4.1. Therapeutic indications

Tolvaptan is indicated to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adults with chronic kidney disease (CKD) stage 1 to 4 at initiation of treatment with evidence of rapidly progressing disease (see section 5.1).

4.2. Posology and method of administration

Tolvaptan treatment must be initiated and monitored under the supervision of physicians with expertise in managing ADPKD and a full understanding of the risks of tolvaptan therapy including hepatic toxicity and monitoring requirements (see section 4.4).

Posology

Tolvaptan is to be administered twice daily in split dose regimens of 45 mg + 15 mg, 60 mg + 30 mg or 90 mg + 30 mg. The morning dose is to be taken at least 30 minutes before the morning meal. The second daily dose can be taken with or without food. According to these split dose regimens the total daily doses are 60 mg, 90 mg, or 120 mg.

Dose titration

The initial dose is 60 mg tolvaptan per day as a split-dose regimen of 45 mg + 15 mg (45 mg taken upon waking and prior the morning meal and 15 mg taken 8 hours later). The initial dose is to be titrated upward to a split-dose regimen of 90 mg tolvaptan (60 mg + 30 mg) per day and then to a target split-dose regimen of 120 mg tolvaptan (90 mg + 30 mg) per day, if tolerated, with at least weekly intervals between titrations. Dose titration has to be performed cautiously to ensure that high doses are not poorly tolerated through overly rapid up-titration. Patients may down-titrate to lower doses based on tolerability. Patients have to be maintained on the highest tolerable tolvaptan dose.

The aim of dose titration is to block activity of vasopressin at the renal V2 receptor as completely and constantly as possible, while maintaining acceptable fluid balance (see section 4.4).

Measurements of urine osmolality are recommended to monitor the adequacy of vasopressin inhibition. Periodic monitoring of plasma osmolality or serum sodium (to calculate plasma osmolarity) and/or body weight should be considered to monitor the risk of dehydration secondary to the aquaretic effects of tolvaptan in case of patient's insufficient water intake.

The safety and efficacy of Tolvaptan in CKD stage 5 have not been explored and therefore tolvaptan treatment should be discontinued if renal insufficiency progresses to CKD stage 5 (see section 4.4).

Therapy must be interrupted if the ability to drink or the accessibility to water is limited (see section 4.4).

Tolvaptan must not be taken with grapefruit juice (see section 4.5). Patients must be instructed to drink sufficient amounts of water or other aqueous fluids (see section 4.4).

Dose adjustment for patients taking strong CYP3A inhibitors

In patients taking strong CYP3A inhibitors (see section 4.5), tolvaptan doses have to be reduced as follows:

Tolvaptan daily split-dose

Reduced dose (once daily)

90 mg + 30 mg

30 mg (further reduction to 15 mg if 30 mg are not well tolerated)

60 mg + 30 mg

30 mg (further reduction to 15 mg if 30 mg are not well tolerated)

45 mg + 15 mg

15 mg

Dose adjustment for patients taking moderate CYP3A inhibitors

In patients taking moderate CYP3A inhibitors, tolvaptan doses have to be reduced as follows:

Tolvaptan daily split-dose

Reduced split-dose

90 mg + 30 mg

45 mg + 15 mg

60 mg + 30 mg

30 mg + 15 mg

45 mg + 15 mg

15 mg + 15 mg

Further reductions have to be considered if patients cannot tolerate the reduced tolvaptan doses.

Special populations

Elderly population

Increasing age has no effect on tolvaptan plasma concentrations. Limited data on the safety and effectiveness of tolvaptan in ADPKD patients aged over 55 are available (see section 5.1).

Renal impairment

Tolvaptan is contraindicated in anuric patients (see section 4.3).

Dose adjustment is not required in patients with renal impairment.

No clinical trials in subjects with indices of glomerular filtration rate <10 mL/min or in patients undergoing dialysis have been conducted. The risk of hepatic damage in patients with severely reduced renal function (i.e. estimated glomerular filtration rate [eGFR] <20) may be increased; these patients should be carefully monitored for hepatic toxicity. Data for patients in CKD early stage 4 are more limited than for patients in stage 1, 2 or 3 (see section 5.1). Limited data are available for patients with CKD late stage 4 (eGFR <25 mL/min/1.73 m2). No data are available for patients with CKD stage 5. Tolvaptan treatment should be discontinued if renal insufficiency progresses to CKD stage 5 (see section 4.4).

Hepatic impairment

In patients with severe hepatic impairment the benefits and risks of treatment with Tolvaptan must be evaluated carefully. Patients must be managed carefully and liver enzymes must be monitored regularly (see section 4.4).

Tolvaptan is contraindicated in patients with elevated liver enzymes and/or signs or symptoms of liver injury prior to initiation of treatment that meet the requirements for permanent discontinuation of tolvaptan (see sections 4.3 and 4.4).

No dose adjustment is needed in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B).

Paediatric population

The safety and efficacy of tolvaptan in children and adolescents has not yet been established. No data are available. Tolvaptan is not recommended in the paediatric age group.

Method of administration

Oral use.

Tablets must be swallowed without chewing and with a glass of water.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to benzazepine or benzazepine derivatives (see section 4.4)

• Elevated liver enzymes and/or signs or symptoms of liver injury prior to initiation of treatment that meet the requirements for permanent discontinuation of tolvaptan (see section 4.4)

• Anuria

• Volume depletion

• Hypernatraemia

• Patients who cannot perceive or respond to thirst

• Pregnancy (see section 4.6)

• Breast-feeding (see section 4.6)

4.4. Special warnings and precautions for use

Idiosyncratic hepatic toxicity

Tolvaptan has been associated with idiosyncratic elevations of blood alanine and aspartate aminotransferases (ALT and AST) with infrequent cases of concomitant elevations in bilirubin-total (BT).

In post-marketing experience with tolvaptan in ADPKD, acute liver failure requiring liver transplantation has been reported.

In a double-blind, placebo-controlled trial in patients with ADPKD, the period of onset of hepatocellular injury (by ALT elevations >3×ULN) was within 3 to 14 months after initiating treatment and these increases were reversible, with ALT returning to <3×ULN within 1 to 4 months. While these concomitant elevations were reversible with prompt discontinuation of tolvaptan, they represent a potential for significant liver injury. Similar changes with other medicinal products have been associated with the potential to cause irreversible and potentially life-threatening liver injury (see section 4.8).

Prescribing physicians must comply fully with the safety measures required below.

To mitigate the risk of significant and/or irreversible liver injury, blood testing for hepatic transaminases and bilirubin is required prior to initiation of tolvaptan, continuing monthly for 18 months and at regular 3-monthly intervals thereafter. Concurrent monitoring for symptoms that may indicate liver injury (such as fatigue, anorexia, nausea, right upper abdominal discomfort, vomiting, fever, rash, pruritus, dark urine or jaundice) is recommended.

If a patient shows abnormal ALT, AST or BT levels prior to initiation of treatment which fulfil the criteria for permanent discontinuation (see below), the use of tolvaptan is contraindicated (see section 4.3). In case of abnormal baseline levels below the limits for permanent discontinuation treatment can only be initiated if the potential benefits of treatment outweigh the potential risks and liver function testing must continue at increased time frequency. The advice of a hepatologist is recommended.

During the first 18 months of treatment, tolvaptan can only be supplied to patients whose physician has determined that liver function supports continued therapy.

At the onset of symptoms or signs consistent with hepatic injury or if clinically significant abnormal ALT or AST increases are detected during treatment, tolvaptan administration must be immediately interrupted and repeat tests including ALT, AST, BT and alkaline phosphatase (AP) must be obtained as soon as possible (ideally within 48 hours to 72 hours). Testing must continue at increased time frequency until symptoms/signs/laboratory abnormalities stabilise or resolve, at which point tolvaptan may be re-initiated.

Current clinical practice suggests that tolvaptan therapy is to be interrupted upon confirmation of sustained or increasing transaminase levels and permanently discontinued if significant increases and/or clinical symptoms of hepatic injury persist.

Recommended guidelines for permanent discontinuation include:

• ALT or AST >8-times ULN

• ALT or AST >5-times ULN for more than 2 weeks

• ALT or AST >3-times ULN and (BT >2-times ULN or International Normalised Ratio [INR] >1.5)

• ALT or AST >3-times ULN with persistent symptoms of hepatic injury noted above.

If ALT and AST levels remain below 3-times the ULN, tolvaptan therapy may be cautiously re‑started, with frequent monitoring at the same or lower doses, as transaminase levels appear to stabilise during continued therapy in some patients.

Access to water

Tolvaptan may cause adverse reactions related to water loss such as thirst, polyuria, nocturia, and pollakiuria (see section 4.8). Therefore, patients must have access to water (or other aqueous fluids) and be able to drink sufficient amounts of these fluids (see section 4.2). Patients have to be instructed to drink water or other aqueous fluids at the first sign of thirst in order to avoid excessive thirst or dehydration.

Additionally, patients have to drink 1 to 2 glasses of fluid before bedtime regardless of perceived thirst and replenish fluids overnight with each episode of nocturia.

Dehydration

Volume status must be monitored in patients taking tolvaptan because treatment with tolvaptan may result in severe dehydration which constitutes a risk factor for renal dysfunction. Accurate monitoring of body weight is recommended. A progressive reduction in body weight could be an early sign of progressive dehydration. If dehydration becomes evident, take appropriate action, which may include the need to interrupt or reduce the dose of tolvaptan and increase fluid intake. Special care must be taken in patients having diseases that impair appropriate fluid intake or who are at an increased risk of water loss e.g. in case of vomiting or diarrhoea.

Urinary outflow obstruction

Urinary output must be secured. Patients with partial obstruction of urinary outflow, for example patients with prostatic hypertrophy or impairment of micturition, have an increased risk of developing acute retention.

Fluid and electrolyte balance

Fluid and electrolyte status must be monitored in all patients. Administration of tolvaptan induces copious aquaresis and may cause dehydration and increases in serum sodium (see section 4.8) and is contraindicated in hypernatraemic patients (see section 4.3). Therefore, serum creatinine, electrolytes and symptoms of electrolyte imbalances (e.g. dizziness, fainting, palpitations, confusion, weakness, gait instability, hyper-reflexia, seizures, coma) have to be assessed prior to and after starting tolvaptan to monitor for dehydration.

During long-term treatment, electrolytes have to be monitored at least every three months.

Serum sodium abnormalities

Pre-treatment sodium abnormalities (hyponatraemia or hypernatraemia) must be corrected prior to initiation with tolvaptan therapy.

Anaphylaxis

In post-marketing experience, anaphylaxis (including anaphylactic shock and rash generalised) has been reported very rarely following administration of tolvaptan. This type of reaction occurred after the first administration of tolvaptan. Patients have to be carefully monitored during treatment. Patients with known hypersensitivity reactions to benzazepines or benzazepine derivatives (e.g. benazepril, conivaptan, fenoldopam mesylate or mirtazapine) may be at risk for hypersensitivity reaction to tolvaptan (see section 4.3).

If an anaphylactic reaction or other serious allergic reactions occur, administration of tolvaptan must be discontinued immediately and appropriate therapy initiated. Since hypersensitivity is a contraindication (see section 4.3) treatment must never be restarted after an anaphylactic reaction or other serious allergic reactions.

Diabetes mellitus

Diabetic patients with an elevated glucose concentration (e.g., in excess of 300 mg/dL) may present with pseudo-hyponatraemia. This condition must be excluded prior and during treatment with tolvaptan.

Tolvaptan may cause hyperglycaemia (see section 4.8). Therefore, diabetic patients treated with tolvaptan must be managed cautiously. In particular this applies to patients with inadequately controlled type II diabetes.

Uric acid increases

Decreased uric acid clearance by the kidney is a known effect of tolvaptan. In a double-blind, placebo-controlled trial of patients with ADPKD, potentially clinically significant increased uric acid (greater than 10 mg/dL) was reported at a higher rate in tolvaptan-patients (6.2 %) compared to placebo-treated patients (1.7 %). Adverse reactions of gout were reported more frequently in tolvaptan-treated patients (28/961, 2.9 %) than in patients receiving placebo (7/483, 1.4 %). In addition, increased use of allopurinol and other medicinal products used to manage gout were observed in the double-blind, placebo-controlled trial. Effects on serum uric acid are attributable to the reversible renal hemodynamic changes that occur in response to tolvaptan effects on urine osmolality and may be clinically relevant. However, events of increased uric acid and/or gout were not serious and did not cause discontinuation of therapy in the double-blind, placebo-controlled trial. Uric acid concentrations are to be evaluated prior to initiation of tolvaptan therapy, and as indicated during treatment based on symptoms.

Effect of tolvaptan on glomerular filtration rate (GFR)

A reversible reduction in GFR has been observed in ADPKD trials at the initiation of tolvaptan treatment.

Chronic Kidney Disease

Limited safety and efficacy data are available for tolvaptan in patients with CKD late stage 4 (eGFR<25 mL/min/1.73 m2). There are no data in patients with CKD stage 5. Tolvaptan treatment should be discontinued if renal insufficiency progresses to CKD stage 5.

Lactose

Tolvaptan contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. is essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on the pharmacokinetics of tolvaptan

CYP3A inhibitors

Concomitant use of medicinal products that are moderate CYP3A inhibitors (e.g. amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) or strong CYP3A inhibitors (e.g. itraconazole, ketoconazole, ritonavir, clarithromycin) increase tolvaptan exposure.

Co-administration of tolvaptan and ketoconazole resulted in a 440% increase in area under time-concentration curve (AUC) and 248% increase in maximum observed plasma concentration (Cmax) for tolvaptan.

Co-administration of tolvaptan and fluconazole, a moderate CYP3A inhibitor, produced a 200% and 80% increase in tolvaptan AUC and Cmax, respectively.

Co-administration of tolvaptan with grapefruit juice, a moderate to strong CYP3A inhibitor, produced a doubling of peak tolvaptan concentrations (Cmax).

Dose reduction of tolvaptan is recommended for patients while taking moderate or strong CYP3A inhibitors (see section 4.2). Patients taking moderate or strong CYP3A inhibitors must be managed cautiously, in particular if the inhibitors are taken more frequently than once a day.

CYP3A inducers

Concomitant use of medicinal products that are potent CYP3A inducers (e.g. rifampicin) will decrease tolvaptan exposure and efficacy. Co-administration of tolvaptan with rifampicin reduces Cmax and AUC for tolvaptan by about 85%. Therefore, concomitant administration of tolvaptan with potent CYP3A inducers (e.g. rifampicin, rifabutin, rifapentin, phenytoin, carbamazepine, and St. John's Wort) is to be avoided.

Co-administration with medicinal products that increase serum sodium concentration

There is no experience from controlled clinical trials with concomitant use of tolvaptan and hypertonic sodium chloride solution, oral sodium formulations, and medicinal products that increase serum sodium concentration. Medicinal products with high sodium content such as effervescent analgesic preparations and certain sodium containing treatments for dyspepsia may also increase serum sodium concentration. Concomitant use of tolvaptan with medicinal products that increase serum sodium concentration may result in a higher risk for developing hypernatraemia (see section 4.4) and is therefore not recommended.

Diuretics

Tolvaptan has not been extensively studied in ADPKD in combination with diuretics. While there does not appear to be a synergistic or additive effect of concomitant use of tolvaptan with loop and thiazide diuretics, each class of agent has the potential to lead to severe dehydration, which constitutes a risk factor for renal dysfunction. If dehydration or renal dysfunction becomes evident, appropriate action must be taken which may include the need to interrupt or reduce doses of tolvaptan and/or diuretics and increased fluid intake. Other potential causes of renal dysfunction or dehydration must be evaluated and addressed.

Effect of tolvaptan on the pharmacokinetics of other products

CYP3A substrates

In healthy subjects, tolvaptan, a CYP3A substrate, had no effect on the plasma concentrations of some other CYP3A substrates (e.g. warfarin or amiodarone). Tolvaptan increased plasma levels of lovastatin by 1.3-to 1.5-fold. Even though this increase has no clinical relevance, it indicates tolvaptan can potentially increase exposure to CYP3A4 substrates.

Transporter substrates

P-glycoprotein substrates: In-vitro studies indicate that tolvaptan is a substrate and competitive inhibitor of P-glycoprotein (P-gp). Steady state digoxin concentrations were increased (1.3-fold in maximum observed plasma concentration [Cmax] and 1.2-fold in area under the plasma concentration-time curve over the dosing interval [AUC]) when co-administered with multiple once daily 60 mg doses of tolvaptan. Patients receiving digoxin or other narrow therapeutic P-gp substrates (e.g. dabigatran) must therefore be managed cautiously and evaluated for excessive effects when treated with tolvaptan.

OATP1B1/OAT3/BCRP and OCT1: In-vitro studies indicate that tolvaptan or its oxobutyric metabolite may have the potential to inhibit OATP1B1, OAT3, BCRP and OCT1 transporters. Co-administration of tolvaptan (90 mg) with rosuvastatin (5 mg), a BCRP substrate, increased rosuvastatin Cmax and AUCt of 54% and 69%, respectively. If BCRP substrates (e.g. sulfasalazine) are co-administered with tolvaptan, patients must be managed cautiously and evaluated for excessive effects of these medicinal products.

Administration of rosuvastatin (OATP1B1 substrate) or furosemide (OAT3 substrate) to healthy subjects with elevated oxobutyric acid metabolite (inhibitor of OATP1B1 and OAT3) plasma concentrations did not meaningfully alter the pharmacokinetics of rosuvastatin or furosemide. Statins commonly used in the tolvaptan phase 3 pivotal trial (e.g. rosuvastatin and pitavastatin) are OATP1B1 or OATP1B3 substrates, however no difference in adverse events profile was observed during the phase 3 pivotal trial for tolvaptan in ADPKD.

If OCT1 substrates (e.g. metformin) are co-administered with tolvaptan, patients must be managed cautiously and evaluated for excessive effects of these medicinal products.

Diuretics or non-diuretic anti-hypertensive medicinal product(s)

Standing blood pressure was not routinely measured in ADPKD trials. Therefore, a risk of orthostatic/postural hypotension due to a pharmacodynamic interaction with tolvaptan cannot be excluded.

Co-administration with vasopressin analogues

In addition to its renal aquaretic effect, tolvaptan is capable of blocking vascular vasopressin V2 receptors involved in the release of coagulation factors (e.g. von Willebrand factor) from endothelial cells. Therefore, the effect of vasopressin analogues such as desmopressin may be attenuated in patients using such analogues to prevent or control bleeding when co-administered with tolvaptan. It is not recommended to administer tolvaptan with vasopressin analogues.

Smoking and alcohol

Data related to smoking or alcohol history in ADPKD trials are too limited to determine possible interactions of smoking or alcohol with efficacy and safety of ADPKD treatment with tolvaptan.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of tolvaptan in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Tolvaptan is not recommended in women of childbearing potential not using contraception.

Tolvaptan is contraindicated during pregnancy (see section 4.3).

Breast-feeding

It is unknown whether tolvaptan is excreted in human breast milk. Studies in rats have shown excretion of tolvaptan in milk. A risk for the newborns/infants cannot be excluded. Tolvaptan is contraindicated during breast-feeding (see section 4.3).

Fertility

Studies in animals showed effects on fertility (see section 5.3). The potential risk for humans is unknown.

4.7. Effects on ability to drive and use machines

Tolvaptan has minor influence on the ability to drive or use machines. When driving vehicles or using machines it has to be taken into account that occasionally dizziness, asthenia or fatigue may occur.

4.8. Undesirable effects

Summary of the safety profile

The pharmacodynamically predictable and most commonly reported adverse reactions are thirst, polyuria, nocturia, and pollakiuria occurring in approximately 55%, 38%, 29% and 23% of patients, respectively. Furthermore, tolvaptan has been associated with idiosyncratic elevations of blood alanine aminotransferase (ALT; 4.4%) and aspartate aminotransferases (AST; 3.1%) with infrequent cases of concomitant elevations in bilirubin-total (BT; 0.2%).

Tabulated list of adverse reactions

The incidences of the adverse drug reactions (ADRs) associated with tolvaptan therapy are tabulated below. The table is based on adverse reactions reported during clinical trials and/or post-marketing use.

All ADRs are listed by system organ class and frequency; very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse reactions is qualified as "not known".

Very common

Common

Uncommon

Not known

Immune system disorders

Anaphylactic shock,

Generalised rash

Metabolism and nutrition disorders

Polydipsia

Dehydration,

Hypernatraemia,

Decreased appetite,

Hyperuricaemia,

Hyperglycaemia,

Gout

Psychiatric disorders

Insomnia

Nervous system disorders

Headache,

Dizziness

Dysgeusia

Syncope,

Cardiac disorders

Palpitations

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Gastrointestinal disorders

Diarrhoea,

Dry mouth

Abdominal pain,

Abdominal distension

Constipation,

Dyspepsia,

Gastroesophageal reflux disease,

Hepatobiliary disorders

Abnormal hepatic function

Acute hepatic failure1

Skin and subcutaneous tissue disorders

Dry skin,

Rash,

Pruritus,

Urticaria

Musculoskeletal and connective tissue disorders

Arthralgia,

Muscle spasms,

Myalgia

Renal and urinary disorders

Nocturia,

Pollakiuria,

Polyuria

General disorders and administration site conditions

Fatigue,

Thirst,

Asthenia,

Investigations

Alanine aminotransferase increased,

Aspartate aminotransferase increased

Weight decreased,

Weight increased,

Bilirubin increased

Blood creatine phosphokinase increased

1 observed in post-marketing with tolvaptan in ADPKD. Liver transplantation was necessary.

Description of selected adverse reactions

Laboratory results

Elevation (>3× upper limit of normal [ULN]) of ALT was observed in 4.4% (42/958) of patients on tolvaptan and 1.0% (5/484) of patients on placebo, while elevation (>3×ULN) of AST was observed in 3.1% (30/958) of patients on tolvaptan and 0.8% (4/484) patients on placebo in a double-blind, placebo-controlled trial in patients with ADPKD. Two (2/957, 0.2%) of these tolvaptan treated-patients, as well as a third patient from an extension open label trial, exhibited increases in hepatic enzymes (>3×ULN) with concomitant elevations in BT (>2×ULN).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Single oral doses up to 480 mg (4 times the maximum recommended daily dose) and multiple doses up to 300 mg once daily for 5 days have been well tolerated in trials in healthy subjects. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst and dehydration/hypovolemia.

No mortality was observed in rats or dogs following single oral doses of 2,000 mg/kg (maximum feasible dose). A single oral dose of 2,000 mg/kg was lethal in mice and symptoms of toxicity in affected mice included decreased locomotor activity, staggering gait, tremor and hypothermia.

In patients with suspected tolvaptan overdose, assessment of vital signs, electrolyte concentrations, ECG and fluid status is recommended. Appropriate replacement of water and/or electrolytes must continue until aquaresis abates. Dialysis may not be effective in removing tolvaptan because of its high binding affinity for human plasma protein (>98%).