Everolimus


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Hormone receptor positive, HER2-negative advanced breast cancer In combination with exemestane: As tab: 10 mg once daily. Advanced renal cell carcinoma; Neuroendocrine tumours of pancreatic, gastrointestinal or lung origin; Renal angiomyolipoma associated with tuberous sclerosis complex As tab: 10 mg once daily. Subependymal giant cell astrocytoma associated with tuberous sclerosis complex As tab, dispersible tab for susp: Individualise dosing based on patient’s BSA and everolimus trough concentrations. Initial: 4.5 mg/m2 once daily, titrated in 2.5 mg increments to attain target trough levels of 5-15 ng/mL. Adjunct in refractory partial seizures associated with tuberous sclerosis complex As dispersible tab for susp: Individualise dosing based on patient’s BSA and everolimus trough concentrations. Initial: 5 mg/m2 once daily, titrated in 1-4 mg increments to attain target trough levels of 5-15 ng/mL. Continue until disease progression or unacceptable toxicity occurs. Dose reduction, interruption, discontinuation and re-initiation may be required according to individual safety and tolerability (refer to detailed product guideline). Prophylaxis of rejection in kidney graft transplant; Prophylaxis of rejection in cardiac graft transplant In combination with ciclosporin for microemulsion and corticosteroids: As tab, dispersible tab for susp: Initial: 0.75 mg bid given as soon as possible after transplantation. Prophylaxis of rejection in liver graft transplant In combination with tacrolimus and corticosteroids: As tab, dispersible tab for susp: Initial: 1 mg bid given approx 4 weeks after transplantation. Everolimus, ciclosporin, and tacrolimus dose adjustments may be required according to individual blood concentrations achieved, tolerability, response, changes in co-medications and clinical situation (refer to detailed product guideline).
Dosage Details
Oral
Advanced renal cell carcinoma
Adult: In patients whose disease progressed on or after treatment with VEGF-targeted therapy: As tab: 10 mg once daily. Continue until disease progression or unacceptable toxicity occurs. Dose reduction, interruption, discontinuation and re-initiation may be required according to individual safety and tolerability (refer to detailed product guideline).

Oral
Hormone receptor positive, HER2-negative advanced breast cancer
Adult: In post-menopausal women without symptomatic visceral disease after recurrence, or progression following treatment with a non-steroidal aromatase inhibitor: In combination with exemestane: As tab: 10 mg once daily. Continue until disease progression or unacceptable toxicity occurs. Dose reduction, interruption, discontinuation and re-initiation may be required according to individual safety and tolerability (refer to detailed product guideline).

Oral
Neuroendocrine tumours of pancreatic origin
Adult: In patients with unresectable or metastatic, well- or moderately-differentiated neuroendocrine tumours of pancreatic origin with progressive disease: As tab: 10 mg once daily. Continue until disease progression or unacceptable toxicity occurs. Dose reduction, interruption, discontinuation and re-initiation may be required according to individual safety and tolerability (refer to detailed product guideline).

Oral
Neuroendocrine tumours of gastrointestinal origin, Neuroendocrine tumours of lung origin
Adult: In patients with unresectable or metastatic, well-differentiated (Grade 1 or 2) non-functional neuroendocrine tumours of gastrointestinal or lung origin with progressive disease: As tab: 10 mg once daily. Continue until disease progression or unacceptable toxicity occurs. Dose reduction, interruption, discontinuation and re-initiation may be required according to individual safety and tolerability (refer to detailed product guideline).

Oral
Renal angiomyolipoma associated with tuberous sclerosis complex
Adult: In patients who are at risk of complications (based on tumour size, presence of aneurysm, presence of multiple or bilateral tumours) but do not require immediate surgery: As tab: 10 mg once daily. Continue until disease progression or unacceptable toxicity occurs. Dose reduction, interruption, discontinuation and re-initiation may be required according to individual safety and tolerability (refer to detailed product guideline).

Oral
Subependymal giant cell astrocytoma associated with tuberous sclerosis complex
Adult: In patients who require therapeutic intervention but are not amenable to surgery: As tab, dispersible tab for susp: Individualise dosing based on patient’s BSA and everolimus trough concentrations. Recommended dose: Initially, 4.5 mg/m2 once daily, titrated by increasing in 2.5 mg increments to attain target trough levels of 5-15 ng/mL based on tolerability for optimal clinical response. Continue until disease progression or unacceptable toxicity occurs. Dose reduction, interruption, discontinuation and re-initiation may be required according to individual safety and tolerability (refer to detailed product guideline).
Child: As tab, dispersible tab for susp: Individualise dosing based on patient’s BSA and everolimus trough concentrations. 1-<3 years Initially, 7 mg/m2 once daily. ≥3 years Same as adult dose.

Oral
Adjunct in refractory partial seizures associated with tuberous sclerosis complex
Adult: In patients whose refractory partial-onset seizures (with or without secondary generalisation) are associated with tuberous sclerosis complex (TSC): As dispersible tab for susp: Individualise dosing based on patient’s BSA and everolimus trough concentrations. Recommended dose: Initially, 5 mg/m2 once daily, titrated by increasing in 1-4 mg increments to attain target trough levels of 5-15 ng/mL based on tolerability for optimal clinical response. Continue until disease progression or unacceptable toxicity occurs. Dose reduction, interruption, discontinuation and re-initiation may be required according to individual safety and tolerability (refer to detailed product guideline).
Child: As dispersible tab for susp: Individualise dosing based on patient’s BSA and everolimus trough concentrations. 2-<6 years 6 mg/m2 once daily. ≥6 years Same as adult dose.

Oral
Prophylaxis of rejection in cardiac graft transplant, Prophylaxis of rejection in kidney graft transplant
Adult: For patients at low to moderate immunological risk receiving an allogeneic renal or cardiac transplant: In combination with ciclosporin for microemulsion and corticosteroids: As tab, dispersible tab for susp: Initially, 0.75 mg bid given as soon as possible after transplantation. Everolimus and ciclosporin dose adjustments may be required according to individual blood concentrations achieved, tolerability, response, changes in co-medications and clinical situation (refer to detailed product guideline).

Oral
Prophylaxis of rejection in liver graft transplant
Adult: In combination with tacrolimus and corticosteroids: As tab, dispersible tab for susp: Initially, 1 mg bid, started at approx 4 weeks after transplantation. Everolimus and tacrolimus dose adjustments may be required according to individual blood concentrations achieved, tolerability, response, changes in co-medications and clinical situation (refer to detailed product guideline).
Special Patient Group
For hormone receptor positive HER2-negative advanced breast carcinoma, advanced renal cell carcinoma, neuroendocrine tumours of pancreatic, gastrointestinal and lung origins, and renal angiomyolipoma associated with TSC

Patients taking moderate CYP3A4/P-gp inhibitors: As tab: Reduce everolimus dose to 5 mg daily or 2.5 mg daily with close monitoring of adverse effects. If the moderate inhibitor is discontinued, consider at least 2-3 days washout period before returning everolimus to the dose used prior to initiation of co-administration.

Patients taking potent CYP3A4 inducers: As tab: Increase everolimus dose from 10 mg daily up to 20 mg daily in 5 mg increments or less, applied on days 4 and 8 following the start of the inducer. If the potent inducer is discontinued, consider at least 3-5 days washout period before returning everolimus to the dose used prior to initiation of co-administration.

For SEGA associated with TSC

Patients taking moderate CYP3A4/P-gp inhibitors: As tab, dispersible tab for susp: Reduce everolimus daily dose by approx 50%, may be further reduced to manage adverse effects. If the moderate inhibitor is discontinued, consider at least 2-3 days washout period before returning everolimus to the dose used prior to initiation of co-administration. Assess everolimus trough concentrations at least 1 week after addition or discontinuation of moderate inhibitor.

Patients taking potent CYP3A4 inducers: As tab, dispersible tab for susp: Titrate dose to attain trough concentrations of 5-15 ng/mL. If the everolimus concentrations are below 5 ng/mL, may increase daily dose in 2.5 mg increments every 2 weeks according to individual trough levels and tolerability. Further dose adjustments may not be required in the addition of another potent inducer, or discontinuation of 1 of multiple inducers. Assess everolimus trough levels 2 weeks after addition or discontinuation, then adjust dose in 2.5 mg increments as necessary to maintain target trough levels. If all potent inducers are discontinued, consider at least 3-5 days washout period before returning everolimus to the dose used prior to initiation of co-administration.

For refractory partial seizures associated with TSC

Patients taking potent CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin): As dispersible tab for susp: Adults and children ≥6 years Initially, 8 mg/m2 once daily; 2-<6 years Initially, 9 mg/m2 once daily. Titrate dose to attain trough concentrations of 5-15 ng/mL. If the everolimus concentrations are below 5 ng/mL, may increase daily dose in 1-4 mg increments according to individual trough levels and tolerability. Further dose adjustments may not be required in the addition of another potent inducer, or discontinuation of 1 of multiple inducers. Assess everolimus trough levels 2 weeks after addition or discontinuation, then adjust dose in 1-4 mg increments as necessary to maintain target trough levels. If all potent inducers are discontinued, consider at least 3-5 days washout period before returning everolimus to the dose used prior to initiation of co-administration.

Pharmacogenomics:

Everolimus is extensively metabolised by CYP3A4 isoenzyme to form 6 less active metabolites. According to clinical research, certain single nucleotide polymorphisms (SNPs) identified may affect everolimus pharmacokinetics, clinically relevant toxicity and tolerability. The study results need further replication but suggest that germline variations may influence everolimus outcomes.

For hormone receptor positive HER2-negative advanced breast cancer

Carriers of CYP3A4 gene rs35599367 variant
Patients with AG genotype may experience 2.7-fold higher concentrations of everolimus while those with GG genotype may have decreased everolimus plasma levels. Other clinical and genetic factors may also influence the everolimus concentrations during treatment.

Carriers of ABCB1 gene rs1045642 variant
Patients with AA genotype may have an increased risk of adverse effect (e.g. mucositis). Individuals with AG genotype also have increased risk of mucositis but less likely as compared to AA genotype, while those with GG genotype may have decreased likelihood of toxicity. Other clinical and genetic factors may also influence the risk of developing mucositis during treatment.

Carriers of RPTOR gene rs9906827 variant
Patients with CC genotype may have increased risk of adverse effect (e.g. non-infectious pneumonitis) and a decreased likelihood of progression-free survival (PFS). Individuals with CT and TT genotypes may have decreased risk of pneumonitis and an increased likelihood of PFS. Other clinical and genetic factors may also influence the risk of developing pneumonitis and likelihood of PFS.

For heart and kidney transplantation

Carriers of CYP3A5 gene rs776746 variant
Patients with CC and CT genotypes may have reduced everolimus clearance while those with TT genotype may have an increased clearance. However, not all studies conducted identified a significant association between certain genotypes and everolimus concentrations. Other clinical and genetic factors may also affect the pharmacokinetics of everolimus.
Hepatic Impairment
Oral:
Hormone receptor positive, HER2-negative advanced breast cancer; Advanced renal cell carcinoma; Neuroendocrine tumours of pancreatic, gastrointestinal, and lung origins; Renal angiomyolipoma associated with tuberous sclerosis complex
Mild (Child-Pugh class A): 7.5 mg daily. Moderate (Child-Pugh class B): 5 mg daily. Severe (Child-Pugh class C): Treatment is only recommended if the potential benefit outweighs the risk. Max: 2.5 mg daily.

Subependymal giant cell astrocytoma associated with tuberous sclerosis complex; Adjunct in refractory partial seizures associated with tuberous sclerosis complex
Mild (Child-Pugh class A): 75% of the recommended initial dose. Moderate (Child-Pugh class B): 50% of the recommended initial dose. Severe (Child-Pugh class C): Treatment is only recommended if the potential benefit outweighs the risk. Max: 25% of the recommended dose. All doses are calculated based on BSA and rounded to the nearest strength.

Prophylaxis of rejection in cardiac and kidney graft transplants
Mild (Child-Pugh class A): Reduce to approx 2/3 of the normal dose e.g. 0.5 mg bid. Moderate (Child-Pugh class B): Reduce to approx 1/2 of the normal dose e.g. 0.5 mg bid. Severe (Child-Pugh class C): Reduce to approx 1/3 of the normal dose e.g. 0.25 mg bid. Further dose titration should be based on therapeutic drug monitoring. All reduced doses are rounded to the nearest strength.

Prophylaxis of rejection in liver graft transplant
Mild (Child-Pugh class A): Reduce to approx 2/3 of the normal dose e.g. 0.75 mg bid. Moderate (Child-Pugh class B): Reduce to approx 1/2 of the normal dose e.g. 0.5 mg bid. Severe (Child-Pugh class C): Reduce to approx 1/3 of the normal dose e.g. 0.5 mg bid. Further dose titration should be based on therapeutic drug monitoring. All reduced doses are rounded to the nearest strength.
Administration
May be taken with or without food. Take consistently either always w/ or always w/o meals. Swallow whole, do not chew/crush. For patients w/ swallowing difficulties, disperse tab in approx 30 mL of water by gently stirring immediately prior to drinking. Rinse the glass w/ the same amount of water & drink the rinse completely. Avoid grapefruit juice.
Reconstitution
Dispersible tab for oral susp: Using an oral syringe: Place the required dose in a 10 mL syringe then draw approx 5 mL of water and 4 mL of air into the syringe. Place the filled syringe into a container (tip up) for 3 minutes until the tablets are suspended. Gently invert the syringe 5 times immediately prior to administration. After taking the prepared susp, draw the same amount of water and air into the same syringe, swirl to re-suspend remaining particles, then administer entire contents. Using a small glass or plastic cup: Place the required dose in a small drinking glass (Max size: 100 mL) with approx 25 mL of water then wait for 3 minutes until the tablets are suspended. Gently stir the susp with a spoon immediately prior to administration. After taking the prepared susp, add another 25 mL of water into the glass or cup, stirred with the same spoon to re-suspend remaining particles, then administer entire contents. Do not break or crush the tablets. In patients with SEGA or seizures associated with TSC, Max of 10 mg dose may be suspended in a single syringe or drinking glass. In transplant patients, Max of 1.5 mg dose may be suspended in a single syringe or plastic cup.
Contraindications
Hypersensitivity to everolimus and other rapamycin derivatives. Lactation. Concomitant use with live vaccines.
Special Precautions
Patients with diabetes mellitus, hyperlipidaemia, history of bleeding disorders or recurrent infections. Peri-surgical period. Not indicated for the treatment of functional carcinoid tumours. Concomitant use with moderate CYP3A4/P-glycoprotein (P-gp) inhibitors, and potent CYPP3A4 inducers. Black race (in transplant patients). Renal and hepatic impairment. Pregnancy.
Adverse Reactions
Significant: Renal arterial and venous graft thrombosis, hepatic artery thrombosis, bone marrow suppression, malignancy (e.g. lymphoma, skin cancer), nephrotoxicity (e.g. proteinuria, mild elevations of serum creatinine), generalised oedema (including peripheral oedema and lymphoedema) and local fluid accumulation (e.g. pericardial or pleural effusion, ascites), metabolic effects (e.g. hyperglycaemia, hypertriglyceridaemia, hyperlipidaemia), wound healing complications (e.g. wound dehiscence, infection, incisional hernia, lymphocele, seroma), mouth ulcers, mucositis or stomatitis, reversible male infertility, severe hypersensitivity reactions (e.g. anaphylaxis, angioedema, dyspnoea, chest pain, flushing).
Blood and lymphatic system disorders: Anaemia, thrombocytopenia, leucopenia, neutropenia, lymphopenia, pancytopenia.
Cardiac disorders: Tachycardia.
Ear and labyrinth disorders: Otitis media.
Eye disorders: Eyelid oedema, conjunctivitis.
Gastrointestinal disorders: Nausea, diarrhoea, vomiting, dry mouth, constipation, abdominal or oral pain, dyspepsia, dysphagia, dysgeusia.
General disorders and administration site conditions: Fatigue, asthenia, pyrexia, pain.
Infections and infestations: Cellulitis.
Investigations: Abnormal hepatic enzymes, weight decreased.
Metabolism and nutrition disorders: Decreased appetite, hypercholesterolaemia, hypophosphataemia, hypokalaemia, dehydration, hypocalcaemia, diabetes mellitus.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.
Nervous system disorders: Headache.
Psychiatric disorders: Insomnia, aggression, irritability, anxiety.
Renal and urinary disorders: UTI, renal tubular necrosis.
Reproductive system and breast disorders: Irregular menstruation, amenorrhoea, erectile dysfunction.
Respiratory, thoracic and mediastinal disorders: Cough, nasopharyngitis, sinusitis, epistaxis.
Skin and subcutaneous tissue disorders: Rash, pruritus, acne, dry skin, mild alopecia, erythema, nail disorders.
Vascular disorders: Hypertension.
Potentially Fatal: Pulmonary toxicity (e.g. non-infectious pneumonitis or fibrosis, interstitial lung disease), acute renal failure, haemorrhage; bacterial, fungal, viral, protozoal infections, including opportunistic infections (e.g. Pneumocystis jirovecii pneumonia, hepatitis B reactivation, polyoma virus infection, sepsis, septic shock), respiratory or hepatic failure.
PO: D (Everolimus may have an FDA pregnancy category C or D depending on the manufacturer.)
Patient Counseling Information
This drug may cause fatigue, if affected, do not drive or operate machinery. Do not switch between brands or dosage forms unless instructed by your doctor, as different brands or dosage forms have varying ways of working in your body.
MonitoringParameters
Monitor LFT, serum creatinine, urinary protein, and BUN at baseline and periodically thereafter; CBC with differential at baseline, every 6 months during the 1st year of treatment, then annually; HbA1c, fasting serum glucose and lipid profile at baseline and annually thereafter. Conduct pregnancy test prior to treatment initiation. In transplant patients, monitor everolimus whole blood concentrations especially for those with hepatic impairment, concomitant CYP3A4 inhibitor or inducer, and during dose adjustments at 4-5 days interval; ciclosporin or tacrolimus levels. In patients with subependymal giant cell astrocytoma (SEGA) or seizures associated with TSC, monitor everolimus whole blood trough levels every 1-2 weeks after treatment initiation, during dose modifications, changing dosage forms from tab to dispersible tab for susp, or every 2 weeks after changes in hepatic function, and initiation or discontinuation of treatment with concomitant CYP3A4/P-gp inhibitor or inducer. Assess for signs and symptoms of infection, non-infectious pneumonitis, stomatitis, or malignancy.
Drug Interactions
Increased risk of angioedema with ACE inhibitors (e.g. ramipril). May increase risk of rhabdomyolysis in transplant patients with HMG-CoA reductase inhibitors (e.g. simvastatin, lovastatin), fibrates. Increased blood concentrations with potent and moderate CYP3A4/P-gp inhibitors (e.g. ketoconazole, telithromycin, nefazodone, ritonavir; erythromycin, imatinib, verapamil, diltiazem, dronedarone, ciclosporin). Decreased exposure with potent and moderate CYP3A4 inducers (e.g. rifampicin; dexamethasone, carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine). May increase adverse effects with narrow therapeutic index CYP3A4 substrates (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine, ergot alkaloid derivatives). May increase the plasma levels of midazolam, octreotide. May increase risk of renal dysfunction, haemolytic uraemic syndrome or thrombotic thrombocytopenic purpura or thrombotic microangiography with calcineurin inhibitors (e.g. ciclosporin, tacrolimus). Increased risk of serious infections with concurrent thymoglobulin induction (in transplant patients).
Potentially Fatal: May diminish the therapeutic effects of live vaccines.
Food Interaction
Reduced systemic exposure with high-fat and low-fat meals. Avoid grapefruit and grapefruit juice as it may increase everolimus plasma concentrations. Avoid St. John’s wort as it may decrease everolimus plasma levels.
Action
Description: Everolimus, a macrolide immunosuppressant and a mechanistic target of rapamycin (mTOR) inhibitor, exerts its antiproliferative and antiangiogenic effects by binding to the intracellular protein, FK binding protein-12 (FKBP-12), to form a complex that blocks mTOR serine-threonine kinase activity and by inhibiting the expression of vascular endothelial growth-factor (VEGF) and hypoxia-inducible factor (HIF-1). It also reduces lipoma volume in patients with angiomyolipoma. Everolimus exerts its immunosuppressive effect by inhibiting the  antigenic and interleukins (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes.
Pharmacokinetics:
Absorption: Rapidly absorbed from the gastrointestinal tract. Reduced systemic exposure with high-fat and low-fat meals. Time to peak plasma concentration: Approx 1-2 hours.
Distribution: Enters breast milk. Apparent volume of distribution: 128-589 L. Plasma protein binding: Approx 74%.
Metabolism: Extensively metabolised in the liver by CYP3A4 isoenzyme to form 6 weak metabolites.
Excretion: Based on solid organ transplant studies, mainly via faeces (80%); urine (approx 5%). Elimination half-life: Approx 30 hours.
Chemical Structure

Chemical Structure Image
Everolimus

Source: National Center for Biotechnology Information. PubChem Database. Everolimus, CID=6442177, https://pubchem.ncbi.nlm.nih.gov/compound/Everolimus (accessed on Jan. 23, 2020)

Storage
Store at 25°C. Protect from light and moisture. Follow applicable procedures for receiving, handling, administration, and disposal.
ATC Classification
L01XE10 - everolimus ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.
L04AA18 - everolimus ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.
References
Afinitor Tablet; Afinitor Disperz Tablet for Suspension (Novartis Pharmaceuticals Corporation). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 16/09/2019.

Anon. Everolimus. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 16/09/2019.

Buckingham R (ed). Everolimus. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 16/09/2019.

Clinical Annotation for rs1045642 (ABCB1); Everolimus; Breast Neoplasms and Mucositis (Level 3 Toxicity/ADR). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 01/10/2019.

Clinical Annotation for rs35599367 (CYP3A4); Everolimus; Breast Neoplasms (Level 3 Metabolism/PK). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 01/10/2019.

Clinical Annotation for rs776746 (CYP3A5); Everolimus; Heart Transplantation, Kidney Transplantation and Organ Transplantation (Level 3 Metabolism/PK). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 01/10/2019.

Clinical Annotation for rs9906827 (RPTOR); Everolimus; Pneumonitis and Progression-free Survival (Level 3 Efficacy, Toxicity/ADR). Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 01/10/2019.

Joint Formulary Committee. Everolimus. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 16/09/2019.

Polymorphisms Associated with Everolimus Pharmacokinetics, Toxicity and Survival in Metastatic Breast Cancer. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 01/10/2019 .

Zortress Tablet (Novartis Pharmaceuticals Corporation). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 16/09/2019.

Disclaimer: This information is independently developed by MIMS based on Everolimus from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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