

Hyperglycaemia, hyperlipidaemia and hypertrigylceridaemia have been reported in clinical trials (see section 4.8). Monitoring of fasting serum glucose is recommended prior to the start of Votubia therapy and periodically thereafter. When possible optimal glycaemic control should be achieved before starting a patient on Votubia.

Haematological parameters

Decreased haemoglobin, lymphocytes, neutrophils and platelets have been reported in clinical trials (see section 4.8). Monitoring of complete blood count is recommended prior to the start of Votubia therapy and periodically thereafter.

Interactions

Co-administration with inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump P-glycoprotein (PgP) should be avoided. If co-administration of a moderate CYP3A4 and/or PgP inhibitor or inducer cannot be avoided, dose adjustments of Votubia may be required (see section 4.5).

Concomitant treatment with potent CYP3A4 inhibitors result in dramatically increased blood concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing recommendations in this situation. Hence, concomitant treatment of Votubia and potent inhibitors is not recommended.

Hepatic impairment

Votubia should not be used in patients with severe hepatic impairment (Child-Pugh class C) (see sections 4.2 and 5.2).

Vaccinations

The use of live vaccines should be avoided during treatment with Votubia (see section 4.5).

Lactose

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Wound healing complications

Impaired wound healing is a class effect of rapamycin derivatives, including Votubia. Caution should therefore be exercised with the use of Votubia in the peri-surgical period.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore, absorption and subsequent elimination of everolimus may be influenced by products that affect CYP3A4 and/or PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP are listed in Table 2 below.

CYP3A4 and PgP inhibitors increasing everolimus concentrations

Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by decreasing metabolism or the efflux of everolimus from intestinal cells.

CYP3A4 and PgP inducers decreasing everolimus concentrations

Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by increasing metabolism or the efflux of everolimus from intestinal cells.

Table 2 Effects of other active substances on everolimus

Active substance by interaction	Interaction – Change in Everolimus AUC/Cmax Geometric mean ratio (observed range)	Recommendations concerning co-administration
Potent CYP3A4/PgP inhibitors
Ketoconazole	AUC ↑15.3-fold (range 11.2-22.5) Cmax ↑4.1-fold (range 2.6-7.0)	Concomitant treatment of Votubia and potent inhibitors is not recommended.
Itraconazole, posaconazole, voriconazole	Not studied. Large increase in everolimus concentration is expected.
Telithromycin, clarithromycin
Nefazodone
Ritonavir, atazanavir, saquinavir, darunavir, indinavir, nelfinavir
Moderate CYP3A4/PgP inhibitors
Erythromycin	AUC ↑4.4-fold (range 2.0-12.6) Cmax ↑2.0-fold (range 0.9-3.5)	Use caution when co-administration of moderate CYP3A4 inhibitors or PgP inhibitors cannot be avoided. If patients require co-administration of a moderate CYP3A4 or PgP inhibitor, reduce the daily dose by approximately 50%. Further dose reduction may be required to manage adverse reactions (see sections 4.2 and 4.4). Everolimus trough concentrations should be assessed approximately 2 weeks after the addition of a moderate CYP3A4 or PgP inhibitor. If the moderate inhibitor is discontinued the Votubia dose should be returned to the dose used prior to initiation of the moderate CYP3A4 or PgP inhibitor and the everolimus trough concentration should be re-assessed approximately 2 weeks later (see sections 4.2 and 4.4)
Verapamil	AUC ↑3.5-fold (range 2.2-6.3) Cmax ↑2.3-fold (range1.3-3.8)
Ciclosporin oral	AUC ↑2.7-fold (range 1.5-4.7) Cmax ↑1.8-fold (range 1.3-2.6)
Fluconazole	Not studied. Increased exposure expected.
Diltiazem
Amprenavir, fosamprenavir	Not studied. Increased exposure expected.
Grapefruit juice or other food affecting CYP3A4/PgP	Not studied. Increased exposure expected (the effect varies widely).	Combination should be avoided.
Potent CYP3A4 inducers
Rifampicin	AUC (range 0-80%) Cmax (range 10-70%)	Avoid the use of concomitant potent CYP3A4 inducers. Patients receiving concomitant potent CYP3A4 inducers may require an increased Votubia dose to achieve the same exposure as patients not taking potent inducers. Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml. If concentrations are below 5 ng/ml, the daily dose may be increased by 2.5 mg every 2 weeks, checking the trough level and assessing tolerability before increasing the dose. If the potent inducer is discontinued the Votubia dose should be returned to the dose used prior to initiation of the potent CYP3A4 inducer and the everolimus trough concentrations should be assessed approximately 2 weeks later (see sections 4.2 and 4.4)
Corticosteroids (e.g. dexamethasone, prednisone, prednisolone)	Not studied. Decreased exposure expected.
Antiepileptic agents (e.g. carbamazepine, phenobarbital, phenytoin)	Not studied. Decreased exposure expected.
Efavirenz, nevirapine	Not studied. Decreased exposure expected.
St John's Wort (Hypericum perforatum )	Not studied. Large decrease in exposure expected.	Preparations containing St John's Wort should not be used during treatment with everolimus

Agents whose plasma concentration may be altered by everolimus

Based on in vitro results, the systemic concentrations obtained after oral daily doses of 10 mg make inhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the gut cannot be excluded; hence everolimus may affect the bioavailability of co-administered substances which are CYP3A4 and/or PgP substrates.

Vaccinations

The immune response to vaccination may be affected and, therefore, vaccination may be less effective during treatment with Votubia. The use of live vaccines should be avoided during treatment with Votubia. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a typhoid vaccines.

4.6 Pregnancy And Lactation

Pregnancy

Women of childbearing potential must use a highly effective method of contraception (e.g. oral, injected, or implanted non-oestrogen-containing hormonal method of birth control, progesterone-based contraceptives, hysterectomy, tubal ligation, complete abstinence, barrier methods, intrauterine device [IUD], and/or female/male sterilisation) while receiving everolimus, and for up to 8 weeks after ending treatment.

There are no adequate data from the use of everolimus in pregnant women. Studies in animals have shown reproductive toxicity effects including embryotoxicity and foetotoxicity (see section 5.3). The potential risk for humans is unknown.

Everolimus is not recommended during pregnancy and in women of childbearing potential not using contraception.

Male patients should not be prohibited from attempting to father children.

Breast-feeding

It is not known whether everolimus is excreted in breast milk. However, in rats, everolimus and/or its metabolites readily pass into the milk (see section 5.3). Therefore, women taking everolimus should not breast-feed.

Fertility

The potential for everolimus to cause infertility in male and female patients is unknown, however secondary amenorrhoea and associated luteinising hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed in female patients (see also section 5.3 for preclinical observations on the male and female reproductive systems).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Patients should be advised to be cautious when driving or using machines if they experience fatigue during treatment with Votubia.

4.8 Undesirable Effects

a) Summary of safety profile

The overall safety profile of Votubia is based on a phase II study for the treatment of SEGA (n=28) and a randomised phase III study for the treatment of metastatic renal cell carcinoma (everolimus, n=274; placebo, n=137) and in further studies in cancer patients. In the pivotal phase II study, 16 of the 28 SEGA patients were exposed to Votubia for

The most common adverse reactions (incidence

b) Tabulated summary of adverse reactions

Table 3 shows the incidence of adverse reactions reported in at least one of the pivotal studies, showing the highest frequency reported. Adverse reactions are listed according to MedDRA system organ class. Frequency categories are defined using the following convention: very common (

Table 3 Adverse reactions reported in a phase II study for the treatment of SEGA and in phase III studies

Infections and infestations
Very common	Infections a, *, upper respiratory tract infections, sinusitis, otitis media
Blood and lymphatic system disorders
Very common	White blood cell count decreased, platelets decreased b, haemoglobin decreased b
Immune system disorders
Not known	Hypersensitivity
Metabolism and nutrition disorders
Very common	Glucose decreased b, cholesterol increased b, triglycerides increased b, glucose increased b, phosphate decreased b, anorexia
Common	Dehydration
Uncommon	New-onset diabetes mellitus
Psychiatric disorders
Common	Anxiety, insomnia
Nervous system disorders
Very common	Abnormal taste
Common	Somnolence, headache
Eye disorders
Common	Ocular hyperaemia, conjunctivitis, eyelid oedema
Cardiac disorders
Uncommon	Congestive cardiac failure
Vascular disorders
Common	Hypertension
Uncommon	Flushing
Not known	Haemorrhage
Respiratory, thoracic and mediastinal disorders
Very common	Pneumonitis c, dyspnoea, epistaxis, cough
Common	Pharyngeal inflammation, respiratory disorder, haemoptysis
Uncommon	Pulmonary embolism
Gastrointestinal disorders
Very common	Stomatitis d, diarrhoea, mucosal inflammation, vomiting, nausea
Common	Gastritis, dry mouth, abdominal pain, dysphagia, dyspepsia
Hepatobiliary disorders
Very common	Alanine aminotransferase increased b, aspartate aminotransferase increased b
Common	Bilirubin increased b
Skin and subcutaneous tissue disorders
Very common	Rash, acne, acneiform dermatitis, dry skin, pruritus
Common	Pityriasis rosea, palmar plantar erythrodysaesthesia, erythema, skin exfoliation, nail disorder, onychoclasis
Uncommon	Angioedema
Renal and urinary disorders
Very common	Creatinine increased b
Common	Renal failure (including acute renal failure)*, proteinuria*
Reproductive system and breast disorders
Common	Secondary amenorrhoea / LH/FSH imbalance
General disorders and administration site conditions
Very common	Fatigue, asthenia, peripheral oedema, pyrexia
Common	Chest pain
Uncommon	Impaired wound healing
Investigations
Common	Blood immunoglobulin G decreased, weight decreased
* see also subsection “c) Description of selected adverse reactions” a Includes all events within the 'infections and infestations' system organ class (such as pneumonia, sepsis, and opportunistic infections [e.g. aspergillosis and candidiasis (see also section 4.4)]). The protocol of the study in patients with SEGA mandated that all infections be classified as adverse drug reactions b Frequency based on determination of abnormal laboratory value (as part of routine laboratory assessment) c Includes interstitial lung disease, lung infiltration, pulmonary alveolar haemorrhage, pulmonary toxicity, and alveolitis d Includes aphthous stomatitis, and mouth and tongue ulceration

c) Description of selected adverse reactions

In clinical studies, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infection is an expected reaction during periods of immunosuppression.

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal outcome) and proteinuria. Monitoring of renal function is recommended (see section 4.4).

d) Paediatric population

In the pivotal phase II study, 22 of the 28 SEGA patients studied were below the age of 18 years. Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

4.9 Overdose

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been given with acceptable acute tolerability in the adult population.

It is essential to assess everolimus blood levels in cases of suspected overdose. General supportive measures should be initiated in all cases of overdose. Everolimus is not considered dialysable to any relevant degree (less than 10% was removed within 6 hours of haemodialysis).

Paediatric population

A limited number of paediatric patients have been exposed to doses higher than 10 mg/m²/day. No signs of acute toxicity have been reported in these cases.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, protein kinase inhibitors, ATC code: L01XE10

Mechanism of action

Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-threonine kinase, the activity of which is known to be upregulated in a number of human cancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR complex-1 (mTORC1) activity.Inhibition of the mTORC1 signalling pathway interferes with the translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in the cell cycle, angiogenesis and glycolysis. Everolimus reduces levels of vascular endothelial growth factor (VEGF), which potentiates tumour angiogenic processes. Everolimus is a potent inhibitor of the growth and proliferation of tumour cells, endothelial cells, fibroblasts and blood-vessel-associated smooth muscle cells and has been shown to reduce glycolysis in solid tumours in vitro and in vivo.

Two primary regulators of mTORC1 signalling are the oncogene suppressors tuberin-sclerosis complexes 1 & 2 (TSC1, TSC2). Loss of either TSC1 or TSC2 leads to elevated rheb-GTP levels, a ras family GTPase, which interacts with the mTORC1 complex to cause its activation. mTORC1 activation leads to a downstream kinase signalling cascade, including activation of the S6 kinases. In tuberous sclerosis complex syndrome, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body. TSC1 mutations account for 20–25% of all mutations identified, and TSC2 mutations account for the remainder.

In a mouse neuronal model of TSC in which TSC1 is ablated in most neurons during cortical development, everolimus improved median survival from 33 days to more than 100 days, and behaviour, phenotype, and weight gain all also markedly improved. There was brain penetration, with accumulation over time with repetitive treatment, and effective reduction of levels of phospho-S6, a downstream marker of mTORC1. Neurofilament abnormalities, myelination and cell enlargement were all improved by the treatment, although dysplastic neuronal features persisted, and there were only modest changes in dendritic spine density and length. Strikingly, mice treated with everolimus for 23 days only (postnatal days 7–30) displayed a persistent improvement in phenotype, with median survival of 78 days. In summary, everolimus is a highly effective therapy for this neuronal model of TSC, with benefit apparently attributable to effects on mTORC1 and Akt signalling and, consequently, cell size and myelination. Although caution is appropriate, the results suggest the possibility that everolimus may have benefit in the treatment of TSC brain disease, including infantile spasms.

Clinical efficacy and safety

A prospective, open-label, single-arm phase II study was conducted to evaluate the safety and efficacy of Votubia in patients with SEGA. Radiological evidence of serial SEGA growth was required for entry.

Change in SEGA volume during the core 6-month treatment phase, as assessed via an independent central radiology review, was the primary efficacy endpoint. After the core treatment phase, patients could be enrolled into an extension phase where SEGA volume was assessed every 6 months.

In total, 28 patients received treatment with Votubia; median age was 11 years (range 3 to 34), 61% male, 86% Caucasian. Thirteen patients (46%) had a secondary smaller SEGA, including 12 in the contralateral ventricle.

Primary SEGA volume was reduced at month 6 compared to baseline (p<0.001 [see Table 4]). No patient developed new lesions, worsening hydrocephalus or increased intracranial pressure, and none required surgical resection or other therapy for SEGA.

Table 4 Change in primary SEGA volume over time

SEGA volume (cm3)	Independent central review
	Baseline	3 months	6 months	12 months	18 months	24 months
	N=28	N=26	N=27	N=26	N=18	N=8
Mean	2.45	1.47	1.33	1.26	1.45	1.05
Range	0.49-14.23	0.25-8.32	0.31-7.98	0.29-8.18	0.33-5.20	0.33-3.66
Reduction from baseline
Mean